A 2-thioacetamide piperazine benzimidazole compound and its preparation method and application

Abstract

The present application relates to the technical field of anti-tumor drugs, and in particular to a 2-thioacetamide piperazine benzimidazole compound and a preparation method and application thereof; the 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 1, #imgabs0# In Formula 1, R 1 The group includes at least one of the following groups: H, -CH 3 ,‑OCH 3 , halogen, ‑OH, ‑NO 2 and CF 3 ; R 2 The group includes at least one of the following groups: H, -CH 3 ,‑OCH 3 , halogen, ‑OH, ‑NO 2 and ‑OCF 3 The 2-thioacetamide piperazine benzimidazole compound can not only increase its inhibitory activity on Fam20C kinase, but also improve its anti-proliferative activity against triple-negative breast cancer tumor cells.

Description

Technical Field

[0001] The present application relates to the technical field of anti-tumor drugs, and in particular to a 2-thioacetamide piperazine benzimidazole compound and a preparation method and application thereof. Background Art

[0002] Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Patients generally lack the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER-2). Patients with triple-negative breast cancer are prone to relapse after chemotherapy, and the five-year survival rate is extremely low. At present, the clinical treatment of breast cancer mainly adopts surgical treatment combined with adjuvant therapy, and adjuvant therapy includes cytotoxic chemotherapy, endocrine or targeted therapy, etc. Among them, although targeted therapy is the most mature treatment for HER-2 positive patients, and targeted therapy uses the most therapeutic drugs, chemotherapy is still the main method for clinical treatment of early and late triple-negative breast cancer patients. However, the current chemotherapy drugs have the disadvantages of poor treatment effect, easy drug resistance and serious side effects in the treatment of triple-negative breast cancer.

[0003] Fam20C is a serine / threonine-specific protein kinase. Its abnormal expression is associated with the occurrence and progression of many cancers, and it also plays an important role in the occurrence of triple-negative breast cancer. The phosphorylation of Fam20C on its substrates such as IGFBP7 and cadherin-2 (CDH2) plays an important role in the adhesion and migration of MDA-MB-231 and U2OS cells. In addition, current studies have shown that the phosphorylation of IGFBP7, a substrate of Fam20C, may be the reason why Fam20C-knockout MDA-MB231 cells have lower malignant invasiveness. Other studies have shown that small molecule inhibitors of Fam20C can inhibit the metastasis of MDA-MB-231 cells, and the mechanism of using this inhibitor in combination with paclitaxel in the treatment of TNBC has also been further clarified, indicating that Fam20C is a potential target for the treatment of TNBC.

[0004] At present, the lack of effective small molecule targeted drugs is the bottleneck of the targeted treatment of triple-negative breast cancer. Based on the characteristics of Fam20C as a potential target for the treatment of TNBC, the development of small molecule inhibitors targeting Fam20C and the identification of more effective drugs are of great significance for the treatment of triple-negative breast cancer. Summary of the invention

[0005] The present application provides a 2-thioacetamide piperazine benzimidazole compound and a preparation method and application thereof to solve the following technical problem: how to provide a more effective small molecule inhibitor targeting Fam20C.

[0006] In a first aspect, the present application provides a 2-thioacetamide piperazine benzimidazole compound, wherein the 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 1,

[0007]

[0008] In Formula 1, the R1 group includes at least one of the following groups:

[0009] H, -CH3, -OCH3, halogen, -OH, -NO2, and -CF3;

[0010] The R2 group includes at least one of the following groups:

[0011] H, -CH3, -OCH3, halogen, -OH, -NO2 and -OCF3.

[0012] Optionally, the R1 group and the R2 group are halogens respectively.

[0013] Optionally, the R1 group is a halogen Cl, and the R2 group is a halogen Br;

[0014] The 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 2.

[0015]

[0016] In a second aspect, the present application provides a method for preparing the 2-thioacetamide piperazine benzimidazole compound described in the first aspect, the method comprising:

[0017] The phenylpiperazine with different substituents is first reacted with triethylamine, chloroacetyl chloride and dichloromethane under ice bath conditions to obtain a first intermediate;

[0018] performing a second reaction on the first intermediate with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate;

[0019] The second intermediate is subjected to a third reaction with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide with different substituents to obtain 2-thioacetamide piperazine benzimidazole compounds.

[0020] Optionally, the first reaction of phenylpiperazine having different substituents with triethylamine, chloroacetyl chloride and dichloromethane under ice bath conditions to obtain a first intermediate comprises the steps of:

[0021] Dissolving phenylpiperazine with different substituents in dichloromethane under ice bath conditions and stirring, then dropping triethylamine and stirring until the substrate is dissolved, then adding chloroacetyl chloride and stirring to obtain a first reaction solution;

[0022] Add ice water to the first reaction liquid to quench it, then extract the reaction liquid with dichloromethane as an extractant and combine the organic phases to obtain an organic phase;

[0023] The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then chromatographed over a silica gel column to obtain the first intermediate.

[0024] Optionally, the second reaction of the first intermediate with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate comprises the steps of:

[0025] Dissolving 2-mercaptobenzimidazole in a tetrahydrofuran solution, adding anhydrous potassium carbonate and stirring, and then adding the first intermediate to react to obtain a second reaction solution;

[0026] The second reaction liquid is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, followed by suction filtration and filter cake washing to remove unconsumed 2-mercaptobenzimidazole, thereby obtaining a first filter cake;

[0027] The first filter cake is dried and then chromatographed using a silica gel column to obtain a second intermediate.

[0028] Optionally, the third reaction of the second intermediate with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide having different substituents to obtain a 2-thioacetamide piperazine benzimidazole compound comprises the steps of:

[0029] The second intermediate is dissolved in N,N-dimethylformamide and anhydrous potassium carbonate is added and stirred, and then benzyl bromide having different substituents is added and heated and stirred to obtain a third reaction solution;

[0030] The third reaction solution is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, followed by suction filtration and filter cake washing to obtain a second filter cake;

[0031] The second filter cake is dried and then chromatographed using a silica gel column to obtain a 2-thioacetamide piperazine benzimidazole compound.

[0032] Optionally, the temperature of the first reaction is ≤0°C, and the time of the first reaction is 4h;

[0033] The temperature of the second reaction is 65°C, and the time of the second reaction is 3h;

[0034] The temperature of the third reaction is 85° C., and the time of the third reaction is 4 hours.

[0035] In a third aspect, the present application provides an application of a 2-thioacetamide piperazine benzimidazole compound, the application comprising: using the 2-thioacetamide piperazine benzimidazole compound described in the first aspect for preparing a therapeutic drug for triple-negative breast cancer.

[0036] In a fourth aspect, the present application provides a pharmaceutical composition for treating triple-negative breast cancer, the pharmaceutical composition comprising the 2-thioacetamide piperazine benzimidazole compound or a pharmaceutically acceptable salt thereof as described in the first aspect.

[0037] The above technical solution provided by the embodiment of the present application has the following advantages compared with the prior art:

[0038] An embodiment of the present application provides a 2-thioacetamide piperazine benzimidazole compound, wherein the 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 1, wherein the R1 group includes at least one of the following groups: H, -CH3, -OCH3, halogen, -OH, -NO2 and -CF3; the R2 group includes at least one of the following groups: H, -CH3, -OCH3, halogen, -OH, -NO2 and -OCF3. Based on the traditional benzimidazole inhibitor targeting Fam20C, different parts of the benzimidazole compound were modified. The hinge region of the compound was connected by a piperazine ring and the connection length was 0 C, which could enhance the inhibitory activity of 2-thioacetamide piperazine benzimidazole compounds on Fam20C kinase and its anti-proliferation activity on triple-negative breast cancer tumor MDA-MB-231 cells. In addition, when R1 is an electron-withdrawing group, it helps to improve the inhibitory activity of the 2-thioacetamide piperazine benzimidazole compound, among which the Cl substituent at the para position has the best activity. When R2 is an electron-withdrawing group, especially a halogen substituent, the halogen substituent at the meta position will greatly improve the inhibitory activity of 2-thioacetamide piperazine benzimidazole compounds. . BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0040] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0041] Figure 1 A schematic diagram of the molecular structure of a 2-thioacetamide piperazine benzimidazole compound provided in an embodiment of the present application;

[0042] Figure 2 for Figure 1 continuation of

[0043] Figure 3 A schematic flow chart of a method for preparing 2-thioacetamide piperazine benzimidazole compounds provided in an embodiment of the present application;

[0044] Figure 4 A detailed schematic diagram of a method for preparing 2-thioacetamide piperazine benzimidazole compounds provided in an embodiment of the present application;

[0045] Figure 5 The present invention provides a schematic diagram of the actual process of preparing 2-thioacetamide piperazine benzimidazole compounds according to an embodiment of the present invention. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0047] Various embodiments of the present application may be presented in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity and should not be understood as a rigid limitation on the scope of the present application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values ​​within the range; for example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which applies regardless of the range; in addition, whenever a numerical range is indicated in this document, it is meant to include any cited numbers (fractions or integers) within the indicated range.

[0048] In this article, the terms including "including" and the like mean "including but not limited to". Relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. "At least one" means one or more, and "plurality" means two or more; "at least one", "at least one of the following" or similar expressions refer to any combination of these items, including any combination of single items or plural items; for example, "at least one of a, b, or c", or "at least one of a, b, and c" can all represent: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, c can be single or multiple. Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in this application can be purchased on the market or prepared by existing methods.

[0049] Figure 1 The molecular structure diagram of a 2-thioacetamide piperazine benzimidazole compound provided in an embodiment of the present application is exemplarily shown;

[0050] like Figure 1 and Figure 2 As shown, the embodiment of the present application provides a 2-thioacetamide piperazine benzimidazole compound, and the 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 1,

[0051]

[0052] In Formula 1, the R1 group includes at least one of the following groups:

[0053] H, -CH3, -OCH3, halogen, -OH, -NO2, and -CF3;

[0054] The R2 group includes at least one of the following groups:

[0055] H, -CH3, -OCH3, halogen, -OH, -NO2 and -OCF3.

[0056] In some optional embodiments, the R1 group and the R2 group are halogens respectively.

[0057] In some optional embodiments, the R1 group is a halogen Cl, and the R2 group is a halogen Br;

[0058] The 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 2.

[0059]

[0060] In these embodiments, based on the formula 1 structure of 2-thioacetamide piperazine benzimidazole compounds, the specific R1 group and R2 group are refined, and the electron-withdrawing group R1 group and the electron-withdrawing group R2 group are used to further improve the Fam20C kinase inhibitory activity of 2-thioacetamide piperazine benzimidazole compounds and the anti-proliferative activity on triple-negative breast cancer tumor MDA-MB-231 cells.

[0061] Figure 3 A schematic flow chart of a method for preparing 2-thioacetamide piperazine benzimidazole compounds provided in an embodiment of the present application is shown exemplarily;

[0062] Based on a general inventive concept, such as Figure 3 As shown, the present application provides a method for preparing the 2-thioacetamide piperazine benzimidazole compound, the method comprising:

[0063] S1. A first reaction of phenylpiperazine having different substituents with triethylamine, chloroacetyl chloride and dichloromethane is carried out under ice bath conditions to obtain a first intermediate;

[0064] S2. performing a second reaction on the first intermediate with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate;

[0065] S3. The second intermediate is subjected to a third reaction with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide having different substituents to obtain a 2-thioacetamide piperazine benzimidazole compound.

[0066] The method is a method for preparing the above-mentioned 2-thioacetamide piperazine benzimidazole compounds. The specific structure of the 2-thioacetamide piperazine benzimidazole compounds can be referred to the above-mentioned embodiments. Since the method adopts part or all of the technical solutions of the above-mentioned embodiments, it at least has all the beneficial effects brought by the technical solutions of the above-mentioned embodiments, which will not be repeated here one by one.

[0067] Figure 4 A detailed schematic diagram of a method for preparing 2-thioacetamide piperazine benzimidazole compounds provided in an embodiment of the present application is exemplarily shown;

[0068] In some optional embodiments, the first reaction of phenylpiperazine having different substituents with triethylamine, chloroacetyl chloride and dichloromethane under ice bath conditions to obtain a first intermediate comprises the steps of:

[0069] S101. Phenylpiperazine having different substituents is dissolved in dichloromethane under ice bath conditions and stirred, triethylamine is added dropwise and stirred until the substrate is dissolved, and chloroacetyl chloride is added and stirred to obtain a first reaction solution;

[0070] S102. adding ice water to the first reaction solution to quench it, and then extracting the reaction solution with dichloromethane as an extractant and combining the organic phase to obtain an organic phase;

[0071] S103. The organic phase is dried using anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then chromatographed using a silica gel column to obtain a first intermediate.

[0072] In these embodiments, phenylpiperazine is used as a substrate, and triethylamine, chloroacetyl chloride and dichloromethane are added to react, so as to obtain a sufficient amount of the first intermediate to finally obtain a 2-thioacetamidepiperazine benzimidazole compound.

[0073] In some optional embodiments, the second reaction of the first intermediate with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate comprises the steps of:

[0074] S201. Dissolving 2-mercaptobenzimidazole in a tetrahydrofuran solution, adding anhydrous potassium carbonate and stirring, and then adding the first intermediate to react to obtain a second reaction solution;

[0075] S202. The second reaction solution is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, and then filtered and the filter cake is washed to remove the unconsumed 2-mercaptobenzimidazole to obtain a first filter cake;

[0076] S203. Drying the first filter cake, and then performing chromatography using a silica gel column to obtain a second intermediate.

[0077] In these embodiments, 2-mercaptobenzimidazole is used as a substrate, and then a first intermediate, anhydrous potassium carbonate and tetrahydrofuran are reacted to obtain a sufficient amount of the second intermediate to finally obtain a 2-thioacetamide piperazine benzimidazole compound.

[0078] In some optional embodiments, the third reaction of the second intermediate with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide having different substituents to obtain a 2-thioacetamide piperazine benzimidazole compound comprises the steps of:

[0079] S301. The second intermediate is dissolved in N,N-dimethylformamide and anhydrous potassium carbonate is added and stirred, and then benzyl bromide having different substituents is added and heated and stirred to obtain a third reaction solution;

[0080] S302. The third reaction solution is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, and then filtered and the filter cake is washed to obtain a second filter cake;

[0081] S303. Dry the second filter cake, and then perform chromatography using a silica gel column to obtain a 2-thioacetamide piperazine benzimidazole compound.

[0082] In these embodiments, the second intermediate is used as a substrate, and then anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide with different substituents are reacted to obtain a sufficient amount of 2-thioacetamide piperazine benzimidazole compounds.

[0083] In some optional embodiments, the temperature of the first reaction is ≤0°C, and the time of the first reaction is 4h;

[0084] The temperature of the second reaction is 65°C, and the time of the second reaction is 3h;

[0085] The temperature of the third reaction is 85° C., and the time of the third reaction is 4 hours.

[0086] In these embodiments, the temperature of the first reaction can be ≤0°C, and the time of the first reaction can be 4h, the temperature of the second reaction can be 65°C, and the time of the second reaction can be 3h, the temperature of the third reaction can be 85°C, and the time of the third reaction can be 4h, and a sufficient amount of the first intermediate can be obtained through the first reaction, a sufficient amount of the second intermediate can be obtained through the second reaction, and a sufficient amount of 2-thioacetamide piperazine benzimidazole compound can be obtained through the third reaction.

[0087] Based on a general inventive concept, an embodiment of the present application provides an application of a 2-thioacetamide piperazine benzimidazole compound, which includes: using the 2-thioacetamide piperazine benzimidazole compound in the preparation of a therapeutic drug for triple-negative breast cancer.

[0088] This application is realized based on the above-mentioned 2-thioacetamide piperazine benzimidazole compounds. The specific structure of the 2-thioacetamide piperazine benzimidazole compounds can refer to the above-mentioned embodiments. Since this application adopts part or all of the technical solutions of the above-mentioned embodiments, it has at least all the beneficial effects brought by the technical solutions of the above-mentioned embodiments, which will not be repeated here one by one.

[0089] Based on a general inventive concept, an embodiment of the present application provides a pharmaceutical composition for treating triple-negative breast cancer, wherein the pharmaceutical composition comprises the 2-thioacetamide piperazine benzimidazole compound or a pharmaceutically acceptable salt thereof.

[0090] The pharmaceutical composition is realized based on the above-mentioned 2-thioacetamide piperazine benzimidazole compound. The specific structure of the 2-thioacetamide piperazine benzimidazole compound can be referred to the above-mentioned embodiment. Since the pharmaceutical composition adopts part or all of the technical solutions of the above-mentioned embodiment, it at least has all the beneficial effects brought by the technical solutions of the above-mentioned embodiment, which will not be repeated here one by one.

[0091] It should be noted that the 2-thioacetamide piperazine benzimidazole compound and its pharmaceutically acceptable salt in the pharmaceutical composition can be prepared into the following pharmaceutical forms:

[0092] Tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders for inhalation or aerosols or sprays, sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral administration (including intravenous, intramuscular or infusion). In addition, sterile water or water-propylene glycol solution can be used as a solvent to prepare liquid preparations containing 2-thioacetamide piperazine benzimidazole compounds and pharmaceutically acceptable salts thereof; the active components of 2-thioacetamide piperazine benzimidazole compounds and pharmaceutically acceptable salts thereof can also be dissolved in polyethylene glycol aqueous solution; aqueous solutions for oral administration can also be prepared by dissolving the active components of 2-thioacetamide piperazine benzimidazole compounds and pharmaceutically acceptable salts thereof in water and adding appropriate colorants, flavoring agents, stabilizers and thickeners as needed; aqueous suspensions for oral use can be prepared by dispersing finely dispersed active components of 2-thioacetamide piperazine benzimidazole compounds and pharmaceutically acceptable salts thereof in water together with viscous substances, which can be natural synthetic gums, resins, methylcellulose, carboxymethylcellulose and other suspending agents known in the pharmaceutical field.

[0093] It should be noted that the pharmaceutical composition may be in unit dosage form, for example, the pharmaceutical composition is divided into unit doses containing appropriate amounts of active ingredients. The unit dosage form may be a packaged preparation, the package including separate quantities of the preparation, such as boxed tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, cachet or tablet or any of these packaged forms may be in appropriate quantities.

[0094] It should be noted that the pharmaceutical composition can also be used in combination with other anti-triple negative breast cancer drugs, for example, such combination therapy can be achieved by administering various therapeutic components simultaneously, sequentially or separately. The application of such combination forms includes the pharmaceutical composition within the effective dose range and other pharmaceutically active agents within the permitted dose range.

[0095] The present application is further described below in conjunction with specific examples. The experimental methods in the following examples that do not specify specific conditions are usually measured according to industry standards; if there are no corresponding industry standards, they are carried out according to common international standards, conventional conditions, or conditions recommended by the manufacturer.

[0096] Example 1

[0097] Figure 5 The actual process diagram of a method for preparing 2-thioacetamide piperazine benzimidazole compounds provided in an embodiment of the present application is exemplarily shown;

[0098] like Figure 3 , Figure 4 and Figure 5 As shown, a method for preparing the 2-thioacetamide piperazine benzimidazole compound comprises:

[0099] Under ice bath conditions, phenylpiperazine (5.6mmol, 1.0equiv) with R1 group of 4-F was dissolved in 20.0mL of dichloromethane and stirred, and triethylamine (11.2mmol, 2.0equiv) was added dropwise. After the substrate was completely dissolved, chloroacetyl chloride (6.7mmol, 1.2equiv) was slowly added dropwise to the solution and stirred for 10min. Subsequently, the ice bath was removed, and the mixture was stirred at room temperature for 4h. The reaction results were monitored by TLC. After the reaction was completed, ice water was added to the reaction solution to quench it, and the reaction solution was extracted with dichloromethane (3×30.0mL). The organic phases were combined, dried with anhydrous Na2SO4, filtered, and the organic phases were concentrated under reduced pressure by a rotary evaporator to obtain a gray crude product. The crude product was purified by silica gel column chromatography (volume ratio of dichloromethane: methanol = 120:1) to obtain a first intermediate as a white solid.

[0100] 2-Mercaptobenzimidazole (1.5mmol, 1.0equiv) was dissolved in 10.0mL tetrahydrofuran solution, and then anhydrous potassium carbonate (3.0mmol, 2.0equiv) was added, stirred at room temperature for 10min, and finally the first intermediate (1.5mmol, 1.0equiv) was added, and the temperature was raised to 65°C for 4h. After the reaction was completed, the reaction solution was cooled to room temperature, and ice water was added to the reaction solution. After the precipitate was completely precipitated, it was filtered, and the filter cake was washed with a small amount of ethanol to remove the unconsumed 2-mercaptobenzimidazole, and the filtrate was discarded. The filter cake was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (volume ratio of dichloromethane: methanol = 100:1) to obtain the second intermediate as a white solid.

[0101] The second intermediate (0.5mmol, 1.0equiv) was dissolved in 6mL of N,N-dimethylformamide, and then anhydrous potassium carbonate (1.1mmol, 2.0equiv) was added, and stirred at room temperature for 10min. Finally, benzyl bromide (0.8mmol, 1.5equiv) with R2 group of 4-CH3 was added, and the reaction temperature was raised to 80°C, and the reaction was stirred at this temperature for 4h. After the reaction was completed, the reaction solution was cooled to room temperature, and ice water was added. After the precipitate was completely precipitated, it was filtered, the filter cake was washed with ice water, the filtrate was discarded, and the filter cake was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (volume ratio of dichloromethane: methanol = 140:1) to obtain Figure 1 The 2-thioacetamide piperazine benzimidazole compound 4a is shown as a white solid.

[0102] Example 2

[0103] Based on the contents disclosed in Example 1, the following modifications are further made:

[0104] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4b is obtained.

[0105] Example 3

[0106] Based on the contents disclosed in Example 1, the following modifications are further made:

[0107] The R1 group of phenylpiperazine is 4-Br, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4c is obtained.

[0108] Example 4

[0109] Based on the contents disclosed in Example 1, the following modifications are further made:

[0110] The R1 group of phenylpiperazine is 3-OCH3, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4d is obtained.

[0111] Example 5

[0112] Based on the contents disclosed in Example 1, the following modifications are further made:

[0113] The R1 group of phenylpiperazine is 4-OCH3, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4e is obtained.

[0114] Example 6

[0115] Based on the contents disclosed in Example 1, the following modifications are further made:

[0116] The R1 group of phenylpiperazine is 3-CH3, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4f is obtained.

[0117] Example 7

[0118] Based on the contents disclosed in Example 1, the following modifications are further made:

[0119] The R1 group of phenylpiperazine is 4-CH3, and the R2 group of benzyl bromide is 4-CH3, and finally 4g of 2-thioacetamidepiperazine benzimidazole compound is obtained.

[0120] Example 8

[0121] Based on the contents disclosed in Example 1, the following modifications are further made:

[0122] The R1 group of phenylpiperazine is -H, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4h is obtained.

[0123] Example 9

[0124] Based on the contents disclosed in Example 1, the following modifications are further made:

[0125] The R1 group of phenylpiperazine is 4-NO2, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4i is obtained.

[0126] Example 10

[0127] Based on the contents disclosed in Example 1, the following modifications are further made:

[0128] The R1 group of phenylpiperazine is 3-OH, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4j is obtained.

[0129] Embodiment 11

[0130] Based on the contents disclosed in Example 1, the following modifications are further made:

[0131] The R1 group of phenylpiperazine is 4-OH, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4k is obtained.

[0132] Example 12

[0133] Based on the contents disclosed in Example 1, the following modifications are further made:

[0134] The R1 group of phenylpiperazine is 4-CF3, and the R2 group of benzyl bromide is 4-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4l is obtained.

[0135] Embodiment 13

[0136] Based on the contents disclosed in Example 1, the following modifications are further made:

[0137] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 2-Cl, and finally 2-thioacetamidepiperazine benzimidazole compound 4m is obtained.

[0138] Embodiment 14

[0139] Based on the contents disclosed in Example 1, the following modifications are further made:

[0140] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 3-Cl, and finally 2-thioacetamidepiperazine benzimidazole compound 4n is obtained.

[0141] Embodiment 15

[0142] Based on the contents disclosed in Example 1, the following modifications are further made:

[0143] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 4-Cl, finally obtaining 2-thioacetamidepiperazine benzimidazole compound 4o.

[0144] Example 16

[0145] Based on the contents disclosed in Example 1, the following modifications are further made:

[0146] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 3-OCH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4p is obtained.

[0147] Embodiment 17

[0148] Based on the contents disclosed in Example 1, the following modifications are further made:

[0149] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 2-CH3, and finally 2-thioacetamidepiperazine benzimidazole compound 4q is obtained.

[0150] Embodiment 18

[0151] Based on the contents disclosed in Example 1, the following modifications are further made:

[0152] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 4-CN, and finally 2-thioacetamidepiperazine benzimidazole compound 4r is obtained.

[0153] Embodiment 19

[0154] Based on the contents disclosed in Example 1, the following modifications are further made:

[0155] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 3-OCF3, and finally 2-thioacetamidepiperazine benzimidazole compound 4s is obtained.

[0156] Embodiment 20

[0157] Based on the contents disclosed in Example 1, the following modifications are further made:

[0158] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 2-Br, and finally 2-thioacetamidepiperazine benzimidazole compound 4t is obtained.

[0159] Embodiment 21

[0160] Based on the contents disclosed in Example 1, the following modifications are further made:

[0161] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 3-Br, and finally 2-thioacetamidepiperazine benzimidazole compound 4u is obtained.

[0162] Embodiment 22

[0163] Based on the contents disclosed in Example 1, the following modifications are further made:

[0164] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 4-Br, and finally 2-thioacetamidepiperazine benzimidazole compound 4v is obtained.

[0165] Embodiment 23

[0166] Based on the contents disclosed in Example 1, the following modifications are further made:

[0167] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is two -Br (3-Br and 5-Br), finally obtaining 2-thioacetamidepiperazine benzimidazole compound 4w.

[0168] Embodiment 24

[0169] Based on the contents disclosed in Example 1, the following modifications are further made:

[0170] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is two -Fs (2-F and 4-F), and finally 2-thioacetamidepiperazine benzimidazole compound 4x is obtained.

[0171] Embodiment 25

[0172] Based on the contents disclosed in Example 1, the following modifications are further made:

[0173] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is 4-F and 2-Cl, finally obtaining 2-thioacetamidepiperazine benzimidazole compound 4y.

[0174] Embodiment 26

[0175] Based on the contents disclosed in Example 1, the following modifications are further made:

[0176] The R1 group of phenylpiperazine is 4-Cl, and the R2 group of benzyl bromide is -H, and finally 2-thioacetamidepiperazine benzimidazole compound 4z is obtained.

[0177] Related experiments and effect data:

[0178] 1. The 2-thioacetamide piperazine benzimidazole compounds obtained in each example were collected and analyzed using nuclear magnetic resonance hydrogen spectrum. The results are as follows:

[0179] 2-Thioacetamide piperazine benzimidazole compound 4a, white solid; yield 63%; 1 H NMR (600MHz, CDCl3): δ7.64(dt,J=7.8,1.0Hz,1H),7.23–7.20(m,2H),7.17(td,J=7.5,1.2Hz,1H),7.10(s,4H),7.00–6.96(m,2H) ,6.88–6.85(m,2H),5.29(s,2H),4.48(s,2H),3.81(dd,J=5.7,2.1Hz,4H),3.11–3.08(m,2H),3.07(t,J=5.2Hz,2H),2.29(s,3H). 13 C NMR (100MHz,CDCl3): 13C NMR (100MHz, CDCl3) δ166.2,159.0,156.6,151.3,147.6,147.6,143.5,138.0,136.6,132.5,129.7,127 .2,122.4,122.2,118.8,118.8,118.3,116.0,115.75,109.5,50.9,50.4,47.7,46.4,42.4,36.3,21.2. HR-ESI-MS m / z 475.2037[M+H] + ,(calcd forC 27 H 28 FN4OS,475.1968).

[0180] 2-Thioacetamide piperazine benzimidazole compound 4b, white solid; yield: 85%; 1 H NMR (600MHz, CDCl3): δ7.65(dt,J=7.8,1.0Hz,1H),7.24–7.20(m,4H),7.17(td,J=7.5,1.2Hz,1H),7.10(s,4H),6.83(d,J=2.2Hz,1H),6 .82(d,J=2.2Hz,1H),5.29(s,2H),4.48(s,2H),3.81(dt,J=12.4,5.2Hz,4H),3.15(t,J=5.2Hz,2H),3.12(t,J=5.3Hz,2H),2.29(s,3H). 13 CNMR (100MHz,CDCl3): 13 C NMR (100MHz, CDCl3) δ166.2,151.3,149.5,143.5,138.0,136.6,132.5,129.7,129.3,12 7.2,125.7,122.4,122.2,118.2,118.0,109.5,49.8,49.4,47.7,46.2,42.2,36.2,21.2. HR-ESI-MS m / z 491.1718[M+H] + ,(calcd for C 27 H 28 ClN4OS,491.1672).

[0181] 2-Thioacetamide piperazine benzimidazole compound 4c, white solid; yield: 98%; 1H NMR (600MHz, CDCl3): δ7.67(dt,J=7.8,1.0Hz,1H),7.40–7.37(m,2H),7.26–7.22(m,2H),7.20(td,J=7.5,1.2Hz,1H),7.12(s,4H),6 .81–6.78(m,2H),5.31(s,2H),4.49(s,2H),3.83(dt,J=11.0,5.2Hz,4H),3.17(t,J=5.2Hz,2H),3.14(t,J=5.3Hz,2H),2.32(s,3H). 13 CNMR (100MHz, CDCl3): δ166.3,151.3,149.9,143.5,138.0,136.6,132.5,132.2,129.7,1 27.2,122.4,122.2,118.4,118.3,113.0,109.5,49.7,49.2,47.7,46.2,42.1,36.1,21.2. HR-ESI-MS m / z 537.1166[M+H] + ,(calcd for C 27 H 28 BrN4OS,535.1167).

[0182] 2-Thioacetamide piperazine benzimidazole compound 4d, white solid; yield: 70%; 1 H NMR (600MHz, CDCl3): δ7.65(d,J=7.9Hz,1H),7.23–7.16(m,4H),7.10(s,4H),6.53(dd,J=8.2,2.3Hz,1H),6. 49–6.43(m,2H),5.29(s,2H),4.48(s,2H),3.80(d,J=6.3Hz,7H),3.18(dt,J=15.6,5.1Hz,4H),2.29(s,3H). 13 C NMR (100MHz, CDCl3): δ166.2,160.8,152.3,151.4,143.6,137.94,136.6,132.5,130 .1,129.7,127.2,122.3,122.2,118.3,109.5,109.5,105.4,103.3,55.4,49.7,49.30 47.7,46.2,42.2,36.3,21.2. HR-ESI-MS m / z 487.2216[M+H] + ,(calcd for C 28 H 31N4O2S,487.2168).

[0183] 2-Thioacetamide piperazine benzimidazole compound 4e, white solid; yield: 95%; 1 H NMR (600MHz, CDCl3): δ7.65(dt,J=7.8,1.0Hz,1H),7.23–7.20(m,2H),7.17(dd,J=7.6,1.2Hz,1H),7.10(s,4H),6.89(d,J=9.2Hz,2H),6.85(d ,J=9.1Hz,2H),5.29(d,J=1.5Hz,2H),4.48(s,2H),3.82–3.79(m,4H),3.77(s,3H),3.06(t,J=5.1Hz,2H),3.04(t,J=5.2Hz,2H),2.29(s,3H). 13 C NMR (100MHz, CDCl3): δ166.1,154.6,151.4,145.3,143.6,137.9,136.6,132.6,129.7,127. 2,122.3,122.2,119.1,118.3,114.7,109.5,55.7,51.4,50.9,47.7,46.5,42.5,36.4,21.2. HR-ESI-MS m / z 487.2216[M+H] + ,(calcd for C 28 H 31 N4O2S,487.2168).

[0184] 2-Thioacetamide piperazine benzimidazole compound 4f, white solid; yield: 73%; 1 H NMR (600MHz, CDCl3): δ7.66(d,J=7.9Hz,1H),7.24–7.20(m,2H),7.19-7.16(m,2H),7.10(s,4H),6.75–6.71(m ,3H),5.29(s,2H),4.48(s,2H),3.80(d,J=5.4Hz,4H),3.16(dt,J=13.0,5.1Hz,4H),2.33(s,3H),2.29(s,3H). 13C NMR (100MHz, CDCl3): δ7.66(d,J=7.9Hz,1H),7.24–7.20(m,2H),7.19-7.16(m,2H),7.10(s,4H),6.75–6.71(m ,3H),5.29(s,2H),4.48(s,2H),3.80(d,J=5.4Hz,4H),3.16(dt,J=13.0,5.1Hz,4H),2.33(s,3H),2.29(s,3H). 13 C NMR (100MHz, CDCl3) δ166.2,151.4,151.0,143.5,139.2,137.9,136.5,132.5,129.7,129.2,127.2 ,122.4,122.2,121.7,118.3,117.7,114.0,109.5,50.0,49.5,47.7,46.4,42.3,36.4,21.9,21.2. HR-ESI-MS m / z 471.2252[M+H] + ,(calcd for C 28 H 31 N4OS,471.2219).

[0185] 2-Thioacetamide piperazine benzimidazole compound 4g, white solid; yield: 76%; 1 H NMR (400MHz, CDCl3): δ7.68–7.62(m,1H),7.24–7.14(m,3H),7.13–7.06(m,6H),6.86–6.81(m,2H) ,5.29(s,2H),4.48(s,2H),3.84–3.77(m,4H),3.11(dt,J=10.0,5.0Hz,4H),2.29(d,J=4.1Hz,6H). 13 C NMR (100MHz, CDCl3): δ166.1,151.4,148.8,143.6,137.9,136.6,132.5,130.4,129.9,129. 7,127.2,122.3,122.2,118.3,117.2,109.4,50.5,50.0,47.7,46.4,42.4,36.4,21.2,20.6. HR-ESI-MS m / z 471.2252[M+H] + ,(calcd for C 28 H 31 N4OS,471.2219).

[0186] 2-Thioacetamide piperazine benzimidazole compound 4h, white solid; yield: 91%; 1 H NMR (600MHz, CDCl3): δ7.65(dt,J=7.7,1.1Hz,1H),7.31–7.27(m,2H),7.23–7.20(m,2H),7.18-7.16(m,1H),7.10( s,4H),6.93-6.90(m,3H),5.29(s,2H),4.47(s,2H),3.83–3.79(m,4H),3.18(dt,J=14.0,5.2Hz,4H),2.29(s,3H). 13 C NMR (100MHz, CDCl3): δ166.2,151.4,150.9,143.6,137.9,136.6,132.5,129.7,129.4,12 7.2,122.3,122.2,120.8,118.3,116.85,109.5,49.9,49.4,47.7,46.3,42.3,36.3,21.2. HR-ESI-MS m / z 457.2088[M+H] + ,(calcd forC 27 H 29 N4OS,457.2062).

[0187] 2-Thioacetamide piperazine benzimidazole compound 4i yellow solid; yield: 95%; 1 H NMR (600MHz, CDCl3): δ8.19–8.12(m,2H),7.63(d,J=7.8Hz,1H),7.24–7.16(m,3H),7.10(s,4H),6.83–6.79(m,2H),5.29(s ,2H),4.45(s,2H),3.90(t,J=5.3Hz,2H),3.82(t,J=5.4Hz,2H),3.47(t,J=5.3Hz,2H),3.43(t,J=5.4Hz,2H),2.29(s,3H). 13 C NMR (100MHz, CDCl3) δ: δ166.6,154.4,151.1,143.4,139.3,138.0,136.6,132.4,129.7,12 7.2,126.1,122.5,122.3,118.2,113.2,109.6,47.74,47.2,46.9,45.6,41.8,35.6,21.2. HR-ESI-MS m / z502.1915[M+H] + ,(calcd for C27 H 28 N5O2S,502.1913).

[0188] 2-Thioacetamide piperazine benzimidazole compound 4j, white solid; yield: 27%; 1 H NMR (600MHz, DMSO-d6): δ9.17(s,1H),7.55–7.53(m,1H),7.48–7.46(m,1H), 7.16–7.12(m,6H),7.00(t,J=8.1Hz,1H),6.40-6.39(m,1H),6.32(t,J=2.3Hz ,1H),6.25-6.23(m,1H),5.37(s,2H),4.51(s,2H),3.69(t,J=5.2Hz,2H),3.6 0(t,J=5.3Hz,2H), 3.17(t,J=5.2Hz,2H), 3.06(t,J=5.3Hz,2H), 2.24(s,3H). 13 C NMR (100MHz, DMSO-d6): δ165.5,158.1,152.1,151.1,142.94,136.9,136.2,133.3,129.6,129.2, 127.1,121.8,121.6,117.6,109.8,106.9,106.6,102.8,48.5,48.1,46.5,45.3,41.5,36.0,20.6. HR-ESI-MS m / z473.2079[M+H] + ,(calcd for C 27 H 29 N4O2S, 473.2011).

[0189] 2-Thioacetamide piperazine benzimidazole compound 4k, white solid; yield: 56%; 1 H NMR (600MHz, DMSO-d6): δ8.91(s,1H),7.55–7.53(m,1H),7.48–7.46(m,1H),7.16–7.14(m,2H),7.12(s,4H),6.82–6.79(m,2H),6.68–6.66 (m,2H),5.37(s,2H),4.51(s,2H),3.68(t,J=5.1Hz,2H),3.59(t,J=5.1Hz,2H),3.01(t,J=5.1Hz,2H),2.91(t,J=5.1Hz,2H),2.24(s,3H). 13CNMR (100MHz, DMSO-d6): δ165.4,151.4,151.1,143.9,142.9,136.9,136.1,133.3,129.2,1 27.1,121.8,121.63,118.5,117.6,115.5,109.9,50.5,50.0,46.5,45.7,41.8,36.0,20.6. HR-ESI-MS m / z 473.2079[M+H] + ,(calcd for C 27 H 29 N4O2S, 473.2011).

[0190] 2-Thioacetamide piperazine benzimidazole compound 41, white solid; yield: 98%; 1 H NMR (400MHz, CDCl3): δ7.66–7.61(m,1H),7.50(d,J=8.7Hz,2H),7.24–7.15(m,3H),7.09(s,4H),6.91(d,J=8 .6Hz,2H),5.29(s,2H),4.46(s,2H),3.82(dt,J=12.9,5.2Hz,4H),3.28(dt,J=10.6,5.3Hz,4H),2.29(s,3H). 13 C NMR (100MHz, CDCl3): δ166.4,152.9,151.2,143.5,138.0,136.6,132.5,129.7,127.2,126.7,12 6.7,126.7,126.6,122.4,122.3,118.3,115.2,109.50,48.5,48.1,47.7,45.9,42.0,35.9,21.2. HR-ESI-MS m / z 525.2022[M+H] + ,(calcd for C 28 H 28 F3N4OS,525.1936).

[0191] 2-Thioacetamide piperazine benzimidazole compound 4m, white solid; yield: 61%; 1H NMR (600MHz, CDCl3): δ7.68 (dt, J=8.1, 0.9Hz, 1H), 7.43 (dd, J=8.0, 1.2Hz, 1 H),7.25–7.20(m,4H),7.18–7.12(m,2H),7.08(td,J=7.6,1.2Hz,1H),6.85–6 .82(m,2H),6.63(dd,J=7.8,1.6Hz,1H),5.44(s,2H),4.48(s,2H),3.84–3.8 1(m,2H),3.79(t,J=5.2Hz,2H),3.17(t,J=5.2Hz,2H),3.12(t,J=5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ166.0,151.7,149.5,143.5,136.4,132.9,132.6,129.9,129.3,129 .3,127.4,125.7,122.6,122.5,118.36,118.1,109.4,49.9,49.4,46.3,45.4,42.2,36.3. HR-ESI-MS m / z 511.1156[M+H] + ,(calcdfor C 26 H 25 Cl2N4OS,511.1126).

[0192] 2-Thioacetamide piperazine benzimidazole compound 4n, white solid; yield: 56%; 1 H NMR (600MHz, CDCl3): δ7.66 (d, J=7.9Hz, 1H), 7.25–7.20 (m, 5H), 7.20–7.15 (m, 3H), 7.06 (dt, J=6.5, 2.0Hz, 1H), 6.85–6. 81 (m, 2H), 5.30 (d, J = 3.8Hz, 2H), 4.48 (s, 2H), 3.81 (dt, J = 10.0, 5.0Hz, 4H), 3.16 (t, J = 5.1Hz, 2H), 3.12 (t, J = 5.2Hz, 2H). 13 C NMR (100MHz, CDCl3): δ166.1,151.3,149.5,143.6,137.6,136.4,135.0,130.4,129.3,128.5, 127.2,125.7,125.3,122.6,122.5,118.4,118.1,109.2,49.86,49.4,47.3,46.2,42.2,36.4. HR-ESI-MSm / z 511.1156[M+H]+ ,(calcd for C 26 H 25 Cl2N4OS,511.1126).

[0193] 2-Thioacetamide piperazine benzimidazole compound 4o, white solid; yield: 64%; 1 H NMR (600MHz, DMSO-d6): δ7.57–7.54(m,1H),7.49–7.47(m,1H),7.41–7.38(m,2H),7.26–7.23(m,3H),7.23(d,J=1.9Hz,1H),7.18–7.15(m,2 H), 6.98–6.95 (m, 2H), 5.44 (s, 2H), 4.52 (s, 2H), 3.71 (t, J = 5.2Hz, 2H), 3.61 (t, J = 5.3Hz, 2H), 3.23 (t, J = 5.2Hz, 2H), 3.12 (t, J = 5.3Hz, 2H). 13 C NMR (100MHz, CDCl3): δ166.1,151.3,149.5,143.6,136.4,134.1,134.0,129.3,129.3 ,128.6,125.8,122.6,122.5,118.4,118.1,109.3,49.9,49.4,47.2,46.2,42.2,36.4. HR-ESI-MS m / z 511.1156[M+H] + ,(calcd for C 26 H 25 Cl2N4OS,511.1126).

[0194] 2-Thioacetamide piperazine benzimidazole compound 4p, white solid; yield: 83%; 1 H NMR (600MHz, CDCl3): δ7.67–7.63(m,1H),7.24–7.16(m,6H),6.84–6.81(m,2H),6.80–6.75(m,2H),6.73(t,J=2.1Hz,1 H), 5.30 (s, 2H), 4.47 (s, 2H), 3.80 (dt, J = 11.3, 5.2Hz, 4H), 3.73 (s, 3H), 3.15 (t, J = 5.1Hz, 2H), 3.12 (t, J = 5.2Hz, 2H). 13C NMR (100MHz, CDCl3): δ166.2,160.1,151.3,149.6,143.5,137.1,136.5,130.1,129.3,125.7,12 2.5,122.3,119.4,118.3,118.1,113.2,113.1,109.5,55.3,49.8,49.4,47.8,46.2,42.2,36.2. HR-ESI-MS m / z507.1688[M+H] + ,(calcd for C 27 H 28 ClN4O2S,507.1621).

[0195] 2-Thioacetamide piperazine benzimidazole compound 4q, white solid; yield: 58%; 1 H NMR (600MHz, CDCl3): δ7.68(d,J=8.0Hz,1H),7.24–7.13(m,6H),7.08–7.02(m,2H),6.84–6.81(m,2H),6.60(d,J=7.7Hz ,1H),5.31(s,2H),4.46(s,2H),3.80(dt,J=17.0,5.2Hz,4H),3.15(t,J=5.2Hz,2H),3.11(t,J=5.3Hz,2H),2.40(s,3H). 13 C NMR (100MHz, CDCl3): δ166.2,151.7,149.5,143.6,136.7,135.4,133.3,130.7,129.3,127.9,12 6.6,125.9,125.7,122.5,122.3,118.3,118.1,109.6,49.9,49.4,46.2,45.9,42.2,36.2,19.4. HR-ESI-MS m / z491.1673[M+H] + ,(calcd for C 27 H 28 ClN4OS,491.1672).

[0196] 2-Thioacetamide piperazine benzimidazole compound 4r: white solid; yield: 67%; 1H NMR (600MHz, DMSO-d6): δ7.83–7.79(m,2H),7.58–7.55(m,1H),7.47(dd,J=7.3,1.9Hz,1H),7.35(d,J=8.1Hz,2H),7.27–7.23(m,2H),7.19–7.15 (m,2H),6.98–6.94(m,2H),5.56(s,2H),4.53(s,2H),3.70(t,J=5.1Hz, 2H), 3.60 (t, J = 5.3Hz, 2H), 3.23 (t, J = 5.2Hz, 2H), 3.11 (t, J = 5.3Hz, 2H). 13 C NMR (100MHz, CDCl3): δ165.9,151.3,149.5,143.6,140.8,136.2,132.9,129.3,127.7,12 5.8,122.8,122.7,118.6,118.4,118.1,112.3,108.9,49.9,49.4,47.3,46.2,42.3,36.6. HR-ESI-MS m / z 502.1502[M+H] + ,(calcd for C 27 H 25 ClN5OS,502.1468).

[0197] 2-Thioacetamide piperazine benzimidazole compound 4s: white solid; yield: 70%; 1 H NMR (600MHz, CDCl3): δ7.66(d,J=8.0Hz,1H),7.32(t,J=8.0Hz,1H),7.26–7.21(m,3H),7.21–7.17(m,2H),7.15–7.12(m,1H),7.10–7 .05(m,2H),6.85–6.81(m,2H),5.35(s,2H),4.49(s,2H),3.81(dt,J=12.6,5.1Hz,4H),3.17(t,J=5.2Hz,2H),3.12(t,J=5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ166.0,151.3,149.8,149.7,149.5,143.5,137.9,136.3,130.6,129.3,12 5.8,125.3,122.7,122.6,120.5,119.7,118.5,118.1,109.2,49.9,49.4,47.3,46.2,42.2,36.5.

[0198] 2-Thioacetamide piperazine benzimidazole compound 4t: white solid; yield: 64%; 1 H NMR (600MHz, CDCl3): δ7.65(dt,J=8.0,1.0Hz,1H),7.44–7.41(m,2H),7.25–7.21(m,3H),7.20–7.17(m,2H),7.08–7.05( m,2H),6.84–6.81(m,2H),5.28(s,2H),4.47(s,2H),3.81(dt,J=12.8,5.2Hz,4H),3.18–3.15(m,2H),3.14–3.11(m,2H). 13 C NMR (100MHz, CDCl3): δ166.0,151.3,149.5,143.5,136.3,134.5,132.2,129.3,128.8, 125.7,122.6,122.5,122.2,118.4,118.1,109.2,49.83,49.4,47.2,46.2,42.2,36.4. HR-ESI-MS m / z557.0621[M+H] + ,(calcdfor C 26 H 25 BrClN4OS,555.0599).

[0199] 2-Thioacetamide piperazine benzimidazole compound 4u: white solid; yield: 73%; 1 H NMR (600MHz, CDCl3): δ7.66(d,J=7.9Hz,1H),7.40(dt,J=7.9,1.5Hz,1H),7.34(d,J=1.9Hz,1H),7.25–7.21(m,3H),7.21–7.15(m,3H),7.10(d t,J=7.8,1.4Hz,1H),6.85–6.82(m,2H),5.30(s,2H),4.49(s,2H),3.81(dt,J=12.7,5.2Hz,4H),3.17(t,J=5.2Hz,2H),3.12(t,J=5.3Hz,2H). 13C NMR (100MHz, CDCl3): δ166.1,151.3,149.6,137.8,136.3,131.5,130.7,130.1,129.3,12 5.8,125.7,123.2,122.7,122.6,118.4,118.1,109.3,49.9,49.4,47.2,46.2,42.2,36.4. HR-ESI-MS m / z 557.0621[M+H] + ,(calcd for C 26 H 25 BrClN4OS,555.0599).

[0200] 2-Thioacetamide piperazine benzimidazole compound 4v: white solid; yield: 63%; 1 H NMR (600MHz, CDCl3): δ7.68(d,J=8.0Hz,1H),7.61(dd,J=7.4,1.8Hz,1H),7.26–7.21(m,3H),7.18-7.15(m,1H),7.15–7.10(m,3H),6.85–6. 82(m,2H),6.58–6.54(m,1H),5.41(s,2H),4.48(s,2H),3.84–3.81(m,2H),3.79(t,J=5.2Hz,2H),3.18(t,J=5.2Hz,2H),3.14–3.10(m,2H). 13 C NMR (100MHz, CDCl3): δ166.0,151.7,149.5,143.5,136.4,134.4,133.1,129.5,129.3,128.0 ,127.4,125.7,122.6,122.5,122.4,118.4,118.1,109.4,49.9,49.4,47.9,46.2,42.2,36.3. HR-ESI-MS m / z[M+H] + ,(calcd for C 26 H 25 BrClN4OS,555.0599).

[0201] 2-Thioacetamide piperazine benzimidazole compound 4w: white solid; yield: 50%; 1H NMR (600MHz, CDCl3): δ7.68–7.65(m,1H),7.58(t,J=1.8Hz,1H),7.26–7.19(m,6H),7.17–7.14(m,1H),6.8 5–6.82(m,2H),5.27(s,2H),4.48(s,2H),3.83–3.79(m,4H),3.17(t,J=5.2Hz,2H),3.13(t,J=5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ165.9,151.2,149.5,143.5,139.4,136.2,134.1,129.3,128.8 ,125.8,123.7,122.9,122.7,118.6,118.1,109.1,49.9,49.4,46.6,46.2,42.2,36.6. HR-ESI-MS m / z 634.9733[M+H] + ,(calcd for C 30 H 28 ClN4OS,634.9706).

[0202] 2-Thioacetamide piperazine benzimidazole compound 4x: white solid; yield: 63%; 1 H NMR (600MHz, CDCl3): δ7.67(d,J=8.0Hz,1H),7.26–7.21(m,3H),7.20–7.16(m,2H),7.12(d,J=8.0Hz,1H),6.85–6.80(m,3H),6.64(dd, J=8.7,5.8Hz,1H),5.39(s,2H),4.49(s,2H),3.83(t,J=5.2Hz,2H),3.79(t,J=5.2Hz,2H),3.19(t,J=5.2Hz,2H),3.12(t,J=5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ165.9,163.4,160.9,151.6,149.5,143.5,136.3,133.4,133.2,129.3,128.9,128.9,128.8 ,128.7,125.8,122.7,122.6,118.5,118.1,117.5,117.3,114.8,114.6,109.3,49.9,49.4,46.2,44.9,42.2,36.4. HR-ESI-MS m / z 529.1055[M+H] + ,(calcdfor C26 H 24 Cl2FN4OS,529.1032).

[0203] 2-Thioacetamide piperazine benzimidazole compound 4y: white solid; yield: 41%; 1 H NMR (600MHz, CDCl3): δ7.67–7.62(m,1H),7.25–7.18(m,5H),7.02-6.98(m,1H),6.88–6.81(m,3H),6.79–6.74 (m,1H),5.35(s,2H),4.49(s,2H),3.81(dt,J=14.3,5.2Hz,4H),3.17(t,J=5.2Hz,2H),3.13(t,J=5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ166.0,151.3,149.5,143.4,136.2,130.2,130.1,130.1,129.3,125.8,122.6,122.5,118.4 ,118.1,112.1,112.1,111.9,111.9,109.2,109.2,104.6,104.33,104.1,49.9,49.4,46.2,42.2,41.1,41.1,36.5. HR-ESI-MS m / z 513.1388[M+H] + ,(calcd for C 26 H 24 ClF2N4OS,513.1327).

[0204] 2-Thioacetamide piperazine benzimidazole compound 4z: white solid; yield: 57%; 1 H NMR (600MHz, DMSO-d6): δ7.57–7.53(m,1H),7.49–7.46(m,1H),7.32(t,J=7.5Hz,2H),7.28–7.20(m,5H),7.18–7.13(m,2H),6.98– 6.95(m,2H),5.43(s,2H),4.52(s,2H),3.71(t,J=5.1Hz,2H),3.61(t,J=5.1Hz,2H),3.23(t,J=5.2Hz,2H),3.12(t,J=5.2Hz,2H). 13CNMR (100MHz, DMSO-d6): δ165.5,151.2,149.5,142.9,136.3,136.2,128.7,127.7,1 27.0,122.8,121.8,121.7,117.7,117.2,109.9,48.2,47.9,46.7,45.2,41.3,36.0. HR-ESI-MS m / z 477.1546[M+H] + ,(calcd for C 26 H 28 ClN4OS,477.1672).

[0205] 2. For the 2-thioacetamide piperazine benzimidazole compounds obtained above, their inhibitory activity on Fam20C enzyme and anti-tumor activity on triple-negative breast cancer cells MDA-MB-231 were investigated in vitro. The results are shown in Table 1, wherein the detection method of the inhibitory activity on Fam20C enzyme: refer to Eur J Med Chem. 2021Jan 15:210:113088.doi:10.1016 / j.ejmech.2020.113088;

[0206] Method for detecting antitumor activity against triple-negative breast cancer cells: Eur J Med Chem. 2021Jan15:210:113088.doi:10.1016 / j.ejmech.2020.113088.

[0207] Table 1 The inhibitory activity of various 2-thioacetamide piperazine benzimidazole compounds on Fam20C enzyme and the anti-tumor activity on triple-negative breast cancer cells

[0208]

[0209] As can be seen from Table 1, the 2-thioacetamide piperazine benzimidazole compound 4u with molecular structure 2 has the strongest anti-proliferation activity against human breast cancer cells MDA-MB-231, and exhibits strong inhibitory activity against Fam20C enzyme, which indicates that a 2-thioacetamide piperazine benzimidazole compound provided in the embodiment of the present application can be used as a new targeted therapeutic drug for triple-negative breast cancer.

[0210] The above is only a specific implementation of the present application, so that those skilled in the art can understand or implement the present application. It will be apparent to those skilled in the art that various modifications to these embodiments are possible, and the general principles defined in the present application can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown in the present application, but will conform to the widest scope consistent with the principles and novel features applied for by the present application.

Claims

1. A 2-thioacetamide piperazine benzimidazole compound, characterized in that: The 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 1, In formula 1, the R1 group is 4-F and the R2 group is 4-CH3; or The R1 group is 4-Cl and the R2 group is 4-CH3; or The R1 group is 4-Br and the R2 group is 4-CH3; or The R1 group is 3-OCH3 and the R2 group is 4-CH3; or The R1 group is 4-OCH3 and the R2 group is 4-CH3; or The R1 group is 3-CH3 and the R2 group is 4-CH3; or The R1 group is 4-CH3 and the R2 group is 4-CH3; or The R1 group is 4-NO2 and the R2 group is 4-CH3; or The R1 group is 3-OH and the R2 group is 4-CH3; or The R1 group is 4-OH and the R2 group is 4-CH3; or The R1 group is 4-CF3 and the R2 group is 4-CH3; or The R1 group is 4-Cl and the R2 group is 2-Cl; or The R1 group is 4-Cl and the R2 group is 3-Cl; or The R1 group is 4-Cl and the R2 group is 4-Cl; or The R1 group is 4-Cl and the R2 group is 3-OCH3; or The R1 group is 4-Cl and the R2 group is 2-CH3; or The R1 group is 4-Cl and the R2 group is 4-CN; or The R1 group is 4-Cl and the R2 group is 3-OCF3; or The R1 group is 4-Cl and the R2 group is 2-Br; or The R1 group is 4-Cl and the R2 group is 3-Br; or The R1 group is 4-Cl and the R2 group is 4-Br; or The R1 group is 4-Cl and the R2 groups are 3-Br and 5-Br; or The R1 group is 4-Cl and the R2 groups are 2-Cl and 4-F; or The R1 group is 4-Cl and the R2 group is -H.

2. The 2-thioacetamide piperazine benzimidazole compound according to claim 1, characterized in that: The 2-thioacetamide piperazine benzimidazole compound has a molecular structure as shown in Formula 2.

3. A method for preparing the 2-thioacetamide piperazine benzimidazole compound according to claim 1 or 2, characterized in that: The method comprises: A first reaction is performed on phenylpiperazine with different substituents with triethylamine, chloroacetyl chloride and dichloromethane under ice bath conditions to obtain a first intermediate; wherein the first intermediate has a molecular structure shown in Formula 3: The first intermediate is subjected to a second reaction with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate; wherein the second intermediate has a molecular structure shown in Formula 4: The second intermediate is subjected to a third reaction with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide with different substituents to obtain 2-thioacetamide piperazine benzimidazole compounds.

4. The method according to claim 3, characterized in that The method comprises the steps of: performing a first reaction on phenylpiperazine with different substituents with triethylamine, chloroacetyl chloride and dichloromethane under ice bath conditions to obtain a first intermediate; Dissolving phenylpiperazine with different substituents in dichloromethane under ice bath conditions and stirring, then dropping triethylamine and stirring until the substrate is dissolved, then adding chloroacetyl chloride and stirring to obtain a first reaction solution; Add ice water to the first reaction liquid to quench it, then extract the reaction liquid with dichloromethane as an extractant and combine the organic phases to obtain an organic phase; The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then chromatographed over a silica gel column to obtain the first intermediate.

5. The method according to claim 3, characterized in that: The second reaction of the first intermediate with 2-mercaptobenzimidazole, anhydrous potassium carbonate and tetrahydrofuran to obtain a second intermediate comprises the steps of: Dissolving 2-mercaptobenzimidazole in a tetrahydrofuran solution, adding anhydrous potassium carbonate and stirring, and then adding the first intermediate to react to obtain a second reaction solution; The second reaction liquid is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, followed by suction filtration and filter cake washing to remove unconsumed 2-mercaptobenzimidazole, thereby obtaining a first filter cake; The first filter cake is dried and then chromatographed using a silica gel column to obtain a second intermediate.

6. The method according to claim 3, characterized in that The third reaction of the second intermediate with anhydrous potassium carbonate, N,N-dimethylformamide and benzyl bromide having different substituents to obtain a 2-thioacetamide piperazine benzimidazole compound comprises the steps of: The second intermediate is dissolved in N,N-dimethylformamide and anhydrous potassium carbonate is added and stirred, and then benzyl bromide having different substituents is added and heated and stirred to obtain a third reaction solution; The third reaction solution is cooled to room temperature, and ice water is added until the precipitate is completely precipitated, followed by suction filtration and filter cake washing to obtain a second filter cake; The second filter cake is dried and then chromatographed using a silica gel column to obtain a 2-thioacetamide piperazine benzimidazole compound.

7. The method according to claim 3, characterized in that The temperature of the first reaction is ≤0°C, and the time of the first reaction is 4h; The temperature of the second reaction is 65°C, and the time of the second reaction is 3h; The temperature of the third reaction is 85° C., and the time of the third reaction is 4 hours.

8. An application of 2-thioacetamide piperazine benzimidazole compounds, characterized in that: The application includes: using the 2-thioacetamide piperazine benzimidazole compound according to claim 1 or 2 in the preparation of a therapeutic drug for triple-negative breast cancer.

9. A pharmaceutical composition for treating triple-negative breast cancer, characterized in that: The pharmaceutical composition comprises the 2-thioacetamide piperazine benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

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