3-naphthylthiophene derivatives, processes for their preparation and use thereof

Abstract

This invention discloses 3-naphthiophene derivatives, their preparation methods, and applications, relating to the field of pharmaceutical technology. Specifically, it relates to 3-naphthiophene derivatives of general formula I and their optically active or racemic mixtures, diastereomer mixtures, and the application of these compounds as SIRT2 inhibitors in the treatment of myocardial fibrosis. This invention also relates to these compounds and their pharmaceutically acceptable salts, pharmaceutical compositions with these compounds as active ingredients, and pharmaceutically acceptable excipients and / or diluents for the above substances. This invention further relates to dosage forms of these compounds containing at least one compound of this structural formula or its salt, in the following dosage forms: tablets, coated tablets, capsules, injectable solutions or ampoules, suppositories, patches, inhalable powder formulations, suspensions, emulsions, and ointments.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to 3-naphthiophene derivatives and their preparation methods, as well as their application in the preparation of anti-myocardial fibrosis drugs. Background Technology

[0002] SIRTs are a class of highly conserved deacetylases from bacteria to humans. There are seven recognized members in the human SIRT family (SIRT1-7), all of which possess highly conserved NAD+. + The SIRT family of proteins, with its binding and catalytic domains, mediates reversible covalent modification of lysine residues in histone or non-histone sites. Based on their core domain sequences, they are classified into four classes: SIRT1–3 (class I), SIRT4 (class II), SIRT5 (class III), and SIRT6 and SIRT7 (class IV). Each SIRT protein has a distinct cellular target and localization. Current accepted research indicates that mammalian SIRTs are primarily localized in subcellular regions by two nuclear proteins (SIRT1 and SIRT6), one cytoplasmic protein (SIRT2), three mitochondrial proteins (SIRT3, SIRT4, and SIRT5), and one nucleolar protein (SIRT7). Each SIRT protein is located in a different subcellular region, and this rich localization means that the SIRT family can provide a variety of cellular functions. The distribution of SIRTs in different subcellular compartments interacts with various transcription factors and participates in the regulation of different metabolic processes, such as regulating apoptosis, glucose homeostasis, stress response, and insulin secretion dysregulation. Some SIRTs can migrate depending on cell or tissue type, developmental stage, metabolic state, and certain stress conditions. Furthermore, they play crucial roles in mitochondrial formation, DNA repair, inflammation development, and autophagy. Sirtuin 2 (SIRT2) is an NAD-dependent... + SIRT2 is a member of the SIRTs protein family of deacetylases, primarily located in the cytoplasm, but it can also be localized in the nucleus during mitosis. Due to its abundant distribution and broad catalytic activity in vivo, SIRT2 is expressed in various organs and tissues, particularly prominent in metabolically related tissues such as the brain, heart, liver, pancreas, kidneys, and adipose tissue. SIRT2 plays a crucial role in normal physiological and pathological processes, involving gluconeogenesis, cardiomyopathy, cell cycle regulation, apoptosis, stress response, autophagy, inflammatory responses, and maintaining genomic stability. Numerous studies have shown that overexpression or dysregulation of SIRT2 is considered a major factor contributing to various human diseases, closely related to the occurrence of cancer, cardiovascular disease, and neurodegenerative diseases. Research indicates that SIRT2 exhibits deacetylation activity on various substrates, and during deacetylation, it interacts with NAD+. +It can couple to produce nicotinamide and O-acetyl-ADP-ribose, and can also catalyze the hydrolysis of long-chain fatty acids in certain substrates. Therefore, SIRT2 can participate in regulating various life activities such as cell cycle, metabolism, aging, inflammatory response, immune response, and gene transcription. SIRT2 has been shown to play an important role in the occurrence and development of various diseases, and its small molecule inhibitors are considered potential interventions for treating related diseases. The discovery of selective SIRT2 inhibitors has attracted widespread attention in recent years, highlighting their potential therapeutic value in drug discovery. To date, a large number of SIRT2 inhibitors have been reported, which can be broadly classified into four categories based on differences in their inhibitory mechanisms of action, namely NAD... + Competitive inhibitors, substrate-competitive inhibitors, substrates and NAD + Inhibitors with dual competition, and inhibitors that bind to selective active sites.

[0003] Myocardial fibrosis is a common pathological process in the end-stage progression of cardiovascular disease and a major cause of poor prognosis in heart failure. Studies show that cardiovascular disease is a leading cause of death worldwide, causing nearly 18 million deaths annually. In recent years, the incidence and mortality rates of cardiovascular disease have been increasing year by year, seriously endangering people's lives and health. Therefore, delaying myocardial fibrosis is crucial for the prognosis of heart disease. The inducing factors of myocardial fibrosis are numerous and complex, and the pathogenesis is not fully understood; therefore, there are currently no drugs specifically for treating myocardial fibrosis. Currently, the clinically supported drugs for delaying the progression of myocardial fibrosis are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), but they are not specifically targeted at the development of fibrosis. Pirfenidone is an FDA-approved drug for the treatment of idiopathic pulmonary fibrosis (IPF), and its effects are believed to be modulated by reducing oxidative stress and TGF-β expression. In animal models of cardiac fibrosis, pirfenidone showed a reduction in atrial fibrosis, limited post-infarction fibrosis expansion, and reduced hypertension-induced cardiac fibrosis. In a clinical trial, 47 patients were randomly assigned to receive either pirfenidone or a placebo. Pirfenidone showed a 1.2% reduction in cardiac fibrosis, but did not improve diastolic function, indicating limited therapeutic efficacy. Therefore, a deeper understanding of the regulatory mechanisms of myocardial fibrosis and the identification of therapeutic targets to develop effective drugs for treating cardiac fibrosis is of significant clinical importance for slowing the progression of heart disease and improving cardiac function.

[0004] TGF-β1 is a crucial mediator of fibroblast activation and plays a key role in the development and progression of cardiac fibrosis. Under the stimulation of various pathological factors, excessive TGF-β1 secretion can drive excessive proliferation of fibroblasts and their transformation into α-SMA-positive myofibroblasts (MFs). MFs are the main source of extracellular matrix (ECM), and excessive ECM deposition alters the original normal structure of the heart, leading to ventricular remodeling, myocardial wall stiffening, decreased compliance, and cardiac chamber enlargement, ultimately severely impairing cardiac function. The canonical Smad signaling pathway mediated by TGF-β1 and its receptor activates fibroblasts and promotes ECM production, playing a crucial role in organ fibrosis. Activated TGF-β1 can induce phosphorylation of its downstream signaling molecules Smad2 and Smad3, subsequently forming an oligomeric complex that enters the nucleus and binds to transcription factors, regulating the expression of fibrosis-related proteins such as α-SMA and CoL-1A1. Therefore, preventing myocardial fibrosis by interfering with the TGF-β / Smad signaling pathway is an important way to slow down myocardial fibrosis.

[0005] Studies have shown that SIRT2 is involved in the process of fibrosis, including fibrosis of the lungs, kidneys, and liver. For example, in pulmonary fibrosis, inhibiting SIRT2 can alleviate the activation of lung fibroblasts through the Smad2 / 3 pathway, thereby improving pulmonary fibrosis. In liver and kidney fibrosis, SIRT2 exhibits a role in promoting fibrosis; blocking SIRT2 can improve liver and kidney fibrosis by inhibiting the activation of hepatic stellate cells and renal interstitial fibroblasts. In the heart, studies have shown that cardiac injury leads to increased SIRT2 expression, and treatment with the SIRT2-specific inhibitor AGK2 improves myocardial remodeling and hypertrophy caused by I / R and TAC. Thus, SIRT2 expression is elevated in various cardiac disease models, and inhibiting SIRT2 can improve different cardiac diseases and thus improve cardiac fibrosis, providing a new target for the prevention and treatment of cardiac fibrosis. With further research, scholars have discovered that TGF-β1 is involved in slowing the occurrence and development of cardiac fibrosis by inhibiting SIRT2. Studies have shown that the phosphorylation level of Smad signaling pathway proteins mediated by TGF-β1 can be significantly inhibited after SIRT2 inhibition. Multiple studies have shown that AGK2, as a specific inhibitor of SIRT2, can inhibit fibroblast activation by suppressing SIRT2 and the TGF-β1 signaling pathway. Therefore, starting from the SIRT2 target and using TGF-β1 and the TGF-β / Smad pathway as validation indicators, the discovery of significantly effective anti-cardiac fibrosis drugs is of great clinical significance for prevention and treatment.

[0006] In summary, based on extensive literature review, this invention designed and synthesized a series of novel 3-naphthiophene derivatives, and conducted anti-myocardial fibrosis activity tests, demonstrating good activity. Summary of the Invention

[0007] The purpose of this invention is to design and synthesize a new class of 3-naphthiophene derivatives based on previous work, and to conduct research on their anti-myocardial fibrosis effects.

[0008] Another object of the present invention is to provide a method for preparing 3-naphthiophene derivatives.

[0009] To achieve the objectives of this invention, the following technical solution is adopted:

[0010] This invention relates to 3-naphthiophene derivatives having the following general formula I, or pharmaceutically acceptable salts thereof:

[0011]

[0012] in:

[0013] R1 and R2 are each independently selected from any one of the following groups: (1) H atom, (2) hydroxyl group, (3) halogen atom, (4) cyano group, (5) nitro group, (6) trihalomethyl group, (7) C1-6 alkyl group, C3-8 cycloalkyl group, C2-6 alkenyl group, C2-6 alkyne group, C1-6 alkylsulfonylamino group, C1-18 alkoxycarbonyl group, C1-18 alkoxysulfonyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C2-6 alkyneoxy group, C1-6 alkylthio group, C2-6 alkenylthio group, C2-6 alkynethio group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C2-6 alkynesulfonyl group, C1-6 alkylsulfinyl group, C2-6 alkenylyl group Sulphinyl, C2-6 alkyne sulfinyl, C3-8 cycloalkenyl, each of the above groups may be substituted by one or more substituents selected from H atom, halogen atom, hydroxyl, cyano, nitro and amino; (8) carbonyl groups substituted by various substituents may be substituted by one or more substituents selected from H atom, hydroxyl, C1-6 alkyl, amino, C1-6 alkylamino, C1-6 alkoxy, C1-6 alkylthio and C3-8 cycloalkyl; (9) amino groups substituted by various substituents may be substituted by one or more substituents selected from H atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynesulfonyl, C1-6 alkylcarbonyl. The substituted group is one or more of the following: C2-6 chain alkenyl carbonyl and C2-6 chain alkynyl carbonyl; (10) substituted with various phenyl groups, substituted with various benzyl groups, substituted with various benzyloxy groups, substituted with various benzoyl groups, substituted with various benzenesulfonyl groups, substituted with various pyridine rings, substituted with various pyrazole rings, substituted with various pyrrole rings, substituted with various pyrimidine rings, substituted with various quinoline rings, substituted with various isoquinoline rings, substituted with various imidazole rings, substituted with various morpholine rings, substituted with various piperazine rings, substituted with various pyridazine rings, substituted with various pyrazine rings, substituted with various piperazine rings, substituted with various thiophene rings, substituted with various thiazole rings, and substituted with various phenyl groups. The isothiazole ring, the benzothiazole ring substituted with various substituted rings, the pyran ring substituted with various substituted rings, the indole ring substituted with various substituted rings, the oxazole ring substituted with various substituted rings, the isoxazole ring substituted with various substituted rings, the triazole ring substituted with various substituted rings, the benzotriazole ring substituted with various substituted rings, the furan ring substituted with various substituted rings, and each of the above groups is arbitrarily replaced by one or more substituents selected from H, halogen, C1-6 alkyl, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonylamino, benzyloxycarbonyl, C1-18 alkoxycarbonyl, C1-18 alkoxysulfonyl, trihalomethyl, hydroxy, cyano, nitro, formyl and amino, (11) adjacent R1 and R2 are connected to form alkylenedioxy.

[0014] Furthermore, R1 and R2 are each independently selected from the following groups: (1) H atom, (2) hydroxyl, (3) halogen atom, (4) nitro, (5) C1-6 alkyl, C1-4 alkoxy, the above groups are unsubstituted or arbitrarily substituted by one or more substituents selected from H atom, halogen atom, hydroxyl, cyano, nitro and amino, (6) phenyl substituted by various substituted, benzyloxy substituted by various substituted, pyridine ring substituted by various substituted, the above groups are arbitrarily substituted by one or more substituents selected from H, halogen, C1-4 alkyl, C1-4 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonylamino, benzyloxycarbonyl, C1-18 alkoxycarbonyl, C1-18 alkoxysulfonyl, trihalomethyl, hydroxymethyl, hydroxyl, cyano, nitro and formyl.

[0015] Furthermore, the 3-naphthiophene derivative is any one of the following compounds or their pharmaceutically acceptable salts:

[0016]

[0017]

[0018]

[0019] The synthetic routes for 3-naphthiophene derivatives of general formula I of the present invention, or pharmaceutically acceptable salts thereof, and optically active forms or racemates, and diastereomer mixtures thereof, include the following:

[0020]

[0021] Starting with 4-bromothiophene-2-carboxaldehyde 1a, it was reacted with cyanoacetic acid via a Knoevenagel reaction to yield carboxylic acid compound 2a. 2a was then coupled with 1-naphthoboric acid via a Suzuki coupling reaction catalyzed by Pd(PPh3)4 to obtain key intermediate 3a. Key intermediate 3a was refluxed in thionyl chloride to synthesize acyl chlorides. Subsequently, under the condition of triethylamine as an acid-binding agent, it underwent an acid-amine condensation reaction with aminopyridine compounds or aliphatic amine compounds with different substitutions to synthesize compounds of general formula I, where R2 represents the corresponding group at the corresponding position in compounds YC-1 to YC-28.

[0022] This invention also relates to 3-naphthiophene derivatives of general formula I and their optically active forms or racemates, diastereomer mixtures, and the use of such compounds as SIRT2 inhibitors in the treatment of myocardial fibrosis. This invention also relates to such compounds and their pharmaceutically acceptable salts, pharmaceutical compositions with such compounds as active ingredients, and pharmaceutically acceptable excipients and / or diluents for the above substances. This invention further relates to dosage forms of such compounds containing at least one compound of this structural formula or a salt thereof, in the form of tablets, coated tablets, capsules, solutions or ampoules for injection, suppositories, patches, inhalable powders, suspensions, emulsions, and ointments.

[0023] The beneficial effects of this invention are:

[0024] This invention relates to the use of 3-naphthiophene derivatives or isomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of anti-myocardial fibrosis drugs. Myocardial fibrosis is a common pathological process in the end-stage of cardiovascular disease and a significant factor contributing to poor prognosis in heart failure. Cardiovascular disease is a leading cause of death worldwide, causing nearly 18 million deaths annually. In recent years, the morbidity and mortality rates of cardiovascular disease have been rising, seriously threatening people's health and lives. Therefore, delaying myocardial fibrosis is crucial for improving the prognosis of heart disease patients. The etiology of myocardial fibrosis is numerous and complex, and its pathogenesis remains unclear. Therefore, there are currently no specific drugs for myocardial fibrosis in clinical practice. This invention provides a deeper understanding of the regulatory mechanisms of myocardial fibrosis and identifies therapeutic targets, which is of significant clinical importance for developing effective drugs to treat myocardial fibrosis, slowing the progression of heart disease, and improving cardiac function. This invention further enriches the diversity of anti-myocardial fibrosis inhibitors, laying the foundation for subsequent bioactivity testing of monomeric compounds, providing active lead compounds for new drug development, and also providing a theoretical basis for in-depth research and development of SIRT2 inhibitors. Attached Figure Description

[0025] Figure 1 The compound's inhibitory activity against SIRT2;

[0026] Figure 2 IC of preferred compounds 50 value;

[0027] Figure 3 YC-5 IC for CFs and CMs 50 value;

[0028] Figure 4 Effects of YC-5 on SIRT2 mRNA levels and SIRT2 enzyme activity in CFs;

[0029] Figure 5YC-5 can inhibit TGF-β1-induced activation of cardiomyocytes;

[0030] Figure 6 Effects of YC-5 on TGF-β1-induced Smad2 / 3 phosphorylation levels;

[0031] Figure 7 Effects of YC-5 on TGF-β1-induced CF proliferation;

[0032] Figure 8 Effects of YC-5 on heart weight ratio and cardiac function;

[0033] Figure 9 Effects of YC-5 on cardiac tissue pathology;

[0034] Figure 10 Effects of YC-5 on α-SMA protein expression in cardiac tissue;

[0035] Figure 11 Effects of YC-5 on the expression of p-Smad2 and p-Smad3 proteins;

[0036] Figure 12 Effects of YC-5 on liver and kidney toxicity.

[0037] Figure 13 Effects of YC-5 on creatinine and blood urea nitrogen levels. Detailed Implementation

[0038] The compounds of the present invention and their preparation will be better understood in conjunction with the following examples, which are intended to illustrate rather than limit the scope of the invention.

[0039] Example 1, Synthesis of (E)-N-(pyridin-4-yl)-2-cyano-3-[4-(naphthyl-1-yl)thiophen-2-yl]acrylamide (YC-1)

[0040] At room temperature, 4-bromothiophene-2-carboxaldehyde (1a, 10.00 g, 52.34 mmol) and cyanoacetic acid (6.68 g, 78.52 mmol) were dissolved in 100 mL of toluene. After complete dissolution, piperidine (0.89 g, 10.47 mmol) and glacial acetic acid (0.94 g, 15.70 mmol) were added dropwise. The reaction mixture was then refluxed for 5 h, monitored by thin-layer chromatography. After completion, the reaction mixture was cooled to room temperature, filtered, and washed with petroleum ether (50 mL × 2) to remove residual toluene. The resulting white solid (2a, 10.14 g) yielded 75.1%.

[0041] Intermediate 2a (5 g, 19.37 mmol) was dissolved in 150 mL of anhydrous ethanol at room temperature. Then, 1-cycloalkanoic acid (4.44 g, 23.25 mmol), K₂CO₃ (4.11 g, 38.75 mmol), and 50 mL of water were added, and the mixture was stirred for 30 min. Pd(PPh₃)₄ (1.34 g, 1.16 mmol) was added, and the mixture was refluxed under nitrogen for 6 h. The reaction was monitored by thin-layer chromatography. After completion, the reaction mixture was hot-filtered to remove insoluble impurities. The filtrate was concentrated under vacuum, stirred in 50 mL of dichloromethane at room temperature, and filtered to obtain a white solid. The solid was washed with (30 mL × 2) dichloromethane, dissolved in 100 mL of water, and the pH was adjusted to 3–4 with hydrochloric acid. Then, the sample was filtered and washed sequentially with saturated sodium bicarbonate aqueous solution (30 mL × 2), water (30 mL × 2), and saturated salt aqueous solution (30 mL × 2), and dried to obtain a yellow solid (3a, 4.24 g), with a yield of 71.7%.

[0042] Dissolve intermediate (E)-2-cyano-3-[4-(naphthyl-1-yl)thiophene-2-yl]acrylic acid (3a, 0.5 g, 1.64 mmol) in 10 mL of thionyl chloride, then add 1 mL of [the solution is missing from the original text]. DMF was refluxed for 1 hour. After the reaction was complete, the reaction mixture was cooled slightly and concentrated to remove the solvent thionyl chloride. Cyclohexane (10 mL × 2) was then added and concentrated again to remove residual thionyl chloride. The resulting red solid acyl chloride was dissolved in 10 mL of dichloromethane and slowly added dropwise at room temperature to a 20 mL solution of 4-aminopyridine (2.31 g, 2.45 mmol) pre-added with triethylamine (0.50 g, 4.91 mmol) in dichloromethane using a constant pressure dropping funnel. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the mixture was washed twice with saturated brine (50 mL × 2), evaporated to dryness, and concentrated to obtain 0.8 g of yellow solid. This solid was dissolved completely in 20 mL of dichloromethane. 2 g of sample silica gel and 10 g of blank silica gel were added and packed into a column. The column was purified by column chromatography with a volume ratio of dichloromethane:methanol = 50:1 to obtain 0.39 g of yellow solid powder, with a yield of 63.49%.

[0043] 1 H NMR (600MHz, DMSO-d6) δ10.00(s,1H),8.71(d,J=10.0Hz,2H),8.53(d,J=5.4Hz,1H),8.35–8. 34(m,1H),8.26(d,J=1.5Hz,1H),8.05–8.01(m,2H),7.95(d,J=5.6Hz,2H),7.67–7.52(m,5H). 13C NMR(150MHz,DMSO-d6)δ160.89,150.11,149.38,146.22,141.82,141.03,136.24,134.75,133.91,133.06, 131.13,129.00,128.96,127.68,127.33,126.71,126.11,125.28,123.86,118.76,116.83.ESI-HRMS:calcd for C 23 H 16 N3OS,[M+H] + ,382.1019; found 382.1019.

[0044] Example 2, (E)-N-(2-bromopyridin-4-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-2)

[0045] The compound in Example 2 was prepared using the same method as in Example 1, except that 2-bromo-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 70.42%.

[0046] 1 H NMR(600MHz,DMSO-d6)δ10.85(s,1H),8.67(s,1H),8.34(s,1H),8.32(d,J=5.6Hz,1H),8.19(s,1H),8.0 5–8.01(m,1H),7.99(d,J=1.9Hz,1H),7.96–7.94(m,1H),7.70(dd,J=5.6,2.0Hz,1H),7.63–7.56(m,4H). 13 C NMR (150MHz, DMSO-d) 6 )δ161.89,151.42,148.02,145.69,142.30,141.82,140.45,136.12,134.69,133.92,133.04,131.13,12 9.02,128.97,127.69,127.33,126.72,126.12,125.23,117.78,116.49,114.38,102.71.ESI-HRMS:calcd for C 23 H 14 BrN3OS,[M+H] + 460.0119; found 460.0116.

[0047] Example 3, (E)-2-cyano-N-(3-methylpyridin-4-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-3)

[0048] The compound in Example 3 was prepared using the same method as in Example 1, except that 3-methyl-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 63.42%.

[0049] 1 H NMR(600MHz,DMSO-d6)δ9.93(s,1H),8.67(s,1H),8.45(s,1H),8.40(d,J=5.3Hz,1H),8.31(s,1H) ,8.21(d,J=1.5Hz,1H),8.05–8.00(m,2H),7.96(d,J=8.5Hz,1H),7.62–7.56(m,5H),2.28(s,3H). 13 C NMR (150MHz, DMSO) δ160.92,151.97,148.35,145.49,143.64,141.73,140.40,136.29,134.20,133.92,133.11,131.14 ,129.01,128.94,127.67,127.32,126.88,126.71,126.12,125.27,118.44,116.92,102.59,15.20.ESI-HRMS:calcdfor C 24 H 18 N3OS,[M+H] + ,396.1171; found 396.1168.

[0050] Example 4, (E)-2-cyano-N-(2-methylpyridin-4-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-4)

[0051] The compound in Example 4 was prepared using the same method as in Example 1, except that 2-methyl-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 53.20%.

[0052] 1H NMR(600MHz,DMSO-d6)δ10.62(s,1H),8.65(s,1H),8.37(d,J=5.6Hz,1H),8.32(s,1H),8.18(s,1H),8 .03(dd,J=17.1,7.8Hz,2H),7.97–7.93(m,1H),7.62–7.57(m,5H),7.51(d,J=4.9Hz,1H),2.46(s,3H). 13 C NMR (150MHz, DMSO) δ167.44,161.62,159.09,150.06,145.15,141.75,140.15,136.19,134.29,133.92,133.09,131.9 9,131.13,129.15,129.00,128.94,127.67,127.31,126.71,126.12,125.24,113.60,112.09,19.12.ESI-HRMS:calcd for C 24 H 18 N3OS,[M+H] + ,396.1171; found 396.1173.

[0053] Example 5, (E)-2-cyano-N-(3-formylpyridin-4-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-5)

[0054] The compound in Example 5 was prepared using the same method as in Example 1, except that 3-formyl-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 56.83%.

[0055] 1 H NMR (600MHz, DMSO-d6) δ11.91(s,1H),10.13(s,1H),9.09(s,1H),8.81(s,1H),8.78(d,J=5.8Hz,1H),8.51(d,J =5.8Hz,1H),8.38(s,1H),8.34(s,1H),8.03(dd,J=15.3,7.7Hz,2H),7.96(d,J=8.0Hz,1H),7.62–7.56(m,4H). 13C NMR (150MHz, DMSO) δ196.39,160.92,157.43,155.95,147.56,145.82,142.08,141.92,136.38,135.51,133.90,132.9 6,131.11,128.99,127.70,127.35,126.72,126.09,118.28,118.25,116.25,113.75,113.74,100.94.ESI-HRMS:calcd for C 24 H 16 N3OS,[M+H] + ,410.0963; found 410.0959.

[0056] Example 6, (E)-N-(3-chloropyridin-4-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-6)

[0057] The compound in Example 6 was prepared using the same method as in Example 1, except that 3-chloro-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 76.47%.

[0058] 1 H NMR(600MHz,DMSO-d6)δ9.99(s,1H),8.71(d,J=10.8Hz,2H),8.53(d,J=5.4Hz,1H),8 .34(s,1H),8.26(s,1H),8.05–8.00(m,2H),7.96(d,J=5.7Hz,2H),7.62–7.56(m,4H). 13 C NMR (150MHz, DMSO-d6) δ160.91,150.09,149.34,146.14,141.81,141.00,136.25,134.71,133.91,133.06,131. 13,129.00,128.96,127.68,127.33,126.72,126.11,125.28,123.90,118.78,116.88,116.84.ESI-HRMS:calcd for C 23 H 14 ClN3OS,[M+H] + ,416.0624; found 416.0630.

[0059] Example 7, (E)-N-(2-chloropyridin-4-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-7)

[0060] The compound in Example 7 was prepared using the same method as in Example 1, except that 2-chloro-4-aminopyridine was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 72.03%.

[0061] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),8.67(s,1H),8.35(d,J=6.1Hz,2H),8.20(d,J=1.5Hz,1H),8.03(dd ,J=16.4,7.6Hz,2H),7.95(d,J=8.1Hz,1H),7.85(s,1H),7.67(dd,J=5.7,1.9Hz,1H),7.63–7.56(m,4H). 13 C NMR(150MHz,DMSO-d6)δ161.90,151.37,150.96,148.36,145.73,141.82,140.48,136.12,134.70,133.92,133.04, 131.13,129.02,128.97,127.69,127.33,126.72,126.13,125.23,116.50,114.08,114.06,102.67.ESI-HRMS:calcd for C 23 H 14 ClN3OS,[M+H] + ,416.0624; found 416.0630.

[0062] Example 8, (E)-2-cyano-3-(4-(naphthio-1-yl)thiophen-2-yl)-N-(pyridin-4-ylmethyl)-acrylamide (YC-8)

[0063] The compound in Example 8 was prepared using the same method as in Example 1, except that 4-aminomethylpyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 58.44%.

[0064] 1H NMR(600MHz,DMSO-d6)δ9.06(t,J=6.0Hz,1H),8.56(s,1H),8.53–8.51(m,2H),8.26(s,1H),8.15(d,J=1.4Hz,1H) ,8.04–7.99(m,2H),7.95(dd,J=8.2,1.4Hz,1H),7.61–7.56(m,4H),7.32(d,J=6.0Hz,2H),4.46(d,J=5.9Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ161.68,150.04,148.32,144.59,141.61,139.94,136.36,133.90,133.57,133.19,131 .15,128.98,128.88,127.64,127.29,126.69,126.09,125.31,122.66,116.95,102.21,42.78.ESI-HRMS:calcd for C 24 H 18 N3OS,[M+H] + ,396.1171; found 396.1174.

[0065] Example 9, (E)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)-N-(2-(pyridin-4-yl)ethyl)acrylamide (YC-9)

[0066] The compound in Example 9 was prepared using the same method as in Example 1, except that 4-aminoethylpyridine was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 54.18%.

[0067] 1 H NMR (600MHz, DMSO-d6) δ8.52(t,J=5.7Hz,1H),8.49(d,J=4.9Hz,2H),8.47(s,1H),8.23(s,1H),8.12(s,1H),8.01(dd,J=18. 9,7.9Hz,2H),7.95(d,J=8.2Hz,1H),7.61–7.53(m,4H),7.28(d,J=5.1Hz,2H),3.51(q,J=6.7Hz,2H),2.87(t,J=7.2Hz,2H). 13C NMR(150MHz,DMSO-d6)δ161.17,149.97,148.63,144.16,141.58,139.77,136.35,133.90,133.34,133.21,131.15 ,128.97,128.87,127.63,127.28,126.69,126.09,125.32,124.73,116.93,102.47,40.57,34.47.ESI-HRMS:calcd for C 25 H 20 N3OS,[M+H] + ,410.1327; found410.1335.

[0068] Example 10, (E)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)-N-(pyridin-3-ylmethyl)-acrylamide (YC-10)

[0069] The compound in Example 10 was prepared using the same method as in Example 1, except that 3-aminomethylpyridine was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 57.28%.

[0070] 1 H NMR (600MHz, DMSO-d6) δ9.06(t,J=5.9Hz,1H),8.58(d,J=2.2Hz,1H),8.54(s,1H),8.49(dd,J=4.8,1.6Hz,1H),8.24(s,1H),8.14(s,1H),8.0 1(dd,J=18.7,8.2Hz,2H),7.95(d,J=8.2Hz,1H),7.75(d,J=7.9Hz,1H),7.61–7.55(m,4H),7.38(dd,J=7.8,4.8Hz,1H),4.47(d,J=5.9Hz,2H). 13 C NMR (150MHz, DMSO-d6)161.51,149.46,148.70,144.50,141.59,139.87,136.38,135.80,134.92,133.91,133. 48,131.16,128.98,127.63,127.28,126.69,126.09,125.32,123.97,116.97,102.33,41.47.ESI-HRMS:calcd for C 24 H 18 N3OS,[M+H] +,396.1171; found396.1170.

[0071] Example 11, (E)-2-cyano-N-(5-methylpyridin-2-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-11)

[0072] The compound in Example 11 was prepared using the same method as in Example 1, except that 2-amino-5-methylpyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 57.41%.

[0073] 1 H NMR(600MHz,DMSO-d6)δ8.94(d,J=7.1Hz,1H),8.48(d,J=1.4Hz,1H),8.19(d,J=1.3Hz,1H), 8.05–8.00(m,3H),7.76(s,1H),7.64–7.55(m,5H),7.44(dd,J=7.1,1.9Hz,1H),2.56(s,3H). 13 C NMR(150MHz,DMSO-d6)δ158.11,157.98,154.94,151.00,142.13,141.03,133.96,133.75,132.87,132.50,131.15,129 .03,128.80,128.06,127.55,127.30,126.69,126.15,125.27,124.95,121.08,117.68,82.33,21.55.ESI-HRMS:calcd forC 24 H 18 N3OS,[M+H] + ,396.1171; found 396.1170.

[0074] Example 12, (E)-2-cyano-N-(4-methylpyridin-2-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-12)

[0075] The compound in Example 12 was prepared using the same method as in Example 1, except that 2-amino-4-methylpyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 55.64%.

[0076] 1H NMR(600MHz,DMSO-d6)δ8.94(d,J=7.1Hz,1H),8.48(d,J=1.4Hz,1H),8.19(d,J=1.3Hz,1H), 8.05–8.00(m,3H),7.76(s,1H),7.64–7.55(m,5H),7.44(dd,J=7.1,1.9Hz,1H),2.56(s,3H). 13 C NMR(150MHz,DMSO-d6)δ158.11,157.98,154.94,151.00,142.13,141.03,133.96,133.75,132.87,132.50,131.15,129 .03,128.80,128.06,127.55,127.30,126.69,126.15,125.27,124.95,121.08,117.68,82.33,21.55.ESI-HRMS:calcd forC 24 H 18 N3OS,[M+H] + ,396.1171; found 396.1170.

[0077] Example 13, (E)-N-(5-chloropyridin-2-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-13)

[0078] The compound in Example 13 was prepared using the same method as in Example 1, except that 2-amino-5-chloropyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 72.43%.

[0079] 1 H NMR (600MHz, DMSO-d6) δ11.01(s,1H),8.74(s,1H),8.47(d,J=2.6Hz,1H),8.31( s,1H),8.14(s,1H),8.10(d,J=9.0Hz,1H),8.05–7.98(m,3H),7.63–7.56(m,5H). 13C NMR(150MHz,DMSO-d6)δ161.72,150.69,147.01,145.04,141.72,140.00,138.59,136.20,134.20,133.92,133.12, 131.14,129.01,128.93,127.66,127.31,126.71,126.48,126.12,125.24,116.72,116.00,103.14.ESI-HRMS:calcd for C 23 H 14 ClN3OS,[M+H] + ,416.0624; found 416.0623.

[0080] Example 14, (E)-N-(4-chloropyridin-2-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-14)

[0081] The compound in Example 14 was prepared using the same method as in Example 1, except that 2-amino-4-chloropyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 73.07%.

[0082] 1 H NMR (600MHz, DMSO-d6) δ8.98(d,J=7.5Hz,1H),8.50(s,1H),8.25(s,1H),8.10(s,1H),8.06–8.00(m,3H),7.65–7.56(m,5H). 13 C NMR (150MHz, DMSO) δ158.47,157.79,151.44,147.64,142.24,140.49,133.95,133.62,133.33,133.23,131.12,1 30.34,129.04,128.85,127.57,127.32,126.69,126.14,125.22,125.16,119.50,117.28,83.55.ESI-HRMS:calcd for C 23 H 14 ClN3OS,[M+H] + ,416.0624; found 416.0628.

[0083] Example 15, (E)-2-cyano-N-(5-fluoropyridin-2-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-15)

[0084] The compound in Example 15 was prepared using the same method as in Example 1, except that 2-amino-5-fluoropyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 51.87%.

[0085] 1 H NMR (600MHz, DMSO-d6) δ9.09 (s, 1H), 8.49 (d, J = 1.4Hz, 1H), 8.38–8.35 (m, 1H), 8.22 (s, 1H), 8.07–7.96 (m, 5H), 7.62–7.57 (m, 4H). 13 C NMR(150MHz,DMSO-d6)δ157.67,157.48,149.57,142.20,140.49,133.96,133.68,133.13,132.80,131.13,129.13, 129.12,128.84,128.81,127.58,127.31,126.70,126.14,125.26,117.31,115.75,115.47,83.04.ESI-HRMS:calcd for C 23 H 15 N3OFS,[M+H] + 400.0920; found 400.0917.

[0086] Example 16, (E)-N-(4-bromopyridin-2-yl)-2-cyano-3-(3-(naphth-1-yl)cyclopentan-1,3-dien-1-yl)acrylamide (YC-16)

[0087] The compound in Example 16 was prepared using the same method as in Example 1, except that 2-amino-4-bromopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 68.82%.

[0088] 1 H NMR (600MHz, DMSO-d6) δ8.87(d,J=7.4Hz,1H),8.49(d,J=1.4Hz,1H),8.27–8. 22(m,1H),8.08–7.96(m,3H),7.70(dd,J=7.4,2.1Hz,1H),7.66–7.55(m,3H). 13C NMR(150MHz,DMSO-d6)δ158.43,157.86,151.12,142.25,140.52,137.35,133.96,133.63,133.32,133.19,131.13, 129.69,129.04,128.84,128.45,127.57,127.31,126.69,126.14,125.23,122.04,117.31,83.59.ESI-HRMS:calcd for C 23 H 14 BrN3OS,[M+Na] + ,481.9939; found 481.9935.

[0089] Example 17, (E)-N-(5-bromopyridin-2-yl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-17)

[0090] The compound in Example 17 was prepared using the same method as in Example 1, except that 2-amino-5-bromopyridine was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 75.43%.

[0091] 1 H NMR(600MHz,DMSO-d6)δ10.99(s,1H),8.73(s,1H),8.55–8.52(m,1H),8.32–8.29(m, 1H),8.13(d,J=1.5Hz,1H),8.11–7.99(m,4H),7.97–7.94(m,1H),7.63–7.55(m,4H). 13 CNMR(150MHz,DMSO-d6)δ161.71,150.95,149.18,145.04,141.74,141.32,139.97,136.20,134.21,133.92,133.11, 131.15,129.01,128.92,127.66,127.29,126.70,126.11,125.25,116.69,116.48,114.95,103.13.ESI-HRMS:calcd for C 23 H 14 BrN3OS,[M+Na] + ,481.9939; found 481.9938.

[0092] Example 18, (E)-2-cyano-N-(2-methoxypyridin-4-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-18)

[0093] The compound in Example 18 was prepared using the same method as in Example 1, except that 2-methoxy-4-aminopyridine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 69.43%.

[0094] 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),8.65(s,1H),8.31(d,J=1.4Hz,1H),8.18(d,J=1.5Hz,1H),8.11(d,J=5.7Hz,1H),8.05– 8.00(m,2H),7.96(dd,J=7.7,1.6Hz,1H),7.63–7.56(m,3H),7.28(dd,J=5.8,1.8Hz,1H),7.22(d,J=1.8Hz,1H),3.85(s,3H). 13 CNMR(150MHz,DMSO-d6)δ165.01,161.63,148.07,147.89,145.23,141.75,140.18,136.19,134.29,133.92,133.09,131 .14,129.01,128.94,127.67,127.30,126.71,126.11,125.25,116.64,109.37,103.07,100.06,53.68.ESI-HRMS:calcd for C 24 H 17 N3O2S, [M+H] + ,412.1120; found 412.1128.

[0095] Example 19, (E)-N-butyl-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-19)

[0096] The compound in Example 19 was prepared using the same method as in Example 1, except that 1-aminobutane was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 62.31%.

[0097] 1H NMR (600MHz, DMSO-d6) δ8.47(s,1H),8.39(t,J=5.7Hz,1H),8.22(s,1H),8.12(s,1H),8.04–7.99(m,2H),7.95(d,J=8.1Hz ,1H),7.61–7.55(m,4H),3.23(q,J=6.8Hz,2H),1.50(dd,J=8.4,6.2Hz,2H),1.32(q,J=7.5Hz,2H),0.90(t,J=7.3Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ161.10,143.80,141.54,139.49,136.42,133.91,133.24,133.09,131.16,128.96,12 7.62,127.26,126.67,126.08,125.32,117.04,104.81,102.91,55.39,31.48,20.03,14.07.ESI-HRMS:calcd for C 22 H 20 N₂ONaS,[M+Na] + ,383.1194; found383.1182.

[0098] Example 20, (E)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)-N-pentylacrylamide (YC-20)

[0099] The compound in Example 20 was prepared using the same method as in Example 1, except that 1-aminopentane was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 59.31%.

[0100] 1 H NMR (600MHz, DMSO-d6) δ8.47(s,1H),8.40(t,J=5.7Hz,1H),8.22(s,1H),8.12(s,1H),8.01(dd,J=19.2,8.1Hz,2H),7. 95(d,J=8.1Hz,1H),7.60–7.55(m,4H),3.23–3.20(m,2H),1.53–1.50(m,2H),1.32–1.27(m,4H),0.88(t,J=7.0Hz,3H). 13C NMR(150MHz,DMSO-d6)δ161.07,143.83,141.54,139.51,136.42,133.91,133.24,133.10,131.16,128.96 ,128.85,127.62,127.26,126.67,126.08,125.32,117.04,102.90,29.04,22.32,14.38.ESI-HRMS:calcd for C 23 H 22 N₂ONaS,[M+Na] + ,397.1351; found 397.1351.

[0101] Example 21, (E)-2-cyano-N-hexyl-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-21)

[0102] The compound in Example 21 was prepared using the same method as in Example 1, except that 1-aminohexane was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 67.96%.

[0103] 1 H NMR(600MHz,DMSO-d6)δ8.47(s,1H),8.39(t,J=5.7Hz,1H),8.22(s,1H),8.12(s,1H),8.03–7.99(m,2H),7.95(d, J=8.2Hz,1H),7.60–7.55(m,4H),3.21(d,J=6.7Hz,2H),1.50(t,J=7.2Hz,2H),1.28(m,6H),0.87(t,J=6.5Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ161.07,143.83,141.54,139.52,136.42,133.91,133.24,133.11,131.16,128.97,128.85,1 27.62,127.27,126.68,126.09,125.32,117.04,102.90,31.44,29.31,28.92,26.52,22.51,14.40.ESI-HRMS:calcd for C 24 H 24 N₂ONaS,[M+Na] + ,411.1507; found411.1500.

[0104] Example 22, (E)-2-cyano-N-isobutyl-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-22)

[0105] The compound in Example 22 was prepared using the same method as in Example 1, except that 2-aminoisobutane was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 63.43%.

[0106] 1 H NMR (600MHz, DMSO-d6) δ8.48(s,1H),8.41(t,J=5.8Hz,1H),8.22(s,1H),8.12(s,1H),8.04–7.99(m,2H),7.95(d ,J=8.1Hz,1H),7.61–7.54(m,4H),3.06(t,J=6.4Hz,2H),1.85(dt,J=13.6,6.8Hz,1H),0.89(s,3H),0.88(s,3H). 13 C NMR (150MHz, DMSO-d6) δ161.31,143.76,141.54,139.47,136.43,133.91,133.25,133.08,131.16,128.97,12 8.85,127.62,127.26,126.67,126.09,125.33,117.08,102.99,47.57,28.45,20.60,20.58.ESI-HRMS:calcd for C 24 H 24 N₂ONaS,[M+Na] + ,383.1194; found 383.1192.

[0107] Example 23, (E)-2-cyano-N-isopropyl-3-(4-(naphthyl-1-yl)thiophen-2-yl)-acrylamide (YC-23)

[0108] The compound in Example 23 was prepared using the same method as in Example 1, except that 2-aminopropane was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 64.5%.

[0109] 1H NMR(600MHz,DMSO-d6)δ8.45(s,1H),8.22(s,1H),8.10(s,1H),8.01(dd,J=19.0,7.9Hz,2 H),7.95(d,J=8.1Hz,1H),7.61–7.55(m,4H),4.05–3.99(m,1H),1.17(s,3H),1.16(s,3H). 13 C NMR (150MHz, DMSO-d6) δ160.57,143.53,141.54,139.25,136.42,133.92,133.25,133.02,131.16,128.99 ,128.86,127.63,127.28,126.69,126.11,125.32,117.08,103.40,42.29,22.47,22.24.ESI-HRMS:calcd for C 21 H 18 N₂ONaS,[M+Na] + ,369.1038; found 369.1035.

[0110] Example 24, (E)-2-cyano-N-isopentyl-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-24)

[0111] The compound in Example 24 was prepared using the same method as in Example 1, except that isopentylamine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 60.27%.

[0112] 1 H NMR (600MHz, DMSO-d6) δ8.46(s,1H),8.38(t,J=5.7Hz,1H),8.22(s,1H),8.11(s,1H),8.01(dd,J=19.3,8.0Hz,2H),7.95(d, J=8.1Hz,1H),7.60–7.55(m,4H),3.24(q,J=6.7Hz,2H),1.62–1.58(m,1H),1.41(d,J=7.2Hz,2H),0.91(s,3H),0.90(s,3H). 13C NMR (150MHz, DMSO-d6) δ161.03,143.80,141.53,139.50,136.42,133.90,133.80,133.09,131.14,128.98,128.8 4,127.62,127.16,126.69,126.06,125.31,117.02,102.91,38.35,37.86,25.70,22.88,22.77.ESI-HRMS:calcd for C 23 H 22 N₂ONaS,[M+Na] + ,397.1351; found397.1345.

[0113] Example 25, (E)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)-N-neopentylacrylamide (YC-25)

[0114] The compound in Example 25 was prepared using the same method as in Example 1, except that neopentylamine was used instead of 4-aminopyridine in step four. A yellow solid powder was obtained, with a yield of 65.49%.

[0115] 1 H NMR(600MHz,DMSO-d6)δ8.47(s,1H),8.30(t,J=6.3Hz,1H),8.22(s,1H),8.12(s,1H),8.01(dd,J =18.7,7.9Hz,2H),7.95(d,J=8.2Hz,1H),7.61–7.55(m,4H),3.07(d,J=6.4Hz,2H),0.90(s,9H). 13 C NMR(150MHz,DMSO-d6)δ161.77,143.61,141.54,139.39,136.44,133.92,133.60,133.05,131.16,128.98 ,127.63,127.27,126.69,126.10,125.33,117.17,105.16,103.25,50.87,33.12,27.77.ESI-HRMS:calcd for C 23 H 22 N₂ONaS,[M+Na] + ,397.1351; found397.1352.

[0116] Example 26, (E)-N-(sec-butyl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-26)

[0117] The compound in Example 26 was prepared using the same method as in Example 1, except that sec-butylamine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 67.84%.

[0118] 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.21(s,1H),8.15(d,J=8.2Hz,1H),8.11(d,J=1.5Hz,1H),8.04–7.99(m,2H),7.96 (d,J=8.3Hz,1H),7.60–7.55(m,4H),3.87–3.82(m,1H),1.56–1.48(m,2H),1.14(d,J=6.7Hz,3H),0.87(t,J=7.4Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ160.83,143.46,141.55,139.21,136.44,133.90,133.27,132.99,131.17,128.99,12 8.86,127.62,127.27,126.68,126.11,125.33,117.10,103.46,47.75,29.03,20.45,11.19.ESI-HRMS:calcd for C 22 H 20 N₂ONaS,[M+Na] + ,383.1194; found 383.1198.

[0119] Example 27, (E)-N-(tert-butyl)-2-cyano-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-27)

[0120] The compound in Example 27 was prepared using the same method as in Example 1, except that tert-butylamine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 67.98%.

[0121] 1 H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.20(s,1H),8.08(s,1H),8.01(dd,J=19.8 ,7.7Hz,2H),7.95(d,J=8.1Hz,1H),7.75(s,1H),7.61–7.55(m,4H),1.37(s,9H). 13CNMR(150MHz,DMSO-d6δ161.18,143.02,141.49,138.92,136.46,133.92,133.29,132.74,131.15,128 .99,128.85,127.61,127.26,126.68,126.11,125.31,117.31,104.52,52.00,28.70.ESI-HRMS:calcd for C 22 H 20 N₂ONaS,[M+Na] + ,383.1194; found 383.1198.

[0122] Example 28, (E)-2-cyano-N-(3-methylbut-2-yl)-3-(4-(naphthyl-1-yl)thiophen-2-yl)acrylamide (YC-28)

[0123] The compound in Example 28 was prepared using the same method as in Example 1, except that 3-methylbutylamine was used instead of 4-aminopyridine in the fourth step. A yellow solid powder was obtained, with a yield of 66.82%.

[0124] 1 H NMR (600MHz, DMSO-d6) δ8.44(s,1H),8.21(s,1H),8.13(d,J=8.5Hz,1H),8.11(d,J=1.5Hz,1H),8.01(dd,J=19.1,7.8Hz,2H),7.96(d,J=7.9Hz, 1H),7.60–7.55(m,4H),3.74(dt,J=8.5,6.7Hz,1H),1.77(q,J=6.8Hz,1H),1.11(d,J=6.8Hz,3H),0.90(d,J=2.8Hz,3H),0.89(d,J=2.9Hz,3H). 13 C NMR (150MHz, DMSO-d6) δ160.89,143.33,141.52,139.13,136.43,133.93,133.28,132.91,131.15,128.99,128.8 3,127.62,127.25,126.69,126.11,125.30,117.15,103.58,51.48,32.92,19.70,19.30,17.72.ESI-HRMS:calcd forC 23 H 22 N₂ONaS,[M+Na] + ,397.1351; found397.1355.

[0125] Pharmacological studies of the product of this invention

[0126] Pharmacological tests have demonstrated that the compounds involved in this invention have anti-myocardial fibrosis activity.

[0127] Substrate fluorescence assay for SIRT2 activity

[0128] Reagent Preparation: Dilution of SIRT2 Direct Assay Buffer (10X): Dilute 3 mL of assay buffer (10X) with 27 mL of HPLC-grade water. The final buffer (50 mM Tris-HCl, pH 8.0, containing 137 mM sodium chloride, 2.7 mM potassium chloride, and 1 mM magnesium chloride) is used for both assay and dilution. Preparation of Human Recombinant SIRT2: Thaw the enzyme on ice, add 270 μL of diluted assay buffer to the vial, and then vortex. The diluted enzyme is stabilized on ice for 4 h. SIRT2 Direct Peptide: Each vial contains 100 μL of a 5 mM peptide solution containing 317-320 amino acids of human p53-binding aminocoumarin (AMC). It is prepared for use in preparing the substrate solution. SIRT2 Direct NAD + This vial contains 500 μL of 50 mM NAD+. + Solution. It is prepared for the preparation of the substrate solution. SIRT2 Direct Nicotinamide: This vial contains 500 μL of 50 mM nicotinamide solution, a Sirtuin inhibitor. It is prepared for the preparation of the reaction termination solution. SIRT2 Direct Developer: This vial contains 100 mg of SIRT2 developer. SIRT2 Direct Fluorescein: This vial contains 50 μL of 10 mM 7-amino-4-methylcoumarin. Preparation of Substrate Solution: In one of the thawed SIRT2 direct peptide vials, add 160 μL of NAD... + Solution and 930 μL of diluted assay buffer. One vial of peptide can prepare enough substrate solution for 79 wells. The substrate solution is stable for 6 hours. After adding 15 μL, the final concentration is 125 μM peptide and 2 mM NAD. + Note: Peptides and NAD + The Km values ​​were 51 and 213 μM, respectively. Add the appropriate reagents to each well according to the instructions, then add 15 μL of substrate solution to all used wells to initiate the reaction. Cap the plate and incubate at 37°C on a shaker for 45 min. Preparation of the reaction termination solution: Place 30 mg of developer into a 5 mL vial, then add 200 μL of nicotinamide and 4.8 mL of diluted assay buffer, and vortex. Remove the plate cap and add 50 μL of the reaction termination solution. Cover with the plate cap and incubate at room temperature for 30 min to unify the units. Remove the plate cap, read the plate using an excitation wavelength of 350-360 nm and an emission wavelength of 450-465 nm, and calculate the drug inhibition rate, such as... Figure 1 and Figure 2 As shown.

[0129] MTT assay for cytotoxicity

[0130] This experiment used primary cell lines (CFs) and cell cultures (CMs). First, CFs in the logarithmic growth phase were taken, digested with trypsin, and then a cell suspension was prepared. The diluted cell suspension was then... 4 Cells were seeded per well in 96-well plates. CMs were directly seeded using primary cell suspensions extracted from the plates. After cell adhesion, the medium was replaced with 0% FBS and cultured for 12 hours under starvation. Subsequently, the serum-free medium was replaced with medium containing YC-5 (0.3, 1, 3, 10, 30, 100 μM) and 0% FBS, and cultured for 60 hours. After 60 hours, 0.1 mg of MTT (5 mg / mL) was added to each well and incubated for 4 hours. The supernatant was discarded, and 150 μL of DMSO was added to each well with shaking for 10 minutes. OD values ​​were measured at 492 nm using a multi-mode microplate reader. Finally, cell viability was calculated using the formula. The IC50 of YC-5 against CFs and CMs was calculated. 50 Value, see Figure 3 .

[0131] Construction of an in vitro myocardial fibrosis cell model induced by TGF-β1

[0132] CF cells were seeded in culture containers (96-well plates, 70mm culture dishes, etc.) at a certain ratio. After attachment, they were starved in 0% FBS medium for 12 hours to synchronize cell growth as much as possible. Then, the medium was changed to 0% FBS medium with or without the drug for 12 hours of pre-protection. The medium for each group was then changed to 0% FBS medium with or without the drug, and TGF-β1 (10ng / mL) was added continuously for 48 hours for stimulation. Subsequent experiments could then be carried out.

[0133] Substrate fluorescence assay to detect the effect of candidate compounds on intracellular SIRT2 activity

[0134] Primary cell lines, after 2-3 passages of cell treatment, are seeded at 75 mm. 2After cell attachment, all groups were starved in 0% FBS medium for 12 hours in culture dishes to synchronize cell growth as much as possible. The drug-treated group had its original culture medium replaced with 0% FBS medium containing the desired drug concentration for 12 hours of pre-protection, while the control group was also cultured in 0% FBS medium. Subsequently, the culture medium for each group was changed to 0% FBS medium containing or without the drug, and TGF-β1 (10 ng / mL) was added for continuous stimulation for 48 hours. For total protein extraction and determination, the original culture medium was discarded, and cells were washed three times with pre-cooled PBS. Cells were digested with trypsin, and digestion was stopped with three times the volume of complete culture medium. The culture dish walls were rinsed several times, and the cell suspension was centrifuged. Next, cells were washed three times with PBS, centrifuged, and the supernatant was discarded. Cells were repeatedly lysed with 150 μL of RIPA lysis buffer, and the liquid was transferred to a 1.5 mL EP tube. The lysis buffer was mixed with a pipette, and lysis was continued on ice for 30 min. After centrifugation at 12000 rpm for 15 min at 4℃, the supernatant was transferred and stored at -20℃. Protein concentration was detected according to the BCA kit method. Activity assay: Cell lysis buffer was diluted with SIRT2 experimental buffer to ensure consistent total protein concentration across groups. Then, 10 μL of protein, 20 μL of SIRT2 buffer, and 20 μL of SIRT2 substrate were added sequentially to each well of a black 96-well plate. The plate was incubated at 37℃ in the dark for 45 min to allow reaction. 50 μL of developing buffer was added to each well, and the plate was incubated at room temperature for 30 min to produce fluorescence. The fluorescence intensity was measured using an automated microplate reader (Ex: 350 nm, Em: 450 nm). Figure 4 As shown.

[0135] RT-PCR detection of the effect of candidate compounds on SIRT2 expression

[0136] Cell processing: Same as the SIRT2 enzyme activity assay described above. RNA extraction: Wear disposable, dust-free sterile gloves and masks before the experiment. All operations should be performed in a fume hood to prevent RNase contamination. Cell lysis: Discard the culture medium, wash twice with 2 mL PBS, trypsin digest, stop digestion with 1-2 volumes of 10% culture medium, gently aspirate cells, transfer to a 15 mL centrifuge, centrifuge at 1000 rcf for 5 min, and discard the supernatant. Add PBS, wash again, centrifuge, and discard the supernatant for subsequent RNA extraction. Add 1 mL of Trizol to the centrifuge, gently aspirate to disperse clumps of cells, transfer to a 1.5 mL EP tube, incubate for lysis for 5 min, and centrifuge at 12000 rcf for 5 min at 4°C. Phase separation: After centrifugation, slowly and steadily remove the centrifuge tube without shaking, and aspirate the supernatant into a 1.5 mL EP tube. Add 200 μL of chloroform (after adding chloroform, the solution separates into an aqueous phase and an organic phase; the RNA is in the aqueous phase. Remove the aqueous phase and precipitate the RNA with isopropanol). Mix by hand (do not vortex, as excessive force can easily break the RNA single strands). Time for 5 minutes. After 5 minutes, centrifuge at 4°C and 12000 rcf for 15 minutes. After centrifugation, slowly and steadily remove the centrifuge tube. Observe that the liquid in the tube will separate into three layers: a red organic phase (bottom layer), a white protein layer (middle layer), and a colorless RNA-containing layer (top layer). RNA precipitation: Transfer the colorless RNA-containing top layer to a new EP tube. Avoid aspirating other liquid layers during the aspiration process, as this will affect the purity of the RNA. Add 500 μL of isopropanol (add 500 μL of isopropanol to 1 mL of trozol for RNA precipitation during lysis), aspirate the supernatant (first use a 1 mL pipette tip, then a 200 μL pipette tip to prevent aspirating cells from the bottom layer during centrifugation), mix by hand, let stand for 10 min, and centrifuge at 4°C, 12000 rcf for 10 min. After centrifugation, a thin layer of white RNA precipitate will be observed. RNA washing: Discard the supernatant, add 1 mL of pre-chilled 75% ethanol, and gently wash with a 200 μL pipette tip (the pipette tip should not touch the precipitate to prevent nucleic acid chain breakage and aggregation), centrifuge at 4°C, 12000 rcf for 5 min. Then repeat the washing process twice more. RNA drying: Carefully aspirate the 75% ethanol solution with a small-range pipette and place the EP tube in a fume hood to air dry for 10 min. RNA dissolution: Add 20 μL of DEPC-treated water to the EP tube to dissolve the precipitate. RNA concentration determination: RNA concentration was determined using the nucleic acid analysis system of the NanoDrop instrument. Before use, the measurement wells were cleaned three times with sterile DEPC water and dried with lens paper. The instrument was first calibrated and zeroed with sterile DEPC water before sample testing. The measurement wells were cleaned with sterile DEPC water and dried with lens paper before each measurement to prevent interference between results from different groups.Each sample should be measured at least three times, and the average value should be taken. An OD260 / OD280 value between 1.8 and 2.1 indicates high RNA purity and is usable; otherwise, discard the sample. Reverse transcription: Prepare the reaction solution according to the kit instructions. Prepare two more reaction tubes than the actual number of reactions to avoid insufficient solution. Add 10 μL of reaction solution to each corresponding reaction tube, mix well, and immediately run the reverse transcription reaction. PCR reaction: Prepare the reaction solution according to the kit instructions. Set up three replicates for each sample. Determine product specificity based on the melting curve. Quantify relative mRNA expression using 2 - ΔΔct. PCR reaction program: 95℃, 10 min; 40 cycles (95℃, 15 s; 60℃, 1 min); 95℃, 15 s; 60℃, 1 min; 95℃, 15 s; 60℃, 15 s. Results are shown below. Figure 4 As shown.

[0137] Western blot detection of target protein

[0138] Cell processing: Discard the original culture medium, wash cells three times with pre-cooled PBS, digest cells with trypsin, stop digestion with three times the volume of complete culture medium, rinse the culture dish walls several times, and centrifuge the cell suspension. Next, wash cells three times with PBS, centrifuge, and discard the supernatant. Then, add an appropriate amount of RIPA lysis buffer containing 1% PMSF according to the cell growth density of each dish, repeatedly pipette to fully lyse the cells, and transfer the liquid to a 1.5 mL EP tube. Use a pipette to mix the lysis buffer and continue lysis on ice for 30 min. Centrifuge at 12000 rcf for 15 min at 4℃, transfer the supernatant, and store at -20℃. Detect protein concentration according to the BCA kit method. Tissue processing: Remove the heart tissue of each group of mice from the -80℃ freezer, weigh it, and cut the heart tissue into small pieces with scissors. Place it in a 1.5 mL EP tube, add RIPA lysis buffer containing 1% PMSF at a ratio of 0.1 g tissue to 1 mL lysis buffer to ensure thorough lysis. Tissue homogenization was performed using an ultrasonic homogenizer at low temperature (5 seconds / cycle, 3 seconds interval). After thorough homogenization, the tissue was vortexed and allowed to stand for 5 minutes, repeated 6 times, followed by centrifugation at 4°C for 15 minutes (12000 rcf). The supernatant (avoiding contact with the bottom precipitate) was transferred to 10 mL EP tubes using a pipette, and the protein-containing supernatant was diluted 10-fold or 20-fold. The protein concentration of the tissue supernatant was determined using the BCA kit method, and the sample protein was diluted to the same concentration. Sample preparation: The protein lysis buffer and loading buffer (5X) of the determined concentration were calculated according to the instructions to ensure a consistent final concentration for each group of protein loading buffers. The mixture was then boiled in a water bath for 10 minutes. After cooling the loading buffer to room temperature, it was stored at -20°C for later use. Gel preparation: Based on the required protein molecular weight, the necessary reagents were added according to the ratio to prepare the upper layer gel. The gel was poured, and 200 μL of isopropanol was added to flatten the gel surface. After standing for 20 minutes to allow the separating gel to solidify, the isopropanol was discarded, and the isopropanol was blotted dry with filter paper. Prepare the stacking gel by adding the required reagents according to the specified ratio. After pouring the stacking gel into the glass gel plate, quickly insert the comb vertically into the glass plate. After the stacking gel solidifies, transfer it to the electrophoresis apparatus and remove the comb in the electrophoresis solution. SDS-PAGE gel electrophoresis: Add 20 μg of sample to each well (20 μg / mL, 10 μL). After sample loading, first set the voltage to 80V for electrophoresis. After the markers separate (about 60 min), adjust the voltage to 100V and continue electrophoresis. Stop electrophoresis when the bromophenol blue reaches the bottom of the glass plate (about 90 min). Transfer membrane: Use wet transfer for electrophoresis. Before use, wet the PVDF membrane with methanol for 30 s and shake it in pre-cooled transfer solution for 15 min to ensure complete wetting of the PVDF membrane. Remove the protein gel from the glass plate and place it on the electrospinning clamp in the following order: sponge-filter paper-PVDF membrane-gel-filter paper-sponge. Place the electrospinning clamp in the electrospinning tank for electrospinning. The electrospinning time depends on the molecular weight of the protein.

[0139] Blocking: Dissolve the protein blocking powder in 1×TBST buffer to prepare a 5% blocking solution. Place the PVDF membrane in the blocking solution and shake on a shaker at room temperature for 2 hours. Co-incubation with primary antibody: After blocking, wash the PVDF membrane three times with 1×TBST buffer for 10 minutes each time. Dilute the antibody to the experimental concentration and immerse the PVDF membrane in the diluted primary antibody solution, incubating overnight at 4°C. Co-incubation with secondary antibody: After primary antibody incubation, wash the PVDF membrane three times with 1×TBST buffer for 10 minutes each time. Then, place the PVDF membrane in a 1:2000 solution of secondary antibody and incubate on a shaker at room temperature for 60 minutes. Chemiluminescence color development: After secondary antibody incubation, wash the PVDF membrane three times with 1×TBST buffer for 10 minutes each time. Evenly drop ECL luminescent solution onto the PVDF membrane, expose, and store. Image J quantitative analysis software was used to measure the image grayscale value, such as... Figure 4 As shown in 5, 6, and 11.

[0140] MTT assay for the effect of drugs on TGF-β1-induced CF proliferation

[0141] CFs in the logarithmic growth phase were digested with trypsin to prepare a single-cell suspension, and then subjected to a 5×10⁻⁶ ppm solution. 4 Cells were seeded at a density of [number] cells / mL in 96-well plates. After cell adhesion, the cells were starved for 12 h. Then, AGK2 (10 μM) and YC-5 (3, 10 μM) drug-containing culture medium were added. After 12 h of drug pre-protection, TGF-β1 (10 ng / mL) was added for continuous stimulation for 24 h. The control group received no TGF-β1 treatment. The OD value of each group of cells was measured, as shown below. Figure 7 As shown.

[0142] Construction of animal models

[0143] Establishment and administration of a TAC-induced rat model of myocardial fibrosis: Sprague Dawley (SD) rats were randomly divided into a sham-operated group, a TAC group, an AGK2 (33.3 mg / kg) group, and a YC-5 (6.67 mg / kg) group. After anesthesia, rats underwent TAC surgery to establish the model. The sternum was transversely severed between the second and third ribs using surgical scissors, muscles were bluntly dissected, the thymus was dissected, the aortic arch was freed, and a 21G constricting needle was placed along the aortic arch. A 7-0 nylon suture was placed between the brachiocephalic artery and the left common carotid artery, and the aortic arch and constricting needle were tied together. The constricting needle was immediately removed. The sham-operated model was the same as described above, except that the chest was opened, the suture was not ligated, and the surgical wound was sutured with interrupted sutures. AGK2 and YC-5 were administered starting the day after model establishment and continued for 21 days. The model groups were fed normally after model establishment. Following riboflavin treatment, blood was collected by enucleation under anesthesia. The blood was centrifuged (3000 rpm, 4°C, 30 min), and the supernatant was collected and frozen in liquid nitrogen for experimental use. The heart was removed, blood was squeezed out, wiped with filter paper, and the heart weight (HW) was measured to compare the heart weight / body weight (HW / BW, mg / kg) ratio. Heart tissue was rapidly frozen in liquid nitrogen for gene and protein expression analysis, or fixed with 4% paraformaldehyde for histological analysis. Establishment and administration of an isoproterenol (ISO)-induced mouse myocardial fibrosis model: Eight-week-old C57BL / 6 mice were randomly divided into a control group, an ISO (20 mg / kg) group, an AGK2 (50 mg / kg) group, and two YC-5 (10 mg / kg) and YC-5 (50 mg / kg) groups. The model groups and the administration groups received subcutaneous injections of ISO 20 mg / kg / day for 21 days. RF and PFD were administered 3 days prior to ISO modeling and continued for 24 days. Mice were anesthetized with sodium pentobarbital after riboflavin treatment. Blood was collected from the eyes of these mice after removal of the eyeballs. Blood was centrifuged (3000 rpm, 4°C, 30 min), and the supernatant was collected and frozen in liquid nitrogen for testing. The heart was removed, blood was squeezed out, wiped with filter paper, and the heart weight (HW) was measured to compare the heart weight / body weight (HW / BW, mg / kg) ratio. Heart tissue was rapidly frozen in liquid nitrogen for gene and protein expression analysis, or fixed with 4% paraformaldehyde for histological analysis, such as... Figure 8 As shown.

[0144] H&E staining

[0145] Hematoxylin-Eosin staining (H&E staining) involves drying paraffin sections in a 60°C oven for 2 hours before staining. After complete dewaxing, the sections are permeated with xylene in sequence, followed by gradient rehydration. Staining is then performed according to the instructions. The sections are mounted with neutral resin, covered with coverslips, and air-dried overnight in a ventilated room. Observation and photography are then performed under an upright microscope. Figure 9 As shown.

[0146] Masson tricolor dyeing

[0147] After preparing 5μm paraffin sections of heart tissue, staining was performed according to the instruction manual, followed by observation and photography using an upright microscope. The blue area of ​​the pathological sections was quantified using ImageJ software to better reflect the degree of fibrosis. Figure 9 , Figure 12 As shown.

[0148] Immunohistochemistry

[0149] A two-step method was used to detect the expression of α-SMA, p-Smad2, and p-Smad3 in cardiac tissue. The obtained paraffin-embedded cardiac sections were dewaxed with toluene and ethanol of different concentrations. Endogenous peroxidase was inactivated with sodium citrate buffer, followed by antigen retrieval at 37°C for 1.5 h. The sections were then incubated overnight with primary antibody at 4°C and incubated with secondary antibody at 37°C for 30 min. DAB staining and hematoxylin reverse staining were performed. Finally, image acquisition and data processing were conducted. Figure 10 and Figure 11 As shown.

[0150] Blood urea nitrogen (BUN) and creatinine (Scr) testing

[0151] Serum from each group of mice was removed from the -80°C freezer and placed on an ice box. Serum creatinine and urea nitrogen levels were measured using a commercially available BUN and Cr assay kit. BUN and Cr concentrations were calculated and statistically analyzed using given formulas, such as... Figure 13 As shown.

[0152] NT-proBNP detection

[0153] Serum from each group of mice was removed from the -80°C freezer and placed on an ice box. Serum NT-proBNP levels were measured using a commercially available NT-proBNP assay kit. NT-proBNP concentrations were calculated and statistically analyzed using a given formula, such as... Figure 8 As shown.

[0154] Hydroxyproline content detection

[0155] Cell treatment: After the cells reached the logarithmic growth phase, the culture dishes containing cells were removed from the incubator, and the cells were diluted and digested according to the instructions of the commercially available assay kit. The hydroxyproline level in the cells was then measured according to the instructions. The concentration of hydroxyproline was calculated and statistically analyzed using a given formula, such as... Figure 5 As shown.

Claims

1. 3-naphthiophene derivatives of general formula I or pharmaceutically acceptable salts thereof: in: R1 is an H atom; R2 is selected from C1-6 alkyl and substituted pyridine rings; the pyridine ring may be optionally substituted by one or more substituents selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, and formyl. 2,3-Naphthiophene derivatives or pharmaceutically acceptable salts thereof, characterized in that, The 3-naphthiophene derivatives are selected from the following compounds: 。 3. The method for preparing the 3-naphthiophene derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, Includes the following steps: Using 4-bromothiophene-2-carboxaldehyde 1a as a starting material, it was reacted with cyanoacetic acid via a Knoevenagel reaction to obtain carboxylic acid compound 2a. 2a was then coupled with 1-naphthoboronic acid via a Suzuki coupling reaction catalyzed by Pd(PPh3)4 to obtain key intermediate 3a. Key intermediate 3a was then refluxed in thionyl chloride to synthesize acyl chloride. Subsequently, under the condition of triethylamine as an acid-binding agent, it underwent an acid-amine condensation reaction with aminopyridine compounds or aliphatic amine compounds with different substitutions to synthesize compounds YC-1~YC-28; where R2 is the corresponding group at the corresponding position in compounds YC-1~YC-28.

4. A pharmaceutical composition, characterized in that, It comprises the 3-naphthiophene derivative of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, characterized in that, The dosage forms of the pharmaceutical composition are tablets, capsules, injectable solutions or ampoules, suppositories, patches, inhalable powders, suspensions, emulsions, and ointments.

6. The use of the 3-naphthiophene derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a SIRT2 inhibitor medicament.

7. Use of the pharmaceutical composition according to claim 4 or 5 in the preparation of a SIRT2 inhibitor drug.

Images