Nitrogen-containing heterocyclic derivative inhibitors, their preparation methods and applications

Abstract

Nitrogen-containing heterocyclic derivative inhibitors, their preparation methods, and applications. Specifically, 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 Chinese patent applications 2022112625520 (filed on October 14, 2022), 2023100954447 (filed on February 6, 2023), 2023101156001 (filed on February 14, 2023), 2023102752651 (filed on March 20, 2023), and 2023102752651 (filed on March 30, 2023). This application claims priority to Chinese patent applications 2023103333265, 2023104650154 (filed April 26, 2023), 2023106311997 (filed May 30, 2023), 2023108187585 (filed July 4, 2023), and 2023110111090 (filed August 10, 2023). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug synthesis, specifically relating to a nitrogen-containing heterocyclic derivative inhibitor, its preparation method, and its application. Background Technology

[0003] Cardiovascular disease (CVD) is a leading cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. 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.

[0004] 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.

[0005] 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.

[0006] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein cholesterol metabolism, affecting approximately 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; studies by Besselin have shown that high-intensity statin therapy can reduce the risk of CAD 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 to bind 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.

[0007] 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.

[0008] 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

[0009] 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:

[0010]

[0011] in:

[0012] Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; preferably 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;

[0013] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic, 7-10 membered bicyclic heterocyclic, 5 membered heteroaryl, 6 membered heteroaryl, 5 membered 5-bicyclic heteroaryl, 5 membered 6-bicyclic heteroaryl, 5 membered 6-bicyclic heteroaryl, 6 membered 5-bicyclic heteroaryl or 6 membered 6-bicyclic heteroaryl;

[0014] Further optimization of 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;

[0015] More preferably, 5-membered 5-membered bicyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl or 6-membered 6-membered bicyclic heteroaryl;

[0016] Ring A is preferably a 5-membered 5-membered bicyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, a 6-membered monoheteroaryl, a 6-membered 5-membered bicyclic heteroaryl, or a 6-membered 6-membered bicyclic heteroaryl; and when ring A is a 6-membered monoheteroaryl... At that time, ring B is not Simultaneously, when ring A is a 6-membered monoheteroaryl group... When ring B is selected from 5-membered 5-membered bicyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl, or 6-membered 6-membered bicyclic heteroaryl; and when ring A is 6-membered 5-membered bicyclic heteroaryl, ring A is not...

[0017] L1 is selected from the bond, -C(O)- or -C(O)NH-;

[0018] 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 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0019] Preferred groups include 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 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) n1R 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, C 6-10Aryl 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;

[0020] 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;

[0021] Or, any two adjacent or non-adjacent R a The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0022] 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 B3 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] Preferred groups include 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 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)ORA3 -(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 C1-3 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;

[0024] 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;

[0025] Or, any two adjacent or non-adjacent R b The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0026] Preferably,

[0027] Or, any two R a and R b The linkage forms a heterocyclic or heteroaryl group, which may optionally be further replaced 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 6-14The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0028] 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.

[0029] Preferred groups include 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 1-6Alkylthio, 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 1-6hydroxyalkyl, 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, 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;

[0030] 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;

[0031] Or, any two adjacent or non-adjacent R c The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0032] 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 RD3 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.

[0033] Preferred groups include 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 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 A2S(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, 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 6-10The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0034] 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;

[0035] Or, any two adjacent or non-adjacent R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0036] Or, any two R c and R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0037] x is 0, 1, 2, or 3;

[0038] y is 0, 1, 2, or 3;

[0039] z can be 0, 1, 2, or 3;

[0040] e can be 0, 1, 2, or 3;

[0041] m is 0, 1, or 2;

[0042] n is 0, 1, 2, 3 or 4;

[0043] n1 is 0, 1, 2, 3 or 4;

[0044] n2 is 0, 1, 2, 3 or 4;

[0045] n3 can be 0, 1, 2, 3 or 4;

[0046] n4 is 0, 1, 2, 3, or 4; and

[0047] The compound is not

[0048] In a preferred embodiment of the invention, the compound is further shown as in general formula (III) or (III-1):

[0049]

[0050] in:

[0051] M1 is selected from N or CH;

[0052] M2 is selected from N or CH;

[0053] M3 is selected from N or CH; and

[0054] M4 is selected from N or CH.

[0055] In a more preferred embodiment of the present invention, the ring A is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0056] Preferably, ring A is selected from C. 6-14 Aryl or 5-14 heteroaryl groups;

[0057] More preferably, ring A is selected from 5-12 membered monocyclic heteroaryl and 8-12 membered bicyclic heteroaryl;

[0058] More preferably, ring A is a 5-membered mono-heteroaryl, a 5-membered 5-membered bicyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, a 6-membered mono-heteroaryl, a 6-membered 5-membered bicyclic heteroaryl, or a 6-membered 6-membered bicyclic heteroaryl.

[0059] More preferably, ring A is selected from pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl, pyridinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl, etc.

[0060] More preferably, ring A is selected from pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl, pyridinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl, etc.

[0061] Pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl or pyridazinyl are preferred.

[0062] Alternatively, ring A is selected from 8-12-membered bicyclic heteroaryl, 8-12-membered heteroaryl fused aryl, 8-14-membered heteroaryl fused cycloalkyl, or 8-14-membered heteroaryl fused heterocyclic group; preferably selected from...

[0063] Further optimization

[0064] Further optimization

[0065] In a preferred embodiment of the invention, the compound is further shown as in general formula (IE):

[0066]

[0067] In a preferred embodiment of the invention, the compound is further shown as in general formula (I-1'):

[0068]

[0069] in:

[0070] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0071] M5 is selected from N or CR5;

[0072] 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 3-8 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 2-4alkenyl, 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;

[0073] 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 NRA2 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, 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, C6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0074] 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, 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;

[0075] Or, any two adjacent or non-adjacent R a The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, or 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;

[0076] 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 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3-OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl 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;

[0077] 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 2-6 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, C1-6 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, 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;

[0078] Or, any two adjacent or non-adjacent R b The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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;

[0079] Or, any two R 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 1-6Haloalkyl, 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;

[0080] Or, R5 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 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0081] 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 6-10The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0082] 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 1-6 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, 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] Or, any two adjacent or non-adjacent R c The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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, C1-6 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;

[0084] 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 6-10 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, 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 1-3Deuterated 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;

[0085] 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, 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;

[0086] Or, any two adjacent or non-adjacent R dThe linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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;

[0087] Or, any two R c and R d The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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;

[0088] x is 0, 1, 2, or 3;

[0089] y is 0, 1, 2, or 3;

[0090] z can be 0, 1, 2, or 3;

[0091] e can be 0, 1, 2, or 3;

[0092] m is 0, 1, or 2;

[0093] n is 0, 1, 2, 3 or 4;

[0094] n1 can be 0, 1, 2, 3 or 4.

[0095] In a preferred embodiment of the invention, the compound is further shown as in general formulas (I-1), (I-2), (I-3), (I-4), or (I-5):

[0096]

[0097] In a more preferred embodiment of the present invention, the ring B is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0098] Preferably, 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;

[0099] 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;

[0100] More preferably, ring B is selected from pyridine, pyrimidine, pyridinone, or pyrimidinone;

[0101] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0102] In a further preferred embodiment, ring B is selected from pyridine, pyrimidine, benzene, etc.

[0103] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0104] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0105] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0106] Preferably, ring B can also be selected from...

[0107] In a preferred embodiment of the invention, the compound is further shown as in general formula (V):

[0108]

[0109] In a preferred embodiment of the invention, the compound is further represented by general formulas (III-A), (III-B), (III-C), (III-D), (III-E), or (III-F):

[0110]

[0111] In a preferred embodiment of the invention, the compound is further shown as in general formula (II'):

[0112]

[0113] in:

[0114] Ring C is selected from C 3-12 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl;

[0115] Preferably, ring C is selected from C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic, 7-10 membered bicyclic heterocyclic, 5 membered mono-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;

[0116] More preferably, C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic nitrogen-containing heterocyclic group, 5-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;

[0117] More preferably, the cyclic C is selected from phenyl, pyrroleyl, ...

[0118] More preferably, the ring C is selected from pyridine, pyrimidine, benzene,

[0119] More preferably, the ring C is selected from pyridine, pyrimidine, benzene,

[0120] Preferably, ring C can also be selected from...

[0121] Rb 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 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkylthio, 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;

[0122] 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 2-6 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, C1-6 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;

[0123] Or, any two adjacent or non-adjacent R b The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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;

[0124] 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, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0125] 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 1-6 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, 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;

[0126] Or, any two adjacent or non-adjacent R c The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, or C. 1-6 Alkyl, C1-6 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;

[0127] 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 6-10 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, 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 with one or more substituents from 5-10 heteroaryl groups;

[0128] 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, 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;

[0129] Preferably,

[0130] Rd 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 1-6Alkylthio, 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;

[0131] 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, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C1-6 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;

[0132] Or, any two adjacent or non-adjacent R d The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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;

[0133] Or, any two R c and R d The linkage forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified 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 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0134] y is 0, 1, 2, or 3;

[0135] z can be 0, 1, 2, or 3;

[0136] e can be 0, 1, 2, or 3;

[0137] m is 0, 1, or 2;

[0138] n is 0, 1, 2, 3 or 4;

[0139] n1 can be 0, 1, 2, 3 or 4.

[0140] In a further preferred embodiment of the invention, the compound is further shown as in general formula (II'-1):

[0141]

[0142] In a further preferred embodiment of the present invention, the R described herein a 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) nNR 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, 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 6-10Aryl 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;

[0143] 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 2-4alkynyl 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;

[0144] Preferably, R a 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)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2S(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 aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0145] 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 2-4alkenyl, 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 It is substituted by one or more substituents in the aryl group and the 5-12 heteroaryl group.

[0146] 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 1-3 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 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 NRB2 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 6-10 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;

[0147] 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 1-3Haloalkyl, 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 It is substituted by one or more substituents in the aryl group and the 5-12 heteroaryl group.

[0148] 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 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 1-3Alkoxy, 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;

[0149] 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 It is substituted by one or more substituents in the aryl group and the 5-12 heteroaryl group.

[0150] In a further preferred embodiment of the present invention, the R described herein dSelected 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, C1-3 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, 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;

[0151] R D1 ~R D3Each 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;

[0152] Preferably,

[0153] R 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 C1-3 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 6-10The 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;

[0154] 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, C2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in the aryl group and the 5-12 heteroaryl group.

[0155] In a further preferred embodiment of the present invention, the R described herein 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 e1 -(CH2) n OR e1 -(CH2) n C(O)R e1 -(CH2) n C(O)OR e1 -(CH2) n S(O) m R e1 -(CH2) n NR e2 R e3 -(CH2) n NR e2 C(O)OR e3 -(CH2) n NR e2 C(O)(CH2) n1 R e3 -(CH2) n NR e2 C(O)NR e2 R e3 -(CH2) n C(O)NR e2 (CH2) n1 R e3 -OC(R) e1 R e2 ) n (CH2) n1 R e3Or -(CH2) n NR e2 S(O) m R e3 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, 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 with one or more substituents from 5-10 heteroaryl groups;

[0156] R e1 ~R e3 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;

[0157] Preferably, R 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 1-3Deuterated 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 e1 -(CH2) n OR e1 -(CH2) n C(O)R e1 -(CH2) n C(O)OR e1 -(CH2) n S(O) m R e1 -(CH2) n NR e2 R e3 -(CH2) n NR e2 C(O)OR e3 -(CH2) n NR e2 C(O)(CH2) n1 R e3 -(CH2) n NR e2 C(O)NR e2 R e3 -(CH2) n C(O)NR e2 (CH2) n1 R e3 -OC(R) e1 R e2 ) n (CH2) n1 R e3 Or -(CH2) n NR e2 S(O) m R e3 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, C3-8 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;

[0158] R e1 ~R e3 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, C1-3 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 in the aryl group and the 5-12 heteroaryl group.

[0159] The present invention further provides compounds of general formula (VI), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0160]

[0161] in:

[0162] X is an amino group, a methylthio group, a halogen, a boric acid, or a borate ester;

[0163] The other groups are as described above.

[0164] The present invention further provides a method for producing a compound of general formula (III-1), comprising the following steps:

[0165]

[0166] in:

[0167] X1 is an amino group, halogen, boric acid, or borate ester;

[0168] The reaction of general formula compound (VI) with general formula compound (VI-1) yields general formula compound (III-1);

[0169] The other groups are as described above.

[0170] The present invention further provides compounds of general formula (VI-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0171]

[0172] in:

[0173] R 11 The group is selected from hydrogen, amino protecting group, 5-6 membered heteroaryl, and 5-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl and 5-6 membered heterocyclic group are optionally further modified 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 2-6alkenyl, 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;

[0174] The amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphoxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0175] Formula (VI-2) is further preferably shown in formula (VI-3):

[0176]

[0177] in:

[0178] X2 is an amino group, halogen, boric acid, or borate ester; the other groups are as described above.

[0179] The present invention further provides a method for producing a compound of general formula (V), comprising the following steps:

[0180] Method 1:

[0181]

[0182] in:

[0183] X3 is a halogen, boric acid, or borate ester;

[0184] The reaction of general formula compound (VI-2) with general formula compound (VI-4) yields general formula compound (V);

[0185] The other groups are as described above.

[0186] Method 2:

[0187]

[0188] in:

[0189] X4 is a formaldehyde group, hydroxymethyl group, or halomethyl group;

[0190] R 12 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups;

[0191] The reaction of general formula compound (VI-3) with general formula compound (VI-5) yields general formula compound (V);

[0192] The other groups are as described above.

[0193] The present invention further relates to a pharmaceutical composition comprising any of the general formula (I) shown in the present invention at a therapeutically effective dose, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0194] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0195] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0196] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0197] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0198] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0199] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0200] The present invention further relates to any of the general formula (I) shown and its stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition thereof in the preparation of a PCSK9 inhibitor medicament.

[0201] The present invention further relates to any of the general formula (I) shown and its stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition thereof in the preparation of an LDL-lowering drug.

[0202] The present invention further relates to the use of general formula (I) and its 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.

[0203] The present invention further relates to general formula (I) and its 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.

[0204] 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.

[0205] 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.

[0206] The present invention also relates to a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in 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.

[0207] Detailed description of the invention

[0208] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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:

[0213] wait.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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:

[0218] wait.

[0219] 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:

[0220] wait.

[0221] 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.

[0222] 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.

[0223] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0224] wait.

[0225] 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.

[0226] 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.

[0227] 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:

[0228]

[0229] 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:

[0230] wait.

[0231] 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.

[0232] 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.

[0233] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0234] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0235] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0236] "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.

[0237] "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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] "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.

[0242] "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).

[0243] "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.

[0244] "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

[0245] 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.

[0246] Example

[0247] 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).

[0248] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] Intermediate 1

[0255] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0256] Intermediate 1 was synthesized by referring to the preparation method of patent WO2020150473A2.

[0257] MS m / z (ESI): 245.1 [M+H] + .

[0258] Intermediate 1 can also be obtained in the following ways:

[0259]

[0260] first step

[0261] 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), and the reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction mixture 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, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to obtain (1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentylcarbamate tert-butyl ester 1B (2.1 g), yield: 55.1%.

[0262] MS m / z (ESI): 345.2 [M+H] + .

[0263] Step 2

[0264] 1B (2.1 g, 6.1 mmol) was dissolved in methanol (10 mL), and a dioxane solution of hydrochloric acid (4 M, 20 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the pH was adjusted to weakly alkaline by adding ammonia-methanol solution (7 M, 10 mL). After further concentration, the residue was purified by silica gel chromatography (elution system A) to obtain (1S,3S)-N. 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g), yield: 87.3%.

[0265] MS m / z (ESI): 245.1 [M+H] + .

[0266] Intermediate 2

[0267] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0268]

[0269] first step

[0270] 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%.

[0271] MS m / z(ESI): 191.1 [M+H] + .

[0272] Step 2

[0273] (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 tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)aminocarbamate 2C (2.9 g), yield: 78.4%.

[0274] MS m / z (ESI): 371.2 [M+H] + .

[0275] Step 3

[0276] 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%.

[0277] MS m / z(ESI): 271.2 [M+H] + .

[0278] Example 1

[0279] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0280] Example 1 can also be obtained in the following way:

[0281]

[0282] first step

[0283] Under nitrogen protection, 1a (10.00 g, 51.55 mmol), bis-pinacol borate (19.64 g, 77.33 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (3.79 g, 5.16 mmol), and potassium acetate (10.10 g, 103.11 mmol) were dissolved in 1,4-dioxane (200 mL), and the mixture was heated to 90 °C and stirred for 3 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain crude product (5,6-difluoro-3-pyridyl)boronic acid 1b (7.60 g). The product was used directly in the next reaction without purification.

[0284] MS m / z(ESI): 160.0 [M+H] + .

[0285] Step 2

[0286] 1b (6.00 g, 37.76 mmol) and hydrogen peroxide (12.84 g, 113.28 mmol, 30% aqueous solution) were dissolved in 1,4-dioxane (100 mL) and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give 5,6-difluoro-3-hydroxypyridine 1c (3.20 g), yield: 64.6%.

[0287] MS m / z(ESI): 132.0 [M+H] + .

[0288] Step 3

[0289] 1c (5.00 g, 38.14 mmol) and cesium carbonate (18.60 g, 57.22 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature and stirred for 30 minutes. Under nitrogen protection, sodium 2-chloro-2,2-difluoroacetate (11.90 g, 76.29 mmol) was added to the reaction mixture, and the mixture was heated to 90 °C and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with water (50 mL) and saturated sodium chloride (50 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give 5-(difluoromethoxy)-2,3-difluoropyridine 1d (2.60 g), yield: 37.6%.

[0290] MS m / z(ESI): 182.0 [M+H] + .

[0291] Step 4

[0292] Following the synthetic method of the first step of intermediate 1, 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 1 was synthesized.

[0293] MS m / z(ESI): 432.2 [M+H] + .

[0294] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,1H),7.80(d,1H),7.60(m,1H),7.42(m,3H),7.04(t,1H),6.93(d,1H),6.72(m ,1H),6.53(d,1H),6.44(m,1H),6.27(m,1H),4.45(m,1H),4.33(m,1H),2.11(m,2H),1.93(m,2H),1.52(m,2H).

[0295] Example 4

[0296] 6'-(((1S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0297]

[0298] first step

[0299] 3-Amino-1,2,4-triazine-6(1H)-one 4a (1 g, 8.92 mmol), trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (3.35 g, 13.4 mmol), and 1,4-diazabicyclo[2.2.2]octane (2.0 g, 17.8 mmol) were dissolved in anhydrous toluene (15 mL), and the reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 6-(difluoromethoxy)-1,2,4-triazine-3-amine 4b (430 mg), yield: 29.7%.

[0300] MS m / z(ESI): 163.0 [M+H] + .

[0301] Step 2

[0302] Under nitrogen protection, 6-(difluoromethoxy)-1,2,4-triazine-3-amine 4b (430 mg, 2.65 mmol), tert-butyl nitrite (410 mg, 3.98 mmol), and cuprous chloride (341 mg, 3.45 mmol) were dissolved in anhydrous acetonitrile (6 mL), and the reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (260 mg), yield: 54.0%.

[0303] MS m / z(ESI): 182.0 [M+H] + .

[0304] Step 3

[0305] Under nitrogen protection, intermediate 2 (80 mg, 0.256 mmol), 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (54 mg, 0.256 mmol), and N,N-diisopropylethylamine (115 mg, 0.888 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The organic phase was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reversed-phase chromatography (ammonium bicarbonate system) to give 6'-(((S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 4 (37 mg), yield: 30.1%.

[0306] MS m / z (ESI): 416.2 [M+H] + .

[0307] Example 12

[0308] 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0309]

[0310] first step

[0311] 3-Chloro-1,2,4-triazole 12a (1 g, 9.66 mmol), cyclopropylboronic acid (1.66 g, 19.3 mmol), copper acetate (2.63 g, 14.5 mmol), 2,2'-bipyridine (2.26 g, 14.5 mmol), and sodium carbonate (2.05 g, 19.3 mmol) were dissolved in 1,2-dichloroethane (20 mL). The reaction mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL). The filtrate was dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-chloro-1-cyclopropyl-1H-1,2,4-triazole 12b (340 mg), yield: 24.5%.

[0312] MS m / z(ESI): 144.0 [M+H] + .

[0313] Step 2

[0314] Following the synthesis method of Example 4, the target product 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 12 was synthesized.

[0315] MS m / z (ESI): 378.2 [M+H] + .

[0316] 1 H NMR(400MHz,CD3OD)δ8.02(s,1H),7.94(d,1H),7.64–7.56(m,2H),7.44(dd,1H),6.67–6.57(m,2H),6.46(t,1H),4.34–4.2 9(m,1H),4.13–4.05(m,1H),3.52–3.44(m,1H),2.28–2.17(m,2H),2.03–1.95(m,2H),1.65–1.52(m,2H),1.14–0.97(m,4H).

[0317] Example 15

[0318] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0319]

[0320] first step

[0321] Under nitrogen protection, 3-bromo-5-chloro-1,2,4-thiadiazole 15a (400 mg, 2.01 mmol), difluoromethyl trifluoromethanesulfonate (803 mg, 4.02 mmol), tris(dibenzylindeneacetone)palladium (184 mg, 0.201 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (170 mg, 0.401 mmol) and potassium hydroxide (169 mg, 3.01 mmol) were dissolved in 1,4-dioxane (6 mL), and the reaction was heated to 100 °C for 6 hours. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added. The organic phase was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-chloro-5-(difluoromethoxy)-1,2,4-thiadiazole 15b (130 mg), yield: 28.1%.

[0322] MS m / z(ESI): 187.0 [M+H] + .

[0323] Step 2

[0324] Following the synthesis method of Example 4, the target product 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 15 was synthesized.

[0325] MS m / z(ESI): 421.1 [M+H] + .

[0326] Example 20

[0327] 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0328]

[0329] first step

[0330] 2-Chloroprene[2,1-f][1,2,4]triazine 20a (50 mg, 0.326 mmol), intermediate 2 (88 mg, 0.326 mmol), and diisopropylethylamine (84 mg, 0.651 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was heated to 110 °C and stirred for 16 hours. After the reaction was brought to room temperature, saturated sodium chloride solution (10 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system A) to obtain 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 20 (85 mg), yield: 67.4%.

[0331] MS m / z(ESI): 388.2 [M+H] + .

[0332] 1 H NMR(400MHz,CD3OD)δ8.67(s,1H),7.98(s,1H),7.63-7.57(m,2H),7.51(dd,1H),7.45(d,1H),6.71(m,2H) ,6.61(dt,2H),6.46(td,1H),4.39-4.26(m,2H),2.34-2.17(m,2H),2.13-1.98(m,2H),1.71-1.57(m,2H).

[0333] Example 22

[0334] 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0335] Example 22 can also be synthesized using the following method:

[0336]

[0337] first step

[0338] ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (1.0 g, 4.99 mmol) and 4-methoxybenzaldehyde (816 mg, 5.99 mmol) were dissolved in methanol (10 mL), and acetic acid (300 mg, 4.99 mmol) was added with stirring. The reaction was carried out at 17 °C with stirring for 16 hours. Sodium cyanoborohydride (941 mg, 14.98 mmol) was added to the reaction solution, and the reaction was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give ((1S,3S)-3-((4-methoxybenzyl)amino)cyclopentyl)carbamate tert-butyl ester 22a (1.2 g), yield: 75%.

[0339] MS m / z(ESI): 321.3 [M+H] + .

[0340] Step 2

[0341] 22a (1.3 g, 4.06 mmol), cyanogen bromide (645 mg, 6.09 mmol), and N,N-diisopropylethylamine (1.0 g, 8.11 mmol) were dissolved in tetrahydrofuran (10 mL) and added with stirring. The reaction was carried out at 18 °C with stirring for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-(N-(4-methoxybenzyl)cyanoamino)cyclopentyl)carbamate 22b (1.2 g), yield: 85.6%.

[0342] MS m / z (ESI): 346.1 [M+H] + .

[0343] Step 3

[0344] Under nitrogen protection, 22b (1.15 g, 3.33 mmol) hydroxylamine hydrochloride (578.4 mg, 8.32 mmol) and triethylamine (1.35 g, 13.32 mmol) were dissolved in isopropanol (10 mL) and heated to 90 °C with stirring for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give tert-butyl carbamate 22c (1.0 g), yield: 79.4%.

[0345] MS m / z(ESI): 379.2 [M+H] + .

[0346] Step 4

[0347] At room temperature, 2,2-difluorocyclopropane-1-carboxylic acid (419 mg, 3.43 mmol) and carbonyl diimidazole (557 mg, 3.43 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred for 0.5 hours. 22c (1.0 g, 2.64 mmol) was dissolved in N,N-dimethylformamide (2 mL) and added dropwise to the reaction solution. The reaction was stirred at room temperature for 1 hour, then heated to 100 °C and stirred for another 1 hour. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride (60 mL × 3), dried, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)(4-methoxybenzyl)amino)cyclopentyl)carbamate 22d (390 mg), yield 31.8%.

[0348] MS m / z (ESI): 465.3 [M+H] + .

[0349] Step 5

[0350] 22d (390 mg, 0.84 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction was stirred at 18 °C for 1 hour. The reaction solution was concentrated, and the pH of the residue was adjusted to 8 by adding ammonia-methanol solution (7 M). The reaction solution was concentrated, and the residue was purified by reversed-phase chromatography (ammonia system) to give (1S,3S)-N1-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine 22e (70 mg), yield 34.1%.

[0351] MS m / z (ESI): 245.2 [M+H] + .

[0352] Step 6

[0353] 22e (60 mg, 0.24 mmol), 2B (60 mg, 0.32 mmol), and N,N-diisopropylethylamine (95 mg, 0.74 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium carbonate system) to give 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 22 (13.5 mg), yield 13.1%.

[0354] MS m / z (ESI): 415.1 [M+H] + .

[0355] 1 H NMR(400MHz, CDCl3)δ7.97(s,1H),7.45(dd,1H),7.35–7.28(m,1H),7.22(dd,1H),6.58(d,1H),6.37(d,1H),6.1 6(t,1H),4.67(d,1H),4.32(d,1H),4.25–4.15(m,1H),4.05–3.95(m,1H),2.85–2.75(m,1H),2.33–1.86(m,8H).

[0356] Example 26

[0357] 6'-(((1S,3S)-3-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0358] Example 26 can also be synthesized using the following preparation method:

[0359]

[0360] first step

[0361] In a hydrogen atmosphere, at 25 °C, [1,2,4]triazolo[1,5-a]pyridine-2-amine 26a (2.7 g, 20.13 mmol) and platinum dioxide (914 mg, 4.03 mmol) were dissolved in a mixture of hydrochloric acid (12 M, 3 mL) and methanol (3 mL) and stirred for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was neutralized to pH 10 with saturated sodium bicarbonate solution. The mixture was extracted five times with a dichloromethane / isopropanol (3:1) mixture. The organic phase was dried, filtered, and concentrated to give 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-2-amine 26b (2.5 g), yield: 89.9%.

[0362] MS m / z (ESI): 139.2 [M+H] + .

[0363] Step 2

[0364] Copper bromide (711.0 mg, 3.18 mmol) and tert-butyl nitrite (820.9 mg, 7.96 mmol) were dissolved in acetonitrile (6 mL), and 26b (220 mg, 1.59 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 0.5 h, then heated to 60 °C and stirred for 1 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL) and filtered. The organic phase was washed with water (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 26c (200 mg), yield: 62.2%.

[0365] MS m / z(ESI): 204.0 [M+H] + .

[0366] Step 3

[0367] Under nitrogen protection, 26C (597.9 mg, 2.96 mmol), intermediate 2 (200 mg, 0.74 mmol), sodium tert-butoxide (213.3 mg, 2.22 mmol), tris(dibenzylacetone)palladium (135.5 mg, 0.15 mmol), and Xantphos (171.2 mg, 0.3 mmol) were dissolved in 1,4-dioxane (8 mL) and microwaved to 130 °C with stirring for 4 hours. The reaction solution was diluted with ethyl acetate (20 mL), and the organic phase was washed with water and saturated brine, dried, filtered, and concentrated. The residue was subjected to preparative HPLC (formic acid system) to yield 26 (9.5 mg) of 6'-(((1S,3S)-3-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 2.9%.

[0368] MS m / z(ESI): 392.2 [M+H] + .

[0369] 1 H NMR(400MHz,DMSO-d6)δ7.91(d,1H),7.60(dd,1H),7.48(t,1H),7.38(dd,1H),6.87(d,1H),6.51(d,1H),6.44(d,1H) ,6.27(t,1H),5.69(d,1H),4.27(q,1H),3.95(q,1H),3.83(t,2H),2.62(t,2H),2.19–1.70(m,8H),1.53–1.39(m,2H).

[0370] Example 27

[0371] 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

[0372]

[0373] first step

[0374] 7-Fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-amine 27a (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 completion of the reaction was detected 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 27b (65 mg), yield: 77.5%.

[0375] MS m / z (ESI): 172.1 [M+H] + .

[0376] Step 2

[0377] Referring to the synthesis method in the first step of Example 20, the target product 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 27 was synthesized.

[0378] The second step can also be synthesized using the method described below:

[0379] Under nitrogen protection, 27b (80 mg, 0.37 mmol), 27c (100 mg, 0.37 mmol), cesium carbonate (241.3 mg, 0.74 mmol), Pd2dba3 (67.8 mg, 0.074 mmol), and xantphos (85.7 mg, 0.15 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction solution was heated to 130 °C and microwaved for 2 hours. The reaction solution was then heated to 130 °C under nitrogen protection and reacted for 16 hours. The reaction solution was filtered and concentrated. The residue was subjected to preparative HPLC (alkaline system) to yield 27 (6.6 mg) of 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, with a yield of 4.08%.

[0380] MS m / z (ESI): 406.2 [M+H] + .

[0381] 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).

[0382] Example 38

[0383] 6'-(((1S,3S)-3-((5-(2-hydroxypropane-2-yl)pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0384] Example 38 can also be synthesized using the following method:

[0385]

[0386] first step

[0387] Following the synthesis method of Example 20, methyl 2-(((1S,3S)-3-((2-keto-2H-[1,3'-bipyridine]-6-yl)amino)cyclopentyl)amino)pyridine-5-carboxylic acid methyl ester 38b was synthesized using methyl 2-chloropyrimidine-5-carboxylic acid ester 38a as the starting material.

[0388] MS m / z (ESI): 407.2 [M+H] + .

[0389] Step 2

[0390] Under nitrogen protection, 38b (35 mg, 0.086 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 0 °C. A tetrahydrofuran solution of methyl magnesium bromide (1 M, 2 mL) was added dropwise to the reaction solution, and the reaction was heated to room temperature and stirred for 1 hour. The reaction was quenched with methanol, concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to give the target product (9 mg), yield: 25.7%.

[0391] MS m / z(ESI): 407.2[M+H]+.

[0392] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,2H),7.92(d,1H),7.60(dd,1H),7.48(ddd,,1H),7.39(dd,1H),7.09(d,1H),6.93(d,1H),6.53(d,1H ),6.44(d,1H),6.27(td,1H),5.01(s,1H),4.37-4.27(m,2H),2.16-2.07(m,2H),1.93-1.81(m,2H),1.54-1.43(m,2H),1.39(s,6H).

[0393] Example 47

[0394] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one

[0395]

[0396] first step

[0397] Under nitrogen protection, 3-bromo-4H-quinolinazin-4-one 47a (1.0 g, 4.46 mmol), (6-fluoropyridin-3-yl)boronic acid (755 mg, 5.36 mmol), bis(diphenylphosphine)ferrocene palladium dichloride (162 mg, 0.223 mmol), and potassium carbonate (1.54 g, 11.5 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 3-(6-fluoropyridin-3-yl)-4H-quinolinazin-4-one 47b (360 mg), yield: 34%.

[0398] MS m / z(ESI): 241.1 [M+H] + .

[0399] Step 2

[0400] 3-(6-fluoropyridin-3-yl)-4H-quinolinazin-4-one 47b (100 mg, 0.416 mmol), intermediate 1 (102 mg, 0.416 mmol), and N,N-diisopropylethylamine (207 μL, 1.25 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 130 °C and stirred for 24 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give the target product 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (47 mg), yield: 24%.

[0401] MS m / z (ESI): 465.2 [M+H] + .

[0402] 1 H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.54(s,1H),8.24(s,2H),8.00(d,2H),7.7 8(d,1H),7.56-7.44(m,2H),7.25-7.17(m,1H),7.03(t,1H),6.95(d,1H),6.60(d 1H),4.32(h,2H),2.23-2.08(m,2H),1.90(dp,2H),1.54(ddt,2H).

[0403] Example 47 can also be obtained by the following synthesis method:

[0404]

[0405] first step

[0406] 47c (120 mg, 0.405 mmol), (6-fluoropyridin-3-yl)boronic acid (103 mg, 0.729 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (29 mg, 0.041 mmol), and potassium carbonate (140 mg, 1.01 mmol) were dissolved in a mixture of dioxane (1.5 mL) and water (0.15 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give ethyl 3-(6-fluoropyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylic acid 47d (110 mg), yield: 87%.

[0407] MS m / z(ESI): 313.1 [M+H] + .

[0408] Step 2

[0409] 47d (102 mg, 0.328 mmol), intermediate 1 (80 mg, 0.328 mmol), and N,N-diisopropylethylamine (143 μL, 0.819 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction mixture was heated to 130 °C and stirred for 24 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give ethyl 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminoamino)pyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylic acid 47e (53 mg), yield: 30%.

[0410] MS m / z (ESI): 537.2 [M+H] + .

[0411] Step 3

[0412] 47e (35 mg, 0.065 mmol) was dissolved in hydrochloric acid (12 M, 5 mL), and the reaction was heated to 100 °C and stirred for 1.5 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give the target product 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (21 mg), yield: 69%.

[0413] MS m / z (ESI): 465.2 [M+H] + .

[0414] 1H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.54(s,1H),8.24(s,2H),8.00(d,2H),7.7 8(d,1H),7.56-7.44(m,2H),7.25-7.17(m,1H),7.03(t,1H),6.95(d,1H),6.60(d 1H),4.32(h,2H),2.23-2.08(m,2H),1.90(dp,2H),1.54(ddt,2H).

[0415] Example 52

[0416] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine

[0417] Example 52 can also be synthesized using the following method:

[0418]

[0419] first step

[0420] Under nitrogen protection, 7-bromopyrazolo[1,5-a]pyridine 52a (150 mg, 0.76 mmol), (6-fluoropyridin-3-yl)boronic acid (139 mg, 0.99 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (56 mg, 0.08 mmol), and cesium carbonate (496 mg, 1.52 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (2 mL), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine 52b (155 mg), yield: 95.49%.

[0421] MS m / z(ESI): 214.1 [M+H] + .

[0422] Step 2

[0423] Intermediate 1 (60 mg, 0.25 mmol), 52b (105 mg, 0.49 mmol), and N,N-dimethylethylamine (79 mg, 0.61 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC (ammonium bicarbonate system) to prepare (1S,3S)-N1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 52 (42.3 mg), yield: 39.36%.

[0424] MS m / z (ESI): 438.2 [M+H] + .

[0425] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,1H),8.24(s,2H),8.07-7.97(m,2H),7.63(d,1H),7.51(d,1H),7.29-7.23(m,1H),7.07(d,1H),7.2 2-6.85(m,1H),6.95(d,1H),6.68(d,1H),6.59(d,1H),4.47-4.23(m,2H),2.24-2.05(m,2H),1.99-1.84(m,2H),1.63-1.45(m,2H).

[0426] Example 53

[0427] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazol[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine

[0428]

[0429] first step

[0430] Under nitrogen protection, 8-bromoimidazole[1,2-a]pyridine 53a (1.0 g, 5.08 mmol), (6-fluoropyridin-3-yl)boronic acid (858 mg, 6.09 mmol), bis(diphenylphosphine)ferrocene palladium dichloride (184 mg, 0.254 mmol), and potassium carbonate (1.75 g, 12.7 mmol) were dissolved in a mixture of dioxane (20 mL) and water (2 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 8-(6-fluoropyridin-3-yl)imidazole[1,2-a]pyridine 53b (415 mg), yield: 38%.

[0431] MS m / z(ESI): 214.1 [M+H] + .

[0432] Step 2

[0433] Following the synthesis method in step 2 of Example 47, the target product (1S,3S)-N was synthesized. 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazol[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine 53.

[0434] MS m / z (ESI): 438.2 [M+H] + .

[0435] 1 H NMR (400MHz, DMSO-d6) δ8.81(d,1H),8.46(d,1H),8.25-8.18(m,3H),7.99(d,1H),7.59(d,1H),7.51(d,1H),7.36(d,1H),7. 03(t,1H),6.93(t,1H),6.88-6.81(m,1H),6.56(d,1H),4.33(dq,2H),2.22-2.07(m,2H),2.00-1.85(m,2H),1.53(ddd,2H).

[0436] Example 56

[0437] 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

[0438]

[0439] first step

[0440] Under nitrogen protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.78 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 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 obtain 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazol[4,5-b]pyrazin-2-one 56b (1.4 g, pale yellow solid), yield: 57.87%.

[0441] MS m / z(ESI): 246.1 [M+H] + .

[0442] Step 2

[0443] 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 56b (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-imidazolium[4,5-b]pyrazin-2-one 56 (41 mg, white solid), yield: 30.47%.

[0444] MS m / z (ESI): 470.1 [M+H] + .

[0445] 1H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(m,2H),7.26-6.82(m,1H), 6.97(d,1H),6.59(d,1H),4.42-4.19(m,2H),3.40(s,3H),2.22-2.05(m,2H),1.95-1.82(m,2H),1.61-1.42(m,2H).

[0446] Example 57

[0447] 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

[0448]

[0449] first step

[0450] Under nitrogen protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.59 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 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 obtain 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 57b (1.3 g), yield: 57.49%.

[0451] MS m / z(ESI): 230.1 [M+H] + .

[0452] Step 2

[0453] Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 57b (72 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL). 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 57 (46 mg), yield: 35.4%.

[0454] MS m / z (ESI): 454.1 [M+H] + .

[0455] 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).

[0456] Example 63

[0457] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0458] Example 63 can also be synthesized using the following method:

[0459]

[0460] first step

[0461] 63a (3.5 g, 20 mmol) was dissolved in acetonitrile (50 mL), and tert-butyl nitrite (3.09 g, 30 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then copper bromide (6.7 g, 30 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was heated to 50 °C and stirred for 1 hour. The reaction solution was filtered, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to give 3,6-dibromo-1,2,4-triazine 63b (1.3 g), yield: 27.3%.

[0462] MS m / z(ESI): 237.9 [M+H] + .

[0463] Step 2

[0464] 63b (1.3 g, 5.44 mmol), (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (1.2 g, 5.99 mmol), and diisopropylethylamine (1.41 g, 10.88 mmol) were dissolved in dioxane (20 mL), and the reaction mixture was heated to 80 °C and stirred for 2 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was washed with water (30 mL × 3) and saturated sodium chloride. The mixture was dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentane)carbamate tert-butyl ester 63c (1.5 g), yield: 76.9%.

[0465] MS m / z (ESI): 358.1 [M+H] + .

[0466] Step 3

[0467] 63c (1.5 g, 4.19 mmol), cyclopropylboronic acid (719 mg, 8.38 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (306.4 mg, 0.42 mmol), and sodium carbonate (1.33 g, 12.56 mmol) were dissolved in dioxane (20 mL) and water (5 mL). The reaction mixture was heated to 120 °C and stirred for 16 hours. The reaction mixture was filtered, and ethyl acetate (100 mL) was added. The organic phase was washed with water (30 mL × 3) and saturated sodium chloride, dried, concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain tert-butyl carbamate 63d (400 mg), yield: 29.9%.

[0468] MS m / z (ESI): 320.2 [M+H] + .

[0469] Step 4

[0470] 63d (400 mg, 1.25 mmol) was dissolved in methanol (5 mL), and 4M dioxane hydrochloride solution (5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the pH was adjusted to weakly alkaline by adding ammonia methanol solution. After further concentration, the residue was separated by silica gel column chromatography (eluting system A) to obtain ((1S,3S)-N 1 -((6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 63e (120 mg), yield: 43.6%.

[0471] MS m / z(ESI): 220.2 [M+H] + .

[0472] Step 5

[0473] 63e (100 mg, 0.456 mmol), 2B (141.3 mg, 0.684 mmol), tris(dibenzylacetone)palladium (41.76 mg, 0.0456 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (42.56 mg, 0.091 mmol) and sodium tert-butoxide (131.5 mg, 1.37 mmol) were dissolved in dioxane (10 mL), and the reaction was heated to 100 °C and stirred for 15 hours. Ethyl acetate (30 mL) was added to the reaction solution. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride, dried, concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 63 (26 mg), yield: 14.6%.

[0474] MS m / z(ESI): 390.2 [M+H] + .

[0475] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.92(d,1H),7.60(dd,1H),7.54(s,1H),7.47(td,1H),7.38(dd,1H),6.93(d,1H),6.53(d,1H),6 .44(d,1H),6.27(t,1H),4.34(m,2H),2.18-2.10(m,2H),2.08-2.02(m,1H),1.98-1.85(m,2H),1.60-1.39(m,2H),1.00-0.86(m,4H).

[0476] Example 64

[0477] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropane-2-yl)-2H-[1,3'-bipyridine]-2-one

[0478] Example 64 can also be synthesized using the following method:

[0479]

[0480] first step

[0481] Following the synthetic method of the first step of intermediate 2, the target product 6'-fluoro-3-(2-hydroxypropane-2-yl)-2H-[1,3'-bipyridine]-2-one 64b was synthesized.

[0482] MS m / z (ESI): 249.1 [M+H] + .

[0483] Step 2

[0484] 64b (150 mg, 0.604 mmol), intermediate 1 (98 mg, 0.403 mmol), and N,N-diisopropylethylamine (104 mg, 0.806 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction mixture was heated to 130 °C and stirred for 24 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropane-2-yl)-2H-[1,3'-bipyridine]-2-one 64 (62 mg), yield: 32.6%.

[0485] MS m / z(ESI): 473.2 [M+H] + .

[0486] 1 H NMR(400MHz, CDCl3)δ8.18(s,2H),8.03(d,1H),7.55(dd,1H),7.41(dd,1H),7.29(dd,1H),6.47(d,1H),6.41(t,1H)6.31(t ,1H),5.89(s,1H),5.22(d,1H),5.00(s,1H),4.41(d,1H),4.26(d,1H),2.33(m,2H),2.05(m,2H),1.77(s,2H),1.58(s,6H).

[0487] Example 68

[0488] 6'-(((1S,3S)-3-((7-Fluoropyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0489] Example 68 can also be synthesized using the following method:

[0490]

[0491] first step

[0492] 2-Chloroprene[2,1-f][1,2,4]triazine 68a (50 mg, 0.325 mmol) and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) (173 mg, 0.488 mmol) were dissolved in acetonitrile (3 mL), and the reaction was carried out by microwave heating to 80 °C. ° Stir for 1 hour. Concentrate the reaction solution, and separate the residue by silica gel column chromatography (elution system B) to obtain 2-chloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine 68b (25 mg), yield: 44.7%.

[0493] MS m / z(ESI): 172.0 [M+H] + .

[0494] Step 2

[0495] 68b (25 mg, 0.146 mmol), intermediate 2 (39.4 mg, 0.146 mmol), and cesium carbonate (95.0 g, 0.291 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazine-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 68 (27 mg), yield: 45.7%.

[0496] MS m / z (ESI): 406.2 [M+H] + .

[0497] 1H NMR(400MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.61(dd,1H),7.48(td,1H),7.40(dd,1H),7.16(d,1H),6.96(d,1H),6.67(t,1H ),6.53(d,1H),6.44(d,1H),6.37(t,1H),6.27(t,1H),4.34-4.19(m,2H),2.21-2.11(m,2H),2.03-1.85(m,2H),1.62-1.46(m,2H).

[0498] Example 75

[0499] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0500] Example 75 can also be synthesized using the following method:

[0501]

[0502] first step

[0503] Under nitrogen protection, intermediate 1 (1.2 g, 4.91 mmol), 2-fluoro-5-nitro-pyridine (768 mg, 5.40 mmol), and cesium carbonate (2.24 g, 6.88 mmol) were dissolved in acetonitrile (15 mL), and the reaction 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 (30 mL × 2). The organic phases were combined, dried, and concentrated to give the crude product (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)-N3-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine 75a (1.79 g), yield: 99.45%. This product was used directly in the next reaction without further purification.

[0504] MS m / z (ESI): 367.1 [M+H] + .

[0505] Step 2

[0506] Under a hydrogen atmosphere, 75a (1.79 g, 4.89 mmol) and palladium on carbon (593 mg, 0.49 mmol, 10%) were dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (5 mL), and stirred at 20 °C for 5 hours. The reaction solution was filtered, and the filtrate was concentrated to give crude product N2-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 75b (1.42 g), yield: 86.40%. It was used directly in the next reaction without further purification.

[0507] MS m / z(ESI): 337.2 [M+H] + .

[0508] Step 3

[0509] Under nitrogen protection, 75b (439 mg, 1.30 mmol) and potassium carbonate (481 mg, 3.48 mmol) were dissolved in N,N-dimethylformamide (7 mL). After stirring at 20 °C for 1 hour, the reaction mixture was heated to 55 °C and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed, and concentrated. The residue was separated by silica gel column chromatography to obtain the crude product, which was then prepared by reversed-phase HPLC to obtain 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 75 (45.2 mg), yield: 25.88%.

[0510] MS m / z (ESI): 454.1 [M+H] + .

[0511] 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.79(d,1H),8.31(d,1H),8.23(s,2H),7.87-7.78(m,1H),7.73(d,1H),7.49(d,1H),7.26- 6.81(m,1H),6.70(d,1H),6.55(d,1H),5.00(s,2H),4.36-4.22(m,2H),2.19-2.03(m,2H),1.97-1.79(m,2H),1.60-1.40(m,2H).

[0512] Example 76

[0513] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0514]

[0515] Example 76 can also be synthesized using the following method:

[0516] Referring to the synthesis method of Example 75, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 76 was synthesized.

[0517] MS m / z (ESI): 454.1 [M+H] + .

[0518] 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.77(d,1H),8.35(d,1H),8.23(s,2H),7.89-7.80(m,1H),7.76-7.69(m,1H),7.47(d,1H),7.2 6-6.82(m,1H),6.71(d,1H),6.55(d,1H),5.03(s,2H),4.38-4.22(m,2H),2.22-2.02(m,2H),1.98-1.78(m,2H),1.62-1.41(m,2H).

[0519] Example 77

[0520] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0521]

[0522] Example 77 can also be synthesized using the following method:

[0523] Following the synthesis method of Example 75, the target product 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 77 was synthesized.

[0524] MS m / z (ESI): 454.1 [M+H] + .

[0525] 1 H NMR(400MHz,DMSO-d6)δ8.83-8.77(m,1H),8.36(d,1H),8.23(s,2H),8.18-8.10(m,1H),7.90-7.83(m,1H),7.59-7.53(m,1H),7.48(d,1H) ),7.25-6.81(m,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.36-4.22(m,2H),2.19-2.05(m,2H),1.97-1.81(m,2H),1.58-1.42(m,2H).

[0526] Example 78

[0527] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0528] Example 78 can also be synthesized using the following method:

[0529]

[0530] first step

[0531] Under nitrogen protection, 3-bromo-5-chloro-1,2,4-thiadiazole (900 mg, 4.51 mmol), cyclopropylboronic acid (775 mg, 9.02 mmol), 1,1-bis(diphenylphosphine)diberberine palladium(II) chloride (164 mg, 0.226 mmol), and potassium carbonate (1.56 g, 11.28 mmol) were dissolved in a mixture of toluene (15 mL), water (5 mL), and ethanol (5 mL). The mixture was heated to 90 °C and stirred for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 mL). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride (30 mL), dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 3-bromo-5-cyclopropyl-1,2,4-thiadiazole 78a (120 mg), yield: 13.0%.

[0532] 1 H NMR (400MHz, CDCl3) δ2.41(m,1H),1.32(m,2H),1.29(m,2H).

[0533] Step 2

[0534] Following the synthesis method of Example 4, the target product 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 78 was synthesized.

[0535] MS m / z (ESI): 395.1 [M+H] + .

[0536] 1 H NMR(400MHz,DMSO-d6)δ7.91(d,1H),7.60(dd,1H),7.47(m,1H),7.41-7.31 (m,2H),6.89(d,1H),6.51(d,1H),6.44(d,1H),6.27(m,1H),4.30-4.25(m, 1H),4.15(m,1H),2.46-2.41(m,1H),2.13-2.06(m,2H),1.93-1.89(m,1H), 1.85-1.81(m,1H),1.55-1.44(m,2H),1.22-1.17(m,2H),1.02-0.98(m,2H).

[0537] Example 82

[0538] N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide

[0539] Example 82 can also be synthesized using the following method:

[0540]

[0541] first step

[0542] Pyridine-2(1H)-one (150 mg, 1.58 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL) at 0 °C. Sodium hydride (69 mg, 1.74 mmol, 60% in mineral oil) was added to the reaction solution with stirring. After stirring for 10 minutes, methyl 2-(bromomethyl)benzoate 82a (361 mg, 1.58 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 6 hours. The reaction solution was quenched with formic acid (1 mL), concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give methyl 2-((2-oxopyridin-1(2H)yl)methyl)benzoate 82b (310 mg), yield: 80.8%.

[0543] MS m / z(ESI): 244.1 [M+H] + .

[0544] Step 2

[0545] 82b (310 mg, 1.27 mmol) and lithium hydroxide (61 mg, 2.55 mmol) were dissolved in a mixture of methanol (3 mL) and water (1 mL) at room temperature and stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain the title product 2-(2-oxopyridin-1(2H)yl)methyl)benzoic acid 82c (190 mg), yield: 65.0%.

[0546] MS m / z(ESI): 230.1 [M+H] + .

[0547] Step 3

[0548] At room temperature, 82c (40 mg, 0.18 mmol), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentan-1,3-diamine (50 mg, 0.18 mmol), triethylamine (54 mg, 0.54 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain the product N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentanyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide 82 (40 mg), yield: 49.3%.

[0549] MS m / z (ESI): 456.2 [M+H] + .

[0550] 1 H NMR(400MHz,DMSO-d6)δ8.66(d,1H),8.23(s,2H),7.75(d,1H),7.41(m,5H),7.03(s,1H),7.01(t ,1H),6.42(d,1H),6.25(d,1H),5.21(s,2H),4.31(m,2H),2.09(m,2H),1.91(t,2H),1.50(m,2H).

[0551] Example 84

[0552] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0553] Example 84 can also be synthesized using the following method:

[0554]

[0555] first step

[0556] Under nitrogen protection, 3-iodobenzoic acid (1.5 g, 6.05 mmol), 2-hydroxypyridine (1.15 g, 12.10 mmol), cuprous iodide (576 mg, 3.02 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (86 mg, 0.605 mmol), and cesium carbonate (3.94 g, 12.10 mmol) were dissolved in 1',4-dioxane (30 mL), and the mixture was heated to 100 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (elution system A) to give compound 3-(2-oxo-1-pyridyl)benzoic acid 84a (1.2 g), yield: 92.2%.

[0557] MS m / z(ESI): 216.1 [M+H] + .

[0558] Step 2

[0559] Under nitrogen protection, intermediate 1 (70 mg, 0.287 mmol), 84a (93 mg, 0.43 mmol), N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (121 mg, 0.43 mmol), and N-methylmorpholine (58 mg, 0.573 mmol) were dissolved in acetonitrile (2 mL), and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 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 reverse C18 chromatography (elution system C) to give 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 84 (79.1 mg), yield: 61.8%.

[0560] MS m / z(ESI): 442.1 [M+H] + .

[0561] 1H NMR(400MHz,DMSO-d6)δ8.47(d,1H),8.23(s,2H),7.93(dt,1H),7.89-7.87(m,1H),7.70(dd,1H),7.62-7.52(m,3H),7.48(d,1H),7.0 3(dd,1H),6.51(d,1H),6.35(td,1H),4.47-4.42(m,1H),4.35-4.30(m,1H),2.14-2.06(m,2H),1.95-1.87(m,2H),1.60-1.50(m,2H).

[0562] Example 87

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

[0564] Example 87 can also be synthesized using the following method:

[0565]

[0566] first step

[0567] Copper bromide (1.13 g, 5.06 mmol) and tert-butyl nitrite (1.74 g, 16.87 mmol) were dissolved in acetonitrile (5 mL). 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine 87a (500 mg, 3.37 mmol) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 0.5 h, then heated to 60 °C and stirred for another 0.5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (30 mL), filtered, and the organic phase was washed with water (30 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to give 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine 87b (530 mg), yield: 74.1%.

[0568] MS m / z(ESI): 214.0 [M+H] + .

[0569] Step 2

[0570] Under nitrogen protection, 87b (211.8 mg, 1.0 mmol), intermediate 2 (90 mg, 0.33 mmol), sodium tert-butoxide (96.0 mg, 1.0 mmol), tris(dibenzylacetone)palladium (61.0 mg, 0.07 mmol), and Ruphos (46.6 mg, 0.1 mmol) were dissolved in 1',4-dioxane (8 mL) and heated to 130 °C with stirring for 16 hours. The reaction mixture was filtered and concentrated. The residue was analyzed by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 87 (30 mg), yield 22.2%.

[0571] MS m / z(ESI): 402.2 [M+H] + .

[0572] 1 H NMR(400MHz,DMSO-d6)δ8.43(d,,1H),7.91(d,1H),7.60(dd,1H),7.47(t,1H),7.39(dd,1H),7.16(s,1H),6.91(d,1H),6.69(d,1H),6.56–6.50 (m,2H),6.44(d,1H),6.26(t,1H),4.34–4.29(m,1H),4.20–4.10(m,1H) ,2.34(s,3H),2.25–2.08(m,2H),2.01–1.81(m,2H),1.64–1.41(m,2H).

[0573] Example 88

[0574] 6'-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0575] Example 88 can also be synthesized using the following method:

[0576]

[0577] first step

[0578] Copper bromide (1.10 g, 4.93 mmol) and tert-butyl nitrite (1.69 g, 16.43 mmol) were dissolved in acetonitrile (5 mL). 6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-amine 88a (500.00 mg, 3.29 mmol) was added to the reaction mixture with stirring. The reaction was stirred at room temperature for 0.5 h, then heated to 60 °C and stirred for another 0.5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (100 mL), filtered, washed with water (100 mL), concentrated, diluted with ethyl acetate (30 mL), filtered, washed with water (30 mL), dried, concentrated, and purified by silica gel column chromatography (elution system C) to give 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine 88b (490 mg), yield: 69.0%.

[0579] MS m / z (ESI): 215.9 [M+H] + .

[0580] Step 2

[0581] Under nitrogen protection, 88b (215.8 mg, 1.0 mmol), intermediate 2 (90 mg, 0.33 mmol), sodium tert-butoxide (96.0 mg, 1.0 mmol), tris(dibenzylideneacetone)palladium (61.0 mg, 0.07 mmol), and Ruphos (46.6 mg, 0.1 mmol) were dissolved in 1',4-dioxane (8 mL) and heated to 130 °C with stirring for 16 hours. The reaction mixture was filtered and concentrated. The residue was analyzed by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 88 (10.5 mg), yield 7.23%.

[0582] MS m / z (ESI): 406.1 [M+H] + .

[0583] 1H NMR (400MHz, DMSO-d6) δ8.96–8.90(m,1H),7.91(d,1H),7.59(d,1H),7.54–7.44(m,2H),7.43–7.37(m,2H),6.91(d,1H),6.71(d,1 H),6.60–6.40(m,2H),6.27(t,1H),4.38–4.26(m,1H),4.23–4.10(m,1H),2.25–2.05(m,2H),2.01–1.81(m,2H),1.65–1.40(m,2H).

[0584] Example 91

[0585] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidin

[0586] Example 91 can also be synthesized using the following method:

[0587]

[0588] first step

[0589] Under nitrogen protection, 2-fluoro-5-iodopyridine 91a (300 mg, 1.35 mmol), 1,1-dioxoisothiazolidinane (326 mg, 2.69 mmol), cuprous iodide (51 mg, 0.27 mmol), dimethylethylenediamine (24 mg, 0.27 mmol), and potassium carbonate (558 mg, 4.04 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was microwaved to 130 °C and stirred for 1 hour. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase 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 (elution system B) to obtain 2-(6-fluoropyridin-3-yl)-1,1-dioxoisothiazolidinane 91b (269 mg), yield: 92.47%.

[0590] MS m / z(ESI): 217.1 [M+H] + .

[0591] Step 2

[0592] Under nitrogen protection, intermediate 1 (75 mg, 0.31 mmol), 91b (133 mg, 0.62 mmol), and diisopropylethylamine (80 mg, 0.62 mmol) were dissolved in dimethyl sulfoxide (1 mL), and the reaction was heated to 125 °C and stirred for 48 hours. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC (ammonium bicarbonate system) to prepare 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazoline 91 (17.1 mg), yield: 12.59%.

[0593] MS m / z(ESI): 441.1 [M+H] + .

[0594] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.87(d,1H),7.49(d,1H),7.41-7.31(m,1H),7.25-6.80(m,1H),6.74(d,1H),6.48(d,1H), 4.36-4.16(m,2H),3.59(t,2H),3.42-3.36(m,2H),2.40-2.29(m,2H),2.16-2.04(m,2H),1.93-1.76(m,2H),1.59-1.38(m,2H).

[0595] Example 92

[0596] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butanesulfonamide

[0597]

[0598] Example 92 can also be synthesized using the following method:

[0599] Following the synthesis method of Example 91, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butanesulfonamide 92 was synthesized.

[0600] MS m / z (ESI): 455.2 [M+H] + .

[0601] 1H NMR (400MHz, DMSO-d6) δ8.23(s,2H),7.88(d,1H),7.46(d,1H),7.36-7.28(m,1H),7.23-6.81(m,1H),6.76(d,1H),6.44( d,1H),4.35-4.18(m,2H),3.57-3.46(m,2H),3.28-3.18(m,2H),2.18-2.03(m,4H),1.95-1.69(m,4H),1.59-1.38(m,2H).

[0602] Example 93

[0603] 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

[0604] Example 93 can also be synthesized using the following method:

[0605]

[0606] first step

[0607] Lithium bis(trimethylsilylamino)ene (1M, 3.6mL) was added to a tetrahydrofuran (3mL) solution of 57b (167mg, 0.73mmol) and iodomethane (517mg, 3.64mmol) at 0℃, and the reaction was stirred at room temperature for 3 hours. A saturated ammonium chloride solution was added to the reaction mixture at 0℃, and the aqueous phase was extracted with ethyl acetate (20mL × 2). The organic phases were combined, dried, concentrated, and 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 93a (110mg), yield: 58.69%.

[0608] MS m / z(ESI): 258.1 [M+H] + .

[0609] Step 2

[0610] Under nitrogen protection, intermediate 1 (100 mg, 0.41 mmol), 93a (70 mg, 0.27 mmol), and diisopropylethylamine (106 mg, 0.82 mmol) were dissolved in dimethyl sulfoxide (1.5 mL), and the reaction was stirred at 130 °C for 48 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-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 93 (32.1 mg), yield: 24.50%.

[0611] MS m / z (ESI): 482.3 [M+H] + .

[0612] 1 H NMR(400MHz,DMSO-d6)δ8.79-8.69(m,1H),8.29-8.19(m,3H),7.86(d,1H),7.68-7.59(m,1H),7.49(d,1H),7.32-7.26(m,1H ),7.23-6.82(m,1H),6.90(d,1H),6.57(d,1H),4.42-4.20(m,2H),2.23-2.03(m,2H),2.01-1.78(m,2H),1.64-1.34(m,8H).

[0613] Example 95

[0614] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5H-pyrrolo[3,4-b]pyridin-5,7(6H)-dione

[0615] Example 95 can also be synthesized using the following method:

[0616]

[0617] first step

[0618] 75b (75 mg, 0.22 mmol), 2,3-pyridinedicarboxylic anhydride (33 mg, 0.22 mmol), and 4-dimethylaminopyridine (3 mg, 0.02 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at 50 °C for 1 hour. Acetic anhydride (46 mg, 0.45 mmol) was added to the reaction solution, and the reaction was heated to 70 °C and stirred for 1 hour. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC to prepare 95 (21.3 mg) of 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione, yield: 20.44%.

[0619] MS m / z (ESI): 468.2 [M+H] + .

[0620] 1 H NMR(400MHz,DMSO-d6)δ9.07-8.99(m,1H),8.42-8.33(m,1H),8.24(s,2H),7.98(d,1H),7.89-7.79(m,1H),7.51(d,1H),7.44-7.3 8(m,1H),7.26-6.81(m,1H),6.98(d,1H),6.57(d,1H),4.38-4.26(m,2H),2.2-2.07(m,2H),1.95-1.83(m,2H),1.60-1.44(m,2H).

[0621] Example 97

[0622] 1-Cyclopropyl-3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

[0623]

[0624] Example 97 can also be synthesized using the following method:

[0625] Following the synthesis method of Example 56, the target product 1-cyclopropyl-3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 97 was synthesized.

[0626] MS m / z(ESI): 496.2 [M+H] + .

[0627] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.09(d,1H),8.00(d,1H),7.90(d,1H),7.56-7.45(m,2H),7.26-6.80(m,1H),6.96(d,1H), 6.58(d,1H),4.40-4.21(m,2H),3.10-2.96(m,1H),2.22-2.03(m,2H),2.00-1.81(m,2H),1.61-1.42(m,2H),1.16-0.95(m,4H).

[0628] Example 99

[0629] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)pyrazole[1,5-a]pyridine-3-methylcyan

[0630] Example 99 can also be synthesized using the following method:

[0631]

[0632] first step

[0633] Under nitrogen protection, 7-bromopyrazole[1,5-a]pyridine 99a (650 mg, 3.3 mmol), (6-fluoropyridin-3-yl)boronic acid (604 mg, 4.29 mmol), bis(diphenylphosphine)ferrocene palladium dichloride (241 mg, 0.33 mmol), and potassium carbonate (1.14 g, 8.25 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 mL) and water (4 mL). The reaction mixture was heated to 100 °C and stirred for 10 hours. The reaction solution was filtered through diatomaceous earth, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine 99b (640 mg), yield: 91.0%.

[0634] MS m / z(ESI): 214.1 [M+H] + .

[0635] Step 2

[0636] 99b (300 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (5 mL) and placed in an ice-water bath. Phosphorus oxychloride (1 mL) was added under nitrogen protection, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (20 mL), and the pH was adjusted to weakly alkaline with sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (30 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 7-(6-fluoropyridin-3-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde 99c (310 mg), yield: 91.3%.

[0637] MS m / z(ESI): 242.1 [M+H] + .

[0638] Step 3

[0639] 99c (200 mg, 0.83 mmol) and hydroxylamine hydrochloride (86 mg, 1.24 mmol) were dissolved in a mixed solution of ethanol (15 mL) and water (5 mL). The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction solution was concentrated, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was filtered, and the filter cake was washed with water and dried to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine-3-carboxaldehyde oxime 99d (150 mg), yield: 70.6%.

[0640] MS m / z(ESI): 257.1 [M+H] + .

[0641] Step 4

[0642] 99d (60 mg, 0.234 mmol) was dissolved in acetic anhydride (5 mL), and the reaction was heated to 130 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with saturated sodium bicarbonate aqueous solution and aqueous solution, respectively, and dried to give 7-(6-fluoropyridin-3-yl)pyrazole[1,5-a]pyridine-3-cyano99e (30 mg), yield: 53.8%.

[0643] MS m / z(ESI): 239.1 [M+H] + .

[0644] Step 5

[0645] 99e (35 mg, 0.147 mmol), intermediate 2 (36 mg, 0.147 mmol), and diisopropylethylamine (40 mg, 0.294 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 130 °C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazole[1,5-a]pyridine-3-cyano 99 (32 mg), yield: 47.1%.

[0646] MS m / z (ESI): 463.2 [M+H] + .

[0647] 1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.55(d,1H),8.24(s,2H),8.00(dd,1H),7.82(dd,1H),7.67(dd,1H),7.50(d,1H),7.30 (dd,1H),7.21(s,1H),7.03(t,1H),6.60(d,1H),4.42-4.29(m,2H),2.21-2.07(m,2H),2.03-1.86(m,2H),1.60-1.46(m,2H).

[0648] Example 102

[0649] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-Fluoropyrazole[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine

[0650] Example 102 can also be synthesized using the following method:

[0651]

[0652] first step

[0653] (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3-(5-(pyrazol[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 52 (30 mg, 0.068 mmol) and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) (24 mg, 0.068 mmol) were dissolved in acetonitrile (2 mL), and the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-Fluoropyrazole[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 102 (7 mg), yield: 22.4%.

[0654] MS m / z (ESI): 456.2 [M+H] + .

[0655] 1 H NMR(400MHz,DMSO-d6)δ8.53(d,1H),8.24(s,2H),8.11(d,1H),7.98(dd,1H),7.60(dd,1H),7.49(d,1H),7.27(dd,1H),7.10 (d,1H),7.03(t,1H),6.98(dd,1H),6.58(d,1H),4.40-4.28(m,2H),2.22-2.07(m,2H),2.03-1.85(m,2H),1.60-1.46(m,2H).

[0656] Example 108

[0657] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

[0658] Example 108 can also be prepared according to the following method:

[0659]

[0660] first step

[0661] Under nitrogen protection, intermediate 1 (300 mg, 1.23 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (301.4 mg, 1.35 mmol), and N,N-diisopropylethylamine (476.3 mg, 3.68 mmol) were dissolved in dimethyl sulfoxide (3 mL) and stirred at 130 °C for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (formic acid system) to give (6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid 108a (250 mg), yield: 55.7%.

[0662] MS m / z(ESI): 366.2[M+H]+.

[0663] Step 2

[0664] Under nitrogen protection, 108a (80 mg, 0.22 mmol), 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (98.6 mg, 0.44 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (15.9 mg, 0.024 mmol), and sodium carbonate (71.0 mg, 0.66 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 108 (39 mg) of 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, yield: 37.1%.

[0665] MS m / z (ESI): 466.2 [M+H] + .

[0666] 1 H NMR(400MHz,DMSO-d6)δ9.07(d,1H),8.56(s,1H),8.46(d,1H),8.24(s,2H),7.95–7.84(m,2H),7.72(d,1H),7.49(d,1H),7.3 9(t,1H),7.03(s,1H),6.79(s,1H),6.55(d,1H),4.40–4.26(m,2H),2.22–2.04(m,2H),1.97–1.82(m,2H),1.59–1.45(m,2H).

[0667] Example 112

[0668] 6'-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0669]

[0670] Following the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 112 was synthesized.

[0671] MS m / z(ESI): 422.1 [M+H] + .

[0672] 1 H NMR(400MHz, DMSO-d6)δ8.62(d,1H),7.91(d,1H),7.59(dd,1H),7.54(d,1H),7.50–7.43(m,1H),7.39(dd,1H),6.96–6.88(m,2H),6.83(d, 1H),6.52(d,1H),6.44(d,1H),6.27(t,1H),4.39–4.26(m,1H),4.21– 4.09(m,1H),2.23–2.06(m,2H),2.00–1.81(m,2H),1.62–1.43(m,2H).

[0673] Example 113

[0674] 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

[0675]

[0676] Under nitrogen protection, 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine 113a (77 mg, 0.29 mmol), intermediate 2 (60 mg, 0.22 mmol), sodium tert-butoxide (64 mg, 0.67 mmol), tris(dibenzylacetone)dipalladium (41 mg, 0.04 mmol), and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (41 mg, 0.09 mmol) were dissolved in 1,4-dioxane (2 mL) and microwaved to 130 °C with stirring for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 113 (31.7 mg), yield: 31.4%.

[0677] MS m / z (ESI): 456.2 [M+H] + .

[0678] 1 H NMR (400MHz, DMSO-d6) δ8.83(d,1H),7.92(s,1H),7.86(s,1H),7.60(d,1H),7.52–7.44(m,1H),7.40(d,1H),7.15(d,1H),7.05(d,1H),6.94( d,1H),6.53(d,1H),6.44(d,1H),6.27(t,1H),4.40–4.29(m,1H),4.27 –4.12(m,1H),2.22–2.09(m,2H),2.03–1.82(m,2H),1.66–1.43(m,2H).

[0679] Example 114

[0680] 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridine]-2-one

[0681] Example 114 can also be prepared by the following method:

[0682]

[0683] first step

[0684] Under nitrogen protection, 63C (241 mg, 0.67 mmol), methyl 2,2-difluoro-2-fluorosulfonyl acetate (259 mg, 1.35 mmol), and cuprous iodide (192 mg, 1.01 mmol) were dissolved in N,N-dimethylformamide (3 mL) and microwaved to 90 °C with stirring for 3 hours. The reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL) and saturated sodium chloride (20 mL). The organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give the title product (1S,3S)-3-(((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate tert-butyl 114a (160 mg), yield: 68.5%.

[0685] MS m / z (ESI): 348.2 [M+H] + .

[0686] Step 2

[0687] Referring to the synthesis method in step four of Example 63, the target product (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine 114b was synthesized.

[0688] MS m / z(ESI): 296.2 [M+H] + .

[0689] Step 3

[0690] Referring to the synthesis method in step 5 of Example 63, the target product 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazine-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridine]-2-one 114 was synthesized.

[0691] MS m / z (ESI): 418.2 [M+H] + .

[0692] 1 H NMR(400MHz,CD3OD)δ8.52(s,1H),7.95(d,1H),7.60(m,2H),7.45(m,1H),6.62(m, 2H),6.46(m,1H),4.62(d,1H),4.39(m,1H),2.29(m,2H),2.11(m,2H),1.68(m,2H)

[0693] Example 115

[0694] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0695]

[0696] Following the synthesis method of Example 75, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one was synthesized.

[0697] MS m / z (ESI): 468.2 [M+H] + .

[0698] 1 H NMR(400MHz,DMSO-d6)δ8.64(d,1H),8.37(d,1H),8.23(s,2H),7.86(dd,1H),7.55(d,1H),7.48(d,1H),7.03(t,1H),6.71( d,1H),6.55(d,1H),4.98(s,2H),4.33-4.26(m,2H),2.57(s,3H),2.18-2.08(m,2H),1.95-1.82(m,2H),1.58-1.44(m,2H).

[0699] Example 116

[0700] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0701]

[0702] Following the synthesis method of Example 75, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one was synthesized.

[0703] MS m / z (ESI): 468.2 [M+H] + .

[0704] 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.34(d,1H),8.23(s,2H),7.85(dd,1H),7.59(s,1H),7.49(d,1H),7.03(t,1H),6.72( d,1H),6.54(d,1H),4.97(s,2H),4.33-4.26(m,2H),2.60(s,3H),2.18-2.08(m,2H),1.95-1.82(m,2H),1.58-1.45(m,2H).

[0705] Example 117

[0706] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-methylpyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine

[0707] Example 117 can also be prepared by the following method:

[0708]

[0709] first step

[0710] 99c (300 mg, 1.24 mmol) was dissolved in methanol (10 mL) under ice bath conditions. Sodium borohydride (47 mg, 1.24 mmol) was added to the reaction solution with stirring. The reaction was heated to room temperature and stirred for 2 hours. Hydrochloric acid (1 M) was added to quench the reaction solution. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain (7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol 117a (240 mg), yield: 79.3%.

[0711] MS m / z(ESI): 244.1 [M+H] + .

[0712] Step 2

[0713] 117a (50 mg, 0.206 mmol), phenyl chlorothiocarbamate (35.5 mg, 0.206 mmol), and 4-dimethylaminopyridine (50.2 mg, 0.412 mmol) were dissolved in acetonitrile (5 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain oxy-((7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methyl)oxy-phenyl thiocarbonate 117b (30 mg), yield: 64.1%.

[0714] MS m / z(ESI): 380.1 [M+H] + .

[0715] Step 3

[0716] Under nitrogen protection, 117b (50 mg, 0.132 mmol), azobisisobutyronitrile (4.3 mg, 0.026 mmol), and tributyltin hydride (4.3 mg, 0.026 mmol) were dissolved in toluene (3 mL) and heated to 130 °C with stirring for 1 hour. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 7-(6-fluoropyridin-3-yl)-3-methylpyrazolo[1,5-a]pyridine 117c (20 mg), yield: 66.8%.

[0717] Step 4

[0718] 117c (20 mg, 0.088 mmol), intermediate 2 (21.5 mg, 0.088 mmol), and diisopropylethylamine (22.7 mg, 0.176 mmol) were dissolved in dimethyl sulfoxide (2 mL) and heated to 130 °C with stirring for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to obtain the target product (1S,3S)-N. 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-methylpyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 117 (12 mg), yield: 30.2%.

[0719] MS m / z (ESI): 452.2 [M+H] + .

[0720] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,1H),8.24(s,2H),8.02(dd,1H),7.83(s,1H),7.54(dd,1H),7.50(d,1H),7.21(dd,1H),7.05(t,1H) ,7.03(s,1H),6.90(dd,1H),6.57(d,1H),4.40-4.30(m,2H),2.30(s,3H),2.18-2.10(m,2H),1.97-1.85(m,2H),1.58-1.49(m,2H).

[0721] Example 118

[0722] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-3-cyano

[0723]

[0724] Following the synthesis method of Example 99, the target product 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-3-cyano was synthesized.

[0725] MS m / z (ESI): 464.2 [M+H] + .

[0726] 1 H NMR(400MHz,DMSO-d6)δ8.95(d,1H),8.84(s,1H),8.76(d,1H),8.27(dd,1H),8.24(s,2H),7.62(d,1H),7.56(d,1H) ,7.52(d,1H),7.04(t,1H),6.65(d,1H),4.44-4.30(m,2H),2.23-2.08(m,2H),1.99-1.86(m,2H),1.59-1.51(m,2H).

[0727] Example 119

[0728] 2-(6-(((1S,3S)-3-((5-(((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidin-1,1-dioxide

[0729] Example 119 can also be prepared by the following method:

[0730]

[0731] first step

[0732] Under nitrogen protection, 1,2-thiazolidin-1,1-dioxide (2 g, 16.5 mmol) and 4-methoxybenzyl chloride (3.10 g, 19.8 mmol) were dissolved in tetrahydrofuran (35 mL) at 0 °C. Sodium hydride (792 mg, 19.8 mmol, 60% purity) was added in portions to the reaction mixture with stirring. The reaction mixture was gradually brought to room temperature and stirred for 16 hours. A saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine, dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 2-(4-methoxybenzyl)isothiazolidin-1,1-dioxide 119b (1.52 g), yield: 38%.

[0733] MS m / z (ESI): 505.1 [2M+Na] + .

[0734] Step 2

[0735] 119b (1 g, 4.14 mmol) was dissolved in tetrahydrofuran (35 mL), and butyllithium (2.5 M, 4.14 mL) was added dropwise to the reaction mixture at -78 °C. The reaction was stirred at -78 °C for 1 hour, and then iodomethane (3.53 g, 24.9 mmol) was added dropwise. The reaction was stirred at -78 °C for another 2 hours, then cooled to room temperature and stirred for 1 hour. The reaction mixture was purified by preparative HPLC (formic acid system) to give 2-(4-methoxybenzyl)-5,5-dimethylisothiazolidinedione 1,1-dioxide 119c (586 mg), yield: 52%.

[0736] MS m / z(ESI): 539.2 [2M+H] + .

[0737] Step 3

[0738] 119c (0.32 g, 1.19 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise to the reaction mixture with stirring, while stirring at room temperature for 4 hours. After the reaction mixture was concentrated, it was diluted with ethyl acetate, the organic phase was washed with saturated sodium chloride water, dried, and concentrated to give 1,1-dioxide 5,5-dimethylisothiazolidinyl 119d (165 mg). The product was used directly in the next reaction without purification.

[0739] MS m / z (ESI): 150.1 [M+H] +

[0740] Step 4

[0741] Following the synthesis method in the first step of Example 91, 2-(6-fluoropyridin-3-yl)-5,5-dimethylisothiazolidinyl 1,1-dioxide 119e (154 mg) was synthesized with a yield of 56%.

[0742] MS m / z (ESI): 245.1 [M+H] + .

[0743] Step 5

[0744] Following the synthesis method in step 2 of Example 91, the target product 2-(6-(((1S,3S)-3-((5-(((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidin-1,1-dioxide 119 (21 mg) was synthesized with a yield of 14%.

[0745] MS m / z (ESI): 469.2 [M+H] + .

[0746] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.88(d,1H),7.46(d,1H),7.35(dd,1H),7.03(t,1H),6.72(d,1H),6.48( d,1H),4.26(dp,2H),3.53(t,2H),2.21(t,2H),2.10(dtd,2H),1.85(qt,2H),1.58–1.42(m,2H),1.39(s,6H).

[0747] Example 120

[0748] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,6-dimethyl-1,2-thiazinane-1,1-dioxide

[0749]

[0750] Following the synthesis method of Example 91, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,6-dimethyl-1,2-thiazinane-1,1-dioxide 120 was synthesized.

[0751] MS m / z (ESI): 483.2 [M+H] + .

[0752] 1H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.85(d,1H),7.47(d,1H),7.28(dd,1H),7.03(t,1H),6.74(d,1H),6.43(d, 1H),4.27(dp,2H),3.50(t,2H),2.10(pd,2H),2.05–1.96(m,2H),1.88–1.76(m,4H),1.49(ddd,2H),1.39(s,6H).

[0753] Example 121

[0754] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-2,3-dihydroisothiazolyl[5,4-b]pyridine 1,1-dioxide

[0755] Example 121 can also be obtained in the following way:

[0756]

[0757] first step

[0758] 2-Aminosulfonyl-N,N-dimethylnicotinamide (4 g, 17.45 mmol), benzyltriethylammonium chloride (40 mg, 0.174 mmol), and sodium carbonate (1.85 g, 17.45 mmol) were dissolved in pure water (2 mL), and the mixture was heated to 60 °C and stirred for 5 hours. After concentrating the reaction solution by half its volume, it was poured into dilute hydrochloric acid (1 N, 100 mL), resulting in the precipitation of a large amount of solid. The solid was filtered and dried to obtain isothiazolo[5,4-b]pyridin-3(2H)-one 1,1-dioxide 121a (1.27 g), yield: 40%.

[0759] MS m / z (ESI): 185.1 [M+H] + .

[0760] 1 H NMR (400MHz, DMSO-d6) δ9.04(dd,1H),8.45(dd,1H),7.93(dd,1H).

[0761] Step 2

[0762] Under nitrogen protection, 121a (194 mg, 1.05 mmol) was dissolved in tetrahydrofuran (4 mL). A tetrahydrofuran solution of lithium aluminum hydride (88 mg, 2.32 mmol) was added dropwise to the reaction mixture at 0 °C (2 mL). The reaction mixture was then stirred at room temperature for 2 hours. After diluting the reaction mixture with ethyl acetate (25 mL), the organic phase was washed with saturated ammonium chloride (10 mL), dried, and concentrated to obtain 150 mg of 2,3-dihydroisothiazolium [5,4-b]pyridine 1,1-dioxide 121b. The product was directly added to the next reaction step without further purification.

[0763] MS m / z(ESI): 171.0 [M+H] + .

[0764] Step 3

[0765] Under nitrogen protection, 2-fluoro-5-iodopyridine (120 mg, 0.54 mmol), 121b (92 mg, 0.54 mmol), cuprous iodide (123 mg, 0.65 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (92 mg, 0.65 mmol) and potassium carbonate (260 mg, 1.88 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 4 hours. After filtration of the reaction solution, the filtrate was diluted with ethyl acetate (25 mL) and water (10 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25 mL × 2), the organic phases were combined, washed with saturated sodium chloride (25 mL), dried, concentrated, and the residue was subjected to silica gel column chromatography (elution system A) to give 2-(6-fluoropyridin-3-yl)-2,3-dihydroisothiazolyl[5,4-b]pyridine 1,1-dioxide 121c (36 mg), yield: 25%.

[0766] MS m / z(ESI): 266.1 [M+H] + .

[0767] Step 4

[0768] Intermediate 1 (32 mg, 0.13 mmol), 121c (35 mg, 0.13 mmol), and N,N-diisopropylethylamine (51 mg, 0.39 mmol) were dissolved in dimethyl sulfoxide (1 mL) and heated to 125 °C with stirring for 16 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-2,3-dihydroisothiazolyl[5,4-b]pyridine 1,1-dioxide 121 (6 mg), yield: 9%.

[0769] MS m / z (ESI): 490.1 [M+H] + .

[0770] 1 H NMR (400MHz, CDCl3) δ8.87–8.77(m,1H),8.18(q,3H),7.90–7.83(m,1H),7.67(dd,1H),7.59(dd,1H),6.41(t,1H),6.47(d,1H ),5.26(d,1H),5.04(s,1H),4.74(s,2H),4.43(p,1H),4.25(s,1H),2.42–2.28(m,2H),2.12–2.02(m,2H),1.58–1.47(m,2H).

[0771] Examples 122 and 123

[0772] 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and 6-(6-(((1S,3S)-3-((5-(bromodifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0773]

[0774] first step

[0775] Sulfophosgene (6.61 g, 57.46 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine 122a (5.00 g, 38.30 mmol) and diisopropylethylamine (7.43 g, 57.46 mmol) in dichloromethane (100 mL) under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was cooled under ice bath conditions, and sodium ethanethiol (6.44 g, 76.61 mmol) was added. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was filtered, the organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give the title product O-(2-chloropyrimidin-5-yl)S-dithiocarbonyl ethyl ester 122b (4.20 g), yield: 46.7%.

[0776] MS m / z(ESI): 235.0 [M+H] + .

[0777] Step 2

[0778] A pyridine hydrofluoride solution (40 mL, containing 70% hydrofluoric acid) was added dropwise to a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (4.87 g, 17.04 mmol) in dichloromethane (100 mL) at -78 °C, and the reaction was stirred for 30 minutes. A solution of 122b (1.00 g, 4.26 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture, and the reaction was heated to 0 °C and stirred for 2 hours. The pH of the reaction mixture was adjusted to 9 using an aqueous sodium carbonate solution. The organic phase was separated, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain a mixture (160 mg) of products 2-chloro-5-(trifluoromethoxy)pyrimidine 122c and 5-(bromodifluoromethoxy)-2-chloropyrimidine 123a.

[0779] 122c MS m / z (ESI): 199.0 [M+H] + .

[0780] 123a MS m / z(ESI): 259.0 [M+H] + .

[0781] Step 3

[0782] 6-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridyl]-7H-pyrrolo[3,4-b]pyridin-5-one (31 mg, 0.10 mmol, synthesized according to Example 75), a mixture of 122c and 123a (40 mg), and diisopropylethylamine (26 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 60 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 122 (6 mg), yield: 12.6%.

[0783] MS m / z (ESI): 472.2 [M+H] + .

[0784] 1 H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.85(d,1H),7.59(dd ,1H),6.63(d,1H),4.96(s,2H),4.40(m,1H),4.32(t,1H),2.28(m,2H),2.00(m,2H),1.61(m,2H).

[0785] And 6-(6-(((1S,3S)-3-((5-(bromodifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 123 (16 mg), yield: 29.8%.

[0786] MS m / z(ESI): 532.1 [M+H] + .

[0787] 1 H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.84(dd,1H),7.59(d d,1H),6.63(d,1H),4.96(s,2H),4.41(m,1H),4.30(m,1H),2.27(dd,2H),2.02(m,2H),1.60(m,2H)

[0788] Example 124

[0789] 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0790]

[0791] first step

[0792] 122a (1.00 g, 7.66 mmol), cesium carbonate (3.24 g, 9.96 mmol), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.31 g, 9.96 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred for 16 hours at room temperature. Ethyl acetate (160 mL) was added to the reaction mixture. The organic phase was washed with water (25 mL) and saturated sodium chloride (25 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to give 2-chloro-5-(2,2,2-trifluoroethoxy)pyrimidine 124a (1.20 g), yield: 73.7%.

[0793] MS m / z(ESI): 213.0 [M+H] + .

[0794] Step 2

[0795] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 124 was synthesized.

[0796] MS m / z (ESI): 486.2 [M+H] + .

[0797] 1 H NMR(400MHz,DMSO-d6)δ8.80(dd,1H),8.36(d,1H),8.20(s,2H),8.15(dd,1H),7.87(dd,1H),7.56(dd,1H),7.10 (d,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.71(q,2H),4.28(q,2H),2.12(m,2H),1.91(m,2H),1.49(m,2H).

[0798] Example 125

[0799] 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0800]

[0801] first step

[0802] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 125 was synthesized.

[0803] MS m / z (ESI): 486.2 [M+H] + .

[0804] 1H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.35(d,1H),8.20(s,2H),8.11(dd,1H),7.87(dd,1H),7.62(dd,1H),7.10 (d,1H),6.69(d,1H),6.55(d,1H),4.93(s,2H),4.71(q,2H),4.28(d,2H),2.11(d,2H),1.90(m,2H),1.49(m,2H).

[0805] Example 126

[0806] 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0807]

[0808] Following the synthesis method of Example 75, the target product 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 126 was synthesized.

[0809] MS m / z(ESI): 429.2 [M+H] + .

[0810] 1 H NMR(400MHz, DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.18(s,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H),7.54(s,1H),6.71(d, 1H),6.56(d,1H),4.93(s,2H),4.36-4.28(m,2H),2.17-2.12(m,2H),2.08-1.85(m,3H),1.59-1.47(m,2H),0.98-0.84(m,4H).

[0811] Example 127

[0812] 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0813]

[0814] first step

[0815] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 127 was synthesized.

[0816] MS m / z (ESI): 428.2 [M+H] + .

[0817] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.34(d,1H),8.11(dd,1H),8.07(s,2H),7.87(dd,1H),7.62(dd,1H),7.01(d,1H),6.68( d,1H),6.55(d,1H),4.93(s,2H),4.29(dd,2H),2.10(m,2H),1.90(m,2H),1.73(m,1H),1.50(m,2H),0.83(m,2H),0.59(m,2H).

[0818] Example 128

[0819] 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0820]

[0821] first step

[0822] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 128 was synthesized.

[0823] MS m / z (ESI): 428.2 [M+H] + .

[0824] 1H NMR(400MHz,DMSO-d6)δ8.80(dd,1H),8.36(d,1H),8.14(dd,1H),8.06(s,2H),7.87(dd,1H),7.56(dd,1H),7.00(d,1H),6.65 (d,1H),6.54(d,1H),4.97(s,2H),4.29(m,2H),2.07(m,2H),1.86(m,2H),1.72(m,1H),1.49(m,2H),0.82(m,2H),0.59(m,2H).

[0825] Example 129

[0826] 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

[0827]

[0828] first step

[0829] Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 129a (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-bisdiphenylphosphine-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 yield 129b (240 mg) of N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate tert-butyl ester, yield: 30.9%.

[0830] MS m / z(ESI): 336.0 [M+H] + .

[0831] Step 2

[0832] 129b (202 mg, 0.60 mmol) was dissolved in methanol (2 mL) at room temperature and stirred. A solution of 1,4-dioxane (4 M, 5 mL) in hydrochloric acid 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 129c (140 mg), yield: 98.6%.

[0833] MS m / z(ESI): 236.2 [M+H] + .

[0834] Step 3

[0835] 129c (150 mg, 0.64 mmol), 2-fluoro-5-nitro-pyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL), and the reaction 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 129d (190 mg), yield: 83.4%.

[0836] MS m / z (ESI): 358.1 [M+H] + .

[0837] Step 4

[0838] In a hydrogen atmosphere, 129d (190 mg, 0.53 mmol) and palladium on carbon (28 mg, 0.026 mmol, purity: 10%) were dissolved in methanol (5 mL) and stirred for 1 hour at room temperature. The reaction solution was filtered, and the filtrate was concentrated to give N2-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine 129e (170 mg), yield: 97.7%.

[0839] MS m / z(ESI): 328.1 [M+H] + .

[0840] Step 5

[0841] 129e (80 mg, 0.24 mmol), methyl 3-(bromomethyl)pyridinecarboxylate (62 mg, 0.27 mmol), and potassium carbonate (101.2 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred for 1 hour. The mixture was then heated to 50 °C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 129 (24.3 mg), yield: 22.4%.

[0842] MS m / z (ESI): 445.2 [M+H] + .

[0843] 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).

[0844] Example 130

[0845] 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0846]

[0847] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 130 was synthesized.

[0848] MS m / z (ESI): 441.2 [M+H] + .

[0849] 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.44(d,1H),8.35(d,1H),8.14–8.08(m,1H),7.88(dd,1H),7.61(dd,1H),7.16(dd,1H),6.69(dd,2H ),6.54(t,2H),4.93(s,2H),4.34–4.22(m,1H),4.20–4.07(m,1H),2.34(s,3H),2.21–2.06(m,2H),2.00–1.81(m,2H),1.63–1.39(m,2H).

[0850] Example 131

[0851] 6-(6-(((1S,3S)-3-(((4-methylquinazolin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0852]

[0853] first step

[0854] Referring to the synthesis method in step 3 of Example 122, the target product 6-(6-(((1S,3S)-3-((4-methylquinazolin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 131 was synthesized.

[0855] MS m / z (ESI): 452.2 [M+H] + .

[0856] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.11(d,1H),7.89(m,2H),7.62(dd,2H),7.40(dd,2H),7.19(d,1H) ,6.72(d,1H),6.57(d,1H),4.93(s,2H),4.50(m1H),4.31(m,1H),2.70(s,3H),2.16(m,2H),1.94(m,2H),1.54(m,2H).

[0857] Example 132

[0858] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one

[0859] Example 132 can also be prepared by referring to the following method.

[0860]

[0861] first step

[0862] At room temperature, 75b (57.7 mg, 0.25 mmol) and potassium carbonate (73.9 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred for 1 hour, then heated to 60 °C and stirred for 4 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to obtain 132 (21 mg) of 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one, yield: 25.9%.

[0863] MS m / z (ESI): 455.2 [M+H] + .

[0864] 1 H NMR (400MHz, DMSO-d6) δ8.89–8.75(m,2H),8.40(d,1H),8.23(s,2H),7.91(dd,1H),7.48(d,1H),7.03(t,1H),6. 74(d,1H),6.56(d,1H),5.02(s,2H),4.36–4.23(m,2H),2.21–2.05(m,2H),1.98–1.81(m,2H),1.62–1.43(m,2H).

[0865] Example 133

[0866] 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0867]

[0868] Following the synthesis method of Example 75, 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 133 was synthesized.

[0869] MS m / z (ESI): 456.2 [M+H] + .

[0870] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.61(d,2H),8.37(d,1H),8.20(d,1H),8.15(d,1H),7.88(dd,1H),7.56(dd,1H) ,6.70(d,1H),6.56(d,1H),4.97(s,2H),4.47-4.28(m,2H),2.18-2.10(m,2H),1.98-1.85(m,2H),1.62-1.48(m,2H).

[0871] Example 134

[0872] 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0873]

[0874] Following the synthesis method of Example 75, 6-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 134 was synthesized.

[0875] MS m / z (ESI): 456.2 [M+H] + .

[0876] 1 H NMR(400MHz,DMSO-d6)δ8.76(d,1H),8.61(d,2H),8.35(d,1H),8.21(d,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H) ,6.72(d,1H),6.56(d,1H),4.93(s,2H),4.45-4.28(m,2H),2.18-2.10(m,2H),1.98-1.85(m,2H),1.62-1.48(m,2H).

[0877] Example 135

[0878] 6'-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0879]

[0880] Following the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 135 was synthesized.

[0881] MS m / z (ESI): 428.2 [M+H] + .

[0882] 1 H NMR(400MHz,DMSO-d6)δ8.40(d,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd, 1H),7.39(dd,1H),7.07(d,1H),6.91(d,1H),6.59–6.49(m,3H),6.44(dt,1 H),6.26(td,1H),4.36–4.25(m,1H),4.20–4.08(m,1H),2.20–2.07(m,2H), 2.02–1.81(m,3H),1.61–1.42(m,2H),1.07–0.98(m,2H),0.84–0.74(m,2H).

[0883] Example 136

[0884] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0885]

[0886] Following the synthesis method of Example 75, the target product 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 136 was synthesized.

[0887] MS m / z(ESI): 472.1 [M+H] + .

[0888] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.32(d,1H),8.23(s,2H),8.09(dd,1H),7.84(dd,1H),7.48(d,1H),7.03(dd,1H ),6.71(d,1H),6.55(d,1H),4.93(s,2H),4.26-4.33(m,2H),2.07-2.17(m,2H),1.83-1.93(m,2H),1.46-1.56(m,2H).

[0889] Example 137

[0890] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0891]

[0892] Following the synthesis method of Example 75, the target product 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 137 was synthesized.

[0893] MS m / z(ESI): 472.1 [M+H] + .

[0894] 1 H NMR(400MHz,DMSO-d6)δ8.82(dd,1H),8.36(d,1H),8.23(s,2H),8.11(dd,1H),7.86(dd,1H),7.48(d,1H),7.03(dd,1H ),6.70(d,1H),6.55(d,1H),4.96(s,2H),4.26-4.33(m,2H),2.07-2.15(m,2H),1.83-1.93(m,2H),1.47-1.56(m,2H).

[0895] Example 138

[0896] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-trifluoromethyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one

[0897]

[0898] Following the synthesis method of Example 75, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-trifluoromethyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 138 was synthesized.

[0899] MS m / z(ESI): 522.2 [M+H] + .

[0900] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.36(d,1H),8.23(s,2H),8.16(d,1H),7.86(dd,1H),7.48(d,1H),7.03(t,1H) ,6.77(d,1H),6.57(d,1H),5.13(s,2H),4.33-4.27(m,2H),2.19-2.05(m,2H),1.97-1.81(m,2H),1.56-1.46(m,2H).

[0901] Example 139

[0902] (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0903]

[0904] Following the synthesis method of Example 52, (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-5-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine 139 was synthesized.

[0905] MS m / z(ESI): 439.2 [M+H] + .

[0906] 1H NMR(400MHz,DMSO-d6)δ8.88–8.80(m,2H),8.53(s,1H),8.23(s,2H),8.21–8.16(m,1H),7.83(dd,1H),7.49(d,1H),7.26–7.2 1(m,1H),7.03(t,1H),6.98(d,1H),6.60(dd,1H),4.41–4.26(m,2H),2.24–2.07(m,2H),2.01–1.82(m,2H),1.62–1.44(m,2H).

[0907] Example 140

[0908] (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0909]

[0910] Following the synthesis method of Example 52, (1S,3S)-N1-(5-([1,2,4]triazolo[1,5-a]pyridin-8-yl)pyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine 140 was synthesized.

[0911] MS m / z(ESI): 439.2 [M+H] + .

[0912] 1 H NMR(400MHz,DMSO-d6)δ8.66(d,1H),8.51(s,1H),8.24(s,2H),8.08(dd,1H),7.77–7.66(m,2H),7.50(d,1H),7.31(dd, 1H),7.21(d,1H),7.03(t,1H),6.61(d,1H),4.45–4.26(m,2H),2.23–2.08(m,2H),2.00–1.84(m,2H),1.62–1.44(m,2H).

[0913] Example 142

[0914] 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0915]

[0916] Following the synthesis method of Example 122, 6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 142 was synthesized.

[0917] MS m / z(ESI): 532.1 [M+H] + .

[0918] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.40(s,2H),8.35(d,1H),8.11(dd,1H),7.87(dd,1H),7.74(dd,1H),7.61(dd,1H ),6.69(d,1H),6.55(d,1H),4.93(s,2H),4.33-4.30(m,2H),2.16-2.10(m,2H),1.93-1.86(m,2H),1.56-1.51(m,2H).

[0919] Example 143

[0920] 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

[0921]

[0922] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 143 was synthesized.

[0923] MS m / z (ESI): 495.2 [M+H] + .

[0924] 1H NMR(400MHz, DMSO-d6)δ8.83(d,1H),8.75(dd,1H),8.35(d,1H),8.15–8.06(m,1H),7.88(dd,1H),7.86(s,1H),7.62(dd,1H),7.15(dd ,1H),7.04(d,1H),6.71(s,1H),6.57(d,1H),4.93(s,2H),4.36–4.15(m,2H),2.23–2.10(m,2H),2.05–1.83(m,2H),1.65–1.42(m,2H).

[0925] Example 144

[0926] 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0927] Example 144 can also be prepared by the following method:

[0928]

[0929] first step

[0930] 14.73 g (142.87 mmol) of tert-butyl nitrite was added dropwise at room temperature to a solution of 6-bromo-1,2,4-triazine-3-amine 144a (5.00 g (28.57 mmol)) in acetonitrile (50 mL) and dimethyl disulfide (10 mL), and the mixture was stirred for 3 hours. The reaction solution was quenched with methanol (515 mL), the organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give the title product 6-bromo-3-(methylthio)-1,2,4-triazine 144b (4.60 g), yield: 78.1%.

[0931] MS m / z(ESI): 205.9 [M+H] + .

[0932] Step 2

[0933] Under nitrogen protection, 144b (2.00 g, 9.71 mmol), methyl 2,2-difluoro-2-fluorosulfonyl acetate (5.59 g, 29.17 mmol), and cuprous iodide (5.55 g, 29.12 mmol) were dissolved in N,N-dimethylformamide (15 mL) and heated to 90 °C with stirring for 3 hours. The reaction mixture was diluted with ethyl acetate (180 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give the title product 3-(methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (710 mg), yield: 37.5%.

[0934] MS m / z(ESI): 196.0 [M+H] + .

[0935] Step 3

[0936] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 144 was synthesized.

[0937] MS m / z (ESI): 457.2 [M+H] + .

[0938] 1 H NMR(400MHz,DMSO-d6)δ9.10,8.60(d,1H),8.75(m,1H),8.70(s,1H),8.36(d,1H),8.11(m,1H),7.88(m,1H),7.62(m ,1H),6.74(m,1H),6.57(d,1H),4.93(s,2H),4.61,4.35(m,1H),4.36(m,1H),2.17(m,2H),2.00(m,2H),1.61(m,2H).

[0939] Example 145

[0940] 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0941] Example 145 can also be prepared by the following method:

[0942]

[0943] first step

[0944] Referring to the synthesis method in step 3 of Example 122, 6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 145 was synthesized.

[0945] MS m / z (ESI): 457.2 [M+H] + .

[0946] 1 H NMR(400MHz,DMSO-d6)δ9.10,8.61(d,1H),8.80(m,1H),8.70(s,1H),8.36(d,1H),8.15(m,1H),7.88(m,1H),7.56(m ,1H),6.73(m,1H),6.56(d,1H),4.96(s,2H),4.61,4.33(m,1H),4.35(m,1H),2.18(m,2H),2.00(m,2H),1.63(m,2H).

[0947] Example 146

[0948] 5,5-Dimethyl-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0949] Example 146 can also be prepared by the following method:

[0950]

[0951] first step

[0952] 3-(methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (390 mg, 2.00 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (420 mg, 2.10 mmol), and diisopropylethylamine (258 mg, 2.00 mmol) were dissolved in N-methylpyrrolidone (5 mL), and the reaction mixture was heated to 90 °C and stirred for 2 hours. Ethyl acetate (25 mL) and water (10 mL) were added to the reaction mixture, and the organic phase was washed with saturated brine. The organic phase was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to obtain ((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate tert-butyl ester 146a (410 mg), yield: 59.07%.

[0953] MS m / z (ESI): 348.2 [M+H] + .

[0954] Step 2

[0955] 146a (410 mg, 1.18 mmol) was dissolved in methanol (3 mL). 1,4-dioxane hydrochloric acid (4 M, 3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in a small amount of methanol. Ammonia was added to adjust the pH to alkaline, and the mixture was concentrated again. The residue was separated by silica gel column chromatography (elution system A) to obtain (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 146b (280 mg), yield: 95.95%.

[0956] MS m / z(ESI): 248.2 [M+H] + .

[0957] Step 3

[0958] Under nitrogen protection, 146b (43 mg, 0.17 mmol), 93a (63 mg, 0.24 mmol), and diisopropylethylamine (56 mg, 0.43 mmol) were dissolved in dimethyl sulfoxide (1.5 mL), and the reaction was heated to 130 °C and stirred for 48 hours. The reaction solution was filtered, and the filtrate was subjected to reversed-phase HPLC (formic acid system) to prepare 146 (28 mg) of 5-dimethyl-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, yield: 33.23%.

[0959] MS m / z (ESI): 485.2 [M+H] +

[0960] 1 H NMR(400MHz,DMSO-d6)δ9.17-8.60(m,1H),8.77-8.74(m,1H),8.71(d,1H),8.24(d,1H),7.87(d,1H),7.70-7.61(m,1H),7.35-7.2 7(m,1H),7.00-6.90(m,1H),6.58(d,1H),4.71-4.24(m,2H),2.27-2.11(m,2H),2.08-1.87(m,2H),1.73-1.52(m,2H),1.45(s,6H).

[0961] Example 147

[0962] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one

[0963]

[0964] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 147 was synthesized.

[0965] MS m / z (ESI): 459.2 [M+H] + .

[0966] 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.66(dd,1H),8.34(d,1H),7.85(dd,1H),7.59(s,1H),7.27(dd,1H),6.86(td,1H),6.73(dd ,2H),6.55(d,1H),4.97(s,2H),4.29(q,1H),4.15(q,1H),2.60(s,3H),2.19-2.08(m,2H),1.99-1.83(m,2H),1.59-1.46(m,2H).

[0967] Example 148

[0968] 6-Methyl-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0969]

[0970] Following the synthesis method of Example 144, 6-methyl-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 148 was synthesized.

[0971] MS m / z (ESI): 471.2 [M+H] + .

[0972] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.80(s,1H),8.70(s,1H),8.35(d,1H),7.86(dd,1H),7.59(s,1H),6.76(d,1 H),6.56(d,1H),4.98(s,2H),4.61(d,1H),4.33(d,1H),2.60(s,3H),2.23–2.13(m,2H),1.99(d,2H),1.59(d,2H).

[0973] Example 149

[0974] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one

[0975]

[0976] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 149 was synthesized.

[0977] MS m / z (ESI): 459.2 [M+H] + .

[0978] 1H NMR(400MHz,DMSO-d6)δ8.69-8.59(m,2H),8.37(d,1H),7.86(dd,1H),7.55(d,1H),7.27(dd,1H),6.86(td,1H),6.73(dd,2H ),6.55(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.57(s,3H),2.21-2.09(m,2H),2.03-1.90(m,2H),1.59-1.44(m,2H).

[0979] Example 151

[0980] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one

[0981]

[0982] Following the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrole[3,4-c]pyridin-1-one 151 was synthesized.

[0983] MS m / z (ESI): 513.2 [M+H] + .

[0984] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.66(t,1H),8.36(d,1H),8.16(s,1H),7.86(dd,1H),7.27(dd,1H),6.86(td,1H),6. 76(dd,2H),6.57(d,1H),5.13(s,2H),4.30(q,1H),4.15(q,1H),2.23-2.07(m,2H),2.03-1.84(m,2H),1.59-1.44(m,2H).

[0985] Example 152

[0986] 6-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0987]

[0988] Following the synthesis method of Example 144, 6-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 152 was synthesized.

[0989] MS m / z (ESI): 525.2 [M+H] + .

[0990] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.10(d,1H),8.86(dd,1H),8.37(d,1H),8.16(s,1H),7.87(dd,1H),6.82 (d,1H),6.58(d,1H),5.14(s,2H),4.42-4.28(m,2H),2.28-2.09(m,2H),2.05-1.97(m,2H),1.75-1.49(m,2H).

[0991] Example 153

[0992] 3-Fluoro-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0993]

[0994] Following the synthesis method of Example 144, 3-fluoro-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 153 was synthesized.

[0995] MS m / z (ESI): 475.2 [M+H] + .

[0996] 1H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.76(s,1H),8.70(s,1H),8.34(d,1H),8.10(dd,1H),7.86(dd,1H),6.78-6.73(m,1H) ,6.56(d,1H),4.94(s,2H),4.36-4.32(m,2H),2.23-2.13(m,2H),2.02-1.91(m,2H),1.69-1.62(m,1H),1.57–1.51(m,1H).

[0997] Example 154

[0998] 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide

[0999]

[1000] Following the synthesis method of Example 121, 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide 154 was synthesized.

[1001] MS m / z(ESI): 493.1 [M+H] + .

[1002] Example 155

[1003] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one

[1004]

[1005] Following the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazol[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrole[3,4-b]pyridin-7-one 155 was synthesized.

[1006] MS m / z (ESI): 513.2 [M+H] + .

[1007] 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.41(d,1H),8.36(d,1H),8.14(d,1H),7.88(dd,1H),7.27(dd,1H),6.86(td,1H),6 .75(dd,2H),6.57(d,1H),5.04(s,2H),4.30(q,1H),4.16(q,1H),2.21-2.10(m,2H),2.03-1.84(m,2H),1.60-1.47(m,2H).

[1008] Example 156

[1009] 6-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[1010]

[1011] Following the synthetic method of Example 143, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 156 was synthesized.

[1012] MS m / z (ESI): 509.2 [M+H] + .

[1013] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.80(s,1H),8.34(d,1H),7.85(d,2H),7.59(s,1H),7.15(dd,1H),7.03(dd,1H),6.72(d, 1H),6.55(d,1H),4.97(s,2H),4.31(q,1H),4.20(q,1H),2.60(s,3H),2.22-2.13(m,2H),2.01-1.86(m,2H),1.61-1.47(m,2H).

[1014] Example 157

[1015] 7-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[1016]

[1017] Following the synthesis method of Example 144, 7-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 157 was synthesized.

[1018] MS m / z (ESI): 524.2 [M+H] + .

[1019] 1 H NMR (400MHz, DMSO-d6) δ9.12–8.63(m,1H),8.70(d,1H),8.38(d,1H),8.05(d,1H),8.01(d,1H),7.84(dd,1H),7.78( t,1H),6.74(d,1H),6.55(d,1H),5.11(s,2H),4.61–4.33(m,2H),2.24–2.12(m,2H),1.96(d,2H),1.69–1.50(m,2H).

[1020] Example 158

[1021] 4-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one

[1022]

[1023] Following the synthesis method of Example 144, 4-(trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isodihydroindol-1-one 158 was synthesized.

[1024] MS m / z (ESI): 524.2 [M+H] + .

[1025] 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.34(d,1H),8.18(s,1H),7.85(dd,1H),7.59(s,1H),7.54(s,1H),6.72(d,1H),6 .55(d,1H),4.97(s,2H),4.32(d,2H),2.60(s,3H),2.17–2.02(m,3H),1.90(dt,2H),1.52(dd,2H),0.98–0.87(m,4H).

[1026] Example 159

[1027] 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[1028]

[1029] Following the synthesis method of Example 144, 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 159 was synthesized.

[1030] MS m / z (ESI): 497.2 [M+H] + .

[1031] Example 161

[1032] 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

[1033]

[1034] Following the synthesis method of Example 129, 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 161 was synthesized.

[1035] MS m / z (ESI): 512.2 [M+H] + .

[1036] 1H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.30(d,1H),7.95(d,1H),7.90–7.77(m,3H),7.27(dd,1H),6.86(t,1H),6.75(d,1 H),6.68(d,1H),6.54(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.15(dd,2H),2.01–1.84(m,2H),1.61–1.44(m,2H).

[1037] Example 162

[1038] 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

[1039]

[1040] Following the synthesis method of Example 129, 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 162 was synthesized.

[1041] MS m / z (ESI): 512.1 [M+H] + .

[1042] 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.36(d,1H),8.03(dd,2H),7.89–7.70(m,2H),7.27(dd,1H),6.86(t,1H) ,6.72(dd,2H),6.54(d,1H),5.10(d,2H),4.22(d,2H),2.21–2.06(m,2H),2.00–1.81(m,2H),1.64–1.42(m,2H).

[1043] Example 163

[1044] 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

[1045]

[1046] Following the synthesis method of Example 143, 3-fluoro-6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 163 was synthesized.

[1047] MS m / z (ESI): 513.2 [M+H] + .

[1048] 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).

[1049] Example 164

[1050] 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

[1051]

[1052] first step

[1053] Diisopropylaminolithium (2M, 1.05mL) was added dropwise to a tetrahydrofuran (5mL) solution of 2-bromo-6-tert-butylpyridine 164a (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, and 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 164b (56mg), yield: 16.51%.

[1054] MS m / z(ESI): 242.0 [M+H] +.

[1055] Step 2

[1056] Under carbon monoxide protection, 164b (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, concentrated, and the residue was separated by silica gel column chromatography to obtain methyl 6-(tert-butyl)-3-formylpyridinecarboxylate 164c (13 mg), yield: 26.84%.

[1057] MS m / z(ESI): 222.1 [M+H] + .

[1058] Step 3

[1059] 129e (23 mg, 0.07 mmol), 164c (13 mg, 0.06 mmol), and acetic acid (5 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (2 mL). The reaction mixture was heated to 60 °C and stirred for 1 hour. After the reaction mixture returned to room temperature, sodium triacetoxyborohydride (62 mg, 0.29 mmol) was added, and the mixture was stirred for 15 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried, concentrated, and the residue was subjected to reversed-phase HPLC to prepare 164 (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%.

[1060] MS m / z (ESI): 501.2 [M+H] + .

[1061] 1H 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).

[1062] The synthesis method of the embodiments can be referred to the above embodiments.

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069] Biological testing evaluation

[1070] 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.

[1071] I. Combining experiments

[1072] 1. Experimental objective: To detect the effect of compounds on the binding of PCSK9 protein using the conventional surface plasmon resonance (SPR) method.

[1073] 2. Experimental Results:

[1074]

[1075]

[1076] Note: E-04: ×10 -4

[1077] 3. Experimental conclusions:

[1078] The compounds in the embodiments of this invention have a good binding effect on PCSK-9 protein, while the compounds have a slow dissociation rate of PCSK9 protein.

[1079] II. Cell Function Experiments

[1080] Test Example 1: Determination of the effect of the compound of the present invention on the concentration of PCSK9 secreted by HepG2 cells

[1081] 1. Experimental objective: To detect the inhibitory effect of the compound on PCSK9.

[1082] 2. Experimental instruments and reagents:

[1083] 2.1 Instruments:

[1084] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water system (THERMO: Pacific T II+Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[1085] 2.2 Reagents:

[1086] CircuLex Human PCSK9 ELISA Kit (MBL: CY-8079);

[1087] DMEM (Gibco: 31966-021)

[1088] FBS (Sigma: S5394)

[1089] Compound plate (Thermo: 1353506)

[1090] Complete culture medium: DMEM + 10% FBS + 1X P / S;

[1091] Experimental culture medium: DMEM + 10% FBS

[1092] Cell line: HepG2 (ATCC: HB-8065)

[1093] 3. Experimental methods:

[1094] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[1095] 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.

[1096] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[1097] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[1098] 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.

[1099] 6) Collect 200 μL of cell culture medium per well and freeze at -80℃ for later use.

[1100] 7) Take the cell culture medium sample out of -80℃ to dissolve, vortex, centrifuge, and set aside.

[1101] 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.

[1102] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[1103] 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.

[1104] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[1105] 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.

[1106] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[1107] 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.

[1108] 15) Add 100 μL of stop solution (1N H2SO4) to each well and mix well.

[1109] 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.

[1110] 4. Experimental data processing methods:

[1111] The OD values ​​read by the microplate reader are used to calculate the actual values ​​for each well. These values ​​are then subtracted from the OD values ​​of the standard group (0 concentration) from the OD values ​​of the control group and the sample. A standard curve is plotted using GraphPad to calculate the sample concentration. If the sample was diluted, the final calculation must be multiplied 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 is plotted using GraphPad. 50 .

[1112] 5. Experimental Results:

[1113]

[1114]

[1115]

[1116] 6. Experimental Conclusion:

[1117] The compounds in the embodiments of this invention showed good inhibitory effects on the concentration of PCSK9 secreted by HepG2 cells in experiments.

[1118] Test Example 2: Determination of the effect of the compound of the present invention on LDLR levels in HepG2 cells

[1119] 1. Experimental objective:

[1120] The effect of the compound on LDLR protein levels was detected.

[1121] 2. Experimental instruments and reagents:

[1122] 2.1 Instruments:

[1123] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water system (THERMO: Pacific T II+Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[1124] 2.2 Reagents:

[1125] Human LDL R Quantikine ELISA Kit (R&D: DLDLR0)

[1126] DMEM (Gibco: 31966-021)

[1127] FBS (Sigma: S5394)

[1128] PBS

[1129] Cell lysis buffer (Thermo: 78503)

[1130] Protease inhibitor (Pierce: 78430)

[1131] Compound plate (Thermo: 1353506)

[1132] Complete culture medium: DMEM + 10% FBS + 1X P / S

[1133] Experimental culture medium: DMEM + 10% FBS

[1134] Cell line: HepG2 (ATCC: HB-8065)

[1135] 3. Experimental methods:

[1136] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[1137] 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.

[1138] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[1139] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[1140] 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.

[1141] 6) Remove the cell culture medium, wash the cells with PBS, and add 50 pL of cell lysis buffer and protein inhibitor.

[1142] 7) Centrifuge to remove lysates and store the sample for later use.

[1143] 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.

[1144] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[1145] 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.

[1146] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[1147] 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.

[1148] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[1149] 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.

[1150] 15) Add 50 μL of stop solution to each well, mix well, and incubate for 20 min.

[1151] 16) Use an ELISA reader to measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm.

[1152] 4. Experimental data processing methods:

[1153] The OD values ​​read by the microplate reader are subtracted from the OD values ​​of the standard group (0 concentration) from the OD values ​​of the standard, control group, and sample to obtain the actual values ​​for each well. A standard curve is then plotted using Graphpad to calculate the sample concentration. If the sample was diluted, the final calculation must be multiplied 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.

[1154] 5. Experimental Results:

[1155]

[1156] 6. Experimental Conclusion:

[1157] In the experiment on the effect of the compound of the embodiment shown in the present invention on the LDLR concentration in HepG2 cells, it shows the effect of increasing the LDLR concentration.

[1158] III. Pharmacokinetic Experiment

[1159] Test Example 1: Pharmacokinetic Determination in Mice

[1160] 1. Experimental Purpose:

[1161] Using C57BL / 6J mice as the test animals, study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral and intravenous administration.

[1162] 2. Test Scheme

[1163] 2.1 Test Drugs:

[1164] The compound of the present invention, self-made;

[1165] 2.2 Test Animals:

[1166] C57 mice, male, purchased from Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013 - 0006 N0.311620400001794).

[1167] 2.3 Drug Preparation:

[1168] Drug preparation for oral administration: 10% Solutol HS15

[1169] Weigh 10 g of Solutol HS15 solid, dissolve it in 90 mL of pure water, mix well and stir and ultrasonicate to form a clear solution.

[1170] Weigh the compound of the present invention and dissolve it in this solution, shake well, ultrasonicate for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[1171] Drug preparation for intravenous administration: 5% DMSO + 10% Solutol HS15 + 85% PBS

[1172] Weigh the compound of the present invention, first add 5% DMSO according to the total volume ratio of administration, vortex and ultrasonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and ultrasonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and ultrasonicate for 5 min, and filter through a 0.22 um filter membrane to obtain a colorless transparent clear solution with a concentration of 0.2 mg / mL.

[1173] 2.4 Administration:

[1174] Three male C57 mice were used. After fasting overnight, they were administered the drug PO at a dose of 5 mg / kg and a volume of 10 mL / kg.

[1175] Three male C57 mice were used. After fasting overnight, they were administered the drug intravenously at a dose of 1 mg / kg and a volume of 5 mL / kg.

[1176] 2.5 Sample Collection:

[1177] Before and after drug administration, at 0.083 (iv), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, 0.04 mL of blood was collected from the orbital cavity of mice, placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4℃ to separate plasma, and stored at -80℃; mice were fed 4 hours after drug administration.

[1178] 2.6 Measurement Results:

[1179] The final determination results were obtained using the LCMS / MS method.

[1180] 3. Experimental Results:

[1181] The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[1182]

[1183]

[1184] 4. Experimental conclusions:

[1185] Pharmacokinetic assays in C57BL / 6J mice showed that the compounds of this invention exhibited significant pharmacokinetic advantage.

[1186] IV. Drug Efficacy Experiment

[1187] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[1188] 1. Experimental objective:

[1189] To evaluate the in vivo efficacy of the compound in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[1190] 2. Experimental Instruments and Reagents

[1191] 2.1 Instruments

[1192] Refrigerator (BCD-268TN, Haier)

[1193] Biosafety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[1194] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[1195] 5mL pipette (Research Plus, Eppendorf)

[1196] 1mL pipette (Research Plus, Eppendorf)

[1197] Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[1198] Centrifuge 5720R, Eppendorf

[1199] Electronic balance (CPA2202S, Sartorius)

[1200] Electronic balance (BSA2202S-CW, Sartorius)

[1201] Ultrasonic cleaner (115F0032, Shanghai Keda)

[1202] Pure water system (Pacific TII, Thermo)

[1203] Magnetic stirrer (08-2G, Chiju)

[1204] Fully automated blood biochemistry analyzer (Hitachi 7180 model)

[1205] 2.2 Reagents

[1206] High-fat diet (Western Diet, D12079B)

[1207] Physiological saline (MA0083-D, meilunbio)

[1208] Solutol HS 15 (102483882, Sigma)

[1209] 2.3 Test Drug: The compound of this invention, prepared in-house.

[1210] 3 Experimental Operation and Data Processing

[1211] 3.1 Animals

[1212] B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[1213] 3.2 Animal Models

[1214] After the animals arrive at the barrier system, allow them to adapt for one week before starting to be fed a high-fat diet. Weigh and record the animals' weight and feed intake weekly.

[1215] 3.3 Grouping and Administration

[1216] a. Grouping is done using a random grouping method.

[1217] c. Based on the grouping results, begin administering the test drug (administration route: oral administration; administration volume: 10 mL / kg; administration frequency: once a day or single administration; administration period: 21 days; solvent: 10% Solutol HS 15 / 90% Saline).

[1218] d. After starting the test drug, weigh and feed twice a week, and collect blood once a week.

[1219] 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.

[1220] 4. Experimental Results:

[1221]

[1222]

[1223] 5. Experimental Conclusion:

[1224] The compounds shown in the embodiments of this invention can effectively reduce LDL-C in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

Claims

1. A compound of general formula (I-1), its stereoisomer, or a pharmaceutically acceptable salt thereof: ； in: Ring B is selected from , , , , or ; R a Selected from halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, or C 3-8 cycloalkyl; R b Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; R c Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; R d Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, oxo, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; x is 1, 2, or 3; y is 0, 1, 2, or 3; z is 0, 1, 2, or 3; and e can be 0, 1, 2, or 3.

2. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, Compounds are further shown as in general formula ( As shown in the image: ； in: M1 is selected from N; M2 is selected from CH; M3 is selected from CH; M4 is selected from CH; and M5 is selected from N; Or M1 is selected from CH; M2 is selected from CH; M3 is selected from N; M4 is selected from CH; and M5 is selected from N.

3. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, characterized in that, R a Selected from halogens, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl; R b Selected from hydrogen, deuterium, halogens, and C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R c Selected from hydrogen, deuterium, halogens, and C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R d Selected from hydrogen, deuterium, halogens, and C 1-3 Alkyl, oxo, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups.

4. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Selected from the following compounds: or .

5. A pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown in claims 1 to 4, their stereoisomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

6. The use of the compound and its stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, or the pharmaceutical composition of claim 5, as a PCSK9 inhibitor in the preparation of a medicament for treating cardiovascular diseases and / or atherosclerotic diseases.

7. The use of the compound and its stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, or the pharmaceutical composition of claim 5, as a PCSK9 inhibitor in the preparation of a medicament for the treatment of stroke, hepatic steatosis, and / or coronary artery disease.

8. The use of the compound and its stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, or the pharmaceutical composition of claim 5, as a PCSK9 inhibitor in the preparation of a medicament for treating hyperlipidemia and / or hyperlipoproteinemia.

9. The use of the compound and its stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, or the pharmaceutical composition of claim 5, as a PCSK9 inhibitor in the preparation of a medicament for treating hypercholesterolemia.

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