Preparation and medical use of a class of isoquinoline-based pcsk9 inhibitors

Abstract

The application belongs to the technical field of medicine, and discloses a kind of isoquinoline PCSK9 inhibitors, preparation method and pharmaceutical composition and purposes thereof.The application specifically discloses a kind of compounds shown in general formula (I) or pharmaceutically acceptable salt thereof, preparation process of the compounds, pharmaceutical composition containing the compounds of general formula (I), and application of the compounds and pharmaceutical composition in reducing LDL-C.

Description

Technical fields:

[0001] This invention relates to the field of pharmaceutical technology, to a class of novel compounds or pharmaceutically acceptable salts thereof, and to the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of PCSK9 inhibitors. Background technology:

[0002] According to statistics from the World Health Organization (WHO), approximately 18 million people worldwide die from cardiovascular disease (CVD) each year, accounting for one-third of all deaths. In China, the "China Cardiovascular Health and Disease Report (2022)" estimates that the number of people suffering from cardiovascular disease in China has already reached over 300 million and is still rising. Cardiovascular disease is the leading cause of death among Chinese residents, accounting for over 40% of all deaths in both urban and rural areas.

[0003] Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major risk factor for cardiovascular disease. Excessive LDL-C deposition in the vascular endothelium leads to atherosclerosis, which in turn triggers a series of serious cardiovascular diseases, such as coronary heart disease, myocardial infarction, stroke, acute coronary syndrome, peripheral artery disease, transient ischemic attack, angina pectoris, and coronary revascularization. Numerous evidence-based studies have confirmed that for every 1 mmol / L reduction in plasma LDL-C, the overall mortality and morbidity of cardiovascular disease decrease by 22%.

[0004] Currently, marketed LDL-C lowering drugs mainly include: statins, fibrates, ezetimibe, bile acid conjugating resins, niacin derivatives, omega-3 fatty acid derivatives, and proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors. Statins are the first-line drugs for lowering plasma LDL-C levels and preventing cardiovascular events. However, statins also present some challenges in clinical use: poor patient adherence: 10-15% of patients taking statins experience statin intolerance symptoms, with the most common side effect, myalgia, occurring in 5-10% of cases. This prevents some patients from taking sufficient doses of statins. Furthermore, some patients experience adverse reactions such as hepatotoxicity, cognitive impairment, hyperglycemia, and rhabdomyolysis. Inadequate treatment: Even with the maximum tolerated dose of statins, approximately 25% of patients still fail to achieve ideal LDL-C levels, resulting in residual cardiovascular risk. Fibrates can reduce LDL-C levels by 20% and the incidence of vascular events by 10-15%. First-generation fibrates used in combination with statins carry a risk of increasing rhabdomyolysis, but newer fibrates have not shown an increased risk of adverse reactions; therefore, the combined use of statins and newer fibrates is encouraged. Ezetimibe lowers circulating LDL-C levels by inhibiting cholesterol absorption and can also reactively upregulate low-density lipoprotein receptor (LDL-R) expression, accelerating plasma LDL-C clearance. As a monotherapy, it reduces LDL-C levels by 15-22% and can be used as second-line treatment in combination with statins. Bile acid conjugating resins and niacin have weaker lipid-lowering effects and can only be used as adjunctive therapy. Omega-3 fatty acids mainly include DHA (doco-sahexaenoic acid) and EPA (eicosapenatenoic acid). Studies have shown that 250 mg / day of DHA or EPA can reduce the incidence of cardiovascular events by 36%. PCSK9 inhibitors are novel LDL-C lowering drugs that have been extensively studied in recent years. They can reduce LDL-C levels by 50-60% on top of the cholesterol-lowering effects of statins. Clinically, the combined use of PCSK9 inhibitors and high-dose statins can reduce the incidence and mortality of cardiovascular events. PCSK9 inhibitors are particularly beneficial for patients with familial hypercholesterolemia, statin intolerance, or those who have not seen a reduction in LDL-C despite using the maximum dose of statins.Currently, all successfully marketed PCSK9 inhibitors are biologics. In 2015, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved the PCSK9 monoclonal antibodies alirocumab and evolocumab for the treatment of familial hypercholesterolemia and atherosclerotic cardiovascular disease. Furthermore, the first siRNA drug for lowering blood lipids, inclisiran, was launched at the end of 2020. As a long-acting lipid-lowering drug, inclisiran only requires two injections per year to effectively reduce circulating LDL-C levels and prevent cardiovascular events. Although biologics are highly effective, their clinical use remains low due to their high price, the need for injections, poor patient adherence, and immune responses. Alirocumab underwent two price reductions in October 2018 and March 2019, and evolocumab also had its price adjusted in December 2019. Although the price decreased by 60%, the clinical usage rate is still less than 1%. Therefore, developing small-molecule oral PCSK9 inhibitors is currently an important research direction for the treatment of high LDL-C. Summary of the Invention:

[0005] The first technical problem to be solved by the present invention is to provide a class of compounds having general formula (Ⅰ) or pharmaceutically acceptable salts thereof;

[0006] The second technical problem to be solved by the present invention is to provide a method for preparing such compounds or pharmaceutically acceptable salts thereof;

[0007] Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0008] Another technical problem to be solved by the present invention is to provide the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof in the preparation of PCSK9 inhibitor drugs.

[0009] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0010]

[0011] The present invention relates to compounds having general formula (Ⅰ) or pharmaceutically acceptable salts thereof, by introducing substituted aryl, aryl-substituted alkyl and alkyl groups at R1, alkyl, halogen, alkoxy groups at R2, aliphatic nitrogen heterocycles, heteroaromatic rings, aromatic rings at R3, aliphatic nitrogen heterocycles, substituted amines at R4, and by changing the substituents to improve the efficacy and toxic side effects of such compounds.

[0012] in,

[0013] X is selected from methylene or carbonyl groups;

[0014] Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution.

[0015] R1 is selected from: H, C1-C16 straight-chain or branched alkyl groups, C6-C16 aryl groups, C6-C16 aryl-substituted C1-C16 alkyl groups, C4-C16 heteroaryl-substituted C1-C16 alkyl groups, and C6-C16 aryl methyl ether-substituted C1-C16 alkyl groups; the aryl group is selected from phenyl, naphthyl, anthraceneyl, phenanthryl, and biphenyl; the heteroaryl group is selected from furanyl, thiopheneyl, imidazolyl, pyrroleyl, thiazolyl, and quinolinyl. , pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy, C1-C16 alkoxy, C1-C16 alkyl;

[0016] R2 is selected from: H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy.

[0017] R3 is selected from: H, C6-C16 aryl, C3-C16 heteroaryl, C6-C16 aryl-substituted amino, C3-C16 heteroaryl-substituted amino, C6-C16 aryl-substituted C1-C16 alkylamino, C6-C16 arylcarbamate, C3-C16 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, biphenyl; the above heteroaryl group is selected from pyrazolyl, thiophene, imidazolyl, pyrroleyl, thiazolyl, pyridinyl, indazole, carbazole, benzene. The aryl, heteroaryl, and aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and imidazolinyl. These aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C3-C16 heteroaryl ring, and C1-C16 alkyl-substituted amino groups.

[0018] R4 is selected from: OH, C1-C16 straight-chain or branched alkylamino groups, C6-C16 aryl-substituted C1-C16 alkylamino groups, C3-C16 heteroaryl-substituted C1-C16 alkylamino groups, C3-C16 aliphatic nitrogen heterocycles, C1-C16 straight-chain or branched ester-substituted C1-C16 alkylamino groups, and C1-C16 straight-chain or branched alkoxy-substituted C1-C16 alkylamino groups; the aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, and biphenyl; the heteroaryl group is selected from pyrrole, thiazolyl, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolyl, imidazolinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy-substituted C1-C16 alkyl, hydroxyl-substituted C1-C16 alkyl, and C3-C16 heteroaryl rings.

[0019] Preferably, X is selected from methylene or carbonyl groups;

[0020] Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution.

[0021] R1 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C14 aryl, C6-C14 aryl-substituted C1-C8 alkyl, C4-C8 heteroaryl-substituted C1-C8 alkyl, C6-C14 aryl methyl ether-substituted C1-C8 alkyl; the above aryl is selected from phenyl, naphthyl, anthracene, biphenyl; the above heteroaryl is selected from furanyl, thiophene, thiazolyl, quinolinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, NH2, aldehyde, carbamoyl, halogen, CN, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C1-C8 straight-chain or branched alkoxy;

[0022] R2 is selected from: H, halogen, C1-C8 straight-chain or branched alkyl, C1-C8 straight-chain or branched alkoxy.

[0023] R3 is selected from: H, C6-C14 aryl, C3-C8 heteroaryl, C6-C14 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C14 aryl-substituted C1-C8 alkylamino, C6-C14 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl and biphenyl; the above heteroaryl group is selected from pyrazolyl, imidazolyl, pyrrolithyl, pyridinyl, indazole, carbazole, benzimidazolyl, indolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, halogen, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C3-C8 heteroaryl ring, and C1-C8 alkyl-substituted amino.

[0024] R4 is selected from: OH, C1-C8 straight-chain or branched alkylamino groups, C6-C14 aryl-substituted C1-C8 alkylamino groups, C3-C8 heteroaryl-substituted C1-C8 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C8 straight-chain or branched ester-substituted C1-C8 alkylamino groups, and C1-C8 straight-chain or branched alkoxy-substituted C1-C8 alkylamino groups; the aryl group is selected from phenyl, naphthyl, and biphenyl; the heteroaryl group is selected from pyrrole, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, COOH, NH2, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy-substituted C1-C8 alkyl, hydroxyl-substituted C1-C8 alkyl, and C3-C14 heteroaryl rings.

[0025] More preferably, X is selected from methylene or carbonyl;

[0026] Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution.

[0027] R1 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0028] R2 is selected from: H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 straight-chain or branched alkoxy;

[0029] R3 is selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino;

[0030] R4 is selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, and C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the aryl group is selected from phenyl; the heteroaryl group is selected from pyrrole. Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

[0031] The preferred compounds represented by general formula (I) include, but are not limited to, the compounds represented by IA or their pharmaceutically acceptable salts.

[0032]

[0033] R5 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0034] R6 is selected from: H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 straight-chain or branched alkoxy.

[0035] R7 is selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino;

[0036] R8 is selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, and C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the aryl group is selected from phenyl; the heteroaryl group is selected from pyrrole. Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

[0037] The preferred compounds represented by formula IA include, but are not limited to, the compounds represented by IA1 or their pharmaceutically acceptable salts.

[0038]

[0040] R 51 Selected from: H, C1-C8 straight-chain or branched alkyl groups, C6-C12 aryl-substituted C1-C4 alkyl groups, C4-C8 heteroaryl-substituted C1-C4 alkyl groups, C6-C12 aryl methyl ether-substituted C1-C4 alkyl groups, wherein the aryl group is selected from phenyl or biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyridinyl, benzofuranyl, or benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogens, CF3, C1-C4 straight-chain or branched alkyl groups, or C1-C4 alkoxy groups;

[0041] R 61 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups;

[0042] R 71 Selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, the substituents being independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino;

[0043] R 81 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the above aryl group is selected from phenyl; the above heteroaryl group is selected from pyrroleyl, Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

[0044] The preferred compounds represented by formula IA include, but are not limited to, the compounds represented by IA1 or their pharmaceutically acceptable salts.

[0045]

[0046] R 52 Selected from: H, halogen, CF3, C1-C8 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups;

[0047] R 62 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups;

[0048] R 72Selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, the substituents being independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino;

[0049] R 82 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the above aryl group is selected from phenyl; the above heteroaryl group is selected from pyrroleyl, Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

[0050] The preferred compounds represented by general formula (I) include, but are not limited to, the compounds represented by IB or their pharmaceutically acceptable salts.

[0051]

[0052] R9 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0053] R 10 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups;

[0054] R 11 Selected from: H, aryl of C6-C8, heteroaryl of C3-C8, aryl-substituted amino of C6-C8, heteroaryl-substituted amino of C3-C8, aryl-substituted C1-C4 alkylamino, arylcarboxamide of C6-C8, aliphatic azacycle of C3-C8; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic azacycle is selected from piperidinyl, morpholinyl, piperazinyl; one or more substituents may be further present on these aryl, heteroaryl, aliphatic azacycles, and the substituents are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaromatic ring, C1-C4 alkyl-substituted amino;

[0055] R 12 Selected from: OH, C1-C4 straight-chain or branched alkylamino, aryl-substituted C1-C4 alkylamino of C6-C8, heteroaryl-substituted C1-C4 alkylamino of C3-C8, aliphatic azacycle of C3-C8, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino; the above aryl is selected from phenyl; the above heteroaryl is selected from pyrrolyl, pyrimidinyl, furyl; the above aliphatic azacycle is selected from piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, cyclohexylimine; one or more substituents may be further present on these aryl, heteroaryl, aliphatic azacycles, and the substituents are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C3-C8 heteroaromatic ring.

[0056] The preferred compounds represented by the general formula (I) include but are not limited to the compounds shown by IC or their pharmaceutically acceptable salts

[0057]

[0058] R 13 Selected from: H, C1-C8 straight-chain or branched alkyl, aryl of C6-C12, aryl-substituted C1-C4 alkyl of C6-C12, heteroaryl-substituted C1-C4 alkyl of C4-C8, arylmethylether-substituted C1-C4 alkyl of C6-C12; the above aryl is selected from phenyl, biphenyl; the above heteroaryl is selected from furyl, thienyl, pyridyl, benzofuryl, benzothienyl; one or more substituents may be further present on these aryl, heteroaryl, and the substituents are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0059] R 14Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups;

[0060] R 15 The aryl group is selected from H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, and C3-C8 aliphatic nitrogen heterocycle; the aryl group is phenyl; the heteroaryl group is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, and pyrimidinyl; the aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, and piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, and C1-C4 alkyl-substituted amino.

[0061] R 16 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, and 1-(2-hydroxyethyl)piperazine.

[0062] The formation of pharmaceutically acceptable salts from the above-mentioned preferred compounds with acids also constitutes part of this invention. The basic nitrogen atom in the compound molecule of this invention can form salts with acids, as long as the acid can form a salt with a base and is pharmaceutically acceptable; there are no particular limitations. Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0063] The second aspect of this invention discloses a method for preparing a compound having general formula (Ⅰ) or a pharmaceutically acceptable salt thereof, the specific preparation route of which is as follows:

[0064]

[0065] in,

[0066] X is selected from methylene or carbonyl groups;

[0067] Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution.

[0068] R1 is selected from: H, C1-C16 straight-chain or branched alkyl groups, C6-C16 aryl groups, C6-C16 aryl-substituted C1-C16 alkyl groups, C4-C16 heteroaryl-substituted C1-C16 alkyl groups, and C6-C16 aryl methyl ether-substituted C1-C16 alkyl groups; the aryl group is selected from phenyl, naphthyl, anthraceneyl, phenanthryl, and biphenyl; the heteroaryl group is selected from furanyl, thiopheneyl, imidazolyl, pyrroleyl, thiazolyl, and quinolinyl. , pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy, C1-C16 alkoxy, C1-C16 alkyl;

[0069] R2 is selected from: H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy.

[0070] R3 is selected from: H, C6-C16 aryl, C3-C16 heteroaryl, C6-C16 aryl-substituted amino, C3-C16 heteroaryl-substituted amino, C6-C16 aryl-substituted C1-C16 alkylamino, C6-C16 arylcarbamate, C3-C16 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, biphenyl; the above heteroaryl group is selected from pyrazolyl, thiophene, imidazolyl, pyrroleyl, thiazolyl, pyridinyl, indazole, carbazole, benzene. The aryl, heteroaryl, and aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and imidazolinyl. These aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C3-C16 heteroaryl ring, and C1-C16 alkyl-substituted amino groups.

[0071] R4 is selected from: OH, C1-C16 straight-chain or branched alkylamino groups, C6-C16 aryl-substituted C1-C16 alkylamino groups, C3-C16 heteroaryl-substituted C1-C16 alkylamino groups, C3-C16 aliphatic nitrogen heterocycles, C1-C16 straight-chain or branched ester-substituted C1-C16 alkylamino groups, and C1-C16 straight-chain or branched alkoxy-substituted C1-C16 alkylamino groups; the aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, and biphenyl; the heteroaryl group is selected from pyrrole, thiazolyl, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolyl, imidazolinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy-substituted C1-C16 alkyl, hydroxyl-substituted C1-C16 alkyl, and C3-C16 heteroaryl rings;

[0072] Step 1: Using different benzaldehydes A1 as starting materials, add them to nitromethane to obtain intermediate B1;

[0073] Step 2: Intermediate B1 undergoes a reduction reaction to obtain intermediate C1;

[0074] Step 3: Intermediate C1 is reacted with isobutyl chloroformate under alkaline conditions to prepare intermediate D1;

[0075] Step 4: Intermediate D1 is reacted with Friedel-Crafts to obtain intermediate E1;

[0076] Step 5: Intermediate E1 is demethylated under BBr3 conditions to prepare intermediate F1;

[0077] Step 6: Intermediate F1 undergoes a coupling reaction to obtain intermediate G1;

[0078] Step 7: Intermediate G1 and intermediate H1 undergo a Buchwald–Hartwig coupling reaction to obtain intermediate I1;

[0079] Step 8: Intermediate I1 undergoes a reduction reaction or hydrolysis reaction to obtain intermediate J1;

[0080] Step 9: Intermediate J1 is introduced into R4 to obtain the target product shown in general formula (Ⅰ).

[0081] A third aspect of the invention also relates to pharmaceutical compositions in which the compounds of the invention are the active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compounds of the invention in their pharmaceutical compositions is typically 0.1-95% by weight.

[0082] The compounds of the present invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0083] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0084] The compounds of this invention can be formulated into conventional formulations, as well as into sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0085] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0086] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.

[0087] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0088] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0089] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0090] To achieve the intended therapeutic purpose and enhance therapeutic efficacy, the medicaments or pharmaceutical compositions of the present invention may be administered using any known method of administration. Exemplary therapeutic agents for combination therapy with one or more compounds of the present invention include, but are not limited to, therapeutic antibodies and cholesterol-lowering agents, such as statins. Useful adjunctive therapeutic agents that can be used in combination formulations and collaborative therapies include, for example, anti-hyperlipidemia agents, anti-dyslipidemia agents, and anti-diabetic agents, including but not limited to cholesterol biosynthesis inhibitors such as HMG-CoA reductase inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin, and atorvastatin); HMG-CoA reductase inhibitors; squalene epoxidase inhibitors or squalene synthase inhibitors (also known as squalene synthase inhibitors); microsomal triglyceride transfer protein (MTP) inhibitors; bile acid chelating anion exchange resins, including but not limited to cholestyramine, cholecystokinin, cholesvelam, or dialkylaminoalkyl derivatives of cross-linked dextran; LDL receptor inducers; fibrates, including but not limited to clofibrate, bezafibrate, fenofibrate, and gemfibrozil; metformin, rosiglitazone; and plasma HDL-raising agents, including but not limited to niacin and fibrates. Classes; agents for treating hypercholesterolemia, including but not limited to cholesterol uptake inhibitors; acyl-CoA cholesterol acyltransferase (ACAT) inhibitors, including but not limited to melinalimide, probucol, niacin and its salts, nicotinamide; cholesterol absorption inhibitors, including but not limited to sitosterol or etimibe; vitamin B6 (pyridoxine) and its pharmaceutically acceptable salts, such as HCl salts; vitamin B12 (cyanocobalamin); vitamin B3 (niacin and nicotinamide); antioxidant vitamins, including but not limited to vitamin C and vitamin E and beta-carotene; beta-blockers; angiotensin II receptor (AT1) antagonists; angiotensin-converting enzyme inhibitors, renin inhibitors; platelet aggregation inhibitors, including but not limited to fibrinogen receptor antagonists, i.e., glycoprotein IIb / IIIa fibrinogen receptor antagonists; hormones, including but not limited to estrogens; insulin; ion exchange resins; omega-3 oils; benflurex; ethyl hexadecanoate and amlodipine. Additional therapies may also include increased exercise, surgery, and dietary changes (such as switching to a low-cholesterol diet). Some herbal medicines can also be effectively used in combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, guar gum, garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimer pantothenic acid, red yeast rice, and royal jelly.

[0091] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds or antibodies (e.g., PCSK9 inhibitors, PCSK9 antibodies).

[0092] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above dosage can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0093] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation. Detailed implementation method:

[0094] The present invention will be described in more detail below with reference to the embodiments listed below, but the present invention is not limited to these embodiments.

[0095] I. Preparation of Compounds 1-65

[0096] 1. Preparation of compounds 1-65

[0097] Example 1, Preparation of Compound 1:

[0098]

[0099] a) Preparation of intermediate B1: 4-Methoxy-3-methylbenzaldehyde (1.50 g, 10.0 mmol) was dissolved in AcOH (30 mL), CH3NO2 (1.07 mL, 20.0 mmol) was added dropwise, followed by AcNH4 (0.77 g, 10.0 mmol). The mixture was stirred at 90 °C for 5 h. After the reaction was complete, the reaction solution was poured into ice water and stirred for 20 min. The suspension was filtered and washed with MeOH (5 mL) to obtain B1 (1.55 g, 80%), which was a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.86 (s, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.69 (s, 1H), 6.93 (d, J = 8.4Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H); 13 C NMR (100MHz, CDCl3) δ161.5,139.5,134.9,131.2,129.8,128.3,122.2,110.5,55.7,16.4; HRMS calcdfor C 10 H 12NO3[M+H] + 194.0812, found 194.0808.

[0100] b) Preparation of intermediate C1: Intermediate B1 (1.94 g, 10.0 mmol) was dissolved in THF (20 mL) and added dropwise to a suspension of LiAlH4 (1.52 mL, 40.0 mmol) in THF (30 mL) under ice-water bath conditions. The reaction was carried out at 70 °C for 5 h. After the reaction was complete, the mixture was quenched with saturated NaHCO3 solution, filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate C1 (1.12 g, 68%), which was a colorless liquid. 1 H NMR (400MHz, CDCl3) δ7.11(s,1H),7.03(d,J=8.4Hz,1H),6.71(s,1H),3.72(s,3H),2.98(t,J=6.4Hz,1H),2.83(t,J=6.4Hz,1H),2.26(s,3H); 13 C NMR (125MHz, CDCl3) δ156.3,131.3,131.2,127.0,126.6,110.0,55.4,43.7,39.0,16.3; HRMS calcd for C 10 H 16 NO[M+H] + 166.1227, found 166.1223.

[0101] c) Preparation of intermediate D1: Intermediate C1 (1.00 g, 6.05 mmol) was dissolved in DMF (20 mL). Under ice-water bath conditions, NEt3 (925 μL, 6.66 mmol) was added, followed by dropwise addition of isobutyl chloroformate (910 mg, 6.66 mmol). After the reaction was complete, a small amount of water was added to quench the reaction. The mixture was extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain intermediate D1 (1.50 g, 94%), a colorless liquid. 1H NMR (500MHz, CDCl3) δ7.00-6.93(m,2H),6.76(d,J=8.0Hz,1H),4.69(s,1H),3.83(d,J=6.5Hz,2H),3.81(s, 3H), 3.39 (q, J = 7.0Hz, 2H), 2.72 (t, J = 7.0Hz, 2H), 2.20 (s, 3H), 1.88 (p, J = 6.5Hz, 1H), 0.91 (d, J = 6.5Hz, 6H); 13 HRMS calcd for C 15 H 24 NO3[M+H] + 266.1751, found 266.1747.

[0102] d) Preparation of intermediate E1: Intermediate D1 (1.50 g, 5.65 mmol) was dissolved in POCl3 (5 mL), and P2O5 (1.20 g, 8.48 mmol) was added. The mixture was heated to 120 °C and reacted for 2 h. The reaction mixture was poured into ice water, extracted with CH2Cl2 (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 3:1) to give intermediate E1 (810 mg, 75%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.84 (s, 1H), 6.62 (s, 1H), 6.10 (s, 1H), 3.88 (s, 3H), 3.56 (t, J = 6.4Hz, 2H), 2.96 (t, J = 6.4Hz, 2H), 2.22 (s, 3H); HRMS calcd for C 30 H 29 N₂O₄[M+H] + 481.2122, found 481.2111.

[0103] e) Preparation of intermediate F1: Under ice-water bath conditions, BBr3 (756 μL, 7.84 mmol) was added to a CH2Cl2 (10 mL) solution of intermediate E1 (750 mg, 3.92 mmol), and the mixture was stirred at room temperature for 0.5 h. The reaction was quenched with a small amount of aqueous solution, extracted with CH2Cl2 (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate F1 (740 mg, 92%) as a yellow solid. 1 HNMR(400MHz,MeOH-d4)δ7.65(s,1H),6.61(s,1H),3.45(d,J=6.8Hz,2H),2.85(t,J=6.8Hz,2H),2.18(s,3H); HRMS calcd for C 28 H 23 N₂O₄[M+H] + 451.1652, found 451.1640.

[0104] f) Preparation of intermediate G1: Intermediate F1 (450 mg, 2.54 mmol) was dissolved in DMF (5 mL), and K2CO3 (526 mg, 3.05 mmol), 2-Picolinic acid (94 mg, 0.76 mmol), CuI (484 mg, 2.54 mmol), and iodobenzene (620 mg, 3.05 mmol) were added sequentially. The mixture was purged with nitrogen and purged three times. The mixture was then reacted at 130 °C for 8 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate G1 (534 mg, 83%) as a brown solid. 1 H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 7.36 (t, J = 8.0Hz, 2H), 7.14 (t, J = 7.5Hz, 1H), 6.99 (d, J = 8. 0Hz,2H),6.60(s,1H),6.09(s,1H),3.53(t,J=6.0Hz,2H),2.86(t,J=6.5Hz,2H),2.30(s,3H); 13 C NMR (100MHz, CDCl3) δ158.8,156.7,131.5,130.0,128.1,123.8,119.0,116.2,40.4,28.3,16.0; HRMS calcd for C28 H 23 N₂O₄[M+H] + 451.1652, found 451.1640.

[0105] g) Preparation of intermediate H1: Methyl 3,5-dibromobenzoate (3.0 g, 10.21 mmol) was dissolved in DMF (60 mL), and CuI (1.56 g, 8.16 mmol), K2CO3 (3.53 g, 25.52 mmol), L-Proline (470 mg, 4.08 mmol), and 4-methylimidazole (1.26 g, 15.31 mmol) were added sequentially. The mixture was purged with nitrogen and purged three times. The mixture was then reacted at 130 °C for 0.5 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to give intermediate H1 (1.36 g, 45%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.12(t,J=1.6Hz,1H),7.97(t,J=1.7Hz,1H),7.83(s,1H),7.71(t,J=2.0Hz,1H),7.06(s,1H),3.97(s,3H),2.31(s,3H); 13 CNMR(100MHz, CDCl3)δ164.9,138.7,134.6,133.5,132.2,131.5,131.0,127.9,123.6,120.5,53.0,13.8; HRMS calcd for C 12 H 12 BrN2O2[M+H] + 295.0077, found 295.0074.

[0106] h) Preparation of intermediate I1: Intermediates G1 (500 mg, 1.97 mmol) and H1 (640 mg, 2.17 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the sequential addition of Pd(dba)2 (1.56 g, 8.16 mmol), Xantphos (3.53 g, 25.52 mmol), and Cs2CO3 (965 mg, 2.96 mmol). The mixture was purged with nitrogen and purged three times, and then reacted at 100 °C for 5 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate I1 (803 g, 87%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.98(t,J=1.4Hz,1H),7.96(s,1H),7.93(dt,J=2.2,1.2Hz,1H ),7.80(d,J=2.3Hz,1H),7.69(s,1H),7.35(t,J=7.7Hz,2H),7.30(s,2H),7.20(s,1 H),7.11(q,J=3.0Hz,2H),7.01–6.94(m,2H),4.11(t,J=6.3Hz,2H),3.99(d,J=1.0H z,4H),3.74(d,J=1.0Hz,1H),3.18(t,J=6.3Hz,2H),2.37(s,4H),2.34(s,3H); HRMS calcd for C 28 H 26 N3O4[M+H] + 468.1918, found 468.1914.

[0107] i) Preparation of intermediate J1: Intermediate I1 (700 mg, 1.50 mmol) was dissolved in THF (20 mL), and LiBHEt3 in THF solution (1.5 mL, 1.50 mmol) was added dropwise under ice-water bath conditions. The reaction was quenched with a small amount of 1N HCl solution, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate J1 (590 mg, 90%) as a yellow solid. 1H NMR(400MHz, CDCl3)δ7.89(s,1H),7.74(s,1H),7.46-7.33(m,6H),7.28(s,1H),7.20(s,1H),7.00(s,1H),6.66 HRMS calcd for C 28 H 23 N₂O₄[M+H] + 451.1652, found 451.1644.

[0108] j) Preparation of Compound 1: Intermediate J1 (100 mg, 0.23 mmol) was dissolved in CH2Cl2, and NEt3 (80 μL, 0.57 mmol) was added, followed by Ms2O (60 mg, 0.34 mmol). The reaction was carried out at room temperature for 15 min, followed by the addition of K2CO3 (78 mg, 0.57 mmol) and (S)-3-Boc-aminopiperidine (55 mg, 0.27 mmol). After the reaction was complete, a small amount of water was added to quench the reaction, and the mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1). The purified product was then dissolved in 1N hydrochloric acid-methanol solution (5 mL), reacted at room temperature for 1 h, concentrated under vacuum to remove the remaining hydrochloric acid, neutralized with ammonia water, and finally concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 5:1) to give compound 1, which was a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.25(s,2H),8.18(s,1H),7.90(s,1H),7.56(s,1H),7.49(s,1H),7.47-7.40(m ,3H),7.32(s,1H),7.19(t,J=7.6Hz,1H),7.05(d,J=8.0Hz,2H),6.77(s,1H),3.98(t,J=6.4Hz,2H),3. 60(d,J=14.0Hz,1H),3.55(d,J=13.6Hz,1H),3.20(s,1H),3.17(s,1H),3.04(t,J=6.4Hz,2H),2.75(d, J=10.8Hz,1H),2.35-2.28(m,2H),2.27(s,3H),2.17(s,3H),1.88-1.69(m,2H),1.53(t,J=8.4Hz,2H);13 C NMR(100MHz,DMSO-d6)δ162.9,157.8,156.1,144.3,140.4,138.9,138.3,137.1,134.8,131.3,130.3(2C),127.0,124.3 ,123.9,123.5,118.6(2C),117.1,116.0,115.8,114.3,61.3,55.2,55.0,52.7,49.0,46.7,31.0,27.5,15.7,13.6; HRMS calcd for C 32 H 36 N5O2[M+H] + 522.2864, found 522.2860.

[0109] Example 2, Preparation of Compound 2:

[0110]

[0111] Preparation of Compound 2: Intermediate J1 (100 mg, 0.23 mmol) was dissolved in CH2Cl2, and NEt3 (80 μL, 0.57 mmol) was added, followed by Ms2O (60 mg, 0.34 mmol). The reaction was carried out at room temperature for 15 min, followed by the addition of K2CO3 (78 mg, 0.57 mmol) and diethylamine (28 μL, 0.27 mmol). After the reaction was complete, a small amount of water was added to quench the reaction, and the mixture was extracted with CH2Cl2 (20 mL × 3). The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain Compound 2 as a white solid. 1 H NMR(400MHz, CDCl3)δ8.04(s,1H),7.77(d,J=1.2Hz,1H),7.38(dd,J=8.6,7.2Hz,2H), 7.34(t,J=2.0Hz,1H),7.30(t,J=2.0Hz,1H),7.26(s,1H),7.18-7.13(m,1H),7.04(t, J=1.2Hz,1H),7.03-7.00(m,2H),6.63(s,1H),4.04-3.94(m,2H),3.62(s,2H),3.02(t ,J=6.4Hz,2H),2.57(q,J=7.2Hz,4H),2.33(s,3H),2.29(s,3H),1.05(t,J=7.2Hz,6H); 13C NMR (100MHz, CDCl3) δ164.3,158.9,156.6,144.3,139.5,137.9,137.8,134.8,132.2,130.1,128.2,1 24.2,123.9,123.3,119.1,118.6,116.9,115.6,114.8,57.4,49.5,47.0,28.4,16.1,13.8,11.9; HRMS calcd forC 31 H 35 N4O2[M+H] + 495.6465, found 495.6460.

[0112] Example 3, Preparation of Compound 3:

[0113]

[0114] Compound 3 was prepared in the same way as in Example 2, except that morpholine was used instead of diethylamine.

[0115] Compound 3: 1 H NMR (400MHz, CDCl3) δ8.04 (s, 1H), 7.78 (d, J = 1.6Hz, 1H), 7.42-7.35 (m, 3H) ,7.29(t,J=1.6Hz,1H),7.24(t,J=1.6Hz,1H),7.19-7.14(m,1H),7.05-7.00 (m,3H),6.63(s,1H),3.99(t,J=6.4Hz,2H),3.72(t,J=4.8Hz,4H),3.54(s, 2H),3.02(t,J=6.4Hz,2H),2.49(t,J=4.8Hz,4H),2.33(s,3H),2.29(s,3H); 13 C NMR (100MHz, CDCl3) δ164.3,159.0,156.5,144.5,141.0,137.9,137.8,134.7,132.2,130.1(2C),128.3,124.1 ,123.9,123.7,119.2(2C),118.9,117.2,115.6,114.8,67.0(2C),63.0,53.8(2C),49.5,28.4,16.1,13.8; HRMS calcd for C 31 H 33 N4O3[M+H] + 509.2548, found 509.2544.

[0116] Example 4, Preparation of Compound 4:

[0117]

[0118] Compound 4 was prepared in the same manner as in Example 1, except that N-Boc-piperazine was used instead of (S)-3-Boc-aminopiperidine.

[0119] Compound 4: 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.16(s,1H),7.90(s,1H),7.57(s,1H ),7.50-7.40(m,4H),7.34(s,1H),7.19(t,J=7.6Hz,1H),7.05(d,J=8.0Hz ,2H),6.77(s,1H),3.98(t,J=6.4Hz,2H),3.62(s,2H),3.07(t,J=5.2Hz,4 H),3.03(d,J=6.4Hz,2H),2.65(t,J=5.2Hz,4H),2.27(s,3H),2.17(s,3H); 13 C NMR (100MHz, CDCl3) δ164.3,159.0,156.5,144.5,141.0,139.7,137.9,137.8,134.7,132.2,130.1(2C),128.3,124 .1,123.9,123.7,119.2(2C),118.9,117.2,115.6,114.8,67.0(2C),63.0,53.8(2C),49.5,28.40,16.1,13.8; HRMS calcd for C 31 H 34 N5O2[M+H] + 508.2708, found 508.2703.

[0120] Example 5, Preparation of Compound 5:

[0121]

[0122] Compound 5 was prepared in the same manner as in Example 2, except that N-(2-methoxyethyl)methylamine was used instead of diethylamine.

[0123] Compound 5: 1H NMR (400MHz, CDCl3) δ8.04 (s, 1H), 7.79 (d, J = 1.2Hz, 1H), 7.42-7.34 (m, 3H), 7.28 ( s,2H),7.16(t,J=7.6Hz,1H),7.05(t,J=1.2Hz,1H),7.02(dd,J=8.8,1.2Hz,2H),6. 62(s,1H),3.99(t,J=6.4Hz,2H),3.63(s,2H),3.53(t,J=5.6Hz,2H),3.35(s,3H),3 .01(t,J=6.4Hz,2H),2.65(t,J=5.6Hz,2H),2.34(s,3H),2.33(s,3H),2.29(s,3H); 13 C NMR (100MHz, CDCl3) δ164.3,159.0,156.6,144.4,139.6,137.9,137.8,134.8,132.2,130.1(2C),128.3,124.2, 123.9,123.4,119.2(2C),118.8,117.1,115.6,114.8,70.8,62.2,59.0,56.6,49.5,43.0,28.4,16.1,13.8; HRMS calcd for C 31 H 35 N4O3[M+H] + 511.2704, found 511.2700.

[0124] Example 6, Preparation of Compound 6:

[0125]

[0126] Compound 6 was prepared in the same manner as in Example 2, except that ethyl sarcosinate was used instead of diethylamine.

[0127] Compound 6: 1H NMR(400MHz, CDCl3)δ8.04(s,1H),7.80(s,1H),7.41-7.36(m,3H),7.30(s,1H), 7.27(s,1H),7.16(t,J=7.6Hz,1H),7.05(s,1H),7.02(d,J=7.6Hz,2H),6.62(s, 1H),4.18(q,J=7.2Hz,2H),3.99(t,J=6.4Hz,2H),3.76(s,2H),3.31(s,2H),3.0 2(t,J=6.4Hz,2H),2.43(s,3H),2.33(s,3H),2.29(s,3H),1.28(t,J=7.2Hz,3H); 13 C NMR(100MHz, CDCl3)170.9,164.3,159.0,156.5,144.5,141.7,137.9,134.7,132.2,130.1(2C),128.3,124.2,1 23.9,123.3,119.2(2C),118.7,117.4,115.6,114.8,60.7,60.6,57.8,49.5,42.5,28.4,16.1,14.4,13.8; HRMS calcd for C 32 H 35 N4O4[M+H] + 539.2653, found 539.2648.

[0128] Example 7, Preparation of Compound 7:

[0129]

[0130] k) Preparation of intermediate K1: Intermediate J1 (200 mg, 0.46 mmol) was dissolved in CH2Cl2 (10 mL), and Dess-Martin reagent (232 mg, 0.55 mmol) was added. The reaction was carried out at room temperature for 15 min. After the reaction was complete, saturated Na2S2O3 solution was added to quench the reaction. The mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate K1 as a white solid. 1H NMR (400MHz, CDCl3) δ10.05(s,1H),8.04(s,1H),8.02(s,1H),7.86-7.82(m,2H),7.73(s,1H),7.41(d,J=7.6Hz,3H),7.18(t,J=7.6H z,1H),7.11(s,1H),7.03(d,J=8.0Hz,2H),6.62(s,1H),4.06(t,J=6.4Hz,2H),3.06(t,J=6.4Hz,2H),2.35(s,3H),2.33(s,3H); HRMS calcd for C 27 H 24 N3O3[M+H] + 438.1813, found 438.1810.

[0131] l) Preparation of compound 7: Intermediate K1 (80 mg, 0.18 mmol) was dissolved in CH2Cl2 (10 mL), and furfurylamine (16 μL, mmol) was added. The mixture was reacted at room temperature for 15 min, and then NaBH3CN (58 mg, 0.91 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, a small amount of water was added to quench the reaction, and the mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to give compound 7 (88 mg, 93%) as a white solid. 1 HNMR(400MHz, CDCl3)δ8.04(d,J=1.2Hz,1H),7.77(d,J=1.2Hz,1H),7.41-7.36(m,3H),7.34 (t,J=2.0Hz,1H),7.30(t,J=1.6Hz,1H),7.26-7.23(m,1H),7.19-7.14(m,1H),7.04-6.99(m ,3H),6.62(s,1H),6.33(dd,J=3.6,2.0Hz,1H),6.21(dd,J=3.6,0.8Hz,1H),3.98(t,J=6.4H z,2H),3.85(s,2H),3.83(s,2H),3.01(t,J=6.4Hz,2H),2.33(s,3H),2.28(d,J=0.8Hz,3H); 13C NMR (100MHz, CDCl3) δ164.3,159.1,156.5,153.5,144.6,142.8,142.1,139.7,138.0,137.9,134.8,132.3,130.1(2C),12 8.3,124.2,123.9,123.1,119.2(2C),118.3,117.2,115.6,114.8,110.3,107.5,52.3,49.5,45.5,28.5,16.1,13.8; HRMS calcdfor C 32 H 31 N4O3[M+H] + 519.2351, found 519.2347.

[0132] Example 8, Preparation of Compound 8:

[0133]

[0134] Compound 8 was prepared in the same way as in Example 7, except that benzylamine was used instead of furfurylamine.

[0135] 1 H NMR (400MHz, MeOD-d4) δ8.07(s,1H),7.94(s,1H),7.63(s,1H),7.52(s,1H),7.46(d,J=7.6Hz,3H),7.43-7.37(m,6H),7.34(s,1H),7.18(t,J=7.6 Hz,1H),7.02(d,J=8.0Hz,2H),6.67(s,1H),4.16(s,2H),4.13(s,2H),4. 02(t,J=6.4Hz,2H),3.05(t,J=6.4Hz,2H),2.31(s,3H),2.25(s,3H); HRMS calcd for C 32 H 31 N4O3[M+H] + 529.6635, found 529.6630.

[0136] Example 9, Preparation of Compound 9:

[0137]

[0138] 1) Preparation of intermediate L1: Intermediate J1 (700 mg, 1.50 mmol) was dissolved in THF (20 mL), and a DIBAL-H THF solution (1.5 mL, 1.50 mmol) was added dropwise at -78 °C. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to give intermediate M1 (590 mg, 90%) as a white solid. 1 H NMR(400MHz, CDCl3)δ7.89(s,1H),7.74(s,1H),7.46-7.37(m,4H),7.36(s,2H),7.28(s,2H),7.20(s,1H),7.00(s, 1H),6.66(s,1H),5.12(s,2H),4.71(s,2H),3.95(t,J=6.4Hz,2H),3.05(t,J=6.4Hz,2H),2.29(s,3H),2.26(s,3H); 13 C NMR (100MHz, CDCl3) δ164.8,160.3,144.8,144.7,139.0,138.2,137.6,136.7,134.6,131.2,128.8(2C),128. 2,127.1(2C),126.3,121.8,121.4,117.2,116.5,114.7,109.2,70.1,64.1,49.5,28.8,16.3,13.5; HRMScalcd for C 27 H 28 N3O2[M+H] + 426.2177, found 426.2174.

[0139] Compound 9: 1H NMR (400MHz, DMSO) δ8.52(d,J=2.5Hz,1H),7.83–7.74(m,2H),7.68(t,J=1.7Hz,1H),7.54–7.44(m,3H),7.42(t,J=7.5Hz, 2H),7.38–7.30(m,1H),7.27(q,J=2.8Hz,1H),7.20(s,1H),6.57(t,J=2.2Hz,1H),5.19(s,2H),3.98(t,J=6.4Hz,2H),3.5 6(d,J=13.4Hz,1H),3.50(d,J=13.5Hz,3H),3.04(t,J=6.5Hz,2H),2.80–2.61(m,3H),2.30(s,3H),2.01(dd,J=11.7,5.0H z,1H),1.75(dd,J=17.0,7.2Hz,2H),1.64(dt,J=13.3,3.9Hz,1H),1.54–1.41(m,1H),1.24(s,1H),1.03(d,J=10.9Hz,1H); 13 C NMR (101MHz, DMSO) δ163.8,155.7,144.5,141.5,141.1,140.2,137.7,131.8,131.7,130.1,129.0,128.3,128.2,128.2,127.8,127.6,123. 7,116.4,114.7,110.6,108.4,69.7,62.4,62.0,53.9,53.6,49.7,48.2,48.0,45.9,40,34.5,33.4,33.1,27.4,24.0,23.8,16.7; HRMScalcd for C 32 H 38 N5O[M+H] + 508.3017, found 508.3014.

[0140] Example 10, Preparation of Compound 10:

[0141]

[0142] Compound 10 was prepared in the same way as in Example 2, except that intermediate L1 was used instead of intermediate J1.

[0143] Compounds: 1H NMR (400MHz, CDCl3) δ7.76 (d, J=1.6Hz, 1H), 7.30 (td, J=7.2, 2.0Hz, 2H), 7.07 (s, 1H) ,7.06-7.01(m,3H),6.95(s,1H),6.93-6.89(m,2H),6.80(t,J=1.6Hz,1H),6.74(t,J =2.0Hz,1H),6.73(s,1H),4.42(s,2H),3.60(s,2H),3.58(t,J=6.0Hz,2H),2.90(t,J =6.0Hz,2H),2.59(q,J=7.6Hz,4H),2.30(s,3H),2.21(s,3H),1.07(d,J=7.2Hz,6H); 13 C NMR (100MHz, CDCl3) δ158.1,153.1,151.4,139.2,138.6,134.9,133.8,129.8(2C),129.6,129.4,128.1,122.5 ,119.5,117.4(2C),115.1,113.4,111.4,105.9,57.9,49.9,47.0(2C),46.1,28.8,16.0,13.9,11.8(2C); HRMS calcd for C 31 H 37 N4O[M+H] + 481.2962, found 481.2959.

[0144] Example 11, Preparation of Compound 11:

[0145]

[0146] Compound 11 was prepared in the same manner as in Example 1, except that 4-chloroiodobenzene was used instead of iodobenzene.

[0147] Compound 11: 1H NMR(400MHz,MeOH-d4)δ9.49(d,J=1.6Hz,1H),8.05(t,J=1.6Hz,1H),8.01-7.90(m,3H ),7.47(s,1H),7.35(d,J=2.0Hz,1H),7.33(d,J=2.4Hz,2H),6.96-6.90(m,2H),4.64(d ,J=13.2Hz,1H),4.58(d,J=13.2Hz,1H),4.18(t,J=6.4Hz,2H),3.87-3.53(m,3H),3.2 1(t,J=6.4Hz,4H),2.46(d,J=1.2Hz,3H),2.32(s,3H),2.26-2.04(m,3H),1.74(s,1H); 13 C NMR(100MHz,DMSO-d6)δ162.6,155.9,153.0,144.1,138.2,137.1,135.0,134.8,134.0,130.7(2C),130.0,128.4,12 6.9,123.6,119.3(2C),117.8,117.3,115.9,114.3,61.1,55.0,52.6,49.0,46.6,27.2,27.0,21.7,15.9,13.5; HRMS calcd forC 32 H 35 ClN5O2[M+H] + 556.2474, found 556.2470.

[0148] Example 12, Preparation of Compound 12:

[0149]

[0150] Compound 12 was prepared in the same manner as in Example 1, except that 4-iodophenylmethyl ether was used instead of iodobenzene.

[0151] Compound 12: 1H NMR (400MHz, DMSO-d6) δ8.21 (s, 2H), 8.15 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.47 (s, 1H), 7.44 (s,1H),7.31(s,1H),7.28(s,1H),7.22(s,1H),6.97(s,4H),4.00(t,J=6.4Hz,2H),3.75(s, 3H),3.58(d,J=13.6Hz,1H),3.53(d,J=13.6Hz,1H),3.19(s,1H),3.08(t,J=6.4Hz,2H),2.7 2(d,J=10.8Hz,1H),2.32(s,3H),2.27(s,2H),2.16(s,3H),1.86-1.67(m,2H),1.51(s,2H); 13 C NMR (100MHz, DMSO-d6) δ162.8,155.5,155.0,149.7,144.2,140.4,138.3,137.1,134.8,133.4,132.8,130.3,128.0,123.4 ,120.2(2C),117.1,115.7,115.4,115.2(2C),114.3,61.2,55.4,55.2,52.7,49.1,46.7,27.3,27.0,21.8,16.0,13.6; HRMS calcd for C 33 H 38 N5O3[M+H] + 552.2970, found 552.2966.

[0152] Example 13, Preparation of Compound 13:

[0153]

[0154] Compound 13 was prepared in the same manner as in Example 1, except that 4-iodophenyl methyl ether was used instead of iodobenzene.

[0155] Compound 13: 1H NMR (400MHz, DMSO-d6) δ8.21 (s, 2H), 8.15 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.47 (s, 1H), 7.44 (s,1H),7.31(s,1H),7.28(s,1H),7.22(s,1H),6.97(s,4H),4.00(t,J=6.4Hz,2H),3.75(s, 3H),3.58(d,J=13.6Hz,1H),3.53(d,J=13.6Hz,1H),3.19(s,1H),3.08(t,J=6.4Hz,2H),2.7 2(d,J=10.8Hz,1H),2.32(s,3H),2.27(s,2H),2.16(s,3H),1.86-1.67(m,2H),1.51(s,2H); 13 C NMR (100MHz, DMSO-d6) δ162.8,155.5,155.0,149.7,144.2,140.4,138.3,137.1,134.8,133.4,132.8,130.3,128.0,123.4 ,120.2(2C),117.1,115.7,115.4,115.2(2C),114.3,61.2,55.4,55.2,52.7,49.1,46.7,27.3,27.0,21.8,16.0,13.6; HRMS calcd for C 33 H 38 N5O3[M+H] + 552.2970, found 552.2966.

[0156] Example 14, Preparation of Compound 14:

[0157]

[0158] Compound 14 was prepared in the same manner as in Example 1, except that 1-ethyl-4-iodobenzene was used instead of iodobenzene.

[0159] Compound 14: 1H NMR (400MHz, DMSO-d6) δ8.15(d,J=1.2Hz,1H),8.04(s,1H),7.54(t,J=2.0Hz,1H),7.47(d,J=1.6Hz,1H),7.44(t, J=1.6Hz,1H),7.34(s,1H),7.23(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),4.01(t,J=6.4Hz,2H),3.58(d,J=14.0Hz, 1H),3.53(d,J=14.0Hz,1H),3.18(d,J=7.2Hz,1H),3.10(t,J=6.4Hz,2H),2.75-2.67(m,1H),2.59(q,J=7.6Hz,2H) ,2.29(s,3H),2.28(s,2H),2.16(s,3H),1.83-1.70(m,2H),1.57-1.44(m,2H),1.23(s,1H),1.17(t,J=7.6Hz,4H); 13 C NMR(100MHz,DMSO-d6)δ162.7,154.7,154.0,144.2,140.4,138.9,138.4,137.1,134.8,134.0,133.5,130.5,129.3(2C),1 28.2,123.4,118.2(2C),117.1,116.7,115.7,114.3,61.3,55.3,52.7,49.1,46.7,27.4,27.0,21.9,16.0,15.7,13.6; HRMS calcd for C 33 H 38 N5O3[M+H] + 550.3177, found 550.3173.

[0160] Example 15, Preparation of Compound 15:

[0161]

[0162] Compound 15 was prepared in the same manner as in Example 1, except that 4-iodotrifluorotoluene was used instead of iodobenzene.

[0163] Compound 15: 1H NMR (400MHz, DMSO-d6) δ8.21 (s, 2H), 8.15 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.47 (s, 1H), 7.44 (s,1H),7.31(s,1H),7.28(s,1H),7.22(s,1H),6.97(s,4H),4.00(t,J=6.4Hz,2H),3.75(s, 3H),3.58(d,J=13.6Hz,1H),3.53(d,J=13.6Hz,1H),3.19(s,1H),3.08(t,J=6.4Hz,2H),2.7 2(d,J=10.8Hz,1H),2.32(s,3H),2.27(s,2H),2.16(s,3H),1.86-1.67(m,2H),1.51(s,2H); 13 C NMR (100MHz, DMSO-d6) δ162.7,159.3,159.2,154.0,152.9,144.1,138.2,138.2,137.1,134.8,134.3,133.5,130.6,129.8,129.7 ,128.3,127.0,120.0,119.9,116.8,116.6,116.6,115.8,114.3,61.2,55.0,52.7,52.7,49.1,27.3,27.0,26.6,16.0,13.6.; HRMS calcd for C 33 H 35 N5O2[M+H] + 590.2738, found 590.2733.

[0164] Example 16, Preparation of Compound 16:

[0165]

[0166] Compound 16 was prepared in the same manner as in Example 1, except that 4-iodobiphenyl was used instead of iodobenzene.

[0167] Compound 16: 1H NMR(400MHz,MeOH-d4)δ9.49(d,J=1.6Hz,1H),8.05(t,J=1.6Hz,1H),8.01-7.90(m,3H ),7.47(s,1H),7.35(d,J=2.0Hz,1H),7.33(d,J=2.4Hz,2H),6.96-6.90(m,2H),4.64(d ,J=13.2Hz,1H),4.58(d,J=13.2Hz,1H),4.18(t,J=6.4Hz,2H),3.87-3.53(m,3H),3.2 1(t,J=6.4Hz,4H),2.46(d,J=1.2Hz,3H),2.32(s,3H),2.26-2.04(m,3H),1.74(s,1H); 13 C NMR(100MHz,DMSO-d6)δ162.6,155.9,153.0,144.1,138.2,137.1,135.0,134.8,134.0,130.7(2C),130.0,128.4,12 6.9,123.6,119.3(2C),117.8,117.3,115.9,114.3,61.1,55.0,52.6,49.0,46.6,27.2,27.0,21.7,15.9,13.5; HRMS calcd forC 38 H 40 N5O2[M+H] + 598.3177, found 598.3172.

[0168] Example 17, Preparation of Compound 17:

[0169]

[0170] Compound 17 was prepared in the same manner as in Example 7, except that propylamine was used instead of furfurylamine.

[0171] Compounds: 1H NMR(400MHz,DMSO-d6)δ9.09(d,J=2.0Hz,1H),7.90(s,1H),7.89(s,1H),7.77(s,1H),7 .70(s,1H),7.70(s,1H),7.68(s,1H),7.64(d,J=8.0Hz,2H),7.50-7.39(m,4H),7.35(t, J=8.0Hz,1H),7.05(d,J=8.8Hz,2H),4.14(s,2H),4.07(t,J=6.4Hz,2H),3.16(t,J=6.4H z,2H),2.83(t,J=7.6Hz,2H),2.32(s,6H),1.61(q,J=7.6Hz,2H),0.91(t,J=7.6Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ162.8,156.6,153.4,144.3,140.6,139.4,136.4,135.4,135.3,134.8,134.7,134.3,130.8,129.0(2C),128. 4(2C),128.0,127.2,126.6,126.5(2C),119.5,118.1(2C),118.0,117.7,117.6,49.9,49.0,48.7,27.0,19.6,16.0,11.1,10.2; HRMS calcd for C 36 H 36 N4O2[M+H] + 556.2838, found 556.2834.

[0172] Example 18, Preparation of Compound 18:

[0173]

[0174] m) Preparation of intermediate M1: Intermediate F1 (500 mg, 2.82 mmol) was dissolved in CH3CN (20 mL), followed by the sequential addition of K2CO3 (1.56 g, 8.16 mmol) and benzyl bromide (400 μL, 3.39 mmol). The mixture was reacted at 90 °C for 2 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate M1 (723 g, 96%) as a white solid. 1H NMR(400MHz,MeOH-d4)δ7.48(d,J=8.0Hz,2H),7.44(s,1H),7.40(t,J=8.0Hz,2H),7.32(t,J=8 .0Hz,1H),7.29(s,1H),5.16(s,1H),3.45(d,J=6.4Hz,2H),2.85(t,J=6.4Hz,2H),2.18(s,3H); 13 C NMR (100MHz, CDCl3) δ166.8,156.1,137.3,132.2,131.3,129.7,128.6,127.9,127.6,127.3,109.9,70.1,40.6,27.5,16.7; HRMS calcd forC 17 H 18 NO2[M+H] + 268.1333, found 268.1331.

[0175] Compound 18 was prepared in the same manner as in Example 1, except that intermediate J2 was used instead of intermediate J1.

[0176] Compound 18: 1 H NMR (400MHz, DMSO-d6) δ8.35(s,2H),8.19(s,1H),7.57(s,1H),7.52(s,1H),7.50(s,1H),7.47(d,J=7.6H z,3H),7.40(t,J=7.6Hz,2H),7.33(d,J=7.2Hz,1H),7.31(s,1H),7.19(s,1H),5.17(s,2H),3.98(t,J=6.4 Hz,2H),3.59(d,J=14.0Hz,1H),3.54(d,J=14.0Hz,1H),3.20(s,1H),3.03(t,J=6.4Hz,2H),2.77(d,J=10. 4Hz,1H),2.40-2.30(m,2H),2.28(s,3H),2.18(s,3H),1.88-1.69(m,2H),1.59-1.45(m,2H),1.22(s,1H); 13C NMR(100MHz,DMSO-d6)δ163.3,155.2,144.4,140.5,138.4,137.2,137.1,134.9,131.3,131.3,129.7,128.5(2C),127.8,1 27.7,127.1(2C),123.4,117.1,115.7,114.3,110.1,69.3,61.3,55.3,52.7,49.2,46.8,27.4,26.9,21.9,16.3,13.6; HRMS calcd forC 33 H 38 N5O2[M+H] + 536.3021, found 536.3017.

[0177] Example 19, Preparation of Compound 19:

[0178]

[0179] Compound 19 was prepared in the same manner as in Example 18, except that N-Boc-piperazine was used instead of (S)-3-Boc-aminopiperidine.

[0180] Compound 19: 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.57(s,1H),7.54(s,1H),7.49(d,J=7.6Hz,3H),7.45-7.39(m,3H),7.35(d,J=7.6Hz,1H),7.33(s,1H),7.21( s,1H),5.19(s,2H),3.99(t,J=6.4Hz,2H),3.57(s,2H),3.05(t,J=6.4Hz ,2H),2.91(d,J=5.2Hz,4H),2.51-2.47(m,4H),2.30(s,3H),2.19(s,4H); 13 C NMR(100MHz,DMSO-d6)δ163.2,155.2,144.3,140.0,138.4,137.2,137.0,134.7,131.3,131.2,129.6,128.5(2C),127. 7,127.3,127.1(2C),123.8,117.4,115.6,114.2,110.1,69.3,61.6,51.5,49.1(2C),44.2(2C),26.9,16.2,13.6; HRMS calcd for C 32 H 36 N5O2[M+H]+ 522.2864, found 522.2860.

[0181] Example 20, Preparation of Compound 20:

[0182]

[0183] Compound 20 was prepared in the same manner as in Example 18, except that 4-Boc-aminopiperidine was used instead of (S)-3-Boc-aminopiperidine.

[0184] Compound 20: 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=1.6Hz,1H),7.55(t,J=2.0Hz,1H),7.53(s,1H),7.48(d,J=7.6Hz, 2H),7.46(s,1H),7.41(t,J=7.6Hz,2H),7.38(s,1H),7.34(t,J=7.6Hz,1H),7.30(s,1H),7.21(s,1H) ,5.19(s,2H),3.99(t,J=6.4Hz,2H),3.54(s,2H),3.04(t,J=6.4Hz,2H),2.93(s,1H),2.88(d,J=11.6 Hz,2H),2.30(s,3H),2.18(s,3H),2.04(t,J=11.6Hz,2H),1.89(d,J=10.4Hz,2H),1.63-1.48(m,2H); 13 C NMR(100MHz,DMSO-d6)δ163.2,155.2,150.0,144.3,138.4,137.2,137.0,134.7,131.3,131.3,129.6,128.6,128.5(2C), 127.7,127.1(2C),123.7,117.3,115.5,114.2,110.2,69.3,61.2,51.0(2C),49.1,47.8,30.3(2C),26.9,16.2,13.6; HRMS calcd for C 33 H 38 N5O2[M+H] + 536.3021, found 536.3017.

[0185] Example 21, Preparation of Compound 21:

[0186]

[0187] Compound 21 was prepared in the same manner as in Example 18, except that 3-(Boc-amino)pyrrolidine was used instead of (S)-3-Boc-aminopiperidine.

[0188] Compound 21: 1 H NMR(400MHz, DMSO-d6)δ8.14(s,1H),7.52(d,J=4.3Hz,2H),7.53(s,1H),7.51(s,1H),7.49-7.43(m,3H),7 .43-7.37(m,3H),7.33(d,J=7.2Hz,1H),7.31(s,1H),7.19(s,1H),5.18(s,2H),3.97(t,J=6.4Hz,2H),3.7 7(s,1H),3.68(d,J=13.6Hz,1H),3.61(d,J=13.6Hz,1H),3.03(t,J=6.4Hz,2H),2.67(q,J=8.0Hz,2H),2.4 5(d,J=8.0Hz,1H),2.36(dd,J=10.0,4.4Hz,1H),2.28(s,3H),2.17(s,3H),2.12-2.03(m,1H),1.50(s,1H); 13 C NMR(100MHz,DMSO-d6)δ163.2,155.2,144.3,141.4,138.4,137.2,137.1,134.7,131.3,131.2,129.6,128.5(2C),127. 7(2C),127.1(2C),123.4,116.9,115.4,114.2,110.1,69.3,61.1,58.7,52.4,50.1,49.2,32.8,26.9,16.2,13.6; HRMS calcd forC 32 H 36 N5O2[M+H] + 522.2864, found 522.2860.

[0189] Example 22, Preparation of Compound 22:

[0190]

[0191] Compound 22 was prepared in the same manner as in Example 2, except that intermediate J2 was used instead of intermediate J1 and 1-(2-pyrimidinyl)piperazine was used instead of diethylamine.

[0192] Compound 22: 1H NMR (400MHz, CDCl3) δ8.30 (d, J=4.8Hz, 2H), 7.80 (s, 1H), 7.67 (s, 1H), 7.46 (d, J= 7.6Hz,2H),7.42-7.36(m,3H),7.33(d,J=7.2Hz,2H),7.28(s,1H),7.05(s,2H),6. 48(t,J=4.8Hz,1H),5.15(s,2H),4.01(t,J=6.4Hz,2H),3.86(t,J=5.2Hz,4H),3. 61(s,2H),3.07(t,J=6.4Hz,2H),2.56(t,J=5.2Hz,4H),2.34(s,3H),2.30(s,3H); 13 C NMR (100MHz, CDCl3) δ164.7,161.8,157.9(2C),156.3,144.6,141.0,139.7,137.9,137.2,134.8,132.8,130.7,129.5,128.7(2C),128.0,127. 9,127.4(2C),123.7,118.9,117.3,114.9,110.7,110.0,77.5,77.4,77 .2,76.8,70.2,62.7,53.2(2C),49.8,43.7(2C),27.8,16.8,13.8; HRMS calcd for C 36 H 38 N7O2[M+H] + 600.3082, found 600.3077.

[0193] Example 23, Preparation of Compound 23:

[0194]

[0195] Preparation of compound 23: Compound 18 was dissolved in HCl methanol solution and reacted for 24 h to obtain compound 23. 1H NMR(400MHz,DMSO-d6)δ8.12(d,J=1.2Hz,1H),7.52(s,1H),7.44(s,1H),7.39(s,1H),7.37(s,1H) ,7.28(s,1H),7.06(s,1H),3.95(t,J=6.4Hz,2H),3.53(d,J=13.2Hz,1H),3.47(d,J=13.2Hz,1H), 2.98(t,J=6.4Hz,2H),2.72(d,J=10.8Hz,2H),2.64(d,J=10.4Hz,1H),2.18(s,3H),2.16(s,3H),1 .99(t,J=10.0Hz,1H),1.81-1.67(m,2H),1.67-1.57(m,1H),1.52-1.39(m,1H),1.08-0.97(m,1H); 13 C NMR(100MHz,DMSO-d6)δ163.4,154.3,144.4,140.9,138.4,137.0,134.7,129.4,129.3,129.2,127.5,1 23.5,117.1,115.6,114.2,113.1,61.8,53.2,49.3,48.6,47.7,33.2,26.9,23.5,16.0,13.6; HRMScalcd for C 26 H 32 N5O2[M+H] +

[0196] 446.2551, found 446.2547.

[0197] Example 24, Preparation of Compound 24:

[0198]

[0199] Compound 24 was prepared in the same manner as in Example 7, except that benzylamine was used instead of furfurylamine.

[0200] Compound 24: 1H NMR(400MHz,MeOD-d4)δ8.04(s,1H),7.56(s,1H),7.50(s,1H),7.45-7.40(m,3H),7.39-7.30(m,7H),7.30-7.24(m,3H),7 .08(s,1H),5.09(s,2H),3.95(t,J=6.4Hz,2H),3.90(s,2H),3.88(s,2H),3.02(t,J=6.4Hz,2H),2.29(s,3H),2.23(s,3H); 13 C NMR(100MHz,MeOD-d4)δ166.5,157.3,145.9,142.0,139.9,139.0,138.8,138.6,136.1,134.1,132.8,130.7,129.9(2C),129.7(2C), 129.6(2C),128.9,128.8,128.5,128.4(2C),125.8,119.9,118.5,116.0,111.4,71.0,53.5,52.8,51.1,28.3,16.7,13.2; HRMScalcd for C 35 H 35 N4O2[M+H] + 543.2755, found 543.2750.

[0201] Example 25, Preparation of Compound 25:

[0202]

[0203] Compound 25 was prepared in the same manner as in Example 7, except that 3,4-dimethoxyphenethylamine was used instead of furfurylamine.

[0204] Compound 25: 1H NMR(400MHz,MeOD-d4)δ9.42(s,1H),7.90(s,1H),7.87(d,J=5.6Hz,2H),7.78(s,1H),7.59(s,1H), 7.45(d,J=7.2Hz,2H),7.36(t,J=7.2Hz,2H),7.30(t,J=7.2Hz,1H),7.18(s,1H),6.95-6.88(m,2H), 6.86(dd,J=8.0,2.0Hz,1H),5.17(s,2H),4.39(s,2H),4.09(t,J=6.4Hz,2H),3.83(s,3H),3.79(s, 3H),3.36(t,J=8.0Hz,2H),3.12(t,J=6.4Hz,2H),3.04(t,J=8.0Hz,2H),2.46(s,3H),2.34(s,3H).; 13 C NMR(100MHz,MeOD-d4)δ166.6,157.4,150.9,149.9,146.6,138.6,137.2,135.4,135.0,134.6,133.1,133.0,130.9,130.3,129.6(2C),129. 5,128.9,128.3(2C),128.2,122.5,122.3,121.5,119.2,113.8,113.4,111.5,71.1,56.5,51.4,50.9,50.0,32.9,28.3,16.7,9.9; HRMScalcd for C 38 H 41 N4O4[M+H] + 617.3123, found 617.3128.

[0205] Example 26, Preparation of Compound 26:

[0206]

[0207] Preparation of compound 26: Intermediate K2 (600 mg, 1.25 mmol) was dissolved in a mixed solution of THF (5 mL) and H2O (5 mL), and LiOH (150 mg, 6.23 mmol) was added. The mixture was reacted at room temperature for 2 h. After the reactants disappeared, the mixture was concentrated under vacuum, and AcOH was added to neutralize the remaining LiOH. The mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain compound 26 (550 mg, 95%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.95-7.90(m,3H),7.55(s,1H),7.53(s,1H),7.47(d,J=7.2Hz,2H),7.40(t,J=7.2Hz,2 H),7.32(t,J=7.2Hz,1H),7.20(s,1H),5.18(s,2H),4.03(t,J=6.4Hz,2H),3.05(t,J=6.4Hz,2H),2.29(s,3H),2.18(s,3H); 13 C NMR(100MHz,DMSO-d6)δ166.3,163.4,155.3,144.6,138.6,137.4,137.2,135.0,132.6,131.5,131.4,129.7 ,128.5(2C),127.7,127.4,127.2(2C),124.2,120.9,117.3,114.3,110.2,69.3,49.0,26.8,16.3,13.6; HRMS calcd for C 28 H 26 N3O4[M+H] + 468.1918, found 468.1914.

[0208] Example 27, Preparation of Compound 27:

[0209]

[0210] Preparation of compound 27: Compound 27 (80 mg, 0.17 mmol) was dissolved in CH2Cl2 (10 mL). Under ice-water bath conditions, HOBT (23 mg, 0.17 mmol), EDCI (34 mg, 0.17 mmol), DIPEA (45 μL, 0.26 mmol), and 1-(2-hydroxyethyl)piperazine (25 mg, 0.19 mmol) were added sequentially. The reaction was carried out at room temperature for 2 h. After the reactants disappeared, a small amount of water was added to quench the reaction. The mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to give compound 27 (93 mg, 94%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7.46 (d, J = 7. 6Hz,2H),7.42-7.29(m,4H),7.27(s,1H),7.06(s,2H),5.15(s,2H),4.01(t ,J=6.4Hz,2H),3.82(s,2H),3.66(t,J=5.2Hz,2H),3.57(s,2H),3.06(d,J =6.4Hz,2H),2.61(t,J=5.2Hz,4H),2.52(s,2H),2.34(s,3H),2.29(s,3H); 13 C NMR (100MHz, CDCl3) δ168.5,164.8,156.3,144.7,140.1,138.1,137.8,137.1,133.2,130.7,129.6,128.7(2C), 128.0,127.5,127.3(2C),121.9,119.2,116.9,110.6,70.2,59.5,57.9,53.4,49.6,47.9,27.7,16.8,13.8; HRMS calcd for C 34 H 38 N5O4[M+H] + 580.2919, found 580.2915.

[0211] Example 28, Preparation of Compound 28:

[0212]

[0213] Compound 28 was prepared in the same manner as in Example 7, except that butylamine was used instead of 1-(2-hydroxyethyl)piperazine.

[0214] Compound 28: 1H NMR (400MHz, CDCl3) δ7.81(s,1H),7.70(s,2H),7.67(s,2H),7.62(s,1H),7.52(s,1H) ,7.45(d,J=7.6Hz,2H),7.38(t,J=7.6Hz,2H),7.31(t,J=7.6Hz,1H),7.03(s,2H),5.1 1(s,2H),3.97(t,J=6.4Hz,2H),3.42(q,J=6.4Hz,2H),3.03(t,J=6.4Hz,2H),2.34(s, 3H), 2.24 (s, 3H), 1.59 (p, J = 7.2Hz, 2H), 1.39 (h, J = 7.2Hz, 2H), 0.93 (t, J = 7.2Hz, 3H); 13 CNMR(100MHz, CDCl3)δ166.0,164.9,156.3,144.6,137.7,137.5,137.1,133.1,130.8,129.6,128.7(2C),128.0, 127.4,127.3(2C),121.9,120.4,116.9,114.6,110.5,70.1,49.7,40.2,31.7,27.6,20.3,16.8,13.9,13.7; HRMS calcd forC 32 H 35 N4O3[M+H] + 523.2704, found 523.2700.

[0215] Example 29, Preparation of Compound 29:

[0216]

[0217] Compound 29 was prepared in the same manner as in Example 7, except that benzylamine was used instead of 1-(2-hydroxyethyl)piperazine.

[0218] Compound 29: 1 H NMR (400MHz, CDCl3) δ7.86(s,1H),7.74(s,1H),7.68(s,1H),7.60(s,1H),7.50-7.42(m,3H),7.38(t,J=7.6Hz,2H),7.31(m,5H ),7.04(s,1H),6.98(s,1H),5.11(s,2H),4.59(s,2H),3.93(t,J=6.4Hz,2H),3.02(t,J=6.4Hz,2H),2.35(s,3H),2.22(s,3H); 13CNMR(100MHz, CDCl3)δ165.8,165.7,165.0,156.3,144.6,138.2,137.6,137.1,134.7,133.1,130.8,129.7,128.8(2C),128.7 (2C),128.2(2C),128.0,127.7,127.3(2C),122.1,120.5,116.9,114.4,110.5,70.1,49.7,44.3,44.2,27.6,16.8,13.6; HRMS calcdfor C 35 H 33 N4O3[M+H] + 557.2548, found 557.2543.

[0219] Example 30, Preparation of Compound 30:

[0220]

[0221] Compound 30 was prepared in the same manner as in Example 7, except that phenylbutanylamine was used instead of 1-(2-hydroxyethyl)piperazine.

[0222] Compound 30: 1 H NMR(400MHz, CDCl3)δ8.03(s,1H),7.73(s,1H),7.64(s,1H),7.55(s,1H),7.46-7.28(m,7H) ,7.24-7.15(m,5H),7.12-7.08(m,1H),7.07(s,1H),7.02(s,1H),5.08(s,2H),4.28(p,J=7.2 Hz,1H),4.02-3.92(m,2H),3.16(qd,J=7.2,2.0Hz,1H),3.06(t,J=6.8Hz,2H),2.73(t,J=7.6 Hz,2H),2.35(s,3H),2.21(s,3H),2.03-1.95(m,1H),1.93-1.82(m,1H),1.37-1.27(m,4H).; 13C NMR (100MHz, CDCl3) δ165.1,165.0,156.2,144.5,141.9,137.5,137.0,134.3,133.2,131.1,129.8,128.6(2C),128.5(2 C),128.5(2C),128.0,127.3(2C),125.9,116.4,114.6,110.4,70.0,49.8,46.2,38.3,32.7,27.5,20.9,16.8,8.6; HRMS calcd for C 38 H 39 N4O3[M+H] + 599.3017, found 599.3013.

[0223] Example 31, Preparation of Compound 31:

[0224]

[0225] Compound 31 was prepared in the same manner as in Example 1, except that intermediate J3 was used instead of intermediate J1.

[0226] Compound 31: 1 H NMR (400MHz, DMSO-d6) δ7.51(s,1H),7.47(d,J=6.8Hz,2H),7.40(t,J=7.6Hz,2H),7.37-7.31(m,3 H),7.29(d,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),7.18(s,1H),5.17(s,2H),3.91(t,J=6.4Hz,2H),3 .55(d,J=13.6Hz,1H),3.48(d,J=13.6Hz,1H),3.13(s,1H),3.00(t,J=6.4Hz,2H),2.80(d,J=10.8 Hz,1H),2.55(d,J=5.2Hz,1H),2.25-2.09(m,2H),1.86(s,1H),1.71(s,1H),1.46(d,J=8.8Hz,2H); 13C NMR(100MHz,DMSO-d6)δ163.1,155.2,143.3,138.6,137.2,131.2,131.1,129.6,128.5(2C),128.3,127.9,1 27.7,127.2(2C),126.1,125.5,124.2,110.1,69.2,61.7,55.5,52.5,49.3,46.9,27.7,27.0,22.3,16.3; RMS calcd for C 29 H 34 N3O2[M+H] + 456.2646, found 456.2643.

[0227] Example 32, Preparation of Compound 32:

[0228]

[0229] Compound 32 was prepared in the same manner as in Example 18, except that 3-(bromomethyl)benzo[b]thiophene was used instead of benzyl bromide.

[0230] Compound 32: 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.95(d,J=7.6Hz,1H),7.83(d,J=7.2Hz,1H),7.60(s,1H),7.53(s,1H),7.50 (s,1H),7.44(s,1H),7.41-7.32(m,3H),7.29(s,1H),7.20(s,1H),5.51(s,2H),3.97(t,J=6.4Hz,2H),3.59-3.44 (m,4H),3.03(t,J=6.4Hz,2H),2.80-2.68(m,2H),2.62(d,J=10.0Hz,1H),2.29(s,3H),2.16(s,3H),2.02(d,J=8. 0Hz,1H),1.83(s,1H),1.78-1.69(m,1H),1.64(d,J=12.8Hz,1H),1.47(d,J=11.0Hz,1H),1.08(d,J=11.0Hz,1H); 13C NMR (100MHz, DMSO-d6) δ163.1,154.7,144.3,141.0,140.9,139.2,139.1,138.4,137.0,134.7,131.7,131.5,129.7,127.7,124. 5,123.7,123.5,122.7,122.5,117.2,115.5,114.2,110.5,65.4,61.7,59.8,54.9,53.1,49.1,47.6,29.0,26.9,16.2,13.6; HRMS calcd for C 35 H 38 N5O2S[M+H] + 592.2741, found 592.2736.

[0231] Example 33, Preparation of Compound 33:

[0232]

[0233] Compound 33 was prepared in the same manner as in Example 18, except that 2-methylbenzyl bromide was used instead of benzyl bromide.

[0234] Compound 33: 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.58(s,1H),7.55(s,1H),7.46(d,J=7.2Hz,2H),7.40(s,1H),7. 31(s,1H),7.29-7.18(m,4H),5.16(s,2H),4.00(t,J=6.4Hz,2H),3.55(d,J=12.8Hz,1H),3.49(d,J=1 3.6Hz,1H),3.06(t,J=6.4Hz,2H),2.77-2.63(m,3H),2.36(s,3H),2.27(s,3H),2.18(s,3H),2.00(t, J=11.2Hz,2H),1.80-1.69(m,2H),1.68-1.59(m,1H),1.47(d,J=12.0Hz,1H),1.01(d,J=11.6Hz,1H); 13C NMR(100MHz,DMSO-d6)δ163.2,155.3,144.3,141.0,138.4,137.0,136.3,135.0,134.7,131.2,131.2,130.1,129.6,128.0,1 27.9,127.7,125.8,123.5,117.2,115.5,114.2,110.0,68.0,62.1,61.8,53.2,49.2,47.8,33.5,26.9,23.6,16.2,13.6; HRMS calcd for C 34 H 40 N5O2[M+H] + 550.3177, found 550.3173.

[0235] Example 34, Preparation of Compound 34:

[0236]

[0237] Compound 34 was prepared in the same manner as in Example 7, except that 3,5-dimethoxybenzyl bromide was used instead of benzyl bromide.

[0238] Compound 34: 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.42(s,1H),6.97(s,2H),6.89(s,1H),6.84(s,2H),6.61(s,2H),6.45(s,1H),5.03( s,2H),4.39(s,2H),3.75(s,7H),3.57(t,J=6.0Hz,2H),3.57(d,J=13.6Hz,1H),3.57(d,J=13.6Hz,1H),3.41(d,J=13.6Hz ,1H),2.88-2.77(m,3H),2.70(d,J=10.4Hz,1H),2.59(d,J=10.0Hz,1H),2.18(s,3H),2.17(s,3H),2.04(s,1H),1.87(s,1 H),1.74(d,J=11.6Hz,1H),1.74(d,J=11.6Hz,1H),1.65(d,J=10.8Hz,1H),1.47(d,J=12.4Hz,1H),1.14(d,J=10.4Hz,1H); 13C NMR(100MHz,DMSO-d6)δ160.5(2C),154.5,151.0,141.0,139.8,138.0,137.9,134.7,132.5,130.3,126.2,124.1,114.4,11 2.3,109.6,109.3,105.0(2C),104.4,99.1,69.0,62.3,55.1(2C),53.1,49.5,47.4,45.5,31.5,27.3,23.1,15.8,13.6; HRMS calcd for C 35 H 42 N5O4[M+H] + 596.3232, found 596.3228.

[0239] Example 35, Preparation of Compound 35:

[0240]

[0241] Compound 35 was prepared in the same manner as in Example 18, except that 3,5-difluorobenzyl bromide was used instead of benzyl bromide.

[0242] Compound 35: 1 H NMR(400MHz, DMSO-d6)δ8.15(d,J=1.6Hz,1H),7.54(t,J=2.0Hz,1H),7.52-7.45(m,6H),7.44(s,1H) ,7.30(s,1H),7.21(s,1H),5.18(s,2H),4.10(s,1H),3.98(t,J=6.4Hz,2H),3.69(d,J=13.6Hz,1H),3 .54(d,J=13.6Hz,1H),3.17(s,3H),3.04(t,J=6.4Hz,2H),2.71(d,J=10.0Hz,1H),2.29(s,3H),2.21 (s,1H),2.17(s,3H),1.84-1.68(m,2H),1.52(d,J=10.4Hz,1H),1.42(d,J=10.8Hz,1H),1.23(s,1H); 13C NMR(100MHz,DMSO-d6)δ163.2,155.0,144.4,140.4,138.4,137.1,136.3,134.8,132.3,131.4,131.3,129.7,128.9(2C),1 28.5(2C),127.7,123.5,117.1,115.7,114.3,110.1,68.5,61.3,55.9,52.7,49.2,46.8,46.7,26.9,22.0,16.2,13.6; HRMS calcd for C 33 H 37 ClN5O2[M+H] + 570.2631, found 570.2627.

[0243] Example 36, Preparation of Compound 36:

[0244]

[0245] Compound 36 was prepared in the same manner as in Example 18, except that 4-chlorobenzyl bromide was used instead of benzyl bromide.

[0246] Compound 36: 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.55(d,J=2.0Hz,1H),7.47(s,2H),7.44(s,1 H),7.30(s,1H),7.25-7.16(m,4H),5.22(s,2H),3.99(t,J=6.4Hz,2H),3.59(d,J=1 3.6Hz,1H),3.54(d,J=13.6Hz,1H),3.04(t,J=6.4Hz,2H),2.72(d,J=10.0Hz,1H), 2.31(s,3H),2.28-2.18(m,2H),2.17(s,3H),1.85-1.69(m,2H),1.56-1.40(m,2H); 13C NMR (100MHz, DMSO-d6) δ163.8,163.7,163.3,161.4,161.2,154.9,144.4,142.1,140.5,138.5,137.2,134.9,131.7,131.5,129.9,127. 8,123.6,117.2,115.8,114.4,110.1,110.0,109.9,109.8,103.2,68.0,61.4,55.9,52.8,49.3,46.9,28.0,26.9,22.0,16.3,13.6; calcd for C 33 H 36 F2N5O2[M+H] + 572.2832, found 572.2828.

[0247] Example 37, Preparation of Compound 37:

[0248]

[0249] Compound 37 was prepared in the same manner as in Example 18, except that 4-fluorobenzyl bromide was used instead of benzyl bromide.

[0250] Compound 37: 1 H NMR(500MHz,MeOH-d4)δ9.52(s,1H),8.06(s,1H),7.98(d,J=6.0Hz,2H),7.94(s,1H), 7.57(s,1H),7.47(t,J=6.0Hz,2H),7.18(s,1H),7.10(t,J=8.5Hz,2H),5.14(s,2H),4 .65(d,J=12.5Hz,1H),4.60(d,J=12.5Hz,1H),4.14(s,2H),3.88-3.53(m,3H),3.26(s ,2H),3.13(s,2H),2.47(s,3H),2.32(d,J=2.0Hz,3H),2.26-2.03(m,3H),1.76(s,1H); 13CNMR(126MHz,MeOD-d4)δ166.5,164.8,162.9,157.2,146.5,137.1,135.1,134.6,133.2,132.9,130.9,130.8,130.4,130. 4,128.2,124.0,122.2,119.4,116.4,116.2,111.5,70.4,61.0,53.5,53.3,51.0,46.5,28.3,27.5,21.9,16.7,10.0; HRMS calcd for C 33 H 37 FN5O2[M+H] + 554.2926, found 554.2922.

[0251] Example 38, Preparation of Compound 38:

[0252]

[0253] Compound 38 was prepared in the same manner as in Example 7, except that propylamine was used instead of furfurylamine.

[0254] Compound 38: 1 H NMR(400MHz,DMSO-d6)δ9.10(d,J=1.6Hz,1H),8.44(s,1H),7.90(q,J=1.6Hz,2H), 7.74(t,J=1.6Hz,1H),7.71(t,J=1.6Hz,1H),7.56-7.48(m,3H),7.28-7.20(m,3H), 5.17(s,2H),4.18(s,2H),4.03(t,J=6.4Hz,2H),3.07(t,J=6.4Hz,2H),2.88(t,J= 8.0Hz,2H),2.33(s,3H),2.29(s,3H),1.63(q,J=7.6Hz,2H),0.93(t,J=7.6Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ163.3,160.5,155.2,144.6,136.4,135.4,134.8,133.4,131.7,131.4,129.8,129.4,129.3 ,127.3,126.7,119.5,118.1,117.6,115.4,115.2,110.1,68.6,49.8,49.1,48.6,26.8,19.5,16.3,11.1,10.2; HRMS calcd for C 31 H 34FN4O2[M+H] + 513.2661, found 513.2657.

[0255] Example 39, Preparation of Compound 39:

[0256]

[0257] Compound 39 was prepared in the same manner as in Example 18, except that 2-bromomethyl-5-trifluoromethylfuran was used instead of benzyl bromide.

[0258] Compound 39: 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.60(s,1H),7.55(s,1H),7.46(s,1H),7.41(s,1H),7.31(s,1H),7.24(d,J=3 .6Hz,1H),7.19(s,1H),6.78(d,J=3.6Hz,1H),5.23(s,2H),3.99(t,J=6.4Hz,2H),3.59-3.46(m,7H),3.04(t,J=6. 4Hz,2H),2.81(s,1H),2.74(d,J=10.4Hz,1H),2.62(d,J=10.8Hz,1H),2.21(s,3H),2.17(s,3H),2.06(t,J=9.6Hz, 1H),1.88(t,J=9.6Hz,1H),1.75(dd,J=12.0,4.4Hz,1H),1.70-1.61(m,1H),1.54-1.41(m,1H),1.21-1.08(m,1H); 13 C NMR(100MHz,DMSO-d6)δ163.1,154.8,154.0,144.3,140.9,139.9,138.4,137.0,134.7,132.0,131.6,129.8,127.8,123.5,1 17.2,115.6,114.2,114.0,114.0,111.2,110.9,62.1,61.7,60.5,53.1,49.1,47.5,32.0,32.0,26.9,23.2,16.0,13.6; HRMS calcd for C 32 H 35 F3N5O3[M+H] + 594.2687, found 594.2683.

[0259] Example 40, Preparation of Compound 40:

[0260]

[0261] Compound 40 was prepared in the same manner as in Example 18, except that 4-bromomethylbiphenyl was used instead of benzyl bromide.

[0262] Compound 40: 1 H NMR (400MHz, DMSO-d6) δ8.31-8.12(m,3H),7.98(s,1H),7.97-7.89(m,3H),7.61(dd,J=8.4,1.6Hz,1H ),7.58-7.50(m,4H),7.49(s,1H),7.45(s,1H),7.29(s,1H),7.21(s,1H),5.35(s,2H),3.98(t,J=6.4 Hz,2H),3.58(d,J=14.0Hz,1H),3.53(d,J=14.0Hz,1H),3.19(s,1H),3.03(t,J=6.4Hz,2H),2.74(d,J =8.0Hz,1H),2.33(s,3H),2.28(s,2H),2.17(s,3H),1.82(s,1H),1.74(d,J=8.0Hz,1H),1.52(s,2H); 13 C NMR (100MHz, DMSO-d6) δ163.2,155.3,144.4,140.4,138.4,137.1,134.9,134.8,132.8,132.5,131.4,131.3,129.7,128.2,127.8,127.7,127. 7,126.4,126.1,125.7,125.3,123.4,117.0,115.7,114.3,110.2,69.4,61.3,55.3,52.7,49.2,46.7,27.4,26.9,21.9,16.3,13.6; HRMScalcd for C 39 H 42 N5O2[M+H] + 612.3334, found 612.3330.

[0263] Example 41, Preparation of Compound 41:

[0264]

[0265] Compound 41 was prepared in the same manner as in Example 7, except that propylamine was used instead of furfurylamine.

[0266] Compound 41: 1H NMR(400MHz,MeOH-d4)δ8.81-8.76(m,1H),7.76(d,J=2.0Hz,1H),7.62(dt,J=11.4,5.9Hz ,9H),7.54(d,J=7.8Hz,2H),7.44(t,J=7.6Hz,2H),7.35(t,J=7.3Hz,1H),7.17(s,1H),5.2 2(s,2H),4.21(s,2H),4.06(t,J=6.5Hz,2H),3.10(t,J=6.5Hz,2H),2.98(t,J=7.8Hz,2H), 2.41(s,3H),2.38(s,3H),1.74(h,J=7.4Hz,2H),1.39-1.29(m,3H),1.05(t,J=7.4Hz,3H); 13 C NMR(100MHz,MeOD-d4)δ166.6,157.3,146.4,142.0,141.9,137.7,137.7,137.6,137.6,137.3,134.4,133.0,130.9,129.9,12 8.8,128.4,128.3,128.2,128.1,127.9,121.3,120.4,118.8,111.6,70.8,52.0,51.0,50.9,28.3,21.5,16.8,11.4,10.6; HRMS calcd for C 37 H 39 N4O2[M+H] + 571.3068, found 571.3064.

[0267] Example 42, Preparation of Compound 42:

[0268]

[0269] Compound 42 was prepared in the same manner as in Example 7, except that benzylamine was used instead of furfurylamine.

[0270] Compound 42: 1H NMR(400MHz,MeOH-d4)δ8.01(d,J=1.6Hz,1H),7.59-7.53(m,5H),7.49(s,1H),7.47(s ,1H),7.46(t,J=2.0Hz,1H),7.40(d,J=2.0Hz,1H),7.38(d,J=1.6Hz,1H),7.37-7.35( m,1H),7.34-7.28(m,5H),7.26(t,J=1.6Hz,1H),7.08(s,1H),5.14(s,2H),3.92(t,J= 6.4Hz,2H),3.84(s,2H),3.81(s,2H),3.00(t,J=6.4Hz,2H),2.31(s,3H),2.22(s,3H); 13 CNMR(125MHz,MeOH-d4)δ166.5,157.2,145.8,142.8,142.0,141.9,139.9 ,139.5,139.0,137.6,136.0,134.0,132.8,130.8,129.9(2C),129.8(2C) ,129.7,129.6(2C),128.8(2C),128.6,128.4,128.1(2C),127.9,125.6,1 19.8,118.3,115.9,111.5,70.7,53.6,52.9,51.1,28.3,16.8,13.2; HRMS calcd for C 41 H 39 N4O2[M+H] + 619.3068, found 619.3063.

[0271] Example 43, Preparation of Compound 43:

[0272]

[0273] Compound 43 was prepared in the same manner as in Example 7, except that (2-bromoethyl)benzene was used instead of benzyl bromide.

[0274] Compound 43: 1H NMR(500MHz,MeOH-d4)δ9.51(s,1H),8.05(s,1H),7.97(d,J=7.0Hz,2H),7.93(s,1H),7. 51(s,1H),7.34-7.26(m,4H),7.24-7.17(m,1H),7.13(s,1H),4.62(q,J=13.1Hz,2H),4.2 3(t,J=6.6Hz,2H),4.13(t,J=6.4Hz,2H),3.78(d,J=25.0Hz,2H),3.61(s,1H),3.22(d,J =14.5Hz,1H),3.11(t,J=6.6Hz,4H),2.46(s,3H),2.22(s,4H),2.11(s,2H),1.74(s,1H); 13 C NMR(125MHz,MeOH-d4)δ166.7,157.5,146.5,139.9,137.1,135.1,134.4,132.9,132.8,130.9,130.8,130.1,1 29.4,128.1,127.5,124.0,122.1,119.3,110.7,70.2,53.2,51.0,46.6,36.7,28.3,21.9,16.6,9.9; HRMScalcd for C 34 H 40 N5O2[M+H] + 550.3177, found 550.3173.

[0275] Example 44, Preparation of Compound 44:

[0276]

[0277] Compound 44 was prepared in the same manner as in Example 7, except that propylamine was used instead of furfurylamine.

[0278] Compound 44: 1H NMR(400MHz,DMSO-d6)δ9.10(d,J=2.0Hz,1H),7.90(s,1H),7.85(t,J=2.0Hz,1H),7.7 1(s,1H),7.67(s,1H),7.44(s,1H),7.36-7.29(m,4H),7.26-7.19(m,1H),7.17(s,1H) ,4.22(t,J=6.4Hz,2H),4.09(s,2H),4.01(t,J=6.4Hz,2H),3.11-2.99(m,4H),2.80(t ,J=7.6Hz,2H),2.32(s,3H),2.16(s,3H),1.59(h,J=7.6Hz,2H),0.92(t,J=7.6Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ163.4,155.4,144.5,138.6,136.4,135.4,134.7,131.4,131.1,129.7,129.1(2C),128.3(2C),127.4,126.4,126 .3,119.1,117.7,117.6,109.4,68.5,50.3,49.1,49.0,40.1,39.9,39.7,39.5,39.3,39.1,38.9,35.0,26.8,20.1,16.1,11.2,10.2; HRMS calcd for C 32 H 37 N4O2[M+H] + 509.2912, found 509.2918.

[0279] Example 45, Preparation of Compound 45:

[0280]

[0281] Compound 45 was prepared in the same manner as in Example 18, except that benzyl 2-bromoethyl ether was used instead of benzyl bromide.

[0282] Compound 45: 1H NMR (400MHz, DMSO-d6) δ8.29(s,2H),8.19(s,1H),7.57(d,J=2.0Hz,1H),7.50(s,1H),7.46(s,1H),7.45(s,1H),7.3 6(d,J=4.0Hz,4H),7.32(s,1H),7.28(dt,J=8.0,4.0Hz,1H),7.18(s,1H),4.59(s,2H),4.18(t,J=4.4Hz,2H),3.99( t,J=6.4Hz,2H),3.81(t,J=4.4Hz,2H),3.60(d,J=14.0Hz,1H),3.55(d,J=14.0Hz,1H),3.20(s,1H),3.03(t,J=6.4H z,2H),2.82-2.71(m,1H),2.37-2.27(m,2H),2.25(s,3H),2.17(s,3H),1.88-1.69(m,2H),1.53(s,2H),1.23(s,1H); 13 C NMR(100MHz,DMSO-d6)δ163.3,155.5,144.4,140.4,138.5,138.3,137.1,134.8,131.2,131.2,129.6,128.3(2C),127.7,127.4( 2C),127.4,123.5,117.1,115.7,114.3,109.8,72.1,68.2,67.7,61.3,55.2,52.7,49.2,46.7,27.3,26.9,21.9,16.1,13.6; HRMS calcd for C 35 H 42 N5O3[M+H] + 580.3283, found 580.3280.

[0283] Example 46, Preparation of Compound 46:

[0284]

[0285] Compound 46 was prepared in the same manner as in Example 7, except that benzylamine was used instead of furfurylamine.

[0286] Compound 46: 1H NMR (400MHz, DMSO-d6) δ8.13(d,J=1.6Hz,1H),7.53(t,J=2.0Hz,1H),7.47(s,1H ),7.48(s,1H),7.44(s,1H),7.40-7.29(m,10H),7.23(t,J=7.2Hz,1H),7.17(s, 1H),4.59(s,2H),4.18(t,J=4.4Hz,2H),3.97(t,J=6.4Hz,2H),3.80(t,J=4.4Hz ,2H),3.78(s,2H),3.75(s,2H),3.03(t,J=6.4Hz,2H),2.24(s,3H),2.17(s,3H); 13 CNMR(100MHz,DMSO-d6)δ163.3,155.5,144.3,142.9,140.4,138.5,138.4,137.0,134.7,131.2,131.1,129.6,128.2(2C),128.1(2C),12 8.1(2C),127.7,127.4,127.4(2C),126.7,122.9,116.6,115.3,114.2,109.9,72.0,68.2,67.7,52.2,51.8,49.2,26.9,16.1,13.6; HRMS calcd for C 37 H 39 N4O3[M+H] + 587.3017, found 587.3012.

[0287] Example 47, Preparation of Compound 47:

[0288]

[0289] Compound 47 was prepared in the same manner as in Example 18, except that bromomethylcyclohexane was used instead of benzyl bromide.

[0290] Compound 47: 1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),8.20(s,1H),7.57(s,1H),7.51(s,1H),7.47(s,1H),7. 40(s,1H),7.32(s,1H),7.15(s,1H),3.99(t,J=6.5Hz,2H),3.80(d,J=6.0Hz,2H),3.60(d,J= 14.0Hz,1H),3.56(d,J=13.6Hz,1H),3.02(t,J=6.4Hz,2H),2.78(d,J=10.8Hz,1H),2.41-2.2 5(m,2H),2.22(s,3H),2.17(s,3H),1.90-1.63(m,9H),1.59-1.47(m,2H),1.32-1.04(m,6H); 13 C NMR (100MHz, DMSO-d6) δ163.3,155.7,144.4,140.3,138.3,137.1,134.8,131.1,130.8,129.5,127.7,123.4,117.1,115 .7,114.3,109.4,72.9,61.2,55.2,52.6,49.2,46.7,37.1,29.3(2C),27.3,26.9,26.1(2C),25.3,21.9,16.0,13.6; HRMS calcd for C 33 H 44 N5O2[M+H] + 542.3490, found 542.3486.

[0291] Example 48, Preparation of Compound 48:

[0292]

[0293] Compound 48 was prepared in the same manner as in Example 7, except that benzylamine was used instead of furfurylamine.

[0294] Compound 48: 1H NMR(400MHz,MeOD-d4)δ8.28(d,J=1.6Hz,1H),7.77(t,J=2.0Hz,1H),7.64(s,1H),7.61(s,1H) ,7.58(s,1H),7.56(s,1H),7.52-7.47(m,5H),7.46(s,1H),7.14(s,1H),4.40(s,2H),4.36(s,2 H),4.09(t,J=6.4Hz,2H),3.84(d,J=6.4Hz,2H),3.12(t,J=6.4Hz,2H),2.31(s,3H),2.30(s,3 H),1.93(d,J=13.2Hz,2H),1.87-1.72(m,3H),1.44-1.26(m,4H),1.17(qd,J=12.0,3.2Hz,2H); 13 C NMR(100MHz,MeOD-d4)δ166.8,157.8,146.4,139.5,139.3,136.0,135.1,134.1,132.5,131.1(2C),130.8,130.6,130.4(2C),130.3,1 HRMS calcd for C 35 H 41 N4O2[M+H] + 549.3225, found 549.3221.

[0295] Example 49, Preparation of Compound 49:

[0296]

[0297] Compound 49 was prepared in the same manner as in Example 1, except that morpholine was used instead of 4-methylimidazole.

[0298] Compound 49: 1H NMR (400MHz, DMSO-d6) δ7.49(s,1H),7.47(d,J=7.6Hz,2H),7.40(t,J=7.6Hz,2H),7.32(t,J=7.6Hz,1H),7.17(s,1H),6 .85(s,1H),6.79(s,1H),6.76(s,1H),5.17(s,2H),3.87(t,J=6.4Hz,2H),3.73(t,J=4.4Hz,4H),3.48(d,J=13.6Hz,1H) ,3.41(d,J=13.6Hz,1H),3.11(t,J=4.8Hz,4H),3.06(q,J=4.0Hz,1H),2.99(t,J=6.4Hz,2H),2.74(d,J=10.4Hz,1H),2. 58-2.53(m,1H),2.27(s,3H),2.18-2.07(m,2H),1.82(s,1H),1.75-1.66(m,1H),1.52-1.44(m,1H),1.42-1.31(m,1H); 13 C NMR(100MHz,DMSO-d6)δ163.0,155.2,151.3,144.1,139.1,137.2,131.1,130.9,129.5,128.4(2C),128.0,127.7,127.1 (2C),116.6,113.0,111.5,110.1,69.2,66.1(2C),62.2,56.5,52.7,49.4,48.5(2C),47.0,28.6,27.0,22.3,16.2; HRMS calcd for C 33 H 41 N4O3[M+H] + 541.3174, found 541.3170.

[0299] Example 50, Preparation of Compound 50:

[0300]

[0301] Compound 50 was prepared in the same manner as in Example 1, except that benzimidazole was used instead of 4-methylimidazole.

[0302] Compound 50: 1H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.79(d,J=7.6Hz,1H),7.72(d,J=8.0Hz,1H),7.66(s,1H),7.55(s,1H),7.47(t,J=7.2 Hz,4H),7.40(t,J=7.2Hz,2H),7.37-7.29(m,3H),7.19(s,1H),5.18(s,2H),4.04(t,J=6.4Hz,2H),3.61(d,J=13.6Hz,1H),3 .55(d,J=13.6Hz,1H),3.05(t,J=6.4Hz,2H),2.76(t,J=11.2Hz,2H),2.68(d,J=8.4Hz,,1H),2.28(s,3H),2.02(t,J=10.8Hz ,1H),1.82(t,J=8.8Hz,1H),1.73(d,J=11.2Hz,1H),1.64(d,J=12.8Hz,1H),1.47(d,J=12.0Hz,1H),1.04(d,J=11.6Hz,1H); 13 C NMR(100MHz,DMSO-d6)δ163.3,155.3,144.3,143.9,143.2,141.3,137.2,135.7,133.0,131.4,131.3,129.6,128.5(2C),127.7 ,127.1(2C),124.0,123.6,122.5,120.4,120.0,118.9,110.7,110.2,69.3,61.6,53.2,49.1,47.7,33.0,26.9,23.5,16.2.HRMS calcd forC 36 H 38 N5O2[M+H] + 572.3021, found 572.3016.

[0303] Example 51, Preparation of Compound 51:

[0304]

[0305] Compound 51 was prepared in the same manner as in Example 1, except that indazole was used instead of 4-methylimidazole.

[0306] Compound 51: 1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.92(t,J=7.6Hz,2H),7.75(t,J=2.0Hz,1H),7.60-7.55(m,2H),7.52(t,J=7.6H z,1H),7.48(d,J=7.2Hz,2H),7.40(t,J=7.2Hz,2H),7.35-7.25(m,3H),7.17(s,1H),5.18(s,2H),4.02(t,J=6.4Hz,2 H),3.60(d,J=13.6Hz,1H),3.53(d,J=13.6Hz,1H),3.04(t,J=6.4Hz,2H),2.79(d,J=9.2Hz,1H),2.74-2.63(m,2H),2 .28(s,3H),1.98(t,J=10.0Hz,1H),1.75(t,J=10.0Hz,2H),1.67-1.57(m,1H),1.54-1.40(m,1H),1.03-0.83(m,1H); 13 C NMR(100MHz,DMSO-d6)δ163.3,155.2,143.9,141.0,139.4,138.1,137.2,135.8,131.3,129.6,128.4(2C),127.8,127.7,127 .6,127.1(2C),125.1,122.7,121.8,121.6,119.2,117.7,110.4,110.2,69.3,62.4,61.9,53.2,33.7,26.9,23.8,16.2; HRMS calcd for C 36 H 38 N5O2[M+H] + 572.3021, found 572.3016.

[0307] Example 52, Preparation of Compound 52:

[0308]

[0309] Compound 52 was prepared in the same manner as in Example 1, except that pyrazole was used instead of 4-methylimidazole.

[0310] Compound 52: 1H NMR (400MHz, DMSO-d6) δ8.49(d,J=2.8Hz,1H),7.77-7.73(m,2H),7.66(t,J=1.6Hz,1H),7.51(s,1H),7.46(d,J=7.2Hz, 2H),7.39(t,J=7.2Hz,2H),7.31(t,J=7.2Hz,1H),7.24(d,J=1.6Hz,1H),7.18(s,1H),6.54(t,J=2.0Hz,1H),5.16(s,2H) ,3.96(t,J=6.4Hz,2H),3.54(d,J=13.6Hz,1H),3.48(d,J=13.6Hz,1H),3.49(s,1H),3.02(t,J=6.4Hz,2H),2.79-2.59( m,3H),2.27(s,3H),2.03-1.92(m,1H),1.82-1.67(m,2H),1.66-1.56(m,1H),1.51-1.38(m,1H),1.01(d,J=10.8Hz,1H); 13 C NMR(100MHz,DMSO-d6)δ163.4,155.3,144.2,141.1,140.8,139.8,137.3,131.4,131.4,129.7,128.6(2C),128.0,127.9 ,127.8,127.3(2C),123.3,116.1,114.4,110.2,108.1,69.3,62.0,61.6,53.2,49.3,47.8,33.1,27.0,23.6,16.3; HRMS calcd for C 32 H 36 N5O2[M+H] + 522.2864, found 522.2860.

[0311] Example 53, Preparation of Compound 53:

[0312]

[0313] Compound 53 was prepared in the same manner as in Example 1, except that 1-(2-pyrimidinyl)piperazine was used instead of 4-methylimidazole.

[0314] Compound 53: 1H NMR (400MHz, DMSO-d6) δ8.39(d,J=4.8Hz,2H),7.50(s,1H),7.47(d,J=7.6Hz,2H),7.40(t,J=7.6Hz,2H),7.33(t, J=7.6Hz,1H),7.17(s,1H),6.90(s,1H),6.84(s,1H),6.76(s,1H),6.66(t,J=4.8Hz,1H),5.17(s,2H),3.93-3.83 (m,6H),3.48(d,J=13.6Hz,1H),3.41(d,J=13.6Hz,1H),3.23(t,J=5.2Hz,4H),3.00(t,J=6.4Hz,2H),2.75(d,J=1 0.8Hz,1H),2.56(s,1H),2.28(s,3H),2.20-1.97(m,2H),1.85-1.61(m,2H),1.57-1.41(m,1H),1.38-1.25(m,2H); 13 C NMR(100MHz,DMSO-d6)δ163.0,161.2,158.0(2C),155.2,151.2,144.1,139.2,137.2,131.1,130.9,129.5,128.4(2C),128.0,127.7, HRMS calcd for C 37 H 44 N7O2[M+H] + 618.3551, found 618.3545.

[0315] Example 54, Preparation of Compound 54:

[0316]

[0317] n) Preparation of intermediate N1: Methyl 3,5-dibromobenzoate (3.0 g, 10.21 mmol) was dissolved in dioxane (60 mL), and Pd(OAc)₂ (115 mg, 0.56 mmol), K₂CO₃ (2.12 g, 15.31 mmol), and pinacol 4-chloropyridine-3-boronate (2.69 g, 11.23 mmol) were added sequentially. The mixture was purged with nitrogen and purged three times. The mixture was then reacted at 100 °C for 0.5 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5:1) to give intermediate N1 (1.50 g, 45%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ8.67(s,1H),8.62(d,J=5.6Hz,1H),8.18(t,J=2.0Hz,1H),8 .08(t,J=2.0Hz,1H),8.05(t,J=2.0Hz,1H),7.74(d,J=5.6Hz,1H),3.91(s,3H); HRMS calcd for C 13 H 10 BrClNO2[M+H] + 325.9578, found 325.9575.

[0318] Compound 54 was prepared in the same manner as in Example 1, except that intermediate N1 was used instead of intermediate H1.

[0319] Compound 54: 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.56(d,J=5.2Hz,1H),8.08(s,2H),7.69(d,J=5.2Hz,1H),7.52(s,1H),7.4 9-7.44(m,4H),7.40(t,J=7.2Hz,2H),7.35(s,1H),7.32(t,J=7.2Hz,1H),7.19(s,1H),5.18(s,2H),4.00(t,J=6. 4Hz,2H),3.64(d,J=13.6Hz,1H),3.57(d,J=13.6Hz,1H),3.18(s,1H),3.03(t,J=6.4Hz,2H),2.81(d,J=10.4Hz, 1H),2.57(s,1H),2.28(s,3H),2.24(s,1H),1.84(d,J=11.6Hz,1H),1.73(s,1H),1.56-1.43(m,2H),1.23(s,1H); 13 C NMR(100MHz,DMSO-d6)δ163.2,155.2,151.2,149.8,143.3,141.1,138.8,137.2,135.1,135.0,131.2,129.6,128.4(2C),128.4 ,127.8,127.7,127.1(2C),126.8,125.5,124.9,124.8,110.1,69.3,61.4,55.4,52.5,49.2,46.8,27.6,26.9,22.1,16.2; HRMS calcd for C 34 H 36 ClN4O2[M+H] + 567.2522, found 567.2518.

[0320] Example 55, Preparation of Compound 55:

[0321]

[0322] o) Preparation of intermediate O1: Methyl 3-bromo-5-nitrobenzoate (1.00 g, 3.85 mmol) was dissolved in dioxane (20 mL), followed by the sequential addition of intermediate M1 (1.03 g, 3.85 mmol), Pd(dba)2 (218 mg, 0.38 mmol), Xantphos (223 mg, 0.38 mmol), and Cs2CO3 (1.88 g, 5.77 mmol). Nitrogen gas was introduced and the mixture was purged three times. The mixture was then reacted at 100 °C for 5 h. The mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10:1) to obtain intermediate O1 (1.58 g, 92%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),8.51(s,1H),8.40(s,1H),7.65(s,1H),7.46(d,J=7.2Hz,2H),7.39(t,J=7.2Hz,2H), 7.32(t,J=7.2Hz,1H),7.07(s,1H),5.14(s,2H),4.06(t,J=6.4Hz,2H),3.98(s,3H),3.10(t,J=6.4Hz,2H),2.35(s,3H); 13 C NMR (100MHz, CDCl3) δ164.8,164.6,156.3,148.4,144.5,137.0,133.4,132.1,131.2,130.7,129 .6,128.7(2C),128.0,127.3,127.1(2C),123.8,121.3,110.6,70.1,53.0,49.4,27.6,16.8; HRMS calcd for C 25 H 23 N₂O₆[M+H] + 447.1551, found 447.1547.

[0323] p) Preparation of intermediate P1: Intermediate O1 (1.0 g, 2.24 mmol) was dissolved in EtOH (12 mL) and H2O (2 mL), and Fe powder (625 mg, 11.20 mmol) and NH4Cl (600 mg, 11.20 mmol) were added. The mixture was reacted at 100 °C for 2 h. After the reaction was complete, the mixture was filtered through diatomaceous earth while hot, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate P1 (800 mg, 86%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.52(s,1H),7.50(d,J=7.6Hz,2H),7.43(t,J=7.6Hz,2H),7.35(t,J=7.2Hz,1H),7.20(s,1H),7.11(s,1H),7.10(s,1H),6 .84(d,J=2.0Hz,1H),5.78(s,1H),5.51(d,J=7.2Hz,1H),5.20(s,2H),3. 87(t,J=6.3Hz,2H),3.83(s,3H),3.01(t,J=6.5Hz,2H),2.30(s,3H); HRMS calcd for C 25 H 25 N₂O₄[M+H] + 417.1809, found 417.1805.

[0324] q) Preparation of intermediate Q1: Intermediate P1 (300 mg, 0.72 mmol) was dissolved in dioxane (10 mL), and Pd(OAc)2 (72 mg, 0.07 mmol), K2CO3 (150 mg, 1.08 mmol), and iodobenzene (220 mg, 1.08 mmol) were added. The mixture was reacted at 100 °C for 4 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, extracted with EtOAc (20 mL × 3), washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate Q1 (312 mg, 88%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ7.67(s,1H),7.60(s,1H),7.52(s,1H),7.46(d,J=7.6Hz,2H),7.38(t,J=7.6Hz,2H),7.35(s,1H),7.34-7.28(m,3H),7.13 HRMS calcdfor C 31 H 29 N₂O₄[M+H] + 493.2122, found 493.2119.

[0325] Compound 55 was prepared in the same manner as in Example 1, except that intermediate Q1 was used instead of intermediate 11.

[0326] Compound 55: 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.51(s,1H),7.47(d,J=7.6Hz,2H),7.40(t,J=7.6Hz,2H),7.32(t,J=7.6Hz,1H),7.23(t ,J=8.0Hz,2H),7.16(s,1H),7.09(d,J=8.0Hz,2H),7.00(t,J=2.0Hz,1H),6.92(s,1H),6.82(t,J=7.2Hz,1H),6.71(s,1H),5. 17(s,2H),3.88(t,J=6.4Hz,2H),3.41(d,J=13.6Hz,1H),3.34(d,J=13.6Hz,1H),2.99(t,J=6.4Hz,2H),2.75(d,J=10.4Hz,1H ),2.71-2.60(m,2H),2.27(s,3H),1.93(t,J=10.8Hz,1H),1.77-1.56(m,3H),1.44(q,J=12.0Hz,1H),0.99(q,J=11.2Hz,1H); 13C NMR(100MHz,DMSO-d6)δ163.0,155.2,143.9,143.4,143.2,140.1,137.2,131.1,131.0,129.5(2C),129.2,128.4(2C),128.0,12 7.7,127.1(2C),119.8,116.9(2C),116.5,114.3,112.4,110.1,69.3,62.4,62.1,53.2,49.3,47.8,33.5,27.0,23.7,16.2; HRMS calcd for C 35 H 39 N4O2[M+H] + 547.3068, found 547.3064.

[0327] Example 56, Preparation of Compound 56:

[0328]

[0329] Compound 56 was prepared in the same manner as in Example 55, except that 3-iodopyridine was used instead of iodobenzene.

[0330] Compound 56: 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.23(d,J=6.0Hz,2H),7.53(s,1H),7.49(d,J=7.2Hz,2H),7.42(t,J= 7.2Hz,2H),7.34(t,J=7.2Hz,1H),7.21(s,2H),7.08(s,1H),7.05-7.00(m,3H),5.20(s,2H),3.96(t,J=6. 4Hz,2H),3.58(d,J=13.6Hz,1H),3.50(d,J=13.6Hz,1H),3.19(s,2H),3.03(t,J=6.4Hz,2H),2.83(d,J=11 .6Hz,1H),2.62(s,1H),2.30(m,3H),2.26-2.14(m,2H),2.08-1.69(m,2H),1.60-1.41(m,2H),1.25(s,4H). 13C NMR (100MHz, DMSO-d6) δ163.1,155.2,148.9,144.0,140.1,139.6,138.4,137.2,134.2,131.2,131.2,129.6,129.6,128. 5,127.9,127.7,127.1,119.4,116.2,110.2,109.3,69.3,61.6,55.3,52.6,49.2,46.9,29.0,27.6,26.9,16.2; HRMScalcd for C 34 H 38 N5O2[M+H] + 548.3021, found 548.3021.

[0331] Example 57, Preparation of Compound 57:

[0332]

[0333] r) Preparation of intermediate R1: Intermediate P1 (300 mg, 0.72 mmol) was dissolved in CH2Cl2 (10 mL), NEt3 (150 μL, 1.08 mmol) was added, and finally benzoyl chloride (120 mg, 0.86 mmol) was added. The reaction was carried out at room temperature for 1 h. The reaction was quenched with a small amount of water, extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to obtain intermediate R1 (352 mg, 94%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.59(s,1H),7.51(s,1H),7.46(d,J=7.6Hz,2H),7.38(t,J=7.6Hz,2H),7.35-7.27(m,4H),7.12(d,J=7.6H z,2H),7.03(s,1H),6.98(t,J=7.2Hz,1H),5.13(s,2H),3.95(t,J=6.4Hz,2H),3.88(d,J=1.6Hz,3H),3.03(t,J=6.4Hz,2H),2.33(s,3H); HRMS calcd for C 32 H 29 N₂O₅[M+H] + 521.2071, found 521.2067.

[0334] Compound 57 was prepared in the same manner as in Example 1, except that intermediate R1 was used instead of intermediate 11.

[0335] Compound 57: 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),7.98(d,J=7.6Hz,2H),7.81(s,1H),7.64(s,1H),7.59(t,J=7.2Hz,1H),7.56-7.49(m,3H),7 .48(d,J=7.2Hz,2H),7.40(t,J=7.2Hz,2H),7.32(t,J=7.2Hz,1H),7.29(s,1H),7.18(s,1H),7.05(s,1H),5.18(s,2H),3.91(t,J= 6.4Hz,2H),3.47(d,J=13.6Hz,1H),3.40(d,J=13.6Hz,1H),3.02(t,J=6.4Hz,2H),2.76(d,J=10.4Hz,1H),2.67(t,J=5.2Hz,3H),2 .28(s,3H),2.26(s,1H),1.95(t,J=10.4Hz,1H),1.79-1.67(m,2H),1.62(d,J=12.8Hz,1H),1.53-1.39(m,1H),1.07-0.93(m,1H); 13 C NMR(100MHz,DMSO-d6)δ165.5,163.1,155.2,143.3,139.5,139.2,138.3,137 .2,134.8,131.6,131.1,131.1,129.6,128.8,128.4(2C),128.4(2C),128.1, 127.9,127.7,127.6(2C),127.1(2C),126.8,121.0,118.1,116.2,110.1,69. 3,62.9,62.4,62.2,54.1,53.2,49.3,47.8,45.6,33.5,27.0,23.7,16.2; HRMS calcd for C 32 H 29 N₂O₅[M+H] + 575.3017, found 575.3013.

[0336] Example 58, Preparation of Compound 58:

[0337]

[0338] Compound 58 was prepared in the same manner as in Example 57, except that 3-dimethylaminobenzoyl chloride was used instead of benzoyl chloride.

[0339] Compound 58:; 13 C NMR(100MHz,DMSO-d6)δ166.2,163.2,155.3,150.3,143.4,139.4,138.7,137.3,135.4,131.2,129.7,129.0,128.5(2C),127.9,127.8, HRMS calcd for C 38 H 44 N5O3[M+H] + 618.3439, found 618.3434.

[0340] Example 59, Preparation of Compound 59:

[0341]

[0342] Preparation of intermediate S1: Intermediate P1 (80 mg, 0.18 mmol) was dissolved in CH2Cl2 (10 mL), and furfurylamine (16 μL, mmol) was added. The mixture was reacted at room temperature for 15 min, and then NaBH3CN (58 mg, 0.91 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, a small amount of water was added to quench the reaction. The mixture was extracted with CH2Cl2 (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2 / MeOH = 10:1) to give compound 7 (88 mg, 93%) as a white solid. 1 HNMR(400MHz, CDCl3)δ8.57(s,1H),8.45(d,J=6.0Hz,1H),8.04(d,J=8.0Hz,1H) ,7.62(s,1H),7.60-7.52(m,1H),7.45(d,J=7.6Hz,2H),7.37(t,J=7.6Hz,2H),7. 32(d,J=8.0Hz,2H),7.06(s,1H),7.01(s,1H),6.91(s,1H),5.12(s,2H),4.40(s, 2H),3.89(t,J=6.4Hz,2H),3.86(s,3H),3.00(t,J=6.4Hz,2H),2.32(s,3H); HRMS calcd for C 32 H 21 N₂O₄[M+H]+ 507.2279, found 507.2275.

[0343] Compound 59 was prepared in the same manner as in Example 1, except that intermediate S1 was used instead of intermediate 11.

[0344] Compound 59: 1 H NMR (400MHz, DMSO-d6) δ8.09(s,2H),7.48(s,1H),7.47(d,J=7.2Hz,2H),7.43-7.35(m,4H),7.32(t,J=7.2Hz,3H),7.23(t, J=7.2Hz,1H),7.15(s,1H),6.53(t,J=2.0Hz,1H),6.48(s,1H),6.46(s,1H),6.31(t,J=6.0Hz,1H),5.16(s,2H),4.26(d,J= 6.0Hz,2H),3.80(t,J=6.4Hz,2H),3.39(d,J=13.6Hz,1H),3.31(d,J=13.6Hz,1H),3.12-3.02(m,1H),2.95(t,J=6.4Hz,2H) ,2.77(d,J=9.2Hz,1H),2.53(d,J=6.8Hz,1H),2.27(s,3H),2.09(s,2H),1.85(s,1H),1.71-1.64(m,1H),1.49-1.33(m,2H); 13 C NMR (100MHz, DMSO-d6) δ162.9,155.2,149.0,144.1,140.1,138.7,137.2,131.0,130.8,129.5,128.5(2C),128.3(2C),128.1,127. 7,127.3(2C),127.1(2C),126.7,113.3,110.3,110.1,108.7,69.2,62.2,55.4,52.5,49.4,47.0,46.6,27.8,27.0,22.3,16.2; HRMS calcd forC 36 H 40 N4O2[M+H] + 560.3151, found 560.3157.

[0345] Example 60, Preparation of Compound 60:

[0346]

[0347] Compound 60 was prepared in the same manner as in Example 1, except that methyl 3,5-dibromobenzoate was replaced with 1,3-dibromobenzene.

[0348] Compound 60: 1 H NMR (400MHz, CDCl3) δ7.81(s,1H),7.67(d,J=1.6Hz,1H),7.52-7.44(m,4H),7.38(t,J=7.6Hz,2H),7.32(d,J=7.6Hz,2H),7.2 3(d,J=8.0Hz,1H),7.04(d,J=5.6Hz,2H),5.15(s,2H),4.00(t,J=6.4Hz,2H),3.07(t,J=6.4Hz,2H),2.34(s,3H),2.30(s,3H); 13 C NMR (100MHz, CDCl3) δ164.6,156.3,144.7,139.5,137.9,137.2,134.7,132.8,130.7,130.3,129.5,128 .7(2C),128.0,127.9,127.4(2C),123.4,118.7,118.6,114.9,110.7,70.2,49.7,27.8,16.8,13.7; HRMS calcd for C 27 H 26 N3O2[M+H] + 424.2020, found 424.2017.

[0349] Example 61, Preparation of Compound 61:

[0350]

[0351] Compound 61 was prepared in the same manner as in Example 1, except that 3-chloro-4-methoxybenzaldehyde was used instead of 4-methoxy-3-methylbenzaldehyde.

[0352] Compound 61: 1H NMR (400MHz, DMSO) δ8.15(s,1H),7.59-7.48(m,3H),7.47(s,1H),7.38(t,J=7.6Hz,2H),7.32(d,J=7.6 Hz,2H),7.23(d,J=8.0Hz,1H),7.32-7.19(m,1H),7.08(s,1H),3.97(t,J=6.4Hz,2H),3.60-3.44(m,2H ),3.00(t,J=6.4Hz,2H),2.81(s,1H),2.75(d,J=10.4Hz,1H),2.64(s,1H),2.20(s,3H),2.18(s,3H),2 .06(m,1H),1.87(s,1H),1.79-1.71(m,1H),1.66(d,J=4.8Hz,1H),1.53-1.45(m,1H),1.25(s,1H); calcdfor C 31 H 33 ClN5O2[M+H] + 542.2318, found 542.2314.

[0353] Example 62, Preparation of Compound 62

[0354]

[0355] Compound 62 was prepared in the same manner as in Example 54, except that pinacol phenylboronic acid was used instead of pinacol 4-chloropyridine-3-boronic acid.

[0356] Compound 62: 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.56(d,J=5.2Hz,1H),8.08(s,2H),7.69(d,J=5.2Hz,1H),7.52(s,1H),7.4 9-7.44(m,4H),7.40(t,J=7.2Hz,2H),7.35(s,1H),7.32(t,J=7.2Hz,1H),7.19(s,1H),5.18(s,2H),4.00(t,J=6. 4Hz,2H),3.64(d,J=13.6Hz,1H),3.57(d,J=13.6Hz,1H),3.18(s,1H),3.03(t,J=6.4Hz,2H),2.81(d,J=10.4Hz, 1H),2.57(s,1H),2.28(s,3H),2.24(s,1H),1.84(d,J=11.6Hz,1H),1.73(s,1H),1.56-1.43(m,2H),1.23(s,1H); 13 C NMR(100MHz,DMSO-d6)δ163.2,155.2,151.2,149.8,143.3,141.1,138.8,137.2,135.1,135.0(2C),131.2,129.6,128.4(2C),128.4 ,127.8,127.7,127.1(2C),126.8,125.5,124.9,124.8(2C),110.1,69.3,61.4,55.4,52.5,49.2,46.8,27.6,26.9,22.1,16.2; HRMS calcd for C 35 H 38 N3O2[M+H] + 532.2959, found 532.2954.

[0357] Example 63, Preparation of Compound 63:

[0358]

[0359] Compound 63 was prepared in the same manner as in Example 1, except that 4-methoxyphenylethylamine was used instead of intermediate C1.

[0360] Compound 63: 1H NMR (400MHz, DMSO-d6) δ8.37(s,2H),8.26(s,1H),7.89(d,J=9.2Hz,1H),7.59 (s,1H),7.52(d,J=8.4Hz,2H),7.36(s,1H),6.95(s,2H),4.02(t,J=6.4Hz,2H ),3.84(s,3H),3.66(s,2H),3.12(t,J=6.4Hz,2H),2.84(s,1H),2.63(s,1H), 2.37(s,2H),2.18(s,3H),1.86(s,1H),1.77(s,1H),1.56(s,2H),1.24(s,1H); 13 C NMR(100MHz,DMSO-d6)δ163.2,162.3,144.4,141.3,138.0,137.0,134.8,130.0(2C),123.7,121.8, 117.3,116.0,114.5,113.1,111.9,61.0,55.5,54.9,52.5,48.9,46.5,28.1,27.2,21.7,13.4; HRMS calcd for C 26 H 32 N5O2[M+H] + 446.2551, found 446.2547.

[0361] Example 64, Preparation of Compound 64:

[0362]

[0363] Compound 64 was prepared in the same manner as in Example 1, except that [2-(3,4-dimethoxyphenyl)ethyl]amine was used instead of intermediate C1.

[0364] Compound 64: 1 H NMR (400MHz, DMSO-d6) δ8.37(s,2H),8.26(s,1H),7.89(s,1H),7.59(s,1H),7.52(s,2H),7.36(s,1H),6.95(s,1H),4.02(t,J=6.4Hz,2H),3.81(s ,3H),3.63(s,3H),3.12(t,J=6.4Hz,2H),2.84(s,1H),2.63(s,1H),2.36 (s,2H),2.16(s,3H),1.83(s,1H),1.75(s,1H),1.55(s,2H),1.23(s,1H); 13C NMR(100MHz,DMSO-d6)δ163.2,162.3,144.4,141.3,138.0,137.0,134.8(2C),130.5,123.7,121.8,11 7.5,116.0,114.5,113.7,111.9,61.9,56.6,55.4,54.9,52.1,48.9,46.5,28.1,27.2,21.7,13.4; HRMS calcd forC 27 H 34 N5O3[M+H] + 476.2657, found 476.2653.

[0365] Example 65, Preparation of Compound 65:

[0366]

[0367] Compound 65 was prepared in the same manner as in Example 1, except that intermediate E1 was used instead of intermediate G1.

[0368] Compound 65: 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.51(s,1H),7.32(s,1H),7.16(s,1H),6.92(s,1H),6. 82(s,1H),6.71(s,1H),3.88(t,J=6.4Hz,2H),3.41(d,J=13.6Hz,1H),3.37(s,3H),3.34(d, J=13.6Hz,1H),2.99(t,J=6.4Hz,2H),2.75(d,J=10.4Hz,1H),2.71-2.60(m,2H),2.27(s,3H ),1.93(t,J=10.8Hz,1H),1.77-1.56(m,3H),1.44(q,J=12.0Hz,1H),0.99(q,J=11.2Hz,1H); 13 C NMR(100MHz,DMSO-d6)δ163.0,155.2,143.9,143.4,143.2,140.1,137.2,131.1,131.0,129.5,127.7,1 16.9,116.5,114.3,112.4,110.1,69.3,62.4,62.1,56.1,53.2,49.3,47.8,33.5,27.0,23.7,16.2; HRMS calcd forC 35 H 39 N4O2[M+H] +547.3068, found 547.3064.

[0369] Pharmacological experiments:

[0370] Experimental methods:

[0371] 2.1 Cell lines and culture

[0372] 293T cells were obtained from the National Experimental Cell Resource Sharing Platform. The 293T cells were cultured in Gibco Dulbecco modified Eagle medium (phenol red-free) containing 10% fetal bovine serum and 100 IU / mL penicillin / streptomycin. The cells were cultured at 37°C in a humidified incubator with a 5% (v / v) CO2 atmosphere.

[0373] 2.2 Luciferase Reporting

[0374] 293T cells were transfected with PCSK9-3'UTR-Luciferase plasmid. The cells were treated with 10 μM compound or control and DMSO for 24 hours. The effect of luciferase reporter gene assay on the transcriptional activity of PCSK9-3'UTR was investigated using a luciferase reporter gene assay kit.

[0375] 2.3 Experimental Results:

[0376] Table 1. Transcriptional activity of compounds on PCSK9-3'UTR (mean ± SD, n = 3)

[0377]

[0378]

[0379] *P<0.05, **P<0.01, ***P<0.001, compared with the negative control DMSO

[0380] in conclusion:

[0381] The compounds involved in this invention have novel structures and exhibit certain inhibitory activity against PCSK9. These compounds replace benzaldehyde as a starting material, making the raw materials simple, readily available, and the synthetic route more concise, efficient, and suitable for industrial production. In summary, the compounds involved in this invention are simple to synthesize, low in cost, and possess good PCSK9 inhibitory activity, facilitating the subsequent development of PCSK9 inhibitors.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, X is selected from methylene or carbonyl groups; Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution. R1 is selected from: H, C1-C16 straight-chain or branched alkyl groups, C6-C16 aryl groups, C6-C16 aryl-substituted C1-C16 alkyl groups, C4-C16 heteroaryl-substituted C1-C16 alkyl groups, and C6-C16 aryl methyl ether-substituted C1-C16 alkyl groups; the aryl group is selected from phenyl, naphthyl, anthraceneyl, phenanthryl, and biphenyl; the heteroaryl group is selected from furanyl, thiopheneyl, imidazolyl, pyrroleyl, thiazolyl, and quinolinyl. , pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy, C1-C16 alkoxy, C1-C16 alkyl; R2 is selected from: H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy. R3 is selected from: H, C6-C16 aryl, C3-C16 heteroaryl, C6-C16 aryl-substituted amino, C3-C16 heteroaryl-substituted amino, C6-C16 aryl-substituted C1-C16 alkylamino, C6-C16 arylcarbamate, C3-C16 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, biphenyl; the above heteroaryl group is selected from pyrazolyl, thiophene, imidazolyl, pyrroleyl, thiazolyl, pyridinyl, indazole, carbazole, benzene. The aryl, heteroaryl, and aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and imidazolinyl. These aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C3-C16 heteroaryl ring, and C1-C16 alkyl-substituted amino groups. R4 is selected from: OH, C1-C16 straight-chain or branched alkylamino groups, C6-C16 aryl-substituted C1-C16 alkylamino groups, C3-C16 heteroaryl-substituted C1-C16 alkylamino groups, C3-C16 aliphatic nitrogen heterocycles, C1-C16 straight-chain or branched ester-substituted C1-C16 alkylamino groups, and C1-C16 straight-chain or branched alkoxy-substituted C1-C16 alkylamino groups; the aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, and biphenyl; the heteroaryl group is selected from pyrrole, thiazolyl, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolyl, imidazolinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy-substituted C1-C16 alkyl, hydroxyl-substituted C1-C16 alkyl, and C3-C16 heteroaryl rings.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X is selected from methylene or carbonyl groups; Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution. R1 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C14 aryl, C6-C14 aryl-substituted C1-C8 alkyl, C4-C8 heteroaryl-substituted C1-C8 alkyl, C6-C14 aryl methyl ether-substituted C1-C8 alkyl; the above aryl is selected from phenyl, naphthyl, anthracene, biphenyl; the above heteroaryl is selected from furanyl, thiophene, thiazolyl, quinolinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, NH2, aldehyde, carbamoyl, halogen, CN, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C1-C8 straight-chain or branched alkoxy; R2 is selected from: H, halogen, C1-C8 straight-chain or branched alkyl, C1-C8 straight-chain or branched alkoxy. R3 is selected from: H, C6-C14 aryl, C3-C8 heteroaryl, C6-C14 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C14 aryl-substituted C1-C8 alkylamino, C6-C14 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl and biphenyl; the above heteroaryl group is selected from pyrazolyl, imidazolyl, pyrrolithyl, pyridinyl, indazole, carbazole, benzimidazolyl, indolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, halogen, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C3-C8 heteroaryl ring, and C1-C8 alkyl-substituted amino. R4 is selected from: OH, C1-C8 straight-chain or branched alkylamino groups, C6-C14 aryl-substituted C1-C8 alkylamino groups, C3-C8 heteroaryl-substituted C1-C8 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C8 straight-chain or branched ester-substituted C1-C8 alkylamino groups, and C1-C8 straight-chain or branched alkoxy-substituted C1-C8 alkylamino groups; the aryl group is selected from phenyl, naphthyl, and biphenyl; the heteroaryl group is selected from pyrrole, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, COOH, NH2, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C8 straight-chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy-substituted C1-C8 alkyl, hydroxyl-substituted C1-C8 alkyl, and C3-C14 heteroaryl rings.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, X is selected from methylene or carbonyl groups; Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution. R1 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy; R2 is selected from: H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 straight-chain or branched alkoxy; R3 is selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino; R4 is selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, and C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the aryl group is selected from phenyl; the heteroaryl group is selected from pyrrole. Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IA. R5 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy; R6 is selected from: H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 straight-chain or branched alkoxy. R7 is selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino; R8 is selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, and C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the aryl group is selected from phenyl; the heteroaryl group is selected from pyrrole. Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in IA1. R 51 Selected from: H, C1-C8 straight-chain or branched alkyl groups, C6-C12 aryl-substituted C1-C4 alkyl groups, C4-C8 heteroaryl-substituted C1-C4 alkyl groups, C6-C12 aryl methyl ether-substituted C1-C4 alkyl groups, wherein the aryl group is selected from phenyl or biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyridinyl, benzofuranyl, or benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogens, CF3, C1-C4 straight-chain or branched alkyl groups, or C1-C4 alkoxy groups; R 61 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups; R 71 Selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, the substituents being independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino; R 81 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the above aryl group is selected from phenyl; the above heteroaryl group is selected from pyrroleyl, Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in IA2. R 52 Selected from: H, halogen, CF3, C1-C8 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups; R 62 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups; R 72 Selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, the substituents being independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino; R 82 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the above aryl group is selected from phenyl; the above heteroaryl group is selected from pyrroleyl, Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

7. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IB. R9 is selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl group is selected from phenyl or biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogen, CF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy; R 10 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups; R 11 Selected from: H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, C3-C8 aliphatic nitrogen heterocycle; the above aryl is phenyl; the above heteroaryl is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, pyrimidinyl; the above aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, the substituents being independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, C1-C4 alkyl-substituted amino; R 12 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, C3-C8 heteroaryl-substituted C1-C4 alkylamino groups, C3-C8 aliphatic nitrogen heterocycles, C1-C4 straight-chain or branched ester-substituted C1-C4 alkylamino groups, C1-C4 straight-chain or branched alkoxy-substituted C1-C4 alkylamino groups; the above aryl group is selected from phenyl; the above heteroaryl group is selected from pyrroleyl, Pyrimidinyl, furanyl; the above-mentioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, NH2, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkyl substituted with C1-C4 alkoxy, C1-C4 alkyl substituted with hydroxyl, and C3-C8 heteroaryl rings.

8. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in formula IC. R 13 Selected from: H, C1-C8 straight-chain or branched alkyl, C6-C12 aryl, C6-C12 aryl-substituted C1-C4 alkyl, C4-C8 heteroaryl-substituted C1-C4 alkyl, C6-C12 aryl methyl ether-substituted C1-C4 alkyl; the above aryl groups are selected from phenyl and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, halogens, CF3, C1-C4 straight-chain or branched alkyl, and C1-C4 alkoxy groups; R 14 Selected from: H, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups; R 15 The aryl group is selected from H, C6-C8 aryl, C3-C8 heteroaryl, C6-C8 aryl-substituted amino, C3-C8 heteroaryl-substituted amino, C6-C8 aryl-substituted C1-C4 alkylamino, C6-C8 arylcarbamate, and C3-C8 aliphatic nitrogen heterocycle; the aryl group is phenyl; the heteroaryl group is selected from pyrazolyl, imidazolyl, pyridinyl, indazolyl, benzimidazolyl, and pyrimidinyl; the aliphatic nitrogen heterocycle is selected from piperidinyl, morpholinyl, and piperazine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, halogen, C1-C4 straight-chain or branched alkyl, C3-C8 heteroaryl ring, and C1-C4 alkyl-substituted amino. R 16 Selected from: OH, C1-C4 straight-chain or branched alkylamino groups, C6-C8 aryl-substituted C1-C4 alkylamino groups, and 1-(2-hydroxyethyl)piperazine.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from 10. A pharmaceutical composition, characterized in that... The compound or pharmaceutically acceptable salt of any one of claims 1-8, and a pharmaceutically acceptable carrier or excipient, containing a pharmaceutically effective amount.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 in the preparation of a PCAK9 inhibitor medicament.

12. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, in, X is selected from methylene or carbonyl groups; Y is selected from H, methylene, and carbonyl. When Y is H, there is no R4 substitution. R1 is selected from: H, C1-C16 straight-chain or branched alkyl groups, C6-C16 aryl groups, C6-C16 aryl-substituted C1-C16 alkyl groups, C4-C16 heteroaryl-substituted C1-C16 alkyl groups, and C6-C16 aryl methyl ether-substituted C1-C16 alkyl groups; the aryl group is selected from phenyl, naphthyl, anthraceneyl, phenanthryl, and biphenyl; the heteroaryl group is selected from furanyl, thiopheneyl, imidazolyl, pyrroleyl, thiazolyl, and quinolinyl. , pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy, C1-C16 alkoxy, C1-C16 alkyl; R2 is selected from: H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 straight-chain or branched alkoxy. R3 is selected from: H, C6-C16 aryl, C3-C16 heteroaryl, C6-C16 aryl-substituted amino, C3-C16 heteroaryl-substituted amino, C6-C16 aryl-substituted C1-C16 alkylamino, C6-C16 arylcarbamate, C3-C16 aliphatic nitrogen heterocycle; the above aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, biphenyl; the above heteroaryl group is selected from pyrazolyl, thiophene, imidazolyl, pyrroleyl, thiazolyl, pyridinyl, indazole, carbazole, benzene. The aryl, heteroaryl, and aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolidinyl, and imidazolinyl. These aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C3-C16 heteroaryl ring, and C1-C16 alkyl-substituted amino groups. R4 is selected from: OH, C1-C16 straight-chain or branched alkylamino groups, C6-C16 aryl-substituted C1-C16 alkylamino groups, C3-C16 heteroaryl-substituted C1-C16 alkylamino groups, C3-C16 aliphatic nitrogen heterocycles, C1-C16 straight-chain or branched ester-substituted C1-C16 alkylamino groups, and C1-C16 straight-chain or branched alkoxy-substituted C1-C16 alkylamino groups; the aryl group is selected from phenyl, naphthyl, anthracene, phenanthrene, and biphenyl; the heteroaryl group is selected from pyrrole, thiazolyl, pyridinyl, pyrimidinyl, and furanyl. The aforementioned aliphatic nitrogen heterocycles are selected from piperidinyl, morpholinyl, piperazine, pyrrolyl, imidazolinyl, and cyclohexylimine; these aryl, heteroaryl, and aliphatic nitrogen heterocycles may have one or more substituents, which are independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy-substituted C1-C16 alkyl, hydroxyl-substituted C1-C16 alkyl, and C3-C16 heteroaryl rings; Step 1: Using different benzaldehydes A1 as starting materials, add them to nitromethane to obtain intermediate B1; Step 2: Intermediate B1 undergoes a reduction reaction to obtain intermediate C1; Step 3: Intermediate C1 is reacted with isobutyl chloroformate under alkaline conditions to prepare intermediate D1; Step 4: Intermediate D1 is reacted with Friedel-Crafts to obtain intermediate E1; Step 5: Intermediate E1 is demethylated under BBr3 conditions to prepare intermediate F1; Step 6: Intermediate F1 undergoes a coupling reaction to obtain intermediate G1; Step 7: Intermediate G1 and intermediate H1 undergo a Buchwald–Hartwig coupling reaction to obtain intermediate I1; Step 8: Intermediate I1 undergoes a reduction reaction or hydrolysis reaction to obtain intermediate J1; Step 9: Intermediate J1 is introduced into R4 to obtain the target product shown in general formula (Ⅰ).

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