Pyridine derivative-containing inhibitor, preparation method therefor, and use thereof

Abstract

The present invention relates to a pyridine derivative-containing inhibitor, a preparation method therefor, and the use thereof. In particular, the present invention relates to a compound represented by the general formula, a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an inhibitor in the treatment of diseases such as cardiovascular diseases and cerebrovascular diseases.

Description

Pyridine derivative inhibitors, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to an inhibitor containing pyridine derivatives, its preparation method, and its application. Background Technology

[0002] Cardiovascular disease (CVD) is a leading cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C on the arterial walls leads to atherosclerosis and can trigger inflammatory responses, resulting in cardiovascular events such as heart attacks and strokes. Although statins can lower serum LDL-C and are currently the main lipid-lowering drugs in clinical practice, patients who are intolerant to statins or who fail to reach their treatment goals when receiving tolerated doses still face risks, such as patients with familial hypercholesterolemia. The discovery of PCSK9 inhibitors provides a more aggressive treatment option for homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when used in combination with statins, can lower LDL-C by 15%-20%, while PCSK9 inhibitors combined with statins can significantly lower LDL-C by 54%-74%. PCSK9 inhibitors can also overcome the intolerable side effects of statins, such as muscle pain.

[0003] PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease highly expressed in the liver. Loss-of-function mutations in the PCSK9 gene are associated with low LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), and it has been clinically validated as a therapeutic target for hyperlipidemia. PCSK9 is synthesized as an enzyme precursor, and after synthesis, it undergoes autocatalytic cleavage within the cell. The propeptide binds to mature PCSK9 and is secreted extracellularly, thus blocking the catalytic activity of PCSK9.

[0004] PCSK9 is a major regulator of low-density lipoprotein receptor (LDLR) levels on the surface of hepatocytes and can inhibit the LDLR circulation pathway. LDLR function is crucial for maintaining cholesterol homeostasis, responsible for the uptake and degradation of low-density lipoprotein. Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100. The LDL / LDLR complex is internalized through receptor-mediated endocytosis. The low intracellular pH environment causes LDLR to release LDL, which then circulates back to the cell membrane. Intracellular free LDL is transported to lysosomes and degraded. Secreted PCSK9 interferes with LDLR circulation by binding to LDLR on the hepatocyte surface. After the PCSK9 / LDLR complex migrates through clathrin-encapsulated pits into the acidic endosomal chamber, a conformational change in LDLR leads to the formation of additional binding sites with PCSK9. Therefore, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR circulation and thus upregulating LDL-C levels.

[0005] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein cholesterol metabolism, affecting 1 in 250 people, characterized by significantly elevated LDL-c levels. Heterozygous FH patients have a 3-4 times higher risk of developing coronary artery disease (CAD) and often develop CAD an average of 10 years earlier than the general population. Statins lower LDL-C in heterozygous FH patients; studies by Besselin suggest that high-intensity statin therapy can reduce the risk of CAD and mortality by 44%. However, in many cases, the reduction in LDL-C is considered insufficient. The complementarity mechanism of statins involves upregulating sterol regulatory element-binding protein 2 (SREBP-2), thereby activating LDL receptors and PCSK9, increasing PCSK9 expression and secretion binding to LDLR, leading to elevated LDL-C levels in the blood. Therefore, while statins lower LDL by inhibiting HMGCoA, they counteract the effects of SREBP; adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatments such as PCSK9 inhibitors are needed.

[0006] PCSK9 macromolecule inhibitors, such as the monoclonal antibody-based drugs Alirocumab and Evolocumab, selectively bind to extracellular PCSK9 and prevent its interaction with LDLR. They have been approved by the FDA for lowering LDL-C levels with a good safety profile. Studies have shown that in heterozygous FH patients who have not reached their LDL-C target after statin monotherapy, once-every-two-week injections of Alirocumab maximally reduce cardiovascular risk. Alirocumab has also shown a moderate increase in "good" cholesterol (HDL-C). Additionally, a PCSK9 siRNA drug, Inclisiran, is currently marketed. It lowers PCSK9 protein expression levels for long-term lipid reduction with a good safety profile. However, both of these drugs require injection and are expensive to produce. Currently, there are no marketed PCSK9 small molecule inhibitors, therefore there is a high demand for oral PCSK9 small molecule inhibitors.

[0007] There are already patent reports on PCSK9 small molecule inhibitors, such as WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ), and WO2022133529 (Nyrada). Currently, AZD-0780 is the most advanced in Phase I clinical trials, while the others are in preclinical development. Several peptides have also been reported, with the most advanced being in Phase II clinical trials. This invention aims to develop an orally administered PCSK9 small molecule inhibitor. Summary of the Invention

[0008] The present invention aims to provide a method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from the amino acid residues Val589 and Ser636 of human PCSK9.

[0009] In a preferred embodiment of the present invention, the inhibitor binds to the amino acid residue Val589 of human PCSK9 but not to the amino acid residue Ser636 of human PCSK9.

[0010] In a preferred embodiment of the present invention, the inhibitor binds to the amino acid residue Gln587 of human PCSK9 in the method.

[0011] In a preferred embodiment of the present invention, the inhibitor binds to the amino acid residue Gly572 of human PCSK9 in the method.

[0012] In a preferred embodiment of the present invention, the inhibitor binds to the amino acid residue Asn586 of human PCSK9 in the method.

[0013] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from human PCSK9, namely Val589 and Ser636, and further binding to amino acid residue Gln587 of human PCSK9.

[0014] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from human PCSK9, namely Val589 and Ser636, and further binding to amino acid residue Gly572 of human PCSK9.

[0015] In a preferred embodiment of the present invention, a method for inhibiting PCSK9 is provided, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to the amino acid residue Val589 of human PCSK9, not binding to the amino acid residue Ser636 of human PCSK9, and further binding to the amino acid residue Gly572 of human PCSK9.

[0016] In a preferred embodiment of the present invention, a method for inhibiting PCSK9 is provided, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to the amino acid residue Val589 of human PCSK9, not binding to the amino acid residue Ser636 of human PCSK9, and further binding to the amino acid residue Gln587 of human PCSK9.

[0017] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, further binds to the amino acid residue Gly572 of human PCSK9, and even further binds to one or more of the amino acid residues Gly640, Arg495, Ala637, and Trp566 of human PCSK9.

[0018] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, further binds to the amino acid residue Gln587 of human PCSK9, and even further binds to one or more of the amino acid residues Gly640, Arg495, Ala637, and Trp566 of human PCSK9.

[0019] In a preferred embodiment of the present invention, the binding ability of the inhibitor in the method to PCSK9 protein is detected by HTRF method, IC50 50 Value less than 3000 nM; preferably, IC 50 Value less than 300 nM; more preferably, IC 50 Value less than 100 nM; most preferably, IC 50 The value is less than 30 nM.

[0020] In a preferred embodiment of the present invention, the SPR method is used to detect the binding ability of the inhibitor in the method to PCSK9 protein, and the KD value is less than 1000 nM; preferably, the KD value is less than 100 nM; more preferably, the KD value is less than 50 nM; and most preferably, the KD value is less than 10 nM.

[0021] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gly572 of human PCSK9, and using HTRF method to detect the binding ability of the inhibitor to PCSK9 protein, IC50, etc. 50 Value less than 3000 nM; preferably, IC 50 Value less than 300 nM; more preferably, IC 50 Value less than 100 nM; most preferably, IC 50 The value is less than 30 nM.

[0022] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gln587 of human PCSK9, and using HTRF method to detect the binding ability of the inhibitor to PCSK9 protein, IC50, etc. 50Value less than 3000 nM; preferably, IC 50 Value less than 300 nM; more preferably, IC 50 Value less than 100 nM; most preferably, IC 50 The value is less than 30 nM.

[0023] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gly572 of human PCSK9, and using the SPR method to detect the binding ability of the inhibitor to PCSK9 protein in the method, wherein the KD value is less than 1000 nM; preferably, the KD value is less than 100 nM; more preferably, the KD value is less than 50 nM; and most preferably, the KD value is less than 10 nM.

[0024] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gln587 of human PCSK9, and using the SPR method to detect the binding ability of the inhibitor to PCSK9 protein in the method, wherein the KD value is less than 1000 nM; preferably, the KD value is less than 100 nM; more preferably, the KD value is less than 50 nM; and most preferably, the KD value is less than 10 nM.

[0025] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from human PCSK9, namely Val589 and Ser636, and further binding to the amino acid residue Asn586 of human PCSK9.

[0026] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from human PCSK9, namely Val589 and Ser636, and further binding to amino acid residue His591 of human PCSK9.

[0027] In a preferred embodiment of the present invention, the inhibitor in the method is an allosteric inhibitor.

[0028] In a preferred embodiment of the invention, the method includes contacting the surface of PCSK9-secreting cells with the inhibitor.

[0029] In a preferred embodiment of the invention, the method includes contacting intracellular PCSK9 with the inhibitor.

[0030] In a preferred embodiment of the invention, the method includes contacting PCSK9 circulating in plasma with the inhibitor.

[0031] In a preferred embodiment of the present invention, the inhibitor in the method comprises a hydrogen bond donor portion and a hydrogen bond acceptor portion that bind to the amino acid residue Val589.

[0032] In a preferred embodiment of the invention, the inhibitor in the method comprises a hydrogen bond donor portion and a hydrogen bond acceptor portion that binds to the amino acid residue Val589.

[0033] In a preferred embodiment of the present invention, the inhibitor in the method comprises a hydrogen bond donor portion that binds to the amino acid residue Gln587, or a hydrogen bond acceptor portion that binds to the amino acid residue Gln587, or a hydrogen bond donor portion and a hydrogen bond acceptor portion that bind to the amino acid residue Gln587.

[0034] In a preferred embodiment of the present invention, the inhibitor in the method comprises a hydrogen bond donor portion that binds to the amino acid residue Gln587, or comprises a hydrogen bond acceptor portion that binds to the amino acid residue Gln587, or comprises a hydrogen bond donor portion and a hydrogen bond acceptor portion that bind to the amino acid residue Gln587.

[0035] In a preferred embodiment of the present invention, the inhibitor further comprises a hydrogen bond donor moiety that binds to the amino acid residue Ala637.

[0036] And / or, the hydrogen-bonded acceptor portion that binds to the amino acid residue His591,

[0037] And / or, the hydrogen bond acceptor portion that binds to the amino acid residue Ser564,

[0038] And / or, the cationic-π interaction moiety that binds to amino acid residue Arg495,

[0039] And / or, the hydrogen bond acceptor portion that binds to the amino acid residue Gly640.

[0040] In a preferred embodiment of the present invention, the inhibitor further comprises a hydrogen bond donor portion that binds to the amino acid residue Gly572.

[0041] In a preferred embodiment of the invention, the inhibitor interacts with at least one residue in the C-terminal M2 domain and at least one residue in the C-terminal M3 domain of PCSK9.

[0042] In a preferred embodiment of the invention, the inhibitor further interacts with at least one residue in the C-terminal M1 domain of PCSK9 in the method.

[0043] In a preferred embodiment of the invention, the inhibitor interacts with at least one residue in the C-terminal M1 domain and at least one residue in the C-terminal M3 domain of PCSK9.

[0044] In a preferred embodiment of the invention, the inhibitor interacts with at least one residue in the C-terminal M1 domain and at least one residue in the C-terminal M2 domain of PCSK9 in the method.

[0045] In a preferred embodiment of the invention, the inhibitor interacts with pockets in PCSK9 between amino acid residues 558-592 in the C-terminal M2 domain and between amino acid residues 631-650 in the C-terminal M3 domain; preferably, the interaction occurs between amino acid residues 558-590 in the C-terminal M2 domain and between amino acid residues 631-650 in the C-terminal M3 domain.

[0046] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridine ring, wherein the nitrogen atom on the pyridine ring acts as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9.

[0047] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridazine ring, wherein the nitrogen atom on the pyridazine ring acts as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9.

[0048] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridazine ring or a pyridine ring with a cyano substituent, wherein the nitrogen atom on the cyano group acts as a hydrogen bond acceptor on the Gln587 amino acid residue of the C-terminal M2 domain of PCSK9.

[0049] In a preferred embodiment of the present invention, the inhibitor in the method comprises a cyano-substituted pyridine-pyrrole ring, wherein the nitrogen atom on the pyridine acts as a hydrogen bond acceptor to the Val589 amino acid residue in the C-terminal M2 domain of PCSK9, the NH atom on the pyrrole acts as a hydrogen bond donor to the Gln587 amino acid residue in the C-terminal M2 domain of PCSK9, and the nitrogen atom on the cyano group acts as a hydrogen bond acceptor to the Gln587 amino acid residue in the C-terminal M2 domain of PCSK9.

[0050] In a preferred embodiment of the present invention, the inhibitor in the method comprises a cyano-substituted imidazopyridine ring, wherein the nitrogen atom on the imidazo acts as a hydrogen bond acceptor and interacts with the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and the nitrogen atom on the cyano acts as a hydrogen bond acceptor and forms a hydrogen bond network with the Asn586 amino acid residue of the C-terminal M2 domain of PCSK9 through a water bridge.

[0051] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridine ring, wherein the nitrogen atom on the pyridine ring acts as a hydrogen bond acceptor and forms a hydrogen bond network with Ser564 and His591 of the C-terminal M2 domain of PCSK9 via a water bridge.

[0052] In a preferred embodiment of the present invention, the inhibitor in the method comprises a diaminocyclopentane structure, wherein an NH group acts as a hydrogen bond donor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9.

[0053] In a preferred embodiment of the present invention, the inhibitor in the method comprises a diaminocyclopentane structure, wherein an NH group acts as a hydrogen bond donor on the Ala637 amino acid residue of the C-terminal M3 domain of PCSK9.

[0054] In a preferred embodiment of the invention, the inhibitor in the method comprises a pyridine ring, which forms a cation-π interaction with Arg495 at the C-terminus of PCSK9.

[0055] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridone ring, wherein the oxygen atom on the pyridone ring acts as a hydrogen bond acceptor on the Gly640 amino acid residue of the C-terminal M3 domain of PCSK9.

[0056] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyrazolopyrazinone ring, wherein the oxygen atom on the pyrazinone ring acts as a hydrogen bond acceptor on the Gly640 amino acid residue of the C-terminal M3 domain of PCSK9.

[0057] In a preferred embodiment of the present invention, the inhibitor in the method comprises an imidazopyrazinone ring, wherein the oxygen atom on the pyrazinone ring acts as a hydrogen bond acceptor on the Gly640 amino acid residue of the C-terminal M3 domain of PCSK9.

[0058] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridone ring, wherein the substituent chlorine atom on the pyridone ring interacts with the Gly572 amino acid residue of the C-terminal M2 domain of PCSK9 by forming a halogen bond.

[0059] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridine ring having a hydrophobic group that forms a hydrophobic interaction with a hydrophobic pocket formed by residues A637 and V644; preferably, the hydrophobic group is selected from halogen, methyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0060] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridone ring, which forms a π-π interaction with Trp566 at the C-terminus of PCSK9.

[0061] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridazine ring and / or a pyridine ring structure with a cyano substituent, wherein the nitrogen atom on the cyano group acts as a hydrogen bond acceptor on the Gln587 amino acid residue of the C-terminal M2 domain of PCSK9, and the nitrogen atom on the pyridine ring and / or the pyridazine ring acts as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9.

[0062] In a preferred embodiment of the present invention, the inhibitor in the method comprises a pyridone ring structure, wherein the substituent chlorine atom on the pyridone ring interacts with the Gly572 amino acid residue of the C-terminal M2 domain of PCSK9 by forming a halogen bond, and a pyridine ring and / or a pyridazine ring structure, wherein the nitrogen atom on the pyridine ring and / or the pyridazine ring acts as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9.

[0063] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, and further binds to the amino acid residue Gly572 of human PCSK9, wherein the inhibitor comprises a pyridazine ring and / or a pyridine ring structure, the nitrogen atom on the pyridazine ring and / or the pyridine ring acting as a hydrogen bond acceptor acting on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and a pyridone ring structure, wherein the substituent chlorine atom on the pyridone ring forms a halogen bond interaction with the Gly572 amino acid residue of the C-terminal M2 domain of PCSK9.

[0064] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, and further binds to the amino acid residue Gln587 of human PCSK9, wherein the inhibitor comprises a pyridazine ring and / or a pyridine ring structure with a cyano substituent, the nitrogen atom on the pyridazine ring and / or the pyridine ring acting as a hydrogen bond acceptor acting on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and the nitrogen atom on the cyano group acting as a hydrogen bond acceptor acting on the Gln587 amino acid residue of the C-terminal M2 domain of PCSK9. A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gly572 of human PCSK9, wherein the inhibitor comprises a nitrogen atom on a pyridazine ring acting as a hydrogen bond acceptor acting on the Val589 amino acid residue in the C-terminal M2 domain of PCSK9, and / or a diaminocyclopentane structure, wherein an NH atom acts as a hydrogen bond donor acting on the Val589 amino acid residue in the C-terminal M2 domain of PCSK9, and a substituent chlorine atom on a pyridone ring forming a halogen bond interaction with the Gly572 amino acid residue in the C-terminal M2 domain of PCSK9, and the binding ability of the inhibitor to PCSK9 protein is detected by HTRF method, IC50 50 Value less than 3000 nM; preferably, IC 50 Value less than 300 nM; more preferably, IC 50 Value less than 100 nM; most preferably, IC 50 The value is less than 30 nM.

[0065] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor, the inhibitor binding to amino acid residue Val589 of human PCSK9, not binding to amino acid residue Ser636 of human PCSK9, and further binding to amino acid residue Gln587 of human PCSK9, wherein the inhibitor comprises a nitrogen atom on a pyridazine ring acting as a hydrogen bond acceptor acting on the Val589 amino acid residue in the C-terminal M2 domain of PCSK9, and / or a diaminocyclopentane structure, wherein an NH atom acts as a hydrogen bond donor acting on the Val589 amino acid residue in the C-terminal M2 domain of PCSK9, and a pyridazine or pyridine ring with a cyano substituent, the nitrogen atom on the cyano group acting as a hydrogen bond acceptor acting on the Gln587 amino acid residue in the C-terminal M2 domain of PCSK9, and the binding ability of the inhibitor to PCSK9 protein is detected by HTRF method, IC50 50 Value less than 3000 nM; preferably, IC 50 Value less than 300 nM; more preferably, IC 50 Value less than 100 nM; most preferably, IC 50 The value is less than 30 nM.

[0066] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, and further binds to the amino acid residue Gly572 of human PCSK9, wherein the inhibitor comprises a nitrogen atom on a pyridazine ring acting as a hydrogen bond acceptor acting on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and / or a diaminocyclopentanol. The alkyl structure, wherein an NH atom acts as a hydrogen bond donor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and the substituent chlorine atom on the pyridone ring interacts with the Gly572 amino acid residue of the C-terminal M2 domain of PCSK9 to form a halogen bond. The binding ability of the inhibitor in the method to PCSK9 protein is detected by the SPR method, and the KD value is less than 1000 nM; preferably, the KD value is less than 100 nM; more preferably, the KD value is less than 50 nM; and most preferably, the KD value is less than 10 nM.

[0067] A preferred embodiment of the present invention relates to a method for inhibiting PCSK9, the method comprising contacting PCSK9 with a PCSK9 inhibitor that binds to the amino acid residue Val589 of human PCSK9, does not bind to the amino acid residue Ser636 of human PCSK9, and further binds to the amino acid residue Gln587 of human PCSK9, wherein the inhibitor comprises a nitrogen atom on a pyridazine ring acting as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9, and / or a diaminocyclopentane structure. One of the NH atoms acts as a hydrogen bond donor, interacting with the Val589 amino acid residue in the C-terminal M2 domain of PCSK9 and the pyridazine or pyridine ring of the cyano substituent. The nitrogen atom on the cyano group acts as a hydrogen bond acceptor, interacting with the Gln587 amino acid residue in the C-terminal M2 domain of PCSK9. The binding ability of the inhibitor to PCSK9 protein in the method is detected by the SPR method, and the KD value is less than 1000 nM; preferably, the KD value is less than 100 nM; more preferably, the KD value is less than 50 nM; and most preferably, the KD value is less than 10 nM.

[0068] Another object of the present invention is to provide a compound represented by general formula (IB), (I-B'), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compounds represented by general formula (IB), (I-B') have the following structures:

[0069] in:

[0070] X is selected from N or CR c-1 ;

[0071] Ring E is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0072] M5 is selected from N or CH; M6 is selected from N or CH; M5 and M6 are not both N;

[0073] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0074] L1 is selected from the bond, -C(O)- or -C(O)NH-;

[0075] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0076] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0077] Or, any two adjacent or non-adjacent R a Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl and 5-14 heteroaryl groups can optionally be further reacted with one or more R groups. a Replaced;

[0078] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0079] R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0080] Or, any two adjacent or non-adjacent R b Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups can optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0081] R c-1 R c-2 Or R c-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2)n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0082] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0083] Or, any two R c-1 R c-2 and R c-3 Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups can optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0084] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, -(CH2) n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NRD2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0085] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0086] Or, any two adjacent or non-adjacent R d Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups can optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0087] Or, R c-2 And one of the R d Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups can optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0088] x is 0, 1, 2, or 3; y 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; m1 is 1 or 2;

[0089] Preferably, the Not for In a preferred embodiment of the present invention, the Selected from 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl;

[0090] Preferred from

[0091] Wherein, the ring C' is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl; preferably from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl or 6-membered nitrogen-containing heteroaryl;

[0092] Ring D' is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl; preferably from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl or 6-membered nitrogen-containing heteroaryl;

[0093] M1 is selected from N or CH; M2 is selected from N or CH; M7 is selected from N or CH;

[0094] M3 is selected from N, O, S or CH; M4 is selected from N, O, S or CH.

[0095] In a preferred embodiment of the invention, the compound is further shown as in general formula (III), (IV) or (V):

[0096] Wherein: L1 is selected from bond, -C(O)- or -C(O)NH-; M1 is selected from N or CH; M2 is selected from N or CH;

[0097] M3 is selected from N, O, S, or CH; M4 is selected from N, O, S, or CH.

[0098] Ring C is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl; preferably from C 3-6Cycloalkyl, 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 or not present;

[0099] Ring D is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl; preferably from C 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group or not present.

[0100] Another object of the present invention is to provide a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as shown in general formulas (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IA-8), (IA-9), (IA-10), (IA-11), (IA-12), (IA-13), (IA-14), (IA-15), (IA-16), (IA-17), (IA-1'), (IA-2'), (IA-3'), (IA-4'), (IA-5'), (IA-6'), (IA-7'), (IA-8'), (IA-9'), (IA-10'), (IA-11'), (IA-4") or (IA-1").

[0101] in:

[0102] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0103] Ring H is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0104] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, alkathio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O)m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0105] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0106] Or, any two adjacent or non-adjacent R a The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0107] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n RB1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0108] R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0109] Or, any two adjacent or non-adjacent R b The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0110] Or, any two R a and R b The linkage forms a heterocyclic or heteroaryl group, which may optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0111] R c-1 R c-2 and R c-3 Selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) nNR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0112] Preferably, R c-1 R c-2 and R c-3 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, More preferably, R c-1 Selected from -F;

[0113] Or, any two R c-1 R c-2 and R c-3 The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0114] R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0115] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0116] Or, any two adjacent or non-adjacent R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0117] Or, any two R c and R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0118] R bb Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m Rcc 、-(CH2) n NR aa R bb 、-(CH2) n C(O)NR aa R bb 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R bb 、-(CH2) n P(O)R aa R bb 、-O(CH2) n P(O)R aa R bb 、-(CH2) n NR cc C(=NH)NR aa R bb 、-(CH2) n NR bb S(O) m R cc 、-OC(R aa R bb ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb 、-CH=CH(CH2) n NR bb C(O)R cc 、-CH=CH(CH2) n NR bb C(O)NR aa R bb 、-C≡C(CH2) n NR aa R bb 、-C≡C(CH2) n NR bb C(O)R cc 、-C≡C(CH2) n NR bb C(O)NR aa Rbb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0119] x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; e is 0, 1, 2, or 3; m is 0, 1, or 2;

[0120] n is 0, 1, 2, 3 or 4; n1 is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3;

[0121] Furthermore, the compound is not...

[0122] In a preferred embodiment of the present invention, the compound is further shown as of general formulas (I'-1-a), (I'-1-a'), and (I'-1-a”):

[0123] Where: X is selected from N or CR c-1 ;

[0124] R a-1 ~R a-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, oxo group, thio group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-12 Aryl, 5-14 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted by one or more substituents of aryl and 5-10 heteroaryl groups, and the C group is... 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0125] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0126] In a more preferred embodiment of the present invention, the compound is further such as general formula (IA-1-a), (IA-2-a), (IA-3-a), (IA-4-a), (IA-5-a), (IA-6-a), (IA-7-a), (IA -8-a), (IA-9-a), (IA-10-a), (IA-11-a), (I-1-aa), (I-1-a'-a), (IA-1-a-1), (IA-2-a-1), (IA-3-a-1), (IA- 4-a-1), (IA-5-a-1), (IA-6-a-1), (IA-7-a-1), (IA-8-a-1), (IA-9-a-1), (IA-10-a-1), (IA-11-a-1), (I-1- aa-1), (IA-12-a), (IA-13-a), (IA-14-a-1), (IA-15-a), (IA-16-a), (IA-17-a), (IA-4-a-2) or (IA-1-a-2):

[0127] In a more preferred embodiment of the present invention, the ring B is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14Aryl or 5-14 heteroaryl groups;

[0128] Preferably, ring B is selected from C. 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic, 7-10 membered bicyclic heterocyclic, 5 membered heteroaryl, 6 membered heteroaryl, 5 membered 5 membered bicyclic heteroaryl, 5 membered 6 membered bicyclic heteroaryl, 6 membered 5 membered bicyclic heteroaryl or 6 membered 6 membered bicyclic heteroaryl;

[0129] More preferably, ring B is selected from C. 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic heterocyclic group, 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl;

[0130] Preferably, ring B is selected from pyridine, pyrimidine, benzene,

[0131] In a further preferred embodiment of the invention, any of the compounds described above, their stereoisomers, or their pharmaceutically acceptable salts are characterized in that the compounds further conform to the general formulas (I'-A-1), (I'-A-2), (I'-A-3), (I'-A-4), (I'-A-5), (I'-A-6), (I'-A-1”), (I'-A-2”), (I'-A-3”), (I'-A-4”), (I'-A-5”), (I'-A-6”), (I'-B-1), (I'-B-2), (I'-B-3), (I'-B-4), (I'-C-1), (I'-C-2), (I'-C-3), (I'-C-4), (I'-D-1), (I'-D-2), (I'-D-2), (I' -D-3), (I'-D-4), (I'-D-5), (I'-F-1), (I'-A-1'), (I'-A-2'), (I'-A-3'), (I' -A-4'), (I'-B-1'), (I'-B-2'), (I'-B-3'), (I'-B-4'), (I'-C-1'), (I'-C-2'), (I'-C-3'), (I'-C-4'), (I'-D-1'), (I'-D-2'), (I'-D-3'), (I'-D-4'), (I'-D- 1"), (I'-D-2"), (I'-D-3"), (I'-D-4"), (I'-D-5"), (I'-D-6") or (I'-D-1"'):

[0132] in:

[0133] X is selected from N or CR c-1 X1 is selected from C, N, and CR. d-1 R d-11 or CR d-1 ;

[0134] X2 is selected from C, N, or CR. d-2 ;

[0135] X3 is selected from C, N, O, S, and CR. d-3 CR d-3 R d-31 or NR d-3 ;

[0136] X4 is selected from C, N, O, S, and CR. d-4 R d-4 CR d-4 or NR d-4 ;

[0137] X5 is selected from C, N, O, S, and CR. d-5 CR d-5 R d-51 or NR d-5 ;

[0138] X6 is selected from C, N, O, S, CR d-6 CR d-6 R d-61 or NR d-6 ;

[0139] X7 is selected from C, N, O, S, CR d-7 CR d-7 R d-71 or NR d-7 ;

[0140] Y1 is selected from C, N, O, S, CR a-1 CR a-1 R a-11 or NR a-1 ;

[0141] Y2 is selected from C, N, or CR. a-2 Y3 is selected from C, N, or CR. a-3 ;

[0142] Y5 is selected from C, N, O, S, CR a-5 CR a-5 R a-51 or NR a-5 ;

[0143] Y7 is selected from C, N, O, S, CR a-7 CR a-7 Ra-71 or NR a-7 ;

[0144] R a-1 ~R a-8 R a-11 R a-51 R a-71 Definition: R in general formula (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IA-8), (IA-9), (IA-10) or (IA-11) a-1 ~R a-4 ;

[0145] R c-1 ~R c-3 Definition: R in general formula (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IA-8), (IA-9), (IA-10) or (IA-11) c-1 R c-2 Or R c-3 The above;

[0146] R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 Definition: R in general formula (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IA-8), (IA-9), (IA-10) or (IA-11) d The above;

[0147] Or, R a-1 ~R a-8 and R b The interconnected components can form a ring-shaped system, wherein the ring-shaped system is C. 3-12 Cycloalkyl or 3-20 membered heterocyclic group; optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0148] R d-1 ~R d-7 and R c-2 The interconnected components can form a ring-shaped system, wherein the ring-shaped system is C. 3-12 Cycloalkyl or 3-20 membered heterocyclic group; optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0149] Ring G is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0150] R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)Rcc 、-(CH2) n C(O)OR cc 、-(CH2) n S(O) m R cc 、-(CH2) n NR aa R bb 、-(CH2) n C(O)NR aa R bb 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R bb 、-(CH2) n P(O)R aa R bb 、-O(CH2) n P(O)R aa R bb 、-(CH2) n NR cc C(=NH)NR aa R bb 、-(CH2) n NR bb S(O) m R cc 、-OC(R aa R bb ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb 、-CH=CH(CH2) n NR bb C(O)R cc 、-CH=CH(CH2) n NR bb C(O)NR aa R bb 、-C≡C(CH2) n NR aa R bb 、-C≡C(CH2) n NRbb C(O)R cc -C≡C(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted with one or more substituents of aryl and substituted or unsubstituted 5-14 heteroaryl groups; q is 0, 1, 2 or 3.

[0151] In a further preferred embodiment of the invention, any of the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof, are characterized in that the compounds further represent the general formulas (IE-1), (IE-2), (IE-3), (IE-1-a), (IE-1-b), (IE-1-c), (IE-2-b), and (IE-2-c):

[0152] It is preferably represented by the general formula (IE-1-1), (IE-2-1), (IE-3-1), (IE-1-1-a), (IE-1-1-b), (IE-1-1-c), (IE-2-1-b), (IE-2-1-c):

[0153] Among them, R aa Selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0154] Ring H is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0155] Ring G is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups;

[0156] R bb R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m Rcc 、-(CH2) n NR aa R bb 、-(CH2) n C(O)NR aa R bb 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R bb 、-(CH2) n P(O)R aa R bb 、-O(CH2) n P(O)R aa R bb 、-(CH2) n NR cc C(=NH)NR aa R bb 、-(CH2) n NR bb S(O) m R cc 、-OC(R aa R bb ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb 、-CH=CH(CH2) n NR bb C(O)R cc 、-CH=CH(CH2) n NR bb C(O)NR aa R bb 、-C≡C(CH2) n NR aa R bb 、-C≡C(CH2) n NR bb C(O)R cc 、-C≡C(CH2) n NR bb C(O)NR aa Rbb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0157] s is 0, 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3.

[0158] In a further preferred embodiment of the invention, any of the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof, are characterized in that the compounds further represent the general formulas (IF-1), (IF-2), (IF-3), (IF-4), (IF-5), (IF-6), (IF-1-a), (IF-2-a), (IF-3-a), (IF-4-a), (IF-1-b), (IF-2-b), (IF-3-b), (IF-4-b), (IF-5-b), (IF-6-b), (IF-1-c), (IF-2-c), (IF-3-c), and (IF-4-c):

[0159] Preferred are general formulas (IF-1-1), (IF-2-1), (IF-3-1), (IF-4-1), (IF-5-1), (IF-6-1), (IF-1-1-a), (IF-2-1-a), (IF-3-1-a), (IF-4-1-a), (IF- 1-1-b), (IF-2-1-b), (IF-3-1-b), (IF-4-1-b), (IF-5-1-b), (IF-6-1-b), (IF-1-1-c), (IF-2-1-c), (IF-3-1-c), (IF-4-1-c):

[0160] in:

[0161] M1 is selected from N or CR aa-1 M2 is selected from N or CR aa-2 M3 is selected from N or CR aa-3 M4 is selected from N or CR aa-4 ;R aa-1 R aa-2 R aa-3 R aa-4 As defined in weight 20, R a The preferred embodiment is R as defined in claim 21. a-1 ~R a-4 The above;

[0162] Or, R aa-1 R aa-2 R aa-3 R aa-4 and R b The interconnected components can form a ring-shaped system, wherein the ring-shaped system is C. 3-12 Cycloalkyl or 3-20 membered heterocyclic group; optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0163] In a further preferred embodiment of the present invention, the R described herein a and R a-1 ~R a-8 R a-11 R a-51 R a-71 R aa R aa- 1 R aa-2 R aa-3 R aa-4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0164] R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0165] Preferably, R a and R a-1 ~R a-8 R a-11 R a-51 R a-71 R aa R aa-1 R aa-2 R aa-3 R aa-4Selected from oxo groups, -O-CH(CH3)2, -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -CH2-CH3, -O-CH2-CF3, -CHF2, -CF3, -CD3, -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, -O-CH-(CH3)2, -C(O)OH, -C(O)CH3, -C(O)NH2, -CF2CH3, -C(O)CF3, -O-CH-(CF3)2.

[0166] In a further preferred embodiment of the present invention, the R of the present invention b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 RB3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0167] R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-12 heteroaryl groups; preferably, R b Selected from -H, -F, cyclopropyl, -NH2, or -OH.

[0168] In a further preferred embodiment of the present invention, the R described herein c and R c-1 ~R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0169] R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0170] Preferably, R c and R c-1 ~R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CD3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0171] More preferably, R c and R c-1 ~R c-3 Selected from -H, -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2,

[0172] In a further preferred embodiment of the present invention, the R described herein d and R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) nNR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0173] R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group;

[0174] Preferably, R d and R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CD3, -CH(CH3)2, -CH2-CH3, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH 2-OH, -O-CH3, -O-CHF2, -CHF2, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH, -C(O)NH2, -O-CF3, -CHF2-CH3,

[0175] In a further preferred embodiment of the present invention, the ring H is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0176] Preferably, the ring H is selected from C 6-10 Aryl, C 3-12 Cycloalkyl; more preferably, the cyclic H is selected from phenyl or cyclopropane.

[0177] In a further preferred embodiment of the present invention, the ring G is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl or 5-14 membered heteroaryl; preferably, ring G is selected from C. 3-8 cycloalkyl;

[0178] More preferably, cycloG is selected from cyclobutane.

[0179] In a further preferred embodiment of the invention, the compound contains Preferred from

[0180] In a further preferred embodiment of the invention, the compound contains Selected from Where R c-1 R c-2 and R c-3 The definition of R is the same as above. c-1 R c-2 and R c-3 The definition of .

[0181] In a further preferred embodiment of the present invention, the R described herein c-1 Selected from F.

[0182] The present invention further provides a compound of general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0183] Wherein, Ry is selected from hydrogen, amino protecting group, 5-6 membered heteroaryl, and 5-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl and 5-6 membered heterocyclic group are optionally further modified by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0184] The amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, methoxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl, or p-methoxyphenyl; the remaining groups are as described above.

[0185] The present invention further provides a method for preparing the compound represented by general formula (I'-A-1), comprising the following steps:

[0186] Wherein, M is a halogen or a methanesulfonate, and the methanesulfonate is preferably a trifluoromethanesulfonate;

[0187] The reaction of general formula compound (INT-1) and general formula compound (VI) yields general formula compound (I'-A-1);

[0188] The other groups are as described above.

[0189] The reaction may optionally include a metal catalyst, catalyst ligand, base, and solvent.

[0190] The metal catalyst is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous chloride, tetra(triphenylphosphine)palladium, palladium acetate, triphenylphosphine dichloride, Pd(dppf)Cl2, or Pd2(dba)3; preferably, the catalyst is selected from cuprous iodide.

[0191] The catalyst ligand is selected from one or more of N,N'-dimethyl-1,2-cyclohexanediamine, (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine, (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine, L-proline, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, Xantphos, Sphos, Xphos, Bretphos, Ruphose, triphenylphosphine, or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; preferably, the catalyst ligand is selected from N,N'-dimethyl-1,2-cyclohexanediamine or (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine or (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine;

[0192] The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, cesium fluoride, sodium trimethylsiloxane, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium bis(trimethylsilylamino)amine, or lithium diisopropylamino; preferably, the base is selected from N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate.

[0193] The solvent is selected from one or more of ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, or xylene; preferably, the solvent is selected from 1,4-dioxane, N,N-dimethylformamide, or dimethyl sulfoxide.

[0194] The reaction temperature is 60-150℃: preferably, the reaction temperature is 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, 130℃ or 140℃; more preferably, the reaction temperature is selected from 100℃ or 110℃ or 120℃.

[0195] The reaction time is 1 hour to 16 hours; preferably, the reaction time is selected from 4 hours, 5 hours, 6 hours, 7 hours or 8 hours.

[0196] In a preferred embodiment of the invention, the inhibitor in the method is a compound having the above-described form or a pharmaceutically acceptable salt thereof.

[0197] In a preferred embodiment of the invention, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is a PCSK8 inhibitor that binds to the amino acid residue Val589 of human PCSK9 but not to the amino acid residue Ser636 of human PCSK9; preferably,

[0198] The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof further binds to the amino acid residue Gly572 of human PCSK9;

[0199] And / or, the compound, its stereoisomer or its pharmaceutically acceptable salt may further bind to the amino acid residue Gln587 of human PCSK9;

[0200] And / or, the compound, its stereoisomer or its pharmaceutically acceptable salt may further bind to the amino acid residue Asn586 of human PCSK9;

[0201] And / or, the compound, its stereoisomer or its pharmaceutically acceptable salt may further bind to the amino acid residue His591 of human PCSK9;

[0202] And / or, the compound, its stereoisomer or its pharmaceutically acceptable salt may further bind to the amino acid residue Ala637 of human PCSK9;

[0203] And / or, the compound, its stereoisomer or its pharmaceutically acceptable salt may further bind to the amino acid residue Arg495 of human PCSK9;

[0204] And / or, the compound, its stereoisomer, or its pharmaceutically acceptable salt may further bind to the amino acid residue Gly640 of human PCSK9.

[0205] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0206] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of PCSK9 inhibitor medicaments.

[0207] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of LDL-lowering drugs.

[0208] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or their symptoms; preferably, in the preparation of medicaments for stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0209] The present invention further relates to any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of methods for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or related diseases or their symptoms, preferably in the preparation of methods for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0210] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, comprising administering to a patient a therapeutically effective dose of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0211] Further, the compound, its stereoisomer, or its pharmaceutically acceptable salt constitutes 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, even more preferably 10% to 50%, even more preferably 15% to 40%, even more preferably 20% to 30%, and even more preferably 20% to 25% (based on the total weight of the pharmaceutical composition).

[0212] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to PCSK9.

[0213] The present invention also relates to methods for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease in mammals, comprising administering to said mammals a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0214] The compounds of the present invention have good solubility (including thermodynamic solubility and kinetic solubility), and their solubility can reach a level of moderate or higher. In particular, the good solubility makes the compounds of the present invention have better drug-like properties. Attached Figure Description

[0215] Figure 1 is a schematic diagram of the crystal structure of PCSK9 bound to compound 83. The arrows indicate hydrogen bond donors and acceptors, and the dotted lines indicate cation-π bonds.

[0216] Figure 2 is a schematic diagram of the crystal structure of PCSK9 bound to compound 298. The arrows indicate hydrogen bond donors and acceptors, and the dotted lines indicate cation-π bonds.

[0217] Figure 3 is a schematic diagram of the crystal structure of PCSK9 bound to compound 301, with arrows indicating hydrogen bond donors and acceptors.

[0218] Figure 4 is a schematic diagram of the crystal structure of PCSK9 bound to compound 310, with arrows indicating hydrogen bond donors and acceptors.

[0219] Figure 5 is a schematic diagram of the crystal structure of PCSK9 bound to compound 261. The arrows indicate hydrogen bond donors and acceptors, and the dotted lines indicate cation-π bonds.

[0220] Figure 6 is a schematic diagram of the crystal structure of PCSK9 bound to compound 411. Arrows indicate hydrogen bond donors and acceptors, and dotted lines indicate cation-π bonds.

[0221] Figure 7 is a schematic diagram of the crystal structure of PCSK9 bound to compound 479. The arrows indicate hydrogen bond donors and acceptors, the dotted lines represent cation-π bonds, and the dots on the lines represent π-π interactions.

[0222] Figure 8 is a schematic diagram of the crystal structure of PCSK9 bound to compound 310. Arrows indicate hydrogen bond donors and acceptors, dotted lines represent cation-π bonds, and dots on lines represent π-π interactions.

[0223] Figure 9 is a schematic diagram of the crystal structure of PCSK9 bound to compound 495. Arrows indicate hydrogen bond donors and acceptors, dotted lines represent cation-π bonds, and dots on lines represent π-π interactions.

[0224] Figure 10 is a schematic diagram of the crystal structure of PCSK9 bound to compound 499. The arrows indicate hydrogen bond donors and acceptors, the dotted lines represent cation-π bonds, and the dots on the lines represent π-π interactions.

[0225] Figure 11 is a schematic diagram of the crystal structure of PCSK9 bound to compound 673. Arrows indicate hydrogen bond donors and acceptors as well as halogen bond interactions. Dotted lines represent cation-π bonds, and dots on lines represent π-π interactions.

[0226] Figure 12 is a schematic diagram of the crystal structure of PCSK9 bound to compound 829. Arrows indicate hydrogen bond donors and acceptors as well as halogen bond interactions. Dotted lines represent cation-π bonds, and dots on lines represent π-π interactions.

[0227] Figure 13 is a schematic diagram of the crystal structure of PCSK9 bound to compound 1011. Arrows indicate hydrogen bond donors and acceptors as well as halogen bond interactions. Dotted lines represent cation-π bonds, and dots on lines represent π-π interactions.

[0228] Detailed description of the invention

[0229] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0230] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0231] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, where the alkylene is either substituted or unsubstituted.

[0232] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexenediyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0233] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0234] wait;

[0235] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0236] wait.

[0237] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0238] wait.

[0239] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0240] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups; or, preferably, it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, further preferably, it contains 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclic groups containing 1 to 3 nitrogen and / or oxygen atoms.

[0241] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0242] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0243] wait.

[0244] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, they are 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered and 5-membered or 5-membered and 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0245] wait.

[0246] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0247] wait.

[0248] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0249] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0250] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0251] wait.

[0252] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0253] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered monocyclic heteroaryl or 8-12-membered bicyclic heteroaryl, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, pyridazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl.

[0254] The bicyclic heteroaryl group is preferably a 5-membered 5-membered bicyclic heteroaryl group, a 5-membered 6-membered bicyclic heteroaryl group, a 6-membered 5-membered bicyclic heteroaryl group, or a 6-membered 6-membered bicyclic heteroaryl group. Non-limiting examples include:

[0255] The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0256] wait.

[0257] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo, or carboxylic acid ester group.

[0258] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0259] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0260] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0261] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0262] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0263] "Alkyne" refers to (CH≡C-), where the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0264] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0265] "Hydroxy" refers to the -OH group. "Halogen" refers to fluorine, chlorine, bromine, or iodine. "Amino" refers to -NH2.

[0266] "Cyano" refers to -CN. "Nitro" refers to -NO2. "Carbonyl" refers to -C(O)-. "Carboxyl" refers to -C(O)OH.

[0267] "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "MeCN" refers to acetonitrile.

[0268] "DMF" refers to N,N-dimethylformamide. "DIPEA" refers to diisopropylethylamine. "TFA" refers to trifluoroacetic acid.

[0269] “DMA” refers to N,N-dimethylacetamide. “Et2O” refers to diethyl ether. “DCE” refers to 1,2-dichloroethane.

[0270] "DIPEA" refers to N,N-diisopropylethylamine. "NBS" refers to N-bromosuccinimide.

[0271] “NIS” refers to N-iodosuccinimide. “Cbz-Cl” refers to benzyl chloroformate. “MeLi” refers to methyllithium.

[0272] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium. “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0273] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0274] "KHMDS" refers to potassium hexamethyldisilamide. "LiHMDS" refers to lithium bistrimethylsilamide.

[0275] “n-BuLi” refers to n-butyllithium. “NaBH(OAc)3” refers to sodium triacetoxyborohydride.

[0276] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0277] In the compounds described in this invention, the enol and lactam structures are tautomers, and those skilled in the art should know that they are the same molecule. They are the same molecule.

[0278] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0279] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0280] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0281] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0282] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0283] The compounds described herein that bind to amino acids or residues refer to the interactions between the compounds of this invention and the PCSK9 protein through interactions including but not limited to hydrogen bonds, halogen bonds, salt bridges, π-π interactions, cation-π interactions, and hydrophobic interactions. Detailed Implementation

[0284] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0285] Example

[0286] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer in the following solvents: deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O), with tetramethylsilane (TMS) as the internal standard (if applicable).

[0287] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0288] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for TLC separation and purification is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0289] The compounds of this invention have significant advantages in terms of drug properties such as solubility, permeability, and safety.

[0290] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0291] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0292] The eluent system for silica gel column chromatography and the developing solvent system for thin-layer chromatography used in the intermediates and the purification compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0293] Unless otherwise specified, in the embodiments of the present invention, the ratio of the mobile phase in the HPLC chiral separation condition and the HPLC chiral analysis condition is a volume ratio.

[0294] Intermediate 1

[0295] (1S,3S)-N1-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0296] Step 1: 2-Chloro-5-(difluoromethoxy)pyrimidine 1A (2.0 g, 11.1 mmol), (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (2.44 g, 12.2 mmol), and diisopropylethylamine (2.86 g, 14.08 mmol) were dissolved in dimethyl sulfoxide (10 mL). The reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated sodium chloride solution (50 mL). The mixture was dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to obtain (1S,3S)-3-((5-(difluoromethoxy)pyrimidine-2-yl)amino)cyclopentylcarbamate tert-butyl ester 1B (2.1 g), yield: 55.1%. MS m / z (ESI): 345.2 [M+H] + .

[0297] Step 2: Dissolve 1B (2.1 g, 6.1 mmol) in methanol (10 mL), add dioxane solution of hydrochloric acid (4 M, 20 mL), and stir the reaction at room temperature for 2 hours. Concentrate the reaction solution, add ammonia methanol solution (7 M, 10 mL) to adjust the pH to weakly alkaline, concentrate again, and purify the residue by silica gel chromatography (elution system A) to obtain (1S,3S)-N. 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine intermediate 1 (1.3 g), yield: 87.3%. MS m / z (ESI): 245.1 [M+H] + .

[0298] Intermediate 2

[0299] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0300] Step 1: 2-Fluoro-5-iodopyridine 2A (5 g, 22.4 mmol), 2-hydroxypyridine (2.35 g, 24.7 mmol), cuprous iodide (427 mg, 2.24 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (159 mg, 1.12 mmol), and cesium carbonate (9.5 g, 29.2 mmol) were dissolved in 1,4-dioxane (75 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into 100 mL of water. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 6'-fluoro-2H-[1,3'-bipyridine]-2-one 2B (3.1 g), yield: 72.7%. MS m / z (ESI): 191.1 [M+H] + .

[0301] Step 2: (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridine]-2-one 2B (2.85 g, 14.9 mmol), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were dissolved in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)aminocarbamate 2C (2.9 g), yield: 78.4%. MS m / z (ESI): 371.2 [M+H] + .

[0302] Step 3: 2.9 g (7.83 mmol) of tert-butyl ((1S,3S)-3-((2-carbonyl-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)aminocarbamate 2C was dissolved in 30 mL of 4 M dioxane hydrochloride solution, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reversed-phase chromatography (eluting system C) to give intermediate 2 (1.5 g) of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 70.9%. MS m / z (ESI): 271.2 [M+H] + .

[0303] Reference Example 1

[0304] 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0305] Step 1: Under nitrogen protection, Reference Example 1a (10.00 g, 51.55 mmol), bis-pinacol borate (19.64 g, 77.33 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (3.79 g, 5.16 mmol), and potassium acetate (10.10 g, 103.11 mmol) were dissolved in 1,4-dioxane (200 mL), and the mixture was heated to 90 °C and stirred for 3 hours. The reaction solution was filtered, and the organic phase was concentrated to obtain the crude product (5,6-difluoro-3-pyridyl)boronic acid (Reference Example 1b, 7.60 g). The product was used directly in the next step of the reaction without purification. MS m / z (ESI): 160.0 [M+H] + .

[0306] Step 2: Reference Example 1b (6.00 g, 37.76 mmol) and hydrogen peroxide (12.84 g, 113.28 mmol, 30% aqueous solution) were dissolved in 1,4-dioxane (100 mL) and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL) and saturated sodium chloride (100 mL). The organic phase was dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to give 5,6-difluoro-3-hydroxypyridine (Reference Example 1c) (3.20 g), yield: 64.6%. MS m / z (ESI): 132.0 [M+H] + .

[0307] Step 3: Reference Example 1c (5.00 g, 38.14 mmol) and cesium carbonate (18.60 g, 57.22 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature and stirred for 30 minutes. Under nitrogen protection, sodium 2-chloro-2,2-difluoroacetate (11.90 g, 76.29 mmol) was added to the reaction solution, and the mixture was 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 (eluting system A) to give 5-(difluoromethoxy)-2,3-difluoropyridine (Reference Example 1d) (2.60 g), yield: 37.6%. MS m / z (ESI): 182.0 [M+H] + .

[0308] Step 4: Following the synthetic method of Intermediate 1 in Step 1, 6'-(((1S,3S)-3-((5-(difluoromethoxy)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one was synthesized (Ref. Example 1). MS m / z (ESI): 432.2 [M+H] + .

[0309] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,1H),7.80(d,1H),7.60(m,1H),7.42(m,3H),7.04(t,1H),6.93(d,1H),6.72(m ,1H),6.53(d,1H),6.44(m,1H),6.27(m,1H),4.45(m,1H),4.33(m,1H),2.11(m,2H),1.93(m,2H),1.52(m,2H).

[0310] See Example 2

[0311] 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

[0312] Step 1: 4-(trifluoromethyl)pyridine-2-amine (5 g, 30.84 mmol) and ethyl N-(thiomethylene)carbamate (4.85 g, 37.01 mmol) were dissolved in 1,2-dichloroethane (50 mL) at room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain N-[[4-(trifluoromethyl)-2-pyridyl]aminomethylthiazolyl]carbamate (Reference Example 2a, 9.05 g). The product did not require purification and was used directly in the next reaction step.

[0313] MS m / z(ESI): 294.1 [M+H] + .

[0314] Step 2: Reference Example 2a (9 g, 30.69 mmol), hydroxylamine hydrochloride (10.66 g, 153.44 mmol), and N,N-diisopropylethylamine (11.90 g, 92.07 mmol) were dissolved in methanol (100 mL) at room temperature and stirred for 20 minutes. The mixture was then heated to 65 °C and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine (Reference Example 2b, 5.0 g), yield: 80.60%. MS m / z (ESI): 203.1 [M+H] + .

[0315] Step 3: Dissolve Reference Example 2b (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). Stir the reaction mixture at room temperature for 0.5 hours, then heat to 70 °C and stir for 2 hours. Concentrate the reaction mixture, dilute the residue with ethyl acetate (150 mL), filter, wash the organic phase with water (100 mL), concentrate, and purify the residue by silica gel column chromatography (elution system A) to give 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (Reference Example 2c, 5 g), yield 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0316] Step 4: Under nitrogen protection, 4.5 g (16.92 mmol) of Reference Example 2c, 3.39 g (16.92 mmol) of N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylacetone)dipalladium (2.32 g, 2.54 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.94 g, 5.07 mmol) were dissolved in 1,4-dioxane (120 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]tert-butyl carbamate (Reference Example 2d, 3.7 g), yield: 56.76%.

[0317] MS m / z (ESI): 386.2 [M+H] + .

[0318] Step 5: At room temperature, dissolve Reference Example 2d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) in methanol (10 mL) and stir for one hour. Concentrate the reaction solution, dilute the residue with methanol, and adjust the pH to 8-10 with saturated sodium bicarbonate solution. After concentration, purify the residue by silica gel column chromatography (elution system A) to give (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 2e) (2.74 g), yield: 100%. MS m / z (ESI): 286.2 [M+H] + .

[0319] Step 6: Dissolve Reference Example 2e (2.74 g, 9.61 mmol), 2-fluoro-5-nitro-pyridine (1.50 g, 10.57 mmol), and cesium carbonate (7.82 g, 24.01 mmol) in N,N-dimethylformamide (40 mL) and heat to 80 °C with stirring for 16 hours. Filter the reaction mixture and concentrate the filtrate. Purify the residue by silica gel column chromatography (elution system B) to give (1S,3S)-N1-(5-nitropyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (Reference Example 2f, 3.8 g), yield: 97.12%.

[0320] MS m / z (ESI): 408.1 [M+H] + .

[0321] Step 7: Under a hydrogen atmosphere, dissolve Reference Example 2f (3.8 g, 9.33 mmol) and palladium on carbon (993 mg, 0.93 mmol, purity: 10%) in methanol (60 mL) and stir at room temperature for 2 hours. Filter the reaction solution and concentrate to obtain N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine (Reference Example 2 g, 3.2 g). The product does not require purification and can be used directly in the next reaction.

[0322] MS m / z(ESI): 378.1 [M+H] +

[0323] Step 8: Dissolve 2 g (2.0 g, 5.30 mmol) of Reference Example, methyl 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 4.24 mmol) and N,N-diisopropylethylamine (2.05 g, 15.90 mmol) in a mixed solvent of tert-butanol (20 mL) and N,N-dimethylformamide (4 mL), stir at room temperature for 1 hour, then heat to 40 °C and stir for 16 hours, and then heat to 80 °C and stir for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to give 6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Reference Example 2, 1.2 g), yield: 45.79%. MS m / z (ESI): 495.2 [M+H] +

[0324] 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).

[0325] See Example 3

[0326] 6-(5-Fluoro-6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0327] Step 1: Reference Example 2e (150 mg, 0.53 mmol), 2,3-difluoro-5-nitro-pyridine (93 mg, 0.58 mmol), and cesium carbonate (428 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to give (1S,3S)-N1-(3-fluoro-5-nitro-2-pyridyl)-N3-[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine (Reference Example 3a, 180 mg), yield: 80.5%. MS m / z (ESI): 426.1 [M+H] + .

[0328] Step 2: Under a hydrogen atmosphere, Reference Example 3a (158 mg, 0.37 mmol) and palladium / carbon (40 mg, 0.037 mmol, purity: 10%) were dissolved in methanol (10 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give 3-fluoro-N2-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridin-2,5-diamine (Reference Example 3b, 131 mg), yield: 88.5%. MS m / z (ESI): 396.1 [M+H] + .

[0329] Step 3: Reference Example 3b (131 mg, 0.33 mmol), methyl 3-(bromomethyl)pyridine-2-carboxylic acid (85 mg, 0.28 mmol), and N,N-diisopropylethylamine (107 mg, 0.83 mmol) were dissolved in a mixed solvent of n-butanol (6 mL) and N,N-dimethylformamide (0.5 mL). The mixture was heated to 40 °C and stirred for 11 hours, then heated to 110 °C and stirred for 5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to give Reference Example 3 (100.4 mg), yield: 70.7%. MS m / z (ESI): 513.2 [M+H] + .

[0330] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.76(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.85(s,1H),7.63(dd,1H),7.14 (dd,1H),7.01(d,1H),6.66(d,1H),4.96(s,2H),4.59–4.15(m,2H),2.24–2.10(m,2H),2.04–1.93(m,2H),1.68–1.51(m,2H).

[0331] Example 18

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

[0333] Step 1: Under nitrogen protection, (1S,3S)-3-aminocyclopentylcarbamate tert-butyl ester (800 mg, 3.99 mmol), 2-chloro-5-difluoromethoxypyridine (789 mg, 4.39 mmol), tris(dibenzylacetone)dipalladium (183 mg, 0.200 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (249 mg, 0.399 mmol), and cesium carbonate (2.60 g, 7.99 mmol) were dissolved in 1,4-dioxane and heated to 100 °C with stirring for 16 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl 18a (850 mg), yield: 62.0%. MS m / z (ESI): 344.1 [M+H] + .

[0334] Step 2: Dissolve 18a (850 mg, 2.48 mmol) in methanol (4 mL). Add dioxane hydrochloride solution (4 M, 4 mL) to the reaction solution with stirring. React at room temperature with stirring for 2 hours. Concentrate the reaction solution to obtain the crude product (1S,3S)-N1-(5-(difluoromethoxy)pyridin-2-yl)cyclopentane-1,3-diamine 18b. This product was used directly in the next reaction without purification. MS m / z (ESI): 244.1 [M+H] + .

[0335] Step 3: Under nitrogen protection, 18b (603 mg, 2.48 mmol), 2-fluoro-5-nitropyridine (526 mg, 3.70 mmol), and N,N-diisopropylethylamine (956 mg, 7.40 mmol) were dissolved in N,N-dimethylformamide (6 mL) and stirred for 16 hours at room temperature. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-N 1 -(5-(difluoromethoxy)pyridin-2-yl)-N 3 -(5-nitropyridin-2-yl)cyclopentane-1,3-diamine 18c (750 mg), yield: 83.2%. MS m / z (ESI): 366.1 [M+H] + .

[0336] Step 4: Under a hydrogen atmosphere, 18C (750 mg, 2.05 mmol) and palladium / carbon (218 mg, 0.205 mmol, purity: 10%) were dissolved in methanol (15 mL), and the reaction was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain N. 2 -((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine 18d (680 mg), yield: 98.8%. MS m / z (ESI): 336.1 [M+H] + .

[0337] Step 5: Under nitrogen protection, 18d (60 mg, 0.179 mmol) was dissolved in a mixture of tert-butanol (3 mL) and 1,2-dichloroethane (1 mL), and methyl 3-(bromomethyl)pyridine-2-carboxylic acid (41 mg, 0.179 mmol) and N,N-diisopropylethylamine (69 mg, 0.537 mmol) were added. The reaction was stirred at room temperature for 16 hours, then heated to 90 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel chromatography (elution system C) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (21.8 mg), yield: 26.9%. MS m / z (ESI): 453.2 [M+H] + .

[0338] 1H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.35(d,1H),8.11(d,1H),7.87(dd,1H),7.86(d,1H),7.61(dd,1H),7.28(dd,1H),6.97(t,1H),6 .72–6.65(m,2H),6.55(d,1H),6.49(d,1H),4.93(s,2H),4.32–4.23(m,2H),2.17–2.11(m,2H),1.88–1.84(m,2H),1.51-1.44(m,2H).

[0339] Example 41

[0340] 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0341] Step 1: Under nitrogen protection, 18b (530 mg, 2.18 mmol), 2,3-difluoro-5-nitropyridine (384 mg, 2.40 mmol), and N,N-diisopropylethylamine (845 mg, 6.54 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-N1-(5-(difluoromethoxy)pyridin-2-yl)-N3-(3-fluoro-5-nitropyridin-2-yl)cyclopentane-1,3-diamine 41a (700 mg), yield: 83.8%. MS m / z (ESI): 384.1 [M+H] + .

[0342] Step 2: Under a hydrogen atmosphere, 41a (700 mg, 1.83 mmol) and palladium / carbon (194 mg, 0.183 mmol, purity: 10%) were dissolved in methanol (7 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain N2-((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)-3-fluoropyridin-2,5-diamine 41b (640 mg). The product was used directly in the next step of the reaction without purification. MS m / z (ESI): 355.1 [M+H] + .

[0343] Step 3: Under nitrogen protection, 41b (60 mg, 0.170 mmol) was dissolved in a mixture of tert-butanol (3 mL) and 1,2-dichloroethane (1 mL). Methyl 3-(bromomethyl)pyridine-2-carboxylic acid (39 mg, 0.170 mmol) and N,N-diisopropylethylamine (66 mg, 0.509 mmol) were added with stirring. The reaction was stirred at room temperature for 16 hours, then heated to 90 °C and stirred for another 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution system C) to give 6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (25.4 mg), yield: 31.8%. MS m / z (ESI): 471.2 [M+H] + .

[0344] 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.25(s,1H),8.12(d,1H),8.03(d,1 H),7.86(s,1H),7.65-7.61(m,1H),7.28(d,1H),6.96(t,1H),6.71-6.65( m,2H),6.50(d,1H),4.96(s,2H),4.53-4.46(m,1H),4.31-4.23(m,1H),2. 19-2.10(m,2H),1.97–1.87(m,2H),1.62-1.55(m,1H),1.52-1.44(m,1H).

[0345] Example 68

[0346] 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino]-5-fluoropyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

[0347] Step 1: 18b (0.7 g, 2.88 mmol), 5-bromo-2,3-difluoropyridine (1.12 g, 5.76 mmol), and N,N-diisopropylethylamine (1.49 g, 11.5 mmol) were dissolved in dimethyl sulfoxide (12 mL), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried, and the concentrated residue was subjected to silica gel column chromatography (elution system A) to give (1S,3S)-N 1 -(5-bromo-3-fluoropyridin-2-yl)-N 3-(5-(difluoromethoxy)pyridin-2-yl)-cyclopentyl-1,3-diamine 68a (0.94 g), yield: 78%. MS m / z (ESI): 345.2 [M+H] + .

[0348] Step 2: Under nitrogen protection, 68a (80 mg, 0.192 mmol), 6,7-dihydroimidazolo[1,2-a]pyrazin-8(5H)-one (26 mg, 0.192 mmol), cuprous iodide (36 mg, 0.192 mmol), trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine (27 mg, 0.192 mmol) and cesium carbonate (187 mg, 0.575 mmol) were dissolved in dioxane (1 mL), and the mixture was heated to 120 °C and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC (formic acid system) to give 68 (31 mg) of 7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino]-5-fluoropyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one, yield: 34%. MS m / z (ESI): 474.2 [M+H] + .

[0349] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.86(d,1H),7.49(dd,1H),7.44(s,1H),7.28(dd,1H),7.18(s,1H),6.97(t,1H),6.72(d,2H),6.48( d,1H),4.48(h,1H),4.40(dd,2H),4.26(h,1H),4.05(dd,2H),2.20-2.08(m,2H),2.01-1.81(m,2H),1.67-1.52(m,1H),1.52-1.40(m,1H).

[0350] Example 298

[0351] 6-(((1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-nitrile

[0352] Step 1: Under nitrogen protection, (1S,3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester (500 mg, 1.34 mmol), pyrimidine-2,4(1H,3H)-dione (225 mg, 2.01 mmol), potassium phosphate (771 mg, 3.35 mmol), cuprous iodide (102 mg, 0.56 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (240 mg, 1.69 mmol) were dissolved in 1,4-dioxane (15 mL), heated to 100 °C, and stirred for 16 hours. After the reaction was complete, dichloromethane (30 mL) was added to the reaction solution, followed by filtration and concentration. The residue was purified by silica gel column chromatography (elution system A) to give a brown solid (1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate (100 mg) 298a, yield: 18.41%. MS m / z (ESI): 406.2 [M+H] + .

[0353] Step 2: At room temperature, 298a (100 mg, 0.25 mmol) was dissolved in dichloromethane (50 mL), and 1,4-dioxane hydrochloric acid solution (4 M, 5 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued to be stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol. Then, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and purified by silica gel column chromatography (elution system A) to obtain a white solid 1-(6-((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 298b (70 mg), yield: 92.95%. MS m / z (ESI): 306.1 [M+H] + .

[0354] Step 3: Under nitrogen protection, a mixture of 2-aminoisononin (3.0 g, 25.18 mmol) and ethyl 2-bromoacetate (25.23 g, 151.1 mmol) was heated to 70 °C and stirred for 2 hours. The reaction mixture was filtered, and the resulting filter cake was washed with ethyl acetate. After drying, the filter cake yielded a yellow solid, 298 c (4.5 g), ethyl 2-(4-cyano-2-iminopyridin-1(2H)-yl)acetate, yield: 87.07%. MS m / z (ESI): 206.1 [M+H] + .

[0355] Step 4: 298c (1.0 g, 4.87 mmol) was added to a phosphorus oxychloride (6.0 mL) solution at room temperature, followed by heating to 90 °C and stirring for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was diluted with saturated sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride (40 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give a white solid 2-chloroimidazolo[1,2-a]pyridine-7-nitrile 298d (100 mg), yield: 11.56%. MS m / z (ESI): 178.2 [M+H] + .

[0356] Step 5: Under nitrogen protection, 298d (58 mg, 0.33 mmol), 298b (100 mg, 0.33 mmol), sodium trimethylsiloxy (74 mg, 0.66 mmol), and [2-(dicyclohexylphosphine)-3-tert-butoxy-6-methoxy-2',6'-diisopropyl-1,1'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-1-yl)palladium bromide (31 mg, 0.033 mmol) were dissolved in a mixture of dimethyl sulfoxide (1.0 mL) and tetrahydrofuran (4.0 mL), and stirred at 90 °C for 6 hours. The reaction solution was diluted with dichloromethane (30 mL, containing 10% methanol), filtered, and the resulting filtrate was diluted with water (50 mL) and then extracted with dichloromethane (30 mL × 2, containing 10% methanol). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried, filtered, concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain a yellow solid 2-(((1S,3S)-3-((5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-fluoropyridin-2-yl)amino)cyclopentyl)amino)imidazo[1,2-a]pyridine-7-nitrile 298 (12 mg), yield: 8.21%. MS m / z (ESI): 447.2 [M+H] + .

[0357] 1 H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.43(d,1H),7.87(d,1H),7.80(s,1H),7.66(d,1H),7.55(dd,1H),7.29(s,1H),7.02(dd,1H ),6.95(d,1H),6.27(d,1H),5.63(d,1H),4.54-4.46(m,1H),4.03-3.98(m,1H),2.18-2.10(m,2H),1.95(t,2H),1.65-1.49(m,2H).

[0358] Example 301

[0359] 7-(5-Fluoro-6-(((1S,3S)-3-((2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one

[0360] Example 301 can also be synthesized by referring to the following method:

[0361] Step 1: Under nitrogen protection, (1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (3 g, 14.98 mmol), 5-bromo-2,3-difluoropyridine (5.81 g, 29.96 mmol), and N,N-diisopropylethylamine (5.81 g, 44.94 mmol) were dissolved in dimethyl sulfoxide (30 mL), and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction solution cooled to room temperature, it was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give a white solid (1S,3S)-3-((5-bromo-3-fluoropyridine-2-yl)amino)cyclopentyl)carbamate tert-butyl ester 301a (4.5 g), yield: 80%. MS m / z (ESI): 375.1 [M+H] + .

[0362] Step 2: Under nitrogen protection, 301a (1.36 g, 3.65 mmol), 6,7-dihydroimidazolo[1,2-a]pyrazin-8(5H)-one (500 mg, 3.65 mmol), cesium carbonate (2.38 g, 7.29 mmol), cuprous iodide (695 mg, 3.65 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (519 mg, 3.65 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was heated to 100 °C and stirred for 16 hours. Dichloromethane (50 mL) was added to the reaction solution, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give a brown solid (1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate 301b (1.2 g), yield: 76%. MS m / z (ESI): 431.1 [M+H] + .

[0363] Step 3: At room temperature, 301b (1.2 g, 2.79 mmol) was dissolved in dichloromethane (40 mL), and 1,4-dioxane hydrochloric acid solution (4 M, 20 mL) was slowly added dropwise with stirring. The reaction was continued with stirring at room temperature for 3 hours. The reaction solution was concentrated, and the residue was dissolved in methanol (20 mL). The solution was adjusted to alkalinity with saturated sodium bicarbonate solution, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give a yellow solid 7-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one 301c (900 mg), yield: 97%. MS m / z (ESI): 331.1 [M+H] + .

[0364] Step 4: Under nitrogen protection and in an ice bath, 6-chloro-1H-pyrrolo[2,3-b]pyridine (3.0 g, 19.66 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the slow addition of sodium hydride (1.04 g, 25.95 mmol, 10%) in portions. The reaction mixture was stirred in an ice bath for 30 minutes, and then a tetrahydrofuran solution of (2-(chloromethoxy)ethyl)trimethylsilane (3.93 g, 23.59 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred for 16 hours. A saturated ammonium chloride solution (50 mL) was added dropwise to the reaction mixture. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give a colorless oily liquid, 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 301d (3.5 g), yield: 62.94%. MS m / z (ESI): 283.2 [M+H] + .

[0365] Step 5: Under nitrogen protection, 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 6 (1.0 g, 3.54 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction solution was cooled to -65 °C with stirring. A 2.5 M, 1.8 mL, 4.5 mmol solution of n-butyllithium was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -65 °C for 1 hour. Subsequently, a tetrahydrofuran (30 mL) solution of elemental iodine (1.17 g, 4.60 mmol) was slowly added dropwise to the reaction solution, and the reaction was slowly raised to room temperature with stirring for 16 hours. The reaction mixture was quenched by dropwise addition of saturated ammonium chloride solution (30 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give a yellow oily liquid, 6-chloro-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 301e (1.2 g), yield: 83.04%. MS m / z (ESI): 409.2 [M+H] + .

[0366] Step 6: Under nitrogen protection, 301e (1.0 g, 2.45 mmol), methyl fluorosulfonyl difluoroacetate (940 mg, 4.89 mmol), and cuprous iodide (466 mg, 2.45 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the mixture was heated to 100 °C and stirred for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture. The organic phase was washed with water (30 mL × 3) and saturated sodium chloride (30 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 6-chloro-2-(trifluoromethyl)-1-((2-trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine 301f (751 mg), yield: 87.4%. MS m / z (ESI): 351.1 [M+H] + .

[0367] Step 7: Under nitrogen protection, 301f (50 mg, 0.142 mmol), 301c (47.1 mg, 5.99 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (13.86 mg, 0.014 mmol) and cesium carbonate (139.3 mg, 0.427 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and dimethyl sulfoxide (0.5 mL). The reaction was heated to 120 °C and stirred for 3 hours. Ethyl acetate (30 mL) was added to the reaction solution. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride (10 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 301 g (50.0 mg) of 7-(6-(((1S,3S)-3-((2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one, yield: 54.4%. MS m / z (ESI): 627.3 [M+H] + .

[0368] Step 8: Dissolve 301 g (50.0 mg, 0.077 mmol) in dioxane (1 mL), and add trifluoroacetic acid (1 mL) dropwise to the reaction solution with stirring. Stir the reaction at room temperature for 1 hour. Concentrate the reaction solution, and purify the residue by preparative HPLC (formic acid system) to obtain 7-(5-fluoro-6-(((1S,3S)-3-((2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one 301 (8.3 mg), yield: 20.8%. MS m / z (ESI): 515.2 [M+H] + .

[0369] 1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),7.89(d,1H),7.62(d,1H),7.49(dd,1H),7.42(s,1H),7.17(s,1H),6.82(d,1H),6.74-6.68(m, 2H),6.40(d,1H),4.53-4.47(m,1H),4.44-4.32(m,3H),4.12-4.03(m,2H),2.24-2.13(m,2H),2.03-1.93(m,2H),1.65-1.49(m,2H).

[0370] Example 310

[0371] 6-(((1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-nitrile

[0372] Example 310 can also be synthesized by referring to the following method:

[0373] Step 1: Under nitrogen protection, 301e (1.0 g, 2.45 mmol), zinc cyanide (216 mg, 1.83 mmol), tris(dibenzylacetone)palladium (224 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (272 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (6.0 mL). The mixture was microwaved to 110 °C and stirred for 1 hour. Water (10 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give a white solid 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-2-nitrile 310a (150 mg), yield: 19.92%. MS m / z (ESI): 308.2 [M+H] + .

[0374] Step 2: Under nitrogen protection, 310a (100 mg, 0.32 mmol), 301c (107 mg, 0.32 mmol), cesium carbonate (212 mg, 0.65 mmol), and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (31.6 mg, 0.033 mmol) were dissolved in a mixture of dimethyl sulfoxide (1.5 mL) and 1,4-dioxane (3.0 mL) and heated to 110 °C with stirring for 4 hours. The reaction solution was dissolved in dichloromethane (30 mL, containing 10% methanol), filtered, and the filtrate was diluted with water and then extracted with dichloromethane (30 mL × 2, containing 10% methanol). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give a yellow solid 6-(((1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-onitrile 310b (90 mg), yield: 46.04%. MS m / z (ESI): 602.2 [M+H] + .

[0375] Steps 3 and 4: At room temperature, 310b (80 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2.0 mL) solution was slowly added dropwise to the reaction solution with stirring. The reaction solution was stirred for 1 hour at room temperature. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (4 mL). Ammonia in methanol solution (7 M, 4.0 mL) was slowly added dropwise to the reaction solution with stirring, and the stirring was continued for 1 hour. The reaction solution was concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain a pale yellow solid 6-(((1S,3S)-3-((3-fluoro-5-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)-1H-pyrrolo[2,3-b]pyridin-2-onitrile 310 (45 mg), yield: 73.64%. MS m / z (ESI): 472.2 [M+H] + .

[0376] 1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),7.89(d,1H),7.61(d,1H),7.50(dd,1H),7.42(s,1H),7.17(s,1H),7.08-7.05(m,2H),6.73(d, 1H),6.44(d,1H),4.54-4.45(m,1H),4.41-4.35(m,3H),4.07-4.04(m,2H),2.22-2.12(m,2H),2.02-1.91(m,2H),1.66-1.47(m,2H).

[0377] Example 402

[0378] 5-Difluoromethoxy-2-(((1S,3S)-3-((3-fluoro-5-(2-methyl-8-oxo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)pyridin-2-yl)amino)cyclopentyl)amino)isoniconitrile

[0379] Step 1: Under nitrogen protection, 4-methyl-1H-imidazolium-2-carboxylic acid (880 mg, 6.98 mmol) was dissolved in ethanol (20 mL). The reaction solution was cooled to 0 °C with stirring. Thionyl chloride (8.3 g, 69.8 mmol) was slowly added dropwise to the reaction solution. The mixture was heated to 75 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated, adjusted to alkalinity with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain ethyl 4-methyl-1H-imidazolium-2-carboxylate 402a (709 mg), yield: 65.9%. MS m / z (ESI): 155.1 [M+H] + .

[0380] Step 2: Under nitrogen protection, 402a (709 mg, 4.57 mmol), tert-butyl 2-bromoethylaminocarbamate (1.43 g, 6.4 mmol), potassium carbonate (1.89 g, 13.71 mmol), and potassium iodide (76 mg, 0.457 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was heated to 85 °C and stirred for 16 hours. After the reaction was complete, ethyl acetate (50 mL) was added to the reaction solution. The organic phase was washed with water (30 mL × 3) and saturated sodium chloride aqueous solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain ethyl 1-(2-((tert-butyloxycarbonyl)amino)ethyl)-4-methyl-1H-imidazolium-2-carboxylate 402b (320 mg), yield: 24.8%. MS m / z (ESI): 298.2 [M+H] + .

[0381] Step 3: Dissolve 402b (320 mg, 1.13 mmol) in dichloromethane (10 mL), and slowly add 1,4-dioxane hydrochloride solution (4 M, 5 mL) dropwise with stirring. After the addition is complete, continue stirring at room temperature for 2 hours. Concentrate the reaction solution, dissolve the residue in methanol, adjust the pH to 8 with saturated sodium bicarbonate solution, and then purify by silica gel column chromatography (elution system A) to obtain ethyl 1-(2-aminoethyl)-4-methyl-1H-imidazolium-2-carboxylate 402c (210 mg), yield: 93.7%. MS m / z (ESI): 198.1 [M+H] + .

[0382] Step 4: Dissolve 402c (210 mg, 1.06 mmol) and triethylamine (536 mg, 5.3 mmol) in ethanol (10 mL), heat to 90 °C, and stir for 3 hours. After the reaction is complete, concentrate the reaction solution, dilute the residue with ethyl acetate (50 mL), wash with saturated sodium chloride (30 mL), dry, filter, concentrate, and purify the residue by silica gel column chromatography (elution system A) to obtain 2-methyl-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one 402d (150 mg), yield: 93.2%. MS m / z (ESI): 152.1 [M+H] + .

[0383] Step 5: 6-Chloro-4-iodopyridin-3-ol (2.0 g, 7.83 mmol) and potassium carbonate (3.25 g, 23.49 mmol) were dissolved in N,N-dimethylformamide (20 mL). Sodium 2-chloro-2,2-difluoroacetate (1.95 g, 12.8 mmol) was added with stirring. The reaction mixture was heated to 100 °C and stirred for 3 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated ammonium chloride aqueous solution (30 mL) and saturated sodium chloride aqueous solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (eluting system B) to obtain 2-chloro-5-difluoromethoxy-4-iodopyridinium 402e (1.82 g), yield: 75.8%. MS m / z (ESI): 305.9 [M+H] + .

[0384] Step 6: Dissolve 402e (1.82 g, 5.96 mmol) and cuprous cyanide (1.12 g, 11.92 mmol) in N-methylpyrrolidone (10 mL) and heat to 120 °C with stirring for 16 hours. After cooling the reaction solution to room temperature, dilute with ethyl acetate (100 mL). Wash the organic phase with saturated ammonium chloride aqueous solution (30 mL) and saturated sodium chloride aqueous solution (30 mL), dry, concentrate, and purify the residue by silica gel column chromatography (eluting system B) to obtain 2-chloro-5-difluoromethoxyisocyanuric acid 402f (1.15 g), yield: 94.3%. MS m / z (ESI): 205.0 [M+H] + .

[0385] Step 7: Under nitrogen protection, 402f (300 mg, 1.47 mmol), (1S,3S)-3-aminocyclopentylaminocarbamate tert-butyl ester (294 mg, 1.47 mmol), tris(dibenzylideneacetone)palladium (134 mg, 0.147 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (183 mg, 0.294 mmol) and cesium carbonate (1.43 g, 4.40 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was heated to 100 °C and stirred for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride aqueous solution (10 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 402 g (510.0 mg) of tert-butyl ((1S,3S)-3-((4-cyano-5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)carboxylate, yield: 94.4%. MS m / z (ESI): 369.2 [M+H] + .

[0386] Step 8: At room temperature, 402 g (510 mg, 1.38 mmol) was dissolved in methanol (3 mL), and a 1,4-dioxane hydrochloric acid solution (4 M, 3 mL) was added with stirring. The reaction was continued with stirring at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in methanol. The solution was then adjusted to pH 8 with saturated sodium bicarbonate solution and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(difluoromethoxy)isonicotinonitrile 402 h (310 mg), yield: 83.5%. MS m / z (ESI): 269.1 [M+H] + .

[0387] Step 9: Under nitrogen protection, 402h (310 mg, 1.16 mmol), 5-bromo-2,3-difluoropyridine (336 mg, 1.73 mmol), and N,N-diisopropylethylamine (299 mg, 2.31 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the mixture was heated to 90 °C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give 2-(((1S,3S)-3-((5-bromo-3-fluoropyridine-2-yl)amino)cyclopentyl)amino)-5-(difluoromethoxy)isonicotinonitrile 402i (320 mg), yield: 62.6%. MS m / z(ESI): 442.0[M+H]+.

[0388] Step 10: Under nitrogen protection, 402i (50 mg, 0.113 mmol), 402d (17.2 mg, 0.113 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (16.1 mg, 0.113 mmol), cuprous iodide (21.5 mg, 0.113 mmol), and cesium carbonate (110 mg, 0.339 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 120 °C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate (30 mL), the organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried, filtered, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 5-difluoromethoxy-2-(((1S,3S)-3-((3-fluoro-5-(2-methyl-8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)pyridin-2-yl)amino)cyclopentyl)amino)isonicotinonitrile 402 (12.5 mg), yield: 21.5%. MS m / z (ESI): 513.2 [M+H] + .

[0389] 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.80(d,1H),7.41(dd,1H),7.27(d,1H),7.09(t,1H),7.06(s,1H),6.81(s,1H),6.66(dd,1H),4.45-4 .38(m,1H),4.27-4.23(m,2H),4.21-4.17(m,1H),3.97-3.93(m,2H), 2.13-2.03(m,2H),2.09(s,3H),1.93-1.79(m,2H),1.56-1.38(m,2H).

[0390] Example 412

[0391] 3-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-4-fluoro-6,7-dihydro-11H-dipyrido[4,3-b:1',2'-d][1,4]oxazaphene-11-one

[0392] Step 1: Methyl hydroxypropionate (10 g, 96.06 mmol), imidazole (7.85 g, 115.27 mmol), and tert-butyldiphenylchlorosilane (31.68 g, 115.27 mmol) were dissolved in dichloromethane (100 mL) and stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain methyl 3-(tert-butyl(diphenyl)silyl)oxypropionate 412a (30 g), yield: 91.19%.

[0393] MS m / z(ESI): 343.1 [M+H] + .

[0394] Step 2: 412a (30 g, 87.59 mmol) and sodium hydroxide (10.51 g, 262.77 mmol) were dissolved in a mixed solvent of methanol (30 mL) and water (30 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated, and the pH of the residual aqueous solution was adjusted to 3 with dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried, filtered, and concentrated to give 3-(tert-butyl(diphenyl)silyl)oxypropionic acid 412b (28 g), yield: 97.32%. MS m / z (ESI): 329.1 [M+H] + .

[0395] Step 3: Dissolve 412b (12g, 30.44mmol) in dichloromethane (100mL), add N,N-dimethylformamide (222.52mg, 3.04mmol) and oxaloyl chloride (7.73g, 60.89mmol) under ice bath conditions, and continue stirring for 2 hours. Concentrate the reaction solution to obtain 3-(tert-butyl(diphenyl)silyl)oxypropionyl chloride 412c (12g), which is used directly in the next step of the reaction without purification.

[0396] Step 4: Dissolve 2,2,6-trimethyl-4H-1,3-dioxin-4-one (12.29 g, 86.47 mmol) in tetrahydrofuran (100 mL), cool to -65 °C, and stir. Add bis(trimethylsilylaminolithium) (1 M, 69.18 mL) dropwise to the reaction solution and stir for 0.5 hours. Add 412c (12 g, 34.59 mmol) of tetrahydrofuran (25 mL) dropwise to the reaction solution and stir for 1 hour. Quench the reaction with formic acid (3.18 g, 69.18 mmol) dropwise, filter, and concentrate. The residue was purified by silica gel column chromatography (elution system B) to 6–(4-(tert-butyl(diphenyl)silyl)oxy)-2-oxobutyl)2,2-dimethyl-1,3-dioxin-4-one 412d (10 g, 22.09 mmol), yield: 63.87%. MS m / z (ESI): 453.1 [M+H] + .

[0397] Step 5: Dissolve 2-chloro-3-fluoro-4-hydroxypyridine (1 g, 6.78 mmol) in acetonitrile (10 mL), and add dropwise a solution of N-bromosuccinimide (1.45 g, 8.13 mmol) in acetonitrile (10 mL). Stir the reaction mixture at room temperature for 2 hours. Concentrate the reaction solution, and purify the residue by silica gel column chromatography (elution system B) to obtain 5-bromo-2-chloro-3-fluoro-4-hydroxypyridine 412e (1.5 g), yield: 97.73%. MS m / z (ESI): 226.0, 228.0, 230.0 [M+H] + .

[0398] Step 6: Dissolve 412e (1.5 g, 6.62 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (3.31 g, 19.87 mmol), and N,N-diisopropylethylamine (4.28 g, 33.12 mmol) in N,N-dimethylformamide (15 mL) and stir at room temperature for 2 hours. Concentrate the reaction solution, and purify the residue by silica gel column chromatography (elution system B) to obtain 2-[(5-bromo-2-chloro-3-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridine 412f (1.7 g), yield: 71.95%. MS m / z (ESI): 356.0, 358.0, 360.0 [M+H] + .

[0399] Step 7: Under nitrogen protection, 412f (1.7g, 4.77mmol), tert-butyl carbamate (669.9mg, 5.72mmol), tris(dibenzylindeneacetone)dipalladium(0) (218.05mg, 0.24mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (275.48mg, 0.48mmol), and cesium carbonate (3.10g, 9.53mmol) were dissolved in 1,4-dioxane (2mL), and the mixture was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 412g (1.7g) of (6-chloro-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)tert-butyl carbamate, yield: 90.78%. MS m / z(ESI): 393.2 [M+H] + .

[0400] Step 8: At room temperature, 412 g (1300 mg, 3.31 mmol) was dissolved in methanol (10 mL), and dioxane hydrochloride solution (4 M, 32.50 mL) was added dropwise. The mixture was stirred for 16 hours. The reaction solution was concentrated to obtain 5-amino-2-chloro-3-fluoro-4-hydroxypyridine 412 h (530 mg), yield: 98.55%. MS m / z (ESI): 163.1 [M+H] + .

[0401] Step 9: Dissolve 412h (600 mg, 3.69 mmol) in 1,4-dioxane (4 mL) and heat to 100 °C with stirring. Add 412d (3.34 g, 7.38 mmol) to the reaction mixture and stir for 1 hour. Add concentrated sulfuric acid (1.09 g, 11.07 mmol) dropwise to the reaction mixture, and allow the reaction to return to room temperature with stirring for 16 hours. Concentrate the reaction mixture, and purify the residue by silica gel column chromatography (elution system A) to obtain 6'-chloro-5'-fluoro-4,4'-dihydroxy-6-(2-hydroxyethyl)-2H-[1,3'-bipyridine]-2-one 412i (700 mg), yield: 63.07%. MS m / z (ESI): 301.1 [M+H] + .

[0402] Step 10: Dissolve 412i (700 mg, 2.33 mmol) and triphenylphosphine (1.22 g, 4.66 mmol) in N,N-dimethylformamide (5 mL), and add diisopropyl azodicarbonate (941.54 mg, 4.66 mmol) dropwise under ice bath conditions. Stir at room temperature for 2 hours. Concentrate the reaction solution, and purify the residue by silica gel column chromatography (elution system A) to obtain 3-chloro-4-fluoro-9-hydroxy-6,7-dihydro-11H-dipyridano[4,3-b:1',2'-d][1,4]oxazazepine-11-one 412j (160 mg), yield: 24.31%. MS m / z (ESI): 283.1 [M+H] + .

[0403] Step 11: Under nitrogen protection, 412J (100 mg, 0.35 mmol), (1S,3S)-N1-(5-(difluoromethoxy)pyridin-2-yl)cyclopentane-1,3-diamine (94.67 mg, 0.39 mmol), tris(dibenzylindeneacetone)dipalladium (22.66 mg, 0.025 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (23.13 mg, 0.05 mmol) and sodium tert-butoxide (102.00 mg, 1.06 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and dimethyl sulfoxide (1 mL), and the mixture was heated to 130 °C and stirred for 1 hour using a microwave oven. The reaction solution was concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 3-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-4-fluoro-9-hydroxy-6,7-dihydro-11H-dipyrido[4,3-b:1',2'-d][1,4]oxazazepine-11-one 412kJ (85mg), yield: 49.08%. MS m / z (ESI): 490.1 [M+H] + .

[0404] Step 12: Under ice bath conditions, dissolve 412kJ (85mg, 0.17mmol), N-phenylbis(trifluoromethanesulfonyl)imide (74.45mg, 0.21mmol), and triethylamine (52.72mg, 0.52mmol) in N,N-dimethylformamide (2mL) and stir at room temperature for 1 hour. Dilute the reaction solution with ethyl acetate (20mL) and wash with saturated saline solution (20mL × 3). After concentration of the organic phase, the residue was purified by silica gel column chromatography (elution system B) to obtain 412 l (60 mg) of 3-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-4-fluoro-11-oxo-7,11-dihydro-6H-dipyrido[4,3-b:1',2'-d][1,4]oxazono-9-yltrifluoromethanesulfonate, yield: 55.59%. MS m / z (ESI): 622.1 [M+H] + .

[0405] Step 13: Under nitrogen protection, 412L (60mg, 0.096mmol), palladium acetate (21.87mg, 0.0096mmol, content: 10%), 1,1'-bis(diphenylphosphine)ferrocene (10.70mg, 0.019mmol), triethylamine (19.54mg, 0.19mmol) and formic acid (8.89mg, 0.19mmol) were dissolved in N,N-dimethylformamide (3mL), and the mixture was heated to 90°C and stirred for 3 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 3-(((1S,3S)-3-((5-(difluoromethoxy)pyridin-2-yl)amino)cyclopentyl)amino)-4-fluoro-6,7-dihydro-11H-dipyrido[4,3-b:1',2'-d][1,4]oxazazepine-11-one 412 (14.8 mg), yield: 32.38%. MS m / z (ESI): 474.1 [M+H] + .

[0406] 1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.85(t,1H),7.42(dd,1H),7.28(dd,1H ),7.16–6.78(m,2H),6.73(d,1H),6.48(d,1H),6.42(dt,1H),6.33(dd,1H), 4.58–4.40(m,2H),4.40–4.33(m,1H),4.31–4.21(m,1H),2.96–2.83(m,2H), 2.22–2.04(m,2H),2.01–1.85(m,2H),1.65–1.53(m,1H),1.51–1.43(m,1H).

[0407] Example 436

[0408] 5'-Fluoro-6'-(((1S,3S)-3-((3-Fluoro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0409] Step 1: Under nitrogen protection, 301a (501.5 mg, 1.34 mmol), 2-pyridone (254.9 mg, 2.68 mmol), cesium carbonate (1.31 g, 4.02 mmol), cuprous iodide (138 mg, 0.67 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (95 mg, 0.67 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, dichloromethane (30 mL) was added to the reaction solution for dilution, followed by filtration and concentration. The residue was purified by silica gel column chromatography (elution system A) to obtain (1S,3S)-3-((5'-fluoro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate tert-butyl ester (278 mg) 436a, yield: 53.4%. MS m / z (ESI): 389.2 [M+H] + .

[0410] Step 2: At room temperature, 436a (278 mg, 0.71 mmol) was dissolved in methanol (3 mL), and 1,4-dioxane hydrochloride solution (4 M, 3 mL) was added with stirring. The reaction was continued with stirring at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in methanol. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, and purified by silica gel column chromatography (elution system A) to obtain 1-(6-((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 436b (178 mg), yield: 86.8%. MS m / z (ESI): 289.2 [M+H] + .

[0411] Step 3: Under nitrogen protection, 6-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 6.55 mmol) was dissolved in a mixture of acetonitrile (10 mL) and pyridine (1 mL). 1-Chloromethyl-4-fluoro-1,4-diazotized bicyclo2,2,2-octanebis(tetrafluoroborate) salt (2.32 g, 6.55 mmol) was added with stirring, and the reaction was carried out at room temperature with stirring for 15 hours. Ethyl acetate (50 mL) was added to the reaction mixture. The organic phase was washed with water (30 mL × 3) and saturated sodium chloride aqueous solution (30 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 436c (320 mg) of 6-chloro-3-fluoro-1H-pyrrolo[2,3-b]pyridine, yield: 28.6%. MS m / z (ESI): 171.0 [M+H] + .

[0412] Step 4: Under nitrogen protection and in an ice bath, dissolve 436C (320 mg, 1.88 mmol) in N,N-dimethylformamide (5 mL), then slowly add sodium hydride (112.6 mg, 2.81 mmol, 60%) in portions. Continue stirring the reaction solution in an ice bath for 30 minutes, then slowly add (2-(chloromethoxy)ethyl)trimethylsilane (406.6 mg, 2.44 mmol) dropwise. Finally, slowly raise the reaction solution to room temperature and continue stirring for 2 hours. A saturated ammonium chloride solution (20 mL) was added dropwise to the reaction mixture. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (50 mL), dried, and concentrated. The residue was separated by silica gel column chromatography (eluting system B) to obtain 436 d (520 mg) of 6-chloro-3-fluoro-1-((2-trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine, yield: 92.1%. MS m / z (ESI): 301.1 [M+H] + .

[0413] Step 5: Under nitrogen protection, 436d (150 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL), and the reaction solution was cooled to -65°C with stirring. A 2.5 M, 0.3 mL, 0.75 mmol solution of n-butyllithium was slowly added dropwise to the reaction solution. The reaction solution was stirred at -65°C for 1 hour. Subsequently, a 3 mL solution of elemental iodine (164.5 mg, 0.65 mmol) in tetrahydrofuran was slowly added dropwise to the reaction solution. The reaction was slowly raised to room temperature and stirred for another 3 hours. The reaction mixture was quenched by adding 10 mL of saturated ammonium chloride solution dropwise. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with 30 mL of saturated sodium chloride aqueous solution, dried, filtered, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to obtain 436e (120 mg) of 6-chloro-3-fluoro-2-iodo-1-((2-trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine, yield: 56.4%. MS m / z (ESI): 427.0 [M+H] + .

[0414] Step 6: Under nitrogen protection, 436e (120 mg, 0.281 mmol), methyl fluorosulfonyl difluoroacetate (108.1 mg, 0.562 mmol), and cuprous iodide (53.6 mg, 0.281 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the mixture was heated to 100 °C and stirred for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture. The organic phase was washed with water (30 mL × 3) and saturated sodium chloride aqueous solution (30 mL), dried, concentrated, and the residue was separated by silica gel column chromatography (eluting system B) to obtain 6-chloro-3-fluoro-2-trifluoromethyl-1-((2-trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine 436f (90 mg), yield: 86.8%. MS m / z (ESI): 369.1 [M+H] + .

[0415] Step 7: Under nitrogen protection, 436f (90 mg, 0.244 mmol), 436b (70 mg, 0.244 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (23.7 mg, 0.024 mmol) and cesium carbonate (238.5 mg, 0.732 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and dimethyl sulfoxide (0.5 mL). The reaction was heated to 120 °C and stirred for 3 hours. Ethyl acetate (30 mL) was added to the reaction solution. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride aqueous solution (10 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 436 g (110.0 mg) of 5'-fluoro-6'-(((1S,3S)-3-((3-fluoro-2-(trifluoromethyl)-1-((2-trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 72.6%. MS m / z (ESI): 621.2 [M+H] + .

[0416] Step 8: Dissolve 436 g (110.0 mg, 0.177 mmol) in dioxane (1 mL), and add trifluoroacetic acid (1 mL) dropwise to the reaction solution with stirring. Stir the reaction at room temperature for 1 hour. Concentrate the reaction solution, and purify the residue by preparative HPLC (formic acid system) to obtain 436 g (55 mg) of 5'-fluoro-6'-(((1S,3S)-3-((3-fluoro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one, yield: 63.3%. MS m / z (ESI): 491.2 [M+H] + .

[0417] 1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),7.85(d,1H),7.65(dd,2H),7.56(dd,1H),7.49(ddd,1H),7.12(d,1H),6.94(dd,1H),6.46(dd, 2H),6.29(td,1H),4.57-4.49(m,1H),4.41-4.34(m,1H),4.12-4.03(m,2H),2.24-2.13(m,2H),2.03-1.91(m,2H),1.68-1.47(m,2H).

[0418] Example 452

[0419] 2-(((1S,3S)-3-((5-(3-cyano-2-oxo-1-pyridyl)-3-fluoro-2-pyridyl)amino)cyclopentyl)amino)imidazo(1,2-a)pyridine-7-nitrile

[0420] Step 1: Under nitrogen protection, 2-oxo-1H-pyridine-3-onitrile (200 mg, 1.67 mmol), 301a (623.18 mg, 1.67 mmol), potassium carbonate (460.27 mg, 3.33 mmol), cuprous iodide (317.13 mg, 1.67 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (236.85 mg, 1.67 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was heated to 120 °C and stirred for 12 hours. Ammonia (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to give N-((1S,3S)-3-((5-(3-cyano-2-oxo-1-pyridyl)-3-fluoro-2-pyridyl)amino)cyclopentyl)carbamate tert-butyl 452a (500 mg), yield: 72.63%. MS m / z (ESI): 414.1 [M+H] + .

[0421] Step 2: Under nitrogen protection, 452a (500 mg, 1.21 mmol) was dissolved in a 1,4-dioxane (4 M, 3.02 mL) solution of hydrochloric acid at room temperature and stirred for 1 hour. After the reaction was complete, the pH was adjusted to 9-10 with saturated sodium bicarbonate. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoro-3-pyridyl)-2-oxo-pyridin-3-onitrile 452b (300 mg), yield: 79.17%. MS m / z (ESI): 314.1 [M+H] + .

[0422] Step 3: Under nitrogen protection, 452b (100 mg, 0.319 mmol), 2-chloroimidazolo(1,2-A)pyridine-7-onitrile (62.35 mg, 0.351 mmol), Gphos Pd G6 Br (30.14 mg, 0.032 mmol), and sodium trimethylsilanolate (71.60 mg, 0.638 mmol) were dissolved in a mixture of N,N-dimethylformamide (0.5 mL) and tetrahydrofuran (2 mL), and the mixture was heated to 110 °C and stirred for 12 hours. Saturated ammonium chloride solution (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (5 mL × 2). The organic phase was dried and concentrated. The residue was prepared by preparative chromatography to obtain 2-(((1S,3S)-3-((5-(3-cyano-2-oxo-1-pyridyl)-3-fluoro-2-pyridyl)amino)cyclopentyl)amino)imidazo(1,2-a)pyridine-7-nitrile 452 (6 mg), yield: 3.90%. MS m / z (ESI): 455.1 [M+H] + .

[0423] 1 H NMR(400MHz,DMSO-d6)δ8.43(d,1H),8.24(dd,1H),8.08(dd,1H),7.91(d,1H),7.79(s,1H),7.67–7.59(m,1H),7.29(s,1H ),7.07(d,1H),7.02(d,1H),6.48(t,1H),6.27(d,1H),4.53(d,1H),4.02(d,1H),2.16(dd,2H),1.96(d,2H),1.57(s,2H).

[0424] Example 475

[0425] 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)pyridin-2-one

[0426] Step 1: Under nitrogen protection, 301a (10 g, 26.72 mmol), 1H-pyridin-2-one (5.08 g, 53.44 mmol), potassium carbonate (7.39 g, 53.44 mmol), cuprous iodide (5.09 g, 26.72 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3.80 g, 26.72 mmol) were dissolved in 1,4-dioxane (200 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (300 mL). The aqueous phase was extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-((1S,3S)-3-((3-fluoro-5-(2-oxo-1-pyridyl)-2-pyridyl)amino)cyclopentyl)carbamate 475a (10 g), yield: 96.35%. MS m / z (ESI): 389.2 [M+H] + .

[0427] Step 2: At room temperature, 475a (10 g, 25.74 mmol) and dioxane hydrochloride solution (4 M, 64.36 mL) were dissolved in methanol (40 mL) and stirred for 2 hours. The pH of the reaction solution was adjusted to 9-10 with saturated sodium bicarbonate solution. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoro-3-pyridyl)pyridin-2-one 475b (5.6 g), yield: 75.45%. MS m / z (ESI): 289.2 [M+H] + .

[0428] Step 3: Under nitrogen protection, 475b (100 mg, 0.347 mmol), 3-chloro-6-(difluoromethoxy)pyridazine (69 mg, 0.382 mmol), Gphos Pd G6 Br (33 mg, 34.68 μmol), and sodium trimethylsilanolate (58 mg, 0.520 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (2 mL), and the mixture was heated to 90 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (30 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to obtain 475 (11.3 mg) of 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)pyridin-2-one, yield: 6.84%. MS m / z (ESI): 433.1 [M+H] + .

[0429] 1 H NMR(400MHz,DMSO-d6)δ7.84(d,1H),7.65(dd,1H),7.62(t,1H),7.55(dd,1H),7.49(ddd,1H),7.11(d,1H),6.97(dd,3H),6.46(d, 1H),6.29(td,1H),4.53(q,1H),4.33(q,1H),2.24–2.09(m,2H),2.02–1.97(m,1H),1.92(td,1H),1.68–1.57(m,1H),1.52(dd,1H).

[0430] Example 479

[0431] 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)pyrimidin-2,4-dione

[0432] Example 479 can also be prepared by the following method:

[0433] Step 1: Under nitrogen protection, 3-chloro-6-(difluoromethoxy)pyridazine (2 g, 11.08 mmol), N-((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (2.66 g, 13.29 mmol), tris(dibenzylideneacetone)palladium (507 mg, 0.554 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (828 mg, 1.33 mmol) were dissolved in 1'4-dioxane (100 mL), and the mixture was heated to 110 °C and stirred for 12 hours. After the reaction was complete, a saturated ammonium chloride solution (100 mL) was added to the reaction solution to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain N-((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)carbamate tert-butyl 479a (2.8 g), yield: 73.40%. MS m / z (ESI): 345.1 [M+H] + .

[0434] Step 2: Under nitrogen protection, 479a (3.5 g, 10.16 mmol) was dissolved in a mixed solution of 1,4-dioxane (4 M, 20 mL) and 1,4-dioxane (20 mL) in hydrochloric acid at room temperature, and stirred for 1 hour. The pH of the reaction solution was adjusted to 9-10 with saturated sodium bicarbonate solution. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give (1S,3S)-N3-(6-(difluoromethoxy)pyridazin-3-yl)cyclopentane-1,3-diamine 479b (1.3 g), yield: 52.37%. MS m / z (ESI): 245.1 [M+H] + .

[0435] Step 3: Under nitrogen protection, 479b (1.1 g, 4.50 mmol), 5-bromo-2,3-difluoropyridine (874 mg, 4.50 mmol), and N,N-diisopropylethylamine (1.75 g, 13.51 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the mixture was heated to 100 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (30 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give (1S,3S)-N3-(5-bromo-3-fluoro-2-pyridyl)-N1-(6-(difluoromethoxy)pyridazin-3-yl)cyclopentane-1,3-diamine 479c (1.4 g), yield: 74.33%. MS m / z (ESI): 419.2 [M+H] + .

[0436] Step 4: Under nitrogen protection, 479c (150 mg, 0.359 mmol), 1H-pyrimidin-2,4-dione (60 mg, 0.538 mmol), potassium phosphate (152 mg, 0.717 mmol), cuprous iodide (27.32 mg, 0.143 mmol), and N-(2-cyanophenyl)pyridinecarboxamide (64 mg, 0.287 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to give 479 (66 mg) of 1-(6-((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)pyrimidine-2,4-dione, yield: 40.28%. MS m / z (ESI): 450.1 [M+H] + .

[0437] 1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),7.87(d,1H),7.65(dd,1H),7.61(t,1H),7.55(dd,1H),7.11(d,1H),7.00–6.95( m,3H),5.64(d,1H),4.51(q,1H),4.33(q,1H),2.16(m,2H),2.00(d,1H),1.94–1.88(m,1H),1.60(m,1H),1.51(m,1H).

[0438] Example 480

[0439] 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)-5-methylpyrimidin-2,4-dione

[0440] Example 480 can also be prepared by the following method:

[0441] Step 1: Under nitrogen protection, 479c (50 mg, 0.120 mmol), 5-methyl-1-hydropyrimidine-2,4-dione (23 mg, 0.180 mmol), N-(2-cyanophenyl)pyridinecarboxamide (21 mg, 0.096 mmol), cuprous iodide (9 mg, 0.048 mmol) and potassium phosphate (51 mg, 0.240 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to give 480 (19 mg) of 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl)-5-methylpyrimidin-2,4-dione, yield: 33.72%. MS m / z (ESI): 464.2 [M+H] + .

[0442] 1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),7.87(d,1H),7.61(t,1H),7.58(d,1H),7.54(dd,1H),7.11(d,1H),6.96(dd,3 H),4.51(q,1H),4.32(q,1H),2.16(ddd,2H),1.99(s,1H),1.91(d,1H),1.78(m,3H),1.65–1.57(m,1H),1.51(m,1H).

[0443] Example 491

[0444] 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridinyl)-6,7-dihydropyrazolo(1,5-a)pyrazin-4-one

[0445] Step 1: Under nitrogen protection, 479c (250 mg, 0.598 mmol), 6,7-dihydro-5H-pyrazolo(1,5-A)pyrazin-4-one (98.38 mg, 0.717 mmol), cuprous iodide (114 mg, 5.98 mmol) and potassium carbonate (165.23 mg, 1.20 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to give 491 (180 mg) of 5-(6-((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridinyl)-6,7-dihydropyrazolo(1,5-a)pyrazin-4-one, yield: 62.03%. MS m / z (ESI): 475.4 [M+H] + .

[0446] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,1H),7.62(d,1H),7.61(s,1H),7.51(dd,1H),7.11(d,1H),7.00–6.95(m,2H),6.83(d,1H),6.7 7(d,1H),4.51(dd,3H),4.33(q,1H),4.14–4.07(m,2H),2.22–2.12(m,2H),1.99(s,1H),1.94–1.87(m,1H),1.63–1.48(m,2H).

[0447] Example 483

[0448] 5-Cyclopropyl-1-(6-(((1S,3S)-3-((6-difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyrimidin-2,4-(1H,3H)-dione

[0449] Example 483 can also be prepared by the following method:

[0450] Step 1: Under nitrogen protection, 479c (50 mg, 0.120 mmol), 5-cyclopropylpyrimidine-2,4(1H,3H)-dione (36.4 mg, 0.239 mmol), cuprous iodide (22.8 mg, 0.120 mmol), N-(2-cyanophenyl)pyridine-2-carboxamide (26.8 mg, 0.120 mmol) and cesium carbonate (116.9 mg, 0.359 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 483 (15.2 mg) of 5-cyclopropyl-1-(6-(((1S,3S)-3-((6-difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)pyrimidine-2,4-(1H,3H)-dione, yield: 25.9%. MS m / z (ESI): 490.2 [M+H] + .

[0451] 1 H NMR(400MHz,DMSO-d6)δ11.42(s,1H),7.85(d,1H),7.61(t,1H),7.52(dd,1H),7.28(d,1H),7.11(d,1H),7.00-6.96(m,2H),6.93(dd,1H),4.53-4 .46(m,1H),4.35-4.28(m,1H),2.23-2.10(m,2H),2.04-1.87(m,2H),1.6 4-1.57(m,2H),1.54-1.49(m,1H),0.70-0.66(m,2H),0.62-0.57(m,2H).

[0452] Example 495

[0453] 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridinyl)-2-methyl-6,7-dihydropyrazolo(1,5-a)pyrazin-4-one

[0454] Example 495 can also be prepared by the following method:

[0455] Step 1: Under nitrogen protection, 479c (50 mg, 0.120 mmol), 2-methyl-6,7-dihydro-5-hydro-pyrazolo(1,5-a)pyrazin-4-one (20 mg, 0.132 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (17 mg, 0.120 mmol), cuprous iodide (23 mg, 0.120 mmol), and potassium carbonate (33 mg, 0.24 mmol) were dissolved in 1,4-dioxane (2 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to give 495 (39 mg) of 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridinyl)-2-methyl-6,7-dihydropyrazolo(1,5-a)pyrazin-4-one, yield: 64.36%. MS m / z (ESI): 489.2 [M+H] + .

[0456] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.62(t,1H),7.49(dd,1H),7.11(d,1H),7.01–6.94(m,2H),6.75(dd,1H),6.60(s,1H),4.50(q,1H), 4.40(dd,2H),4.33(q,1H),4.07(dd,2H),2.22(s,3H),2.20–2.07(m,2H),2.03–1.98(m,1H),1.90(m,1H),1.65–1.56(m,1H),1.52(m,1H).

[0457] Example 499

[0458] 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino-5-fluoropyridin-3-yl)-3-fluoro-6,7-dihydropyrazole[1,5-a]pyrazin-4(5H)-one

[0459] Example 499 can also be prepared by the following method:

[0460] Step 1: At room temperature, methyl 4-fluoro-1H-pyrazole-5-carboxylate (2.0 g, 13.88 mmol), N-Boc-bromoethylamine (9.33 g, 41.64 mmol), and potassium carbonate (5.75 g, 41.64 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (20 mL × 3), and the organic phase was dried and concentrated. The residue was separated by silica gel column chromatography (eluting system B) to obtain methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-fluoro-1H-pyrazole-5-carboxylate 499b (2.7 g), yield: 67.7%. MS m / z (ESI): 288.1 [M+H] + .

[0461] Step 2: At room temperature, 499b (2.7 g, 9.40 mmol) was dissolved in methanol (10 mL), and a solution of dioxane hydrochloric acid (4 M, 7.05 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated to obtain product 499c (1.6 g). This product was used directly in the next step of the reaction without purification. MS m / z (ESI): 188.1 [M+H] + .

[0462] Step 3: At room temperature, 499c (1.6 g, 8.55 mmol) and potassium carbonate (2.36 g, 17.10 mmol) were dissolved in methanol (20 mL), heated to 70°C and stirred for 2 hours; the reaction mixture was cooled to room temperature, filtered, concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 3-fluoro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 499d (1.2 g). Yield: 90.5%; MS m / z (ESI): 156.1 [M+H] + .

[0463] Step 4: Under nitrogen protection, 479c (800 mg, 1.91 mmol), 499d (386 mg, 2.49 mmol), cuprous iodide (364 mg, 1.91 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (272 mg, 1.91 mmol) and cesium carbonate (1.87 g, 5.74 mmol) were dissolved in dioxane (30 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluting system B) to obtain a crude product with a purity of 95%. Further purification by preparative HPLC (formic acid system) yielded 499 mg (750 mg) of 5-(6-(((1S,3S)-3-((6-difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-3-fluoro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one, yield: 79.6%. MS m / z (ESI): 493.2 [M+H] + .

[0464] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,1H),7.71(d,1H),7.62(t,1H),7.50(dd,1H),7.11(d,1H),6.98(d,2H),6.79(dd,1H ),4.59–4.40(m,3H),4.59–4.42(m,1H),4.14–4.03(m,2H),2.25–2.08(m,2H),2.05–1.86(m,2H),1.68–1.44(m,2H).

[0465] Example 501

[0466] 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0467] Example 501 can also be prepared by the following method:

[0468] Step 1: Ethyl 4-methylpyrazole-3-carboxylate (1 g, 6.49 mmol), 2-(tert-butoxycarbonylamino)ethyl bromide (4.36 g, 19.46 mmol), and potassium carbonate (2.69 g, 19.46 mmol) were dissolved in N,N-dimethylformamide (10 mL), and stirred at 20 °C for 16 hours. The reaction solution was filtered, the filtrate was diluted with ethyl acetate (50 mL), washed with saturated brine (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to give ethyl 2-[2-(tert-butoxycarbonylamino)ethyl]-4-methylpyrazole-3-carboxylate (1 g) 501a, yield: 51.85%. MS m / z (ESI): 298.1 [M+H] + .

[0469] Step 2: Dissolve 501a (1 g, 3.36 mmol) in ethanol (10.00 mL), and add dropwise a 1,4-dioxane hydrochloric acid solution (4 M, 16.8 mL). Stir at room temperature for 1 hour. Concentrate the reaction solution to obtain ethyl 2-(2-aminoethyl)-4-methyl-pyrazole-3-carboxylic acid ester 501b (660 mg). The product does not require purification and can be used directly in the next step of the reaction. MS m / z (ESI): 198.1 [M+H] + .

[0470] Step 3: Dissolve 501b (510 mg, 2.59 mmol) and potassium carbonate (1.79 g, 12.93 mmol) in ethanol (10 mL), heat to 50 °C and stir for 16 hours. Filter the reaction solution and concentrate. Separate the residue by silica gel column chromatography (elution system A) to obtain 3-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one 501c (390 mg), yield: 99.78%. MS m / z (ESI): 152.1 [M+H] + .

[0471] Step 4: Under nitrogen protection, 479c (70 mg, 0.17 mmol), 501c (50.60 mg, 0.33 mmol), cuprous iodide (31.88 mg, 0.17 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (23.81 mg, 0.17 mmol), and potassium carbonate (46.20 mg, 0.33 mmol) were dissolved in 1',4-dioxane (7 mL), and the mixture was heated to 110 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was separated by preparative HPLC (formic acid system) to yield 501 (53.5 mg) of 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one, yield: 65.44%. MS m / z (ESI): 489.2 [M+H] + .

[0472] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.71(d,1H),7.49(dd,1H),7.44(d,1H),7.11(d,1H),7.02–6.93(m,2H),6.74( dd,1H),4.59–4.26(m,4H),4.12–3.96(m,2H),2.23(s,3H),2.20–2.09(m,2H),2.05–1.85(m,2H),1.67–1.45(m,2H).

[0473] Example 543

[0474] 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridyl]-3-methylpyrimidin-2,4-dione

[0475] Example 543 can also be prepared by the following method:

[0476] Step 1: Under nitrogen protection, 479c (50 mg, 0.120 mmol), 3-methyl-1H-pyrimidin-2,4-dione (23 mg, 0.180 mmol), N-(2-cyanophenyl)pyridinecarboxamide (21 mg, 0.096 mmol), cuprous iodide (9 mg, 0.048 mmol) and potassium phosphate (51 mg, 0.240 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 120 °C and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC to give 1-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoro-3-pyridinyl]-3-methylpyrimidine-2,4-dione 543 (13.9 mg), yield: 24.49%. MS m / z (ESI): 464.1 [M+H] + .

[0477] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.72(d,1H),7.62(t,1H),7.55(dd,1H),7.11(d,1H),7.01–6.95(m,3H),5.78 (d,1H),4.52(q,1H),4.33(q,1H),3.19(s,3H),2.17(td,2H),1.99(m,1H),1.90(m,1H),1.60(m,1H),1.51(m,1H).

[0478] Example 587

[0479] 5-(6-(((1S,3S)-3-((6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-3-fluoro-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0480] Step 1: At room temperature, 2-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (250 mg, 1.65 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (1.17 g, 3.31 mmol) were dissolved in acetonitrile (3 mL), and the mixture was heated to 65 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was separated by silica gel column chromatography (elution system A) to give 3-fluoro-2-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one 587a (88 mg), yield: 31.46%. MS m / z (ESI): 170.1 [M+H] + .

[0481] Step 2: Under nitrogen protection, 479c (60 mg, 0.143 mmol), 587a (49 mg, 0.287 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (20 mg, 0.143 mmol), cuprous iodide (27 mg, 0.143 mmol), and potassium carbonate (40 mg, 0.287 mmol) were dissolved in 2 mL of 1',4-dioxane. The mixture was microwaved to 130°C and stirred for 1 hour. The reaction solution was then filtered and concentrated. The residue was separated by preparative HPLC (formic acid system) to yield 587 (42.6 mg) of 5-(6-(difluoromethoxy)pyridazin-3-yl)amino)cyclopentyl)amino)-5-fluoropyridin-3-yl)-3-fluoro-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one, yield: 58.63%. MS m / z (ESI): 507.1 [M+H] + .

[0482] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.62(t,1H),7.50(dd,1H),7.11(d,1H),6.98(d,2H),6.79(d,1H),4. 50(q,1H),4.41–4.27(m,3H),4.10–4.02(m,2H),2.25–2.08(m,5H),2.05–1.85(m,2H),1.67–1.45(m,2H).

[0483] Example 601

[0484] 1-(6-((1S,3S)-3-(3-fluoro-5-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile

[0485] Example 601 can also be prepared by the following method:

[0486] Step 1: 3,6-Dichloropyridazine (4 g, 27 mmol), tert-butyl cyanoacetate (4.5 g, 31.9 mmol), and cesium carbonate (17.5 g, 53.7 mmol) were dissolved in N,N-dimethylformamide (40 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give 2-(6-chloropyridazine-3-yl)-2-cyanoacetate tert-butyl 601a (4 g), yield: 58.6%. MS m / z (ESI): 254.1. [M+H] + .

[0487] Step 2: Under nitrogen protection, 601a (1 g, 4.0 mmol) and p-toluenesulfonic acid (180 mg, 1.2 mmol) were dissolved in toluene (40 mL), and the reaction was stirred at 100 °C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give 2-(6-chloropyridazine-3-yl)acetonitrile 601b (0.2 g), yield: 32.5%. MS m / z (ESI): 154.0 [M+H] + .

[0488] Step 3: Dissolve 601b (300 mg, 2.0 mmol), 1,2-dibromoethane (404 mg, 2.2 mmol), and benzyltributylammonium chloride (609 mg, 2.0 mmol) in acetonitrile (6 mL). Add 3 mL of 50% sodium hydroxide aqueous solution under ice bath conditions and stir at room temperature for 2 hours. Dilute the reaction solution with ethyl acetate (20 mL), wash three times with saturated brine (10 mL), dry and concentrate the organic phase, and separate the residue by silica gel column chromatography (eluting system A) to obtain 1-(6-chloropyridazine-3-yl)cyclopropylnitrile 601c (200 mg), yield: 57.0%. MS m / z (ESI): 180.0 [M+H] + .

[0489] Step 4: Under nitrogen protection, (1S,3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester (373 mg, 1.0 mmol), 6,7-dihydro-2-methylpyrazol[1,5-A]pyrazin-4(5H)-one (200 mg, 1.3 mmol), cuprous iodide (190 mg, 1.0 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (142 mg, 1.0 mmol) and cesium carbonate (650 mg, 2.0 mmol) were dissolved in dioxane (10 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give 601 d (400 mg) of ((1S,3S)-3-((3-fluoro-5-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate, yield: 90%. MS m / z (ESI): 445.2 [M+H] + .

[0490] Step 5: Dissolve 601d (400 mg, 0.9 mmol) in dichloromethane (5 mL) and dioxane solution (5 mL) of hydrochloric acid. Stir the reaction mixture at 25 °C for 1 hour. Concentrate the reaction mixture, dilute the residue with methanol (20 mL), adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, concentrate, and separate the residue by silica gel column chromatography (eluting system A) to obtain 5-(-(((1S,3S)-3-aminocyclopentyl)amino)-5-fluoropyridin-3-yl)-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 601e (280 mg), yield: 90%. MS m / z (ESI): 345.2 [M+H] + .

[0491] Step 6: Under nitrogen protection, 601e (69 mg, 0.2 mmol), 601c (36 mg, 0.2 mmol), cesium carbonate (130 mg, 0.4 mmol), and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (19 mg, 0.02 mmol) were dissolved in dioxane (3 mL), and the reaction was stirred at 110 °C for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by HPLC (elution system A) to give 1-(6-((1S,3S)-3-(3-fluoro-5-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyridin-2-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 601 (35 mg), yield: 35.8%. MS m / z (ESI): 488.2 [M+H] + .

[0492] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.49(dd,1H),7.27(dd,1H),7.03(d,1H),6.86–6.80(m,1H),6.76(dd,1H),6.60(s,1H), 4.50(q,1H),4.39(dq,3H),4.10–4.03(m,2H),2.22(s,3H),2.15(dd,2H),2.04–1.88(m,2H),1.72(q,2H),1.64–1.46(m,4H).

[0493] Example 673

[0494] 1-(6-((1S,3S)-3-((3-chloro-5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazine-3-yl)cyclopropane-1-nitrile

[0495] Example 673 can also be prepared by the following method:

[0496] Step 1: Under nitrogen protection, 601c (400 mg, 2.2 mmol), (1S,3S)-3-aminocyclopentylcarbamate tert-butyl ester (664 mg, 3.3 mmol), tris(dibenzylacetone)dipalladium (200 mg, 0.2 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (275 mg, 0.4 mmol), and cesium carbonate (1.4 g, 4.4 mmol) were dissolved in dioxane (20 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to give (1S,3S)-3-((6-(1-cyanocyclopropyl)pyridazin-3-yl)amino)cyclopentyl)carbamate tert-butyl ester 673a (400 mg), yield: 52.9%. MS m / z (ESI): 344.2. [M+H] + .

[0497] Step 2: Dissolve 673a (400 mg, 1.2 mmol) in dichloromethane (10 mL) and dioxane solution (10 mL) in hydrochloric acid. Stir the reaction mixture at 25 °C for 1 hour. Concentrate the reaction mixture, dilute the residue with methanol (20 mL), adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, concentrate, and separate the residue by silica gel column chromatography (eluting system A) to obtain 1-(6-((1S,3S)-3-aminocyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 673b (270 mg), yield: 92%. MS m / z (ESI): 244.2 [M+H] + .

[0498] Step 3: 673b (270 mg, 1.1 mmol), 5-bromo-2,3-difluoropyridine (637 mg, 3.3 mmol), and N,N-diisopropylethylamine (709 mg, 5.5 mmol) were dissolved in dimethyl sulfoxide (15 mL), and the reaction was stirred at 100 °C for 16 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed three times with saturated brine (10 mL), the organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluting system A) to obtain 1-(6-((1S,3S)-3-((5-bromo-3-fluoropyridine-2-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 673c (380 mg), yield: 82.8%. MS m / z (ESI): 417.1 [M+H] + .

[0499] Step 4: Under nitrogen protection, 673c (42 mg, 0.1 mmol), 3-chloro-2-hydroxypyridine (26 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.1 mmol) and cesium carbonate (65 mg, 0.2 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to HPLC (elution system A) to give 1-(6-((1S,3S)-3-((3-chloro-5'-fluoro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 673 (13 mg), yield: 27.9%. MS m / z (ESI): 466.2 [M+H] + .

[0500] 1 H NMR(400MHz,DMSO-d6)δ7.88(d,1H),7.83(dd,1H),7.71(dd,1H),7.61(dd,1H),7.26(d,1H),7.05(dd,2H),6.82(d, 1H),6.32(t,1H),4.53(q,1H),4.39(q,1H),2.18(dp,2H),2.03–1.88(m,2H),1.78–1.70(m,2H),1.67–1.49(m,4H).

[0501] Example 764

[0502] 2-(6-((1S,3S)-3-((3-chloro-5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazine-3-yl)-2-methylcyclopropane-1-nitrile

[0503] Step 1: Under nitrogen protection, 3,6-dichloropyridazine (2 g, 13.42 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.37 g, 14.10 mmol), Pd(dppf)Cl2 (982.32 mg, 1.34 mmol), and sodium carbonate (2.85 g, 26.85 mmol) were dissolved in a mixture of water (5 mL) and 1,4-dioxane (30 mL). The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was diluted with saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system D) to give 764a (1.2 g), yield: 76.54%. MS m / z (ESI): 155, 157 [M+H] + .

[0504] Step 2: Under nitrogen protection, 764a (200 mg, 1.29 mmol), 1-methylimidazole (319 mg, 3.88 mmol), and 5,10,15,20-tetraphenyl-21H,23H-porphyrin cobalt(II) (43 mg, 0.065 mmol) were dissolved in toluene (5 mL). The reaction mixture was stirred at 20 °C for 5 minutes, and then ethyl azide (266 mg, 2.33 mmol) was added dropwise to the reaction mixture. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was diluted with saturated ammonium chloride solution (60 mL), and the aqueous phase was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated sodium chloride (60 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system D) to obtain 764b (100 mg), yield: 32.2%. MS m / z(ESI): 241.1 [M+H] + .

[0505] Step 3: Under nitrogen protection, 764b (500 mg, 2.08 mmol), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (499 mg, 2.49 mmol), cesium carbonate (2.03 g, 6.23 mmol), and Pd-PEPPSI-IHept-Cl (202 mg, 0.208 mmol) were dissolved in dimethyl sulfoxide (5 mL) and heated to 100 °C with stirring for 12 hours. The reaction mixture was diluted with saturated sodium chloride solution (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride (60 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system D) to obtain 764c (700 mg), yield: 83.3%. MS m / z (ESI): 405.1 [M+H]+ .

[0506] Step 4: Under nitrogen protection, 764c (700 mg, 1.73 mmol) was dissolved in tetrahydrofuran (8.0 mL). While stirring, a solution of lithium hydroxide (726 mg, 17.31 mmol) in water (2 mL) was added dropwise. The reaction was stirred at 40 °C for 16 hours. The pH was adjusted to 6-7 by adding 10 mL of dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution system A) to obtain 764d (500 mg), yield: 76.7%. MS m / z (ESI): 377 [M+H] + .

[0507] Step 5: Under nitrogen protection, 764d (500 mg, 1.07 mmol) was dissolved in dichloromethane (10.0 mL). HATU (601.31 mg, 1.59 mmol), diisopropylethylamine (1.37 g, 10.63 mmol, 1.85 mL), and ammonium chloride (355 mg, 6.64 mmol) were slowly added to the reaction mixture with stirring. After the addition was complete, the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated sodium chloride solution (30 mL). The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 764e (450 mg), yield: 90%. MS m / z (ESI): 376 [M+H] + .

[0508] Step 6: Under nitrogen protection, 764e (200 mg, 0.53 mmol) was dissolved in acetonitrile (5 mL), and phosphorus oxychloride (816.76 mg, 5.33 mmol) was added dropwise to the reaction mixture with stirring. The reaction was heated to 80 °C and stirred for 1 hour. The reaction mixture was diluted with saturated ammonium chloride solution (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 764f (100 mg), yield: 72%. MS m / z (ESI): 258 [M + H] + .

[0509] Step 7: Under nitrogen protection, 764f (50 mg, 0.19 mmol), 3-chloro-1-(5,6-difluoro-3-pyridyl)pyridin-2-one (47.14 mg, 0.194 mmol), and diisopropylethylamine (100.45 mg, 0.777 mmol, 0.135 mL) were dissolved in dimethyl sulfoxide (4 mL) and heated to 100 °C with stirring for 2 hours. The reaction mixture was diluted with saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried, filtered, concentrated, and the residue was purified by C-18 reversed column chromatography (formic acid system) to obtain 764 (16 mg), yield: 20%. MS m / z (ESI): 480 [M+H] + .

[0510] 1 H NMR(400MHz,DMSO-d6)δ7.87(d,1H),7.82(dd,1H),7.69(dd,1H),7.60(dd, 1H),7.34(d,1H),7.02(d,1H),6.90(d,1H),6.77(d,1H),6.31(t,1H),4.52( h,1H),4.37(p,1H),2.24(dd,1H),2.15(tq,2H),2.01(dt,1H),1.89(dq,1H) ,1.76(dd,1H),1.67–1.60(m,1H),1.60(s,3H),1.51(dq,1H),1.38(dd,1H).

[0511] Example 768

[0512] 1-(6-(((1S,3S)-3-((3-fluoro-5-(4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)pyridin-2-yl)aminocyclopentyl)amino)pyrazin-3-yl)cyclopropane-1-onitrile

[0513] Under nitrogen protection, 673c (2 g, 4.79 mmol), pyrazolo[1,5-a]pyrazin-4(5H)-one (777 mg, 5.75 mmol), cesium carbonate (3.12 g, 9.59 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (681 mg, 4.79 mmol) and cuprous iodide (912 mg, 4.79 mmol) were dissolved in dioxane (60 mL), and the mixture was heated to 110 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 1-(6-(((1S,3S)-3-((3-fluoro-5-(4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)pyridin-2-yl)aminocyclopentyl)amino)pyrazin-3-yl)cyclopropane-1-onitrile 768 (1.7 g), yield: 75.2%. MS m / z (ESI): 472.2 [M+H] + .

[0514] 1 H NMR (400MHz, DMSO-d6) δ7.95(dd,2H),7.84(d,1H),7.61(dd,1H),7.27(d,1H),7.17(d,1H),7.10(d,1H),7.05–6.97(m,2H),6. 82(d,1H),4.54(q,1H),4.39(q,1H),2.18(tt,2H),2.03(dt,1H),1.92(td,1H),1.72(q,2H),1.66–1.59(m,3H),1.53(dt,1H).

[0515] Example 801

[0516] 1-(6-((1S,3S)-3-((3-cyclopropyl-5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazine-3-yl)cyclopropane-1-nitrile

[0517] Example 801 can also be prepared by the following method:

[0518] Step 1: Under nitrogen protection, 673c (42 mg, 0.1 mmol), 3-cyclopropyl-2-hydroxypyridine (27 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.1 mmol) and cesium carbonate (65 mg, 0.2 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to HPLC (elution system A) to give 1-(6-((1S,3S)-3-((3-cyclopropyl-5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 801 (20 mg), yield: 42.4%. MS m / z (ESI): 472.2 [M+H] + .

[0519] 1 H NMR(400MHz,DMSO-d6)δ7.83(d,1H),7.55(dd,1H),7.44(dd,1H),7.27(d,1 H),7.06–6.98(m,2H),6.93(d,1H),6.82(d,1H),6.19(t,1H),4.53(q,1H), 4.39(q,1H),2.24–2.11(m,2H),2.06–1.98(m,2H),1.91(dd,1H),1.72(q,2 H),1.68–1.58(m,3H),1.53(dt,1H),0.89–0.82(m,2H),0.67–0.61(m,2H).

[0520] Example 828

[0521] 5-(5-fluoro-6-(((1S,3S)-3-((6-(trifluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0522] Step 1: Under nitrogen protection, 301a (200 mg, 0.53 mmol), 2-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (88.9 mg, 0.59 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (76.0 mg, 0.53 mmol), cuprous iodide (101.8 mg, 0.53 mmol), and potassium carbonate (221.2 mg, 1.60 mmol) were dissolved in 1,4-dioxane (3 mL), and the mixture was heated to 110 °C and stirred for 3 hours. The reaction solution was filtered, and the filtrate was diluted with ethyl acetate (50 mL) and washed with concentrated ammonia (40 mL × 3). The organic phase was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 828a (211 mg, 0.47 mmol), yield: 88.8%. MS m / z (ESI): 445.1 [M+H] + .

[0523] Step 2: Dissolve 828a (211 mg, 0.47 mmol) in methanol (2 mL), add dioxane hydrochloride (4 M, 3 mL) dropwise, and stir at room temperature for 1 hour. Concentrate the reaction solution, adjust the pH of the residue to 10 with saturated sodium bicarbonate solution, and purify the residue by silica gel column chromatography (elution system A) to obtain 828b (150 mg, 0.43 mmol), yield: 91.7%. MS m / z (ESI): 345.1 [M+H] + .

[0524] Step 3: Under nitrogen protection, 828b (70.0 mg, 0.20 mmol), 828c (44.5 mg, 0.24 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (16.1 mg, 0.02 mol), and cesium carbonate (132.1 mg, 0.41 mmol) were dissolved in 1',4-dioxane (3 mL), and the mixture was heated to 110 °C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was separated by preparative HPLC (formic acid system) to obtain 828 (31.8 mg, 0.06 mmol), yield: 31.9%. MS m / z (ESI): 491.2 [M+H] + .

[0525] 1H NMR(400MHz,DMSO-d6)δ7.89(d,1H),7.71(d,1H),7.64(d,1H),7.50(dd,1H),6.94(d,1H),6.79(dd,1H),6.60(s,1H ),4.59–4.45(m,2H),4.43–4.36(m,2H),4.12–4.00(m,2H),2.30–2.12(m,5H),2.11–1.89(m,2H),1.71–1.48(m,2H).

[0526] Example 829

[0527] 3-Chloro-5'-Fluoro-6'-(((1S,3S)-3-((6-(trifluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0528] Step 1: Under nitrogen protection, 3-chloro-6-(trifluoromethyl)pyridazine (8 g, 43.8 mmol), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (11.41 g, 57.0 mmol), tris(dibenzylacetone)dipalladium(0) (2.01 g, 2.2 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.73 g, 4.4 mmol), and potassium carbonate (15.12 g, 109.6 mmol) were dissolved in 1,4-dioxane (180 mL), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was then poured into water (200 mL), and the aqueous phase was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed successively with water (150 mL) and saturated sodium chloride solution (150 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 829a (10.0 g, 28.9 mmol), yield: 65.9%. MS m / z (ESI): 347.1 [M+H] + .

[0529] Step 2: Dissolve 829a (10 g, 28.87 mmol) in ethyl acetate (100 mL), add HCl / EA (4 M, 72.2 mL), and stir for 1 hour. Filter the reaction mixture, and wash the filter cake twice with ethyl acetate (50 mL). Dissolve the filter cake in water (100 mL), adjust the pH to 10 with saturated sodium carbonate solution, and concentrate. Separate the residue by silica gel column chromatography (elution system A) to obtain 829b (5.8 g, 16.3 mmol), yield: 56.5%. MS m / z (ESI): 247.1 [M+H] + .

[0530] Step 3: Under an oxygen atmosphere, 2,3-difluoropyridine-5-boronic acid (13 g, 81.8 mmol), 3-chloro-2-hydroxypyridine (21 g, 163 mmol), copper acetate (29 g, 163.6 mmol), and pyridine (40 mL, 490 mmol) were dissolved in dichloromethane (350 mL), and the reaction was stirred at 25 °C for 16 hours. The reaction solution was concentrated, and the residue was poured into ammonia water (300 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined and washed successively with water (200 mL) and saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was slurried with a mixture of petroleum ether / ethyl acetate (8:1), filtered, and the resulting white solid was 3-chloro-5',6'-difluoro-2H-[1,3'-bipyridine]-2-one 829c (10 g), yield: 50%. MS m / z(ESI): 243.2 [M+H] + .

[0531] Step 4: Dissolve 829b (5.2 g, 21.1 mmol), 829c (6.66 g, 27.5 mmol), and N,N-diisopropylethylamine (8.19 g, 63.4 mmol) in dimethyl sulfoxide (30 mL), heat to 110 °C and stir for 16 hours. Dilute the reaction solution with ethyl acetate (200 mL), wash with saturated ammonium chloride solution (150 mL x 2) and saturated brine (150 mL x 2), and concentrate. Purify the residue by silica gel column chromatography (elution system B) to obtain 829 (6.0 g, 12.8 mmol), yield: 60.6%. MS m / z (ESI): 469.1 [M+H] + .

[0532] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,1H),7.83(dd,1H),7.70(dd,2H),7.67–7.56(m,2H),7.06(d,1H),6. 94(d,1H),6.32(t,1H),4.64–4.44(m,2H),2.27–2.14(m,2H),2.08–1.92(m,2H),1.68–1.52(m,2H).

[0533] Example 895

[0534] 1-(6-((1S,3S)-3-((5'-fluoro-2-oxo-3-(trifluoromethyl)-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazine-3-yl)cyclopropane-1-nitrile

[0535] Step 1: Under nitrogen protection, 673c (50 mg, 0.12 mmol), 2-hydroxy-3-trifluoromethylpyridine (29 mg, 0.18 mmol), cuprous iodide (23 mg, 0.12 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (17 mg, 0.12 mmol) and cesium carbonate (117 mg, 0.36 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to preparative HPLC (formic acid system) to give 1-(6-((1S,3S)-3-((5'-fluoro-2-oxo-3-(trifluoromethyl)-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 895 (30 mg), yield: 50.1%. MS m / z (ESI): 500.2 [M+H] + .

[0536] 1 H NMR(400MHz,DMSO-d6)δ8.04-8.01(m,2H),7.90(d,1H),7.63(dd,1H),7.27(d,1H),7.05(t,2H),6.82(d,1H),6.44(t,1H),4.58 -4.50(m,1H),4.43-4.36(m,1H),2.25-2.10(m,2H),2.06-1.99(m,1H),1.95-1.88(m,1H),1.75-1.71(m,2H),1.67-1.48(m,4H).

[0537] Example 897

[0538] 1-(6-((1S,3S)-3-((3-(difluoromethyl)-5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridazine-3-yl)cyclopropane-1-nitrile

[0539] Step 1: Under nitrogen protection, 673c (50 mg, 0.12 mmol), 3-(difluoromethyl)pyridin-2(1H)-one (26 mg, 0.18 mmol), cuprous iodide (23 mg, 0.12 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (17 mg, 0.12 mmol) and cesium carbonate (117 mg, 0.36 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 120 °C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to preparative HPLC (formic acid system) to give 1-(6-((1S,3S)-3-((3-(trifluoromethyl)-5'-fluoro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyridazin-3-yl)cyclopropane-1-onitrile 897 (13.0 mg), yield: 22.5%. MS m / z (ESI): 482.2 [M+H] + .

[0540] 1 H NMR(400MHz,DMSO-d6)δ7.90-7.87(m,2H),7.83(dd,1H),7.60(dd,1H),7.27(d,1H),7.03(d,2H),6.86(t,1H),6.82(d,1H),6.43(t,1H ),4.57-4.49(m,1H),4.42-4.35(m,1H),2.25-2.12(m,2H),2.06-1.98(m,1H),1.95-1.88(m,1H),1.75-1.70(m,2H),1.67-1.48(m,4H).

[0541] Example 1010

[0542] 3-Cyclopropyl-6'-((1S,3S)-3-((6-(difluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one

[0543] Step 1: Under nitrogen protection, methyl 6-chloropyridazine-3-carboxylate (1 g, 5.79 mmol), (1S,3S)-3-aminocyclopentylcarboxylate tert-butyl ester (1.16 g, 5.79 mmol), and N,N-diisopropylethylamine (1.50 g, 11.6 mmol) were dissolved in dimethyl sulfoxide (10 mL) and heated to 120 °C with stirring for 8 hours. The reaction solution was cooled to room temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed successively with water (100 mL × 2) and saturated sodium chloride solution (100 mL), dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give methyl 6-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)pyridazine-3-carboxylate 1010a (1.5 g), yield: 77.0%. MS m / z (ESI): 337.1 [M+H] + .

[0544] Step 2: Under ice bath conditions, 1010a (900 mg, 2.68 mmol) was dissolved in tetrahydrofuran (9 mL). Lithium borohydride solution (1 M, 3.22 mL) was added dropwise to the reaction mixture with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was slowly poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-3-((6-(hydroxymethyl)pyridazin-3-yl)amino)cyclopentyl)carbamate tert-butyl ester 1010b (800 mg), yield: 96.8%. MS m / z (ESI): 309.2 [M+H] + .

[0545] Step 3: Under ice bath conditions, 1010b (800 mg, 2.59 mmol) was dissolved in dichloromethane (8 mL). While stirring, Dysmart reagent (1.65 g, 3.89 mmol) was added to the reaction mixture. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL). The mixture was dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-3-((6-formylpyridazin-3-yl)amino)cyclopentyl)carbamate tert-butyl ester 1010c (600 mg), yield: 75.5%. MS m / z (ESI): 307.1 [M+H] + .

[0546] Step 4: Under ice bath conditions, 1010c (600 mg, 1.96 mmol) was dissolved in dichloromethane (6 mL). Diethylaminosulfur trifluoride (3.16 g, 19.6 mmol) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was then slowly added dropwise to a saturated sodium bicarbonate ice-water solution (50 mL). The aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL). The mixture was dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give (1S,3S)-3-((6-(difluoromethyl)pyridazin-3-yl)amino)cyclopentyl)carbamate tert-butyl ester 1010d (210 mg), yield: 32.7%. MS m / z (ESI): 329.2 [M+H] + .

[0547] Step 5: Dissolve 1010d (140 mg, 0.426 mmol) in 2 M dioxane hydrochloride solution (4 mL) and react at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure to obtain (1S,3S)-N 1 -(6-(difluoromethyl)pyridazin-3-yl)cyclopentane-1,3-diamine 1010e, the crude product can be used directly in the next reaction without purification. MS m / z (ESI): 229.1 [M+H] + .

[0548] Step 6: Under an oxygen atmosphere and at room temperature, 2,3-difluoropyridine-5-boronic acid (200 mg, 1.26 mmol), 3-cyclopropylpyridine-2(1H)-one (170 mg, 1.26 mmol), copper acetate (343 mg, 1.89 mmol), and pyridine (199 mg, 2.52 mmol) were dissolved in dichloromethane (4 mL) and stirred for 16 hours. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by silica gel chromatography (elution system B) to give 1010 f (185 mg) of 3-cyclopropyl-1-(5,6-difluoro-3-pyridyl)pyridine-2-one, yield: 59.2%. MS m / z (ESI): 249.1 [M+H] + .

[0549] Step 7: Under nitrogen protection, 1010e (0.206 mmol), 1010f (51 mg, 0.206 mmol), and N,N-diisopropylethylamine (80 mg, 0.618 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 110 °C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by reversed-phase C18 chromatography (formic acid system) to give 1010 (21 mg) of 3-cyclopropyl-6'-((1S,3S)-3-((6-(difluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one, yield: 22.3%. MS m / z (ESI): 457.1 [M+H] + .

[0550] 1 H NMR(400MHz,DMSO-d6)δ7.84(d,1H),7.56(dd,1H),7.51(d,1H),7.47–7.43(m,2H),7.02(dd,1H),6.97(d,1H),6.94(d,1H),6.91(t,1H),6.19 (t,1H),4.58–4.53(m,1H),4.50-4.45(m,1H),2.25–2.15(m,2H),2.05 –1.94(m,3H),1.67–1.53(m,2H),0.88–0.83(m,2H),0.66–0.62(m,2H).

[0551] Example 1011

[0552] 3-Chloro-6'-((1S,3S)-3-((6-(difluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one

[0553] Step 1: Under nitrogen protection, 1010e (0.219 mmol), 829c (53 mg, 0.219 mmol), and N,N-diisopropylethylamine (85 mg, 0.657 mmol) were dissolved in dimethyl sulfoxide (2 mL) and heated to 110 °C with stirring for 16 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, filtered, concentrated, and the residue was purified by reversed C18 chromatography (formic acid system) to give 3-chloro-6'-((1S,3S)-3-((6-(difluoromethyl)pyridazin-3-yl)amino)cyclopentyl)amino)-5'-fluoro-2H-[1,3'-bipyridine]-2-one 1011 (34.1 mg), yield: 34.5%. MS m / z (ESI): 451.1 [M+H] + .

[0554] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,1H),7.83(d,1H),7.70(dd,1H),7.61(d,1H),7.51(d,1H),7.46(d,1H),7.06(d,1H),6.94(d,1H),6.91 (t,1H),6.32(t,1H),4.58-4.53(m,1H),4.50-4.45(m,1H),2.25–2.15(m,2H),2.09–2.02(m,1H),1.98–1.92(m,1H),1.67–1.52(m,2H).

[0555] Example 1169

[0556] 1-(6-(((1S,3S)-3-((5'-fluoro-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)amino)pyridine-3-yl)cyclopropyl-1-carboxynitrile

[0557] Under nitrogen protection, 436b (50 mg, 0.173 mmol), 1-(6-chloropyridin-3-yl)cyclopropanecarboxynitrile (46.5 mg, 0.26 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridin-κN)-palladium (16.9 mg, 0.0173 mmol), and cesium carbonate (169 mg, 0.52 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and dimethyl sulfoxide (0.5 mL). The reaction was heated to 110 °C and stirred for 2 hours. Ethyl acetate (30 mL) was added to the reaction solution. The organic phase was washed with saturated sodium chloride aqueous solution (15 mL × 3), dried, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 1169 (25 mg) of 1-(6-(((1S,3S)-3-((5'-fluoro-2-oxo-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)amino)pyridin-3-yl)cyclopropyl-1-carboxynitrile, yield: 33.5%. MS m / z (ESI): 431.2 [M+H] + .

[0558] 1 H NMR(400MHz,DMSO-d6)δ7.98(d,1H),7.84(d,1H),7.64(dd,1H),7.57-7.46(m,2H),7.34(dd,1H),6.94(d,1H),6.78(d,1H),6.46(d, 2H),6.29(t,1H),4.55-4.47(m,1H),4.32-4.25(m,1H),2.18-2.08(m,2H),1.99-1.84(m,2H),1.65-1.45(m,4H),1.40-1.30(m,2H).

[0559] The synthesis method of the embodiments can be referred to the above embodiments.

[0560] Biological test evaluation

[0561] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0562] I. Protein and Cellular Function Experiments

[0563] Test Example 1: Determination of the binding ability of the compounds of the present invention to PCSK9 protein.

[0564] 1. Experimental objective: To detect the effect of compounds on the binding of PCSK9 protein using the HTRF method.

[0565] 2. Experimental Methods:

[0566] 1) Prepare a 1x experimental buffer solution with the following components: 20mM HEPES, 150mM NaCl, 1mM CaCl2, 0.01% Tween 20, and 0.01% BSA;

[0567] 2) Prepare a 2.5x final concentration PCSK9-His working solution (30nM) using 1x experimental buffer. Add 8uL of protein solution to each well of the 384-well plate except for the low control wells, and add 8uL of 1x experimental buffer to the low control wells.

[0568] 3) Preparation of compound working solution: First, the compound in the storage solution is uniformly serially diluted with DMSO (300 uM top, 3-fold, 10 doses). Then, 3.33 uL of each serially diluted compound is pipetted into 96.7 uL of 1x experimental buffer and mixed thoroughly to obtain the prepared compound working solution (10x).

[0569] 4) Pipette 2 μL of the compound into the corresponding well and incubate at 25°C for 10 minutes;

[0570] 5) Prepare a working solution of the probe compound at a final concentration of 4x using 1x experimental buffer (90 nM), mix thoroughly, add 5 μL to each well, and incubate at 25°C for 10 minutes;

[0571] 6) Prepare a 4x final concentration Anti-His Tb working solution (4x) using 1x experimental buffer, add 5 μL to each well, and incubate at 25°C for 2 hours;

[0572] 7) Envision reading HTRF665 / 615 program.

[0573] 3. Experimental data processing methods:

[0574] The IC was calculated using XLfit's four-parameter log(inhibitor) vs. response--variable slope (four parameters) model to fit the compound concentration, corresponding inhibition rate, and nonlinearity. 50 .

[0575] 4. Experimental Results:

[0576] 5. Experimental conclusions: As can be seen from the data in the table, the compounds in the embodiments of this invention have a significant binding effect on PCSK-9 protein, showing a strong binding ability.

[0577] Test Example 2: Determination of the effect of the compound of the present invention on the concentration of PCSK9 secreted by HepG2 cells

[0578] 1. Experimental objective: To detect the inhibitory effect of the compound on PCSK9.

[0579] 2. Experimental instruments and reagents:

[0580] 2.1 Instruments:

[0581] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water system (THERMO: Pacific T II+Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[0582] 2.2 Reagents:

[0583] CircuLex Human PCSK9 ELISA Kit (MBL: CY-8079), DMEM (Gibco: 31966-021), FBS (Sigma: S5394), compound plate (Thermo: 1353506), complete culture medium: DMEM + 10% FBS + 1X P / S; experimental culture medium: DMEM + 10% FBS, cell line: HepG2 (ATCC: HB-8065)

[0584] 3. Experimental methods:

[0585] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0586] 2) Digest and resuspend the cells in experimental culture medium, and seed 25,000 cells / well / 200μL into a 96-well cell culture plate and incubate at 37°C and 5% CO2 for 20-24 hours.

[0587] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[0588] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[0589] 5) Add the diluted compound to the cell culture plate at 250 μL per well and incubate at 37°C with 5% CO2 for 48 hours.

[0590] 6) Collect 200 μL of cell culture medium per well and freeze at -80℃ for later use.

[0591] 7) Take the cell culture medium sample out of -80℃ to dissolve, vortex, centrifuge, and set aside.

[0592] 8) Prepare standard curves: Add the corresponding volume of dilution buffer to each standard tube in sequence. Take the corresponding volume of standard from the original tube or the previous concentration tube in the order of concentration 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, 0 ng / mL and dilute it in sequence.

[0593] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[0594] 10) According to the plate map settings for standard curve wells and sample wells, add 100 μL of the corresponding standard and culture medium sample to each well, with 2 replicates. Seal with adhesive tape, place on a shaker at room temperature, gently shake to mix, and incubate for 1 hour.

[0595] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0596] 12) Add 100 μL of HRP-conjugated detection antibody to each well, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 1 hour.

[0597] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0598] 14) Add 100 μL of Substrate reagent to each well, protect from light, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 10-20 minutes.

[0599] 15) Add 100 μL of stop solution (1N H2SO4) to each well and mix well.

[0600] 16) Measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm using an ELISA reader. Perform the detection within 30 minutes after the reaction is terminated.

[0601] 4. Experimental Data Processing Method: The OD values ​​read by the microplate reader were subtracted from the OD values ​​of the standard group (0 concentration) from those of the standard, control group, and sample to obtain the actual values ​​for each well. A standard curve was then plotted using GraphPad to calculate the sample concentration. If the sample was over-diluted, the final calculation needed to multiply by the corresponding dilution factor to obtain the actual sample concentration. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to different concentrations, the IC50 was plotted using GraphPad. 50 .

[0602] 5. Experimental Results:

[0603] 6. Experimental conclusions: As can be seen from the data in the table, the compounds in the embodiments of this invention show a significant inhibitory effect on PCSK9 secretion in HepG2 cells.

[0604] Test Example 3: Determination of the effect of the compound of the present invention on LDLR levels in HepG2 cells

[0605] 1. Experimental objective: To detect the effect of the compound on LDLR protein levels.

[0606] 2. Experimental instruments and reagents:

[0607] 2.1 Instruments:

[0608] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water system (THERMO: Pacific T II+Micropure), plate washer (Thermo: WELLWASH VERSA), microplate shaker (Thermo: 88882006)

[0609] 2.2 Reagents:

[0610] Human LDL R Quantikine ELISA Kit (R&D: DLDLR0), DMEM (Gibco: 31966-021), FBS (Sigma: S5394), PBS, cell lysis buffer (Thermo: 78503), protease inhibitor (Pierce: 78430), compound plate (Thermo: 1353506), complete medium: DMEM + 10% FBS + 1X P / S, experimental medium: DMEM + 10% FBS, cell line: HepG2 (ATCC: HB-8065).

[0611] 3. Experimental methods:

[0612] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0613] 2) Digest and resuspend the cells in experimental culture medium, and seed 25,000 cells / well / 200μL into a 96-well cell culture plate and incubate at 37°C and 5% CO2 for 20-24 hours.

[0614] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[0615] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[0616] 5) Add the diluted compound to the cell culture plate at 250 μL per well and incubate at 37°C with 5% CO2 for 48 hours.

[0617] 6) Remove the cell culture medium, wash the cells with PBS, and add 50 pL of cell lysis buffer and protein inhibitor.

[0618] 7) Centrifuge to remove lysates and store the sample for later use.

[0619] 8) Prepare the standard curve: Add the corresponding volume of dilution buffer to each standard tube in sequence. Take the corresponding volume of standard from the original tube or the previous concentration tube in sequence and dilute it in sequence.

[0620] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[0621] 10) Add 80 μL of the corresponding standard and sample to each well according to the standard and sample wells set in the plate map, with 2 replicates. Wells without standards are used as background values. Seal with adhesive tape, place on a shaker at room temperature, gently shake to mix, and incubate for 2 hours.

[0622] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0623] 12) Add 200 μL of Human LDLR conjugate to each well, seal with an adhesive label, place on a shaker to mix thoroughly, and incubate for 2 hours.

[0624] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0625] 14) Add 200 μL of Substrate solution to each well, protect from light, seal with adhesive tape, place on a shaker to mix thoroughly, and incubate for 20 minutes.

[0626] 15) Add 50 μL of stop solution to each well, mix well, and incubate for 20 min.

[0627] 16) Use an ELISA reader to measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm.

[0628] 4. Experimental data processing methods:

[0629] The OD values read by the microplate reader are obtained by subtracting the OD value of the 0 concentration in the standard sample group from the OD values of the standard samples, the control group, and the samples, and then the actual values of each well are obtained. A standard curve is plotted using Graphpad to calculate the concentration of the samples. If the sample detection has been diluted, the corresponding dilution factor needs to be multiplied during the final calculation to obtain the actual concentration of the sample. The percentage increase in concentration % = (actual concentration of the control - actual concentration of the sample) / actual concentration of the control * 100.

[0630] 5. Experimental results:

[0631] Through the above protocol, it is found that the compounds of the present invention have an effect of increasing the LDLR expression level in HepG2 cells, and an increase in expression of about 20% to 200% is shown in the experiment.

[0632] Among the preferred compounds, the percentage increase in the LDLR expression level in HepG2 cells by the compounds of the present invention is greater than about 10%, more preferably greater than about 20%, further preferably greater than about 50%, still further preferably greater than about 80%, and most preferably greater than 100% receptor expression increase among the compounds listed in the present invention.

[0633] 6. Experimental conclusion: As can be seen from the data in the table, the compounds of the embodiments shown in the present invention show an effect of increasing the LDLR concentration in the experiment on the effect of the compounds on the LDLR concentration in HepG2 cells.

[0634] II. Pharmacokinetics and other experiments

[0635] Test Example 1. Pharmacokinetic determination in mice

[0636] 1. Experimental purpose: Using C57BL / 6J mice as the test animals, study the pharmacokinetic behavior of the compounds of the present invention after oral and intravenous administration in mice (plasma).

[0637] 2. Test protocol

[0638] 2.1 Test drug: The compounds of the present invention, self-made;

[0639] 2.2 Test animals: C57 mice, male, purchased from Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013 - 0006 N0.311620400001794).

[0640] 2.3 Drug preparation: Drug preparation for oral administration: 10% Solutol HS15

[0641] Weigh 10 g of Solutol HS15 solid, dissolve it in 90 mL of purified water, mix well and stir and ultrasonicate to form a clear solution.

[0642] Weigh out the compound of the present invention, dissolve it in the solution, shake well, and sonicate for 15 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg / mL.

[0643] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0644] Weigh the compound of the present invention, add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[0645] 2.4 Administration: Three male C57 mice were administered the drug via PO after fasting overnight. The dose was 5 mg / kg and the administration volume was 10 mL / kg.

[0646] Three male C57 mice were used. After fasting overnight, they were administered the drug intravenously at a dose of 1 mg / kg and a volume of 5 mL / kg.

[0647] 2.5 Sample collection: Before and after drug administration, 0.083 (iv), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after drug administration, 0.04 mL of blood was collected from the orbital cavity and placed in EDTA-K2 tubes. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4℃ and stored at -80℃. The mice were fed 4 hours after drug administration.

[0648] 2.6 Measurement Results: The final measurement results were obtained using the LCMS / MS method.

[0649] 3. Experimental Results:

[0650] 4. Experimental conclusions: The compounds of this invention exhibit good PK advantages, with high exposure levels (AUC), long half-life, and long mean residence time.

[0651] Test Example 2: Pharmacokinetic Evaluation Test of Oral Administration in SD Rats

[0652] 1. Research objective: To investigate the pharmacokinetic behavior of the compound of this invention in rats (plasma) after oral administration at a dose of 5 mg / kg, using SD rats as test animals.

[0653] 2. Experimental Design:

[0654] 2.1 Experimental reagents: The compounds in the embodiments of this invention were prepared in-house.

[0655] 2.2 Experimental animals: 3 male SD rats per example, provided by Zhejiang Vital River Laboratory Animal Technology Co., Ltd., animal production license number: SCXK(Zhejiang) 2024-0001).

[0656] 2.3 Formulation prescription: Preparation of orally administered drug: 0.5% CMC-Na (1% Tween 80)

[0657] Weigh 0.50 g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200 Cps), dissolve it in 99 mL of pure water, add 1 mL of Tween 80, and mix and stir evenly overnight to form a clear solution.

[0658] Weigh the compound of the example and add it to a 20 mL glass bottle. Add this solution and sonicate for 10 minutes to obtain a homogeneous suspension solution with a concentration of 0.5 mg / mL.

[0659] 2.4 Administration: 3 male SD rats, after fasting overnight, were administered p.o. respectively; the p.o. dose was 5 mg / kg, and the administration volume was 10 mL / kg.

[0660] 2.5 Sample collection:

[0661] Blood collection: About 0.2 mL of jugular vein blood was collected from rats before and 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration, placed in an EDTA-K2 anticoagulant tube, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at -80°C; the rats were fed 4 h after administration.

[0662] 2.6 Sample treatment:

[0663] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile for precipitation, mix and centrifuge at 3500×g for 5-2'0 minutes.

[0664] 2) Take the supernatant solution after treatment for LC / MS / MS analysis of the concentration of the test compound. LC / MS / MS analysis instrument: AB Sciex API 4000 Qtrap.

[0665] 2.7 Liquid phase analysis:

[0666] ● Liquid phase conditions: Shimadzu LC-20AD pump

[0667] ● Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[0668] ● Flow rate: 0.4 mL / min

[0669] ● Elution time: 0-4.0 minutes, eluent as follows:

[0670] 3. Experimental Results and Analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The results of the rat pharmacokinetic experiment are shown in Table 3 below:

[0671] 4. Experimental Conclusions: The data in the table show that, in the rat pharmacokinetic evaluation experiment, the compound of this invention exhibits a good PK advantage, with a high exposure limit (AUC), long half-life, and long mean residence time.

[0672] Test Example 3: In vitro metabolic stability study of the compound of the present invention in rat liver microsomes

[0673] 1. Experimental objective: The objective of this experiment is to evaluate the metabolic stability of the compound in phase I and part of phase II of rat liver microsomes.

[0674] 2. Experimental Design

[0675] 2.1 Drug Preparation: The compounds of this invention were prepared into 10 mM stock solutions using DMSO (or other suitable solutions) and stored at -20°C for later use. The compounds of this invention were prepared in-house.

[0676] 2.2 Experimental Procedure

[0677] 1) Prepare buffer solution: Take 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dissolve them in ultrapure water and bring the volume to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0678] 2) Preparation of working solution: Add 2 μL of the compound stock solution to 998 μL of phosphate buffer to achieve a final concentration of 20 μM. The ratio and final concentration can be adjusted according to the properties of the compound.

[0679] 3) Prepare liver microsome working solution: 156.3 μL of 20 mg / mL microsomes, diluted to 5 mL with 100 mM phosphate buffer, mixed well, with a final concentration of 0.625 mg / mL.

[0680] 4) Prepare NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

[0681] 5) Prepare the pore-drilling agent (Alamethicin): Weigh 1 mg of Alamethicin and add it to 200 μL of methanol to prepare a solution of 5 mg / mL. Then take 10 μL of this solution and add it to 990 μL of phosphate buffer (pH 7.4) to obtain a final concentration of 50 μg / mL.

[0682] 6) Prepare the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution and store it in a refrigerator at 2-8℃.

[0683] 7) Incubation Procedure: Add 400 μL of prepared liver microsomes, 25 μL of the compound working solution (20 μM), and 25 μL of Alamethicin (50 μg / mL) sequentially to a 96-well plate, and pre-incubate at 37°C for 10 min. Then add 50 μL of prepared NADPH / UDPGA to initiate the reaction and incubate at 37°C. The total reaction volume is 500 μL. The final concentrations of each component are as follows:

[0684] At time points of 0, 5, 15, 30, 60 and 120 min, 50 μL of each sample was taken and 200 μL of cold stop solution containing internal standard was added to terminate the reaction. The sample was centrifuged at 3500 rpm for 10 min and the supernatant was taken for LC-MS / MS analysis.

[0685] 2.4 Chromatographic Analysis

[0686] 1) Chromatographic conditions:

[0687] Instrument: Shimadzu LC-20AD; Column: Phenomenex C18 (50*4.6mm, 5μm particle size); Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile; Wash gradient: 0.2–1.6 min 5% A to 95% A, 3.0–3.1 min 95% A to 5% A; Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 μL.

[0688] 2) Mass spectrometry conditions:

[0689] Instrument: API4000 liquid chromatography-mass spectrometry system, AB Sciex; Ion source: electrospray ionization source (ESI); Dry gas: N2, temperature 500℃; Electrospray voltage: 5000V; Detection mode: positive ion detection; Scan mode: reaction monitoring (MRM); Scan time: 0.8401s.

[0690] 3. Data Processing: Calculate the raw data using the following formula:

[0691] Residual percentage % = (Peak area ratio of compound to internal standard at any time point) / (Peak area ratio of compound to internal standard at 0 minutes) × 100

[0692] T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0693] In vitro intrinsic clearance rate of liver microsomes (CL) was calculated using Ke. int ) and hepatic intrinsic clearance (CL) int,liver )

[0694] CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL)

[0695] CL int,liver =CL int × Liver microsomal protein content (mg / g) × Liver weight to body weight ratio

[0696] Based on the well-stirred model, the in vivo liver clearance rate (CL) was estimated. int,liver )

[0697] CL = (CL) int,liver ×fu×Qh) / (CL int,liver ×fu+Qh), where fu represents the free fraction in the blood, which is 1 by default. The parameters in the formula are shown in the table below.

[0698] 4. Experimental Data

[0699] 5. Experimental conclusions: The results show that the compounds in the advantageous embodiments of the present invention all exhibit slow metabolism in rat liver microsomes.

[0700] Test Example 4: Caco-2 Cell Permeability Test

[0701] 1. Experimental objective: The purpose of this experiment is to test the bidirectional permeability of the compound through the Caco-2 cell model and to evaluate whether it is transported by efflux transporters.

[0702] 2. Experimental instruments and reagents

[0703] 2.1 Instruments

[0704] HTS Transwell-96Well(Corning,Cat.No.3391)

[0705] Millicell Cell Impedance Analyzer (Millipore)

[0706] Vision(Nexcelom Bioscience LLC)

[0707] Infinite 200PRO microplate reader(Tecan)

[0708] MTS2 / 4orbital shaker(IKA Labortechnik)

[0709] Mass spectrometer (SCIEX API 4000) and liquid chromatograph (Shimadzu LC 30-AD)

[0710] Automatic sampler (Shimadzu SIL 30-ACMP), centrifuge, and pipette (Eppendorf)

[0711] 2.2 Reagents

[0712] Caco-2 cells (American type culture collection)

[0713] Hepes(Solarbio)Penicillin(Solarbio)Streptomycin(Solarbio)

[0714] Trypsin / EDTA(Solarbio)DMSO(Solarbio)

[0715] Hank's balanced salt solution,HBSS(Gibco)

[0716] Non-essential amino acids,NEAA (Gibco)Fetal bovine serum(AUS)

[0717] Dulbecco's Modified Eagle's Medium(DMEM,HyClone Corporation)

[0718] Test compound

[0719] 3. Experimental Procedure

[0720] 3.1 Preparation of Caco-2 cells

[0721] 1) Add 50 μL and 25 mL of cell culture medium to each well of the upper and lower chambers of the Transwell, respectively. Then, before cell seeding, incubate the HTS transwell plate at 37°C and 5% CO2 for 1 hour.

[0722] 2) Dilute Caco-2 cells to 6.86 x 10⁻⁶ using culture medium. 5 Cells / mL, and 50 μL of cell suspension was added to the filter wells of a 96-well HTS Transwell plate. Cells were cultured for 14–18 days in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity. Cell culture should begin no later than 24 hours after initial inoculation, with the cell culture medium changed every other day.

[0723] 3.2 Assessment of Cell Monolayer Integrity

[0724] 1) Remove the culture medium from each well in the upper and lower chambers of the Transwell and add preheated fresh culture medium.

[0725] 2) Measure the transepithelial resistance (TEER) of a cell monolayer.

[0726] 3) After the measurement is completed, put the plate back into the incubator.

[0727] The TEER value is calculated according to the following equation:

[0728] TEER measurement (ohm) x membrane area (cm²) 2 ) = TEER value (ohm·cm) 2 )

[0729] TEER > 230 ohm·cm 2 This indicates that the Caco-2 monolayer has good quality.

[0730] 3.3 Solution Preparation

[0731] 1) Prepare 2 mM stock solutions of the test compound and positive control compound using DMSO, respectively. Dilute the stock solutions with HBSS (10 mM HEPES, pH 7.4) to obtain 10 μM working solutions of the test compound and positive control compound. Metoprolol, digoxin, and atenolol were used as control compounds. The final concentration of DMSO in the incubation system was 0.5%.

[0732] 3.4 Drug Transport Analysis

[0733] 1) Remove the Caco-2 cell plate from the incubator. Wash the cells twice with preheated HBSS (10 mM HEPES, pH 7.4). Incubate the cell plate at 37°C for 30 minutes.

[0734] 2) Determine the drug transport rate from the top membrane side to the outer substrate side. Add 125 μL of working solution to the delivery end (top membrane side), and immediately remove 50 μL of sample from the delivery end and transfer it to a new 96-well plate containing 400 μL of stop solution containing internal standards (200 nM caffeine, 100 nM alprazolam, and 100 nM tolbutamide) as the initial delivery end sample (DOA). Vortex at 1000 rpm for 10 minutes. Add 235 μL of transport buffer to the receiving end (outer substrate side).

[0735] 3) Determine the drug transport rate from the lateral side of the substrate to the apical side. Add 285 μL of working solution to the delivery end (lateral side of the substrate), and immediately remove 50 μL of sample from the delivery end and transfer it to a new 96-well plate containing 400 μL of stop solution containing internal standards (200 nM caffeine, 100 nM alprazolam, and 100 nM tolbutamide) as the initial delivery end sample (DOB). Vortex at 1000 rpm for 10 minutes. Add 75 μL of transport buffer to the receiving end (apical side of the substrate). Both the apical side to lateral side and the lateral side to apical side directions need to be measured simultaneously.

[0736] 4) Add 50 μL of working solution to 400 μL of stop solution containing internal standard to prepare C0 sample. After incubation for 2 hours, add 50 μL of working solution to stop solution to prepare C2 sample.

[0737] 5) Incubate the cell plate at 37°C for 2 hours.

[0738] 6) At the end of incubation, remove 50 μL of sample from both the dosing end (top membrane side in the AB direction, outer side of the base in the BA direction) and the receiving end (outer side of the base in the AB direction, top membrane side in the BA direction), and add 8 volumes of stop solution containing internal standard. Shake all samples for 10 minutes and centrifuge at 4000 rpm and 4°C for 30 minutes. Transfer the supernatant and mix with an appropriate amount of ultrapure water for LC-MS / MS analysis.

[0739] 7) To determine fluorescein leakage after 2 hours of incubation, a fluorescein stock solution was prepared using DMSO and diluted to a final concentration of 100 μM with HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescein solution was added to the top membrane side of each Transwell, and 300 μL of HBSS (10 mM HEPES, pH 7.4) solution was added to the outer side of the substrate. The cell plate was incubated at 37°C for 30 minutes. 80 μL of sample was removed from each well and transferred to a new 96-well plate. Fluorescence signals were read at 480 nM excitation and 530 nM emission wavelengths (for monitoring monolayer integrity).

[0740] 4. Data Analysis: Fluorescent yellow leakage can be calculated using the following equation:

[0741] Apparent permeability can be calculated using the following equation:

[0742] The outflow ratio can be calculated using the following equation:

[0743] The recovery rate can be calculated using the following equation:

[0744] The remaining percentage of the compound after 2 hours of incubation can be calculated using the following equation:

[0745] 5. Sample Analysis

[0746] Liquid phase conditions: Shimadzu LC 30AD

[0747] Chromatographic column: Biphemyl 2.7μm, 2.1×50mm

[0748] Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is a 0.1% acetonitrile solution.

[0749] Elution time: 0-1.2 minutes, eluent as follows:

[0750] 6. Experimental Results

[0751] 7. Experimental conclusion: In the Caco-2 permeability experiment, the compound of the present invention has high permeability and low efflux ratio.

[0752] Test Example 5: hERG Potassium Channel Inhibitory Activity Test

[0753] 1. Research objective: To investigate the inhibitory effect of the compound on the activity of the hERG potassium ion channel.

[0754] 2. Experimental instruments and reagents:

[0755] 2.1 Reagents

[0756] DMEM Gibco Fetal Bovine Serum (FBS) Avantor G418 GPC TrypLE TM Express Gibco

[0757] 2.2 Instruments and Consumables

[0758] HEKA (Germany) IPA & EPC10 data acquisition software Sutter Instrument (USA) &

[0759] HEKA (Germany) SutterPatch & PatchMaster peristaltic pumps; LEADFLUID (China) BT103S irrigation system

[0760] MappingLab(UK)MVC-801

[0761] 3. Experimental Methods

[0762] 3.1 Cell Culture: The HEK-293 cell line stably expressing the hERG potassium channel was used. hERG potassium channel cells were purchased from Creacell (catalog number: A-0320). Cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% carbon dioxide.

[0763] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Incubate with Express solution at 37°C for approximately 0.5 min. Once the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed the cells into 6 cm cell culture dishes, with a seeding density of 2.5 × 10⁵ cells per dish (final volume: 5 mL).

[0764] To maintain cellular electrophysiological activity, cell density must not exceed 80%. Before patch-clamp assays, cells are treated with TrypLE. TM Express cells were isolated, and 4 × 10³ cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the cells were tested.

[0765] 3.2 Extracellular fluid: K-007-1

[0766] 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, with NaOH adjusted to pH 7.4.

[0767] Intracellular fluid: K-002-2

[0768] 20mM KCl, 115mM K-Aspartic, 1mM MgCl2·6H2O, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, KOH adjust pH=7.2.

[0769] Extracellular fluid was stored at 4°C for two weeks. Intracellular fluid was prepared, aliquoted into 1 mL tubes, and stored at -20°C. Freshly thawed intracellular fluid was used daily for experiments. All intracellular fluid was used within three months. After three months, the old intracellular fluid was discarded and freshly prepared.

[0770] 3.3 Compound Preparation: The compounds were prepared into 10 mM or 30 mM stock solutions in 100% DMSO (Sigma-Aldrich, D2650). Before the experiment, the stock solutions of the test compounds were diluted with DMSO to obtain solutions of 1000-fold or 333-fold concentrations for each test, and then diluted with extracellular fluid to the required concentrations of 1000-fold or 333-fold.

[0771] 3.4 Patch-clamp assay: The voltage stimulation protocol for whole-cell patch-clamp recording of hERG currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to excite the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. A 0.5 s stimulation at -50 mV is used as the leakage current detection. Experimental data are acquired using an IPA amplifier (Sutter Instrument) or an EPC10 amplifier (HEKA) and stored in SutterPatch (with Igor Pro) or PatchMaster software.

[0772] The patch-clamp procedure begins by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, is then placed into a microelectrode holder. A coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then applied, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0773] Once the current amplitude stabilized in the control extracellular solution, drug administration began. For each drug concentration, the current was measured after reaching equilibrium (approximately 5 minutes). Multiple concentrations were measured for each test compound. Blank control extracellular solution and working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, with fluid replacement performed using a peristaltic pump during recording. The current detected in extracellular solution without the compound served as a control for each cell. Each concentration was measured independently in triplicate using at least three cells. All electrophysiological experiments were performed at room temperature.

[0774] 3.5 Experimental Data Processing: First, the peak tail current after each drug concentration was processed. compound Peak tail current (and blank control) control Normalize, and then calculate the inhibition rate corresponding to each drug concentration, i.e. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) were calculated, with data expressed as Mean ± SE. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)) was used to calculate the IC50 value for each compound, and a nonlinear fit was applied to the concentration-effect curve, where IC50... 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0775] 4. Experimental Results

[0776] 5. Experimental conclusion: The compound of this invention has no strong inhibitory effect on hERG potassium ion channels.

[0777] III. Drug Efficacy Experiment

[0778] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0779] 1. Experimental objective: To evaluate the in vivo efficacy of the compound in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0780] 2. Experimental Instruments and Reagents

[0781] 2.1 Instruments

[0782] Refrigerator (BCD-268TN, Haier), Biosafety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory), Clean Bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.), 5mL Pipettes (Research Plus, Eppendorf), 1mL Pipettes (Research Plus, Eppendorf), Constant Temperature Water Bath (HWS-12, Shanghai Yiheng Science), Centrifuge (Centrifuge 5720R, Eppendorf), Electronic Balance (CPA2202S, Sartorius), Electronic Balance (BSA2202S-CW, Sartorius), Ultrasonic Cleaner (115F0032, Shanghai Kedao), Pure Water System (Pacific TII, Thermo), Magnetic Stirrer (08-2G, Chijiu), Fully Automated Blood Biochemistry Analyzer (Hitachi 7180, HITACHI)

[0783] 2.2 Reagents: High-fat diet (Western Diet, D12079B), physiological saline (MA0083-D, meilunbio)

[0784] Solutol HS 15 (102483882, Sigma)

[0785] 2.3 Test Drug: The compound of this invention, prepared in-house.

[0786] 3 Experimental Operation and Data Processing

[0787] 3.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[0788] 3.2 Animal Model: After animals arrive at the barrier system, they are allowed to adapt for one week before being fed a high-fat diet. Animal weight and feed intake are recorded weekly.

[0789] 3.3 Grouping and Administration

[0790] a. Grouping is done using a random grouping method.

[0791] c. Based on the grouping results, begin administering the test drug (administration route: oral administration; administration volume: 10 mL / kg; administration frequency: once a day or single administration; administration period: 21 days; solvent: 10% Solutol HS 15 / 90% Saline).

[0792] d. After starting the test drug, weigh and feed twice a week, and collect blood once a week.

[0793] e. Process data using software such as Excel. Body weight change rate (BWC) (%) = (Weight at the end of treatment - Weight at the beginning of treatment) / Weight at the beginning of treatment × 100%; Feed intake (g / mice / day) = (Previous feed addition + Previous feed residue - Current feed residue) / Number of animals / Number of feeding days; Calculation of blood biochemical inhibition rate: Using the blood biochemical results of the Vehicle group tested in the same batch as a baseline, normalize the data of each treatment group, and then calculate the percentage of TC and LDL-C according to the formulas: TC change percentage (%) = (TC value after administration - TC value before administration) / TC value before administration * 100%; LDL-C change percentage (%) = (LDL-C value after administration - LDL-C value before administration) / LDL-C value before administration * 100%. Detect PCSK9 in plasma using ELISA.

[0794] 4. Experimental conclusion: The compounds in the embodiments of this invention can effectively reduce LDL-C in the B6-hPCSK9 transgenic mouse model of hyperlipidemia.

Claims

1. A method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue of human PCSK9, namely Val589 and Ser636; preferably, the inhibitor binds to the amino acid residue Val589 of human PCSK9 but not to the amino acid residue Ser636 of human PCSK9.

2. A method for inhibiting PCSK9, the method comprising contacting PCSK9 with an inhibitor of PCSK9, the inhibitor binding to at most one amino acid residue from amino acid residues Val589 and Ser636 of human PCSK9, and further binding to amino acid residue Gly572 of human PCSK9.

3. The method according to any one of claims 1-2, characterized in that, The inhibitor comprises a hydrogen bond donor portion and a hydrogen bond acceptor portion that bind to the amino acid residue Val589; preferably, it comprises one hydrogen bond donor portion and one hydrogen bond acceptor portion. And / or, the inhibitor contains a hydrogen bond donor portion that binds to the amino acid residue Gly572 or a portion that forms a halogen bond; And / or, the inhibitor comprises a hydrogen bond receptor moiety that binds to the amino acid residue Gln587; preferably, the hydrogen bond receptor moiety is a single hydrogen bond receptor moiety.

4. The method according to any one of claims 1-3, characterized in that, The inhibitor further comprises a hydrogen bond donor moiety that binds to the amino acid residue Ala637; preferably, the inhibitor comprises a diaminocyclopentane structure, wherein an NH group acts as a hydrogen bond donor on the Ala637 amino acid residue in the C-terminal M3 domain of PCSK9. And / or, a hydrogen bond acceptor moiety that binds to amino acid residue His591 via water molecule-mediated binding; preferably, the inhibitor comprises a pyridine ring, wherein the nitrogen atom on the pyridine ring acts as a hydrogen bond acceptor, forming a hydrogen bond network with Ser564 and His591 of the C-terminal M2 domain of PCSK9 via a water bridge. And / or, a cationic-π interaction moiety that binds to the amino acid residue Arg495; preferably, the inhibitor comprises a pyridine ring that forms a cationic-π interaction with Arg495 at the C-terminus of PCSK9; And / or, a hydrogen bond acceptor portion that binds to the amino acid residue Gly640; preferably, the inhibitor comprises a pyrazolopyrazinone ring or an imidazopyrazinone ring, wherein the oxygen atom on the pyrazinone ring acts as a hydrogen bond acceptor on the Gly640 amino acid residue in the C-terminal M3 domain of PCSK9.

5. The method according to any one of claims 1-4, characterized in that, The inhibitor contains a pyridine ring, and the nitrogen atom on the pyridine ring acts as a hydrogen bond acceptor to the Val589 amino acid residue in the C-terminal M2 domain of PCSK9. And / or, the inhibitor contains a pyridazine ring, the nitrogen atom on which acts as a hydrogen bond acceptor on the Val589 amino acid residue of the C-terminal M2 domain of PCSK9; And / or, the inhibitor has a pyridazine or pyridine ring with a cyano substituent, and the nitrogen atom on the cyano acts as a hydrogen bond acceptor on the Gln587 amino acid residue of the C-terminal M2 domain of PCSK9. And / or, the inhibitor comprises a pyridone ring, wherein the substituent chlorine atom on the pyridone ring acts as a hydrogen bond acceptor on the Gly572 amino acid residue of the C-terminal M2 domain of PCSK9.

6. The method according to any one of claims 1-5, characterized in that, The inhibitor interacts with pockets in PCSK9 between amino acid residues 558-592 in the C-terminal M2 domain and between amino acid residues 631-650 in the C-terminal M3 domain; preferably, it interacts with pockets in PCSK9 between amino acid residues 558-590 in the C-terminal M2 domain and between amino acid residues 631-650 in the C-terminal M3 domain.

7. Compounds represented by the following formulas: (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IA-8), (IA-9), (IA-10), (IA-11), (IA-12), (IA-13), (IA-14), (IA-15), (IA-16), (IA-17), (IA-1'), (IA-2'), (IA-3'), (IA-4'), (IA-5'), (IA-6'), (IA-7'), (IA-8'), (IA-9'), (IA-10'), (IA-11'), (IA-4") or (IA-1"), their stereoisomers, or their pharmacokinetically acceptable salts: in: Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; Ring H is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, alkathio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino, alkyl, alkenyl, alkynyl, alkylthio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted. R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R a The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted. R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted. R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R b The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted. Preferably, Or, any two R a and R b The linkage forms a heterocyclic or heteroaryl group, which may optionally be further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; R c-1 R c-2 and R c-3 Selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Preferably, R c-1 R c-2 and R c-3 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, More preferably, R c-1 Selected from -F; Or, any two R c-1 R c-2 and R c-3 The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted. R d Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted. R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted; Or, any two adjacent or non-adjacent R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted. Or, any two R c and R d The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted. R bb Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb -C≡C(CH2) n NR aa R bb -C≡C(CH2) n NR bb C(O)R cc -C≡C(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3; e can be 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; p is 0, 1, 2, or 3; and The compound is not 8. The compound according to claim 7, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, The compounds are further described by formula (IA-1-a), (IA-2-a), (IA-3-a), (IA-4-a), (IA-5-a), (IA-6-a), (IA-7-a), (IA-8-a), (IA-9-a), (IA-10-a), (IA-11-a), (IA-1-aa), (IA-1-a-1), (IA-2-a-1), (IA-3-a-1), (IA-4-a-1), (IA-5- a-1), (IA-6-a-1), (IA-7-a-1), (IA-8-a-1), (IA-9-a-1), (IA-10-a-1), (IA-11-a-1), (I-1-aa-1), ( IA-12-a), (IA-13-a), (IA-14-a-1), (IA-15-a), (IA-16-a), (IA-17-a), (IA-4-a-2) or (IA-1-a-2) indicated:

9. The compound according to any one of claims 7-8, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Preferably, ring B is selected from C. 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic, 7-10 membered bicyclic heterocyclic, 5 membered heteroaryl, 6 membered heteroaryl, 5 membered 5 membered bicyclic heteroaryl, 5 membered 6 membered bicyclic heteroaryl, 6 membered 5 membered bicyclic heteroaryl or 6 membered 6 membered bicyclic heteroaryl; More preferably, ring B is selected from C. 3-6 Cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 7-10-membered bicyclic heterocyclic group, 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl; Preferably, ring B is selected from pyridine, pyrimidine, benzene, More preferably, ring B is selected from pyridine, pyrimidine, benzene, 10. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, characterized in that, The compounds are further described by formula (I'-A-1), (I'-A-2), (I'-A-3), (I'-A-4), (I'-A-5), (I'-A-6), (I'-A-1”), (I'-A-2”), (I'-A-3”), (I'-A-4”), (I'-A-5”), (I'-A-6”), (I'-B-1), (I'-B-2), (I'-B-3), (I'-B-4), (I'-C-1), (I'-C-2), (I'-C-3), (I'-C-4), (I'-D-1), (I'-D-2), (I'-D-3), (I'-D-4), (I'-D-5), ( I'-F-1), (I'-A-1'), (I'-A-2'), (I'-A-3'), (I'-A-4'), (I'-B-1'), (I '-B-2'), (I'-B-3'), (I'-B-4'), (I'-C-1'), (I'-C-2'), (I'-C-3'), (I '-C-4'), (I'-D-1'), (I'-D-2'), (I'-D-3'), (I'-D-4'), (I'-D-1”), (I '-D-2”), (I'-D-3”), (I'-D-4”), (I'-D-5”), (I'-D-6”) or (I'-D-1”) Indication: in: X is selected from N or CR c-1 X1 is selected from C, N, and CR. d-1 R d-11 or CR d-1 ; X2 is selected from C, N, or CR. d-2 X3 is selected from C, N, O, S, and CR. d-3 CR d-3 R d-31 or NR d-3 ; X4 is selected from C, N, O, S, and CR. d-4 R d-41 CR d-4 or NR d-4 ; X5 is selected from C, N, O, S, and CR. d-5 CR d-5 R d-51 or NR d-5 ; X6 is selected from C, N, O, S, CR d-6 CR d-6 R d-61 or NR d-6 ; X7 is selected from C, N, O, S, CR d-7 CR d-7 R d-71 or NR d-7 ; Y1 is selected from C, N, O, S, CR a-1 CR a-1 R a-11 or NR a-1 ; Y2 is selected from C, N, or CR. a-2 Y3 is selected from C, N, or CR. a-3 ; Y5 is selected from C, N, O, S, CR a-5 CR a-5 R a-51 or NR a-5 ; Y7 is selected from C, N, O, S, CR a-7 CR a-7 R a-71 or NR a-7 ; R a-1 ~R a-8 R a-11 R a-51 R a-71 As defined in weight 20, R a The preferred embodiment is R as defined in claim 21. a-1 ~R a-4 The above; R c-1 ~R c-3 As defined in weight 20, R c-1 R c-2 and R c-3 The above; R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 As defined in weight 20, R d The above; Or, R a-1 ~R a-8 and R b The interconnected components can form a ring-shaped system, wherein the ring-shaped system is C. 3-12 Cycloalkyl or 3-20 membered heterocyclic group; optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; R d-1 ~R d-7 and R c-2 The interconnected components can form a ring-shaped system, wherein the ring-shaped system is C. 3-12 Cycloalkyl or 3-20 membered heterocyclic group; optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1- 6-Deuterated Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Ring G is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb -C≡C(CH2) n NR aa R bb -C≡C(CH2) n NR bb C(O)R cc -C≡C(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1- 6-Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; q can be 0, 1, 2 or 3.

11. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 7-10, characterized in that, Compounds of formula (IE-1), (IE-2), (IE-3), (IE-1-a), (IE-1-b), (IE-1-c), (IE-2-b), (IE-2-c) shown: Preferred are general formulas (IE-1-1), (IE-2-1), (IE-3-1), (IE-1-1-a), (IE-1-1-b), (IE-1-1-c), (IE-2-1- b), (IE-2-1-c) shown: Among them, R aa Selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Ring H is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; Ring G is selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; R bb R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb -C≡C(CH2) n NR aa R bb -C≡C(CH2) n NR bb C(O)R cc -C≡C(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group of 5-14 heteroaryl groups, either substituted or unsubstituted; R aa Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1- 6-Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; s can be 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q can be 0, 1, 2 or 3.

12. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 7-11, characterized in that, R a and R a-1 ~R a-8 R a-11 R a-51 R a-71 R aa R aa-1 R aa-2 R aa-3 R aa-4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R A1 -(CH2) n OR A1 -(CH2) n C(O)R A1 -(CH2) n C(O)OR A1 -(CH2) n S(O) m R A1 -(CH2) n NR A2 R A3 -(CH2) n NR A2 C(O)OR A3 -(CH2) n NR A2 C(O)(CH2) n1 R A3 -(CH2) n NR A2 C(O)NR A2 R A3 -(CH2) n C(O)NR A2 (CH2) n1 R A3 -OC(R) A1 R A2 ) n (CH2) n1 R A3 Or -(CH2) n NR A2 S(O) m R A3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; R A1 ~R A3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Preferably, R a and R a-1 ~R a-8 R a-11 R a-51 R a-71 R aa R aa-1 R aa-2 R aa-3 R aa-4 Selected from -H, -O-CHF2, -O-CF3, -O-CF2Cl, -O-CF2Br, -O-CH2-CHF2, -CH2-CH3, -O-CH2-CF3, -CHF2, -CF3, -CD3, -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, -O-CH-(CH3)2, -C(O)OH, -C(O)CH3, -C(O)NH2, -CF2CH3, -C(O)CF3, -O-CH-(CF3)2, More preferably, R a and R a-1 ~R a-8 R a-11 R a-51 R a-71 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, -C(O)OH、 -C(O)CH3 And / or, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R B1 -(CH2) n OR B1 -(CH2) n C(O)R B1 -(CH2) n C(O)OR B1 -(CH2) n S(O) m R B1 -(CH2) n NR B2 R B3 -(CH2) n NR B2 C(O)OR B3 -(CH2) n NR B2 C(O)(CH2) n1 R B3 -(CH2) n NR B2 C(O)NR B2 R B3 -(CH2) n C(O)NR B2 (CH2) n1 R B3 -OC(R) B1 R B2 ) n (CH2) n1 R B3 Or -(CH2) n NR B2 S(O) m R B3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; R B1 ~R B3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Preferably, R b Selected from -H, -F, cyclopropane, -NH2, or -OH; And / or, R c and R c-1 ~R c-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R C1 -(CH2) n OR C1 -(CH2) n C(O)R C1 -(CH2) n C(O)OR C1 -(CH2) n S(O) m R C1 -(CH2) n NR C2 R C3 -(CH2) n NR C2 C(O)OR C3 -(CH2) n NR C2 C(O)(CH2) n1 R C3 -(CH2) n NR C2 C(O)NR C2 R C3 -(CH2) n C(O)NR C2 (CH2) n1 R C3 -OC(R) C1 R C2 ) n (CH2) n1 R C3 Or -(CH2) n NR C2 S(O) m R C3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; R C1 ~R C3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Preferably, R c and R c-1 ~R c-3 Selected from -F, -Cl, -O-CH3, -CN, -CF3, -CH3, -O-CF3, -O-CH3, -O-CH(CH3)2, More preferably, R c-1 Selected from F; And / or, R d and R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, oxo group, thio group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, -(CH2) n R D1 -(CH2) n OR D1 -(CH2) n C(O)R D1 -(CH2) n C(O)OR D1 -(CH2) n S(O) m R D1 -(CH2) n NR D2 R D3 -(CH2) n NR D2 C(O)OR D3 -(CH2) n NR D2 C(O)(CH2) n1 R D3 -(CH2) n NR D2 C(O)NR D2 R D3 -(CH2) n C(O)NR D2 (CH2) n1 R D3 -OC(R) D1 R D2 ) n (CH2) n1 R D3 Or -(CH2) n NR D2 S(O) m R D3 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkylthio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-12 heteroaryl groups may optionally be further substituted, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The amino group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups; the C group is substituted with one or more substituents of aryl and 5-10 heteroaryl groups. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; R D1 ~R D3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted by one or more substituents in the 5-12 membered heteroaryl group; Preferably, R d and R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 Selected from oxo groups, -O-CH(CH3)2, -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CD3, -CH(CH3)2, -CH2-CH3, -C(CH3)3, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -O-CH3, -O-CHF2, -CHF2, -CH2-NH2, -CH2-OH, -NH2, -OH, -C(O)OH, -C(O)NH2, -O-CF3, -CHF2-CH3. More preferably, R d and R d-1 ~R d-7 R d-11 R d-31 R d-41 R d-51 R d-61 R d-71 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, Or -C(O)NH2.

13. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 7-12, characterized in that, Selected from the following compounds:

14. A compound of general formula (VI), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: Ry is selected from hydrogen, an amino protecting group, a 5-6 membered heteroaryl group, or a 5-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl group and the 5-6 membered heterocyclic group are optionally further modified by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; The amino protecting group is selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, phosphoxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; The remaining groups are as described in claim 10.

15. A method for preparing the compound of general formula (I'-A-1) as described in claim 10, characterized in that, It includes the following steps: Where M is a halogen; The reaction of general formula compound (INT-1) and general formula compound (VI) yields general formula compound (I'-A-1); Ry is as described in claim 14; The other groups are as described in claim 10; The characteristic feature is that a metal catalyst, a catalyst ligand, a base, and a solvent may be optionally added during the reaction; The metal catalyst is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous chloride, tetra(triphenylphosphine)palladium, palladium acetate, triphenylphosphine dichloride palladium, Pd(dppf)Cl2, or Pd2(dba)3; preferably, the catalyst is selected from cuprous iodide; The catalyst ligand is selected from one or more of N,N'-dimethyl-1,2-cyclohexanediamine, (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine, (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine, L-proline, N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, Xantphos, Sphos, Xphos, Bretphos, Ruphose, triphenylphosphine, or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; preferably, the catalyst ligand is selected from N,N'-dimethyl-1,2-cyclohexanediamine, (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine, or (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine; The alkali is selected from one or more of triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, cesium fluoride, sodium trimethylsiloxane, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium bis(trimethylsilylamino)amine, or lithium diisopropylamino; preferably, the alkali is selected from N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate. The solvent is selected from one or more of ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, or xylene; preferably, the solvent is selected from 1,4-dioxane, N,N-dimethylformamide, or dimethyl sulfoxide.

16. The method according to any one of claims 1-6, characterized in that, The inhibitor is any compound shown in claims 7-13, its stereoisomer, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown in claims 7-13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

18. The use of any compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, as shown in any of claims 7-13, in the preparation of a PCSK9 inhibitor medicament.

19. The use of any compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, as shown in any of claims 7-13, in the preparation of an LDL-lowering drug.

20. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 7-13, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating cardiovascular diseases, cerebrovascular diseases, atherosclerosis, and / or related diseases or symptoms thereof; preferably, in the preparation of a medicament for stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

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