INHIBITOR WHICH IS A NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE, A METHOD FOR ITS PRODUCTION AND ITS APPLICATION

Abstract

A nitrogen-containing heterocyclic derivative inhibitor, a preparation method therefor and the use thereof. Specifically disclosed are a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an inhibitor in treating diseases such as cardiovascular and cerebrovascular diseases, wherein the definition of each substituent in the general formula (I) are the same as those defined in the description.

Description

Nitrogen-containing heterocyclic derivative inhibitor, preparation method and application thereof

[0001] This application claims the rights of Chinese Patent Application No. 2022112625520 filed on October 14, 2022, Chinese Patent Application No. 2023100954447 filed on February 6, 2023, Chinese Patent Application No. 2023101156001 filed on February 14, 2023, Chinese Patent Application No. 2023102752651 filed on March 20, 2023, and Chinese Patent Application No. 2023102752651 filed on March 30, 2023. This application claims priority from Chinese Patent Application No. 2023103333265, Chinese Patent Application No. 2023104650154 filed on April 26, 2023, Chinese Patent Application No. 2023106311997 filed on May 30, 2023, Chinese Patent Application No. 2023108187585 filed on July 4, 2023, and Chinese Patent Application No. 2023110111090 filed on August 10, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of drug synthesis, and in particular relates to a nitrogen-containing heterocyclic derivative inhibitor, a preparation method and an application thereof. Background Art

[0003] Cardiovascular disease (CVD) is the leading cause of death worldwide. High levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C in the arterial lining can lead to atherosclerosis and potentially trigger an inflammatory response, leading to cardiovascular events such as heart attack and stroke. While statins lower serum LDL-C and are currently the mainstay of lipid-lowering therapy in clinical practice, patients who are intolerant to statins or who fail to achieve treatment goals at tolerated doses remain at risk, such as those with familial hypercholesterolemia. The discovery of PCSK9 inhibitors offers a more aggressive approach for patients with homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when combined with a statin, can lower LDL-C by 15%-20%, while the combination of a PCSK9 inhibitor and a statin can significantly reduce LDL-C by 54%-74%. PCSK9 inhibitors can also overcome intolerable side effects of statins, such as muscle pain.

[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 lower LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), and it has been clinically validated as a therapeutic target for hyperlipidemia. PCSK9 is synthesized as a precursor enzyme, which undergoes autocatalytic cleavage within the cell. The propeptide binds to mature PCSK9 and is secreted extracellularly. This propeptide binding blocks PCSK9's catalytic activity.

[0005] PCSK9 is a major regulator of low-density lipoprotein receptor (LDLR) levels on the hepatocyte surface and can inhibit the LDLR recycling pathway. LDLR function is crucial for maintaining cholesterol homeostasis and is responsible for the uptake and degradation of low-density lipoprotein (LDL). Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100. The LDL / LDLR complex is internalized through receptor-mediated endocytosis. The low intracellular pH environment triggers LDL release from the LDLR, which then recycles back to the cell membrane. Free intracellular LDL is then transported to the lysosome for degradation. Secreted PCSK9 interferes with LDLR recycling by binding to the LDLR on the hepatocyte surface. After the PCSK9 / LDLR complex migrates through clathrin-coated pits into the acidic endosomal compartment, conformational changes in the LDLR lead to the formation of additional binding sites for PCSK9. Consequently, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR recycling and thereby upregulating LDL-C levels.

[0006] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein (LDL) cholesterol metabolism that affects 1 in 250 people and is characterized by significantly elevated LDL-C levels. Heterozygous FH patients have a three- to four-fold increased risk of developing coronary artery disease (CAD), and CAD often develops an average of 10 years earlier. Statins lower LDL cholesterol in heterozygous FH patients. In a study by Besselin et al., high-intensity statin therapy reduced the risk of CHD and mortality by 44%. However, in many cases, LDL-C reduction is considered insufficient. The counteracting mechanism of statins is upregulation of sterol regulatory element binding protein 2 (SREBP-2), which activates the LDL receptor and PCSK9. This increases PCSK9 expression and secretion, which binds to the LDLR and leads to elevated LDL-C levels. Therefore, while statins lower LDL cholesterol by inhibiting HMG-CoA, they counteract the effects of SREPB. Adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatment approaches such as PCSK9 inhibitors are needed.

[0007] Alirocumab and evolocumab, monoclonal antibody-based macromolecular inhibitors of PCSK9, selectively bind to extracellular PCSK9 and prevent its interaction with the LDLR. They have been approved by the FDA for lowering LDL-C levels with a favorable safety profile. Studies have shown that in heterozygous FH patients who have not achieved their LDL-C target on statin therapy alone, alirocumab, administered by injection every two weeks, provides the greatest reduction in cardiovascular risk. Alirocumab has also been shown to modestly increase "good" cholesterol (HDL-C). Inclisiran, a PCSK9 siRNA drug currently on the market, is reportedly designed to reduce PCSK9 protein expression for long-term lipid-lowering effects and has a favorable safety profile. However, both drugs require injection, are expensive to produce, and are therefore expensive. To date, there are no marketed small-molecule PCSK9 inhibitors, leading to a high demand for oral small-molecule PCSK9 inhibitors.

[0008] Patents for small molecule PCSK9 inhibitors have been published, including WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ), and WO2022133529 (Nyrada). Currently, AZD-0780, the most advanced candidate, is in Phase I clinical trials, while the others are in preclinical development. Several peptides have also been reported, with the most advanced in Phase II clinical trials. The present invention seeks to develop orally available small molecule PCSK9 inhibitors.

[0009] Summary of the Invention

[0010] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0011] in:

[0012] Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably 5-membered monoheteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered monoheteroaryl, 6-membered and 5-membered bicyclic heteroaryl or 6-membered and 6-membered bicyclic heteroaryl;

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

[0014] Further optimization of C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5 membered heteroaryl, 6 membered heteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered and 5-membered bicyclic heteroaryl, or 6-membered and 6-membered bicyclic heteroaryl;

[0015] More preferably, it is a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heterocyclyl, a 6-membered and 5-membered bicyclic heteroaryl, or a 6-membered and 6-membered bicyclic heteroaryl;

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

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

[0018] R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) 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, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0019] Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) 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, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0020] R A1 ~R A3 each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0021] Or, any two adjacent or non-adjacent R a Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0022] R b is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)ORB3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)NR B2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0023] Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NRA2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0024] R B1 ~R B3 each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0025] Or, any two adjacent or non-adjacent R b Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0026] Preferably,

[0027] Or, any two R a and R b The heterocyclic group and heteroaryl group are optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0028] R c is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 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, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0029] Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0030] R C1 ~R C3each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0031] Or, any two adjacent or non-adjacent R c Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0032] R d is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m RD3 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0033] Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2S(O) m R A3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0034] R D1 ~R D3 each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0035] Or, any two adjacent or non-adjacent R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0036] Or, any two R c and R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

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

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

[0039] z is 0, 1, 2, or 3;

[0040] e is 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 is 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 present invention, the compound is further represented by the general formula (III) or (III-1):

[0049] in:

[0050] M1 is selected from N or CH;

[0051] M2 is selected from N or CH;

[0052] M3 is selected from N or CH; and

[0053] M4 is selected from N or CH.

[0054] In a more preferred embodiment of the present invention, the ring A of the present invention is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0055] Preferably, ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl;

[0056] More preferably, ring A is selected from 5-12 membered monocyclic heteroaryl, 8-12 membered bicyclic heteroaryl;

[0057] More preferably, Ring A is a 5-membered monoheteroaryl, a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered monoheteroaryl, a 6-membered and 5-membered bicyclic heteroaryl, or a 6-membered and 6-membered bicyclic heteroaryl;

[0058] More preferably, ring A is selected from pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl, pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl,

[0059] Still further preferably, ring A is selected from pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl, pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl,

[0060] Preferably pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl or pyridazinyl;

[0061] 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 heterocyclyl; preferably

[0062] Further selected from

[0063] Further selected from

[0064] In a preferred embodiment of the present invention, the compound is further represented by general formula (IE):

[0065] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1'):

[0066] in:

[0067] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0068] M5 is selected from N or CR5;

[0069] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0070] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3, the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0071] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0072] Or, any two adjacent or non-adjacent R a The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0073] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)NR B2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n(CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0074] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0075] Or, any two adjacent or non-adjacent R b The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0076] Or, any two R a and R b The 5-12 membered heterocyclic group or 5-12 membered heteroaryl group is linked to form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0077] Alternatively, R5 and R b The 5-12 membered heterocyclic group or 5-12 membered heteroaryl group is linked to form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0078] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0079] RC1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0080] Or, any two adjacent or non-adjacent R c The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0081] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2)n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0082] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0083] Or, any two adjacent or non-adjacent R d The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0084] Or, any two R c and R d The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0085] x is 0, 1, 2, or 3;

[0086] y is 0, 1, 2, or 3;

[0087] z is 0, 1, 2, or 3;

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

[0089] m is 0, 1, or 2;

[0090] n is 0, 1, 2, 3 or 4;

[0091] n1 is 0, 1, 2, 3 or 4.

[0092] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1), (I-2), (I-3), (I-4) or (I-5):

[0093] In a more preferred embodiment of the present invention, the ring B of the present invention is selected from C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0094] Preferably, ring B is selected from C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered and 5-membered bicyclic heteroaryl, or 6-membered and 6-membered bicyclic heteroaryl;

[0095] More preferably, ring B is selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group;

[0096] Further preferably, ring B is selected from pyridine, pyrimidine, pyridone or pyrimidone;

[0097] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0098] In another preferred embodiment, ring B is selected from pyridine, pyrimidine, benzene,

[0099] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0100] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

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

[0102] Preferably, ring B can also be selected from

[0103] In a preferred embodiment of the present invention, the compound is further represented by general formula (V):

[0104] In a preferred embodiment of the present invention, the compound is further represented by formula (III-A), (III-B), (III-C), (III-D), (III-E) or (III-F):

[0105] In a preferred embodiment of the present invention, the compound is further represented by the general formula (II'):

[0106] in:

[0107] Ring C is selected from C 3-12 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl;

[0108] Preferably, ring C is selected from C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5-membered monoheteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered and 5-membered bicyclic heteroaryl, or 6-membered and 6-membered bicyclic heteroaryl;

[0109] 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 group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group;

[0110] More preferably, ring C is selected from phenyl, pyrrolidinyl,

[0111] More preferably, ring C is selected from pyridine, pyrimidine, benzene,

[0112] More preferably, ring C is selected from pyridine, pyrimidine, benzene,

[0113] Preferably, ring C can also be selected from

[0114] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)NR B2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0115] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0116] Or, any two adjacent or non-adjacent R b The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0117] R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) nNR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0118] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0119] Or, any two adjacent or non-adjacent R c The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0120] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R 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 group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0121] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0122] Preferably,

[0123] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-12 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0124] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0125] Or, any two adjacent or non-adjacent R d The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0126] Or, any two R c and R d The cycloalkyl, heterocyclic, aryl or heteroaryl groups are linked to form cycloalkyl, heterocyclic, aryl or heteroaryl groups, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups can be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0127] y is 0, 1, 2, or 3;

[0128] z is 0, 1, 2, or 3;

[0129] e is 0, 1, 2, or 3;

[0130] m is 0, 1, or 2;

[0131] n is 0, 1, 2, 3 or 4;

[0132] n1 is 0, 1, 2, 3 or 4.

[0133] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II'-1):

[0134] In a further preferred embodiment of the present invention, the R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n(CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0135] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1- 3 alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0136] Preferably, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0137] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1- 3 alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0138] In a further preferred embodiment of the present invention, the R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)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, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0139] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0140] In a further preferred embodiment of the present invention, the R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NRC2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0141] R C1 ~RC3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0142] In a further preferred embodiment of the present invention, the R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0143] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1- 3 alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0144] Preferably,

[0145] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、- (CH2) n C(O)R D1、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0146] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1- 3 alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0147] In a further preferred embodiment of the present invention, the R 4’ Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R 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, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0148] R e1 ~R e3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0149] Preferably, R 4’ Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R e1 、-(CH2) n ORe1 、-(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, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0150] R e1 ~R e3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0151] The present invention further provides a compound represented by general formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0152] in:

[0153] X is amino, methylthio, halogen, boronic acid or boric acid ester;

[0154] The other groups are as described above.

[0155] The present invention further provides a method for preparing a compound represented by general formula (III-1), comprising the following steps:

[0156] in:

[0157] X1 is amino, halogen, boronic acid or boric acid ester;

[0158] The compound of the general formula (VI) reacts with the compound of the general formula (VI-1) to obtain the compound of the general formula (III-1);

[0159] The other groups are as described above.

[0160] The present invention further provides a compound represented by general formula (VI-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0161] in:

[0162] R 11 is selected from hydrogen, amino protecting groups, 5-6 membered heteroaryl, 5-6 membered heterocyclic groups, wherein the 5-6 membered heteroaryl and 5-6 membered heterocyclic groups are optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0163] The amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-dimethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0164] The general formula (VI-2) is further preferably represented by the general formula (VI-3):

[0165] in:

[0166] X2 is amino, halogen, boronic acid or boronic ester; the other groups are as described above.

[0167] The present invention further provides a method for preparing a compound represented by general formula (V), comprising the following steps:

[0168] Method 1:

[0169] in:

[0170] X3 is halogen, boric acid or boric acid ester;

[0171] The compound of the general formula (VI-2) reacts with the compound of the general formula (VI-4) to obtain the compound of the general formula (V);

[0172] The other groups are as described above.

[0173] Method 2:

[0174] in:

[0175] X4 is formaldehyde, hydroxymethyl or halomethyl;

[0176] R 12 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 alkyl halide;

[0177] The compound of the general formula (VI-3) reacts with the compound of the general formula (VI-5) to obtain the compound of the general formula (V);

[0178] The other groups are as described above.

[0179] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0180] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0181] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0182] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0183] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose 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.

[0184] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0185] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0186] The present invention further relates to the use of any of the general formula (I) and its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of PCSK9 inhibitor drugs.

[0187] The present invention further relates to the use of any of the general formula (I) and its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of LDL-lowering drugs.

[0188] The present invention further relates to the use of the general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or their symptoms; preferably, in the preparation of drugs for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0189] The present invention further relates to the use of the general formula (I) and its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in preparing a method for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms, preferably, in preparing a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0190] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, which comprises administering to a patient a therapeutically effective dose of a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0191] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with PCSK9.

[0192] The present invention also relates to a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0193] Detailed Description of the Invention

[0194] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0195] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0196] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0197] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0198] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0199] wait.

[0200] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0201] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1 to 3 nitrogen atoms, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups; or, preferably, it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, further preferably, it contains 1 to 3 nitrogen and / or oxygen atoms, a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterocyclic group.

[0202] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0203] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered and 5-membered or 5-membered and 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0204] wait.

[0205] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0206] wait.

[0207] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0208] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0209] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0210] wait.

[0211] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0212] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 12-membered, more preferably a 5- or 6-membered monocyclic heteroaryl group or an 8-12-membered bicyclic heteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, pyridazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0213] The bicyclic heteroaryl is preferably a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered and 5-membered bicyclic heteroaryl, or a 6-membered and 6-membered bicyclic heteroaryl. Non-limiting examples include:

[0214] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0215] wait.

[0216] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo or carboxylate.

[0217] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0218] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0219] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0220] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0221] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0222] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0223] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0224] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0225] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0226] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0227] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0228] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0229] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0230] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0231] Example

[0232] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O). The internal standard (if any) is tetramethylsilane (TMS).

[0233] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0234] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0235] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0236] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0237] The eluent systems for silica gel column chromatography and the developing solvent systems for thin-layer chromatography used for the intermediates and purified compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0238] Unless otherwise specified, in the examples of the present invention, the ratios in the mobile phases in the HPLC chiral separation conditions and HPLC chiral analysis conditions are volume ratios.

[0239] Intermediate 1

[0240] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0241] Referring to the preparation method of patent WO2020150473A2, intermediate 1 was synthesized.

[0242] MS m / z(ESI):245.1[M+H] + .

[0243] Intermediate 1 can also be obtained by the following method:

[0244] first step

[0245] 2-Chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) were dissolved in dimethyl sulfoxide (10 mL). 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 x 2). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to obtain tert-butyl (1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylcarboxylate 1B (2.1 g) in a yield of 55.1%.

[0246] MS m / z(ESI):345.2[M+H] + .

[0247] Step 2

[0248] 1B (2.1 g, 6.1 mmol) was dissolved in methanol (10 mL), and a solution of hydrochloric acid in dioxane (4 M, 20 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and ammonia methanol solution (7 M, 10 mL) was added to adjust the pH to weak alkalinity. 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%.

[0249] MS m / z(ESI):245.1[M+H] + .

[0250] Intermediate 2

[0251] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0252] first step

[0253] 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 mixture was cooled to room temperature and poured into 100 mL of water. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to give 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (3.1 g) in a yield of 72.7%.

[0254] MS m / z(ESI):191.1[M+H] + .

[0255] Step 2

[0256] Dissolve tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 130°C and stir for 16 hours. Cool the reaction mixture to room temperature, pour it into water (100 mL), and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to give tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g) in a yield of 78.4%.

[0257] MS m / z(ESI):371.2[M+H] + .

[0258] Step 3

[0259] Tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g, 7.83 mmol) was dissolved in 4 M hydrochloric acid in dioxane (30 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase chromatography (eluent system C) to provide 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one intermediate 2 (1.5 g) in a 70.9% yield.

[0260] MS m / z(ESI):271.2[M+H] + .

[0261] Example 1

[0262] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0263] Example 1 can also be obtained by the following method:

[0264] first step

[0265] Under nitrogen, 1a (10.00 g, 51.55 mmol), bis(pinacol borate) (19.64 g, 77.33 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (3.79 g, 5.16 mmol), and potassium acetate (10.10 g, 103.11 mmol) were dissolved in 1,4-dioxane (200 mL) and heated to 90°C with stirring for 3 hours. The reaction mixture was filtered, and the organic phase was concentrated to afford crude (5,6-difluoro-3-pyridyl)boronic acid 1b (7.60 g), which was used in the next reaction without further purification.

[0266] MS m / z(ESI):160.0[M+H] + .

[0267] Step 2

[0268] 1b (6.00 g, 37.76 mmol) and hydrogen peroxide (12.84 g, 113.28 mmol, 30% aqueous solution) were dissolved in 1,4-dioxane (100 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried and concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to provide 5,6-difluoro-3-hydroxypyridine 1c (3.20 g) in a 64.6% yield.

[0269] MS m / z(ESI):132.0[M+H] + .

[0270] Step 3

[0271] 1c (5.00 g, 38.14 mmol) and cesium carbonate (18.60 g, 57.22 mmol) were dissolved in N,N-dimethylformamide (30 mL) and stirred at room temperature for 30 minutes. Under nitrogen, sodium 2-chloro-2,2-difluoroacetate (11.90 g, 76.29 mmol) was added to the reaction mixture, 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 isolated by silica gel column chromatography (eluent system A) to provide 5-(difluoromethoxy)-2,3-difluoropyridine 1d (2.60 g) in a 37.6% yield.

[0272] MS m / z(ESI):182.0[M+H] + .

[0273] Step 4

[0274] Referring to 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'-bipyridyl]-2-one 1 was synthesized.

[0275] MS m / z(ESI):432.2[M+H] + .

[0276] 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).

[0277] Example 4

[0278] 6'-(((1S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0279] first step

[0280] 3-Amino-1,2,4-triazin-6(1H)-one 4a (1 g, 8.92 mmol), trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (3.35 g, 13.4 mmol), and 1,4-diazabicyclo[2.2.2]octane (2.0 g, 17.8 mmol) were dissolved in anhydrous toluene (15 mL) and stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to afford 6-(difluoromethoxy)-1,2,4-triazin-3-amine 4b (430 mg) in a 29.7% yield.

[0281] MS m / z(ESI):163.0[M+H] + .

[0282] Step 2

[0283] Under nitrogen, 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 heated to 70°C with stirring for 2 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (elution system B) to provide 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (260 mg) in a 54.0% yield.

[0284] MS m / z(ESI):182.0[M+H] + .

[0285] Step 3

[0286] Under nitrogen, intermediate 2 (80 mg, 0.256 mmol), 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (54 mg, 0.256 mmol), and N,N-diisopropylethylamine (115 mg, 0.888 mmol) were dissolved in dimethyl sulfoxide (2 mL) and stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The organic phase was washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by reverse phase chromatography (ammonium bicarbonate system) to give 6'-(((S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 4 (37 mg) in a 30.1% yield.

[0287] MS m / z(ESI):416.2[M+H] + .

[0288] Example 12

[0289] 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0290] first step

[0291] 3-Chloro-1,2,4-triazole 12a (1 g, 9.66 mmol), cyclopropylboronic acid (1.66 g, 19.3 mmol), cupric 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 and filtered. The filtrate was washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to obtain 3-chloro-1-cyclopropyl-1H-1,2,4-triazole 12b (340 mg) in a yield of 24.5%.

[0292] MS m / z(ESI):144.0[M+H] + .

[0293] Step 2

[0294] Referring to 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.

[0295] MS m / z(ESI):378.2[M+H] + .

[0296] 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).

[0297] Example 15

[0298] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0299] first step

[0300] 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(dibenzylideneindeneacetone)dipalladium (184 mg, 0.201 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (170 mg, 0.401 mmol) and potassium hydroxide (169 mg, 3.01 mmol) were dissolved in 1,4-dioxane (6 mL) and the reaction was heated to 100 ° C for 6 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, and the organic phase was washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to give 3-chloro-5-(difluoromethoxy)-1,2,4-thiadiazole 15b (130 mg) in a yield of 28.1%.

[0301] MS m / z(ESI):187.0[M+H] + .

[0302] Step 2

[0303] Referring to 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'-bipyridyl]-2-one 15 was synthesized.

[0304] MS m / z(ESI):421.1[M+H] + .

[0305] Example 20

[0306] 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0307] first step

[0308] 2-Chloropyrrolo[2,1-f][1,2,4]triazine 20a (50 mg, 0.326 mmol), intermediate 2 (88 mg, 0.326 mmol), and diisopropylethylamine (84 mg, 0.651 mmol) were dissolved in dimethyl sulfoxide (3 mL) and the reaction mixture was heated to 110°C with stirring for 16 hours. The reaction mixture was cooled to room temperature, and saturated sodium chloride solution (10 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 20 (85 mg) in a yield of 67.4%.

[0309] MS m / z(ESI):388.2[M+H] + .

[0310] 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).

[0311] Example 22

[0312] 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0313] Example 22 can also be synthesized by the following method:

[0314] first step

[0315] Tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1.0 g, 4.99 mmol) and 4-methoxybenzaldehyde (816 mg, 5.99 mmol) were dissolved in methanol (10 mL). Acetic acid (300 mg, 4.99 mmol) was added with stirring. The reaction was stirred at 17°C 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 provide tert-butyl ((1S,3S)-3-((4-methoxybenzyl)amino)cyclopentyl)carbamate 22a (1.2 g) in a 75% yield.

[0316] MS m / z(ESI):321.3[M+H] + .

[0317] Step 2

[0318] 22a (1.3 g, 4.06 mmol), cyanogen bromide (645 mg, 6.09 mmol), and N,N-diisopropylethylamine (1.0 g, 8.11 mmol) were dissolved in tetrahydrofuran (10 mL) and added with stirring. The reaction was stirred at 18°C ​​for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system C) to provide tert-butyl ((1S,3S)-3-(N-(4-methoxybenzyl)cyanamido)cyclopentyl)carbamate 22b (1.2 g) in an 85.6% yield.

[0319] MS m / z(ESI):346.1[M+H] + .

[0320] Step 3

[0321] Under nitrogen, 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 provide tert-butyl ((1S,3S)-3-((E)-2-hydroxy-1-(4-methoxybenzyl)guanidino)cyclopentyl)carbamate 22c (1.0 g) in a yield of 79.4%.

[0322] MS m / z(ESI):379.2[M+H] + .

[0323] Step 4

[0324] At room temperature, 2,2-difluorocyclopropane-1-carboxylic acid (419 mg, 3.43 mmol) and carbonyldiimidazole (557 mg, 3.43 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred for 0.5 h. 22c (1.0 g, 2.64 mmol) was dissolved in N,N-dimethylformamide (2 mL) and added dropwise to the reaction mixture. The reaction was stirred at room temperature for 1 h, then heated to 100°C and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride (60 mL x 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) in a 31.8% yield.

[0325] MS m / z(ESI):465.3[M+H] + .

[0326] Step 5

[0327] 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 ammonia methanol solution (7 M) was added to the residue to adjust the pH to 8. The reaction solution was concentrated, and the residue was purified by reverse phase chromatography (aqueous ammonia system) to provide (1S,3S)-N1-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine 22e (70 mg) in a 34.1% yield.

[0328] MS m / z(ESI):245.2[M+H] + .

[0329] Step 6

[0330] 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 with stirring 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'-bipyridyl]-2-one 22 (13.5 mg) in a yield of 13.1%.

[0331] MS m / z(ESI):415.1[M+H] + .

[0332] 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).

[0333] Example 26

[0334] 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'-bipyridyl]-2-one

[0335] Example 26 can also be synthesized by referring to the following preparation method:

[0336] first step

[0337] Under a hydrogen atmosphere, [1,2,4]triazolo[1,5-a]pyridin-2-amine 26a (2.7 g, 20.13 mmol) and platinum dioxide (914 mg, 4.03 mmol) were dissolved in a mixture of hydrochloric acid (12 M, 3 mL) and methanol (3 mL) and stirred at 25°C for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was neutralized with saturated sodium bicarbonate solution to pH 10. The mixture was extracted five times with a mixture of dichloromethane and isopropanol (3:1). The organic phase was dried, filtered, and concentrated to afford 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 26b (2.5 g) in an 89.9% yield.

[0338] MS m / z(ESI):139.2[M+H] + .

[0339] Step 2

[0340] 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 hours, then heated to 60°C and stirred for 1 hour. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL) and filtered. The organic phase was washed with water (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 26c (200 mg) in a 62.2% yield.

[0341] MS m / z(ESI):204.0[M+H] + .

[0342] Step 3

[0343] Under nitrogen, 26c (597.9 mg, 2.96 mmol), intermediate 2 (200 mg, 0.74 mmol), sodium tert-butoxide (213.3 mg, 2.22 mmol), tris(dibenzylideneacetone)palladium (135.5 mg, 0.15 mmol), and Xantphos (171.2 mg, 0.3 mmol) were dissolved in 1'4-dioxane (8 mL) and heated to 130°C in a microwave oven with stirring for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and the organic phase was washed with water and saturated brine, dried, filtered, and concentrated. The residue was purified by preparative HPLC (formic acid system) to give 6'-(((1S,3S)-3-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 26 (9.5 mg) in a 2.9% yield.

[0344] MS m / z(ESI):392.2[M+H] + .

[0345] 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).

[0346] Example 27

[0347] 6'-((3-(((1S,3S)-7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0348] first step

[0349] 7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 27a (100 mg, 0.657 mmol) was dissolved in acetonitrile and stirred under ice. Sodium nitrite (91 mg, 1.31 mmol) was added to the reaction solution and stirring continued for 1 minute. Hydrochloric acid (4 M, 0.41 mL) was added dropwise to the reaction solution. The reaction was warmed to room temperature and stirred continuously. The reaction was completed using thin-layer chromatography. Saturated sodium bicarbonate solution was added dropwise to the reaction solution until the pH reached 7. The reaction solution was extracted with dichloromethane (10 mL x 3). The organic phase was dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to afford 2-chloro-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 27b (65 mg) in a yield of 77.5%.

[0350] MS m / z(ESI):172.1[M+H] + .

[0351] Step 2

[0352] Referring to the synthesis method of 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.

[0353] The second step can also be synthesized by referring to the following method:

[0354] Under nitrogen, 27b (80 mg, 0.37 mmol), 27c (100 mg, 0.37 mmol), cesium carbonate (241.3 mg, 0.74 mmol), Pd2dba3 (67.8 mg, 0.074 mmol), and xantphos (85.7 mg, 0.15 mmol) were dissolved in 1'4-dioxane (2 mL). The reaction mixture was heated to 130°C and microwaved for 2 hours. The reaction mixture was then heated to 130°C under nitrogen for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (basic system) to give 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 27 (6.6 mg) in a yield of 4.08%.

[0355] MS m / z(ESI):406.2[M+H] + .

[0356] 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).

[0357] Example 38

[0358] 6'-(((1S,3S)-3-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0359] Example 38 can also be synthesized by the following method:

[0360] first step

[0361] By referring to the synthesis method of Example 20, 2-chloropyrimidine-5-carboxylic acid methyl ester 38a was used as the starting material to synthesize 2-(((1S,3S)-3-((2-keto-2H-[1,3'-bipyridyl]-6-yl)amino)cyclopentyl)amino)pyridine-5-carboxylic acid methyl ester 38b.

[0362] MS m / z(ESI):407.2[M+H] + .

[0363] Step 2

[0364] Under nitrogen, 38b (35 mg, 0.086 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 0°C. Methylmagnesium bromide in tetrahydrofuran (1 M, 2 mL) was added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with methanol and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to afford the desired product (9 mg) in a 25.7% yield.

[0365] MS m / z(ESI):407.2[M+H]+.

[0366] 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).

[0367] Example 47

[0368] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one

[0369] first step

[0370] Under nitrogen, 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(diphenylphosphino)ferrocenepalladium 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 isolated by silica gel column chromatography (eluent system A) to afford 3-(6-fluoropyridin-3-yl)-4H-quinolinazin-4-one 47b (360 mg) in a 34% yield.

[0371] MS m / z(ESI):241.1[M+H] + .

[0372] Step 2

[0373] 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) 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 the desired product, 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (47 mg) in a 24% yield.

[0374] MS m / z(ESI):465.2[M+H] + .

[0375] 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).

[0376] Example 47 can also be obtained by the following synthesis method:

[0377] first step

[0378] 47c (120 mg, 0.405 mmol), (6-fluoropyridin-3-yl)boronic acid (103 mg, 0.729 mmol), bis(diphenylphosphino)ferrocenepalladium 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 isolated by silica gel column chromatography (eluent system A) to give ethyl 3-(6-fluoropyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylate 47d (110 mg) in 87% yield.

[0379] MS m / z(ESI):313.1[M+H] + .

[0380] Step 2

[0381] 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-carboxylate 47e (53 mg) in a 30% yield.

[0382] MS m / z(ESI):537.2[M+H] + .

[0383] Step 3

[0384] 47e (35 mg, 0.065 mmol) was dissolved in hydrochloric acid (12 M, 5 mL) and the reaction was heated to 100°C with stirring for 1.5 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give the desired product, 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one 47 (21 mg) in a 69% yield.

[0385] MS m / z(ESI):465.2[M+H] + .

[0386] 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).

[0387] Example 52

[0388] (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

[0389] Example 52 can also be synthesized by the following method:

[0390] first step

[0391] Under nitrogen, 7-bromopyrazolo[1,5-a]pyridine 52a (150 mg, 0.76 mmol), (6-fluoropyridin-3-yl)boronic acid (139 mg, 0.99 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium 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 mixture was cooled to room temperature, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine 52b (155 mg) in a 95.49% yield.

[0392] MS m / z(ESI):214.1[M+H] + .

[0393] Step 2

[0394] Intermediate 1 (60 mg, 0.25 mmol), 52b (105 mg, 0.49 mmol) and N,N-dimethylethylamine (79 mg, 0.61 mmol) were dissolved in dimethyl sulfoxide (1 mL) and the reaction was heated to 130°C and stirred for 16 hours. The reaction solution was filtered and the filtrate was subjected to reverse phase HPLC (ammonium bicarbonate system) to obtain (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(Pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 52 (42.3 mg), yield: 39.36%.

[0395] MS m / z(ESI):438.2[M+H] + .

[0396] 1H NMR(400MHz,DMSO-d6)δ8.56(d,1H),8.24(s,2H),8.07-7.97(m,2H),7.63(d,1H),7.51(d,1H),7.29-7.23(m,1H),7.07(d,1H),7.2 2-6.85(m,1H),6.95(d,1H),6.68(d,1H),6.59(d,1H),4.47-4.23(m,2H),2.24-2.05(m,2H),1.99-1.84(m,2H),1.63-1.45(m,2H).

[0397] Example 53

[0398] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazo[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine

[0399] first step

[0400] Under nitrogen, 8-bromoimidazole[1,2-a]pyridine 53a (1.0 g, 5.08 mmol), (6-fluoropyridin-3-yl)boronic acid (858 mg, 6.09 mmol), bis(diphenylphosphino)ferrocenepalladium 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 mixture was filtered through celite and concentrated. The residue was isolated by silica gel column chromatography (eluent system A) to afford 8-(6-fluoropyridin-3-yl)imidazole[1,2-a]pyridine 53b (415 mg) in a 38% yield.

[0401] MS m / z(ESI):214.1[M+H] + .

[0402] Step 2

[0403] Referring to the synthesis method of the second step of Example 47, the target product (1S, 3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(imidazo[1,2-a]pyridin-8-yl)pyridin-2-yl]cyclopentane-1,3-diamine 53.

[0404] MS m / z(ESI):438.2[M+H] + .

[0405] 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).

[0406] Example 56

[0407] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

[0408] first step

[0409] Under nitrogen, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.78 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL), and the reaction was heated to 100 °C and stirred for 3 h. The reaction solution was returned to room temperature, and a saturated sodium chloride solution (120 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to give 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazole[4,5-b]pyrazin-2-one 56b (1.4 g, light yellow solid) in a yield of 57.87%.

[0410] MS m / z(ESI):246.1[M+H] + .

[0411] Step 2

[0412] Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 56b (77 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL) and stirred at 130°C for 48 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was separated by reverse-phase preparative HPLC (ammonium bicarbonate system) to afford 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 56 (41 mg, white solid) in a 30.47% yield.

[0413] MS m / z(ESI):470.1[M+H] + .

[0414] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(m,2H),7.2 6-6.82(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).

[0415] Example 57

[0416] 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

[0417] first step

[0418] Under nitrogen, 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). The reaction was heated to 100 ° C and stirred for 3 hours. The reaction solution was returned to room temperature, and a saturated sodium chloride solution (120 mL) was added to the reaction solution. 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 (eluent system A) to give 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 57b (1.3 g) in a yield of 57.49%.

[0419] MS m / z(ESI):230.1[M+H] + .

[0420] Step 2

[0421] 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) and stirred at 130°C for 48 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was separated by reverse-phase preparative HPLC (formic acid system) to afford 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) in a 35.4% yield.

[0422] MS m / z(ESI):454.1[M+H] + .

[0423] 1H 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).

[0424] Example 63

[0425] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0426] Example 63 can also be synthesized by the following method:

[0427] first step

[0428] 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, followed by the addition of copper bromide (6.7 g, 30 mmol). After stirring at room temperature for 1 hour, the reaction mixture was heated to 50°C and stirred for 1 hour. The reaction mixture was filtered and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to afford 3,6-dibromo-1,2,4-triazine 63b (1.3 g) in a 27.3% yield.

[0429] MS m / z(ESI):237.9[M+H] + .

[0430] Step 2

[0431] 63b (1.3 g, 5.44 mmol), tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (1.2 g, 5.99 mmol), and diisopropylethylamine (1.41 g, 10.88 mmol) were dissolved in dioxane (20 mL) and the reaction was heated to 80°C with stirring for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water (30 mL × 3) and saturated sodium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentane)carbamate 63c (1.5 g) in a yield of 76.9%.

[0432] MS m / z(ESI):358.1[M+H] + .

[0433] Step 3

[0434] 63c (1.5 g, 4.19 mmol), cyclopropylboronic acid (719 mg, 8.38 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)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 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, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give tert-butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentane)carbamate 63d (400 mg) in a yield of 29.9%.

[0435] MS m / z(ESI):320.2[M+H] + .

[0436] Step 4

[0437] 63d (400 mg, 1.25 mmol) was dissolved in methanol (5 mL), and 4 M hydrochloric acid dioxane solution (5 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and ammonia methanol solution was added to adjust the pH to weak alkalinity. After further concentration, the residue was separated by silica gel column chromatography (eluent 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%.

[0438] MS m / z(ESI):220.2[M+H] + .

[0439] Step 5

[0440] 63e (100 mg, 0.456 mmol), 2B (141.3 mg, 0.684 mmol), tris(dibenzylideneacetone)dipalladium (41.76 mg, 0.0456 mmol), 2-bicyclohexylphosphino-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 h. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with water (10 mL × 3) and saturated sodium chloride, dried, and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give the target product 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 63 (26 mg) in a yield of 14.6%.

[0441] MS m / z(ESI):390.2[M+H] + .

[0442] 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).

[0443] Example 64

[0444] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one

[0445] Example 64 can also be synthesized by the following method:

[0446] first step

[0447] Referring to the synthetic method of the first step of intermediate 2, the target product 6'-fluoro-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one 64b was synthesized.

[0448] MS m / z(ESI):249.1[M+H] + .

[0449] Step 2

[0450] 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-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one 64 (62 mg) in a 32.6% yield.

[0451] MS m / z(ESI):473.2[M+H] + .

[0452] 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).

[0453] Example 68

[0454] 6'-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0455] Example 68 can also be synthesized by the following method:

[0456] first step

[0457] 2-Chloropyrrolo[2,1-f][1,2,4]triazine 68a (50 mg, 0.325 mmol) and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (173 mg, 0.488 mmol) were dissolved in acetonitrile (3 mL) and the reaction was heated to 80°C in a microwave oven. °The mixture was stirred for 1 hour. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give 2-chloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine 68b (25 mg) in a yield of 44.7%.

[0458] MS m / z(ESI):172.0[M+H] + .

[0459] Step 2

[0460] 68b (25 mg, 0.146 mmol), intermediate 2 (39.4 mg, 0.146 mmol), and cesium carbonate (95.0 g, 0.291 mmol) were dissolved in N,N-dimethylformamide (3 mL) and the reaction was heated to 100°C with stirring for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 68 (27 mg) in a 45.7% yield.

[0461] MS m / z(ESI):406.2[M+H] + .

[0462] 1 H 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).

[0463] Example 75

[0464] 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

[0465] Example 75 can also be synthesized by the following method:

[0466] first step

[0467] Under nitrogen, intermediate 1 (1.2 g, 4.91 mmol), 2-fluoro-5-nitro-pyridine (768 mg, 5.40 mmol), and cesium carbonate (2.24 g, 6.88 mmol) were dissolved in acetonitrile (15 mL) and the reaction mixture was heated to 80°C with stirring for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried, and concentrated to afford the crude product (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)-N3-(5-nitropyridin-2-yl)cyclopentane-1,3-diamine 75a (1.79 g) in a yield of 99.45%. The product was used directly in the next reaction without further purification.

[0468] MS m / z(ESI):367.1[M+H] + .

[0469] Step 2

[0470] Under a hydrogen atmosphere, 75a (1.79 g, 4.89 mmol) and palladium on carbon (593 mg, 0.49 mmol, 10% content) were dissolved in a mixture of methanol (15 mL) and tetrahydrofuran (5 mL) and stirred at 20°C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated to afford the crude product, N2-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 75b (1.42 g), in an 86.40% yield. The product was used directly in the next reaction without further purification.

[0471] MS m / z(ESI):337.2[M+H] + .

[0472] Step 3

[0473] Under nitrogen, 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 was heated to 55°C and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed, and concentrated. The residue was purified by silica gel column chromatography to obtain the crude product, which was then purified by reverse-phase HPLC to afford 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 75 (45.2 mg) in a yield of 25.88%.

[0474] MS m / z(ESI):454.1[M+H] + .

[0475] 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).

[0476] Example 76

[0477] 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

[0478] Example 76 can also be synthesized by the following method:

[0479] 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.

[0480] MS m / z(ESI):454.1[M+H] + .

[0481] 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).

[0482] Example 77

[0483] 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

[0484] Example 77 can also be synthesized by the following method:

[0485] Referring to 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.

[0486] MS m / z(ESI):454.1[M+H] + .

[0487] 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).

[0488] Example 78

[0489] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0490] Example 78 can also be synthesized by the following method:

[0491] first step

[0492] Under nitrogen, 3-bromo-5-chloro-1,2,4-thiadiazole (900 mg, 4.51 mmol), cyclopropylboronic acid (775 mg, 9.02 mmol), 1,1-bis(diphenylphosphino)diboronium 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 sequentially with water (30 mL) and saturated sodium chloride (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel chromatography (elution system B) to provide 3-bromo-5-cyclopropyl-1,2,4-thiadiazole 78a (120 mg) in a 13.0% yield.

[0493] 1 H NMR (400MHz, CDCl3) δ2.41(m,1H),1.32(m,2H),1.29(m,2H).

[0494] Step 2

[0495] Referring to 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'-bipyridyl]-2-one 78 was synthesized.

[0496] MS m / z(ESI):395.1[M+H] + .

[0497] 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).

[0498] Example 82

[0499] N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide

[0500] Example 82 can also be synthesized by the following method:

[0501] first step

[0502] Pyridin-2(1H)-one (150 mg, 1.58 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylformamide (3 mL) at 0°C. Sodium hydride (69 mg, 1.74 mmol, 60% in mineral oil) was added to the reaction mixture with stirring. After stirring for 10 minutes, methyl 2-(bromomethyl)benzoate 82a (361 mg, 1.58 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 6 hours. The reaction mixture was quenched with formic acid (1 mL) and concentrated. The residue was isolated by silica gel column chromatography (eluent system A) to afford methyl 2-((2-oxopyridin-1(2H)yl)methyl)benzoate 82b (310 mg) in an 80.8% yield.

[0503] MS m / z(ESI):244.1[M+H] + .

[0504] Step 2

[0505] 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) and stirred at room temperature for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to give the title product, 2-(2-oxopyridin-1(2H)yl)methyl)benzoic acid 82c (190 mg), in a 65.0% yield.

[0506] MS m / z(ESI):230.1[M+H] + .

[0507] Step 3

[0508] 82c (40 mg, 0.18 mmol), (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine (50 mg, 0.18 mmol), triethylamine (54 mg, 0.54 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was separated by preparative HPLC (formic acid system) to give the product, N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide 82 (40 mg) in a yield of 49.3%.

[0509] MS m / z(ESI):456.2[M+H] + .

[0510] 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).

[0511] Example 84

[0512] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0513] Example 84 can also be synthesized by the following method:

[0514] first step

[0515] Under nitrogen, 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), heated to 100°C, and stirred for 6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (elution system A) to afford compound 3-(2-oxo-1-pyridyl)benzoic acid 84a (1.2 g) in a 92.2% yield.

[0516] MS m / z(ESI):216.1[M+H] + .

[0517] Step 2

[0518] Under nitrogen, intermediate 1 (70 mg, 0.287 mmol), 84a (93 mg, 0.43 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (121 mg, 0.43 mmol), and N-methylmorpholine (58 mg, 0.573 mmol) were dissolved in acetonitrile (2 mL) and stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed sequentially with water (30 mL) and saturated sodium chloride solution (30 mL), dried, filtered, and the filtrate was concentrated. 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) in a yield of 61.8%.

[0519] MS m / z(ESI):442.1[M+H] + .

[0520] 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).

[0521] Example 87

[0522] 6'-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0523] Example 87 can also be synthesized by the following method:

[0524] first step

[0525] 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]pyridin-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 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 provide 2-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine 87b (530 mg) in a yield of 74.1%.

[0526] MS m / z(ESI):214.0[M+H] + .

[0527] Step 2

[0528] Under nitrogen, 87b (211.8 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 purified by preparative HPLC (ammonium bicarbonate) to afford 6'-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 87 (30 mg) in a 22.2% yield.

[0529] MS m / z(ESI):402.2[M+H] + .

[0530] 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).

[0531] Example 88

[0532] 6'-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0533] Example 88 can also be synthesized by the following method:

[0534] first step

[0535] 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]pyridin-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 0.5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (100 mL), filtered, and the organic phase was washed with water (100 mL) and concentrated. The residue was diluted with ethyl acetate (30 mL), filtered, and the organic phase was washed with water (30 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to provide 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine 88b (490 mg) in a 69.0% yield.

[0536] MS m / z(ESI):215.9[M+H] + .

[0537] Step 2

[0538] Under nitrogen, 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 purified by preparative HPLC (ammonium bicarbonate system) to give 6'-(((1S,3S)-3-((6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 88 (10.5 mg) in a 7.23% yield.

[0539] MS m / z(ESI):406.1[M+H] + .

[0540] 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).

[0541] Example 91

[0542] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidine

[0543] Example 91 can also be synthesized by the following method:

[0544] first step

[0545] Under nitrogen, 2-fluoro-5-iodopyridine 91a (300 mg, 1.35 mmol), 1,1-dioxoisothiazolidine (326 mg, 2.69 mmol), cuprous iodide (51 mg, 0.27 mmol), dimethylethylenediamine (24 mg, 0.27 mmol), and potassium carbonate (558 mg, 4.04 mmol) were dissolved in 1,4-dioxane (5 mL) and heated in a microwave oven at 130°C with stirring for 1 hour. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to afford 2-(6-fluoropyridin-3-yl)-1,1-dioxoisothiazolidine 91b (269 mg) in a 92.47% yield.

[0546] MS m / z(ESI):217.1[M+H] + .

[0547] Step 2

[0548] Under nitrogen, 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 heated to 125°C with stirring for 48 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (ammonium bicarbonate system) to obtain 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidine 91 (17.1 mg) in a yield of 12.59%.

[0549] MS m / z(ESI):441.1[M+H] + .

[0550] 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).

[0551] Example 92

[0552] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butane sultam

[0553] Example 92 can also be synthesized by the following method:

[0554] Referring to 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-butanesulfonam 92 was synthesized.

[0555] MS m / z(ESI):455.2[M+H] + .

[0556] 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).

[0557] Example 93

[0558] 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

[0559] Example 93 can also be synthesized by the following method:

[0560] first step

[0561] To a solution of 57b (167 mg, 0.73 mmol) and iodomethane (517 mg, 3.64 mmol) in tetrahydrofuran (3 mL) was added lithium bis(trimethylsilylamide) (1 M, 3.6 mL) at 0°C. The reaction was allowed to warm to room temperature and stirred for 3 hours. Saturated ammonium chloride solution was added to the reaction mixture at 0°C, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 6-(6-fluoropyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 93a (110 mg) in a yield of 58.69%.

[0562] MS m / z(ESI):258.1[M+H] + .

[0563] Step 2

[0564] Under nitrogen, 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 mixture was heated to 130°C and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to afford 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 93 (32.1 mg) in a yield of 24.50%.

[0565] MS m / z(ESI):482.3[M+H] + .

[0566] 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).

[0567] Example 95

[0568] 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

[0569] Example 95 can also be synthesized by the following method:

[0570] first step

[0571] 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 mixture, and the reaction was heated to 70°C and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was purified by reverse phase HPLC to obtain 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione 95 (21.3 mg) in a yield of 20.44%.

[0572] MS m / z(ESI):468.2[M+H] + .

[0573] 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).

[0574] Example 97

[0575] 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

[0576] Example 97 can also be synthesized by the following method:

[0577] Referring to 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.

[0578] MS m / z(ESI):496.2[M+H] + .

[0579] 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).

[0580] Example 99

[0581] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0582] Example 99 can also be synthesized by the following method:

[0583] first step

[0584] Under nitrogen, 7-bromopyrazolo[1,5-a]pyridine 99a (650 mg, 3.3 mmol), (6-fluoropyridin-3-yl)boronic acid (604 mg, 4.29 mmol), bis(diphenylphosphino)ferrocenepalladium dichloride (241 mg, 0.33 mmol), and potassium carbonate (1.14 g, 8.25 mmol) were dissolved in a mixture of 1,4-dioxane (16 mL) and water (4 mL). The reaction mixture was heated to 100°C and stirred for 10 hours. The reaction mixture was filtered through celite and concentrated. The residue was isolated by silica gel column chromatography (eluent system B) to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine 99b (640 mg) in a 91.0% yield.

[0585] MS m / z(ESI):214.1[M+H] + .

[0586] Step 2

[0587] 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 and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into ice water (20 mL), and the pH was adjusted to weak alkaline by adding aqueous sodium hydroxide. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (30 mL), dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde 99c (310 mg) in a 91.3% yield.

[0588] MS m / z(ESI):242.1[M+H] + .

[0589] Step 3

[0590] 99c (200 mg, 0.83 mmol) and hydroxylamine hydrochloride (86 mg, 1.24 mmol) were dissolved in a mixture of ethanol (15 mL) and water (5 mL). The reaction mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was filtered. The filter cake was washed with water and dried to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde oxime 99d (150 mg) in a yield of 70.6%.

[0591] MS m / z(ESI):257.1[M+H] + .

[0592] Step 4

[0593] 99d (60 mg, 0.234 mmol) was dissolved in acetic anhydride (5 mL) and the reaction was heated to 130°C with stirring for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with saturated sodium bicarbonate solution and then with water, and dried to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-cyano 99e (30 mg) in a yield of 53.8%.

[0594] MS m / z(ESI):239.1[M+H] + .

[0595] Step 5

[0596] 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 with stirring 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)pyrazolo[1,5-a]pyridine-3-carbonitrile 99 (32 mg) in a yield of 47.1%.

[0597] MS m / z(ESI):463.2[M+H] + .

[0598] 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).

[0599] Example 102

[0600] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-fluoropyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine

[0601] Example 102 can also be synthesized by the following method:

[0602] first step

[0603] (1S,3S)-N 1 -(5-difluoromethoxy)pyrimidin-2-yl)-N 3-(5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 52 (30 mg, 0.068 mmol) and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (24 mg, 0.068 mmol) were dissolved in acetonitrile (2 mL) and 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-fluoropyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane-1,3-diamine 102 (7 mg), yield: 22.4%.

[0604] MS m / z(ESI):456.2[M+H] + .

[0605] 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).

[0606] Example 108

[0607] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

[0608] Example 108 can also be prepared as follows:

[0609] first step

[0610] Under nitrogen, Intermediate 1 (300 mg, 1.23 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (301.4 mg, 1.35 mmol), and N,N-diisopropylethylamine (476.3 mg, 3.68 mmol) were dissolved in dimethyl sulfoxide (3 mL) and heated to 130°C with stirring for 16 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (formic acid system) to give (6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid 108a (250 mg) in a 55.7% yield.

[0611] MS m / z(ESI):366.2[M+H]+.

[0612] Step 2

[0613] Under nitrogen, 108a (80 mg, 0.22 mmol), 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-one (98.6 mg, 0.44 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (15.9 mg, 0.024 mmol), and sodium carbonate (71.0 mg, 0.66 mmol) were dissolved in a mixture of 1'4-dioxane (5 mL) and water (0.5 mL). 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 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 108 (39 mg) in a 37.1% yield.

[0614] MS m / z(ESI):466.2[M+H] + .

[0615] 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).

[0616] Example 112

[0617] 6'-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0618] Referring to 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'-bipyridyl]-2-one 112 was synthesized.

[0619] MS m / z(ESI):422.1[M+H] + .

[0620] 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).

[0621] Example 113

[0622] 6'-(((1S,3S)-3-((7-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0623] Under nitrogen, 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(dibenzylideneacetone)dipalladium (41 mg, 0.04 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41 mg, 0.09 mmol) were dissolved in 1,4-dioxane (2 mL) and heated to 130°C in a microwave oven 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'-bipyridyl]-2-one 113 (31.7 mg) in 31.4% yield.

[0624] MS m / z(ESI):456.2[M+H] + .

[0625] 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).

[0626] Example 114

[0627] 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one

[0628] Example 114 can also be prepared according to the following method:

[0629] first step

[0630] Under nitrogen, 63c (241 mg, 0.67 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (259 mg, 1.35 mmol), and cuprous iodide (192 mg, 1.01 mmol) were dissolved in N,N-dimethylformamide (3 mL) and heated to 90°C in a microwave oven with stirring for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL) and saturated sodium chloride (20 mL). The organic phase was dried and concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to afford the title product, tert-butyl (1S,3S)-3-(((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate 114a (160 mg) in a 68.5% yield.

[0631] MS m / z(ESI):348.2[M+H] + .

[0632] Step 2

[0633] Referring to the synthesis method of the fourth step of Example 63, the target product (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 114b was synthesized.

[0634] MS m / z(ESI):296.2[M+H] + .

[0635] Step 3

[0636] Referring to the synthesis method of the fifth step of Example 63, the target product 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridine]-2-one 114 was synthesized.

[0637] MS m / z(ESI):418.2[M+H] + .

[0638] 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)

[0639] Example 115

[0640] 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

[0641] 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)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one was synthesized.

[0642] MS m / z(ESI):468.2[M+H] + .

[0643] 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).

[0644] Example 116

[0645] 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

[0646] 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)-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one was synthesized.

[0647] MS m / z(ESI):468.2[M+H] + .

[0648] 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).

[0649] Example 117

[0650] (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

[0651] Example 117 can also be prepared according to the following method:

[0652] first step

[0653] Compound 99c (300 mg, 1.24 mmol) was dissolved in methanol (10 mL) under ice-cooling. Sodium borohydride (47 mg, 1.24 mmol) was added to the reaction mixture with stirring. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with hydrochloric acid (1 M). The reaction mixture was concentrated, and the residue was isolated by silica gel column chromatography (eluent system B) to afford (7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol 117a (240 mg) in a yield of 79.3%.

[0654] MS m / z(ESI):244.1[M+H] + .

[0655] Step 2

[0656] 117a (50 mg, 0.206 mmol), phenyl chlorothioformate (35.5 mg, 0.206 mmol), and 4-dimethylaminopyridine (50.2 mg, 0.412 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to afford oxy-((7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methyl)oxy-phenylcarbonothioate 117b (30 mg) in a 64.1% yield.

[0657] MS m / z(ESI):380.1[M+H] + .

[0658] Step 3

[0659] Under nitrogen, 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 (eluent system B) to afford 7-(6-fluoropyridin-3-yl)-3-methylpyrazolo[1,5-a]pyridine 117c (20 mg) in a 66.8% yield.

[0660] Step 4

[0661] 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%.

[0662] MS m / z(ESI):452.2[M+H] + .

[0663] 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).

[0664] Example 118

[0665] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-cyano

[0666] Referring to 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]pyrimidine-3-cyano was synthesized.

[0667] MS m / z(ESI):464.2[M+H] + .

[0668] 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).

[0669] Example 119

[0670] 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide

[0671] Example 119 can also be prepared according to the following method:

[0672] first step

[0673] Under nitrogen, 1,2-thiazolidine-1,1-dioxide (2 g, 16.5 mmol) and 4-methoxybenzyl chloride (3.10 g, 19.8 mmol) were dissolved in tetrahydrofuran (35 mL) at 0°C. Sodium hydride (792 mg, 19.8 mmol, 60% content) was added portionwise to the reaction mixture with stirring. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain 2-(4-methoxybenzyl)isothiazolidine 1,1-dioxide 119b (1.52 g) in a 38% yield.

[0674] MS m / z(ESI):505.1[2M+Na] + .

[0675] Step 2

[0676] 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 to the reaction mixture. The reaction was stirred at -78°C for another 2 hours, then brought to room temperature and stirred for 1 hour. The reaction mixture was purified by preparative HPLC (formic acid system) to afford 2-(4-methoxybenzyl)-5,5-dimethylisothiazolidine 1,1-dioxide 119c (586 mg) in a 52% yield.

[0677] MS m / z(ESI):539.2[2M+H] + .

[0678] Step 3

[0679] 119c (0.32 g, 1.19 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise to the reaction mixture with stirring, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to afford 5,5-dimethylisothiazolidine 1,1-dioxide 119d (165 mg), which was used directly in the next step without purification.

[0680] MS m / z(ESI):150.1[M+H] +

[0681] Step 4

[0682] Referring to the synthesis method of the first step of Example 91, 2-(6-fluoropyridin-3-yl)-5,5-dimethylisothiazolidine 1,1-dioxide 119e (154 mg) was synthesized with a yield of 56%.

[0683] MS m / z(ESI):245.1[M+H] + .

[0684] Step 5

[0685] Referring to the synthesis method of the second step of Example 91, the target product 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide 119 (21 mg) was synthesized with a yield of 14%.

[0686] MS m / z(ESI):469.2[M+H] + .

[0687] 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).

[0688] Example 120

[0689] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,6-dimethyl-1,2-thiazinane-1,1-dioxide

[0690] Referring to 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.

[0691] MS m / z(ESI):483.2[M+H] + .

[0692] 1 H 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).

[0693] Example 121

[0694] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-2,3-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide

[0695] Example 121 can also be obtained as follows:

[0696] first step

[0697] 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 heated to 60°C with stirring for 5 hours. The reaction solution was concentrated to half its volume and poured into dilute hydrochloric acid (1N, 100 mL). A large amount of solid precipitated, which was filtered and dried to give isothiazolo[5,4-b]pyridin-3(2H)-one 1,1-dioxide 121a (1.27 g) in a 40% yield.

[0698] MS m / z(ESI):185.1[M+H] + .

[0699] 1 H NMR (400MHz, DMSO-d6) δ9.04(dd,1H),8.45(dd,1H),7.93(dd,1H).

[0700] Step 2

[0701] Under nitrogen, 121a (194 mg, 1.05 mmol) was dissolved in tetrahydrofuran (4 mL). A solution of lithium aluminum hydride (88 mg, 2.32 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction mixture at 0°C. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (25 mL), and the organic phase was washed with saturated ammonium chloride (10 mL), dried, and concentrated to afford 2,3-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide 121b (150 mg). This product was used in the next step without further purification.

[0702] MS m / z(ESI):171.0[M+H] + .

[0703] Step 3

[0704] Under nitrogen, 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 mixture was heated to 100°C and stirred for 4 h. The reaction solution was filtered, and the filtrate was diluted with ethyl acetate (25 mL) and water (10 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, washed with saturated sodium chloride (25 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 2-(6-fluoropyridin-3-yl)-2,3-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide 121c (36 mg) in a yield of 25%.

[0705] MS m / z(ESI):266.1[M+H] + .

[0706] Step 4

[0707] 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-dihydroisothiazo[5,4-b]pyridine 1,1-dioxide 121 (6 mg) in a 9% yield.

[0708] MS m / z(ESI):490.1[M+H] + .

[0709] 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).

[0710] Example 122 and Example 123

[0711] 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)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0712] first step

[0713] Thiophosgene (6.61 g, 57.46 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine 122a (5.00 g, 38.30 mmol) and diisopropylethylamine (7.43 g, 57.46 mmol) in dichloromethane (100 mL) under ice. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled in an ice bath, and sodium ethanethiolate (6.44 g, 76.61 mmol) was added to the reaction mixture, and the reaction mixture was stirred under ice bath for 1 hour. The reaction mixture was filtered, the organic phase was concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to afford the title product, O-(2-chloropyrimidin-5-yl) S-dicarbonylethyl dithioate 122b (4.20 g), in a 46.7% yield.

[0714] MS m / z(ESI):235.0[M+H] + .

[0715] Step 2

[0716] A solution of hydrogen fluoride in pyridine (40 mL, containing 70% hydrofluoric acid) was added dropwise to a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (4.87 g, 17.04 mmol) in dichloromethane (100 mL) at -78°C, and the reaction was stirred for 30 minutes. A solution of 122b (1.00 g, 4.26 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture, and the temperature was raised to 0°C with stirring for 2 hours. The reaction mixture was adjusted to pH 9 with aqueous sodium carbonate solution, the organic phase was separated, and the residue was concentrated by silica gel column chromatography (eluent system B) to afford a mixture of 2-chloro-5-(trifluoromethoxy)pyrimidine 122c and 5-(bromodifluoromethoxy)-2-chloropyrimidine 123a (160 mg).

[0717] 122c MS m / z(ESI):199.0[M+H] + .

[0718] 123a MS m / z(ESI):259.0[M+H]+ .

[0719] Step 3

[0720] 6-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]-7H-pyrrolo[3,4-b]pyridin-5-one (31 mg, 0.10 mmol, for its synthesis see 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 with stirring 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) in a yield of 12.6%.

[0721] MS m / z(ESI):472.2[M+H] + .

[0722] 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).

[0723] 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%.

[0724] MS m / z(ESI):532.1[M+H] + .

[0725] 1H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.84(dd,1H),7.59(d d,1H),6.63(d,1H),4.96(s,2H),4.41(m,1H),4.30(m,1H),2.27(dd,2H),2.02(m,2H),1.60(m,2H)

[0726] Example 124

[0727] 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

[0728] first step

[0729] Compound 122a (1.00 g, 7.66 mmol), cesium carbonate (3.24 g, 9.96 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.31 g, 9.96 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred at room temperature for 16 hours. Ethyl acetate (160 mL) was added to the reaction solution, and the organic phase was washed with water (25 mL) and saturated sodium chloride (25 mL), dried, and concentrated. The residue was isolated by silica gel column chromatography (eluent system B) to afford 2-chloro-5-(2,2,2-trifluoroethoxy)pyrimidine 124a (1.20 g) in a 73.7% yield.

[0730] MS m / z(ESI):213.0[M+H] + .

[0731] Step 2

[0732] Referring to the synthesis method of the third step 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.

[0733] MS m / z(ESI):486.2[M+H] + .

[0734] 1H 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).

[0735] Example 125

[0736] 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

[0737] first step

[0738] Referring to the synthesis method of the third step 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.

[0739] MS m / z(ESI):486.2[M+H] + .

[0740] 1 H NMR(400MHz,DMSO-d6)δ8.75(dd,1H),8.35(d,1H),8.20(s,2H),8.11(dd,1H),7.87(dd,1H),7.62(dd,1H),7.10 (d,1H),6.69(d,1H),6.55(d,1H),4.93(s,2H),4.71(q,2H),4.28(d,2H),2.11(d,2H),1.90(m,2H),1.49(m,2H).

[0741] Example 126

[0742] 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0743] Referring to the synthesis method of Example 75, the target product 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 126 was synthesized.

[0744] MS m / z(ESI):429.2[M+H] + .

[0745] 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).

[0746] Example 127

[0747] 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

[0748] first step

[0749] Referring to the synthesis method of the third step 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.

[0750] MS m / z(ESI):428.2[M+H] + .

[0751] 1H 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).

[0752] Example 128

[0753] 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

[0754] first step

[0755] Referring to the synthesis method of the third step 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.

[0756] MS m / z(ESI):428.2[M+H] + .

[0757] 1 H 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).

[0758] Example 129

[0759] 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

[0760] first step

[0761] Under nitrogen, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 129a (500 mg, 2.31 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (510 mg, 2.55 mmol), cesium carbonate (1.51 g, 4.63 mmol), tris(dibenzylideneacetone)dipalladium (424 mg, 0.46 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL) and heated to 130°C in a microwave oven with stirring for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) and preparative HPLC (formic acid system) to give tert-butyl N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate 129b (240 mg) in a yield of 30.9%.

[0762] MS m / z(ESI):336.0[M+H] + .

[0763] Step 2

[0764] 129b (202 mg, 0.60 mmol) was dissolved in methanol (2 mL) and stirred at room temperature. A solution of hydrochloric acid in 1,4-dioxane (4 M, 5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (ammonia system) to afford (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 129c (140 mg) in a 98.6% yield.

[0765] MS m / z(ESI):236.2[M+H] + .

[0766] Step 3

[0767] 129c (150 mg, 0.64 mmol), 2-fluoro-5-nitro-pyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL) and the reaction mixture was heated to 80°C with stirring for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to afford (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) in an 83.4% yield.

[0768] MS m / z(ESI):358.1[M+H] + .

[0769] Step 4

[0770] Under a hydrogen atmosphere, 129d (190 mg, 0.53 mmol) and palladium on carbon (28 mg, 0.026 mmol, 10% content) were dissolved in methanol (5 mL) and stirred for 1 hour at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford N2-((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 129e (170 mg) in a 97.7% yield.

[0771] MS m / z(ESI):328.1[M+H] + .

[0772] Step 5

[0773] 129e (80 mg, 0.24 mmol), methyl 3-(bromomethyl)picolinate (62 mg, 0.27 mmol), and potassium carbonate (101.2 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 hour. The mixture was then heated to 50°C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to afford 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 129 (24.3 mg) in a yield of 22.4%.

[0774] MS m / z(ESI):445.2[M+H] + .

[0775] 1H 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).

[0776] Example 130

[0777] 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

[0778] Referring to 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.

[0779] MS m / z(ESI):441.2[M+H] + .

[0780] 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).

[0781] Example 131

[0782] 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

[0783] first step

[0784] Referring to the synthesis method of the third step 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.

[0785] MS m / z(ESI):452.2[M+H] + .

[0786] 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(m 1H),4.31(m,1H),2.70(s,3H),2.16(m,2H),1.94(m,2H),1.54(m,2H).

[0787] Example 132

[0788] 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

[0789] Example 132 can also be prepared according to the following method

[0790] first step

[0791] 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 at room temperature for 1 hour. The mixture was then heated to 60°C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 132 (21 mg) in a yield of 25.9%.

[0792] MS m / z(ESI):455.2[M+H] + .

[0793] 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).

[0794] Example 133

[0795] 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

[0796] Referring to 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.

[0797] MS m / z(ESI):456.2[M+H] + .

[0798] 1H 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).

[0799] Example 134

[0800] 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

[0801] Referring to 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.

[0802] MS m / z(ESI):456.2[M+H] + .

[0803] 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).

[0804] Example 135

[0805] 6'-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0806] Referring to 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'-bipyridyl]-2-one 135 was synthesized.

[0807] MS m / z(ESI):428.2[M+H] + .

[0808] 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).

[0809] Example 136

[0810] 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

[0811] Referring to 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.

[0812] MS m / z(ESI):472.1[M+H] + .

[0813] 1H 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).

[0814] Example 137

[0815] 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

[0816] Referring to 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.

[0817] MS m / z(ESI):472.1[M+H] + .

[0818] 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).

[0819] Example 138

[0820] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-trifluoromethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0821] 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)-6-trifluoromethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 138 was synthesized.

[0822] MS m / z(ESI):522.2[M+H] + .

[0823] 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).

[0824] Example 139

[0825] (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

[0826] Referring to 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.

[0827] MS m / z(ESI):439.2[M+H] + .

[0828] 1 H 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).

[0829] Example 140

[0830] (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

[0831] Referring to 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.

[0832] MS m / z(ESI):439.2[M+H] + .

[0833] 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).

[0834] Example 142

[0835] 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

[0836] Referring to 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.

[0837] MS m / z(ESI):532.1[M+H] + .

[0838] 1H 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).

[0839] Example 143

[0840] 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

[0841] Referring to 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.

[0842] MS m / z(ESI):495.2[M+H] + .

[0843] 1 H NMR(400MHz, DMSO-d6)δ8.83(d,1H),8.75(dd,1H),8.35(d,1H),8.15–8.06(m,1H),7.88(dd,1H),7.86(s,1H),7.62(dd,1H),7.15(dd ,1H),7.04(d,1H),6.71(s,1H),6.57(d,1H),4.93(s,2H),4.36–4.15(m,2H),2.23–2.10(m,2H),2.05–1.83(m,2H),1.65–1.42(m,2H).

[0844] Example 144

[0845] 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

[0846] Example 144 can also be prepared according to the following method:

[0847] first step

[0848] Tert-Butyl nitrite (14.73 g, 142.87 mmol) was added dropwise 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) at room temperature and stirred for 3 hours. The reaction was quenched with methanol (515 mL), the organic phase was concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to afford the title product, 6-bromo-3-(methylthio)-1,2,4-triazine 144b (4.60 g), in a yield of 78.1%.

[0849] MS m / z(ESI):205.9[M+H] + .

[0850] Step 2

[0851] Under nitrogen, 144b (2.00 g, 9.71 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (5.59 g, 29.17 mmol), and cuprous iodide (5.55 g, 29.12 mmol) were dissolved in N,N-dimethylformamide (15 mL) and heated to 90°C with stirring for 3 hours. The reaction solution was diluted with ethyl acetate (180 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried and concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to give the title product, 3-(methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (710 mg), in a 37.5% yield.

[0852] MS m / z(ESI):196.0[M+H] + .

[0853] Step 3

[0854] Referring to the synthesis method of the third step 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.

[0855] MS m / z(ESI):457.2[M+H] + .

[0856] 1H NMR(400MHz,DMSO-d6)δ9.10,8.60(d,1H),8.75(m,1H),8.70(s,1H),8.36(d,1H),8.11(m,1H),7.88(m,1H),7.62(m ,1H),6.74(m,1H),6.57(d,1H),4.93(s,2H),4.61,4.35(m,1H),4.36(m,1H),2.17(m,2H),2.00(m,2H),1.61(m,2H).

[0857] Example 145

[0858] 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

[0859] Example 145 can also be prepared according to the following method:

[0860] first step

[0861] Referring to the synthesis method of the third step 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.

[0862] MS m / z(ESI):457.2[M+H] + .

[0863] 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).

[0864] Example 146

[0865] 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

[0866] Example 146 can also be prepared according to the following method:

[0867] first step

[0868] 3-(Methylthio)-6-(trifluoromethyl)-1,2,4-triazine 144c (390 mg, 2.00 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (420 mg, 2.10 mmol), and diisopropylethylamine (258 mg, 2.00 mmol) were dissolved in N-methylpyrrolidone (5 mL). The reaction was heated to 90°C and stirred for 2 hours. Ethyl acetate (25 mL) and water (10 mL) were added to the reaction solution, and the organic phase was washed with saturated brine and concentrated. The residue was separated by silica gel column chromatography (elution system A) to provide tert-butyl ((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate 146a (410 mg) in a yield of 59.07%.

[0869] MS m / z(ESI):348.2[M+H] + .

[0870] Step 2

[0871] 146a (410 mg, 1.18 mmol) was dissolved in methanol (3 mL). 1,4-dioxane hydrochloride (4 M, 3 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in a small amount of methanol. Ammonia 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 afford (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 146b (280 mg) in a 95.95% yield.

[0872] MS m / z(ESI):248.2[M+H] + .

[0873] Step 3

[0874] Under nitrogen, 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 heated to 130°C with stirring for 48 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (formic acid system) to afford 5-dimethyl-6-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 146 (28 mg) in a 33.23% yield.

[0875] MS m / z(ESI):485.2[M+H] +

[0876] 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).

[0877] Example 147

[0878] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0879] Referring to the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 147 was synthesized.

[0880] MS m / z(ESI):459.2[M+H] + .

[0881] 1H 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).

[0882] Example 148

[0883] 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

[0884] Referring to 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.

[0885] MS m / z(ESI):471.2[M+H] + .

[0886] 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).

[0887] Example 149

[0888] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0889] Referring to the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 149 was synthesized.

[0890] MS m / z(ESI):459.2[M+H] + .

[0891] 1 H 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).

[0892] Example 151

[0893] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

[0894] Referring to the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 151 was synthesized.

[0895] MS m / z(ESI):513.2[M+H] + .

[0896] 1H 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).

[0897] Example 152

[0898] 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

[0899] Referring to 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.

[0900] MS m / z(ESI):525.2[M+H] + .

[0901] 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).

[0902] Example 153

[0903] 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

[0904] Referring to 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.

[0905] MS m / z(ESI):475.2[M+H] + .

[0906] 1 H NMR(400MHz,DMSO-d6)δ9.11(d,1H),8.76(s,1H),8.70(s,1H),8.34(d,1H),8.10(dd,1H),7.86(dd,1H),6.78-6.73(m,1H) ,6.56(d,1H),4.94(s,2H),4.36-4.32(m,2H),2.23-2.13(m,2H),2.02-1.91(m,2H),1.69-1.62(m,1H),1.57–1.51(m,1H).

[0907] Example 154

[0908] 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide

[0909] Referring to the synthesis method of Example 121, 2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide 154 was synthesized.

[0910] MS m / z(ESI):493.1[M+H] + .

[0911] Example 155

[0912] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0913] Referring to the synthesis method of Example 129, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 155 was synthesized.

[0914] MS m / z(ESI):513.2[M+H] + .

[0915] 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).

[0916] Example 156

[0917] 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

[0918] Referring to the synthesis method of Example 143, 6-methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one 156 was synthesized.

[0919] MS m / z(ESI):509.2[M+H] + .

[0920] 1H 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).

[0921] Example 157

[0922] 7-(Trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one

[0923] Referring to 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)isoindolin-1-one 157 was synthesized.

[0924] MS m / z(ESI):524.2[M+H] + .

[0925] 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).

[0926] Example 158

[0927] 4-(Trifluoromethyl)-2-(6-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one

[0928] Referring to 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)isoindolin-1-one 158 was synthesized.

[0929] MS m / z(ESI):524.2[M+H] + .

[0930] 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.34(d,1H),8.18(s,1H),7.85(dd,1H),7.59(s,1H),7.54(s,1H),6.72(d,1H),6 .55(d,1H),4.97(s,2H),4.32(d,2H),2.60(s,3H),2.17–2.02(m,3H),1.90(dt,2H),1.52(dd,2H),0.98–0.87(m,4H).

[0931] Example 159

[0932] 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

[0933] Referring to the synthesis method of Example 144, 6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 159 was synthesized.

[0934] MS m / z(ESI):497.2[M+H] + .

[0935] Example 161

[0936] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one

[0937] Referring to the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl)isoindol-1-one 161 was synthesized.

[0938] MS m / z(ESI):512.2[M+H] + .

[0939] 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,1H),8.30(d,1H),7.95(d,1H),7.90–7.77(m,3H),7.27(dd,1H),6.86(t,1H),6.75(d,1 H),6.68(d,1H),6.54(d,1H),4.98(s,2H),4.29(q,1H),4.15(q,1H),2.15(dd,2H),2.01–1.84(m,2H),1.61–1.44(m,2H).

[0940] Example 162

[0941] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one

[0942] Referring to the synthesis method of Example 129, 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one 162 was synthesized.

[0943] MS m / z(ESI):512.1[M+H] + .

[0944] 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).

[0945] Example 163

[0946] 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

[0947] Referring to 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.

[0948] MS m / z(ESI):513.2[M+H] + .

[0949] 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).

[0950] Example 164

[0951] 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

[0952] first step

[0953] To a solution of 2-bromo-6-tert-butylpyridine 164a (300 mg, 1.40 mmol) in tetrahydrofuran (5 mL) was added lithium diisopropylamide (2 M, 1.05 mL) dropwise at -78°C. The reaction was stirred at -78°C for 1 hour, and then N,N-dimethylformamide (410 mg, 5.60 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-bromo-6-(tert-butyl)nicotinaldehyde 164b (56 mg) in a yield of 16.51%.

[0954] MS m / z(ESI):242.0[M+H] + .

[0955] Step 2

[0956] Under carbon monoxide protection, 164b (53 mg, 0.22 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (16 mg, 0.02 mmol), and triethylamine (44 mg, 0.44 mmol) were dissolved in a mixture of N,N-dimethylformamide (1 mL) and methanol (2 mL). The reaction was heated to 80°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford methyl 6-(tert-butyl)-3-formylpicolinate 164c (13 mg) in a yield of 26.84%.

[0957] MS m / z(ESI):222.1[M+H] + .

[0958] Step 3

[0959] Compound 129e (23 mg, 0.07 mmol), compound 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 stirred for 15 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse phase HPLC to give 2-(tert-butyl)-6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 164 (15.8 mg) in a yield of 53.72%.

[0960] MS m / z(ESI):501.2[M+H] + .

[0961] 1 H NMR(400MHz,DMSO-d6)δ8.70-8.62(m,1H),8.34(d,1H),8.02(d,1H),7.89- 7.80(m,1H),7.68(d,1H),7.31-7.22(m,1H),6.90-6.82(m,1H),6.75(d,1H ),6.68(d,1H),6.56(d,1H),4.86(s,2H),4.35-4.23(m,1H),4.22-4.08(m, 1H),2.22-2.07(m,2H),2.03-1.81(m,2H),1.63-1.42(m,2H),1.37(s,9H).

[0962] The synthesis method of the embodiment can refer to the above embodiment.

[0963] Biological test evaluation

[0964] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0965] 1. Combined Experiment

[0966] 1. Experimental purpose: Use conventional surface plasmon resonance (SPR) method to detect the effect of compounds on PCSK9 protein binding.

[0967] 2. Experimental results: Note: E-04: ×10 -4

[0968] 3. Experimental conclusions:

[0969] The example compounds shown in the present invention have a good binding effect on the PCSK-9 protein and the dissociation rate of the compounds from the PCSK9 protein is slow.

[0970] 2. Cell Function Experiment

[0971] Test Example 1: Determination of the Effect of the Compounds of the Invention on the Concentration of PCSK9 Secreted by HepG2 Cells

[0972] 1. Experimental purpose: To detect the inhibitory effect of compounds on PCSK9.

[0973] 2. Experimental instruments and reagents:

[0974] 2.1 Instruments:

[0975] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), water purifier (THERMO: Pacific T II + Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[0976] 2.2 Reagents:

[0977] CircuLex Human PCSK9 ELISA Kit (MBL: CY-8079);

[0978] DMEM (Gibco: 31966-021)

[0979] FBS (Sigma: S5394)

[0980] Compound plate (Thermo: 1353506)

[0981] Complete culture medium: DMEM + 10% FBS + 1X P / S;

[0982] Experimental culture medium: DMEM + 10% FBS

[0983] Cell line: HepG2 (ATCC: HB-8065)

[0984] 3. Experimental methods:

[0985] 1) HepG2 cells were cultured in complete medium at 37°C, 5% CO2 until they reached 70% to 90% confluency.

[0986] 2) The digested cells were resuspended in experimental culture medium, and 25,000 cells / well / 200 μL were seeded into a 96-well cell culture plate, and cultured at 37° C., 5% CO 2 for 20-24 hours.

[0987] 3) Remove the culture medium from the cell culture plate and add 200 μl of experimental culture medium to each well to wash once.

[0988] 4) Prepare the positive control compound and the test compound: dilute the positive control compound and the test compound on a compound plate.

[0989] 5) Add 250 μL of the diluted compound to each well of the cell culture plate and incubate at 37° C., 5% CO 2 for 48 hours.

[0990] 6) Collect 200 μL of cell culture medium from each well and freeze at -80°C for later use.

[0991] 7) Take out the cell culture medium sample from -80°C, dissolve it, vortex it, centrifuge it, and set aside.

[0992] 8) Prepare the standard curve: Add the corresponding volume of Dilution buffer to each standard tube in sequence. Dilute the standard sample from the original tube or the previous concentration tube in the order of 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, and 0 ng / mL.

[0993] 9) Prepare wash buffer: Dilute 10x wash buffer to 1x with Milli-Q and set aside.

[0994] 10) Add 100 μL of the corresponding standard and culture medium sample to each well, following the designated wells on the plate map. Repeat in duplicate. Apply self-adhesive coverslips, place on a plate shaker at room temperature, gently shake to mix, and incubate for 1 hour.

[0995] 11) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0996] 12) Add 100 μL of HRP-conjugated detection antibody to each well, apply self-adhesive coverslips, place on a shaker to mix thoroughly, and incubate for 1 hour.

[0997] 13) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[0998] 14) Add 100 μL of substrate reagent to each well, protect from light, affix a self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 10-20 minutes.

[0999] 15) Add 100 μL of Stop solution (1N H2SO4) to each well and mix thoroughly.

[1000] 16) Measure the optical density (OD) of each well at 450 nm using a microplate reader within 30 minutes of reaction termination.

[1001] 4. Experimental data processing method:

[1002] The OD value read by the microplate reader is used to subtract the OD value of the standard group with a concentration of 0 from the OD value of the standard, control group, and sample to obtain the actual value of each well. The standard curve is drawn using Graphpad to calculate the concentration of the sample. If the sample is diluted, the corresponding dilution factor must be multiplied in the final calculation to obtain the actual concentration of the sample. Inhibition rate = (actual concentration of control - actual concentration of sample) / actual concentration of control * 100. Based on the inhibition rate corresponding to different concentrations, the IC is drawn using Graphpad. 50 .

[1003] 5. Experimental results:

[1004] 6. Experimental conclusions:

[1005] The example compounds of the present invention showed a good inhibitory effect in the experiment on the concentration of PCSK9 secreted by HepG2 cells.

[1006] Test Example 2: Determination of the Effect of the Compounds of the Invention on LDLR Levels in HepG2 Cells

[1007] 1. Experimental purpose:

[1008] The effects of the compounds on LDLR protein levels were examined.

[1009] 2. Experimental instruments and reagents:

[1010] 2.1 Instruments:

[1011] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), water purifier (THERMO: Pacific T II + Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[1012] 2.2 Reagents:

[1013] Human LDL R Quantikine ELISA Kit (R&D: DLDLR0)

[1014] DMEM (Gibco: 31966-021)

[1015] FBS (Sigma: S5394)

[1016] PBS

[1017] Cell lysis buffer (Thermo: 78503)

[1018] Protease inhibitor (Pierce: 78430)

[1019] Compound plate (Thermo: 1353506)

[1020] Complete culture medium: DMEM + 10% FBS + 1X P / S

[1021] Experimental culture medium: DMEM + 10% FBS

[1022] Cell line: HepG2 (ATCC: HB-8065)

[1023] 3. Experimental methods:

[1024] 1) HepG2 cells were cultured in complete medium at 37°C, 5% CO2 until they reached 70% to 90% confluency.

[1025] 2) The digested cells were resuspended in experimental culture medium, and 25,000 cells / well / 200 μL were seeded into a 96-well cell culture plate, and cultured at 37° C., 5% CO 2 for 20-24 hours.

[1026] 3) Remove the culture medium from the cell culture plate and add 200 μl of experimental culture medium to each well to wash once.

[1027] 4) Prepare the positive control compound and the test compound: dilute the positive control compound and the test compound on a compound plate.

[1028] 5) Add 250 μL of the diluted compound to each well of the cell culture plate and incubate at 37° C., 5% CO 2 for 48 hours.

[1029] 6) Remove the cell culture medium, wash the cells with PBS, and add 50 μL of cell lysis buffer and protein inhibitors.

[1030] 7) Centrifuge, remove the lysate, and store the sample for future use.

[1031] 8) Prepare the standard curve: Add the corresponding volume of Dilution buffer to each standard tube in turn. Take the corresponding volume of the standard from the original tube or the previous concentration tube and dilute it in sequence.

[1032] 9) Prepare wash buffer: Dilute 10x wash buffer to 1x with Milli-Q and set aside.

[1033] 10) Add 80 μL of the corresponding standard and sample to each well, as assigned to the marker and sample wells on the plate map, in duplicate. The well without the standard serves as the background well. Apply a self-adhesive cover slip, place on a plate shaker at room temperature, gently shake to mix, and incubate for 2 hours.

[1034] 11) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[1035] 12) Add 200 μL of Human LDLR conjugate to each well, apply a self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 2 hours.

[1036] 13) Place the plate on a plate washer and set the volume of washing solution to 350 μL per well. Repeat 4 times to wash the plate.

[1037] 14) Add 200 μL of substrate solution to each well, protect from light, apply self-adhesive sealant, place on a shaker to mix thoroughly, and incubate for 20 minutes.

[1038] 15) Add 50 μL of Stop solution to each well and mix thoroughly for 20 minutes.

[1039] 16) Measure the optical density (OD) of each well in sequence at a wavelength of 450 nm using a microplate reader.

[1040] 4. Experimental data processing method:

[1041] Subtract the OD value of the standard sample group (0 concentration) from the OD values ​​of the standard sample, control group, and sample from the OD values ​​of the standard sample, to determine the actual value for each well. Use GraphPad to plot a standard curve and calculate the sample concentration. If the sample is diluted, multiply the dilution factor to obtain the actual sample concentration. Percentage increase in concentration (%) = (Actual control concentration - Actual sample concentration) / Actual control concentration * 100.

[1042] 5. Experimental results:

[1043] 6. Experimental conclusions:

[1044] The experiment on the effect of the example compounds of the present invention on the LDLR concentration in HepG2 cells showed that the compounds increased the LDLR concentration.

[1045] 3. Pharmacokinetics Experiment

[1046] Test Example 1: Pharmacokinetics in mice

[1047] 1. Experimental purpose:

[1048] C57BL / 6J mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral and intravenous administration.

[1049] 2. Experimental Plan

[1050] 2.1 Investigational Drugs:

[1051] The compound of the present invention is homemade;

[1052] 2.2 Experimental Animals

[1053] C57 mice, male, were purchased from Shanghai Bikai Laboratory Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

[1054] 2.3 Drug preparation:

[1055] Oral drug formulation: 10% Solutol HS15

[1056] Weigh 10 g of Solutol HS15 solid, dissolve it in 90 mL of purified water, mix well, stir and ultrasonicate to form a clear solution.

[1057] The compound of the present invention was weighed and dissolved in the solution, shaken and ultrasonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[1058] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[1059] The compound of the present invention was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve the compound. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[1060] 2.4 Administration:

[1061] Three male C57 mice were fasted overnight and PO-administered at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[1062] Three male C57 mice were fasted overnight and administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[1063] 2.5 Sample collection:

[1064] Before administration and at 0.083 (iv), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, 0.04 mL of blood was collected from the eye sockets of mice, placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 minutes at 4°C to separate plasma, and stored at -80°C; food was taken 4 hours after administration.

[1065] 2.6 Measurement results:

[1066] The final determination results were obtained using LCMS / MS method.

[1067] 3. Experimental results:

[1068] The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[1069] 4. Experimental conclusions:

[1070] The results of pharmacokinetic assays in C57BL / 6J mice showed that the compound of the present invention exhibited significant PK advantages.

[1071] IV. Drug Efficacy Experiment

[1072] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse hyperlipidemia animal model

[1073] 1. Experimental purpose:

[1074] The in vivo efficacy of the compound was evaluated in the B6-hPCSK9 transgenic mouse hyperlipidemia animal model.

[1075] 2 Experimental instruments and reagents

[1076] 2.1 Instruments

[1077] Refrigerator (BCD-268TN, Haier)

[1078] Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[1079] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd. )

[1080] 5 mL pipette (Research Plus, Eppendorf)

[1081] 1 mL pipette (Research Plus, Eppendorf)

[1082] Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[1083] Centrifuge (Centrifuge 5720R, Eppendorf)

[1084] Electronic balance (CPA2202S, Sartorius)

[1085] Electronic balance (BSA2202S-CW, Sartorius)

[1086] Ultrasonic cleaner (115F0032, Shanghai Kedao)

[1087] Water purifier (Pacific TII, Thermo)

[1088] Magnetic stirrer (08-2G, Chijiu)

[1089] Fully automatic blood biochemistry analyzer (Hitachi 7180 model, HITACHI)

[1090] 2.2 Reagents

[1091] High-fat diet (Western Diet, D12079B)

[1092] Normal saline (MA0083-D, meilunbio)

[1093] Solutol HS 15 (102483882, Sigma)

[1094] 2.3 Test drug: Compound of the present invention, homemade

[1095] 3 Experimental operation and data processing

[1096] 3.1 Animals

[1097] B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[1098] 3.2 Animal Model

[1099] After the animals arrived at the barrier system, they were acclimated for 1 week and then started to be fed a high-fat diet. The animals were weighed and their food intake was recorded once a week.

[1100] 3.3 Grouping and Dosing

[1101] a. Grouping was done by random grouping.

[1102] c. According to the grouping results, the test drug was started (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once / day or single administration; administration cycle: 21 days; solvent: 10% Solutol HS 15 / 90% Saline).

[1103] d. After the start of the test drug administration, the animals were weighed and fed twice a week, and blood was collected once a week.

[1104] e. Data were processed using Excel or other software. Body weight change (BWC) (%) = (weight at the end of treatment - weight at the start of treatment) / weight at the start of treatment × 100%; food intake (g / mice / day) = (previous feed addition + previous feed remainder - current feed remainder) / number of animals / number of feeding days; Calculation of blood biochemical inhibition rate: Using the blood biochemical results of the vehicle group tested in the same batch as the baseline, the data of each treatment group were normalized, and the percentages of TC and LDL-C were calculated according to the following formulas: TC percentage change (%) = (post-dose TC value - pre-dose TC value) / pre-dose TC value × 100%; LDL-C percentage change (%) = (post-dose LDL-C value - pre-dose LDL-C value) / pre-dose LDL-C value × 100%. Plasma PCSK9 was detected by ELISA.

[1105] 4 Experimental results:

[1106] 5. Experimental conclusion:

[1107] The example compounds shown in the present invention can effectively reduce LDL-C in the B6-hPCSK9 transgenic mouse hyperlipidemia animal model.

Claims

1. A compound represented by the general formula (I-1) or a stereoisomer or pharmaceutically acceptable salt thereof Where ring B is selected from Ra is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C3-8 cycloalkyl; Rb is selected from hydrogen, deuterium, or hydroxyl; Rc is selected from hydrogen, deuterium or halogen; Rd is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 deuteroalkyl or C1-6 haloalkyl; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; z is 0, 1, 2, or 3; e is equal to 0, 1, 2, or 3.

2. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further represented by the general formula (V) where 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. A compound or stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Ra is selected from hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 haloalkyl or C3-6 cycloalkyl; Rd is selected from hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 deuteroalkyl or C1-3 haloalkyl.

4. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound is selected from the following compounds:

5. A compound represented by the general formula (VI) or a stereoisomer or pharmaceutically acceptable salt thereof Where X is amino, halogen, boronic acid or boronate and each of the other groups is as defined in paragraph 2.

6. A compound represented by the general formula (VI-3), or a stereoisomer or pharmaceutically acceptable salt thereof Where X2 is amino, halogen, boronic acid, or boronate; M5 represents N and each of the other groups is as defined in paragraph 2.

7. A method for producing a compound represented by the general formula (V) according to claim 2, wherein the method comprises the following step: Where X3 is a halogen, boronic acid, or boronate; R11 is selected from hydrogen, an amino protecting group, a 5-6-membered heteroaryl, and a 5-6-membered heterocyclyl, wherein the 5-6-membered heteroaryl and 5-6-membered heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuteroalkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12-membered heterocyclyl, C6-14 aryl, and 5-14-membered heteroaryl; the protecting group for the amino group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl-2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; providing a reaction of a compound of general formula (VI-2) with a compound of general formula (VI-4) to obtain a compound of general formula (V).

8. A method for producing a compound represented by the general formula (V) according to claim 2, wherein the method comprises the following step: Where X4 represents a formaldehyde group, hydroxymethyl or halomethyl; R12 is selected from C1-6alkyl, C1-6deuteroalkyl or C1-6haloalkyl; providing a reaction of a compound of general formula (VI-3) with a compound of general formula (VI-5) to obtain a compound of general formula (V) and each of the other groups is as defined in paragraph 7.

9. A pharmaceutical composition containing a therapeutically effective dose of a compound of general formula (I-1) and its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. The use of a compound of general formula (I-1) and its stereoisomer or pharmaceutically acceptable salt according to any of claims 1 to 4 or a pharmaceutical composition according to claim 9 in the production of a medicinal product which is a PCSK9 inhibitor.

11. The use of a compound of general formula (I-1) and its stereoisomer or pharmaceutically acceptable salt according to any of claims 1 to 4 or a pharmaceutical composition according to claim 9 in the production of a medicinal product that lowers LDL levels.

12. The use of a compound of general formula (I-1) and its stereoisomer or pharmaceutically acceptable salt according to any of claims 1 to 4 or a pharmaceutical composition according to claim 9 in the preparation of a medicinal product for the treatment of cardiovascular disease, cerebrovascular disease, atherosclerosis and / or a disease associated therewith or a symptom thereof.

13. The use of a compound of general formula (I-1) and its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 9 in the preparation of a medicinal product for hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, abnormal change in lipoprotein levels, atherosclerosis, liver steatosis, metabolic syndrome and / or coronary artery disease.

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