3-naphthyl thiophene derivative as well as preparation method and application thereof

Abstract

The invention discloses a 3-naphthyl thiophene derivative as well as a preparation method and application thereof, relates to the technical field of medicines, and in particular relates to the 3-naphthyl thiophene derivative as shown in a general formula I, an optical active body or racemate of the 3-naphthyl thiophene derivative, a diastereoisomer mixture of the 3-naphthyl thiophene derivative and application of the compound serving as an SIRT2 inhibitor in the aspect of resisting myocardial fibrosis. The invention also relates to the compounds, pharmaceutically acceptable salts of the compounds, pharmaceutical compositions taking the compounds as active ingredients, and pharmaceutically acceptable excipients and / or diluents of the compounds. The invention also relates to an administration dosage form of the compound containing at least one compound with the structural formula or the salt thereof. The dosage form can be tablets, coated tablets, capsules, solutions or ampoules for injection, suppositories, patches, inhalable powder preparations, suspensions, emulsions and ointments. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to 3-naphthylthiophene derivatives and a preparation method thereof, as well as application of the derivatives in the preparation of anti-myocardial fibrosis drugs. Background Art

[0002] SIRTs are a class of deacetylases that are highly conserved from bacteria to humans. There are seven recognized members of the human SIRTs family (SIRT1-7), all of which have highly conserved NAD + Binding domain and catalytic domain can mediate the reversible covalent modification of lysine residues in histone or non-histone sites. According to the different core domain sequences, they are divided into 4 categories: SIRT1-3 belong to category I, SIRT4 belongs to category II, SIRT5 belongs to category III, and SIRT6 and SIRT7 belong to category IV. Each protein in the SIRTs family has different cellular targets and cellular localizations. Currently recognized studies have shown that the subcellular localization of mammalian SIRTs mainly includes two nuclear proteins (SIRT1, SIRT6), one cytoplasmic protein (SIRT2), three mitochondrial proteins (SIRT3, SIRT4 and SIRT5) and one nucleolar protein (SIRT7). Each SIRTs protein is located in different subcellular regions, and the rich localization also means that the SIRTs family can bring about a variety of cellular functions. The distribution of SIRTs in different subcellular compartments interacts with a variety of transcription factors and participates in the regulation of different metabolic processes, such as regulating different metabolic processes, cell apoptosis, glucose homeostasis, stress response, and insulin secretion disorders. Some SIRTs can migrate depending on cell or tissue type, developmental stage, metabolic state, and certain stress conditions. In addition, they also play key roles in mitochondrial formation, DNA repair, inflammation development, and autophagy. Sirtuin 2 (SIRT2) is a NAD-dependent + A member of the SIRTs protein family of deacetylases, it is mainly present in the cytoplasm, but it can also be localized in the nucleus during mitosis. SIRT2 can be expressed in a variety of organs and tissues due to its large distribution in the body and its wide catalytic activity. It is particularly prominent in metabolism-related tissues, such as the brain, heart, liver, pancreas, kidneys and adipose tissue. SIRT2 plays a key role in normal physiological or pathological processes, involving gluconeogenesis, cardiomyopathy, regulation of the cell cycle, apoptosis, stress response, autophagy, inflammatory response and maintenance of genome stability. A large number of studies have shown that overexpression or dysregulation of SIRT2 is considered to be the main factor leading to a variety of human diseases, and is closely related to the occurrence of cancer, cardiovascular disease and neurodegenerative diseases. Studies have shown that SIRT2 exhibits deacetylation activity in a variety of substrates and interacts with NAD during the deacetylation process. +It couples to produce nicotinamide and O-acetyl-ADP-ribose, and can also catalyze the hydrolysis of long-chain fatty acids of 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 many diseases, and its small molecule inhibitors are considered to be potential intervention factors for the treatment of related diseases. The discovery of SIRT2 selective inhibitors has attracted widespread attention in recent years, thus emphasizing its potential therapeutic value in drug discovery. So far, a large number of SIRT2 inhibitors have been reported, which can be roughly divided into four categories according to the differences in the mechanism of action of the inhibitors, namely NAD + Competitive Inhibitors, Substrate Competitive Inhibitors, Substrates, and NAD + Dual competitive inhibitors, inhibitors that bind to selective active sites.

[0003] Myocardial fibrosis is a common pathological process in the progression of cardiovascular disease to the terminal stage, and is also an important cause of poor prognosis of heart failure. Studies have shown that cardiovascular disease is the leading cause of death worldwide, with nearly 18 million deaths each year. In recent years, the prevalence and mortality of cardiovascular diseases 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. Myocardial fibrosis is caused by many and complex factors, and the pathogenesis is not yet fully understood, so there is no clinical treatment for myocardial fibrosis. At present, there is evidence to support that clinical treatment drugs that can delay the progression of myocardial fibrosis are angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), but they do not specifically target the development of fibrosis. Pirfenidone is an FDA-approved drug for the treatment of idiopathic pulmonary fibrosis (IPF), which is believed to regulate its effects by reducing oxidative stress and TGF-β expression. In animal models of cardiac fibrosis, pirfenidone has been shown to reduce atrial fibrosis, limit post-infarction fibrosis expansion, and alleviate cardiac fibrosis caused by hypertension. In a clinical trial, 47 patients were randomly assigned to receive pirfenidone or placebo. Pirfenidone was shown to reduce cardiac fibrosis by 1.2%, but did not improve the diastolic function of the heart, and the therapeutic effect was limited. Therefore, developing effective drugs for the treatment of cardiac fibrosis by gaining a deep understanding of the regulatory mechanism of myocardial fibrosis and confirming therapeutic targets has important clinical significance for delaying the progression of heart disease and improving cardiac function.

[0004] TGF-β1 is an important mediator of CFs activation and plays a key role in the occurrence and development of cardiac fibrosis. Under the stimulation of various pathological factors, over-secreted TGF-β1 can drive CFs to overproliferate and transform into α-SMA-positive myofibroblasts (MFs). MFs are the main source of extracellular matrix (ECM), and the excessive deposition of ECM changes the original normal structure of the heart, leading to ventricular remodeling, myocardial wall stiffness, decreased compliance and cardiac cavity enlargement, and finally seriously impairing cardiac function. The classical Smad signaling pathway mediated by TGF-β1 and its receptor activates fibroblasts and promotes the production of ECM, playing a key role in organ fibrosis. Activated TGF-β1 can induce phosphorylation of its downstream signaling molecules Smad2 and Smad3, and the oligomeric complexes formed subsequently enter the nucleus and bind to transcription factors, regulating the expression of fibrosis-related proteins such as α-SMA and CoL-1A1. Therefore, preventing the occurrence of 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, inhibition of 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, and 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 damage can lead to increased SIRT2 expression, and treatment with the SIRT2-specific inhibitor AGK2 will improve myocardial remodeling and hypertrophy caused by I / R and TAC. It can be seen that SIRT2 expression is increased in a variety of heart disease models, and inhibition of SIRT2 can improve different heart diseases and then improve cardiac fibrosis, which provides a new target for the prevention and treatment of cardiac fibrosis. With the progress of a large number of studies, some scholars have further found that the process of slowing down the occurrence and development of cardiac fibrosis by inhibiting SIRT2 is related to TGF-β1. Studies have shown that the phosphorylation level of Smad signaling pathway proteins mediated by TGF-β1 can be significantly inhibited after inhibiting SIRT2. Many studies have shown that AGK2, as a specific inhibitor of SIRT2, can inhibit the activation of fibroblasts by inhibiting SIRT2 and the TGF-β1 signaling pathway. Therefore, starting from the SIRT2 target, using the TGF-β1 and TGF-β / Smad pathways as validation indicators, the discovery of effective anti-cardiac fibrosis drugs is of great significance for clinical prevention and treatment.

[0006] In summary, based on a large amount of literature research, the present invention designed and synthesized a series of new 3-naphthylthiophene derivatives, and conducted anti-myocardial fibrosis activity tests, which showed good activity. Summary of the invention

[0007] The purpose of the present invention is to design and synthesize a new class of 3-naphthylthiophene derivatives based on the original work, and to conduct research on anti-myocardial fibrosis.

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

[0009] In order to achieve the purpose of the present invention, the following technical scheme is adopted:

[0010] The present invention relates to 3-naphthylthiophene derivatives or pharmaceutically acceptable salts thereof having the following general formula I:

[0011]

[0012] in:

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

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

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

[0016]

[0017]

[0018]

[0019] The synthetic route of the 3-naphthylthiophene derivatives or pharmaceutically acceptable salts thereof, and their optically active forms or racemates, and diastereoisomer mixtures represented by the general formula I of the present invention includes the following:

[0020]

[0021] 4-Bromothiophene-2-carboxaldehyde 1a is used as a raw material, and cyanoacetic acid is reacted with Knoevenagel to obtain carboxylic acid compound 2a, and 2a and 1-naphthaleneboric acid are reacted with Suzuki coupling reaction under the catalysis of Pd(PPh3)4 to obtain key intermediate 3a. The key intermediate 3a is refluxed in thionyl chloride to synthesize acid chloride, and then triethylamine is used as an acid-binding agent to react with different substituted aminopyridine compounds or fatty amine compounds to synthesize compounds of general formula I, wherein R2 is the corresponding group at the corresponding position of compounds YC-1 to YC-28.

[0022] The present invention also relates to 3-naphthylthiophene derivatives shown in general formula I and their optically active forms or racemates, diastereoisomer mixtures, and the use of such compounds as SIRT2 inhibitors in anti-myocardial fibrosis. The present invention also relates to such compounds and their pharmaceutically acceptable salts and pharmaceutical compositions with such compounds as active ingredients, as well as pharmaceutically acceptable excipients and / or diluents for the above substances. The present invention also relates to dosage forms of such compounds containing at least one such structural formula compound or its salt, and the dosage forms are: tablets, coated tablets, capsules, injection solutions or ampoules, suppositories, patches, inhalable powder preparations, suspensions, emulsions and ointments.

[0023] Beneficial effects of the present invention:

[0024] The 3-naphthylthiophene derivatives or isomers thereof or pharmaceutically acceptable salts thereof of the present invention are used to prepare anti-myocardial fibrosis drugs. Myocardial fibrosis is a common pathological process of cardiovascular disease development to the terminal stage, and is also an important factor in the poor prognosis of heart failure. Cardiovascular disease is the main cause of death worldwide, causing nearly 18 million deaths each year. In recent years, the morbidity and mortality of cardiovascular diseases have continued to rise, seriously threatening people's health and life. Therefore, delaying myocardial fibrosis is crucial to improving the prognosis of patients with heart disease. The causes of myocardial fibrosis are numerous and complex, and its pathogenesis is still unclear. Therefore, there is currently no specific drug for myocardial fibrosis in clinical practice. The present invention deeply understands the regulatory mechanism of myocardial fibrosis, determines the therapeutic target, and has important clinical significance for developing effective drugs for the treatment of myocardial fibrosis to slow down the progression of heart disease and improve cardiac function. The present invention further enriches the diversity of anti-myocardial fibrosis inhibitors, and on this basis, lays a foundation for subsequent monomer compounds to carry out relevant biological activity tests, provides active lead compounds for new drug development, and also provides a theoretical basis for the in-depth research and development of SIRT2 inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 : Inhibitory activity of compounds on SIRT2;

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

[0027] Figure 3 :IC of YC-5 on CFs and CMs 50 value;

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

[0029] Figure 5: YC-5 can inhibit TGF-β1-induced cardiac fibroblast activation;

[0030] Figure 6 :Effect of YC-5 on Smad2 / 3 phosphorylation level induced by TGF-β1;

[0031] Figure 7 :Effect of YC-5 on TGF-β1-induced proliferation of CFs;

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

[0033] Fig. 9 :Effects of YC-5 on cardiac histopathology;

[0034] Fig.10 :Effects of YC-5 on the expression of α-SMA protein in cardiac tissue;

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

[0036] Fig.12 : Effects of YC-5 on hepato-renal toxicity. Fig.13 : Effects of YC-5 on creatinine and urea nitrogen levels. DETAILED DESCRIPTION

[0037] The compounds of the present invention and their preparation will be better understood in conjunction with the following examples, which are intended to illustrate but not to limit the scope of the invention.

[0038] Example 1, Synthesis of (E)-N-(pyridin-4-yl)-2-cyano-3-[4-(naphthalen-1-yl)thiophen-2-yl]acrylamide (YC-1)

[0039] 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 and 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 yield of the obtained white solid (2a, 10.14 g) was 75.1%.

[0040] At room temperature, intermediate 2a (5 g, 19.37 mmol) was dissolved in 150 mL of anhydrous ethanol. Subsequently, 1-cyclopentaneboronic acid (4.44 g, 23.25 mmol), K2CO3 (4.11 g, 38.75 mmol) and 50 mL of water were added, stirred for 30 min, Pd(PPh3)4 (1.34 g, 1.16 mmol) was added, refluxed under nitrogen for 6 h, and the reaction process was monitored by thin layer chromatography. After completion, the reaction mixture was hot filtered to remove insoluble impurities. The filtrate was concentrated in vacuo, stirred in 50 mL of dichloromethane at room temperature, filtered to obtain a white solid, washed with (30 mL × 2) of dichloromethane, dissolved in 100 mL of water, and adjusted to pH 3-4 with hydrochloric acid. The product was then filtered and washed with saturated aqueous sodium bicarbonate solution (30 mL×2), water (30 mL×2), and saturated saline solution (30 mL×2) in sequence, and dried to obtain a yellow solid (3a, 4.24 g) with a yield of 71.7%.

[0041] Take the intermediate (E)-2-cyano-3-[4-(naphthalen-1-yl)thiophen-2-yl]acrylic acid (3a, 0.5 g, 1.64 mmol), add 10 mL of thionyl chloride to dissolve, add 1 mL DMF, reflux reaction for 1h, after TLC monitoring the reaction of the raw materials, slightly cool, concentrate the reaction solution to remove the solvent thionyl chloride, then add cyclohexane (10mL×2) and concentrate again to remove the residual thionyl chloride, dissolve the obtained red solid acid chloride with 10mL of dichloromethane, slowly add it dropwise to a dichloromethane (20mL) solution of 4-aminopyridine (2.31g, 2.45mmol) pre-added with triethylamine (0.50g, 4.91mmol) using a constant pressure dropping funnel at room temperature, react under stirring at room temperature, monitor the reaction by TLC, after monitoring the reaction completion, wash twice with saturated brine (50mL×2), evaporate to dryness and concentrate to obtain 0.8g of yellow solid, which is completely dissolved with 20mL of dichloromethane, add 2g of sample-mixed silica gel, and 10g of blank silica gel to load the column, with a volume ratio of dichloromethane:methanol=50:1 as the eluent, and purify by column chromatography to obtain 0.39g of yellow solid powder, with a yield of 63.49%.

[0042] 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.

[0043] Example 2, (E)-N-(2-bromopyridin-4-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-2)

[0044] The preparation method of the compound of Example 2 is the same as that of Example 1, except that 2-bromo-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 70.42%.

[0045] 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 (150 MHz, 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.

[0046] Example 3, (E)-2-cyano-N-(3-methylpyridin-4-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-3)

[0047] The preparation method of the compound of Example 3 is the same as that of Example 1, except that 3-methyl-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 63.42%.

[0048] 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.

[0049] Example 4, (E)-2-cyano-N-(2-methylpyridin-4-yl)-3-(4-(naphthalen-1-yl)thiophene-2-yl)acrylamide (YC-4)

[0050] The preparation method of the compound of Example 4 is the same as that of Example 1, except that 2-methyl-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 53.20%.

[0051] 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.

[0052] Example 5, (E)-2-cyano-N-(3-formylpyridin-4-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-5)

[0053] The preparation method of the compound of Example 5 is the same as that of Example 1, except that 3-formyl-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 56.83%.

[0054] 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.

[0055] Example 6, (E)-N-(3-chloropyridin-4-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-6)

[0056] The preparation method of the compound of Example 6 is the same as that of Example 1, except that 3-chloro-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 76.47%.

[0057] 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.

[0058] Example 7, (E)-N-(2-chloropyridin-4-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-7)

[0059] The preparation method of the compound of Example 7 is the same as that of Example 1, except that 2-chloro-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 72.03%.

[0060] 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.

[0061] Example 8, (E)-2-cyano-3-(4-(naphthalen-1-yl)thiophene-2-yl)-N-(pyridin-4-ylmethyl)-acrylamide (YC-8)

[0062] The preparation method of the compound of Example 8 is the same as that of Example 1, except that 4-aminomethylpyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 58.44%.

[0063] 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.

[0064] Example 9, (E)-2-cyano-3-(4-(naphthalen-1-yl)thiophene-2-yl)-N-(2-(pyridin-4-yl)ethyl)acrylamide (YC-9)

[0065] The preparation method of the compound of Example 9 is the same as that of Example 1, except that 4-aminoethylpyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 54.18%.

[0066] 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.

[0067] Example 10, (E)-2-cyano-3-(4-(naphthalen-1-yl)thiophene-2-yl)-N-(pyridin-3-ylmethyl)-acrylamide (YC-10)

[0068] The preparation method of the compound of Example 10 is the same as that of Example 1, except that 3-aminomethylpyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 57.28%.

[0069] 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.

[0070] Example 11, (E)-2-cyano-N-(5-methylpyridin-2-yl)-3-(4-(naphthalen-1-yl)thiophene-2-yl)acrylamide (YC-11)

[0071] The preparation method of the compound of Example 11 is the same as that of Example 1, except that 2-amino-5-methylpyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 57.41%.

[0072] 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.

[0073] Example 12, (E)-2-cyano-N-(4-methylpyridin-2-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-12)

[0074] The preparation method of the compound of Example 12 is the same as that of Example 1, except that 2-amino-4-methylpyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 55.64%.

[0075] 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.

[0076] Example 13, (E)-N-(5-chloropyridin-2-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-13)

[0077] The preparation method of the compound of Example 13 is the same as that of Example 1, except that 2-amino-5-chloropyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 72.43%.

[0078] 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.

[0079] Example 14, (E)-N-(4-chloropyridin-2-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-14)

[0080] The preparation method of the compound of Example 14 is the same as that of Example 1, except that 2-amino-4-chloropyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 73.07%.

[0081] 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.

[0082] Example 15, (E)-2-cyano-N-(5-fluoropyridin-2-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-15)

[0083] The preparation method of the compound of Example 15 is the same as that of Example 1, except that 2-amino-5-fluoropyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 51.87%.

[0084] 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.

[0085] Example 16, (E)-N-(4-bromopyridin-2-yl)-2-cyano-3-(3-(naphthalen-1-yl)cyclopenta-1,3-dien-1-yl)acrylamide (YC-16)

[0086] The preparation method of the compound of Example 16 is the same as that of Example 1, except that 2-amino-4-bromopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 68.82%.

[0087] 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.

[0088] Example 17, (E)-N-(5-bromopyridin-2-yl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-17)

[0089] The preparation method of the compound of Example 17 is the same as that of Example 1, except that 2-amino-5-bromopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 75.43%.

[0090] 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.

[0091] Example 18, (E)-2-cyano-N-(2-methoxypyridin-4-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-18)

[0092] The preparation method of the compound of Example 18 is the same as that of Example 1, except that 2-methoxy-4-aminopyridine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 69.43%.

[0093] 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.

[0094] Example 19, (E)-N-butyl-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-19)

[0095] The preparation method of the compound of Example 19 is the same as that of Example 1, except that 1-aminobutane is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 62.31%.

[0096] 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.

[0097] Example 20, (E)-2-cyano-3-(4-(naphthalen-1-yl)thiophene-2-yl)-N-pentyl acrylamide (YC-20)

[0098] The preparation method of the compound of Example 20 is the same as that of Example 1, except that 1-aminopentane is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 59.31%.

[0099] 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.

[0100] Example 21, (E)-2-cyano-N-hexyl-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-21)

[0101] The preparation method of the compound of Example 21 is the same as that of Example 1, except that 1-aminohexane is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 67.96%.

[0102] 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.

[0103] Example 22, (E)-2-cyano-N-isobutyl-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-22)

[0104] The preparation method of the compound of Example 22 is the same as that of Example 1, except that 2-aminoisobutane is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 63.43%.

[0105] 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.

[0106] Example 23, (E)-2-cyano-N-isopropyl-3-(4-(naphthalen-1-yl)thiophen-2-yl)-acrylamide (YC-23)

[0107] The preparation method of the compound of Example 23 is the same as that of Example 1, except that 2-aminopropane is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 64.5%.

[0108] 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.

[0109] Example 24, (E)-2-cyano-N-isopentyl-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-24)

[0110] The preparation method of the compound of Example 24 is the same as that of Example 1, except that isopentylamine is used in place of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 60.27%.

[0111] 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.

[0112] Example 25, (E)-2-cyano-3-(4-(naphthalen-1-yl)thiophene-2-yl)-N-neopentyl acrylamide (YC-25)

[0113] The preparation method of the compound of Example 25 is the same as that of Example 1, except that neopentylamine is used in place of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 65.49%.

[0114] 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.

[0115] Example 26, (E)-N-(sec-butyl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-26)

[0116] The preparation method of the compound of Example 26 is the same as that of Example 1, except that sec-butylamine is used in place of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 67.84%.

[0117] 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.

[0118] Example 27, (E)-N-(tert-butyl)-2-cyano-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-27)

[0119] The preparation method of the compound of Example 27 is the same as that of Example 1, except that tert-butylamine is used in place of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 67.98%.

[0120] 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.

[0121] Example 28, (E)-2-cyano-N-(3-methylbutan-2-yl)-3-(4-(naphthalen-1-yl)thiophen-2-yl)acrylamide (YC-28)

[0122] The preparation method of the compound of Example 28 is the same as that of Example 1, except that 3-methylbutylamine is used instead of 4-aminopyridine in the fourth step to obtain a yellow solid powder with a yield of 66.82%.

[0123] 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.

[0124] Pharmacological studies of the product of the present invention

[0125] Pharmacological tests have shown that the compounds of the present invention have anti-myocardial fibrosis activity

[0126] Substrate fluorescence assay to detect SIRT2 activity

[0127] Reagent preparation: Dilution of SIRT2 direct assay buffer (10X): Dilute 3 mL of detection 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) should be used for detection and dilution reagents. Configuration 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 stable on ice for 4 h. SIRT2 direct peptide: Each vial contains 100 μL of 5 mM peptide solution containing amino acids 317-320 of human p53 conjugated aminocoumarin (AMC). It is ready for making substrate solution. SIRT2 direct NAD + : This vial contains 500 μL of 50 mM NAD + Solution. It is ready to be used to make substrate solution. SIRT2 Direct Nicotinamide: This vial contains 500 μL of 50 mM Nicotinamide solution, a Sirtuin inhibitor. It is ready to be used to make reaction stop solution. SIRT2 Direct Developer: This vial contains 100 mg of SIRT2 Developer. SIRT2 Direct Fluorophore; 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 makes 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 ​​are 51 and 213 μM, respectively. Add the corresponding reagents to each well according to the instructions, and then add 15 μL of substrate solution to all used wells to initiate the reaction. Cover the plate and incubate on a shaker at 37°C for 45 minutes. Preparation of the reaction stop solution: put 30 mg of the 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 cover and add 50 μL of the reaction stop solution. Cover with the plate cover and incubate at room temperature for 30 minutes. Remove the plate cover and read the plate using an excitation wavelength of 350-360 nm and an emission wavelength of 450-465 nm to calculate the drug inhibition rate, such as Figure 1 and Figure 2 shown.

[0128] MTT assay for cytotoxicity

[0129] In this experiment, primary CFs and CMs were used. First, CFs in the logarithmic growth phase were digested with trypsin to prepare a cell suspension. The diluted cell suspension was diluted to 1×10 4 100 cells / well were inoculated in a 96-well plate. CMs were directly spotted with the extracted primary cell suspension. After the cells adhered, the culture medium was replaced with 0% FBS and starved for 12 hours. Subsequently, the serum-free culture medium was replaced with a culture medium containing YC-5 (0.3, 1, 3, 10, 30, 100 μM) 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. Finally, the supernatant was discarded, 150 μL of DMSO was added to each well and shaken for 10 minutes, and the OD value was detected at a wavelength of 492 nm using a multifunctional microplate reader. Finally, the cell survival rate was calculated according to the formula. IC value of YC-5 for CFs and CMs 50 Value, see Figure 3 .

[0130] Construction of in vitro myocardial fibrosis cell model induced by TGF-β1

[0131] CFs cells were inoculated in a culture container (96-well plate, 70 mm culture dish, etc.) according to a certain ratio. After adherence, they were starved for 12 hours using 0% FBS culture medium to synchronize cell growth as much as possible. Then, they were replaced with 0% FBS culture medium containing or without drugs for pre-protection for 12 hours. The culture medium of each group was then replaced with 0% FBS culture medium containing or without drugs and TGF-β1 (10 ng / mL) was added for continuous stimulation for 48 hours, and then subsequent experiments could be carried out.

[0132] Substrate fluorescence assay to detect the effect of candidate compounds on SIRT2 activity in cells

[0133] Primary CFs of cell treatment for 2-3 generations were seeded in 75 mm 2In the culture dish, after the cells adhered to the wall, each group was replaced with 0% FBS culture medium for starvation culture for 12h, aiming to synchronize cell growth as much as possible. The drug group replaced the original culture medium with 0% FBS culture medium containing the required drug concentration for pre-protection for 12h, and the control group was also replaced with 0% FBS culture medium for culture. Subsequently, the culture medium of each group was replaced with 0% FBS culture medium containing or without drugs, and TGF-β1 (10ng / mL) was added at the same time for continuous stimulation for 48h. Total protein extraction and determination The original culture medium was discarded, the cells were washed three times with pre-cooled PBS, the cells were digested with trypsin, and the digestion was terminated with three times the volume of complete culture medium, the culture dish wall was blown several times, and the cell suspension was centrifuged. Next, the cells were washed 3 times with PBS, centrifuged, and the supernatant was discarded. Use 150μL of RIPA lysis solution, repeatedly blow the cells to fully lyse the cells, and transfer the liquid to a 1.5mL EP tube, use a pipette to blow the lysis solution evenly, and continue to lyse on ice for 30min. After centrifugation at 4°C and 12,000 rpm for 15 minutes, transfer the supernatant and store at -20°C. Detect the protein concentration according to the BCA kit method. Activity detection: dilute the cell lysate with SIRT2 experimental buffer to make the total protein concentration of each group consistent. Then, add 10 μL of protein, 20 μL of SIRT2 buffer and 20 μL of SIRT2 substrate to a black 96-well plate in sequence, incubate at 37°C in the dark for 45 minutes to allow the system to react, add 50 μL of developer to each well, and incubate at room temperature for 30 minutes to generate fluorescence. The fluorescence intensity released in this process is measured using an automatic microplate reader (Ex: 350 nm, Em: 450 nm), such as Figure 4 shown.

[0134] RT-PCR detection of the effects of candidate compounds on SIRT2 expression

[0135] Cell treatment: Same as the above-mentioned experiment to detect SIRT2 enzyme activity in cells. RNA extraction: Wear disposable sterile gloves and masks without powder and dust before the experiment, and all operations are completed in the fume hood to prevent RNase contamination. Cell lysis: Pour out the culture medium, wash twice with 2mL PBS, digest with trypsin, terminate digestion with 1-2 times the volume of 10% culture medium, blow off the cells appropriately, transfer to a 15mL centrifuge bucket, centrifuge at 1000rcf for 5min, and discard the supernatant. Add PBS to blow, centrifuge again, discard the supernatant, and use it for subsequent RNA extraction. Pipette 1mL of Trizol into the centrifuge bucket, blow to disperse the clumped cells and fully lyse and transfer to a 1.5mL EP tube, let it stand for 5min, and centrifuge at 12000rcf for 5min at 4℃. Phase separation: After the centrifugation, slowly and steadily remove the centrifuge tube to avoid shaking, and aspirate the supernatant into a 1.5mL EP tube. Add 200μL of chloroform (after adding chloroform, the solution is divided into aqueous phase and organic phase, and RNA is in the aqueous phase. Take out the aqueous phase and use isopropanol to precipitate and recover RNA), shake by hand (do not vortex, too much force will easily break the RNA single strand), and time for 5 minutes. Five minutes later, centrifuge in a microcentrifuge at 4°C, 12000rcf for 15 minutes. After the centrifugation is completed, slowly and steadily remove the centrifuge tube, and observe that the liquid in the tube will be layered, red organic phase (lower layer), white protein layer (middle layer) and colorless RNA-containing layer (upper layer). RNA precipitation: Pipette the upper colorless RNA-containing layer into a new EP tube. During the aspiration process, avoid absorbing other layers of liquid to affect the purity of the RNA. Add 500μL isopropanol (500μL isopropanol should be added to 1mL trozol during lysis to precipitate RNA), aspirate the supernatant (first use a 1mL pipette tip, then a 200μL pipette tip, the purpose is to prevent the centrifuged cells at the bottom from being aspirated), shake well by hand, let stand for 10min, and centrifuge at 4℃, 12000rcf for 10min. A thin layer of white RNA precipitate can be observed after the centrifugation. RNA cleaning: Pour off the upper layer, add 1mL of pre-cooled 75% ethanol, and gently blow with a 200μL pipette tip (the pipette tip should not touch the precipitate to prevent the nucleic acid chain from breaking and not gathering together), 4℃, 12000rcf, centrifuge for 5min. Then repeat the washing twice as above. RNA drying: Carefully aspirate the 75% ethanol solution with a small-range pipette, and place the EP tube in a fume hood for ventilation and drying for 10min. RNA dissolution: Add 20μL of DEPC-treated water to the EP tube to dissolve the precipitate. RNA concentration determination: RNA concentration was determined using the NanoDrop analyzer's nucleic acid analysis system. The measuring hole was cleaned three times with sterile DEPC water before use and wiped dry with lens paper. The instrument was first calibrated and zeroed with sterile DEPC water. The sample could be tested only after calibration and zeroing. Before each measurement, the measuring hole was cleaned with sterile DEPC water and wiped dry with lens paper to prevent interference between the results of different groups.Each sample was measured at least three times, and the results were averaged. The OD260 / OD280 value of the sample between 1.8-2.1 indicates that the RNA purity is high and can be used, otherwise it is discarded. Reverse transcription: Prepare the reaction solution according to the operating procedures of the kit. When preparing, it should be prepared according to an amount that is 2 more than the actual number of reactions to avoid insufficient reaction solution. Add 10μL of reaction solution to each corresponding reaction tube, mix well and immediately perform reverse transcription reaction on the machine. PCR reaction: Prepare the reaction solution according to the operating procedures of the kit. Set up 3 replicates for each sample, determine the product specificity based on the melting curve, and calculate the relative expression of mRNA using 2-△△ct. PCR reaction program: 95℃, 10min; 40 cycles (95℃, 15s; 60℃, 1min); 95℃, 15s; 60℃, 1min; 95℃, 15s; 60℃, 15s, the results are as follows. Figure 4 shown.

[0136] Western Blot detection of target protein

[0137] Cell treatment: discard the original culture medium, wash the cells three times with pre-cooled PBS, digest the cells with trypsin, terminate the digestion with three times the volume of complete culture medium, blow the culture dish wall several times, and centrifuge the cell suspension. Next, wash the cells 3 times with PBS, centrifuge, and discard the supernatant. According to the cell growth density of each group of dishes, add an appropriate amount of RIPA lysis buffer containing 1% PMSF, repeatedly blow the cells to fully lyse the cells, and transfer the liquid to a 1.5mL EP tube, use a pipette to blow the lysis buffer evenly, and continue to lyse on ice for 30min. Centrifuge at 4℃, 12000rcf for 15min, transfer the supernatant, and store at -20℃. Detect protein concentration according to the BCA kit method. Tissue treatment: Take the heart tissue of each group of mice out of the -80℃ refrigerator, weigh it, and cut the heart tissue into pieces with scissors and put it into a 1.5mL EP tube. Add RIPA lysis buffer containing 1% PMSF at a ratio of 0.1g tissue to 1mL lysis buffer for subsequent full fragmentation. Use an ultrasonic crusher to homogenize the tissue under low temperature conditions (5s / time, 3s interval). After the tissue is fully ground, vortex and stand for 5min, repeat 6 times, and then place it in a 4℃ high-speed centrifuge for 15min (12000rcf). Use a pipette to transfer the supernatant (do not touch the bottom precipitate) to a 10mL EP tube and dilute the protein-containing supernatant by 10 times or 20 times. Use the BCA kit method to measure the protein concentration of the tissue supernatant and dilute the sample protein to the same concentration. Sample preparation: Calculate the protein lysate and loading buffer (5X) with the measured concentration according to the proportion in the instructions, so that the final concentration of each group of protein loading buffer is consistent, and then boil it in a water bath for 10min. After cooling the loading buffer at room temperature, store it in a -20℃ refrigerator for use. Glue preparation: According to the required protein molecular weight, add the required reagents according to the proportion to prepare the upper layer of glue, pour the glue, and add 200μL of isopropanol to flatten the glue surface. After standing for 20min to solidify the separation gel, discard the isopropanol and absorb the isopropanol with filter paper. Add the required reagents in proportion to prepare the concentrated gel. After the concentrated gel is poured into the glass gel plate, quickly insert the comb vertically into the glass plate. After the concentrated gel solidifies, transfer it to the electrophoresis device and pull out the comb in the electrophoresis solution. SDS-PAGE gel electrophoresis: 20μg of sample is added to each well (20μg / mL, 10μL). After the sample is loaded, first set the voltage to 80V for electrophoresis. After the Marker is separated (about 60min), adjust the voltage to 100V and continue electrophoresis. When bromophenol blue runs to the bottom of the glass plate, the electrophoresis can be terminated (about 90min). Transfer: Use wet transfer for electrophoresis. The PVDF membrane is soaked in methanol for 30s before use, and shaken in the pre-cooled electrotransfer solution for 15min to completely soak the PVDF membrane. Remove the protein gel from the glass plate and place it on the electrotransfer clamp in the order of sponge-filter paper-PVDF membrane-gel-filter paper-sponge. Place the electrotransfer clamp in the electrotransfer tank for electrotransfer. The electrotransfer time depends on the molecular weight of the protein.

[0138] Blocking: Dissolve the protein blocking powder into 5% blocking solution with 1×TBST buffer, 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 in 1×TBST buffer for 3 times, 10 minutes each time. Dilute the antibody to the experimental concentration, soak the PVDF membrane in the diluted primary antibody liquid, and incubate in a refrigerator at 4°C overnight. Co-incubation with secondary antibody: After the primary antibody incubation, wash the PVDF membrane in 1×TBST buffer for 3 times, 10 minutes each time. Then place the PVDF membrane in 1:2000 secondary antibody and incubate on a shaker at room temperature for 60 minutes. Chemiluminescence color development: After the secondary antibody incubation, wash the PVDF membrane in 1×TBST buffer for 3 times, 10 minutes each time. Evenly drop ECL luminescent liquid on the PVDF membrane, expose and save. Use Image J quantitative analysis software to measure the grayscale value of the image, such as Figure 4 , as shown in Figures 5, 6, and 11.

[0139] MTT assay to detect the effect of drugs on TGF-β1-induced CFs proliferation

[0140] CFs in the logarithmic growth phase were obtained and digested with trypsin to prepare a single cell suspension. 4 Cells were seeded at a density of 100 cells / mL in a 96-well plate. After the cells adhered to the wall, they were starved for 12 hours. Then, AGK2 (10 μM) and YC-5 (3, 10 μM)-containing culture medium were added. After 12 hours of drug pre-protection, TGF-β1 (10 ng / mL) was added for continuous stimulation for 24 hours. The control group was not treated with TGF-β1. The OD value of each group of cells was measured, as shown in Figure 2. Figure 7 shown.

[0141] Construction of animal models

[0142] Establishment and administration of TAC-induced rat myocardial fibrosis model: Sprague Dawley (SD) rats were randomly divided into sham operation group, TAC group, AGK2 (33.3 mg / kg) bracket question group and YC-5 (6.67 mg / kg) group and YC-5 (33.3 mg / kg) group. After anesthesia, the rats underwent TAC surgery to establish the model. The sternum was transected between the second and third ribs using surgical scissors, the muscles were bluntly separated, the thymus was stripped, the aortic arch was freed, and a 21G constriction needle was placed along the aortic arch. A 7-0 nylon suture was placed between the innominate artery and the left common carotid artery and the aortic arch and constriction needle were tied together, and the constriction needle was immediately removed. The sham operation was the same as described above, only the chest was opened, the line was not ligated, and the surgical wound was sutured with interrupted sutures. AGK2 and YC-5 were administered starting on the second day after modeling for a total of 21 days. The model group was routinely fed after modeling. After riboflavin treatment, the eyeballs were removed under anesthesia and blood was collected. The blood was centrifuged (3000 rpm, 4°C, 30 min) and the supernatant was removed and frozen in liquid nitrogen for experiments. The heart was removed, the blood was squeezed out, and the heart weight (HW) was weighed to compare the heart weight / body weight (HW / BW, mg / kg) ratio. Heart tissue was quickly frozen in liquid nitrogen for gene and protein expression analysis, or fixed with 4% paraformaldehyde for histological analysis. Establishment and administration of isoproterenol (ISO)-induced mouse myocardial fibrosis model: 8-week-old C57BL / 6 mice were randomly divided into control group, ISO (20 mg / kg) group, AGK2 (50 mg / kg) group, YC-5 (10 mg / kg) group and YC-5 (50 mg / kg) group. The model group and the drug group were subcutaneously injected with ISO 20 mg / kg / d for 21 days. RF and PFD were administered starting 3 days before ISO modeling and for a total of 24 days. After riboflavin treatment, mice were anesthetized with sodium pentobarbital. The eyeballs of these mice were removed to collect blood. The blood was centrifuged (3000 rpm, 4°C, 30 min) and the supernatant was removed and frozen in liquid nitrogen for experiments. The heart was removed, the blood was squeezed out, wiped with filter paper, and the heart weight (HW) was weighed to compare the heart weight / body weight (HW / BW, mg / kg) ratio. Heart tissue was quickly frozen in liquid nitrogen for gene and protein expression analysis, or fixed with 4% paraformaldehyde for histological analysis, such as Figure 8 shown.

[0143] H&E staining

[0144] Hematoxylin-Eosin Staining (H&E staining) Before staining, place the paraffin sections in a 60℃ drying oven for 2 hours. After the paraffin on the slide is completely dewaxed, it is permeabilized with xylene in sequence and then rehydrated in a gradient manner. Then, stain according to the instructions, seal the slide with neutral gum, cover it with a cover glass, and place it in a ventilated kitchen to air dry overnight. Then, observe and take pictures under an upright microscope. Fig. 9 shown.

[0145] Masson's trichrome stain

[0146] The prepared 5 μm paraffin sections of cardiac tissue were processed and stained according to the instructions, and observed and photographed under an upright microscope. The blue area of ​​the pathological sections was quantified using Image J software to better reflect the degree of fibrosis. Fig. 9 , Fig.12 shown.

[0147] Immunohistochemistry

[0148] The expression of α-SMA, p-Smad2, and p-Smad3 in cardiac tissue was detected by a two-step method. The obtained cardiac paraffin sections were dewaxed with toluene and different concentrations of ethanol, and antigen retrieval was performed after inactivation of endogenous peroxidase with sodium citrate buffer, blocked at 37°C for 1.5h, and then incubated with primary antibody at 4°C overnight and with secondary antibody at 37°C for 30min. DAB staining, hematoxylin counterstaining, and finally image acquisition and data processing were performed, such as Fig.10 and Fig.11 shown.

[0149] Blood urea nitrogen (BUN) and creatinine (Scr) testing

[0150] The serum of each group of mice was taken out from the -80℃ refrigerator and placed on an ice box. The levels of creatinine and urea nitrogen in serum were measured using commercially available BUN and Cr assay kits. The concentrations of BUN and Cr were calculated and statistically analyzed using the given formulas, as follows: Fig.13 shown.

[0151] NT-proBNP test

[0152] The serum of each group of mice was taken out from the -80℃ refrigerator and placed on an ice box. The NT-proBNP level in the serum was measured using a commercially available NT-proBNP assay kit. The NT-proBNP concentration was calculated and statistically analyzed using the given formula, as follows: Figure 8 shown.

[0153] Hydroxyproline content detection

[0154] Cell treatment: After the cells grow to the logarithmic growth phase, take out the culture dishes containing cells from the incubator, dilute and digest according to the instructions of the commercially available assay kit, and measure the hydroxyproline level in the cells according to the instructions. The concentration of hydroxyproline is calculated and counted using the given formula, such as Figure 5 shown.

Claims

1. 3-naphthylthiophene derivatives or pharmaceutically acceptable salts thereof represented by general formula I: in: R1 and R2 are each independently selected from any one of the following groups: (1) an H atom, (2) a hydroxyl group, (3) a halogen atom, (4) a cyano group, (5) a nitro group, (6) a trihalomethyl group, (7) a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylsulfonylamino group, a C1-18 alkoxycarbonyl group, a C1-18 alkoxysulfonyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C2-6 alkenylthio group, a C2-6 alkynylthio group, a C1-6 alkylsulfonyl group, a C2-6 alkenylsulfonyl group, a C2-6 alkynylsulfonyl group, a C1-6 alkylsulfinyl group, a C2-6 alkenyl sulfinyl, C2-6 alkynylsulfinyl, C3-8 cycloalkenyl, each of which is arbitrarily substituted by one or more substituents selected from the group consisting of H atoms, halogen atoms, hydroxyl groups, cyano groups, nitro groups and amino groups; (8) various substituted carbonyl groups, which are arbitrarily substituted by one or more substituents selected from the group consisting of H atoms, hydroxyl groups, C1-6 alkyl groups, amino groups, C1-6 alkylamino groups, C1-6 alkoxy groups, C1-6 alkylthio groups and C3-8 cycloalkyl groups; (9) various substituted amino groups, which are arbitrarily substituted by one or more substituents selected from the group consisting of H atoms, C1-6 alkyl groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C1-6 alkylsulfonyl groups, C2-6 alkenylsulfonyl groups, C2-6 alkynylsulfonyl groups, C1-6 alkylcarbonyl groups , C2-6 alkenylcarbonyl and C2-6 alkynylcarbonyl substituted with one or more substituents, (10) substituted with various substituted phenyl, various substituted benzyl, various substituted benzyloxy, various substituted benzoyl, various substituted benzenesulfonyl, various substituted pyridine ring, various substituted pyrazole ring, various substituted pyrrole ring, various substituted pyrimidine ring, various substituted quinoline ring, various substituted isoquinoline ring, various substituted imidazole ring, various substituted morpholine ring, various substituted piperazine ring, various substituted pyridazine ring, various substituted pyrazine ring, various substituted piperidine ring, various substituted thiophene ring, various substituted thiazole ring, various substituted isothiazole ring, benzothiazole ring with various substitutions, pyran ring with various substitutions, indole ring with various substitutions, oxazole ring with various substitutions, isoxazole ring with various substitutions, triazole ring with various substitutions, benzotriazole ring with various substitutions, furan ring with various substitutions, the above groups are arbitrarily substituted by one or more substituents selected from H, halogen, C1-6 alkyl, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 alkanesulfonylamino, benzyloxycarbonyl, C1-18 alkoxycarbonyl, C1-18 alkoxysulfonyl, trihalomethyl, hydroxyl, cyano, nitro, formyl and amino groups, (11) adjacent R1 and R2 are connected to form an alkylenedioxy group.

2. The 3-naphthylthiophene derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the general formula I, R1 and R2 are each independently selected from the following groups: (1) H atom, (2) hydroxyl group, (3) halogen atom, (4) nitro group, (5) C1-6 alkyl group, C1-4 alkoxy group, each of the above groups is unsubstituted or substituted by one or more substituents selected from H atom, halogen atom, hydroxyl group, cyano group, nitro group and amino group, (6) phenyl group substituted with various substituents, benzyloxy group substituted with various substituents, pyridine ring substituted with various substituents, each of the above groups is substituted by one or more substituents selected from H, halogen, C1-4 alkyl group, C1-4 alkylamino group, C3-7 cycloalkyl group, C1-6 alkoxy group, C1-6 alkanesulfonylamino group, benzyloxycarbonyl group, C1-18 alkoxycarbonyl group, C1-18 alkoxysulfonyl group, trihalomethyl group, hydroxymethyl group, hydroxyl group, cyano group, nitro group and formyl group.

3. The 3-naphthylthiophene derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The 3-naphthylthiophene derivatives are selected from the following compounds:

4. The method for preparing the 3-naphthylthiophene derivative or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The steps include: 4-Bromothiophene-2-carboxaldehyde 1a is used as a raw material and reacted with cyanoacetic acid to obtain a carboxylic acid compound 2a through a Knoevenagel reaction. 2a and 1-naphthaleneboric acid are reacted with Suzuki coupling reaction under the catalysis of Pd(PPh3)4 to obtain a key intermediate 3a. The key intermediate 3a is refluxed in thionyl chloride to synthesize an acyl chloride. Subsequently, it is reacted with differently substituted aminopyridine compounds or fatty amine compounds under the condition of triethylamine as an acid-binding agent to undergo an acid-amine condensation reaction to synthesize compounds YC-1 to YC-28; wherein R2 is the corresponding group at the corresponding position of compounds YC-1 to YC-28.

5. A pharmaceutical composition, characterized in that It comprises the 3-naphthylthiophene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that The dosage forms of the pharmaceutical composition include tablets, coated tablets, capsules, injection solutions or ampoules, suppositories, patches, inhalable powder preparations, suspensions, emulsions and ointments.

7. Use of the 3-naphthylthiophene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as a SIRT2 inhibitor in the treatment of myocardial fibrosis.

8. Use of the pharmaceutical composition according to claim 5 or 6 as a SIRT2 inhibitor in anti-myocardial fibrosis.

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