CN105859633B - A kind of 2- thiacetamides benzimidazoles compound and its preparation method and application - Google Patents

Abstract

The present invention provides a 2-thioacetamide benzimidazole compound and its preparation method and application. The 2-thioacetamide benzimidazole compound has a structure shown in formula I, which has obvious inhibitory effect on HCV virus , the anti-HCV viral therapeutic index is higher than the current clinical drug interferon α-1b (IFNα-1b) and ribavirin (Ribavirin), which can be used as an anti-HCV drug candidate, and the preparation method of the present invention is simple and has high yield, Suitable for industrial production.

Description

A kind of 2-thioacetamide benzimidazole compound and its preparation method and application

technical field

The invention belongs to the technical field of medicine preparation, and relates to a 2-thioacetamide benzimidazole compound and its preparation method and application.

Background technique

Hepatitis C virus (Hepatitis C Virus, HCV) is the non-A non-B hepatitis disease virus of parenteral transmission that was first successfully cloned by Choo et al. in 1989. Studies have shown that HCV is one of the main pathogens that cause chronic hepatitis, generally blood spread. Hepatitis C is another important infectious disease that has attracted global attention after hepatitis B and AIDS. There are 120 to 180 million people in the world who are infected with HCV, accounting for 2 to 3% of the total population, and there are 3 to 4 million new infections every year. In increasing cases, 70% to 90% become chronic infection, and about 30% develop progressive liver disease, including liver cirrhosis or liver cancer. The HCV infection rate in the general population in my country is 2.5-4.9%, and the estimated number of infected people exceeds 40 million.

Due to the biological characteristics of the HCV virus itself, there is currently no effective vaccine to prevent it clinically. Domestic treatment of chronic hepatitis C (CHC) mainly adopts the strategy of combining interferon drugs and broad-spectrum antiviral drug ribavirin, but this therapy has certain toxic and side effects, and the antiviral efficacy is affected by genotype, viral load, etc. Affected by many factors, the effective rate of treatment is less than 50%. Direct antiviral drugs (DAAs) can specifically and target inhibit the replication of HCV, and have become a research hotspot in anti-HCV treatment. The discovered DAA targets mainly include endogenous ribosome entry site (IRES), structural proteins (E1, E2) and non-structural proteins NS2, NS3, NS5A and NS5B. In recent years, direct antiviral drugs (DAAs) have developed rapidly, and a variety of DAAs have been approved by the US FDA. Patients resistant to interferon (IFN) therapy offer hope. But so far, the clinical experience of DAA is limited. Some problems such as drug tolerance, combined use and drug resistance, and high price limit the popularization and use of DAA. Direct anti-HCV drugs.

Contents of the invention

Aiming at the problems existing in the prior art, the object of the present invention is to provide a kind of 2-thioacetamide benzimidazole compound and its preparation method and application.

For reaching this purpose, the present invention adopts following technical scheme:

In one aspect, the present invention provides a 2-thioacetamide benzimidazole compound, which has the structure shown in formula I:

In formula I, R ₁ is any one of H, halogen, -NO ₂ , -SO ₂ NH ₂ , substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C1-C10 alkoxy Or a combination of at least two; R ₂ is cyclohexylmethyl or benzyl.

In the present invention, the compound represented by formula I can be named as 2-(1-benzyl or cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(phenyl or substituted phenyl)acetamide compound. Preferably, the halogen is any one or a combination of at least two of F, Cl, Br or I.

In the present invention, the benzene ring connected by R ₁ may be mono-substituted or multi-substituted, that is, R ₁ does not only mean that there is only one substituent on the benzene ring, it may also have two or more substituents.

In the present invention, the substituted or unsubstituted C1-C10 alkyl can be substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl, specifically It may be methyl, ethyl, propyl, butyl or trifluoromethyl, preferably methyl or trifluoromethyl.

In the present invention, the substituted or unsubstituted C1-C10 alkoxy may be substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkoxy, Specifically, it may be methoxy, ethoxy or propoxy, etc., preferably methoxy.

Preferably, the 2-thioacetamide benzimidazole compound in the present invention is any one or a combination of at least two of the compounds with structures shown in Table 1.

Table 1

On the other hand, the present invention provides the preparation method of 2-thioacetamide benzimidazole compound as described in the first aspect, described method comprises the following steps:

(1) Aniline shown in formula II reacts with acid halide compound shown in formula X to obtain α-halogenated-aromatic amide shown in formula III, and the reaction formula is as follows:

(2) Reaction of the α-halogenated-aromatic amide obtained in step (1) with 2-mercaptobenzimidazole to obtain 2-(1H-benzimidazole-2-thiol)-N-phenylethane shown in formula IV Amide, the reaction formula is as follows:

(3) The 2-(1H-benzimidazole-2-sulfenyl)-N-phenylacetamide obtained in step (2) reacts with bromomethylcyclohexane or benzyl bromide to obtain 2-sulfur shown in formula I Acetamide benzimidazole compounds, the reaction formula is as follows:

Wherein, R ₁ is any one of H, halogen, -NO ₂ , -SO ₂ NH ₂ , substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted C1-C10 alkoxy, or at least A combination of _two ; R2 is cyclohexylmethyl or benzyl, and R and R' are halogen.

In the preparation method of the present invention, the molar ratio of the substituted aniline described in step (1) to the acid halide compound shown in formula X is 1:(1-1.5), such as 1:1, 1:1.1, 1:1.2, 1 :1.3, 1:1.4 or 1:1.5.

Preferably, the acid halide compound represented by formula X is bromoacetyl bromide or chloroacetyl chloride.

In step (1) of the above-mentioned preparation method, R and R' are halogen, and the halogen is F, Cl, Br or I, preferably Br or Cl, and R and R' can be the same halogen or different halogens. halogen, preferably R and R' are the same halogen, when R and R' are bromine at the same time, the acyl halide compound shown in formula X is bromoacetyl bromide, when R and R' are chlorine at the same time, the acid halide compound shown in formula X The acid halide compound is chloroacetyl chloride.

Preferably, step (1) is carried out in the presence of a weakly basic reagent.

Preferably, the weakly alkaline reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine.

Preferably, the molar ratio of the weakly basic reagent to aniline shown in formula II is (1-4):1, such as 1:1, 1.3:1, 1.5:1, 1.8:1, 2:1, 2.2: 1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, or 4:1.

Preferably, the solvent used in the reaction described in step (1) is any one or a combination of at least two of dichloromethane, chloroform or acetone.

Preferably, the reaction temperature in step (1) is 0-30°C, such as 0°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C °C or 30 °C.

Preferably, the reaction time of step (1) is 1-8 hours, such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours Hours, 6.5 hours, 7 hours, 7.5 hours or 8 hours.

Preferably, the molar ratio of α-halo-aromatic amide to 2-mercaptobenzimidazole in step (2) is 1:(1-4), for example 1:1, 1:1.3, 1:1.5, 1:1.8 , 1:2, 1:2.3, 1:2.5, 1:2.8, 1:3, 1:3.3, 1:3.5, 1:3.8, or 1:4.

Preferably, the reaction in step (2) is carried out in the presence of a weakly basic reagent.

Preferably, the weakly alkaline reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine.

Preferably, the molar ratio of the weakly basic reagent to 2-mercaptobenzimidazole is (1-4):1, such as 1:1, 1.3:1, 1.5:1, 1.8:1, 2:1, 2.2 :1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, or 4:1.

Preferably, the solvent used in the reaction described in step (2) is any one or a combination of at least two of DMF, acetone or tetrahydrofuran.

Preferably, the reaction temperature in step (2) is 60-90°C, such as 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C, 78°C, 80°C, 83°C, 85°C °C, 88°C or 90°C.

Preferably, the reaction time in step (2) is 5-24 hours, such as 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 21 hours , 22 hours, 23 hours or 24 hours.

Preferably, the mol ratio of 2-(1H-benzimidazole-2-thio)-N-phenylacetamide to bromomethylcyclohexane or benzyl bromide in step (3) is 1:(1- 2), for example 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

Preferably, step (3) is carried out in the presence of a weakly basic reagent.

Preferably, the weakly alkaline reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine.

Preferably, the molar ratio of the weakly basic reagent to 2-(1H-benzimidazole-2-thio)-N-phenylacetamide is (1-4):1, for example 1:1, 1.3: 1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, or 4:1.

Preferably, the solvent used in the reaction described in step (3) is any one or a combination of at least two of pyridine, DMF, dichloromethane or chloroform.

Preferably, the reaction temperature in step (3) is 50-100°C, such as 50°C, 53°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C °C, 78°C, 80°C, 83°C, 85°C, 88°C, 90°C, 95°C or 100°C.

Preferably, the reaction time in step (3) is 3-6 hours, such as 3 hours, 3.4 hours, 3.8 hours, 4 hours, 4.5 hours, 4.8 hours, 5 hours, 5.3 hours, 5.5 hours, 5.8 hours or 6 hours. Hour.

As a preferred technical scheme of the present invention, the preparation method of the 2-thioacetamide benzimidazole compound comprises the following steps:

(1) Aniline represented by formula II with a molar ratio of 1:(1-1.5) and acid halide compound represented by formula X are reacted at 0-30° C. for 1-8 hours in the presence of a weakly basic reagent to obtain formula III Represents α-halogenated-aromatic amides;

(2) The α-halogenated-aromatic amide obtained in step (1) with a molar ratio of 1: (1-4) and 2-mercaptobenzimidazole were reacted at 60-90°C in the presence of a weakly basic reagent for 5 -24 hours, to obtain 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide shown in formula IV;

(3) 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide and bromomethylcyclohexane or benzyl bromide obtained in step (2) of (1-2) base bromide, in the presence of a weakly basic reagent, react at 50-100° C. for 1-8 hours to obtain 2-thioacetamide benzimidazole compounds shown in formula I.

In another aspect, the present invention provides the use of the 2-thioacetamide benzimidazole compound as described in the first aspect in the preparation of anti-hepatitis C virus drugs.

The 2-thioacetamide benzimidazole compound of the present invention can be used as a candidate active ingredient of an anti-hepatitis C virus drug, and has obvious anti-HCV activity.

Compared with the prior art, the present invention has the following beneficial effects:

The 2-thioacetamide benzimidazole compound prepared by the present invention has obvious inhibitory effect on HCV virus, and the anti-HCV virus therapeutic index is higher than that of existing clinical drugs interferon alpha-1b (IFN alpha-1b) and ribavirin (Ribavirin). ), can be used as an anti-HCV drug candidate, and the preparation method of the present invention is simple and has high yield, and is suitable for industrial production.

Detailed ways

The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the embodiments are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention.

Example 1

In this example, the compound of formula I-1 is prepared by the following steps, which specifically include the following steps:

(1) Add aniline (0.1mol), 100mL of anhydrous CH ₂ Cl ₂ and anhydrous NaHCO ₃ (8.4g, 0.1mol) into a 500ml dry flask, stir for a while, and slowly add in 50mL of CH ₂ in an ice-water bath Bromoacetyl bromide (20.18 g, 0.1 mol) in Cl ₂ solution was added dropwise and stirred at room temperature for 3 h. Thin-layer chromatography (TLC) tracked the reaction until the raw material point disappeared, evaporated the solvent under reduced pressure, added water and stirred to precipitate a solid, and suction filtered to obtain each α-bromo-arylamide.

(2) Add 2-mercaptobenzimidazole (0.01mol, 1.50g), 20mL DMF and K ₂ CO ₃ (0.01mol, 1.38g) into a 100mL flask, stir for a while, then add various α-bromo-styrene Amide (0.01 mol), stirred at 80°C for 12 hours. TLC tracked the reaction until the raw material point disappeared, stopped the reaction, poured the reaction solution into ice water and stirred to precipitate a precipitate, suction filtered, washed with ice water, and dried to obtain 2-(1H-benzimidazole-2-thio)-N- Crude phenylacetamide, this product can be directly used in the next reaction without further purification.

(3) Add 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide (2mmol), 3mLDMF and K ₂ CO ₃ (2mmol, 0.28g) into a 50mL flask, stir for a while, add Bromomethylcyclohexane (3 mmol, 0.53 g) or benzyl bromide (3 mol, 0.51 g) was stirred at 70° C. for 5 hours, followed by TLC until the starting point disappeared, and the reaction was stopped. The reaction solution was poured into ice water, extracted three times with ethyl acetate, the ethyl acetate was distilled off under reduced pressure, the solid was precipitated by adding ethanol, filtered with suction, washed with ethanol, and dried to obtain the crude product of formula I-1, which was purified by column chromatography or used The pure product can be obtained by recrystallization from an appropriate solvent, which is a white crystal, yield: 79.1%, mp: 135.2-135.7°C.

The obtained product was characterized by H NMR and mass spectrometry, and the results are as follows: ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.06-1.23 (m, 5H, cyclohexyl), 1.67-1.76 (m, 6H, cyclohexyl) Hexyl), 3.92-3.93 (d, 2H, J=7.2, CH ₂ -cyclohexyl), 4.04 (s, 2H, S-CH ₂ ), 7.06-7.36 (m, 5H, Ph-H), 7.60-7.62 (d, 2H, Ph-H), 7.76-7.78 (m, 2H, Ph-H), 11.42 (s, 1H, NH); m/z 380.4 (M ⁺ +1).

Example 2

In this example, the compounds of formula I-2 to formula I-42 were prepared, and the preparation method was different from that of the compound of formula I-1 in Example 1 only in that the aniline described in step (1) was of formula I- 2 to the corresponding aniline with R in the structure of the compound of formula I-42 (for example, aniline is used for the preparation of the I-2 compound, p-methylaniline is used for the preparation of the I-3 compound, and p-methylaniline is used for the preparation of the I-5 compound. I-9 compound was prepared using I-36 compound was prepared using According to formula I-2 to formula I-42 in the compound structure R2 is different, and in step (3) adopts bromomethylcyclohexane or benzyl bromide (for example, adopts benzyl bromide when I-2 compound is prepared, I- 3 The compound is prepared by bromomethylcyclohexane), except that the preparation method is the same as that of the compound of formula I-1 in Example 1.

The properties, yields and structural characterization results of the prepared compounds of formula I-2 to formula I-42 are as follows:

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-phenylacetamide (I-2), white crystals, yield: 53.6%, mp: 130.3-130.9°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 4.04 (s, 2H, S-CH ₂ ), 5.31 (s, 2H, CH ₂ -Ph), 7.06-7.10 (m, 1H, Ph-H) ,7.21-7.36(m,9H,Ph-H),7.57-7.59(d,2H,Ph-H),7.77-7.79(m,2H,Ph-H),11.25(s,1H,NH);m /z 374.1(M ⁺⁺ 1).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-Np-tolylacetamide (I-3), white crystal, yield: 63.5%, mp: 127.7-128.4°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.02-1.19 (m, 5H, cyclohexyl), 1.62-1.90 (m, 6H, cyclohexyl), 2.27 (s, 3H, CH ₃ ), 3.88- 3.89 (d, 2H, J=3.2, CH ₂ -cyclohexyl), 3.99 (s, 2H, S-CH ₂ ), 7.06-7.30 (m, 4H, Ph-H), 7.42-7.72 (m, 4H, Ph-H), 11.22 (s, 1H, NH); m/z 394.2 (M ⁺⁺ 1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-Np-tolylacetamide (I-4), white crystal, yield: 12.9%, mp: 130.1-132.0℃. ¹ HNMR(CDCl ₃ ,400MHz), δ(ppm):2.28(s,3H,CH ₃ ),4.01(s,2H,S-CH ₂ ),5.28(s,2H,CH ₂ -Ph),7.07- 7.34 (m, 9H, Ph-H), 7.42-7.44 (d, 2H, Ph-H), 7.73-7.75 (d, 2H, Ph-H), 11.10 (s, 1H, NH); m/z 388.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(4-sulfaphenyl)acetamide (I-5), white crystal, yield: 76.3%, mp: 206.5-206.9°C. ¹ HNMR (DMSO, 400MHz), δ (ppm): 1.05-1.13 (m, 6H, cyclohexyl), 1.52-1.65 (m, 5H, cyclohexyl), 4.00-4.02 (d, 2H, J=7.2, CH ₂ -cyclohexyl), 4.38(s,2H,S-CH ₂ ),7.14-7.18(m,2H,Ph-H),7.27(s,2H,NH ₂ ),7.50-7.53(m,2H,Ph -H), 7.72-7.77 (m, 4H, Ph-H), 10.84 (s, 1H, NH); m/z 459.5 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(4-sulfaphenyl)acetamide (I-6), white crystal, yield: 11.0%, mp: 238.5- 238.9°C. ¹ HNMR (DMSO, 400MHz), δ (ppm): 4.40 (s, 2H, S-CH ₂ ), 5.45 (s, 2H, CH ₂ -Ph), 7.15-7.18 (m, 2H, Ph-H), 7.15-7.29(m,5H,Ph-H),7.26(s,2H,NH ₂ ),7.50-7.56(m,2H,Ph-H),7.72-7.78(m,4H,Ph-H),10.84 (s, 1H, NH); m/z 453.2 (M ⁺ +1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(4-fluorophenyl)acetamide (I-7), white crystal, yield: 88.0%, mp: 137.1-137.8°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):1.00-1.29(m,5H,cyclohexyl),1.63-1.91(m,6H,cyclohexyl),3.89-3.93(d,2H,CH ₂ -ring Hexyl), 3.98(s, 2H, S-CH ₂ ), 6.94-7.51(m, 4H, Ph-H), 7.52-7.72(m, 4H, Ph-H), 11.44(s, 1H, NH); m/z 398.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(4-fluorophenyl)acetamide (I-8), white crystal, yield: 63.9%, mp: 155.2- 156.1°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.00(s,2H,S-CH ₂ ),5.29(s,2H,CH ₂ -Ph),6.95-7.34(m,9H,Ph-H) , 7.50-7.54 (m, 2H, Ph-H), 7.73-7.75 (d, 2H, Ph-H), 11.32 (s, 1H, NH); m/z 392.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3,5-difluorophenyl)acetamide (I-9), white crystals, yield: 72.2% , mp: 149.2-149.8°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.18-1.67 (m, 5H, cyclohexyl), 1.71-1.88 (m, 6H, cyclohexyl), 3.90-3.92 (d, 2H, J=7.6, CH ₂ -cyclohexyl), 3.96(s,2H,S-CH ₂ ),6.47-6.52(m,1H,Ph-H),7.17-7.33(m,4H,Ph-H),7.71-7.74(m , 2H, Ph-H), 11.94 (s, 1H, NH); m/z 416.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3,5-difluorophenyl)acetamide (I-10), white crystals, yield: 67.2%, mp : 143.4-143.9°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 3.96 (s, 2H, S-CH ₂ ), 5.28 (s, 2H, CH ₂ -Ph), 6.47-6.52 (m, 1H, Ph-H) , 7.15-7.35 (m, 9H, Ph-H), 7.73-7.76 (m, 2H, Ph-H), 11.81 (s, 1H, NH); m/z 410.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(4-nitrophenyl)acetamide (I-11), white crystal, yield: 70.7%, mp : 166.5-167.4°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.04-1.20 (m, 5H, cyclohexyl), 1.64-1.91 (m, 6H, cyclohexyl), 3.92-3.95 (d, 2H, J=15.2, CH ₂ -cyclohexyl), 3.96(s,2H,S-CH ₂ ),7.26-7.36(m,4H,Ph-H),7.72-7.75(m,2H,Ph-H),8.16-8.19(m , 2H, Ph-H), 12.31 (s, 1H, NH); m/z 425.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(4-nitrophenyl)acetamide (I-12), white crystal, yield: 23.9%, mp: 218.9 -219.8°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 4.02 (s, 2H, S-CH ₂ ), 5.31-5.33 (s, 2H, S-CH ₂ ), 7.19-7.37 (m, 8H, Ph- H), 7.72-7.78 (m, 3H, Ph-H), 8.17-8.19 (m, 2H, Ph-H), 12.20 (s, 1H, NH); m/z 419.1 (M ⁺ +1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2,4-difluorophenyl)acetamide (I-13), white crystal, yield: 84.2% , mp: 114.6-115.5°C. ¹ HNMR (CDCl ³ , 400MHz), δ (ppm): 1.02-1.18 (m, 5H, cyclohexyl), 1.62-1.71 (m, 6H, cyclohexyl), 3.86-3.87 (d, 2H, J=7.2CH ₂ -cyclohexyl),4.02(s,2H,S-CH ₂ ),6.76-6.81(m,2H,Ph-H),7.23-7.72(m,4H,Ph-H),8.36-8.37(m, 1H, Ph-H), 11.65 (s, 1H, NH); m/z 416.2 (M ⁺⁺ 1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2,4-difluorophenyl)acetamide (I-14), white crystals, yield: 18.3%, mp : 153.7-154.5°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.10(s,2H,S-CH ₂ ),5.30(s,2H,CH ₂ -Ph),6.80-6.88(m,2H,Ph-H) ,7.21-7.37(m,7H,Ph-H),7.76-7.78(m,2H,Ph-H),8.36-8.41(m,1H,Ph-H),11.59(s,1H,NH);m ^/z410.1(M++1 ).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2-fluorophenyl)acetamide (I-15), white crystals, yield: 75.5%, mp: 112.7-113.6°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.02-1.19 (m, 5H, cyclohexyl), 1.63-1.88 (m, 6H, cyclohexyl), 3.86-3.88 (d, 2H, J=7.6, CH ₂ -cyclohexyl), 4.05(s,2H,S-CH ₂ ),6.96-7.29(m,5H,Ph-H),7.73-7.75(m,2H,Ph-H),8.38-8.42(m , 1H, Ph-H), 11.57 (s, 1H, NH); m/z 398.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2-fluorophenyl)acetamide (I-16), white crystal, yield: 85.9%, mp: 157.8- 158.5°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.05(s,2H,S-CH ₂ ),5.23(s,2H,CH ₂ -Ph),6.96-7.31(m,10H,Ph-H) , 7.75-7.78 (m, 2H, Ph-H), 8.37-8.41 (m, 1H, Ph-H), 11.46 (s, 1H, NH); m/z 392.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3,5-dimethylphenyl)acetamide (I-17), white crystals, yield: 36.8 %, mp: 104.8-105.8°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):1.09-1.26(m,5H,cyclohexyl),1.69-1.98(m,6H,cyclohexyl),2.27-2.37(s,6H,2CH ₃ ), 3.94-3.96 (d, 2H, J=7.6, CH ₂ -cyclohexyl), 4.04 (S-CH ₂ ), 6.76 (s, 1H, Ph-H), 7.25-7.38 (m, 4H, Ph-H) , 7.783-7.80 (m, 2H, Ph-H), 11.22 (s, 1H, NH); m/z 408.3 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3,5-dimethylphenyl)acetamide (I-18), white crystals, yield: 12.5%, mp: 138.8-139.9°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):2.23(s,6H,2CH ₃ ),3.96-3.97(s,2H,S-CH ₂ ),5.22(s,2H,CH ₂ -Ph), 6.67 (s, 1H, Ph-H), 7.14-7.30 (m, 9H, Ph-H), 7.72-7.74 (d, 2H, Ph-H), 11.01 (s, 1H, NH); m/z 402. 3(M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2-bromophenyl)acetamide (I-19), white crystals, yield: 54.5%, mp: 107.9-108.7°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.26-1.75 (m, 5H, cyclohexyl), 1.90-1.96 (m, 6H, cyclohexyl), 3.91-3.92 (d, 2H, J=7.2, CH ₂ -cyclohexyl), 4.20(s,2H,S-CH ₂ ),6.94-6.98(m,1H,Ph-H),7.24-7.32(m,3H,Ph-H),7.49-7.51(m ,2H,Ph-H),7.72-7.74(m,1H,Ph-H),8.23-8.25(m,1H,Ph-H),10.38(s,1H,NH); m/z 458.2(M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2-bromophenyl)acetamide (I-20), white crystal, yield: 71.8%, mp: 141.4- 142.6°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 4.17 (s, 2H, S-CH ₂ ), 5.26 (s, 2H, CH ₂ -Ph), 6.92-6.94 (m, 1H, Ph-H) ,7.15-7.29(m,8H,Ph-H),7.44-7.47(m,1H,Ph-H),7.70-7.72(m,1H,Ph-H),8.18-8.21(m,1H,Ph-H) H), 10.26 (s, 1H, NH); m/z 452.0 (M ⁺ -2).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3-trifluoromethylphenyl)acetamide (I-21), white crystals, yield: 78.2% , mp: 114.7-115.2°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.03-1.22 (m, 5H, cyclohexyl), 1.63-1.92 (m, 6H, cyclohexyl), 3.89-3.93 (d, 2H, J＝18.8CH ₂ -cyclohexyl), 3.98(s,2H,S-CH ₂ ),7.12-7.32(m,4H,Ph-H),7.58-7.72(m,4H,Ph-H),11.67(s,1H, NH); m/z 448.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3-trifluoromethylphenyl)acetamide (I-22), white crystals, yield: 96.2%, mp : 152.7-153.5°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.00(s,2H,S-CH ₂ ),5.28(s,2H,CH ₂ -Ph),7.07-7.33(m,10H,Ph-H) , 7.58-7.60 (d, 2H, Ph-H), 7.73-7.75 (d, 1H, Ph-H), 11.53 (s, 1H, NH); m/z 442.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2-chlorophenyl)acetamide (I-23), white crystals, yield: 84.5%, mp: 113.9-114.6°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.02-1.19 (m, 5H, cyclohexyl), 1.63-1.71 (m, 6H, cyclohexyl), 3.86-3.88 (d, 2H, J=7.6CH ₂ -cyclohexyl), 4.15(s,2H,S-CH ₂ ),6.96-7.69(m,6H,Ph-H),8.31-8.32(d,1H,Ph-H),8.33-8.34(d, 1H, Ph-H), 10.67 (s, 1H, NH); m/z 414.1 (M ⁺⁺ 1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2-chlorophenyl)acetamide (I-24), white crystal, yield: 79.7%, mp: 139.3- 140.7°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.17(s,2H,S-CH ₂ ),5.27(s,2H,CH ₂ -Ph),6.97-7.01(m,1H,Ph-H) ,7.17-7.32(m,10H,Ph-H),7.69-7.71(d,1H,Ph-H),8.31-8.34(d,1H,Ph-H),10.59(s,1H,NH);m ^/z408.3(M++1 ).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2,4-dichlorophenyl)acetamide (I-25), white crystals, yield: 44.6% , mp: 122.9-123.9°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.17-1.19 (m, 6H, cyclohexyl), 1.63-1.92 (m, 5H, cyclohexyl), 3.87-3.89 (d, 2H, J=7.6CH ₂ -cyclohexyl), 4.13(s,2H,S-CH ₂ ),7.18-7.30(m,4H,Ph-H),7.64-7.66(m,2H,Ph-H),8.30-8.32(d, 1H, Ph-H), 10.83 (s, 1H, NH); m/z 449.1 (M ⁺⁺ 2).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2,4-dichlorophenyl)acetamide (I-26), white crystals, yield: 73.5%, mp : 184.3-184.9°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 4.15 (s, 2H, S-CH ₂ ), 5.27 (s, 2H, CH ₂ -Ph), 7.17-7.34 (m, 10H, Ph-H) , 7.68-7.70 (m, 1H, Ph-H), 8.30-8.32 (d, 1H, Ph-H), 10.76 (s, 1H, NH); m/z 443.0 (M ⁺⁺ 2).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2-trifluoromethylphenyl)acetamide (I-27), white crystals, yield: 89.4% , mp: 114.3-115.0°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.04-1.18 (m, 5H, cyclohexyl), 1.67-1.92 (m, 6H, cyclohexyl), 3.88-3.90 (d, 2H, J=7.6, CH ₂ -cyclohexyl), 4.12-4.13(s,2H,S-CH ₂ ),7.19-7.25(m,4H,Ph-H),7.52-7.66(m,3H,Ph-H),7.94-7.98 (m, 1H, Ph-H), 10.69 (s, 1H, NH); m/z 448.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2-trifluoromethylphenyl)acetamide (I-28), white crystals, yield: 62.3%, mp : 139.0-139.7°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.09(s,2H,S-CH ₂ ),5.23(s,2H,CH ₂ -Ph),7.14-7.26(m,9H,Ph-H) , 7.46-7.64 (m, 3H, Ph-H), 7.93 (s, 1H, Ph-H), 10.52 (s, 1H, NH); m/z 442.1 (M ⁺ +1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3-methoxyphenyl)acetamide (I-29), white crystals, yield: 85.5%, mp: 108.0-108.9°C. ¹ HNMR (CDCl ₃ , 400MHz), δ(ppm): 1.24 (m, 5H, cyclohexyl), 1.63-1.91 (m, 6H, cyclohexyl), 3.77 (s, 3H, OCH ₃ ), 3.88-3.90 ( d, J=7.2, 2H, CH ₂ -cyclohexyl), 3.99 (s, 2H, S-CH ₂ ), 6.59-6.62 (m, 1H, Ph-H), 7.03-7.05 (m, 1H, Ph- H),7.14-7.18(m,1H,Ph-H),7.25-7.33(m,4H,Ph-H),7.72-7.74(m,1H,Ph-H),11.44(s,1H,NH) ; m/z 410.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3-methoxyphenyl)acetamide (I-30), white crystals, yield: 49.6%, mp: 126.5-127.4°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):3.79(s,3H,OCH ₃ ),3.99(s,2H,S-CH ₂ ),5.24(s,2H,CH ₂ -Ph),6.59- 6.61(m,1H,Ph-H),7.02-7.04(m,1H,Ph-H),7.13-7.33(m,10H,Ph-H),7.73-7.75(m,1H,Ph-H), 11.310 (s, 1H, NH); m/z 404.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3-nitrophenyl)acetamide (I-31), white crystals, yield: 70.7%, mp : 125.6-126.5°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.10-1.18 (m, 5H, cyclohexyl), 1.64-1.89 (m, 6H, cyclohexyl), 3.91-3.93 (d, J=7.2, 2H, CH ₂ -cyclohexyl), 4.00(s,2H,S-CH ₂ ),7.30-7.45(m,4H,Ph-H),7.43-7.45(m,1H,Ph-H),7.88-7.90(m , 2H, Ph-H), 8.52 (m, 1H, Ph-H), 12.23 (s, 1H, NH); m/z 425.4 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3-nitrophenyl)acetamide (I-32), white crystal, yield: 71.7%, mp: 189.7 -190.6°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.01(s,2H,S-CH ₂ ),5.31(s,2H,CH ₂ -Ph),7.19-7.46(m,9H,Ph-H) ,7.79-7.81(m,1H,Ph-H),7.89-7.92(m,2H,Ph-H),8.50-8.51(m,1H,Ph-H),12.09(s,1H,NH);m ^/z419.1(M++1 ).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(4-methoxyphenyl)acetamide (I-33), white crystal, yield: 73.3%, mp: 142.0-142.7°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):1.06-1.17(m,5H,cyclohexyl),1.63-1.72(m,6H,cyclohexyl),3.75(s,3H,OCH ₃ ),3.88- 3.89 (d, J=7.6, 2H, CH ₂ -cyclohexyl), 3.99 (s, 2H, S-CH ₂ ), 6.80-6.83 (m, 2H, Ph-H), 7.25-7.31 (m, 3H, Ph-H), 7.47-7.49 (m, 2H, Ph-H), 7.70-7.72 (m, 1H, Ph-H), 11.22 (s, 1H, NH); m/z 410.2 (M ⁺ +1) .

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(4-methoxyphenyl)acetamide (I-34), white crystals, yield: 24.8%, mp: 140.1-141.0°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):3.79(s,3H,OCH ₃ ),4.03(s,2H,S-CH ₂ ),5.31(s,2H,CH ₂ -Ph),6.84- 6.86(m,2H,Ph-H),7.21-7.36(m,7H,Ph-H),7.48-7.51(m,2H,Ph-H),7.75-7.77(m,2H,Ph-H), 11.11 (s, 1H, NH); m/z 404.1 (M ⁺ +1).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3,4-dimethoxyphenyl)acetamide (I-35), white crystals, yield: 79.6%, mp: 159.6-160.4°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):1.03-1.17(m,5H,cyclohexyl),1.63-1.90(m,6H,cyclohexyl),3.82-3.89(s,6H,2OCH ₃ ), 3.91-3.94(d,2H,CH ₂ -cyclohexyl),3.99(s,2H,S-CH ₂ ),6.75-6.77(m,1H,Ph-H),6.96-6.99(m,1H,Ph- H), 7.25-7.35 (m, 4H, Ph-H), 7.69-7.71 (m, 1H, Ph-H), 11.31 (s, 1H, NH); m/z 440.2 (M ⁺ +1).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3,4-dimethoxyphenyl)acetamide (I-36), white crystals, yield: 40.3% , mp: 133.7-134.9°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):3.82-3.87(m,6H,2OCH ₃ ),4.00(s,2H,S-CH ₂ ),5.28(s,2H,CH ₂ -Ph), 6.75-6.82(m,1H,Ph-H),6.96-7.02(m,1H,Ph-H),7.20-7.38(m,9H,Ph-H),7.72-7.78(m,1H,Ph-H ), 11.17 (s, 1H, NH); m/z 434.1 (M ⁺⁺ 1).

2-(1-cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(4-bromophenyl)acetamide (I-37), white crystals, yield: 76.4%, mp: 148.9-149.8°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.03-1.29 (m, 5H, cyclohexyl), 1.66-2.08 (m, 6H, cyclohexyl), 3.93-3.96 (d, J=12.0, 2H, CH ₂ -cyclohexyl), 4.01(s,2H,S-CH ₂ ),7.28-7.36(m,3H,Ph-H),7.39-7.41(m,2H,Ph-H),7.49-7.52(m , 2H, Ph-H), 7.73-7.75 (m, 1H, Ph-H), 11.65 (s, 1H, NH); m/z 457.1 (M ⁺ -2).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(4-bromophenyl)acetamide (I-38), white crystal, yield: 33.2%, mp: 171.1- 172.3°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):3.95(s,2H,S-CH ₂ ),5.26(s,2H,CH ₂ -Ph),7.17-7.19(m,3H,Ph-H) ,7.23-7.25(m,3H,Ph-H),7.27-7.40(m,2H,Ph-H),7.43-7.47(m,3H,Ph-H),7.72-7.77(m,2H,Ph-H) H), 11.48 (s, 1H, NH); MS (ESI): m/z 451.0 (M ⁺ -2).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(2,5-dichlorophenyl)acetamide (I-39), white crystals, yield: 89.2% , mp: 135.4-136.5°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.09-1.23 (m, 5H, cyclohexyl), 1.63-1.89 (m, 6H, cyclohexyl), 3.87-3.89 (d, J=7.2, 2H, CH ₂ -cyclohexyl), 4.13(s,2H,S-CH ₂ ),6.95-6.97(m,1H,Ph-H),7.19-7.28(m,4H,Ph-H),7.65-7.67(m , 1H, Ph-H), 8.45 (s, 1H, Ph-H), 10.86 (s, 1H, NH); m/z 449.1 (M ⁺ +2).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(2,5-dichlorophenyl)acetamide (I-40), white crystals, yield: 45.2%, mp : 135.0-135.7°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):4.14-4.15(s,2H,S-CH ₂ ),5.26-5.26(s,2H,CH ₂ -Ph),6.95-6.98(m,1H, Ph-H),7.19-7.31(m,9H,Ph-H),7.68-7.70(m,1H,Ph-H),8.44-8.46(m,1H,Ph-H),10.78(s,1H, NH); m/z 443.0 (M ⁺ +2).

2-(1-Cyclohexylmethyl-1H-benzimidazole-2-thio)-N-(3-trifluoromethyl-4-chlorophenyl)acetamide (I-41), white crystals, product Rate: 83.0%, mp: 140.0-142.0°C. ¹ HNMR (CDCl ₃ , 400MHz), δ (ppm): 1.12-1.28 (m, 5H, cyclohexyl), 1.67-1.93 (m, 6H, cyclohexyl), 3.93-3.95 (d, 2H, J=7.6, CH ₂ -cyclohexyl), 4.01(s,2H,S-CH ₂ ),7.33-7.42(m,4H,Ph-H),7.73-7.81(m,2H,Ph-H),7.97-7.98(m , 1H, Ph-H), 12.17 (s, 1H, NH); m/z 438.1 (M ⁺⁺ 2).

2-(1-Benzyl-1H-benzimidazole-2-thio)-N-(3-trifluoromethyl-4-chlorophenyl)acetamide (I-42), white crystals, yield: 52.5%, mp: 151.0-152.0°C. ¹ HNMR(CDCl ₃ ,400MHz),δ(ppm):3.98(s,2H,S-CH ₂ ),5.29(s,2H,CH ₂ -Ph),7.18-7.20(m,2H,Ph-H) ,7.24-7.35(m,6H,Ph-H),7.37-7.39(m,1H,Ph-H),7.73-7.78(m,2H,Ph-H),7.92(m,1H,Ph-H) , 11.99 (s, 1H, NH); m/z 477.1 (M ⁺⁺ 2).

Example 3

In this example, the in vitro anti-HCV activity of the compounds of formula I-1 to formula I-35 was evaluated, and the human liver cancer cell line Huh 7.5.1 was used to evaluate the anti-HCV activity at the cell level in vitro. The method is described as follows:

MTT method to detect drug cytotoxicity: take Huh 7.5.1 cells in logarithmic growth phase, spread 9× ¹⁰³ cells/well on a 96-well plate, and add 2 μL DMSO to serially dilute the drug for 5-fold dilution after 5 hours of attachment. For 5 dilutions, three replicate wells are set for each gradient, and blank control (medium only), cell control, drug color control, DMSO control and anti-HCV positive drug ribavirin control are set at the same time, with a final volume of 200 μL/well . Place the culture plate in a 37°C, 5% _CO2 incubator for cultivation. On the third day, 20 μL of 5 mg/mL MTT solution was added to the experimental wells, and incubated at 37° C., 5% CO ₂ for 4 hours. Discard the supernatant, add 150 μL/well of DMSO, shake and dissolve for 10 minutes, measure the OD ₄₉₀ value on a microplate reader, and calculate the drug IC ₅₀ with Graphad Prism 5.0 (IC ₅₀ : half inhibitory concentration, the cell growth inhibition 50% of the desired concentration) value. Calculation formula: cell growth inhibition rate (%)=(1-OD value of test well/OD value of control well)×100%.

HCV replication inhibition test: Huh 7.5.1 cells in the logarithmic growth phase were spread on a 96-well plate at 9×10 ³ cells/well, and after 5 hours of attachment, 2 μL of DMSO was added to serially dilute the drug, 5-fold dilution, 5 For each dilution, three replicate wells were set up for each gradient. Virus was added at the same time, and cell control, virus control, anti-HCV positive control (IFNα-1b and ribavirin), and DMSO control were set up, with a final volume of 200 μL/well. The culture plate was placed in a 37°C, 5% CO ₂ incubator for cultivation. After 3 days, the supernatant was collected and centrifuged at 3000rpm/min for 10min, and the clarified supernatant was taken for RNA load detection. The HCV replication inhibition rate and EC ₅₀ were calculated with Graphad Prism 5.0 (EC ₅₀ : half effect concentration, the drug dose that causes 50% of the subjects to produce a specific effect). Calculation formula: HCV replication inhibition rate (%)=(1-HCV RNA load in test well/HCV RNA load in control well)×100%.

Anti-HCV drug efficacy evaluation: Therapeutic index (Therapeutic index, TI) is the ratio of the half inhibitory concentration IC ₅₀ of the drug on cells to the half effective concentration on the virus, which represents the safety of the drug. The larger the value, the safer it is.

The anti-HCV clinical treatment drug Ribavirin (Ribavirin) was used as a positive control. Synthetic compound I has been screened for drug cytotoxicity and anti-HCV virus activity according to the above-mentioned method, and specific test data (IC ₅₀ , EC ₅₀ and TI value) are shown in Table 2, as can be seen from Table 2, all compounds have the effect on HCV virus replication With obvious inhibitory effect, their therapeutic index is 5-10 times higher than that of ribavirin, and they can be used as anti-HCV lead compounds and drug candidates for further research and development.

Table 2

The applicant declares that the present invention illustrates the 2-thioacetamide benzimidazole compound of the present invention and its preparation method and use through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must Rely on the above-mentioned embodiment to implement. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Claims (26)

1. A 2-thioacetamide benzimidazole compound is characterized in that, the 2-thioacetamide benzimidazole compound is any one or a combination of at least two of the compounds with the following structures: 2. the preparation method of 2-thioacetamide benzimidazole compound according to claim 1, is characterized in that, described method comprises the following steps: (1) Aniline shown in formula II reacts with acid halide compound shown in formula X to obtain α-halogenated-aromatic amide shown in formula III, and the reaction formula is as follows: (2) Reaction of the α-halogenated-aromatic amide obtained in step (1) with 2-mercaptobenzimidazole to obtain 2-(1H-benzimidazole-2-thiol)-N-phenylethane shown in formula IV Amide, the reaction formula is as follows: (3) The 2-(1H-benzimidazole-2-sulfenyl)-N-phenylacetamide obtained in step (2) reacts with bromomethylcyclohexane or benzyl bromide to obtain 2-sulfur shown in formula I Acetamide benzimidazole compounds, the reaction formula is as follows: Wherein, R ₁ is 4-SO ₂ NH ₂ , 3-methoxy or 4-F; R ₂ is cyclohexyl or phenyl, and R and R' are halogen. 3. The preparation method according to claim 2, characterized in that the mol ratio of the substituted aniline in step (1) to the acyl halide compound shown in formula X is 1:(1-1.5). 4. The preparation method according to claim 2, characterized in that the acyl halide compound shown in formula X is bromoacetyl bromide or chloroacetyl chloride. 5. The preparation method according to claim 2, characterized in that step (1) is carried out in the presence of weakly alkaline reagents. 6. The preparation method according to claim 5, characterized in that, the weakly alkaline reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine. 7. preparation method according to claim 5, is characterized in that, the mol ratio of described weak basic reagent and aniline shown in formula II is (1-4):1. 8. The preparation method according to claim 2, wherein the solvent used in the reaction of step (1) is any one or a combination of at least two of methylene chloride, chloroform or acetone. 9. The preparation method according to claim 2, characterized in that the reaction temperature in step (1) is 0-30°C. 10. The preparation method according to claim 2, characterized in that the reaction time of step (1) is 1-8 hours. 11. The preparation method according to claim 2, characterized in that the molar ratio of α-halogenated-arylamide and 2-mercaptobenzimidazole in step (2) is 1:(1-4). 12. The preparation method according to claim 2, characterized in that the reaction in step (2) is carried out in the presence of a weakly basic reagent. 13. The preparation method according to claim 12, characterized in that, the weakly basic reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine. 14. preparation method according to claim 12, is characterized in that, the mol ratio of described weak basic reagent and 2-mercaptobenzimidazole is (1-4):1. 15. The preparation method according to claim 2, characterized in that, the solvent used in the reaction of step (2) is any one or a combination of at least two of DMF, acetone or tetrahydrofuran. 16. The preparation method according to claim 2, characterized in that the reaction temperature in step (2) is 60-90°C. 17. The preparation method according to claim 2, characterized in that the reaction time in step (2) is 5-24 hours. 18. The preparation method according to claim 2, characterized in that, step (3) described 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide and bromomethylcyclohexane Or the molar ratio of benzyl bromide is 1:(1-2). 19. The preparation method according to claim 2, characterized in that step (3) is carried out in the presence of a weakly basic reagent. 20. The preparation method according to claim 19, wherein the weakly basic reagent is any one or a combination of at least two of sodium bicarbonate, potassium carbonate or triethylamine. 21. preparation method according to claim 19, is characterized in that, the mol ratio of described weakly basic reagent and 2-(1H-benzimidazole-2-sulfenyl)-N-phenylacetamide is (1 -4):1. 22. The preparation method according to claim 2, characterized in that the solvent used in the reaction of step (3) is any one or a combination of at least two of pyridine, DMF, methylene chloride or chloroform. 23. The preparation method according to claim 2, characterized in that the reaction temperature in step (3) is 50-100°C. 24. The preparation method according to claim 2, characterized in that the reaction time in step (3) is 3-6 hours. 25. The preparation method according to claim 2, characterized in that, the preparation method comprises the following steps: (1) Aniline represented by formula II with a molar ratio of 1:(1-1.5) and acid halide compound represented by formula X are reacted at 0-30° C. for 1-8 hours in the presence of a weakly basic reagent to obtain formula III Represents α-halogenated-aromatic amides; (2) The α-halogenated-aromatic amide obtained in step (1) with a molar ratio of 1: (1-4) and 2-mercaptobenzimidazole were reacted at 60-90°C in the presence of a weakly basic reagent for 5 -24 hours, to obtain 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide shown in formula IV; (3) 2-(1H-benzimidazole-2-thiol)-N-phenylacetamide and bromomethylcyclohexane or benzyl bromide obtained in step (2) of (1-2) base bromide, in the presence of a weakly basic reagent, react at 50-100° C. for 3-6 hours to obtain 2-thioacetamide benzimidazole compounds shown in formula I. 26. The use of the 2-thioacetamide benzimidazole compound according to claim 1 in the preparation of anti-hepatitis C virus drugs.