Cyclopentane derivative-containing inhibitor as well as preparation method and application thereof

Abstract

The invention relates to an inhibitor containing cyclopentane derivatives as well as a preparation method and application of the inhibitor. Particularly, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound as an inhibitor in treatment of cardiovascular diseases, cerebrovascular diseases and other diseases, and substituents in the general formula (I) are as defined in the specification. # imgabs0 #

Description

[0001] This application claims priority to Chinese patent application 2023108187585 with an application date of 2023 / 07 / 04, Chinese patent application 2023110111090 with an application date of 2023 / 08 / 10, Chinese patent application 2023112278017 with an application date of 2023 / 09 / 21, Chinese patent application 2023115526771 with an application date of 2023 / 11 / 17, Chinese patent application 2024100528285 with an application date of 2024 / 01 / 12, Chinese patent application 2024101732814 with an application date of 2024 / 02 / 06, Chinese patent application 2024104079374 with an application date of 2024 / 04 / 03, and Chinese patent application 2024104260552 with an application date of 2024 / 04 / 09. This application cites the full text of the above-mentioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of drug synthesis, and in particular relates to a cyclopentane derivative-containing 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 can lower serum LDL-C and are currently the mainstay of lipid-lowering therapy in clinical practice, patients who are intolerant to statins or who fail to achieve treatment goals at tolerated doses remain at risk, such as those with familial hypercholesterolemia. The discovery of PCSK9 inhibitors offers a more aggressive approach for patients with homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when combined with a statin, can reduce LDL-C by 15%-20%, while the combination of a PCSK9 inhibitor and a statin can significantly reduce LDL-C by 54%-74%. PCSK9 inhibitors can also overcome intolerable side effects of statins, such as muscle pain.

[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 was shown to reduce the risk of CHD and mortality by 44%. However, in many cases, LDL-C reduction is considered insufficient. The counteracting mechanism of statins is upregulation of sterol regulatory element binding protein 2 (SREBP-2), which activates the LDL receptor and PCSK9. This increases PCSK9 expression and secretion, which binds to the LDLR and leads to elevated LDL-C levels. Therefore, while statins lower LDL cholesterol by inhibiting HMG-CoA, they counteract the effects of SREPB. Adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatment approaches such as PCSK9 inhibitors are needed.

[0007] Alirocumab and evolocumab, monoclonal antibody-based macromolecular PCSK9 inhibitors, 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, is currently on the market. It reduces PCSK9 protein expression, resulting in long-term lipid-lowering effects and 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. Summary of the Invention

[0009] 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:

[0010]

[0011] in:

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

[0013] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0014] L1 is selected from a bond, -(CH2) n -、-(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CH2) n1-, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa (CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n C(O)NR aa R bb -, -(CH2) n NR cc C(O)R dd -, -(CH2) n S(O) m NR aa R bb - and -(CH2) n NR cc S(O) m R dd -;

[0015] R aa 、R bb 、R cc 和R ddeach independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0016] Alternatively, any two adjacent or non-adjacent substituents are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted;

[0017] Preferably, 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 RA3 or -(CH2) n NR A2 S(O) m R A3 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0019] 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;

[0020] 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;

[0021] R b is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 RB3 、-(CH2) n C(O)NR B2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0022] 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;

[0023] 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;

[0024] Preferably,

[0025] 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 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0026] Rc 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;

[0027] 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;

[0028] 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;

[0029] 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;

[0030] 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;

[0031] 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;

[0032] 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;

[0033] x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; z is 0, 1, 2, or 3; e is 0, 1, 2, or 3; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; n1 is 0, 1, 2, 3, or 4; n2 is 0, 1, 2, 3, or 4; n3 is 0, 1, 2, 3, or 4; n4 is 0, 1, 2, 3, or 4; and

[0034] The compound is not

[0035] In a preferred embodiment of the present invention, the compound is further represented by formula (IA):

[0036]

[0037] in:

[0038] Ring A is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from 5-membered nitrogen-containing heteroaryl, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl;

[0039] Ring B is selected from C 3-8Cycloalkyl, 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered and 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered and 5-membered bicyclic nitrogen-containing heterocyclic group or 6-membered and 6-membered bicyclic nitrogen-containing aryl group;

[0040] R c-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1R 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;

[0041] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; preferably, R c-1 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0042] Or, R c-1 Preferably selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2)n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4Alkynyl, 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;

[0043] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0044] Preferably, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0045] Rc-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 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, C1-3 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;

[0046] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0047] Preferably, R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0048] R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)ORC3 、-(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;

[0049] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 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;

[0050] Preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0051] More preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0052] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; and

[0053] The compound is not

[0054] Preferably, ring A is not The other groups are as described above.

[0055] In a preferred embodiment of the present invention, the compound is further represented by general formula (II):

[0056]

[0057] in:

[0058] Ring A is selected from heterocyclic groups or heteroaryl groups, and Ring A is not

[0059] L1 is selected from a bond, -(CH2) n -、-(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CH2) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n O(CR aa R bb ) n1 -、-(CR aa R bb ) n3 S(CH2) n4 -、-(CH2) n S(CR aa R bb ) n3 -、-(CR aa R bb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-、-(CH2) n P(O) pR aa -、-(CH2) n S(O) m -、-(CH2) n C(O)NR aa R bb -、-(CH2) n NR cc C(O)R dd -、-(CH2) n S(O) m NR aa R bb - and -(CH2) n NR cc S(O) m R dd -;

[0060] R aa 、R bb、 R cc and R dd each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0061] Alternatively, any two adjacent or non-adjacent substituents are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted;

[0062] Preferably, L1 is selected from a bond, -C(O)- or -C(O)NH-;

[0063] 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 RA1 、-(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 1-3Alkoxy, 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;

[0064] 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, C1-6 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;

[0065] Preferably,

[0066] 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 of aryl and 5-10 membered heteroaryl;

[0067] R A1 ~R A3are 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;

[0068] 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, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C2-6 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;

[0069] 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;

[0070] 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 1-6Hydroxyalkyl, 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;

[0071] 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;

[0072] Preferably,

[0073] 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, 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;

[0074] 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;

[0075] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, 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, C1-6 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;

[0076] 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 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0077] 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 C1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0078] R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0079] Preferably,

[0080] 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, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0081] 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;

[0082] 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, C1-6 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 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;

[0084] x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; n4 is 0, 1, 2, 3 or 4.

[0085] In a preferred embodiment of the present invention, the compound is further represented by formula (III), (III-1) or (III-2):

[0086]

[0087] in:

[0088] Ring E is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group or 6-membered nitrogen-containing heteroaryl group;

[0089] M1 is selected from N or CH;

[0090] M2 is selected from N or CH;

[0091] M3 is selected from N or CH;

[0092] M4 is selected from N or CH;

[0093] M6 is selected from N or CH; and

[0094] M7 is selected from N or CH;

[0095] The other groups are as described above.

[0096] 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;

[0097] Preferably, ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl;

[0098] More preferably, ring A is selected from 5-12 membered monocyclic heteroaryl, 8-12 membered bicyclic heteroaryl;

[0099] 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;

[0100] More preferably, ring A is selected from 5-membered heteroaryl, 7-membered heteroaryl; preferably pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl, Further preferably, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazole, oxazolyl,

[0101] Alternatively, ring A is selected from pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl Preferably pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl or pyridazinyl;

[0102] 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

[0103] Further selected from

[0104] Further selected from

[0105] In a preferred embodiment of the present invention, the compound is further represented by formula (IA), (IB), (IC), (ID), (IE) or (IF):

[0106]

[0107] in:

[0108] M1 is selected from N or CR1;

[0109] M2 is selected from N or CR2;

[0110] M3 is selected from N or CR3;

[0111] M4 is selected from N, O, S or CR4;

[0112] Preferably, at least one heteroatom is present in M1, M2, M3 and M4;

[0113] R1 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, -(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 of aryl and 5-10 membered heteroaryl;

[0114] 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, C1-6 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;

[0115] Alternatively, any two adjacent or non-adjacent R1s are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups 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 6-14substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0116] R2 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, -(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, C2-6 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;

[0117] 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 6-14Aryl 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;

[0118] Alternatively, any two adjacent or non-adjacent R2 groups are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thioxo, 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] R3 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, -(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, 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;

[0120] R c1 ~R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, 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;

[0121] Alternatively, any two adjacent or non-adjacent R3 groups are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups 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;

[0122] R4 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, -(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 of aryl and 5-10 membered heteroaryl;

[0123] 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, C1-6 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;

[0124] Alternatively, any two adjacent or non-adjacent R4 groups are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thioxo, 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;

[0125] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4.

[0126] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1') or (I-2'):

[0127]

[0128] in:

[0129] Ring B is absent; or is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0130] Preferably, ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0131] L1 is selected from a bond, -(CH2) n -、-(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CH2) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n O(CR aa R bb ) n1 -、-(CR aa R bb ) n3 S(CH2) n4 -、-(CH2) n S(CR aa R bb ) n3 -、-(CR aa R bb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-、-(CH2) n P(O) p R aa -、-(CH2) nS(O) m -、-(CH2) n C(O)NR aa R bb -、-(CH2) n NR cc C(O)R dd -、-(CH2) n S(O) m NR aa R bb - and -(CH2) n NR cc S(O) m R dd -;

[0132] R aa 、R bb 、R cc and R dd each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0133] Alternatively, any two adjacent or non-adjacent substituents are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl or heteroaryl group may be further substituted;

[0134] Preferably, L1 is selected from a bond, -C(O)-, -C(O)NH-, -C(O)NCH3- or -C(O)N(CH3)2;

[0135] M5 is selected from N or CR5;

[0136] 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, C1-6 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;

[0137] 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 RA1 、-(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 1-3Alkyl, 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;

[0138] 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 6-14Aryl 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;

[0139] 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, 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;

[0140] 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) nOR 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, C1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0141] 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 2-6 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;

[0142] Or, any two adjacent or non-adjacent R bThe 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;

[0143] 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, 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;

[0144] 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, C6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0145] 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;

[0146] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, 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 3-12Cycloalkyl, 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;

[0147] 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 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0148] 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 RD1 、-(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, C1-3 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;

[0149] 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 1-6Halogenated 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;

[0150] 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;

[0151] 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 1-6Alkoxy, 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;

[0152] x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; z is 0, 1, 2 or 3; e is 0, 1, 2 or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4.

[0153] 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), (I-5), (I-6) or (I-7):

[0154]

[0155] The groups are as described above.

[0156] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1-a), (I-2-a) or (I-4-a):

[0157]

[0158] in:

[0159] R a-1 ~R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)RA1 、-(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, C2-4 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;

[0160] 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, C2-6 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;

[0161] m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n1 is 0, 1, 2, 3 or 4;

[0162] The other groups are as described above.

[0163] In a more preferred embodiment of the present invention, the ring B 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;

[0164] 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;

[0165] 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;

[0166] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0167] Further preferably, ring B is selected from pyridine, pyrimidine, pyridone or pyrimidone;

[0168] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0169] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0170] More preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0171] In a preferred embodiment of the present invention, the compound is further represented by the general formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G) or (III-H):

[0172]

[0173]

[0174] in:

[0175] Ring D is selected from 5-12 membered heterocyclic groups or 5-12 membered heteroaryl groups, wherein the 5-12 membered heterocyclic groups and 5-12 membered heteroaryl groups may be further substituted with 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 or 5-14 membered heteroaryl is substituted with one or more substituents;

[0176] The other groups are as described above.

[0177] In a preferred embodiment of the present invention, the compound is further represented by the general formula (IA-1), (I-1-a'), (I-2-a'), (I-4-a') or (III-2-1):

[0178]

[0179] The other groups are as described above.

[0180] 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, C2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0181] R A1 ~RA3 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;

[0182] Preferably, 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, C3-8 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, C1-3 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;

[0183] 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 6-10substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0184] More preferably,

[0185] R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0186] More preferably,

[0187] R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0188] More preferably,

[0189] R a Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3-CHF2, -CF3, -CH2-OH, -CH2- CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2,

[0190]

[0191] In a further preferred embodiment of the present invention, the R a-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-4 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, C1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 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;

[0192] R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C1-3 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;

[0193] Preferably,

[0194] R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0195] More preferably,

[0196] R a-1 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0197] In a further preferred embodiment of the present invention, the R a-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2) n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0198] 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;

[0199] Preferably,

[0200] R a-2 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0201] More preferably,

[0202] R a-2 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0203] In a further preferred embodiment of the present invention, the R a-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R A1 、-(CH2) n OR A1 、-(CH2) n C(O)R A1 、-(CH2)n C(O)OR A1 、-(CH2) n S(O) m R A1 、-(CH2) n NR A2 R A3 、-(CH2) n NR A2 C(O)OR A3 、-(CH2) n NR A2 C(O)(CH2) n1 R A3 、-(CH2) n NR A2 C(O)NR A2 R A3 、-(CH2) n C(O)NR A2 (CH2) n1 R A3 、-OC(R A1 R A2 ) n (CH2) n1 R A3 or -(CH2) n NR A2 S(O) m R A3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-8 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;

[0204] 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, C3-8 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;

[0205] Preferably,

[0206] R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0207] More preferably,

[0208] R a-3 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0209] In a further preferred embodiment of the present invention, the R a-4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 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 C1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0210] 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, C1-3 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;

[0211] Preferably,

[0212] R a-4 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CD3, -CH2-OH, -CH2-C HF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0213] More preferably,

[0214] R a-4Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2 , -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3,

[0215] In a further preferred embodiment of the present invention, the R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)NRB2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0216] R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-12 membered heteroaryl group are substituted by one or more substituents.

[0217] In a further preferred embodiment of the present invention, the R a and R b The 5-12 membered heterocyclic group or 5-12 membered heteroaryl group is linked to form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group may be further substituted with deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 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.

[0218] 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, C2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C1-3 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;

[0219] R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0220] Preferably,

[0221] R c Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0222] More preferably,

[0223] R c Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0224] In a further preferred embodiment of the present invention, the R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-12 membered heteroaryl groups may be further substituted, and may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 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 1-3Alkyl, 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;

[0225] 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 6-10Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0226] Preferably,

[0227] 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, 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;

[0228] 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 1-3Deuterated 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 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;

[0229] More preferably,

[0230] R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CD3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0231] More preferably,

[0232] R dSelected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH,

[0233]

[0234] More preferably,

[0235] R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH,

[0236] In a further preferred embodiment of the present invention, the compound Selected from

[0237] In a further preferred embodiment of the present invention, the compound Selected from where R c-1 、R c-2 and R c-3 The definition is the same as R c Preferably, R c-1 、R c-2 and R c-3 The definition of R is as above c-1 、R c-2 and R c-3 Definition of .

[0238] The present invention further provides a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0239]

[0240] in:

[0241] X2 is amino, nitro, halogen, boronic acid or boric acid ester;

[0242] The other groups are as described above.

[0243] In a further preferred embodiment of the present invention, the compound is selected from:

[0244]

[0245] The present invention further provides a method for preparing the compound represented by general formula (IA), comprising the following steps:

[0246]

[0247] in:

[0248] X3 is hydroxy, amino, methylthio, halogen, boric acid or boric acid ester;

[0249] The compound of formula (IV) reacts with the compound of formula (IV-1) to obtain the compound of formula (IA);

[0250] The other groups are as described above.

[0251] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0252] The present invention further relates to the use of any compound of the general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of PCSK9 inhibitor drugs.

[0253] The present invention further relates to the use of any compound of the general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of LDL-lowering drugs; preferably, the LDL is LDL-C.

[0254] The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms; preferably, in the preparation of a drug for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0255] The present invention further relates to the use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a method for treating cardiovascular disease, cerebrovascular disease, atherosclerosis and / or related diseases or their symptoms, preferably in preparing a method for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0256] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0257] Furthermore, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0258] 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.

[0259] 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.

[0260] Detailed Description of the Invention

[0261] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0266] wait;

[0267] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0268] wait.

[0269] 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:

[0270] wait.

[0271] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0272]

[0273] 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.

[0274] 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.

[0275] 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.

[0276] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0277]

[0278] wait.

[0279] 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:

[0280]

[0281] wait.

[0282] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0283]

[0284] wait.

[0285] 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:

[0286]

[0287] wait.

[0288] 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.

[0289] 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.

[0290] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0291]

[0292] wait.

[0293] 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.

[0294] 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.

[0295] 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:

[0296]

[0297] 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:

[0298]

[0299] wait.

[0300] 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.

[0301] 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.

[0302] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0303] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0304] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0305] "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.

[0306] "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.

[0307] 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.

[0308] "Hydroxy" refers to an -OH group.

[0309] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0310] "Amino" refers to -NH2.

[0311] "Cyano" refers to -CN.

[0312] "Nitro" refers to -NO2.

[0313] "Carbonyl" refers to -C(O)-.

[0314] "Carboxyl" refers to -C(O)OH.

[0315] "THF" refers to tetrahydrofuran.

[0316] "EtOAc" refers to ethyl acetate.

[0317] "MeOH" refers to methanol.

[0318] "DMF" refers to N,N-dimethylformamide.

[0319] "DIPEA" refers to diisopropylethylamine.

[0320] "TFA" refers to trifluoroacetic acid.

[0321] "MeCN" refers to acetylene glycol.

[0322] "DMA" refers to N,N-dimethylacetamide.

[0323] "Et2O" refers to diethyl ether.

[0324] "DCE" refers to 1,2-dichloroethane.

[0325] "DIPEA" refers to N,N-diisopropylethylamine.

[0326] "NBS" refers to N-bromosuccinimide.

[0327] "NIS" refers to N-iodosuccinimide.

[0328] "Cbz-Cl" refers to benzyl chloroformate.

[0329] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0330] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0331] "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0332] "KHMDS" refers to potassium hexamethyldisilazide.

[0333] "LiHMDS" refers to lithium bis(trimethylsilylamide).

[0334] "MeLi" refers to methyllithium.

[0335] "n-BuLi" refers to n-butyllithium.

[0336] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0337] 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.

[0338] The enol structure and the lactam structure in the compound of the present invention are tautomers, and those skilled in the art should know that they are the same molecule. for the same molecule.

[0339] 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.

[0340] "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.

[0341] "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.

[0342] 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.

[0343] "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

[0344] 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.

[0345] Example

[0346] 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).

[0347] 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).

[0348] 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.

[0349] The compound of the present invention has significant advantages in drugability such as solubility, permeability, and safety.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] Unless otherwise specified, in the examples of the present invention, the ratios of the mobile phases in the HPLC chiral separation conditions and HPLC chiral analysis conditions are volume ratios.

[0354] Intermediate 1

[0355] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0356]

[0357] Referring to the preparation method of patent WO2020150473A2, intermediate 1 was synthesized.

[0358] MS m / z(ESI):245.1[M+H] + .

[0359] Intermediate 1 can also be obtained by the following method:

[0360]

[0361] Step 1: Dissolve 2-chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) in dimethyl sulfoxide (10 mL). Heat the reaction mixture to 100°C and stir for 5 hours. Cool the reaction mixture to room temperature, pour it into water (50 mL), and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to obtain tert-butyl (1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylcarboxylate 1B (2.1 g) in a yield of 55.1%. MS m / z(ESI):345.2[M+H] + .

[0362] Step 2: 1B (2.1 g, 6.1 mmol) was dissolved in methanol (10 mL), and a solution of hydrochloric acid in dioxane (4 M, 20 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and ammonia methanol solution (7 M, 10 mL) was added to adjust the pH to a weak alkaline state. After further concentration, the residue was purified by silica gel chromatography (elution system A) to obtain (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g), yield: 87.3%. MS m / z (ESI): 245.1 [M+H] + .

[0363] Intermediate 2

[0364] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0365]

[0366] Step 1: Dissolve 2-fluoro-5-iodopyridine 2A (5 g, 22.4 mmol), 2-hydroxypyridine (2.35 g, 24.7 mmol), cuprous iodide (427 mg, 2.24 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (159 mg, 1.12 mmol), and cesium carbonate (9.5 g, 29.2 mmol) in 1,4-dioxane (75 mL). Heat the reaction to 100°C and stir for 16 hours. Cool the reaction mixture to room temperature, pour it into 100 mL of water, and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to afford 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (3.1 g) in a 72.7% yield. MS m / z (ESI): 191.1 [M+H] + .

[0367] Step 2: Dissolve tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridyl]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 130°C and stir for 16 hours. Cool the reaction mixture to room temperature, pour it into water (100 mL), and extract the aqueous phase with ethyl acetate (100 mL x 2). The organic phases were combined, washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried, and concentrated. The residue was purified by silica gel chromatography (elution system B) to afford tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g) in a 78.4% yield. MS m / z (ESI): 371.2 [M+H] + .

[0368] Step 3: Dissolve tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridyl]-6'-yl)amino)cyclopentyl)carbamate 2C (2.9 g, 7.83 mmol) in 4 M hydrochloric acid in dioxane (30 mL) and stir at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse phase chromatography (eluent system C) to afford 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one intermediate 2 (1.5 g) in a 70.9% yield. MS m / z (ESI): 271.2 [M+H] + .

[0369] Example 1

[0370] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0371] Example 1 can also be obtained in the following manner:

[0372]

[0373] Step 1: Under nitrogen, 1a (10.00 g, 51.55 mmol), bis-pinacol boronate (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), heated to 90°C, and stirred for 3 hours. The reaction mixture was filtered, and the organic phase was concentrated to obtain crude (5,6-difluoro-3-pyridyl)boronic acid 1b (7.60 g), which was used directly in the next reaction without purification. MS m / z (ESI): 160.0 [M+H] + .

[0374] Step 2: Dissolve 1b (6.00 g, 37.76 mmol) and hydrogen peroxide (12.84 g, 113.28 mmol, 30% aqueous solution) in 1,4-dioxane (100 mL) and stir at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 5,6-difluoro-3-hydroxypyridine 1c (3.20 g) in a yield of 64.6%. MS m / z (ESI): 132.0 [M+H] + .

[0375] Step 3: Dissolve 1c (5.00 g, 38.14 mmol) and cesium carbonate (18.60 g, 57.22 mmol) in N,N-dimethylformamide (30 mL) at room temperature and stir for 30 minutes. Under nitrogen protection, sodium 2-chloro-2,2-difluoroacetate (11.90 g, 76.29 mmol) was added to the reaction solution and heated to 90°C and stirred for 3 hours. The reaction solution was diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with water (50 mL) and saturated sodium chloride (50 mL). The organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 5-(difluoromethoxy)-2,3-difluoropyridine 1d (2.60 g) with a yield of 37.6%. MS m / z (ESI): 182.0 [M+H] + .

[0376] Step 4: Referring to the synthetic method of Intermediate 1, step 1, 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 1 was synthesized. MS m / z (ESI): 432.2 [M+H] + .

[0377] 1H 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).

[0378] Example 4

[0379] 6'-(((1S,3S)-3-((6-(difluoromethoxy)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0380]

[0381] Step 1: 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). The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, 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 afford 6-(difluoromethoxy)-1,2,4-triazin-3-amine 4b (430 mg) in a 29.7% yield. MS m / z (ESI): 163.0 [M+H] + .

[0382] Step 2: 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). The reaction mixture was heated to 70°C and stirred 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 afford 3-chloro-6-(difluoromethoxy)-1,2,4-triazine 4c (260 mg) in a 54.0% yield. MS m / z (ESI): 182.0 [M+H] + .

[0383] Step 3: 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). The reaction mixture was heated to 80°C and stirred for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, and the organic phase was washed 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 obtain 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 yield of 30.1%. MS m / z(ESI):416.2[M+H] + .

[0384] Example 12

[0385] 6'-(((1S,3S)-3-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0386]

[0387] Step 1: Dissolve 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) in 1,2-dichloroethane (20 mL). Heat the reaction to 80°C and stir for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was 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 3-chloro-1-cyclopropyl-1H-1,2,4-triazole 12b (340 mg) in a 24.5% yield. MS m / z (ESI): 144.0 [M+H] + .

[0388] Step 2: 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'-bipyridyl]-2-one 12 was synthesized. MS m / z (ESI): 378.2 [M+H] + .

[0389] 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).

[0390] Example 15

[0391] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0392]

[0393] Step 1: 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 mixture was cooled to room temperature, and ethyl acetate (50 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 silica gel chromatography (elution system B) to provide 3-chloro-5-(difluoromethoxy)-1,2,4-thiadiazole 15b (130 mg) in a yield of 28.1%. MS m / z (ESI): 187.0 [M+H] + .

[0394] Step 2: 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. MS m / z (ESI): 421.1 [M+H] + .

[0395] Example 20

[0396] 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0397]

[0398] Step 1: 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). The reaction mixture was heated to 110°C and stirred 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%. MS m / z(ESI):388.2[M+H] + .

[0399] 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).

[0400] Example 22

[0401] 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0402] Example 22 can also be synthesized by the following method:

[0403]

[0404] Step 1: Dissolve tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1.0 g, 4.99 mmol) and 4-methoxybenzaldehyde (816 mg, 5.99 mmol) in methanol (10 mL). Add acetic acid (300 mg, 4.99 mmol) with stirring. The reaction is stirred at 17°C for 16 hours. Sodium cyanoborohydride (941 mg, 14.98 mmol) is added to the reaction mixture, and the reaction is stirred for 1 hour. The reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (elution system C) to give tert-butyl ((1S,3S)-3-((4-methoxybenzyl)amino)cyclopentyl)carbamate 22a (1.2 g) in a 75% yield. MS m / z (ESI): 321.3 [M+H] + .

[0405] Step 2: Dissolve 22a (1.3 g, 4.06 mmol), cyanogen bromide (645 mg, 6.09 mmol), and N,N-diisopropylethylamine (1.0 g, 8.11 mmol) in tetrahydrofuran (10 mL) and add with stirring. The reaction mixture 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 give tert-butyl ((1S,3S)-3-(N-(4-methoxybenzyl)cyanamido)cyclopentyl)carbamate 22b (1.2 g) in an 85.6% yield. MS m / z (ESI): 346.1 [M+H] + .

[0406] Step 3: 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 give tert-butyl ((1S,3S)-3-((E)-2-hydroxy-1-(4-methoxybenzyl)guanidino)cyclopentyl)carbamate 22c (1.0 g) in a yield of 79.4%. MS m / z (ESI): 379.2 [M+H] + .

[0407] Step 4: Dissolve 2,2-difluorocyclopropane-1-carboxylic acid (419 mg, 3.43 mmol) and carbonyldiimidazole (557 mg, 3.43 mmol) in N,N-dimethylformamide (10 mL) at room temperature and stir for 0.5 h. Dissolve 22c (1.0 g, 2.64 mmol) in N,N-dimethylformamide (2 mL) and add the resulting mixture dropwise to the reaction mixture. Stir the mixture at room temperature for 1 h, then heat to 100°C and stir 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. MS m / z (ESI): 465.3 [M+H] + .

[0408] Step 5: 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 give (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. MS m / z (ESI): 245.2 [M+H] + .

[0409] Step 6: 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). The reaction mixture was heated to 130°C and stirred for 16 hours. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (ammonium carbonate system) to give 6'-(((1S,3S)-3-((5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 22 (13.5 mg) in a 13.1% yield. MS m / z (ESI): 415.1 [M+H] + .

[0410] 1H 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).

[0411] Example 26

[0412] 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

[0413] Example 26 can also be synthesized by referring to the following preparation method:

[0414]

[0415] Step 1: 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) at 25°C and stirred for 48 hours. The reaction mixture was filtered and the filtrate 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. MS m / z (ESI): 139.2 [M+H] + .

[0416] Step 2: Dissolve copper bromide (711.0 mg, 3.18 mmol) and tert-butyl nitrite (820.9 mg, 7.96 mmol) in acetonitrile (6 mL). Add 26b (220 mg, 1.59 mmol) with stirring. The reaction mixture was stirred at room temperature for 0.5 h, then heated to 60°C and stirred for 1 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL) and filtered. The organic phase was washed with water (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system C) to afford 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine 26c (200 mg) in a 62.2% yield. MS m / z (ESI): 204.0 [M+H]+ .

[0417] Step 3: 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. MS m / z (ESI): 392.2 [M+H] + .

[0418] 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).

[0419] Example 27

[0420] 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

[0421]

[0422] Step 1: Dissolve 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 27a (100 mg, 0.657 mmol) in acetonitrile under ice and stir. Add sodium nitrite (91 mg, 1.31 mmol) to the reaction mixture and continue stirring for 1 minute. Add hydrochloric acid (4 M, 0.41 mL) dropwise to the reaction mixture. Warm the reaction mixture to room temperature and continue stirring. Completion of the reaction is confirmed by thin-layer chromatography. Add saturated sodium bicarbonate solution dropwise to pH 7. The reaction mixture is extracted with dichloromethane (10 mL x 3). The organic phase is dried and concentrated. The residue is isolated 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 77.5% yield. MS m / z (ESI): 172.1 [M+H]. + .

[0423] Step 2: 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.

[0424] The second step can also be synthesized by referring to the following method:

[0425] 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 solution was heated to 130°C and microwaved for 2 hours. The reaction solution was then heated to 130°C under nitrogen for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC (basic system) to give 6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 27 (6.6 mg) in a 4.08% yield. MS m / z (ESI): 406.2 [M+H] + .

[0426] 1H NMR(400MHz,DMSO-d6)δ8.69–6.59(m,1H),7.92(d,1H),7.60(dd,1H),7.51–7.35(m,2H),7.27(dd,1H),6.97–6.82(m,2H),6.74(d,1H) ,6.52(d,1H),6.44(d,1H),6.26(t,1H),4.35–4.28(m,1H),4.20–4.10(m,1H),2.20–2.07(m,2H),2.00–1.82(m,2H),1.60–1.42(m,2H).

[0427] Example 38

[0428] 6'-(((1S,3S)-3-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0429] Example 38 can also be synthesized by the following method:

[0430]

[0431] Step 1: 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. MS m / z (ESI): 407.2 [M+H] + .

[0432] Step 2: Under nitrogen, 38b (35 mg, 0.086 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 0°C. Methylmagnesium bromide (1 M, 2 mL) in tetrahydrofuran was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched with methanol and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate) to afford the desired product (9 mg) in a 25.7% yield. MS m / z (ESI): 407.2 [M+H]+.

[0433] 1H 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).

[0434] Example 47

[0435] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-quinolin-4-one

[0436]

[0437] Step 1: 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. MS m / z (ESI): 241.1 [M+H] + .

[0438] Step 2: 3-(6-Fluoropyridin-3-yl)-4H-quinolinazin-4-one 47b (100 mg, 0.416 mmol), intermediate 1 (102 mg, 0.416 mmol), and N,N-diisopropylethylamine (207 μL, 1.25 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 130°C and stirred for 24 hours. The reaction solution was purified by preparative HPLC (formic acid system) to give the 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. MS m / z (ESI): 465.2 [M+H] + .

[0439] 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).

[0440] Example 47 can also be obtained by the following synthesis method:

[0441]

[0442] Step 1: Dissolve 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) in a mixture of dioxane (1.5 mL) and water (0.15 mL). Heat the reaction to 90°C and stir 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 ethyl 3-(6-fluoropyridin-3-yl)-4-oxo-4H-quinoline-1-carboxylate 47d (110 mg) in 87% yield. MS m / z (ESI): 313.1 [M+H] + .

[0443] Step 2: Dissolve 47d (102 mg, 0.328 mmol), intermediate 1 (80 mg, 0.328 mmol), and N,N-diisopropylethylamine (143 μL, 0.819 mmol) in dimethyl sulfoxide (2 mL). Heat the reaction mixture to 130°C and stir for 24 hours. The reaction mixture was purified by preparative HPLC (formic acid system) to afford 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. MS m / z (ESI): 537.2 [M+H]. + .

[0444] Step 3: Dissolve 47e (35 mg, 0.065 mmol) in hydrochloric acid (12 M, 5 mL) and heat the reaction to 100°C with stirring for 1.5 hours. The reaction mixture was purified by preparative HPLC (formic acid system) to afford 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. MS m / z (ESI): 465.2 [M+H] + .

[0445] 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).

[0446] Example 52

[0447] (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

[0448] Example 52 can also be synthesized by the following method:

[0449]

[0450] Step 1: 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 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 purified 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. MS m / z (ESI): 214.1 [M+H]. + .

[0451] Step 2: 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%. MS m / z (ESI): 438.2 [M+H] + .

[0452] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,1H),8.24(s,2H),8.07-7.97(m,2H),7.63(d,1H),7.51(d,1H),7.29-7.23(m,1H),7.07(d,1H),7.2 2-6.85(m,1H),6.95(d,1H),6.68(d,1H),6.59(d,1H),4.47-4.23(m,2H),2.24-2.05(m,2H),1.99-1.84(m,2H),1.63-1.45(m,2H).

[0453] Example 53

[0454] (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

[0455]

[0456] Step 1: 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. MS m / z (ESI): 214.1 [M+H] + .

[0457] Step 2: Referring to the synthesis method of Step 2 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. MS m / z (ESI): 438.2 [M+H] + .

[0458] 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).

[0459] Example 56

[0460] 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

[0461]

[0462] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 1-methyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.78 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL). The reaction was heated to 100 ° C and stirred for 3 hours. The reaction mixture was returned to room temperature, and saturated sodium chloride solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 56b (1.4 g, light yellow solid) in a yield of 57.87%. MS m / z (ESI): 246.1 [M+H]. + .

[0463] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 1-(6-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 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 yield of 30.47%. MS m / z(ESI):470.1[M+H] + .

[0464] 1 H NMR(400MHz,DMSO-d6)δ8.24(s,2H),8.11(d,1H),8.01(d,1H),7.91(d,1H),7.57-7.45(m,2H),7.26-6.82(m,1H), 6.97(d,1H),6.59(d,1H),4.42-4.19(m,2H),3.40(s,3H),2.22-2.05(m,2H),1.95-1.82(m,2H),1.61-1.42(m,2H).

[0465] Example 57

[0466] 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

[0467]

[0468] Step 1: Under nitrogen protection, 2-fluoro-5-iodopyridine 56a (2.2 g, 9.87 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.59 g, 11.84 mmol), cuprous iodide (188 mg, 0.99 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (281 mg, 1.97 mmol) and potassium phosphate (4.19 g, 19.73 mmol) were dissolved in dimethyl sulfoxide (40 mL). 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%.

[0469] MS m / z(ESI):230.1[M+H] + .

[0470] Step 2: Intermediate 1 (70 mg, 0.29 mmol), 6-(6-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 57b (72 mg, 0.32 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was heated to 130°C and stirred for 48 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was separated by reverse phase preparative HPLC (formic acid system) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 57 (46 mg) in a yield of 35.4%. MS m / z(ESI):454.1[M+H] + .

[0472] 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).

[0473] Example 63

[0474] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0475] Example 63 can also be synthesized by the following method:

[0476]

[0477] Step 1: Dissolve 63a (3.5 g, 20 mmol) in acetonitrile (50 mL) and add tert-butyl nitrite (3.09 g, 30 mmol). Stir at room temperature for 30 minutes, then add 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 isolated 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. MS m / z (ESI): 237.9 [M+H] + .

[0478] Step 2: Dissolve 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) in dioxane (20 mL). Heat the reaction to 80°C and stir for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution. The organic phase was washed with water (30 mL x 3) and saturated sodium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to afford 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%. MS m / z (ESI): 358.1 [M+H].

[0479] Step 3: Dissolve 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) in dioxane (20 mL) and water (5 mL). Heat the reaction to 120°C and stir for 16 hours. The reaction mixture was filtered, and ethyl acetate (100 mL) was added. The organic phase was washed with water (30 mL x 3) and saturated sodium chloride, dried, and concentrated. The residue was isolated by silica gel column chromatography (eluent system B) to afford 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%. MS m / z (ESI): 320.2 [M+H] + .

[0480] Step 4: 63d (400 mg, 1.25 mmol) was dissolved in methanol (5 mL), 4 M hydrochloric acid dioxane solution (5 mL) was added, and 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%. MS m / z (ESI): 220.2 [M+H] + .

[0481] Step 5: 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. 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 obtain the desired product, 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 63 (26 mg), in a yield of 14.6%. MS m / z (ESI): 390.2 [M+H] + .

[0482] 1H 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).

[0483] Example 64

[0484] 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino]-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one

[0485] Example 64 can also be synthesized by the following method:

[0486]

[0487] Step 1: Following the synthesis method of Intermediate 2, Step 1, the target product 6'-fluoro-3-(2-hydroxypropan-2-yl)-2H-[1,3'-bipyridyl]-2-one 64b was synthesized. MS m / z (ESI): 249.1 [M+H] + .

[0488] Step 2: 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 with stirring 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. MS m / z (ESI): 473.2 [M+H] + .

[0489] 1H 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).

[0490] Example 68

[0491] 6'-(((1S,3S)-3-((7-fluoropyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one Example 68 can also be synthesized using the following method:

[0492]

[0493] Step 1: Dissolve 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) in acetonitrile (3 mL). The reaction was heated to 80°C in a microwave oven and stirred for 1 hour. The reaction solution was concentrated, and the residue was isolated by silica gel column chromatography (eluent system B) to afford 2-chloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine 68b (25 mg) in a 44.7% yield. MS m / z (ESI): 172.0 [M+H] + .

[0495] Step 2: 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). The reaction was heated to 100°C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (NH4 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. MS m / z (ESI): 406.2 [M+H] + .

[0496] 1H NMR(400MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.61(dd,1H),7.48(td,1H),7.40(dd,1H),7.16(d,1H),6.96(d,1H),6.67(t,1H ),6.53(d,1H),6.44(d,1H),6.37(t,1H),6.27(t,1H),4.34-4.19(m,2H),2.21-2.11(m,2H),2.03-1.85(m,2H),1.62-1.46(m,2H).

[0497] Example 75

[0498] 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

[0499] Example 75 can also be synthesized by the following method:

[0500]

[0501] Step 1: 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). The reaction mixture was heated to 80°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (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 step without further purification. MS m / z (ESI): 367.1 [M+H] + .

[0502] Step 2: 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 give 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. MS m / z (ESI): 337.2 [M+H] +.

[0503] Step 3: 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 mixture was heated to 55°C and stirred for 48 hours. Saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed, and concentrated. The residue was 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%. MS m / z (ESI): 454.1 [M+H]. + .

[0504] 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).

[0505] Example 76

[0506] 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

[0507]

[0508] Example 76 can also be synthesized using the following method: 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. MS m / z (ESI): 454.1 [M+H] + .

[0509] 1H 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).

[0510] Example 77

[0511] 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

[0512]

[0513] Example 77 can also be synthesized by the following method: 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. MS m / z (ESI): 454.1 [M+H] + .

[0514] 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).

[0515] Example 78

[0516] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0517] Example 78 can also be synthesized by the following method:

[0518]

[0519] Step 1: 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 afford 3-bromo-5-cyclopropyl-1,2,4-thiadiazole 78a (120 mg) in a 13.0% yield.

[0520] 1 H NMR (400MHz, CDCl3) δ2.41(m,1H),1.32(m,2H),1.29(m,2H).

[0521] Step 2: 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. MS m / z (ESI): 395.1 [M+H] + .

[0522] 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).

[0523] Example 82

[0524] N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide

[0525] Example 82 can also be synthesized by the following method:

[0526]

[0527] Step 1: 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 80.8% yield. MS m / z (ESI): 244.1 [M+H] + .

[0528] Step 2: Dissolve 82b (310 mg, 1.27 mmol) and lithium hydroxide (61 mg, 2.55 mmol) in a mixture of methanol (3 mL) and water (1 mL) at room temperature and stir for 3 hours. The reaction mixture was filtered, the filtrate concentrated, and the residue separated by preparative HPLC (formic acid system) to afford the title product, 2-(2-oxopyridin-1(2H)yl)methyl)benzoic acid 82c (190 mg), in a 65.0% yield. MS m / z (ESI): 230.1 [M+H] + .

[0529] Step 3: 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) at room temperature and stirred for 16 hours. The reaction mixture was concentrated, and the residue was separated by preparative HPLC (formic acid system) to afford N-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)-2-((2-oxopyridin-1(2H)-yl)methyl)benzamide 82 (40 mg) in a 49.3% yield. MS m / z (ESI): 456.2 [M+H] + .

[0530] 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).

[0531] Example 84

[0532] 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0533] Example 84 can also be synthesized by the following method:

[0534]

[0535] Step 1: 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. MS m / z (ESI): 216.1 [M+H]. + .

[0536] Step 2: 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). The reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL 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 concentrated. The residue was purified by reverse-phase C18 chromatography (elution system C) to afford 6'-(((1S,3S)-3-((5-cyclopropyl-1,2,4-thiadiazol-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 84 (79.1 mg) in a 61.8% yield. MS m / z (ESI): 442.1 [M+H] + .

[0537] 1 H 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).

[0538] Example 87

[0539] 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

[0540] Example 87 can also be synthesized by the following method:

[0541]

[0542] Step 1: Dissolve copper bromide (1.13 g, 5.06 mmol) and tert-butyl nitrite (1.74 g, 16.87 mmol) in acetonitrile (5 mL). Add 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine 87a (500 mg, 3.37 mmol) 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%. MS m / z (ESI): 214.0 [M+H]. + .

[0543] Step 2: 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. MS m / z(ESI):402.2[M+H] + .

[0544] 1H 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).

[0545] Example 88

[0546] 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

[0547] Example 88 can also be synthesized by the following method:

[0548]

[0549] Step 1: Dissolve copper bromide (1.10 g, 4.93 mmol) and tert-butyl nitrite (1.69 g, 16.43 mmol) in acetonitrile (5 mL). Add 6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 88a (500.00 mg, 3.29 mmol) 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). The residue was concentrated, 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. MS m / z(ESI):215.9[M+H] + .

[0550] Step 2: 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 yield of 7.23%. MS m / z (ESI): 406.1 [M+H] + .

[0551] 1 H 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).

[0552] Example 91

[0553] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,1-dioxoisothiazolidine

[0554] Example 91 can also be synthesized by the following method:

[0555]

[0556] Step 1: 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. MS m / z (ESI): 217.1 [M+H]. + .

[0557] Step 2: 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). The reaction mixture was heated to 125°C and stirred 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%. MS m / z (ESI): 441.1 [M+H] + .

[0558] 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).

[0559] Example 92

[0560] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,4-butane sultam

[0561]

[0562] Example 92 can also be synthesized by the following method:

[0563] 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-butane sultam 92 was synthesized. MS m / z (ESI): 455.2 [M+H] + .

[0564] 1 H 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).

[0565] Example 93

[0566] 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

[0567] Example 93 can also be synthesized by the following method:

[0568]

[0569] Step 1: 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%. MS m / z (ESI): 258.1 [M+H]. + .

[0570] Step 2: 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). 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%. MS m / z (ESI): 482.3 [M+H]. + .

[0571] 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).

[0572] Example 95

[0573] 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

[0574] Example 95 can also be synthesized by the following method:

[0575]

[0576] Step 1: Dissolve 75b (75 mg, 0.22 mmol), 2,3-pyridinedicarboxylic anhydride (33 mg, 0.22 mmol), and 4-dimethylaminopyridine (3 mg, 0.02 mmol) in tetrahydrofuran (2 mL) and stir 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 afford 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%. MS m / z (ESI): 468.2 [M+H]. + .

[0578] 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).

[0579] Example 97

[0580] 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

[0581]

[0582] Example 97 can also be synthesized by the following method:

[0583] 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. MS m / z (ESI): 496.2 [M+H] + .

[0584] 1H 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).

[0585] Example 99

[0586] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile Example 99 can also be synthesized using the following method:

[0587]

[0588] Step 1: 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. MS m / z (ESI): 214.1 [M+H] + .

[0589] Step 2: Dissolve 99b (300 mg, 1.41 mmol) in N,N-dimethylformamide (5 mL) and place 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 mixture was poured into ice water (20 mL) and the pH was adjusted to a weakly alkaline state with 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. MS m / z (ESI): 242.1 [M+H] + .

[0590] Step 3: Dissolve 99c (200 mg, 0.83 mmol) and hydroxylamine hydrochloride (86 mg, 1.24 mmol) in a mixture of ethanol (15 mL) and water (5 mL). Heat the mixture to 50°C with stirring for 2 hours. The reaction mixture was concentrated, added with saturated aqueous sodium bicarbonate (10 mL), filtered, and 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 70.6% yield. MS m / z (ESI): 257.1 [M+H] + .

[0591] Step 4: Dissolve 99d (60 mg, 0.234 mmol) in acetic anhydride (5 mL). Heat the reaction to 130°C with stirring for 2 hours. Cool the reaction mixture to room temperature, filter, and wash the filter cake with saturated sodium bicarbonate solution and then with water. Dry to afford 7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-cyano 99e (30 mg) in a 53.8% yield. MS m / z (ESI): 239.1 [M+H] + .

[0592] Step 5: 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). The reaction was heated to 130°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 99 (32 mg) in a yield of 47.1%. MS m / z (ESI): 463.2 [M+H] + .

[0593] 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).

[0594] Example 102

[0595] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-(3-fluoropyrazolo[1,5-a]pyridin-7-yl)pyridin-2-yl)cyclopentane

[0596] -1,3-diamine

[0597] Example 102 can also be synthesized by the following method:

[0598]

[0599] Step 1: (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%. MS m / z (ESI): 456.2 [M+H] + .

[0600] 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).

[0601] Example 108

[0602] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one Example 108 can also be prepared as follows:

[0603]

[0604] Step 1: 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 afford (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. MS m / z (ESI): 366.2 [M+H].

[0605] Step 2: 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. MS m / z (ESI): 466.2 [M+H] + .

[0606] 1H NMR(400 MHz, 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),7.39(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).

[0607] Example 115

[0608] 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0609]

[0610] Referring to the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 115 was synthesized. MS m / z (ESI): 438.2 [M+H] + .

[0611] 1 H NMR(400 MHz,DMSO-d6)δ8.73(d,1H),7.92(d,1H),7.66–7.54(m,2H),7.52–7.36(m,2H),7.09(t,1H),7.01(dd,1H),6.91(dd,2H ),6.53(d,1H),6.44(d,1H),6.27(td,1H),4.38–4.11(m,2H),2.21–2.09(m,2H),2.03–1.84(m,2H),1.63–1.44(m,2H).

[0612] Example 117

[0613] 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0614] Example 117 can also be obtained by the following method:

[0615]

[0616] Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 117a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction mixture was heated to 125°C and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added to the reaction mixture, and the mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL x 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 117b (445 mg) in a yield of 67.26%. MS m / z(ESI):177.1[M+H] + .

[0617] Step 2: Dissolve 117b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL). Heat the reaction to 70°C. Add tert-butyl nitrite (458 mg, 4.44 mmol) and stir at 70°C for 1.5 hours. Add saturated ammonium chloride solution to the reaction mixture, extract the aqueous phase with ethyl acetate (20 mL x 2). Combine the organic phases, dry them, and concentrate to remove most of the solvent. Add petroleum ether / ethyl acetate (1 / 1, 10 mL) to the residue, stir at 0°C for 15 minutes, and filter to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 117c (320 mg) in a 51.05% yield. MS m / z (ESI): 240.0 [M+H]. + .

[0618] Step 3: Sodium borohydride (29 mg, 0.76 mmol) was added to a solution of 117c (140 mg, 0.58 mmol) in methanol (4 mL) at 0°C and stirred for 1 hour. Saturated ammonium chloride solution was slowly added dropwise to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-ol 117d (136 mg) in a yield of 96.33%. MS m / z (ESI): 242.0 [M+H]. +

[0619] Step 4: Under nitrogen, 117d (66 mg, 0.27 mmol), intermediate 2 (57 mg, 0.21 mmol), RuphosPd G4 (18 mg, 0.002 mmol), and sodium tert-butoxide (61 mg, 0.63 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was heated to 130°C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to afford 6'-(((1S,3S)-3-((7-(1-hydroxyethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 117 (1 mg) in a 1.10% yield. MS m / z(ESI):432.2[M+H] + .

[0620] 1 H NMR(400MHz,DMSO-d6)δ8.49(d,1H),7.92(d,1H),7.61-7.56(m,1H),7.51-7.44(m,1H) ,7.42-7.36(m,1H),7.26(s,1H),6.92(d,1H),6.86-6.81(m,1H),6.57(d,1H),6.53(d,1 H),6.44(d,1H),6.30-6.23(m,1H),5.42(d,1H),4.81-4.69(m,1H),4.39-4.24(m,1H),4 .22-4.09(m,1H),2.20-2.09(m,2H),2.02-1.82(m,2H),1.62-1.43(m,2H),1.34(d,3H).

[0621] Example 118

[0622] 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

[0623]

[0624] 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 118 was synthesized. MS m / z (ESI): 422.1 [M+H] + .

[0625] 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).

[0626] Example 119

[0627] 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

[0628]

[0629] Under nitrogen, 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine 119a (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 119 (31.7 mg) in a 31.4% yield. MS m / z (ESI): 456.2 [M+H] + .

[0630] 1H 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).

[0631] Example 125

[0632] 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one

[0633] Example 125 can also be prepared according to the following method:

[0634]

[0635] Step 1: 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 solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL) and saturated sodium chloride (20 mL). The organic phase was dried and concentrated, and the residue was isolated by silica gel column chromatography (eluent system A) to give the title product, tert-butyl (1S,3S)-3-(((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate 125a (160 mg) in a yield of 68.5%. MS m / z (ESI): 348.2 [M+H] + .

[0636] Step 2: Referring to the synthesis method of Step 4 of Example 63, the target product (1S,3S)-N1-(6-(trifluoromethyl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 125b was synthesized. MS m / z (ESI): 296.2 [M+H] + .

[0637] Step 3: Referring to the synthesis method of Step 5 of Example 63, the target product 6'-(((1S,3S)-3-((6-(trifluoromethyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amine)-2H-[1,3'-bipyridyl]-2-one 125 was synthesized. MS m / z (ESI): 418.2 [M+H] + .

[0639] 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)

[0640] Example 128

[0641] 6'-(((1S,3S)-3-((7-(3,3-difluoroazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0642]

[0643] The reaction mixture was synthesized according to the synthesis method of Example 20 to obtain the target product 6'-(((1S,3S)-3-((7-(3,3-difluoroazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 128. MS m / z (ESI): 479.2 [M+H] + .

[0644] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.92(d,1H),7.60(dd,1H),7.47(td,1H),7.40(dd,1H),7.34(d,1H),6.91(d,1H),6.74(d,1H),6.53 (d,1H),6.44(d,1H),6.27(td,1H),6.04(d,1H),4.30(q,1H),4.21-4.15(m,5H),2.19-2.11(m,2H),2.00-1.83(m,2H),1.59-1.46(m,2H).

[0645] Example 131

[0646] 6'-(((1S,3S)-3-((6-(3-Hydroxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0647] Example 131 can also be prepared according to the following method:

[0648]

[0649] Step 1: Dissolve 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine 131a (500 mg, 1.87 mmol) in tetrahydrofuran (15 mL) at room temperature. Add sodium borohydride (141.7 mg, 3.75 mmol) with stirring, followed by isopropanol (0.5 mL) and stir for 1 hour. The reaction mixture was filtered, concentrated, and dissolved in dichloromethane (20 mL). Then, 2,3-dichloro-5,6-dicyanobenzoquinone (637.9 mg, 2.81 mmol) was added and the reaction was stirred at room temperature for 1 hour. Dichloromethane (30 mL) was added to the reaction solution, and the organic phase was washed with water (10 mL × 3) and saturated sodium chloride solution (10 mL), dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give 6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine 131b (320 mg) in a yield of 73.5%. MS m / z (ESI): 232.0 [M+H] + .

[0650] Step 2: 131b (170 mg, 0.731 mmol), intermediate 2 (200 mg, 0.731 mmol), and potassium carbonate (202 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction was heated to 100°C and stirred for 3 hours. The reaction mixture was filtered, and the residue was separated by silica gel column chromatography (eluent system B) to give 6'-(((1S,3S)-3-((6-bromopyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 131c (300 mg) in 88.0% yield. MS m / z (ESI): 466.1 [M+H] + .

[0651] Step 3: Under nitrogen protection, 131c (100 mg, 0.214 mmol), 3-hydroxyazetidine hydrochloride (117.5 mg, 1.07 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (34.1 mg, 0.043 mmol) and cesium carbonate (698.7 mg, 2.14 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 100 ° C and stirred for 16 hours. The reaction mixture was filtered and purified by preparative HPLC (ammonium bicarbonate system) to afford the desired product, 6'-(((1S,3S)-3-((6-(3-hydroxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 131 (15 mg), in a 15.3% yield. MS m / z (ESI): 459.2 [M+H]. + .

[0652] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.18(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.55(d,1H),4.51(m,1H),4.31(m,1H),4.15(m,1H),3. 98(t,2H),3.42(t,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.46(m,2H).

[0653] Example 144

[0654] 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

[0655]

[0656] 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. MS m / z (ESI): 468.2 [M+H] + .

[0657] 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).

[0658] Example 145

[0659] 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

[0660]

[0661] 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. MS m / z (ESI): 468.2 [M+H] + .

[0662] 1 H 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).

[0663] Example 147

[0664] (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

[0665] Example 147 can also be prepared according to the following method:

[0666]

[0667] Step 1: Dissolve 99c (300 mg, 1.24 mmol) in methanol (10 mL) under ice. Add sodium borohydride (47 mg, 1.24 mmol) to the reaction mixture with stirring. Warm the reaction mixture to room temperature and stir for 2 hours. Quench the mixture with hydrochloric acid (1 M). The reaction mixture is concentrated, and the residue is isolated by silica gel column chromatography (eluent system B) to afford (7-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol 147a (240 mg) in a 79.3% yield. MS m / z (ESI): 244.1 [M+H]. + .

[0669] Step 2: 147a (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 147b (30 mg) in a 64.1% yield. MS m / z (ESI): 380.1 [M+H] + .

[0670] Step 3: Under nitrogen, 147b (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 isolated by silica gel column chromatography (eluent system B) to afford 7-(6-fluoropyridin-3-yl)-3-methylpyrazolo[1,5-a]pyridine 147c (20 mg) in a 66.8% yield.

[0671] Step 4: 147c (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 147 (12 mg), yield: 30.2%. MS m / z (ESI): 452.2 [M+H] + .

[0672] 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).

[0673] Example 148

[0674] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-cyano

[0675]

[0676] 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. MS m / z (ESI): 464.2 [M+H] + .

[0677] 1H 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).

[0678] Example 151

[0679] 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide

[0680] Example 151 can also be prepared according to the following method:

[0681]

[0682] Step 1: 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 151b (1.52 g) in a 38% yield. MS m / z (ESI): 505.1 [2M+Na] + .

[0683] Step 2: Dissolve 151b (1 g, 4.14 mmol) in tetrahydrofuran (35 mL) and add butyl lithium (2.5 M, 4.14 mL) dropwise to the reaction mixture at -78°C. After stirring at -78°C for 1 hour, iodomethane (3.53 g, 24.9 mmol) was added dropwise to the reaction mixture. The reaction mixture 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 151c (586 mg) in a 52% yield. MS m / z (ESI): 539.2 [2M+H] + .

[0684] Step 3: 151c (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 151d (165 mg). The product was used directly in the next step without purification. MS m / z (ESI): 150.1 [M+H] +

[0685] Step 4: Following the synthesis method of Example 91, step 1, 2-(6-fluoropyridin-3-yl)-5,5-dimethylisothiazolidine 1,1-dioxide 151e (154 mg) was synthesized in a 56% yield. MS m / z (ESI): 245.1 [M+H] + .

[0686] Step 5: Referring to the synthesis method of Step 2 of Example 91, the target product 2-(6-(((1S,3S)-3-((5-((difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,5-dimethylisothiazolidine-1,1-dioxide 151 (21 mg) was synthesized in a 14% yield. 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 152

[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]

[0691] 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 152 was synthesized. 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 153

[0694] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-1,2,5-thiadiazolidine 1,1-dioxide

[0695] Example 153 can also be prepared according to the following method:

[0696]

[0697] Step 1: Under nitrogen protection, dissolve chlorosulfonyl isocyanate (4 g, 28.26 mmol) in dichloromethane (80 mL) at 0°C, and add tert-butanol (2.41 g, 32.50 mmol) in dichloromethane (10 mL) dropwise to the reaction solution with stirring. Stir for 30 minutes under ice bath to obtain tert-butyl (chlorosulfonyl)carbamate solution; separately, dissolve 2-chloroethylamine hydrochloride (3.77 g, 32.50 mmol) in dichloromethane (30 mL), and add the above tert-butyl (chlorosulfonyl)carbamate solution and triethylamine (14.29 g, 141.24 mmol) under ice bath. Keep the reaction temperature in the bottle always below 5°C. After the addition is completed, transfer to room temperature and react for 2 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with 0.1N hydrochloric acid solution (150 mL × 3), dried, filtered, and concentrated to obtain a pale yellow oil. This was dissolved in dimethyl sulfoxide (40 mL), potassium carbonate (15.62 g, 113.05 mmol) was added, and stirred at room temperature for 16 hours. The reaction mixture was diluted with 200 mL of water, the pH was adjusted to weak acidity with formic acid, and the mixture was extracted with ethyl acetate (100 mL × 3), dried, filtered, and concentrated to obtain tert-butyl 1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide 153b (1.61 g) as a white solid in a 26% yield. MS m / z (ESI): 221.1 [MH] -

[0698] 1 H NMR (400MHz, CDCl3) δ3.89(t,2H),3.54(dt,2H),1.54(s,9H).

[0699] Step 2: Dissolve intermediate 1 (340 mg, 1.39 mmol), 2-fluoro-5-iodopyridine (621 mg, 2.78 mmol) and N,N-diisopropylethylamine (540 mg, 4.18 mmol) in dimethyl sulfoxide (5 mL), heat to 115°C and stir for 16 hours. The reaction solution was diluted with ethyl acetate, washed twice with saturated brine, dried, and the concentrated residue was purified by silica gel column chromatography (elution system A) to obtain (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine 153c (225 mg), yield: 36%. MS m / z (ESI): 448.0 [M+H] +

[0700] Step 3: Under nitrogen, 153c (120 mg, 0.27 mmol), 153b (120 mg, 0.54 mmol), cuprous iodide (11 mg, 0.054 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.108 mmol) and potassium carbonate (130 mg, 0.94 mmol) were dissolved in dioxane (2 mL). The reaction was heated to 100°C and stirred for 3 h. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined layers were washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give tert-butyl 5-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide 153d (125 mg) in an 86% yield. MS m / z (ESI): 542.2 [M+H] +

[0701] Step 4: 153d (120 mg, 0.22 mmol) was dissolved in dichloromethane, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by preparative HPLC (formic acid system) to give 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-1,2,5-thiadiazolidine 1,1-dioxide 153 (43 mg) in a 44% yield. MS m / z (ESI): 442.1 [M+H] + .

[0702] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.82(d,1H),7.55(d,2H),7.48(d,1H),7.03(t,1H),6.67(d,1H),4 .30(q,1H),4.22(s,1H),3.74(t,2H),3.45(q,2H),2.27–2.04(m,2H),1.96–1.78(m,2H),1.52(td,2H).

[0703] Example 154

[0704] 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-1,2,6-thiadiazinane 1,1-dioxide

[0705]

[0706] Example 154 can also be prepared by referring to the following method: Referring to the synthesis method of Example 153, the target product 2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-1,2,6-thiadiazinane 1,1-dioxide 154 was synthesized. MS m / z (ESI): 456.1 [M+H] + .

[0707] 1 H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.87(d,1H),7.46(t,2H),7.23(s,1H),7.03(t,1H),6.55(d,1H) ,4.27(dt,2H),3.52(t,2H),3.35(q,2H),2.23–2.03(m,2H),1.89(tt,2H),1.80(d,2H),1.50(td,2H).

[0708] Example 155

[0709] 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

[0710] Example 155 can also be obtained as follows:

[0711]

[0712] Step 1: Dissolve 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) in pure water (2 mL). Heat to 60°C and stir 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 afford isothiazolo[5,4-b]pyridin-3(2H)-one 1,1-dioxide 155a (1.27 g) in 40% yield. MS m / z (ESI): 185.1 [M+H] + .

[0713] 1 H NMR (400MHz, DMSO-d6) δ9.04(dd,1H),8.45(dd,1H),7.93(dd,1H).

[0714] Step 2: Under nitrogen, 155a (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 155b (150 mg). The product was used in the next step without further purification. MS m / z (ESI): 171.0 [M+H] + .

[0715] Step 3: Under nitrogen protection, 2-fluoro-5-iodopyridine (120 mg, 0.54 mmol), 155b (92 mg, 0.54 mmol), cuprous iodide (123 mg, 0.65 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (92 mg, 0.65 mmol) and potassium carbonate (260 mg, 1.88 mmol) were dissolved in dioxane (2 mL) and the reaction was heated to 100°C and stirred for 4 h. The reaction mixture 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 x 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 155c (36 mg) in a 25% yield. MS m / z (ESI): 266.1 [M+H] + .

[0716] Step 4: Intermediate 1 (32 mg, 0.13 mmol), 155c (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-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide 155 (6 mg) in a 9% yield. MS m / z (ESI): 490.1 [M+H] + .

[0717] 1H 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).

[0718] Example 158 and Example 159

[0719] 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

[0720]

[0721] Step 1: Thiophosgene (6.61 g, 57.46 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine 158a (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. 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 158b (4.20 g), in a 46.7% yield. MS m / z (ESI): 235.0 [M+H] + .

[0722] Step 2: 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. The reaction was stirred for 30 minutes. A solution of 158b (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 and stirred for 2 hours. The reaction mixture was adjusted to pH 9 with aqueous sodium carbonate. The organic phase was separated and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to afford a mixture of 2-chloro-5-(trifluoromethoxy)pyrimidine 158c and 5-(bromodifluoromethoxy)-2-chloropyrimidine 159a (160 mg). 158c MS m / z (ESI): 199.0 [M+H] + .159a MS m / z(ESI):259.0[M+H] + .

[0723] Step 3: 6-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridinyl]-7H-pyrrolo[3,4-b]pyridin-5-one (31 mg, 0.10 mmol, its synthesis method is referred to Example 75), a mixture of 158c and 159a (40 mg), and diisopropylethylamine (26 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 60°C and stirred for 16 h. The reaction mixture 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 158 (6 mg) in a 12.6% yield. MS m / z (ESI): 472.2 [M+H] + .

[0724] 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).

[0725] 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 159 (16 mg), yield: 29.8%. MS m / z (ESI): 532.1 [M+H] + .

[0726] 1 H NMR(400MHz,CD3OD)δ8.78(dd,1H),8.36(d,1H),8.25(s,2H),8.21(dd,1H),7.84(dd,1H),7.59(d d,1H),6.63(d,1H),4.96(s,2H),4.41(m,1H),4.30(m,1H),2.27(dd,2H),2.02(m,2H),1.60(m,2H)

[0727] Example 160

[0728] 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

[0729]

[0730] Step 1: 158a (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 for 16 hours at room temperature. 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 160a (1.20 g) in 73.7% yield. MS m / z (ESI): 213.0 [M+H] + .

[0731] Step 2: Referring to the synthesis method of Step 3 of Example 158, 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 160 was synthesized. MS m / z (ESI): 486.2 [M+H] + .

[0732] 1 H NMR(400MHz,DMSO-d6)δ8.80(dd,1H),8.36(d,1H),8.20(s,2H),8.15(dd,1H),7.87(dd,1H),7.56(dd,1H),7.10 (d,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.71(q,2H),4.28(q,2H),2.12(m,2H),1.91(m,2H),1.49(m,2H).

[0733] Example 161

[0734] 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

[0735]

[0736] Step 1: Referring to the synthesis method of Step 3 of Example 158, 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 161 was synthesized. MS m / z (ESI): 486.2 [M+H] + .

[0737] 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).

[0738] Example 162

[0739] 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

[0740]

[0741] 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 was synthesized. MS m / z (ESI): 429.2 [M+H] + .

[0742] 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).

[0743] Example 164

[0744] 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

[0745]

[0746] first step

[0747] Referring to the synthesis method of the third step of Example 158, 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 164 was synthesized. MS m / z (ESI): 428.2 [M+H] + .

[0748] 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).

[0749] Example 165

[0750] 6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]

[0751] Pyridin-5-one

[0752]

[0753] Step 1: Referring to the synthesis method of Step 3 of Example 158, 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 165 was synthesized. MS m / z (ESI): 428.2 [M+H] + .

[0754] 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).

[0755] Example 166

[0756] 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

[0757]

[0758] Step 1: Under nitrogen, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 166a (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 afford tert-butyl N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate 166b (240 mg) in a 30.9% yield. MS m / z (ESI): 336.0 [M+H] + .

[0759] Step 2: Dissolve 166b (202 mg, 0.60 mmol) in methanol (2 mL) at room temperature with stirring. Add a 4 M solution of hydrochloric acid in 1,4-dioxane (5 mL). Stir the reaction mixture at room temperature for 1 hour. Concentrate the mixture, and purify the residue 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 166c (140 mg) in a 98.6% yield. MS m / z (ESI): 236.2 [M+H]. + .

[0760] Step 3: 166c (150 mg, 0.64 mmol), 2-fluoro-5-nitro-pyridine (91 mg, 0.64 mmol), and cesium carbonate (416 mg, 1.28 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to 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 166d (190 mg) in 83.4% yield. MS m / z (ESI): 358.1 [M+H] + .

[0761] Step 4: Under a hydrogen atmosphere, 166d (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 166e (170 mg) in a 97.7% yield. MS m / z (ESI): 328.1 [M+H] + .

[0762] Step 5: 166e (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 (NH4 bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 166 (24.3 mg) in a yield of 22.4%. MS m / z (ESI): 445.2 [M+H] + .

[0763] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.66(t,1H),8.35(d,1H),8.11(d,1H),7.88(dd,1H),7.62(dd,1H),7.27(dd,1H),6.86(td,1H),6.75(d ,1H),6.70(d,1H),6.56(d,1H),4.93(s,2H),4.38–4.24(m,1H),4.22– 4.09(m,1H),2.24–2.10(m,2H),2.03–1.82(m,2H),1.66–1.39(m,2H).

[0764] Example 167

[0765] 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0766]

[0767] Referring to the synthesis method of Example 166, 6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 167 was synthesized. MS m / z (ESI): 445.2 [M+H] + .

[0768] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.65(d,1H),8.36(d,1H),8.14(d,1H),7.87(dd,1H),7.56(dd,1H),7.27(dd,1H),6.86(td,1H),6.74(d ,1H),6.67(d,1H),6.54(d,1H),4.97(s,2H),4.34–4.22(m,1H),4.20– 4.07(m,1H),2.22–2.06(m,2H),2.00–1.81(m,2H),1.63–1.43(m,2H).

[0769] Example 168

[0770] 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

[0771]

[0772] Referring to the synthesis method of Example 166, 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 168 was synthesized. MS m / z (ESI): 441.2 [M+H] + .

[0773] 1H 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).

[0774] Example 169

[0775] 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0776]

[0777] Referring to the synthesis method of Example 166, 6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 169 was synthesized. MS m / z (ESI): 441.2 [M+H] + .

[0778] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.43(d,1H),8.36(d,1H),8.14(dd,1H),7.87(dd,1H),7.56(dd,1H),7.16(s,1H),6.73–6.62(m,2H ),6.54(t,2H),4.97(s,2H),4.38–4.22(m,1H),4.20–4.07(m,1H),2.34(s,3H),2.22–2.06(m,2H),2.02–1.79(m,2H),1.62–1.38(m,2H).

[0779] Example 170

[0780] 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

[0781]

[0782] Step 1: Referring to the synthesis method of Step 3 of Example 158, 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 170 was synthesized. MS m / z (ESI): 452.2 [M+H] + .

[0783] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.11(d,1H),7.89(m,2H),7.62(dd,2H),7.40(dd,2H),7.19(d,1H) ,6.72(d,1H),6.57(d,1H),4.93(s,2H),4.50(m1H),4.31(m,1H),2.70(s,3H),2.16(m,2H),1.94(m,2H),1.54(m,2H).

[0784] Example 172

[0785] 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

[0786] Example 172 can also be prepared by referring to the following method

[0787]

[0788] Step 1: Dissolve 75b (57.7 mg, 0.25 mmol) and potassium carbonate (73.9 mg, 0.53 mmol) in N,N-dimethylformamide (3 mL) at room temperature and stir for 1 hour. Then, heat to 60°C and stir 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 172 (21 mg) in a yield of 25.9%. MS m / z (ESI): 455.2 [M+H] + .

[0789] 1H 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).

[0790] Example 173

[0791] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one

[0792]

[0793] Referring to the synthesis method of Example 75, 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 173 was synthesized. MS m / z (ESI): 455.2 [M+H] + .

[0794] 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),9.23(s,1H),8.37(d,1H),8.23(s,2H),7.87(dd,1H),7.48(d,1H),7.03( t,1H),6.77(d,1H),6.56(d,1H),5.02(s,2H),4.36–4.23(m,2H),2.24–2.05(m,2H),1.89(m,2H),1.52(m,2H).

[0795] Example 175

[0796] 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

[0797]

[0798] 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 was synthesized. MS m / z (ESI): 456.2 [M+H] + .

[0799] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.61(d,2H),8.37(d,1H),8.20(d,1H),8.15(d,1H),7.88(dd,1H),7.56(dd,1H) ,6.70(d,1H),6.56(d,1H),4.97(s,2H),4.47-4.28(m,2H),2.18-2.10(m,2H),1.98-1.85(m,2H),1.62-1.48(m,2H).

[0800] Example 176

[0801] 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

[0802]

[0803] 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 was synthesized. MS m / z (ESI): 456.2 [M+H] + .

[0804] 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).

[0805] Example 177

[0806] 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0807]

[0808] Referring to the synthesis method of Example 131, 6'-(((1S,3S)-3-((6-(3-hydroxy-3-methylazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 177 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0809] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7 .40(dd,1H),7.19(d,1H),6.91(d,1H),6.61(d,1H),6.53(d,1H),6.44(d,1H),6 .27(t,1H),5.86(d,1H),5.45(d,1H),4.30(q,1H),4.15(q,1H),3.66(d,2H),3. 52(d,2H),2.15-2.12(m,2H),2.03-1.82(m,2H),1.57-1.45(m,2H),1.24(s,3H).

[0810] Example 178

[0811] 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0812]

[0813] Referring to the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-(difluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 178 was synthesized. MS m / z (ESI): 454.1 [M+H] + .

[0814] 1H NMR(400MHz, DMSO-d6)δ8.63(d,1H),7.91(d,1H),7.62–7.56(m,1H),7.47(ddd,1H),7.42(s,1H),7.39(dd,1H),7.13(d,1H),6.92(d,1H),6.78–6. 69(m,2H),6.52(d,1H),6.44(dd,1H),6.27(td,1H),4.37–4.25(m,1H),4. 20–4.07(m,1H),2.19–2.08(m,2H),2.00–1.82(m,2H),1.63–1.41(m,2H).

[0815] Example 179

[0816] 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0817]

[0818] Referring to the synthesis method of Example 27, 6'-(((1S,3S)-3-((7-(trifluoromethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 179 was synthesized. MS m / z (ESI): 472.2 [M+H] + .

[0819] 1 H NMR(400MHz,DMSO-d6)δ8.74(d,1H),7.92(d,1H),7.60(dd,1H),7.51–7.44(m,2H),7.40(dd,1H),6.98–6.87(m,3H),6.52(d,1 H),6.44(dd,1H),6.27(td,1H),4.37–4.26(m,1H),4.22–4.11(m,1H),2.20–2.07(m,2H),2.00–1.82(m,2H),1.61–1.43(m,2H).

[0820] Example 180

[0821] 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

[0822]

[0823] 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 180 was synthesized. MS m / z (ESI): 428.2 [M+H] + .

[0824] 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).

[0825] Example 181

[0826] 6'-(((1S,3S)-3-((7-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0827] Example 181 can also be prepared according to the following method:

[0828]

[0829] Step 1: Dissolve tert-butyl nitrite (1.45 g, 14.08 mmol) and copper bromide (3.15 g, 14.08 mmol) in acetonitrile (50 mL) at room temperature and stir. The reaction mixture was heated to 70°C. 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 181a (2.0 g, 9.39 mmol) was added portionwise to the reaction mixture and stirred for 2 hours. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to afford 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine 181b (2.5 g) in a 96.2% yield. MS m / z (ESI): 275.9 [M+H] + .

[0830] Step 2: Under nitrogen protection, 181b (500 mg, 1.81 mmol), 3-hydroxyazetidine hydrochloride (989 mg, 1.07 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (163.7 mg, 0.18 mmol) and cesium carbonate (1.76 g, 5.42 mmol) were dissolved in 1,4-dioxane (20 mL), heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to afford 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)azetidine-3-hydroxy 181c (100 mg) in a 20.6% yield. MS m / z (ESI): 269.0 [M+H] + .

[0831] Step 3: Under nitrogen protection, 181c (100 mg, 0.372 mmol), intermediate 2 (100.5 mg, 0.372 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (35 mg, 0.074 mmol) and cesium carbonate (363 mg, 1.11 mmol) were dissolved in 1,4-dioxane (10 mL) and heated to 130 °C with stirring for 16 h. The reaction mixture was concentrated and purified by preparative HPLC (ammonium bicarbonate system) to afford the desired product, 6'-(((1S,3S)-3-((7-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 181 (10 mg), in a 5.87% yield. MS m / z (ESI): 459.2 [M+H]. + .

[0832] 1H NMR(400MHz,DMSO-d6)δ8.14(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H),7.4 1(dd,1H),6.97(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H),6.2 7(td,1H),6.17(d,1H),5.60(d,1H),4.53(m,1H),4.37-4.26(m,1H),4.10(t,2H), 3.90(d,1H),3.67(d,2H),2.22-2.14(m,2H),1.93-1.90(m,2H),1.55-1.51(m,2H).

[0833] Example 182

[0834] 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0835]

[0836] Example 182 can also be prepared by referring to the following method: Referring to the synthesis method of Example 181, the target product 6'-(((1S,3S)-3-((7-(3-hydroxy-3-methylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 182 was synthesized. MS m / z (ESI): 473.2 [M+H] + .

[0837] 1 H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.92(d,1H),7.60(dd,1H),7.48(td,1H), 7.41(dd,1H),6.98(d,1H),6.62(d,1H),6.53(d,1H),6.44(dd,1H),6.32(dd,1H ),6.27(td,1H),6.18(d,1H),5.52(d,1H),4.33(t,1H),3.95-3.86(m,1H),3.8 2-3.74(m,4H),2.24-2.10(m,2H),1.91(t,2H),1.57-1.48(m,2H),1.41(s,3H).

[0838] Example 184

[0839] 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0840] Example 184 can also be prepared according to the following method:

[0841]

[0842] Step 1: Under nitrogen, 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 184a (800 mg, 3.76 mmol), tributyl(1-ethoxyethylene)tin (1.76 g, 4.88 mmol), and bistriphenylphosphine palladium dichloride (264 mg, 0.38 mmol) were dissolved in dioxane (8 mL). The reaction was heated to 125°C and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and dilute hydrochloric acid (3 mL, 3 M) was added and stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (25 mL x 6). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 184b (445 mg) in a yield of 67.26%. MS m / z(ESI):177.1[M+H] + .

[0843] Step 2: Dissolve 184b (460 mg, 2.61 mmol) and copper bromide (583 mg, 2.61 mmol) in acetonitrile (10 mL) and heat to 70°C with stirring. Tert-butyl nitrite (458 mg, 4.44 mmol) was added to the reaction mixture, and the reaction was stirred at 70°C for 1.5 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated to remove most of the solvent. To the residue was added PE / EA (1 / 1, 10 mL), and the mixture was stirred at 0°C for 15 minutes. Filtering afforded 1-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethan-1-one 184c (320 mg) in a 51.05% yield. MS m / z (ESI): 240.0 [M+H]. + .

[0844] Step 3: To a solution of 184c (80 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added methylmagnesium bromide (1 M, 0.7 mL) dropwise at 0°C. The reaction was allowed to warm to room temperature and stirred for 1 hour. Saturated sodium chloride solution was added to the reaction mixture at 0°C, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)propan-2-ol 184d (60 mg) in a yield of 70.30%. MS m / z (ESI): 256.0 [M+H]. + .

[0845] Step 4: Under nitrogen, 184d (50 mg, 0.2 mmol), intermediate 2 (63 mg, 0.23 mmol), RuphosPd G4 (17 mg, 0.02 mmol), and sodium tert-butoxide (56 mg, 0.59 mmol) were dissolved in dioxane (1 mL) and the reaction was heated to 130°C with stirring for 16 hours. The reaction solution was cooled to room temperature, and saturated sodium chloride solution was added. The aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to afford 6'-(((1S,3S)-3-((7-(2-hydroxypropan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 184 (8.7 mg) in a 10.00% yield. MS m / z(ESI):446.2[M+H] + .

[0846] 1 H NMR(400MHz,DMSO-d6)δ8.47(d,1H),7.92(d,1H),7.63-7.57(m,1H),7.50 -7.44(m,1H),7.42-7.37(m,1H),7.35(d,1H),6.98-6.86(m,2H),6.60-6.4 9(m,2H),6.44(d,1H),6.31-6.21(m,1H),5.27(s,1H),4.35-4.26(m,1H),4 .20-4.10(m,1H),2.22-2.07(m,2H),2.02-1.80(m,2H),1.62-1.37(m,8H).

[0847] Example 187

[0848] 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

[0849]

[0850] 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 187 was synthesized. MS m / z (ESI): 472.1 [M+H] + .

[0851] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.32(d,1H),8.23(s,2H),8.09(dd,1H),7.84(dd,1H),7.48(d,1H),7.03(dd,1H ),6.71(d,1H),6.55(d,1H),4.93(s,2H),4.26-4.33(m,2H),2.07-2.17(m,2H),1.83-1.93(m,2H),1.46-1.56(m,2H).

[0852] Example 188

[0853] 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

[0854]

[0855] 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 188 was synthesized. MS m / z (ESI): 472.1 [M+H] + .

[0856] 1H 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).

[0857] Example 194

[0858] 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

[0859]

[0860] 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 194 was synthesized. MS m / z (ESI): 522.2 [M+H] + .

[0861] 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).

[0862] Example 195

[0863] 4-Amino-2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindol-1-one

[0864] Example 195 can also be prepared according to the following method:

[0865]

[0866] Step 1: Under nitrogen, methyl 3-bromo-2-methylbenzoate 195a (1.52 g, 6.64 mmol), N-bromosuccinimide (1.30 g, 7.30 mmol), and benzoyl peroxide (230 mg, 0.66 mmol) were dissolved in carbon tetrachloride (25 mL). The reaction mixture was heated to 85°C and stirred for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to afford methyl 3-bromo-2-(bromomethyl)benzoate 195b (2 g) in a 97.87% yield.

[0867] Step 2: Following the synthesis method of Example 75, 4-bromo-2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindolin-1-one 195c (198 mg) was synthesized in 75.19% yield. MS m / z (ESI): 531.1 [M+H] + .

[0868] 1 H NMR(400MHz,DMSO-d6)δ8.35(d,1H),8.23(s,2H),7.87(d,1H),7.85-7.81(m,1H),7.77(d,1H),7.55-7.45(m,2H),7.2 4-6.82(m,1H),6.67(d,1H),6.54(d,1H),4.86(s,2H),4.37-4.22(m,2H),2.13(m,2H),1.96-1.79(m,2H),1.51(m,2H).

[0869] Step 3: Under nitrogen, 195c (105 mg, 0.2 mmol), cuprous iodide (8 mg, 0.04 mmol), L-proline (9 mg, 0.08 mmol), aqueous ammonia (0.5 mL), and potassium carbonate (82 mg, 0.59 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction was heated to 85°C and stirred for 16 h. Saturated ammonium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried, and concentrated. The residue was purified by reverse-phase HPLC to afford 4-amino-2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)isoindol-1-one 195 (45.2 mg) in a yield of 48.93%. MS m / z (ESI): 468.2 [M+H]. + .

[0870] 1H NMR(400MHz,DMSO-d6)δ8.28(d,1H),8.23(s,2H),7.84-7.75(m,1H),7.47(d,1H),7.23-7.16(m,1H),7.23-6.83(m,1H),6.92(d,1H),6.8 0(d,1H),6.60(d,1H),6.53(d,1H),5.48(s,2H),4.63(s,2H),4.37-4 .20(m,2H),2.20-2.01(m,2H),1.97-1.78(m,2H),1.61-1.39(m,2H).

[0871] Example 196

[0872] (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

[0873]

[0874] 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 196 was synthesized. MS m / z (ESI): 439.2 [M+H] + .

[0875] 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).

[0876] Example 197

[0877] (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

[0878]

[0879] 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 197 was synthesized. MS m / z (ESI): 439.2 [M+H] + .

[0880] 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).

[0881] Example 216

[0882] 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

[0883]

[0884] Referring to the synthesis method of Example 158, 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 216 was synthesized.

[0885] MS m / z(ESI):532.1[M+H] + .

[0886] 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).

[0887] Example 217

[0888] 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

[0889]

[0890] Referring to the synthesis method of Example 166, 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 217 was synthesized. MS m / z (ESI): 495.2 [M+H] + .

[0891] 1 H NMR(400MHz, DMSO-d6)δ8.83(d,1H),8.75(dd,1H),8.35(d,1H),8.15–8.06(m,1H),7.88(dd,1H),7.86(s,1H),7.62(dd,1H),7.15(dd ,1H),7.04(d,1H),6.71(d,1H),6.57(d,1H),4.93(s,2H),4.36–4.15(m,2H),2.23–2.10(m,2H),2.05–1.83(m,2H),1.65–1.42(m,2H).

[0892] Example 217 can also be prepared according to the following method:

[0893]

[0894] Step 1: Dissolve 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and ethyl N-(thiomethylene)carbamate (4.85 g, 37.01 mmol) in 1,2-dichloroethane (50 mL) at room temperature and stir for 16 hours. The reaction mixture was concentrated to afford ethyl N-[[4-(trifluoromethyl)-2-pyridinyl]carbamoylthioyl]carbamate 217a (9.05 g), which was used directly in the next step without purification. MS m / z (ESI): 294.1 [M+H] + .

[0895] Step 2: Dissolve 217a (9 g, 30.69 mmol), hydroxylamine hydrochloride (10.66 g, 153.44 mmol), and N,N-diisopropylethylamine (11.90 g, 92.07 mmol) in methanol (100 mL) and stir at room temperature for 20 minutes. Then, heat to 65°C and stir for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine 217b (5.0 g) in 80.60% yield. MS m / z (ESI): 203.1 [M+H] + .

[0896] Step 3: Dissolve 217b (5 g, 24.74 mmol) and copper bromide (5.52 g, 24.74 mmol) in acetonitrile (50 mL) and add tert-butyl nitrite (12.75 g, 123.68 mmol). The reaction was stirred at room temperature for 0.5 h, then heated to 70°C and stirred for 2 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (150 mL), filtered, and the organic phase was washed with water (100 mL) and concentrated. The residue was purified by silica gel column chromatography (elution system A) to afford 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine 217c (5 g) in 75.99% yield. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0897] Step 4: Under nitrogen, 217c (4.5 g, 16.92 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (3.39 g, 16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylideneacetone)dipalladium (2.32 g, 2.54 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (2.94 g, 5.07 mmol) were dissolved in 1'4-dioxane (120 mL). The reaction mixture was heated to 130°C and stirred for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give tert-butyl N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]carbamate 217d (3.7 g) in a 56.76% yield. MS m / z (ESI): 386.2 [M+H]. + .

[0898] Step 5: Dissolve 217d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) in methanol (10 mL) and stir at room temperature for one hour. The reaction mixture was concentrated, and the residue was diluted with methanol and adjusted to pH 8-10 with saturated sodium bicarbonate solution. After concentration, the residue was purified by silica gel column chromatography (elution system A) to afford (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 217e (2.74 g) in 100% yield. MS m / z (ESI): 286.2 [M+H] + .

[0899] Step 6: Dissolve 217e (2.74 g, 9.61 mmol), 2-fluoro-5-nitro-pyridine (1.50 g, 10.57 mmol), and cesium carbonate (7.82 g, 24.01 mmol) in N,N-dimethylformamide (40 mL), heat to 80°C, and stir for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to afford (1S,3S)-N1-(5-nitropyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 217f (3.8 g) in a 97.12% yield. MS m / z (ESI): 408.1 [M+H] + .

[0900] Step 7: Under a hydrogen atmosphere, 217f (3.8 g, 9.33 mmol) and palladium on carbon (993 mg, 0.93 mmol, purity: 10%) were dissolved in methanol (60 mL) and stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to afford N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 217 g (3.2 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 378.1 [M+H] +

[0901] Step 8: Dissolve 217 g (2.0 g, 5.30 mmol) of methyl 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 4.24 mmol) and N,N-diisopropylethylamine (2.05 g, 15.90 mmol) in a mixed solvent of tert-butanol (20 mL) and N,N-dimethylformamide (4 mL). Stir at room temperature for 1 hour, then heat to 40°C and stir for 16 hours, and then heat to 80°C and stir for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 217 (1.2 g) in a 45.79% yield. MS m / z (ESI): 495.2 [M+H] +

[0902] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.75(dd,1H),8.35(d,1H),8.10(d,1H),7.92–7.82(m ,2H),7.61(dd,1H),7.15(dd,1H),7.02(d,1H),6.69(d,1H),6.56(d,1H),4.92(s,2H),4.32 4.13(m,2H),2.23–2.10(m,2H),2.04–1.85(m,2H),1.67–1.43(m,2H).

[0903] Example 218

[0904] 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0905]

[0906] Referring to the synthesis method of Example 166, 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 218 was synthesized. MS m / z (ESI): 495.2 [M+H] + .

[0907] 1 H NMR(400MHz,DMSO-d6)δ8.85–8.74(m,2H),8.36(d,1H),8.14(dd,1H),7.91–7.83(m,2H),7.56(dd,1H),7.15(dd,1H),7.04 (d,1H),6.69(d,1H),6.55(d,1H),4.97(s,2H),4.36–4.15(m,2H),2.23–2.10(m,2H),2.05–1.83(m,2H),1.65–1.42(m,2H).

[0908] Example 238

[0909] 6-(6-(((1S,3S)-3-((5-methyl-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0910] Example 238 can also be prepared according to the following method:

[0911]

[0912] Step 1: Dissolve 6-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (120 mg, 0.38 mmol) and sodium acetate (95.4 mg, 1.16 mmol) in tetrahydrofuran (3 mL). Cool the mixture to 0°C and add cyanogen bromide (123.2 mg, 1.16 mmol) with stirring. Return the mixture to room temperature and stir for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated to afford N-((1S,3S)-3-((5-(7-carbonyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyridin-2-yl)amino)cyclopentyl)cyanamide 238a (128 mg) in a 98.7% yield. MS m / z(ESI):335.2[M+H] +.

[0913] Step 2: 238a (108 mg, 0.32 mmol), hydroxylamine hydrochloride (179.6 mg, 2.58 mmol), and triethylamine (261.5 mg, 2.58 mmol) were dissolved in isopropanol (5 mL) and the reaction was heated to 50°C with stirring for 1 hour. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate system) to give 2-hydroxy-1-((1S,3S)-3-((5-(7-carbonyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyridin-2-yl)amino)cyclopentyl)guanidine 238b (20 mg) in a yield of 16.8%. MS m / z (ESI): 368.2 [M+H] + .

[0914] Step 3: Dissolve 238b (20 mg, 0.05 mmol) and glacial acetic acid (3.27 mg, 0.05 mmol) in trimethyl orthoacetate (1.31 g, 10.9 mmol) and stir at 60°C for 1 hour. The reaction solution was concentrated, and the residue was purified by preparative HPLC (NH4 bicarbonate system) to give 6-(6-(((1S,3S)-3-((5-methyl-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 238 (4.3 mg) in an 18.6% yield. MS m / z (ESI): 392.2 [M+H] + .

[0915] 1 H NMR (400MHz, CD3OD) δ8.78–8.69(m,1H),8.36(d,1H),8.12(d,1H),7.88(dd,1H),7.64(dd,1H),6.62(d,1H),4.94( s,2H),4.37–4.21(m,1H),4.02–3.91(m,1H),2.42(s,3H),2.30–2.14(m,2H),2.11–1.88(m,2H),1.72–1.51(m,2H).

[0916] Example 240

[0917] 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[0918] Example 240 can also be prepared according to the following method:

[0919]

[0920] Step 1: Under nitrogen, 2-fluoro-5-iodopyridine 240a (2 g, 8.97 mmol), 3-pyridazinone (948.00 mg, 9.87 mmol), cuprous iodide (342 mg, 1.79 mmol), trans-(1S,2S)-N,N'-dimethylcyclohexanediamine (255 mg, 1.79 mmol), and potassium carbonate (2.48 g, 17.94 mmol) were dissolved in dimethyl sulfoxide (30 mL) and heated to 130°C with stirring for 16 hours. The reaction mixture was filtered, the filtrate diluted with saturated sodium chloride solution, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to afford 2-(6-fluoropyridin-3-yl)pyridazin-3(2H)-one 240b (856 mg) in a yield of 49.93%. MS m / z(ESI):192.0[M+H] + .

[0921] Step 2: Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 240c (710 mg, 3.29 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (856 mg, 4.27 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (228 mg, 0.39 mmol) and cesium carbonate (3.21 g, 9.86 mmol) were dissolved in 1,4-dioxane (25 mL) and the reaction was heated to 130 ° C and stirred for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to give tert-butyl ((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)carbamate 240d (473 mg) in a yield of 42.91%. MS m / z (ESI): 336.2 [M+H]+ .

[0923] Step 3: To a solution of 240d (473 mg, 1.41 mmol) in dichloromethane (4 mL) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (3.53 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved with a small amount of dichloromethane and methanol. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline. The mixture was concentrated, and the residue was separated by silica gel column chromatography to afford (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 240e (310 mg) in a 93.43% yield. MS m / z (ESI): 236.1 [M+H] +

[0924] Step 4: Under nitrogen, 240e (74 mg, 0.31 mmol), 240b (50 mg, 0.26 mmol), and diisopropylethylamine (101 mg, 0.78 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) and the reaction mixture was heated to 130°C with stirring for 48 hours. The reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC to afford 2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one 240 (16.8 mg) in a 15.80% yield. MS m / z (ESI): 407.1 [M+H] + .

[0925] 1 H NMR(400MHz,DMSO-d6)δ8.69-8.62(m,1H),8.10(d,1H),8.04-7.98(m,1H),7 .55-7.49(m,1H),7.48-7.43(m,1H),7.30-7.23(m,1H),7.05-6.99(m,1H),6 .94(d,1H),6.89-6.82(m,1H),6.75(d,1H),6.53(d,1H),4.39-4.26(m,1H), 4.22-4.07(m,1H),2.21-2.09(m,2H),2.01-1.83(m,2H),1.63-1.42(m,2H).

[0926] Example 245

[0927] 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

[0928] Example 245 can also be prepared according to the following method:

[0929]

[0930] Step 1: tert-Butyl nitrite (14.73 g, 142.87 mmol) was added dropwise to a solution of 6-bromo-1,2,4-triazin-3-amine 245a (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 245b (4.60 g), in a 78.1% yield. MS m / z (ESI): 205.9 [M+H] + .

[0931] Step 2: Under nitrogen, 245b (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 245c (710 mg), in a yield of 37.5%. MS m / z (ESI): 196.0 [M+H] + .

[0932] Step 3: Referring to the synthesis method of Step 3 of Example 158, 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 245 was synthesized. MS m / z (ESI): 457.2 [M+H] + .

[0933] 1 H NMR(400MHz,DMSO-d6)δ9.10,8.60(d,1H),8.75(m,1H),8.70(s,1H),8.36(d,1H),8.11(m,1H),7.88(m,1H),7.62(m ,1H),6.74(m,1H),6.57(d,1H),4.93(s,2H),4.61,4.35(m,1H),4.36(m,1H),2.17(m,2H),2.00(m,2H),1.61(m,2H).

[0934] Example 246

[0935] 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

[0936] Example 246 can also be prepared according to the following method:

[0937]

[0938] Step 1: Referring to the synthesis method of Step 3 of Example 158, 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 246 was synthesized. MS m / z (ESI): 457.2 [M+H] + .

[0939] 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).

[0940] Example 247

[0941] 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0942]

[0943] Referring to the synthesis method of Example 27, 6'-(((1S,3S)-3-((6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 247 was synthesized. MS m / z (ESI): 402.2 [M+H] + .

[0944] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.91(d,1H),7.60(dd,1H),7.47(ddd,1H),7.39(dd,1H),7.28(d,2H),6.92(d,1H),6.53(d,2H),6 .44(d,1H),6.26(td,1H),4.36–4.26(m,1H),4.22–4.08(m,1H),2.27(s,3H),2.20–2.09(m,2H),1.99–1.82(m,2H),1.59–1.44(m,2H).

[0945] Example 249

[0946] 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one

[0947]

[0948] Referring to the synthesis method of Example 27, 6'-(((1S,3S)-3-((6,7-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridyl]-2-one 249 was synthesized. MS m / z (ESI): 424.2 [M+H] + .

[0949] 1 H NMR(400MHz,DMSO-d6)δ9.22(dd,1H),8.15(s,1H),7.91(d,1H),7.63–7.54(m,2H),7.47(ddd,1H),7.39(dd,1H),6.92(d,1H),6.80(d,1H),6 .52(d,1H),6.47–6.41(m,1H),6.27(td,1H),4.38–4.26(m,1H),4.20– 4.08(m,1H),2.20–2.08(m,2H),2.03–1.83(m,2H),1.63–1.42(m,2H).

[0950] Example 251

[0951] 6'-(((1S,3S)-3-((5-cyclopropyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)cyclopentyl)amino]-2H-[1,3'-bipyridyl]-2-one

[0952] Example 251 can also be prepared according to the following method:

[0953]

[0954] Step 1: Sodium hydride (1.19 g, 29.8 mmol, 60% content) was dissolved in tetrahydrofuran (50 mL). Benzyl alcohol (3.22 g, 29.8 mmol) was added with stirring. The reaction was stirred at room temperature for 30 minutes, followed by the addition of 2,6-dibromo-3-aminopyridine (5 g, 19.8 mmol). The reaction was heated to 70°C and stirred for 12 hours. The reaction solution was diluted with ethyl acetate (100 mL) and saturated ammonium chloride (50 mL), filtered through celite, and the organic phase was washed with saturated sodium chloride (50 mL), dried, and concentrated. The residue was puri...

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: Ring A is selected from 6-membered and 5-membered bicyclic heteroaryl, 5-membered monoheteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 6-membered monoheteroaryl or 6-membered and 6-membered bicyclic heteroaryl; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; L1 is selected from a bond, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR aa (CH2) n1 -, -(CH2) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH2) n4 -, -(CH2) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH2) n NR cc -, -(CH2) n NR aa (CR bb R cc ) n -, -(CH2) n NR aa C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n C(O)NR aa R bb -, -(CH2) n NR cc C(O)R dd -, -(CH2) n S(O) m NR aa R bb - and -(CH2) n NR cc S(O) m R dd -； R aa , R bb、 R cc and R dd each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Alternatively, any two adjacent or non-adjacent substituents are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl or heteroaryl group may be further substituted; Preferably, L1 is selected from a bond, -C(O)- or -C(O)NH-; R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, 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, heterocyclic, aryl and heteroaryl groups may be further substituted; R A1 ~R A3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; 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; R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R B1 、-(CH2) n OR B1 、-(CH2) n C(O)R B1 、-(CH2) n C(O)OR B1 、-(CH2) n S(O) m R B1 、-(CH2) n NR B2 R B3 、-(CH2) n NR B2 C(O)OR B3 、-(CH2) n NR B2 C(O)(CH2) n1 R B3 、-(CH2) n NR B2 C(O)NR B2 R B3 、-(CH2) n C(O)NR B2 (CH2) n1 R B3 、-OC(R B1 R B2 ) n (CH2) n1 R B3 or -(CH2) n NR B2 S(O) m R B3 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; R B1 ~R B3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; 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; Preferably, Or, any two R a and R b The heterocyclic group and the heteroaryl group may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 selected from aryl and 5-14 membered heteroaryl; R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, 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, heterocyclic, aryl and heteroaryl groups may be further substituted; R C1 ~R C3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; 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; R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R D1 、-(CH2) n OR D1 、-(CH2) n C(O)R D1 、-(CH2) n C(O)OR D1 、-(CH2) n S(O) m R D1 、-(CH2) n NR D2 R D3 、-(CH2) n NR D2 C(O)OR D3 、-(CH2) n NR D2 C(O)(CH2) n1 R D3 、-(CH2) n NR D2 C(O)NR D2 R D3 、-(CH2) n C(O)NR D2 (CH2) n1 R D3 、-OC(R D1 R D2 ) n (CH2) n1 R D3 or -(CH2) n NR D2 S(O) m R D3 , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; R D1 ~R D3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; 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; 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; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; z is 0, 1, 2, or 3; e is 0, 1, 2, or 3; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; n4 is 0, 1, 2, 3 or 4; and The compound is not 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IA): in: Ring A is selected from 5-membered nitrogen-containing heteroaryl, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl; Ring B is selected from C 3-8 Cycloalkyl, 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 5-membered bicyclic nitrogen-containing heteroaryl group, 6-membered and 6-membered bicyclic nitrogen-containing heteroaryl group, 5-membered and 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered and 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered and 5-membered bicyclic nitrogen-containing heterocyclic group or 6-membered and 6-membered bicyclic nitrogen-containing aryl group; R c-1 Selected from halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R c-1 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, R c-2 is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably R c-2 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, R c-3 is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, More preferably, R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; and The compound is not 3. The compound according to any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IA-1):

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (III), (III-1) or (III-2): in: Ring E is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12 membered heteroaryl; preferably selected from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group or 6-membered nitrogen-containing heteroaryl group; M1 is selected from N or CH; M2 is selected from N or CH; M3 is selected from N or CH; M4 is selected from N or CH; M6 is selected from N or CH; and M7 is selected from N or CH.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridazinyl Preferably pyridyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl or pyridazinyl; 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 6. The compound according to any one of claims 1 or 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IA), (IB), (IC), (ID), (IE) or (IF): in: M1 is selected from N or CR1; M2 is selected from N or CR2; M3 is selected from N or CR3; M4 is selected from N, O, S or CR4; Preferably, at least one heteroatom is present in M1, M2, M3 and M4; R1 is 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R a1 ~R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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 selected from aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R1s are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 selected from aryl and 5-14 membered heteroaryl; R2 is 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R b1 ~R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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 selected from aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R2 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 selected from aryl and 5-14 membered heteroaryl; R3 is 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R c1 ~R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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 selected from aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R3 groups are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 selected from aryl and 5-14 membered heteroaryl; R4 is 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R d1 ~R d3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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 selected from aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R4 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 selected from aryl and 5-14 membered heteroaryl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4.

7. The compound according to any one of claims 1, 5 or 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (I-2') or (I-5): in: L1 is selected from a bond, -C(O)-, -C(O)NH-, -C(O)NCH3- or -C(O)N(CH3)2; M5 is selected from N or CR5; R5 is 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted by one or more substituents.

8. The compound according to any one of claims 1 to 2, 5 or 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (I-1-a), (I-2-a) or (I-4-a): in: R a-1 ~R a-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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 and 5-10 membered heteroaryl are substituted with one or more substituents, wherein the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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 selected from aryl and 5-14 membered heteroaryl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n1 is 0, 1, 2, 3 or 4.

9. The compound according to any one of claims 1 to 3 or 5 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: 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; 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; More preferably, ring B is selected from pyridine, pyrimidine, benzene, 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R a selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3-CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, or, R a-1 ~R a-4 are each independently 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R A1 ~R A3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R a-1 ~R a-4 Each independently selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -O-CH2-CF3, -CHF2, -CF3, -CH2-OH, -CH2-CHF2, -CH(CH3)-OH, -(CH2)3-OH, -C(CH3)2-OH, -OH, -O-CH3, -CH3, -CF3, -F, -Cl, -CN, -NHCH3, -NH2, -CH2-CF3, and / or, R b is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; R B1 ~R B3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, 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; and / or, R c is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -(CH2) n R C1 、-(CH2) n OR C1 、-(CH2) n C(O)R C1 、-(CH2) n C(O)OR C1 、-(CH2) n S(O) m R C1 、-(CH2) n NR C2 R C3 、-(CH2) n NR C2 C(O)OR C3 、-(CH2) n NR C2 C(O)(CH2) n1 R C3 、-(CH2) n NR C2 C(O)NR C2 R C3 、-(CH2) n C(O)NR C2 (CH2) n1 R C3 、-OC(R C1 R C2 ) n (CH2) n1 R C3 or -(CH2) n NR C2 S(O) m R C3 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; R C1 ~R C3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R c Choose -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, and / or, R d is 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic 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 Haloalkyl, 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; R D1 ~R D3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, 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 Haloalkyl, 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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; Preferably, R d Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -CH2-NH2, -CH2-OH, -NH2, -OH, 11. A compound of the general formula (I) or (I') according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

12. A compound represented by general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof: in: X2 is amino, nitro, halogen, boronic acid or boronic ester; The other groups are as described in claim 2.

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

14. A method for preparing the compound represented by the general formula (IA) as claimed in claim 2, characterized in that: The following steps are included: in: X3 is hydroxy, amino, methylthio, halogen, boric acid or boric acid ester; The compound of the general formula (IV) reacts with the compound of the general formula (IV-1) to obtain the compound of the general formula (IA); The other groups are as described in claim 2.

15. A pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I) as shown in any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of a compound of formula (I) according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 in the preparation of a PCSK9 inhibitor drug.

17. Use of the compound of general formula (I) according to any one of claims 1 to 11, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 15 in the preparation of a drug for lowering LDL.

18. Use of the compound of formula (I) as shown in any one of claims 1 to 11, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as described in claim 15 in the preparation of drugs for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or their related diseases or their symptoms; preferably, use ... in the preparation of drugs for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

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