N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses an N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound as well as a preparation method and an application of the N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound. The N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound prepared by the preparation method disclosed by the invention can play a dual role in inhibiting the activity of JNK2 kinase and interfering the combination of JNK2 and upstream protein MKK7. Experiments show that the N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound can inhibit the activity of JNK2 kinase, the inhibitory activity IC50 of the preferable compound 1l to the JNK2 is 0.99 M, and the N-phenyl-6-oxo-1, 6-dihydropyridine-3-formamide compound can inhibit the combination of the JNK2 and upstream protein MKK7. In addition, the compound 1l also shows a good treatment effect on mouse type 2 diabetic nephropathy (T2DM) induced by high fat diet and streptozotocin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, its preparation method, and its application. Background Technology

[0002] The mitogen-activated protein kinase (MAPK) signaling pathway is a crucial bridge for converting extracellular signals into intracellular responses. MAPK plays a key role in the regulation of immune responses and is closely associated with a variety of diseases, including acute lung injury. The MAPK signaling cascade consists of at least three kinases (MAP3K, MAPKK, and MAPK), and this phosphorylation cascade efficiently amplifies signal transduction. c-Jun N-terminal kinase 2 (JNK2), as a key node in the MAPK pathway, enhances cellular signal transduction. After binding to and being phosphorylated and activated by upstream kinases MKK7 or MKK4, JNK2 phosphorylates c-Jun, a core component of transcription factor activator protein-1 (AP-1).

[0003] Although several JNK2 inhibitors have been reported, some of which have entered clinical trials for the treatment of autoimmune diseases, pulmonary fibrosis, and cancer, none have yet received market approval. This situation is mainly attributed to the following challenges: First, most inhibitors lack sufficient selectivity for JNK subtypes (JNK1, JNK2, and JNK3), leading to potential off-target effects; second, the high conservation of kinase catalytic sites makes the development of highly selective inhibitors extremely challenging; and third, some candidate compounds have shown limited efficacy or unacceptable toxicity in clinical trials.

[0004] Currently reported JNK2 inhibitors are all ATP-competitive kinase inhibitors, inhibiting the activity of the kinase by binding to its ATP-binding pocket. However, this mechanism of action, due to its highly conserved nature, often leads to selectivity issues. Notably, no inhibitors have been reported that can inhibit the binding of JNK2 to upstream or downstream proteins. Novel inhibitors, such as protein-protein interaction inhibitors, may offer higher subtype selectivity and better safety profiles by blocking the interaction of JNK2 with specific scaffold proteins or upstream kinases, thus representing a new direction for research.

[0005] Multiple studies have shown that the JNK2 pathway is abnormally activated in animal models of kidney injury, including those induced by hyperglycemia. Inhibiting JNK function through pharmacological intervention has a significant protective effect on the kidneys of diabetic animals, indicating that JNK2 is a potential therapeutic target for diabetic nephropathy. Developing inhibitors with novel skeletal structures and mechanisms of action to provide safe and effective treatments for clinical use is an urgent and meaningful research topic. Future research should focus on: using structural biology techniques to resolve the complex structures of JNK2 and its ligands to guide rational drug design; these innovative strategies are expected to drive breakthroughs in the field of JNK2 inhibitor research and provide new strategies for the treatment of diabetic nephropathy. Summary of the Invention

[0006] The purpose of this invention is to provide an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, its preparation method and application. This compound can inhibit the kinase activity of JNK2 and inhibit the binding of JNK2 to the upstream protein MKK7, and has significant anti-inflammatory activity. It can be used to prepare drugs for treating diabetic nephropathy.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, which is a compound with the structure shown in Formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof: ; Formula I R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl; R2 is one of hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, p-methoxybenzyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-aldehyde benzyl, p-methoxybenzyl, p-chlorobenzyl, acryloyl, 2-methylacryloyl, 3-methyl-2-butenoyl, and 2-butenoyl.

[0008] Preferably, the following compounds or their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are used: Compound 1a: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1b: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1c: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1d: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-propyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1e: 1-Benzyl-N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1f: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(cyclohexylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1g: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(2-(dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1h: N-(4-((7-hydroxy-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1i: N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1j: N-(4-((6-ethoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1k: N-(4-((6-propoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1l: N-(4-((6-isopropoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1m: N-(4-((6-methoxy-7-((4-methylbenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1n: N-(4-((7-((4-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1o: N-(4-((7-((2-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1p: N-(4-((7-(((3-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1q: N-(4-((7-((4-formylbenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1r: N-(4-((6-methoxy-7-((4-methoxybenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1S: N-(4-((6-methoxy-7-((4-chlorobenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1t: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester; Compound 1u: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester of methacrylate; Compound 1v: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester of 3-methylbut-2-enoic acid; Compound 1w: (E)-But-2-enoic acid 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbamoyl)phenoxy]quinoline-7-yl ester.

[0009] This invention also provides a method for preparing N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds, the synthetic route of which is shown in the figure below. Figure 1 As shown, it includes the following steps: (1) 7-benzyloxy-4-chloro-6-methoxyquinoline was reacted with p-nitrophenol in chlorobenzene solution. After the reaction was completed, the reaction mixture was poured into pre-cooled petroleum ether and filtered to obtain product A1. (2) Dissolve product A1 in dimethylformamide, add tetrahydroxydiboron and bipyridine to react, add water after the reaction is complete, filter to obtain product A2; (3) Dissolve product A2 in dimethylformamide, add pyridone-3-carboxylic acid compound, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (HATU) and diisopropylethylamine (DIPEA) to react, and after the reaction is completed, add water to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is benzyl; (4) Dissolve the compound prepared in step (3) in ethanol, add palladium on carbon, and react under hydrogen to obtain N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is hydrogen. (5) Dissolve the compound prepared in step (4) in dimethylformamide, add potassium carbonate and haloalkanes to react, and after the reaction is completed, add water to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is one of methyl, ethyl, propyl, isopropyl, benzyl, p-methoxybenzyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-aldehyde benzyl, p-methoxybenzyl, and p-chlorobenzyl; (6) Dissolve the compound prepared in step (4) in dimethylformamide, add triethylamine and acyl chloride compound to react, and add water after the reaction to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is one of acryloyl, 2-methacryloyl, 3-methyl-2-butenoyl, and 2-butenoyl.

[0010] Preferably, in step (1), the molar ratio of 7-benzyloxy-4-chloro-6-methoxyquinoline to p-nitrophenol is 1:1~5; the reaction temperature is 100~150℃; and the reaction time is 6~12h.

[0011] Preferably, in step (2), the molar ratio of product A1 to tetrahydroxydiboron and bipyridine is 1:2~5:0.1~1; the reaction temperature is 0~40℃; and the reaction time is 1~5h.

[0012] Preferably, in step (3), the molar ratio of product A2, pyridone-3-carboxylic acid compound, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, and diisopropylethylamine is 1:1~2.5:1~3:2~5; the reaction temperature is 0~50℃; and the reaction time is 1~12h.

[0013] Preferably, the mass ratio of the compound to palladium on carbon in step (4) is 1:0.01~0.1; the reaction temperature is 0~90℃; and the reaction time is 1~12h.

[0014] Preferably, the molar ratio of the compound, halohydrocarbon compound, and potassium carbonate in step (5) is 1:1~2.5:1~3; the reaction temperature is 0~100℃; and the reaction time is 1~12h.

[0015] Preferably, the molar ratio of the compound, acyl chloride compound, and triethylamine in step (6) is 1:1~2.5:1~3; the reaction temperature is 0~30℃; and the reaction time is 1~12h.

[0016] The present invention also provides the use of an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound or an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound prepared by the above preparation method in the preparation of a drug for treating diabetic nephropathy.

[0017] The present invention also provides a pharmaceutical formulation comprising an active ingredient and pharmaceutical excipients; the active ingredient comprising one of the above-mentioned N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds or an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound prepared by the above-mentioned preparation method; the pharmaceutical formulation is one of the following: injection, tablet, capsule, aerosol, suppository, film, drop pill, ointment, controlled-release agent, sustained-release agent, or nano-formulation.

[0018] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: The N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds prepared in this invention exhibit a dual effect of inhibiting JNK2 kinase activity and interfering with the binding of JNK2 to the upstream protein MKK7. Experiments show that the above-mentioned N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds can inhibit JNK2 kinase activity. The preferred compound 11 has an IC50 of 0.99 M for JNK2 inhibition and can also inhibit the binding of JNK2 to the upstream protein MKK7. Furthermore, compound 11 also shows good therapeutic effects on type 2 diabetic nephropathy (T2DM) induced by a high-fat diet and streptozotocin in mice. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0020] Figure 1 This is a synthetic route diagram for the N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds of the present invention; Figure 2 The results show the affinity screening of N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds with JNK2. Figure 3 The results of the interaction study between compound 1l and JNK2 in Example 14 are shown. Among them, A is the response value and time change curve of compound 1l and JNK2 at different concentrations in the SPR experiment, B is the thermal stability experiment of compound 1l on JNK2 protein in the cell thermal displacement experiment, C is the change curve of JNK2 protein level and incubation temperature in the thermal displacement experiment, and D is a schematic diagram of the docking of compound 1l and JNK2. Figure 4 Example 14 shows the inhibitory activity of compound 11 on JNK2 kinase and its interference with the MKK7-JNK2 interaction; where A is the inhibition rate curve of compound 11 on JNK2 kinase activity at different concentrations, and B is the result of CO-IP experiment verifying the interference of compound 11 on the interaction between JNK2 and MKK7 proteins. Figure 5 The figure shows the therapeutic effect of compound 11 of Example 14 on a mouse model of type 2 diabetic nephropathy induced by a high-fat diet and streptozotocin. In the figure, A is the blood glucose change curve of mice in different treatment groups over time, B is the statistical graph of serum creatinine content of mice in different groups, C is the statistical graph of urine nitrogen content of mice in different groups, D is the H&E staining image of representative kidney tissue sections of mice in different treatment groups, E is the PAS staining image of representative kidney tissue sections of mice in different treatment groups, and the table in the figure shows the statistical results of serum creatinine and urine nitrogen content of mice in different treatment groups. Detailed Implementation

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] Example 1: Preparation of 7-benzyloxy-6-methoxy-4-(4-nitrophenoxy)quinoline (A1): 7-Benzyloxy-4-chloro-6-methoxyquinoline (10 g, 33.4 mmol) was added to a 100 mL two-necked flask, followed by the addition of anhydrous chlorobenzene (40 mL) to dissolve it. Then, p-nitrophenol (11.6 g, 83.5 mmol) was added, and the mixture was heated to 130 °C and stirred for 12 h. The reaction was then stopped. The reaction solution was cooled to room temperature and poured into 10 times its volume of petroleum ether, resulting in the precipitation of a yellow solid product. The product was filtered, and the filter cake was dissolved in 200 mL of dichloromethane and washed three times with 50 mL of 1 M sodium hydroxide solution. The organic phase was concentrated under reduced pressure and dried under vacuum to obtain a yellow solid A1 (11.4 g, 85%). 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J =5.2 Hz, 1H), 8.39 – 8.32 (m, 2H), 7.57 – 7.52 (m, 3H), 7.46 – 7.40 (m, 3H),7.37 (d, J = 7.3 Hz, 1H), 7.32 – 7.27 (m, 2H), 6.71 (d, J = 5.2 Hz, 1H), 5.37(s, 2H), 4.03 (s, 3H). Example 2: Synthesis of 4-(4-aminophenoxy)-7-benzyloxy-6-methoxyquinoline (A2): Add A1 (8 g, 20 mmol) to a 100 mL two-necked flask, then add anhydrous DMF (30 mL) to dissolve it. Cool the solution to 0 °C in an ice-water bath, then add tetrahydroxydiboron (4.48 g, 50 mmol) and bipyridine (312 mg, 2 mmol). Stir the reaction for 2 h, then stop the reaction. Quench with water (100 mL), and extract three times with 100 mL of ethyl acetate each time. Combine the organic phases and wash twice with 50 mL of saturated brine each time. Dry the mixture with magnesium sulfate and concentrate under reduced pressure to obtain a pale yellow solid product A2 (6.4 g, 86%). 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J= 5.4 Hz, 1H), 7.63 (s, 1H),7.58 – 7.51 (m, 3H), 7.42 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.05– 6.96 (m, 2H), 6.83 – 6.72 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H), 5.36 (s, 2H), 4.08 (s, 3H). Example 3: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (1a): Add A2 (100 mg, 0.27 mmol) to a 10 mL reaction tube, then add anhydrous DMF (5 mL) to dissolve it, followed by 6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.2 equivalents, 0.32 mmol) and DIPEA (74 mmol). The mixture of 0.54 mmol L and HATU (153 mg, 0.41 mmol) was stirred for 6 h, and the reaction was stopped. The mixture was quenched with water (20 mL) and extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and washed twice with 50 mL of saturated brine each time. After drying with magnesium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product. After purification by column chromatography, a white solid compound 1a (130 mg, 95%) was obtained. 1 H NMR (400 MHz, CDCl3) δ9.09 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.84 – 7.70(m, 2H), 7.57 (s, 1H), 7.54 – 7.49 (m, 2H), 7.46 (s, 1H), 7.38 (s, 1H), 7.21(d, J = 8.9 Hz, 2H), 7.04 (s, 1H), 6.47 (d, J = 5.1 Hz, 1H), 5.31 (s, 2H), 4.03 (s, 3H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.59, 160.33, 159.19,151.99, 151.05, 149.98, 148.75, 146.72, 137.89, 136.17, 134.53, 130.13,129.64, 128.70(2C), 128.16, 127.52(2C), 121.82(2C), 121.79(2C), 116.24,109.46, 103.45, 99.70, 70.75, 56.25, 40.75. MS (ESI, +ve) m / z (M+H) + calcdfor C 29 H 25 N4O5 509.2. Found 509.2. HPLC purity > 96%. Example 4: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1b) Referring to Example 3, compound 1b was obtained as a white solid (16 mg, 85%) from 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid. mp = 237.8 – 238.6 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.02 (dd, J =9.5, 2.7 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.63 – 7.50 (m, 4H), 7.49 – 7.34(m, 3H), 7.29 (d, J = 8.6 Hz, 2H), 6.56 – 6.41 (m, 2H), 5.33 (s, 2H), 3.97 (s, 3H), 3.56 (s, 3H). 13C NMR (100 MHz, DMSO) δ 163.09, 162.33, 160.56,152.02, 150.05, 149.97, 149.29, 146.61, 143.30, 138.57, 137.10, 136.99,129.03(2C), 128.56, 128.46(2C), 122.41(2C), 121.83(2C), 118.41, 115.80,113.03, 109.61, 103.70, 99.82, 70.42, 56.29, 37.93. MS (ESI, +ve) m / z (M+H) + calcd for C 30 H 26 N3O5 508.2, found 508.4. HPLC purity > 99%. Example 5: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1c) Referring to Example 3, compound 1c was obtained as a white solid (110 mg, 79%) from 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid. mp = 97.0 – 97.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.13 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.00 (dd, J =9.5, 2.7 Hz, 1H), 7.90 – 7.80 (m, 2H), 7.58 – 7.50 (m, 4H), 7.45 (t, J = 7.4Hz, 2H), 7.42 – 7.34 (m, 1H), 7.32 – 7.25 (m, 2H), 6.50 (d, J = 4.6 Hz, 1H), 6.49 (s, 1H), 5.33 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).13 C NMR (100 MHz, CDCl3) δ 162.83, 162.32, 160.93, 152.10,150.65, 150.01, 148.60, 146.45, 141.04, 137.28, 135.99, 135.83, 128.75(2C),128.27, 127.56(2C), 122.54(2C), 121.63(2C), 119.35, 116.29, 114.18, 109.09,103.43, 99.85, 70.84, 56.24, 45.82, 14.64. MS (ESI, +ve) m / z (M+H) + calcd forC 31 H 28 N3O5 522.2, found 522.2. HPLC purity > 99%. Example 6: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1-propyl-1,6-dihydropyridine-3-carboxamide (1d) Referring to Example 3, compound 1d was obtained as a white solid (115 mg, 80%) using 1-propyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a starting material. mp = 113.7 – 114.5 °C. 1 H NMR (400 MHz, Chloroform- d ) δ9.28 (s, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 9.5, 2.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 7.49 (d, J = 7.0Hz, 2H), 7.44 (s, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.34 – 7.26 (m, 1H), 7.19 –7.08 (m, 2H), 6.49 (dd, J= 13.7, 7.4 Hz, 2H), 5.29 (s, 2H), 4.05 (s, 3H), 3.90 (q, J = 7.5, 6.0 Hz, 2H), 1.74 (q, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) δ 163.06, 161.82, 160.55, 152.02, 150.05,150.00, 149.28, 146.60, 142.45, 138.44, 137.04, 136.99, 129.03(2C), 128.55,128.47(2C), 122.51(2C), 121.82(2C), 118.91, 115.80, 113.15, 109.60, 103.70,99.82, 70.41, 56.28, 51.28, 22.52, 11.33. MS (ESI, +ve) m / z (M+H) + calcd forC 32 H 30 N3O5 536.2, found 536.2. HPLC purity > 99%. Example 7: Synthesis of 1-benzyl-N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (1e) Referring to Example 3, compound 1e was obtained as a white solid (120 mg, 77%) from 1-benzyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid. mp = 102.1 – 102.8 °C. 1 H NMR (400 MHz, Chloroform- d ) δ9.29 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H), 7.90 (dd, J = 9.5, 2.6 Hz, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.59 (s, 1H), 7.54 – 7.42 (m,3H), 7.37 (t, J = 7.4 Hz, 2H), 7.34 – 7.20 (m, 6H), 7.13 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 9.5 Hz, 1H), 6.44 (d, J = 5.3 Hz, 1H), 5.28 (s, 2H), 5.09 (s, 2H), 4.04 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) δ 162.92, 161.82, 160.45,151.97, 150.08, 150.02, 149.36, 146.75, 142.65, 138.75, 137.32, 137.01,136.95, 129.14(2C), 129.02(2C), 128.54, 128.46(2C), 128.22(2C), 122.58(2C),121.80(2C), 119.20, 115.80, 113.62, 109.72, 103.71, 99.80, 70.40, 56.27, 52.50. MS (ESI, +ve) m / z (M+H) + calcd for C 36 H 30 N3O5 584.2, found 584.2. HPLC purity > 96%. Example 8: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(cyclohexylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (1f) Referring to Example 3, compound 1f was obtained as a white solid (100 mg, 64%) from 1-cyclohexylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid. mp = 104.9 – 105.8 °C. 1 H NMR (400 MHz, CDCl3) δ9.14 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.20 (d, J= 2.6 Hz, 1H), 7.94 (dd, J = 9.5, 2.6 Hz, 1H), 7.83 – 7.75 (m, 2H), 7.60 (s, 1H), 7.51 (d, J = 7.0 Hz,2H), 7.46 (s, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 7.3 Hz, 1H), 7.24 –7.13 (m, 2H), 6.53 (d, J = 9.5 Hz, 1H), 6.48 (d, J = 5.3 Hz, 1H), 5.31 (d, J = 2.3 Hz, 2H), 4.06 (s, 3H), 3.77 (d, J = 7.3 Hz, 2H), 1.81 (ddp, J = 11.2,7.3, 3.7 Hz, 1H), 1.76 – 1.66 (m, 4H), 1.65 – 1.58 (m, 2H), 1.30 – 1.28 (m,1H), 1.19 – 1.15 (m, 2H), 0.99 – 0.89 (m, 1H). 13 C NMR (100 MHz, DMSO) δ162.99, 162.00, 160.46, 151.98, 150.04, 149.34, 146.74, 142.75, 138.33,137.01, 136.98, 129.02(2C), 128.54, 128.46(2C), 122.59(2C), 121.78(2C),118.89, 115.81, 112.86, 109.71, 103.70, 99.80, 70.40, 56.27, 55.29, 37.11,30.31(2C), 26.39, 25.68(2C). MS (ESI, +ve) m / z (M+H) + calcd for C 36 H 36 N3O5590.3, found 590.3. HPLC purity > 96%. Example 9: Synthesis of N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(2-(dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (1 g) Referring to Example 3, using N,N-dimethylaminoethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a starting material, 1 g of the compound was obtained as a white solid (100 mg, 45%). mp = 104.9 – 105.8 °C 1 H NMR (400 MHz, Chloroform- d ) δ 8.46 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.4 Hz,2H), 7.43 – 7.27 (m, 4H), 7.21 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 5.4 Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H), 3.00 (s, 12H). 13 C NMR(100 MHz, CDCl3) δ 162.70, 161.84, 160.85, 151.91, 150.43, 149.89, 148.90,146.71, 144.17, 141.98, 136.28, 136.02, 128.73(2C), 128.14, 127.52(2C),122.13(2C), 121.62(2C), 121.36, 116.29, 109.55, 107.08, 103.43, 99.81, 70.76,56.25, 38.66, 38.59. MS (ESI, +ve) m / z (M+Na) + calcd for C 34 H 34 N4NaO5 601.2, found 600.6. HPLC purity > 98%. Example 10: Synthesis of N-(4-((7-hydroxy-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1h) Under nitrogen protection, compound 1b (228 mg, 0.4 mmol) was added to a 25 mL three-necked flask, followed by dissolution in anhydrous ethanol (10 mL). Palladium on carbon (10%, 20 mg) was then added. The gas in the reaction flask was purged with hydrogen three times, and a hydrogen balloon was placed in the atmosphere. The mixture was heated to 60 °C and stirred for 6 h. After the reaction was complete, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain a pale green solid product 1 h (126 mg, 77%). mp = 263.5 – 263.9 °C. 1 H NMR (400 MHz, DMSO-) d 6) δ 10.17 (s, 1H), 8.58 (d, J = 2.6 Hz, 1H), 8.46 (d, J =5.4 Hz, 1H), 8.01 (dd, J = 9.5, 2.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.54(s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.7 Hz, 2H), 6.49 (d, J = 9.5 Hz, 1H), 6.45 (d, J = 5.5 Hz, 1H), 3.96 (s, 3H), 3.55 (s, 3H). 13 C NMR (100 MHz, DMSO)δ 162.62, 161.86, 160.63, 151.39, 149.39, 148.01, 145.57, 142.82, 138.12,136.69, 121.94(2C), 121.35(2C), 117.93, 114.65, 112.55, 109.96, 102.47,99.49, 55.78, 37.45. MS (ESI, +ve) m / z (M+H) + calcd for C 23 H 20 N3O5 418.1, found418.2. HPLC purity > 95%. Example 11: Synthesis of N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1i) Compound 1h (83 mg, 0.2 mmol) was added to a 10 mL reaction tube, followed by dissolution in anhydrous DMF (4 mL). Potassium carbonate (41 mg, 0.3 mmol) and methyl iodide (15 µL, 0.24 mmol) were then added, and the mixture was stirred for 12 h. After the reaction was complete, 10 mL of water was added to quench the reaction, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a white solid product 1i (126 mg, 77%). mp = 263.5 – 263.9 ℃. 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 8.58 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.4 Hz, 1H), 8.01 (dd, J = 9.5, 2.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.7Hz, 2H), 6.49 (d, J = 9.5 Hz, 1H), 6.45 (d, J = 5.5 Hz, 1H), 3.96 (s, 3H), 3.55 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 162.62, 161.86, 160.63, 151.39,149.39, 148.01, 145.57, 142.82, 138.12, 136.69, 121.94(2C), 121.35(2C),117.93, 114.65, 112.55, 109.96, 102.47, 99.49, 55.78, 37.45. MS (ESI, +ve) m / z (M+H) + calcd for C 23 H 20 N3O5 418.1, found 418.2. HPLC purity > 95%. Example 12: N Synthesis of -(4-((6-ethoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1j) Referring to Example 11, compound 1j was obtained as a white solid (50 mg, 50%) from bromoethane. mp = 244.5 – 245.0 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 8.68 (s, 1H), 8.48 (d, J =5.3 Hz, 1H), 8.30 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.75 (d, J = 8.3 Hz,2H), 7.57 (s, 1H), 7.42 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 9.4Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 4.06 (s, 3H), 3.62 (s, 3H), 1.58 (t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.83,162.54, 160.79, 152.37, 150.96, 149.85, 148.62, 146.78, 142.21, 136.86,135.33, 122.47(2C), 121.68(2C), 119.31, 116.00, 113.61, 108.26, 103.36,99.58, 64.54, 56.17, 38.37, 14.54. MS (ESI, +ve) m / z (M+H) + calcd forC 25 H 24 N3O5 446.2, found 446.2. HPLC purity > 99%. Example 13: Synthesis of N-(4-((6-propoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1k) Referring to Example 11, compound 1K was obtained as a white solid (66 mg, 72%) from n-propyl bromide. mp = 254.8 – 255.5 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 8.93 (s, 1H), 8.48 (d, J =5.4 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.94 (dd, J = 9.6, 2.4 Hz, 1H), 7.79(d, J = 8.5 Hz, 2H), 7.58 (s, 1H), 7.43 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 9.5 Hz, 1H), 6.49 (d, J = 5.3 Hz, 1H), 4.15 (t, J = 6.8 Hz, 2H), 4.05 (s, 3H), 3.62 (s, 3H), 1.98 (h, J = 7.21 Hz, 2H) 1.11 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.86, 162.61, 161.02, 152.73, 150.79,150.05, 148.24, 146.41, 142.24, 137.10, 135.54, 122.52(2C), 121.67(2C),119.23, 115.97, 113.68, 107.96, 103.28, 99.62, 70.54, 56.25, 38.39, 31.69,29.72, 22.18, 10.47. MS (ESI, +ve) m / z (M+H) + calcd for C 26 H 26 N3O5 460.2, found460.2. HPLC purity > 96%. Example 14: Synthesis of N-(4-((6-isopropoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1l) Referring to Example 11, compound 1L was obtained as a white solid (71 mg, 77%) from isopropyl bromide. mp = 250.1 – 250.8 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 8.82 (s, 1H), 8.38 (d, J =5.4 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 9.5, 2.6 Hz, 1H), 7.67(d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.32 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 9.5 Hz, 1H), 6.38 (d, J = 5.3 Hz, 1H), 4.69 (hept, J = 6.0 Hz,1H), 3.94 (s, 3H), 3.51 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 162.94, 162.66, 160.94, 151.51, 150.89, 150.49, 148.50, 146.60,142.18, 137.24, 135.51, 122.53(2C), 121.692C), 119.25, 115.91, 113.82,109.31, 103.33, 99.84, 71.24, 56.28, 38.42, 21.80(2C). HRMS (ESI, +ve) m / z (M+H) + calcd for C 26 H 26 N3O5 460.1867, found 460.1866. HPLC purity > 99%. Example 15: Synthesis of N-(4-((6-methoxy-7-((4-methylbenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1m) Referring to Example 11, compound 1m was obtained as a white solid (89 mg, 86%) from p-methylbenzyl bromide. mp = 142.4 – 143.5 °C. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.57 – 8.34 (m,1H), 8.30 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 9.5, 2.6 Hz, 1H), 7.78 (d, J =8.5 Hz, 2H), 7.59 (s, 1H), 7.48 (s, 1H), 7.38 (d, J = 7.7 Hz, 2H), 7.23 –7.13 (m, 4H), 6.53 (d, J = 9.5 Hz, 1H), 6.48 (d, J = 5.3 Hz, 1H), 5.26 (s,2H), 4.05 (s, 3H), 3.57 (s, 3H), 2.34 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ162.85, 162.64, 161.13, 152.34, 150.62, 150.15, 148.19, 146.07, 142.11,138.10, 137.27, 135.73, 132.86, 129.43(2C), 127.70(2C), 122.47(2C), 121.63(2C), 119.16, 116.22, 113.70, 108.74, 103.40, 99.81, 70.87, 56.25, 38.31,21.25. MS (ESI, +ve) m / z (M+H) + calcd for C 31 H 28 N3O5 522.2, found 522.2. HPLC purity > 97%. Example 16: Synthesis of N-(4-((7-(((4-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1n) Referring to Example 11, compound 1n was obtained as a white solid (73 mg, 70%) from 4-fluorobenzyl bromide. mp = 142.4 – 143.5 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 (d, J = 2.7 Hz, 1H), 8.50(d, J = 5.3 Hz, 1H), 8.02 (dd, J = 9.5, 2.7 Hz, 1H), 7.87 (dd, J = 9.1, 2.4Hz, 2H), 7.64 – 7.58 (m, 2H), 7.57 (s, 1H), 7.53 (s, 1H), 7.33 – 7.25 (m,4H), 6.55 – 6.48 (m, 2H), 3.97 (s, 3H), 3.56 (s, 3H). 13 C NMR (100 MHz, DMSO)δ163.07, 162.31, 162.40(d, J = 244.0 Hz, 2C), 160.45, 151.85, 149.97, 149.39,146.76, 143.28, 138.55, 137.08, 133.25(d, J = 3.0 Hz, 1C), 130.73(d, J = 8.3Hz, 2C), 122.40(2C), 121.82(2C), 118.40, 115.84(d, J = 21.4 Hz, 2C), 115.82,113.03, 109.76, 103.68, 99.81, 69.67, 56.25, 55.41, 37.93. MS (ESI, +ve) m / z (M+H) + calcd for C 30 H 25 FN3O5 526.2, found 526.2. HPLC purity > 96%. Example 17: Synthesis of N-(4-((7-((2-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1o) Referring to Example 11, compound 1o was obtained as a white solid (69 mg, 66%) from 2-fluorobenzyl bromide. mp = 123.9 – 124.5 °C 1 H NMR (400 MHz, Chloroform- d δ 8.70 (s, 1H), 8.48 (d, J =5.3 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.90 (dd, J = 9.4, 2.6 Hz, 1H), 7.76(d, J = 8.5 Hz, 2H), 7.61 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.25 – 7.16 (m, 3H), 7.12 (t, J = 9.2 Hz, 1H), 6.57 (d, J = 9.5 Hz, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.38 (s, 2H), 4.07 (s, 3H), 3.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.83, 162.54, 160.87, 160.58(d, J =247.2 Hz, 1C) 151.91, 150.83, 149.97, 148.66, 146.44, 142.17, 136.89, 135.41,130.06(d, J = 8.1 Hz, 1C), 129.75(d, J = 3.8 Hz, 1C), 124.43(d, J = 3.6 Hz, 1C), 123.23(d, J= 14.0 Hz, 1C), 122.46(2C), 121.69(2C), 119.32, 116.42,115.54(d, J = 21.0 Hz, 1C), 113.58, 109.08, 103.52, 99.92, 64.62(d, J = 4.0Hz, 1C), 56.27, 38.37. MS (ESI, +ve) m / z (M+H) + calcd for C 30 H 25 FN3O5 526.2,found 526.2. HPLC purity > 97%. Example 18: Synthesis of N-(4-((7-(((3-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1p) Referring to Example 11, compound 1p was obtained as a white solid (81 mg, 77%) from 3-fluorobenzyl bromide. mp = 174.6 – 174.8 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 8.55 (d, J = 2.6Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.01 (dd, J = 9.4, 2.6 Hz, 1H), 7.93 –7.82 (m, 2H), 7.57 (s, 1H), 7.54 – 7.46 (m, 2H), 7.42 – 7.34 (m, 2H), 7.32 –7.25 (m, 2H), 7.25 – 7.16 (m, 1H), 6.51 (d, J = 3.3 Hz, 1H), 6.49 (s, 1H), 5.35 (s, 2H), 3.98 (s, 3H), 3.56 (s, 3H). 13 C NMR (100 MHz, DMSO) δ163.08,162.72(d, J= 243.8 Hz, 1C), 162.33, 160.53, 151.76, 149.98, 149.35, 146.61,143.25, 139.96(d, J = 7.5 Hz, 1C), 138.55, 137.09, 131.11(d, J = 8.3 Hz, 1C),124.22, 124.19, 122.43(2C), 121.79(2C), 118.40, 115.94, 115.26(d, J = 21.0Hz, 1C), 114.90(d, J = 21.7 Hz, 1C), 113.04, 109.75, 103.74, 99.92, 69.53,56.32(d, J = 8.0 Hz, 1C), 37.94. MS (ESI, +ve) m / z (M+H) + calcd for C 30 H 25 FN3O5526.2, found 526.2. HPLC purity > 97%. Example 19: Synthesis of N-(4-((7-(((4-formylbenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1q) Referring to Example 11, compound 1q was obtained as a white solid (57 mg, 53%) from 4-formylbenzyl bromide. mp = 151.3 – 151.7 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 10.05 (s, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.07 – 7.96 (m, 3H), 7.90 – 7.82 (m, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.51 (s, 1H), 7.29 (d, J= 9.0 Hz, 2H), 6.53 – 6.47 (m, 2H), 5.47 (s, 2H), 3.99 (s, 3H), 3.56 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 193.32, 163.09, 162.31, 160.46,151.64, 149.96, 149.49, 146.71, 143.97, 143.31, 138.56, 137.10, 136.27,130.28(2C), 128.47(2C), 122.40(2C), 121.85(2C), 118.41, 115.94, 113.02,109.99, 103.75, 99.94, 69.68, 56.36, 37.93. MS (ESI, +ve) m / z (M+H) + calcdfor C 31 H 26 N3O6 526.2, found 536.2. HPLC purity > 97%. Example 20: Synthesis of N-(4-((6-methoxy-7-((4-methoxybenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1r) Referring to Example 11, compound 1r was obtained as a white solid (56 mg, 53%) from 4-methoxybenzyl bromide. mp = 130.4 – 131.2 °C 1 H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.01 (dd, J = 9.5, 2.6 Hz, 1H), 7.95– 7.80 (m, 2H), 7.53 (d, J = 10.9 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.36 –7.23 (m, 2H), 7.00 (d, J= 8.5 Hz, 2H), 6.58 – 6.45 (m, 2H), 5.23 (s, 2H), 3.95 (s, 3H), 3.79 (s, 3H), 3.56 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 163.09,162.33, 160.58, 159.69, 152.11, 150.07, 149.95, 149.20, 146.57, 143.29,138.57, 137.10, 130.36(2C), 128.80, 122.41(2C), 121.82(2C), 118.41, 115.71,114.40(2C), 113.03, 109.46, 103.65, 99.74, 70.24, 56.23, 55.63, 37.94. MS(ESI, +ve) m / z (M+H) + calcd for C 31 H 27 N3O6 538.2, found 538.4. HPLC purity >95%. Example 21: Synthesis of N-(4-((6-methoxy-7-((4-chlorobenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (1s) Referring to Example 11, compound 1s was obtained as a white solid (74 mg, 68%) from 4-chlorobenzyl bromide. mp = 133.6 – 133.9 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 8.55 (d, J = 2.7Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.01 (dd, J = 9.5, 2.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.63 – 7.41 (m, 6H), 7.29 (d, J = 8.6 Hz, 2H), 6.59 – 6.40 (m,2H), 5.32 (s, 2H), 3.97 (s, 3H), 3.56 (s, 3H). 13C NMR (100 MHz, DMSO) δ163.08, 162.33, 160.47, 151.75, 149.96, 149.40, 146.69, 143.26, 138.56,137.07, 136.08, 133.13, MS (ESI,+ve) m / z (M+H) + calcd for C 30 H 25 ClN3O5 542.1, found 542.2. HPLC purity > 98%. Example 22: Synthesis of 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamate)phenoxy]quinoline-7-yl ester (1t) Add the compound (83 mg, 0.2 mmol) to a 10 mL reaction tube for 1 h, then add DMF (4 mL) to dissolve it. After dissolution, add TEA (55 mL). L (0.4 mmol) and acryloyl chloride (0.22 mmol). The reaction was carried out at room temperature for 12 h, then quenched with water (10 mL), and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH, v / v ratio 10:1) to give compound 1t as a white solid (80 mg, 85%). mp = 113.0 – 113.7 ℃. 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.02 (dd, J = 9.5, 2.7Hz, 1H), 7.93 – 7.86 (m, 2H), 7.84 (s, 1H), 7.75 (s, 1H), 7.38 – 7.30 (m,2H), 6.67 – 6.58 (m, 2H), 6.56 – 6.43 (m, 2H), 6.24 (dd,J = 10.2, 1.5 Hz,1H), 3.97 (s, 3H), 3.56 (s, 3H). 13 C NMR (100 MHz, DMSO) δ 163.98, 163.13,162.34, 161.00, 150.85, 150.10, 149.67, 145.03, 143.67, 143.31, 138.58,137.35, 134.89, 127.57, 122.45(2C), 121.97(2C), 120.06, 118.42, 113.04,104.90, 101.27, 56.81, 37.95. MS (ESI, +ve) m / z (M+H) + calcd for C 26 H 22 N3O6472.1, found 472.2. HPLC purity > 99%. Example 23: Synthesis of 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamate)phenoxy]quinoline-7-yl ester (1u) of methacrylate Referring to Example 22, compound 1u was obtained as a white solid (87 mg, 90%) from 2-methacryloyl chloride. mp = 120.2 – 120.7 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.02 (dd, J = 9.5, 2.7 Hz, 1H), 7.89(d, J = 8.6 Hz, 2H), 7.81 (s, 1H), 7.74 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 5.2 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H), 6.38 (s, 1H), 5.98 (s,1H), 3.97 (s, 3H), 3.56 (s, 3H), 2.07 (s, 3H).13 C NMR (100 MHz, DMSO- d 6) δ165.21, 163.12, 162.35, 160.86, 150.88, 150.15, 149.70, 145.27, 143.97,143.28, 138.58, 137.30, 135.22, 128.93, 122.46(2C), 122.17, 121.96(2C),119.98, 118.42, 113.05, 104.83, 101.18, 56.80, 37.96, 18.58. HRMS (ESI, +ve) m / z (M+H) + calcd for C 27 H 24 N3O6 486.1660, found 486.1658. HPLC purity > 95%. Example 24: Synthesis of 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamate)phenoxy]quinoline-7-yl ester (1v) of 3-methylbut-2-enoic acid Referring to Example 22, compound 1v was obtained as a white solid (84 mg, 84%) from 3-methyl-2-butenoyl chloride. mp = 141.1 – 141.6 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 9.5, 2.7 Hz,1H), 7.92 – 7.81 (m, 2H), 7.73 (d, J = 9.8 Hz, 2H), 7.40 – 7.23 (m, 2H), 6.61(d, J = 5.2 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H), 6.16 – 6.00 (m, 1H), 3.96 (s, 3H), 3.56 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6) δ163.88, 163.12, 162.36, 161.66, 160.73, 151.13, 150.10, 149.82, 145.47,143.78, 143.24, 138.58, 137.22, 122.48(2C), 122.30, 121.90(2C), 119.87,118.43, 114.63, 113.08, 104.83, 101.01, 56.70, 37.93, 27.57, 20.76. MS (ESI,+ve) m / z (M+H) + calcd for C 28 H 25 N3O6 500.2, found 500.2. HPLC purity > 98%. Example 25: Synthesis of (E)-but-2-enoic acid 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamate)phenoxy]quinoline-7-yl ester (1w) Following the synthesis of compound 1t in Example 22, compound 1w was obtained as a white solid (88 mg, 91%) from 2-butenoyl chloride as a starting material. mp = 125.4 – 125.9 °C 1 H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 9.6, 2.7Hz, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.73 (s, 1H), 7.32 (d, J =8.6 Hz, 2H), 7.21 (dd, J = 15.4, 7.1 Hz, 1H), 6.62 (d, J = 5.2 Hz, 1H), 6.50(d, J = 9.4 Hz, 1H), 6.23 (dd, J= 15.6, 2.1 Hz, 1H), 3.96 (s, 3H), 3.55 (s,3H), 2.05 – 1.92 (m, 3H). 13 C NMR (100 MHz, DMSO) δ 164.01, 163.13, 162.37,160.87, 151.01, 150.09, 149.77, 149.14, 145.22, 143.85, 143.25, 138.59,137.26, 122.49(2C), 122.08, 121.91(2C), 121.41, 119.96, 118.44, 113.08,104.88, 101.15, 56.74, 37.93, 18.51. MS (ESI, +ve) m / z (M+H) + calcd forC 27 H 24 N3O6 486.2, found 486.2. HPLC purity > 96%. Example 26: N Affinity screening of phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds with JNK2 This invention evaluates the surface plasmon resonance (SPR) of the surface. N The affinity of phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds for JNK2 was investigated. The specific experimental method was as follows: JNK2 protein (dissolved in acetate buffer at pH 7.4) was activated with 40 mM EDC and 10 mM NHS aqueous solution and then immobilized on a sensor chip (CM5). A PBS buffer containing 0.1% sodium dodecyl sulfate, 5% DMSO, and 0.05% Tween-20 was used as the run buffer, and the compound sample concentration was prepared to be 10... M. Buffer solution containing the test sample flows simultaneously through the reference cell and the experimental cell. The machine outputs the difference between the two corresponding values. The experimental results are acquired and processed using GE Healthcare's Biacore 4000 evaluation software. The experimental results are as follows: Figure 2 As shown: Compounds 1a, 1d, 1e, 1f, 1g, 1i, 1k, 1l, 1t, 1u, 1v, and 1w prepared in the examples have a strong affinity for JNK2.

[0023] Example 27: Validation of the target of the compound in the example

[0024] Taking compound 1l as an example, this invention tested the binding constant Kd of the compound with JNK2 using SPR. The experimental method was as follows: Compound samples of different concentrations were prepared using PBS buffer containing 0.1% sodium dodecyl sulfate, 5% DMSO, and 0.05% Tween-20 as the running buffer. Buffers containing different concentrations of the test samples flowed simultaneously through the reference cell and the experimental cell. The machine provided the difference between the two corresponding values. The experimental results were collected and processed using GE Healthcare's Biacore 4000 evaluation software. The results are as follows... Figure 3 As shown in Figure A, in the SPR experiment, the corresponding value RU increases with increasing compound concentration. The binding constant between compound 1l and JNK2 was calculated to be 8.16 using evaluation software. 10 -5 M.

[0025] This invention also verified through a cell thermal displacement experiment that compound 11 of the example could bind to JNK2 intracellularly, enhancing its thermal stability. The experimental method was as follows: RAW cells were added to a DMSO solution containing compound 11 or a blank DMSO control. After culturing the cells for 4 hours, they were washed twice with PBS. The cells were then resuspended in PBS solution and evenly divided into 6 aliquots. The cell suspension was heated in a gradient manner for 3 minutes, cooled to room temperature, and centrifuged. The supernatant was discarded, and loading buffer was added. The cells were heated at 100°C for 5 minutes, and the protein content was analyzed by Western blotting. The results are as follows: Figure 3 B, Figure 3 As shown in C, compound 1l in 10 M concentration can significantly increase the thermal stability of JNK2.

[0026] This invention also predicted the binding mode of compound 1l with JNK2 (PDB ID: 3NPC) using Auto-Dock, and the results are as follows: Figure 3 As shown in D, the carbonyl oxygen and amino hydrogen on the amide bond in compound 1l form hydrogen bonds with Asp169 and Glu73 of JNK2, respectively, thereby enhancing the binding stability. The positively charged quinoline ring in compound 1l not only forms a salt bridge with Asp169 but also undergoes π-π stacking and cation-π interactions with His149. The methoxy and isopropyl groups located at the pocket entrance form hydrogen bonds with Arg73 and hydrophobic interactions with ARG192, respectively.

[0027] Example 28: Inhibitory effect of the compound on JNK2 kinase activity and interference with JNK2-MKK7 protein interaction

[0028] Taking compound 1l as an example, the present invention evaluated NThe inhibitory effect of phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds on JNK2 kinase activity. The experimental method was as follows: 10 μL of phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds were added to a 96-well plate. L contains a JNK2 kinase solution, followed by the addition of a DMSO solution containing the test compound and 10 L of buffer containing enzyme substrate and ATP, incubated at 25°C for 1 hour, then 20 L of buffer solution was added. The reaction was terminated with L detection solution, and the reaction was allowed to proceed at room temperature for 1 hour. The inhibition rate was calculated by determining the ratio of 665nm / 615nm, and the results are as follows: Figure 4 As shown in Figure A, compound 11 exhibits moderate inhibitory activity against JNK2, with an IC50 of 990 nM. This invention verifies the effect of compound 11 on the JNK2-MKK7 protein interaction using a CO-IP experiment. The experimental method is as follows: the test compound is added to cell lysis buffer and incubated at room temperature for 2 h. Primary antibody is then added and incubated for another 2 h. Finally, protein A / G beads are added, and the mixture is incubated at 0 °C for 12 h. After centrifugation, the supernatant is discarded, the precipitate is washed with PBS, centrifuged again, the supernatant is discarded, 1x loading buffer is added, and the mixture is heated at 100 °C for 5 min. Protein content is then detected by Western blotting. The results are as follows: Figure 4 As shown in B: at 40 M and 60 Under M conditions, compound 1l can inhibit the binding of MKK7 to JNK2.

[0029] Example 29: Therapeutic effect of the compound in the example on LPS-induced acute lung injury in mice.

[0030] Taking compound 1l as an example, the present invention evaluated NThe therapeutic effect of phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds on type 2 diabetic nephropathy induced by a high-fat diet plus streptozotocin in mice was investigated. The specific experimental method was as follows: Male C57BL / 6 mice (weighing 18-22g) were acclimatized for 7 days under standard conditions (12h light / dark cycle, temperature 22℃) with free access to food and water. After 4 weeks of high-fat diet, a single intraperitoneal injection of STZ (100mg / kg, 10mL / kg citrate buffer, pH 4.5) was administered. The control group was fed a normal diet and injected with citrate buffer. One week after STZ administration, blood glucose was measured via the tail vein using a glucometer. Mice with fasting blood glucose levels higher than 16.7mmol / L were classified as T2DM. The T2DM group maintained a high-fat diet throughout the treatment period. Eight weeks after the establishment of type 2 diabetes mellitus (T2DM) (four weeks after STZ administration), diabetic animals were randomly divided into four groups: T2DM group, T2DM + irbesartan group, T2DM + 1l (5 mg / kg, low dose) group, and T2DM + 1l (10 mg / kg, high dose) group; six mice in each group. Compound 1l (5 mg / kg, 10 mg / kg) was administered by gavage every two days for 10 weeks. Blood glucose levels were recorded weekly. After 10 weeks of treatment, mice were sacrificed under sodium pentobarbital anesthesia, and blood and kidney tissue were collected for further analysis. Experimental results are as follows: Figure 5 As shown in Figure A, blood glucose levels in mice significantly increased after administration of a high-fat diet and STZ. Neither the positive control drug irbesartan nor compound 11 had a significant hypoglycemic effect, and compound 11 alone had no effect on blood glucose levels in normal mice. Figure 5 B, Figure 5 As shown in Figure C, diabetic nephropathy model mice exhibited significant renal insufficiency, manifested by elevated serum creatinine and blood urea nitrogen levels. Compound 11 and the positive control drug irbesartan significantly reduced serum creatinine and blood urea nitrogen levels in mice, indicating that compound 11 can alleviate renal insufficiency in diabetic nephropathy mice, and at high doses, it showed superior therapeutic effects compared to irbesartan. Figure 5 D, Figure 5 As shown in the H&E and PAS staining results of mouse kidney tissue, mice with diabetic nephropathy induced by a high-fat diet and streptozotocin showed glomerular hypertrophy, basement membrane thickening, and matrix proliferation. The above symptoms were significantly improved in the group treated with compound 11.

[0031] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, characterized in that, Compounds with structures as shown in Formula I, or their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs: ； Formula I R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl; R2 is one of hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, p-methoxybenzyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-aldehyde benzyl, p-methoxybenzyl, p-chlorobenzyl, acryloyl, 2-methylacryloyl, 3-methyl-2-butenoyl, and 2-butenoyl.

2. The N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 1, characterized in that, The following compounds or their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs: Compound 1a: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1b: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1c: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1d: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-propyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1e: 1-Benzyl-N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1f: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(cyclohexylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1g: N-(4-((7-(benzyloxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-(2-(dimethylamino)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1h: N-(4-((7-hydroxy-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1i: N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1j: N-(4-((6-ethoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1k: N-(4-((6-propoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1l: N-(4-((6-isopropoxy-7-hydroxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1m: N-(4-((6-methoxy-7-((4-methylbenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1n: N-(4-((7-((4-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1o: N-(4-((7-((2-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1p: N-(4-((7-(((3-fluorobenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1q: N-(4-((7-((4-formylbenzyl)oxy)-6-methoxyquinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1r: N-(4-((6-methoxy-7-((4-methoxybenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1S: N-(4-((6-methoxy-7-((4-chlorobenzyl)oxy)quinoline-4-yl)oxy)phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; Compound 1t: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester; Compound 1u: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester of methacrylate; Compound 1v: 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-carbamoyl)phenoxy]quinoline-7-yl ester of 3-methylbut-2-enoic acid; Compound 1w: (E)-But-2-enoic acid 6-methoxy-4-[4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbamoyl)phenoxy]quinoline-7-yl ester.

3. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 1 or 2, characterized in that, Includes the following steps: (1) 7-Benzyloxy-4-chloro-6-methoxyquinoline was reacted with p-nitrophenol in chlorobenzene solution. After the reaction was completed, the reaction mixture was poured into pre-cooled petroleum ether and filtered to obtain product A1. (2) Dissolve product A1 in dimethylformamide, add tetrahydroxydiboron and bipyridine to react, add water after the reaction is complete, filter to obtain product A2; (3) Dissolve product A2 in dimethylformamide, add pyridone-3-carboxylic acid compound, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea and diisopropylethylamine to react, and after the reaction is completed, add water to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is benzyl; (4) Dissolve the compound prepared in step (3) in ethanol, add palladium on carbon, and react under hydrogen to obtain N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is hydrogen. (5) Dissolve the compound prepared in step (4) in dimethylformamide, add potassium carbonate and haloalkanes to react, and after the reaction is completed, add water to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compounds, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is one of methyl, ethyl, propyl, isopropyl, p-methoxybenzyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-aldehyde benzyl, p-methoxybenzyl, and p-chlorobenzyl; (6) Dissolve the compound prepared in step (4) in dimethylformamide, add triethylamine and acyl chloride compound to react, and add water after the reaction to precipitate N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound, wherein R1 is one of hydrogen, methyl, ethyl, propyl, benzyl, cyclohexylmethylene, and dimethylaminoethyl, and R2 is one of acryloyl, 2-methacryloyl, 3-methyl-2-butenoyl, and 2-butenoyl.

4. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 3, characterized in that, In step (1), the molar ratio of 7-benzyloxy-4-chloro-6-methoxyquinoline to p-nitrophenol is 1:1~5; the reaction temperature is 100~150℃; and the reaction time is 6~12h. In step (2), the molar ratio of product A1 to tetrahydroxydiboron and bipyridine is 1:2~5:0.1~1; the reaction temperature is 0~40℃; and the reaction time is 1~5h.

5. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 4, characterized in that, In step (3), the molar ratio of product A2, pyridone-3-carboxylic acid compound, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, and diisopropylethylamine is 1:1~2.5:1~3:2~5; the reaction temperature is 0~50℃; and the reaction time is 1~12h.

6. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 5, characterized in that, In step (4), the mass ratio of the compound to palladium on carbon is 1:0.01~0.1; the reaction temperature is 0~90℃; and the reaction time is 1~12h.

7. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 6, characterized in that, In step (5), the molar ratio of the compound, the halohydrocarbon compound, and potassium carbonate is 1:1~2.5:1~3; the reaction temperature is 0~100℃; and the reaction time is 1~12h.

8. The method for preparing an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound according to claim 7, characterized in that, In step (6), the molar ratio of the compound, acyl chloride compound, and triethylamine is 1:1~2.5:1~3; the reaction temperature is 0~30℃; and the reaction time is 1~12h.

9. The use of an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound as described in claim 1 or 2, or an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound prepared by the preparation method described in any one of claims 3 to 8, in the preparation of a medicament for treating diabetic nephropathy.

10. A pharmaceutical preparation, characterized in that, The formulation includes an active ingredient and pharmaceutical excipients; the active ingredient includes an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound as described in claim 1 or 2, or an N-phenyl-6-oxo-1,6-dihydropyridine-3-carboxamide compound prepared by the preparation method described in any one of claims 3 to 8; the pharmaceutical preparation is one of the following: injection, tablet, capsule, aerosol, suppository, film, drop pill, ointment, controlled-release agent, sustained-release agent, or nano-formulation.

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