阅读说明：本技术 一种异喹啉类化合物及其制备方法和应用 (Isoquinoline compound and preparation method and application thereof ) 是由 王震 郝荣荣 张威 郝珂 于 2021-09-29 设计创作，主要内容包括：本发明公开了一种异喹啉类化合物及其制备方法和应用,涉及化学合成技术领域。该异喹啉类化合物为吲哚并[2,1-a]异喹啉类化合物或苯并咪唑并[2,1-a]异喹啉-6(5H)酮类化合物,制备方法为：将1-(2,3-二苯基-1H-吲哚-1-基)-2-甲基丙烯基-1-酮类化合物或1-甲基丙烯酰基-2-芳基-苯并咪唑类化合物以及S-苯基苯硫代磺酸盐类化合物溶于有机溶剂中,加入氧化苯甲酸叔丁酯与催化量的溴化铜,在110℃下反应得到异喹啉类化合物。本发明的合成过程无需重氮化合物参与,具有原料廉价易得、反应条件温和、操作简便、区域选择性高、产率高的特点,有利于工业化生产。(The invention discloses an isoquinoline compound and a preparation method and application thereof, and relates to the technical field of chemical synthesis. The isoquinoline compound is an indolo [2,1-a ] isoquinoline compound or a benzimidazole [2,1-a ] isoquinoline-6 (5H) ketone compound, and the preparation method comprises the following steps: dissolving 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-ketone compounds or 1-methacryloyl-2-aryl-benzimidazole compounds and S-phenyl benzene sulphosulfonate compounds in an organic solvent, adding tert-butyl oxybenzoate and catalytic amount of copper bromide, and reacting at 110 ℃ to obtain the isoquinoline compounds. The synthesis process of the invention does not need diazo compounds, has the characteristics of cheap and easily obtained raw materials, mild reaction conditions, simple and convenient operation, high regioselectivity and high yield, and is beneficial to industrial production.)

1. An isoquinoline compound, which is characterized in that the isoquinoline compound is an indolo [2,1-a ] isoquinoline compound with a structure shown in a formula (I) or a benzimidazole [2,1-a ] isoquinoline-6 (5H) ketone compound with a structure shown in a formula (II);

wherein R is₁Is hydrogen, bromine or chlorine; r₂Is methyl or phenyl; r₃Is methyl, ethyl, butyl or benzyl; r₄Is hydrogen or methyl; r₅Methyl, phenyl, 4-methylphenyl or 4-fluorophenyl; r₆Is hydrogen, methyl, methoxy, tert-butyl, benzyloxy, bromine or fluorine; r₇Is hydrogen, methoxy or fluorine.

2. The isoquinoline compound of claim 1, comprising a compound of the following structure:

3. the method for preparing the isoquinoline compound of claim 1 or 2, wherein the method for preparing the indolo [2,1-a ] isoquinoline compound having the structure of the formula (i) comprises the following steps:

dissolving a 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-ketone compound and an S-phenyl benzene sulphosulfonate compound in an organic solvent, adding tert-butyl peroxybenzoate and a catalyst, heating to 110 ℃, reacting overnight, extracting, washing, drying, removing the solvent and separating after the reaction is finished to obtain a compound with the structure shown in the formula (I);

the preparation method of the benzimidazole [2,1-a ] isoquinoline-6 (5H) ketone compound with the structure of formula (II) comprises the following steps:

dissolving a 1-methacryloyl-2-aryl-benzimidazole compound and an S-phenylbenzene thiosulfonate compound in an organic solvent, adding tert-butyl peroxybenzoate and a catalyst, heating to 110 ℃, reacting overnight, and after the reaction is finished, extracting, washing, drying, removing the solvent and separating to obtain a compound with the structure shown in the formula (II);

the catalyst is copper bromide.

4. The method for preparing isoquinoline compounds according to claim 3, wherein the structural formula of the 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one compounds is shown as formula (III), and the structural formula of the 1-methacryloyl-2-aryl-benzimidazole compounds is shown as formula (IV):

wherein R is₁Is hydrogen, bromine or chlorine; r₂Is methyl or phenyl; r₃Is methyl, ethyl, butyl or benzyl; r₄Is hydrogen or methyl; r₆Is hydrogen, methyl, methoxy, tert-butyl, benzyloxy, bromine or fluorine; r₇Is hydrogen, methoxy or fluorine.

5. The method for preparing isoquinoline compounds according to claim 3, wherein the structural formula of the S-phenylbenzene thiosulfonate compound is:

formula (V)

Wherein R is₅Is methyl, phenyl, p-methylphenyl or 4-fluorophenyl.

6. The method for preparing isoquinoline compounds according to claim 3, wherein the molar ratio of 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one compounds, S-phenylbenzenesulfonic acid salts compounds and tert-butyl peroxybenzoate is 1: 1: 3;

the molar ratio of the 1-methacryloyl-2-aryl-benzimidazole compound to the S-phenylbenzene sulfosulfonate compound to the tert-butyl peroxybenzoate is 1: 1: 3.

7. the method of claim 3, wherein the reaction is carried out overnight for 10 to 15 hours.

8. The use of isoquinoline compounds according to claim 1 or 2 and pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment and prevention of cancer.

9. The use of claim 8, wherein the cancer comprises gastric cancer, bladder cancer and cervical cancer.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to an isoquinoline compound and a preparation method and application thereof.

Background

Indolo [2,1-a ] isoquinoline and benzimidazolo [2,1-a ] isoquinolin-6 (5H) one compounds have various biological activities, have achieved satisfactory multifaceted effects in recent years, and are receiving increasing attention from chemical researchers all over the world. At present, the available isoquinoline compounds are mostly prepared by taking 2-phenyl indole compounds or benzimidazole compounds and diazo compounds as raw materials and reacting under the heating condition of a metal catalyst. However, in the above preparation process, the synthesis steps are complicated, the diazo compounds and metal catalysts used are expensive and unsafe, and the reaction needs to be heated and even carried out under the protection of inert gas, so the existing reaction is not an optimized and economical synthesis method.

Tumor (tumor) refers to a new organism (neograwth) formed by local tissue cell proliferation under the action of various tumorigenic factors, and the new organism mostly presents space-occupying blocky protrusions. Malignant tumors are called carcinomas (cancer). Modern biological studies have shown that tumor development is closely related to the development and deregulation of the Cellular pathways of the body (kumar y., Cellular and molecular mechanisms in Cancer mechanisms review: a comprehensive review, expert. rev. clin. innunol,2014,10(1): 41-62; EI-Sibai m., Cancer cell resistance mechanism: a mini review, clin. trans. oncol.,2014,16(6): 511-516.). Each cellular pathway in the human body is crucial to maintain the normal physiological functions of the body, and regulates the proliferation and apoptosis of cells through the responsive cellular pathways. However, due to the stimulation and influence of external factors or internal factors, the body loses control over the cell pathway, and the growth of cells is not controlled, so that canceration occurs (Engel J., Current view on the mechanism of action of Perifosine in cancer, Anticancer Agents Medium. chem.,2014,14(4): 629-635.). The tissue cells after canceration grow continuously without being regulated and draw the nutrition required by the growth of normal cells, thereby causing the failure of normal cells and tissues and leading the patient to lose life finally.

Initially, in order to treat such diseases, pharmacians developed some therapeutic drugs, such as cyclophosphamide (cyclophosphamide), cisplatin (cis-platinum), and carboplatin (paraplatin). Although these chemotherapeutic agents are effective in killing cancer cells, they also kill normal cells due to their low selectivity, causing serious toxic side effects such as vomiting and alopecia, etc. (Gulied A., Cyclophosphamide-induced systemic hypothermia, a ray but polypeptide segment side effect: a case report, on. targets. Ther.,2014,30(7): 1641-1645). With the continuous progress of biological techniques and methods, kinases closely related to tumorigenesis and tumor development are continuously discovered and further confirmed as medicinal targets, such as Epidermal Growth Factor Receptor (EGFR), phosphatidylinositol kinase receptor (PI3K), Fibroblast Growth Factor Receptor (FGFR), and anaplastic lymphoma kinase receptor (ALK). Pharmaceutical scientists have diligently made efforts to develop small molecule selective inhibitors with various structural types, such as Gefitinib (Gefitinib), Icotinib (Icotinib), Imatinib (Imatinib) and Crizotinib (Crizotinib), aiming at different kinds of medicinal targets, and have achieved great clinical success. However, with the continuous use of drugs, problems of kinase mutation, decrease in drug action effect, etc. have been revealed (Bums T.F., Personalized treatment of EGFR mutation and ALK-reactive drugs in NSCLC, Expert Optin. Pharmaother., 2014,15(18): 2693. quadrature. 2708; Zhang A., Discovery of novel 2, 4-diaminopyridine analogs (DAAPanalogs) flowing through potential inhibition activity bone with type and reactive ALK kinases, J.Med.chem.,2015,58(1): 197. 211). Therefore, the development of new antitumor drugs is of great significance.

Disclosure of Invention

The invention aims to provide an isoquinoline compound and a preparation method and application thereof, which aim to solve the problems in the prior art, ensure that the preparation method of the isoquinoline compound is simple and safe, and the product has the activity of inhibiting the proliferation of tumor cells.

In order to achieve the purpose, the invention provides the following scheme:

the invention provides an isoquinoline compound, which is an indolo [2,1-a ] isoquinoline compound with a structure shown in a formula (I) or a benzimidazole [2,1-a ] isoquinoline-6 (5H) ketone compound with a structure shown in a formula (II);

wherein R is₁Is hydrogen, bromine or chlorine; r₂Is methyl or phenyl; r₃Is methyl, ethyl, butyl or benzyl; r₄Is hydrogen or methyl; r₅Methyl, phenyl, 4-methylphenyl or 4-fluorophenyl; r₆Is hydrogen, methyl, methoxy, tert-butyl, benzyloxy, bromine or fluorine; r₇Is hydrogen, methoxy or fluorine.

Further, the isoquinoline compounds comprise compounds with the following structures:

further, the preparation method of the indolo [2,1-a ] isoquinoline compound with the structure of the formula (I) comprises the following steps: dissolving a 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-ketone compound and an S-phenyl benzene sulphosulfonate compound in an organic solvent, adding tert-butyl peroxybenzoate and a catalyst, heating to 110 ℃, reacting overnight, extracting, washing, drying, removing the solvent and separating after the reaction is finished to obtain a compound with the structure shown in the formula (I);

the preparation method of the benzimidazole [2,1-a ] isoquinoline-6 (5H) ketone compound with the structure of formula (II) comprises the following steps: dissolving a 1-methacryloyl-2-aryl-benzimidazole compound and an S-phenylbenzene thiosulfonate compound in an organic solvent, adding tert-butyl peroxybenzoate and a catalyst, heating to 110 ℃, reacting overnight, and after the reaction is finished, extracting, washing, drying, removing the solvent and separating to obtain a compound with the structure shown in the formula (II);

the catalyst is copper bromide.

The organic solvent is 1, 2-dichloroethane or dimethylformamide.

Further, the structural formula of the 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one compound is shown as the formula (III), and the structural formula of the 1-methacryloyl-2-aryl-benzimidazole compound is shown as the formula (IV):

wherein R is₁Is hydrogen, bromine or chlorine; r₂Is methyl or phenyl; r₃Is methyl, ethyl, butyl or benzyl; r₄Is hydrogen or methyl; r₆Is hydrogen, methyl, methoxy, tert-butyl, benzyloxy, bromine or fluorine; r₇Is hydrogen, methoxy or fluorine.

Further, the structural formula of the S-phenyl benzene sulpho-sulfonate compound is as follows:

wherein R is₅Is methyl, phenyl, p-methylphenyl or 4-fluorophenyl.

Further, the molar ratio of the 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one compound, the S-phenyl benzene sulphosulfonate compound and the tert-butyl peroxybenzoate is 1: 1: 3;

the molar ratio of the 1-methacryloyl-2-aryl-benzimidazole compound to the S-phenylbenzene sulfosulfonate compound to the tert-butyl peroxybenzoate is 1: 1: 3.

the catalyst used is a catalytic amount, more specifically:

the mol ratio of the 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one compound, the S-phenyl benzene sulphosulfonate compound, the tert-butyl peroxybenzoate and the copper bromide is 1: 1: 3: 0.1;

the molar ratio of the 1-methacryloyl-2-aryl-benzimidazole compound to the S-phenylbenzene sulfosulfonate compound to the tert-butyl peroxybenzoate to the copper bromide is 1: 1: 3: 0.1.

further, the reaction time is 10-15 h.

The invention also provides application of the isoquinoline compounds and pharmaceutically acceptable salts thereof in preparing medicaments for treating and preventing cancers.

Further, the cancer includes gastric cancer, bladder cancer and cervical cancer.

The reaction mechanism of the preparation method is as follows:

the invention discloses the following technical effects:

when the sulfonated indolo [2,1-a ] isoquinoline and benzimidazolo [2,1-a ] isoquinoline-6 (5H) ketone compounds are synthesized, diazo compounds are not needed to participate in the reaction, the reaction system is simple and safe, the reaction cost is low, and the synthesized isoquinoline compounds show the activity of inhibiting the proliferation of tumor cells.

The synthesis method of the indolo [2,1-a ] isoquinoline and benzimidazolo [2,1-a ] isoquinoline-6 (5H) ketone compound has the characteristics of cheap and easily obtained raw materials, mild reaction conditions, simple and convenient operation, high regioselectivity and high yield, and is favorable for industrial production.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.

Example 1

A preparation method of 5-methyl-12-phenyl-5- ((phenylsulfonyl) methyl) indole [2, 1-alpha ] isoquinoline-6 (5H) -ketone (1) comprises the following steps:

1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (tert-butyl peroxybenzoate) (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE (dichloroethylene), the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily matter.

The specific results are as follows:

yield: 85 percent.¹H NMR(500MHz,CDCl₃)δ8.49(d,J＝8.2Hz,1H),7.53–7.41(m,6H),7.37(dd,J＝8.1,1.1Hz,1H),7.34–7.28(m,2H),7.22–7.18(m,4H),7.13(dd,J＝7.9,0.8Hz,1H),6.99(td,J＝7.7,1.3Hz,1H),6.95–6.85(m,1H),4.52(d,J＝14.5Hz,1H),3.90(d,J＝16.3Hz,1H),1.61(s,3H).¹³C NMR(126MHz,CDCl₃)δ170.59,140.25,134.49,134.34,134.06,133.24,132.42,130.22,129.35,129.15,128.86,128.23,128.05,127.76,127.40,126.86,126.01,125.48,125.19,124.77,120.98,119.52,116.89,64.40,46.69,31.54.HRMS(ESI):Calcd for C₃₀H₂₄NO₃S[M+H]⁺478.1478,found 478.1460。

Example 2:

a preparation method of 5-butyl-12-phenyl-5- ((phenylsulfonyl) methyl) indole [2, 1-alpha ] isoquinoline-6 (5H) -ketone (2) comprises the following steps:

1- (2, 3-diphenyl-1H-indol-1-yl) -2-butyl propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE, the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 35 percent.¹H NMR(400MHz,CDCl₃)δ8.58(d,J＝8.2Hz,1H),7.63–7.48(m,7H),7.45(dd,J＝8.0,1.0Hz,1H),7.43–7.37(m,1H),7.35–7.27(m,3H),7.23(t,J＝7.7Hz,2H),7.17–7.12(m,1H),7.05(td,J＝7.6,1.3Hz,1H),7.01–6.96(m,1H),4.57(d,J＝14.6Hz,1H),3.92(d,J＝14.6Hz,1H),2.34–2.11(m,1H),1.89–1.72(m,1H),1.19–1.00(m,2H),0.97–0.79(m,2H),0.67(t,J＝7.3Hz,3H).¹³C NMR(101MHz,CDCl₃)δ170.20,140.22,134.10,133.10,133.00,132.40,130.24,129.33,128.77,128.20,128.04,127.69,127.33,126.73,126.65,125.93,125.23,124.76,120.91,119.45,116.99,64.97,50.47,44.82,25.27,22.40,13.57.HRMS(ESI):Calcd for C₃₃H₃₀NO₃S[M+H]⁺520.1947,found 520.1913。

Example 3:

a preparation method of 5-benzyl-12-phenyl-5- ((phenylsulfo) methyl) indole [2, 1-alpha ] isoquinoline-6 (5H) -ketone (3) comprises the following steps:

dissolving 1- (2, 3-diphenyl-1H-indol-1-yl) -2-benzyl propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring for reaction at 100 ℃ for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily matter.

The specific results are as follows:

yield: 46 percent.¹H NMR(500MHz,CDCl₃)δ8.53(d,J＝8.2Hz,1H),7.58–7.52(m,2H),7.44–7.34(m,4H),7.33–7.29(m,1H),7.25(dd,J＝14.9,7.5Hz,3H),7.17–7.13(m,1H),7.14–7.08(m,1H),7.08–7.01(m,2H),6.88(ddd,J＝11.2,9.1,4.2Hz,2H),6.69(t,J＝7.7Hz,2H),6.69(t,J＝7.7Hz,2H),6.37(d,J＝7.1Hz,2H),4.78(d,J＝14.6Hz,1H),4.12(d,J＝14.6Hz,1H),3.33(d,J＝12.4Hz,1H),2.94(d,J＝12.4Hz,1H).¹³C NMR(126MHz,CDCl₃)δ169.44,140.76,133.96,133.90,133.33,133.12,131.92,131.82,130.00,129.50,129.08,128.91,128.72,127.95,127.62,127.56,127.39,127.28,127.12,127.02,125.79,125.21,124.51,120.44,119.24,116.58,63.23,52.79,50.85.HRMS(ESI):Calcd for C₃₆H₂₈NO₃S[M+H]⁺554.1791,found 554.1775。

Example 4:

a preparation method of 3,4, 12-trimethyl-5- ((phenylsulfonyl) methyl) indole [2,1-a ] isoquinoline-6 (5H) -ketone (4) comprises the following steps:

2-methyl-1- (3-methyl-2- (4-methylphenyl) -1H-indol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after completion of the reaction, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was chromatographed on a silica gel column to give an oily substance.

The specific results are as follows:

yield: 71 percent.¹H NMR(400MHz,CDCl₃)δ8.56–8.51(m,1H),7.92(d,J＝8.2Hz,1H),7.62–7.54(m,1H),7.48–7.42(m,2H),7.40–7.32(m,3H),7.27–7.22(m,2H),7.14(d,J＝8.1Hz,1H),6.91(s,1H),4.59(d,J＝14.8Hz,1H),3.96(d,J＝14.7Hz,1H),2.65(s,3H),2.17(s,3H),1.61(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.26,140.43,137.44,134.29,134.15,133.08,132.56,129.44,128.80,128.66,127.65,125.58,125.10,124.36,123.75,118.27,116.91,114.24,64.45,46.46,31.61,21.31,11.58.HRMS(ESI):Calcd for C₂₆H₂₄NO₃S[M+H]⁺430.1478,found 430.1477。

Example 5:

a process for the preparation of 10-bromo-5-methyl-12-phenyl-5- ((phenylsulfo) methyl) indol [2,1- α ] isoquinolin-6 (5H) -one (5) comprising the steps of:

1- (5-bromo-2, 3-diphenyl-1H-indol-1-yl) -2-butyl propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 62 percent.¹H NMR(400MHz,CDCl₃)δ8.45(d,J＝8.7Hz,1H),7.65–7.37(m,11H),7.29(t,J＝7.7Hz,2H),7.21(d,J＝7.6Hz,1H),7.12–7.06(m,1H),6.99(dt,J＝17.8,5.3Hz,1H),4.59(d,J＝14.6Hz,1H),3.99(d,J＝14.6Hz,1H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.65,140.18,134.67,134.22,133.34,132.98,130.30,130.13,129.52,128.91,128.71,128.51,128.46,127.73,127.54,126.89,125.65,124.74,122.16,119.93,118.30,118.25,64.45,46.64,31.49.HRMS(ESI):Calcd for C₃₀H₂₃BrNO₃S[M+H]⁺556.0584,found 556.0532。

Example 6:

a process for the preparation of 10-chloro-5-methyl-5- ((methylsulfo) methyl) -12-phenylindol [2, 1-alpha ] isoquinolin-6- (5H) -one (6) comprising the following steps:

1- (5-chloro-2, 3-diphenyl-1H-indol-1-yl) -2-butyl propenyl-1-one (0.1mmol), S-methyl methanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 49 percent.¹H NMR(400MHz,CDCl₃)δ8.68–8.37(m,1H),7.52–7.33(m,7H),7.31–7.21(m,2H),7.16(d,J＝1.9Hz,1H),7.04–6.92(m,1H),4.35(d,J＝14.7Hz,1H),3.74(d,J＝14.7Hz,1H),2.60(s,3H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.86,134.46,132.74,132.15,131.58,129.52,129.24,129.07,128.43,127.77,127.46,126.67,125.10,125.05,123.87,119.30,118.21,116.69,61.95,45.91,43.05,30.03.HRMS(ESI):Calcd for C₂₅H₂₁ClNO₃S[M+H]⁺450.0931,found 450.0929。

Example 7:

a process for the preparation of 10-bromo-5-ethyl-12-phenyl-5- ((phenylsulfo) methyl) indol [2,1- α ] isoquinolin-6 (5H) -one (7) comprising the steps of:

1- (5-bromo-2, 3-diphenyl-1H-indol-1-yl) -2-ethylpropenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 52 percent.¹H NMR(400MHz,CDCl₃)δ8.40(d,J＝8.7Hz,1H),7.44(tdd,J＝17.8,15.7,6.6Hz,8H),7.33–7.28(m,2H),7.23–7.18(m,3H),7.07(d,J＝7.4Hz,1H),7.03–6.97(m,1H),6.94(dd,J＝11.1,4.1Hz,1H),4.49(d,J＝14.6Hz,1H),3.88(d,J＝14.6Hz,1H),2.21(dt,J＝14.5,7.3Hz,1H),1.82(dq,J＝14.8,7.4Hz,1H),0.49(t,J＝7.3Hz,3H).¹³C NMR(101MHz,CDCl₃)δ170.21,140.21,134.17,133.35,133.25,132.85,132.70,130.48,130.15,129.50,128.85,128.67,128.49,128.45,127.70,127.49,126.74,126.49,125.40,122.12,119.87,118.32,118.28,64.67,51.09,38.31,7.99.HRMS(ESI):Calcd for C₃₁H₂₅BrNO₃S[M+H]⁺570.0739,found 570.0732。

Example 8:

a process for the preparation of 10-bromo-3, 5, 12-trimethyl-5- ((phenylsulfo) methyl) indol [2,1-a ] isoquinolin-6 (5H) -one (8) comprising the steps of:

1- (5-bromo-3-methyl-2- (4-tolyl) -1H-indol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after completion of the reaction, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oil.

The specific results are as follows:

yield: 58 percent.¹H NMR(400MHz,CDCl₃)δ8.42(d,J＝8.7Hz,1H),7.92(t,J＝13.7Hz,1H),7.75–7.64(m,1H),7.49–7.37(m,3H),7.25(dd,J＝8.5,7.0Hz,2H),7.20–7.11(m,1H),7.19–7.08(m,1H),6.91(d,J＝13.9Hz,1H),4.54(d,J＝12.3Hz,1H),3.96(d,J＝14.8Hz,1H),2.59(s,3H),2.13(s,3H),1.61(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.38,140.35,137.99,134.47,134.32,133.18,132.93,130.66,128.93,128.72,128.19,127.70,127.59,125.27,123.26,121.15,118.28,117.81,113.21,64.49,46.42,31.54,21.33,11.54.HRMS(ESI):Calcd for C₂₆H₂₃BrNO₃S[M+H]⁺508.0583,found 508.0588。

Example 9:

a process for the preparation of 10-chloro-5-methyl-12-phenyl-5- ((phenylsulfo) methyl) indol [2,1- α ] isoquinolin-6 (5H) -one (9) comprising the steps of:

1- (5-chloro-2, 3-diphenyl-1H-indol-1-yl) -2-butyl propenyl-1-one (0.1mmol), S-phenyl benzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: and 69 percent.¹H NMR(500MHz,CDCl₃)δ8.43(d,J＝8.7Hz,1H),7.55–7.40(m,7H),7.39–7.31(m,2H),7.27(ddd,J＝8.7,4.0,2.1Hz,1H),7.24–7.19(m,2H),7.16–7.11(m,2H),7.03–6.99(m,1H),6.95–6.89(m,1H),4.50(d,J＝14.8Hz,1H),3.90(d,J＝14.8Hz,1H),1.61(s,3H).¹³C NMR(126MHz,CDCl₃)δ170.61,140.19,134.66,133.79,133.36,133.33,132.62,130.49,130.43,130.12,129.51,128.90,128.50,128.44,127.72,127.53,126.89,125.99,125.63,124.79,120.05,119.13,117.93,64.46,46.62,31.49.HRMS(ESI):Calcd for C₃₀H₂₃ClNO₃S[M+H]⁺512.1088,found 512.1029。

Example 10:

a process for the preparation of 10-bromo-5-methyl-5- ((methylsulfo) methyl) -12-phenylindol [2, 1-alpha ] isoquinolin-6- (5H) -one (10) comprising the steps of:

1- (5-bromo-2, 3-diphenyl-1H-indol-1-yl) -2-butyl propenyl-1-one (0.1mmol), S-methyl methanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 54 percent.¹H NMR(400MHz,CDCl₃)δ8.68–8.37(m,1H),7.52–7.33(m,7H),7.31–7.21(m,2H),7.16(d,J＝1.9Hz,1H),7.04–6.92(m,1H),4.35(d,J＝14.7Hz,1H),3.74(d,J＝14.7Hz,1H),2.60(s,3H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.86,134.46,132.74,132.15,131.58,129.52,129.24,129.07,128.43,127.77,127.46,126.67,125.10,125.05,123.87,119.30,118.21,116.69,61.95,45.91,43.05,30.03.HRMS(ESI):Calcd for C₂₅H₂₁ClNO₃S[M+H]⁺450.0931,found 450.0929。

Example 11:

a preparation method of 5-methyl-12-phenyl-5- ((p-toluenesulfonyl) methyl) indole [2, 1-alpha ] isoquinoline-6 (5H) -ketone (11) comprises the following steps:

1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one (0.1mmol), S-4-methylphenyl p-toluenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE, the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 81 percent.¹H NMR(400MHz,CDCl₃)δ8.53(t,J＝33.1Hz,1H),8.11(d,J＝8.0Hz,1H),7.64–7.35(m,9H),7.27(dd,J＝10.8,5.7Hz,2H),7.16(t,J＝7.6Hz,1H),7.01(dd,J＝16.5,8.0Hz,3H),4.67(d,J＝14.6Hz,1H),3.95(d,J＝14.6Hz,1H),2.32(s,3H),1.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.35,144.57,136.51,134.49,134.27,134.05,133.71,132.34,130.17,129.37,129.31,129.25,129.18,128.50,128.23,128.07,127.99,127.35,127.15,125.92,125.40,125.07,124.72,120.85,119.44,116.86,64.41,46.53,31.86,21.33.HRMS(ESI):Calcd for C₃₁H₂₆NO₃S[M+H]⁺492.1634,found 492.1642。

Example 12:

a process for the preparation of 5- (((4-fluorophenyl) sulfonyl) methyl) -5-methyl-12-phenylindole [2.1- α ] isoquinolin-6 (5H) -one (12) comprising the steps of:

dissolving 1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one (0.1mmol), S-4-fluorophenyl p-fluorophenyl sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring at 100 ℃ for reaction for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 65 percent.¹H NMR(500MHz,CDCl₃)δ8.52(t,J＝36.9Hz,1H),7.53–7.41(m,7H),7.37(dt,J＝7.7,3.8Hz,1H),7.35(s,1H),7.25–7.19(m,2H),7.13(dt,J＝6.8,3.4Hz,1H),7.03(tt,J＝10.3,5.1Hz,1H),6.96–6.91(m,1H),6.88–6.79(m,2H),4.49(dd,J＝48.0,23.0Hz,1H),3.91(d,J＝14.7Hz,1H),1.61(s,3H).¹³C NMR(126MHz,CDCl₃)δ169.42,165.49,163.45,135.08,133.36,133.22,132.89,131.31,129.72,129.64,129.11,128.34,127.94,127.45,127.24,127.05,126.43,125.78,125.10,124.46,124.17,123.84,120.11,118.55,115.74,115.12,114.94,63.53,45.65,30.51.HRMS(ESI):Calcd for C₃₀H₂₃FNO₃S[M+H]⁺496.1383,found 496.1349。

Example 13:

a process for the preparation of 5-methyl-5- ((methylsulfo) methyl) -12-phenylindole [2,1- α ] isoquinolin-6- (5H) -one (13) comprising the steps of:

1- (2, 3-diphenyl-1H-indol-1-yl) -2-methylpropenyl-1-one (0.1mmol), S-methylmethanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE, the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 74 percent.¹H NMR(400MHz,CDCl₃)δ8.79–8.38(m,1H),7.51–7.30(m,8H),7.26–7.19(m,3H),7.02–6.95(m,1H),4.44(dd,J＝52.9,15.1Hz,1H),3.78(dd,J＝35.6,14.2Hz,1H),2.74(s,3H),1.63(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.87,134.33,133.28,132.82,131.37,129.16,128.26,127.98,127.39,127.18,126.53,125.12,125.00,124.90,124.24,123.79,120.24,118.61,115.62,61.85,46.03,43.07,30.06.HRMS(ESI):Calcd for C₂₅H₂₂NO₃S[M+H]⁺416.1321,found 416.1307。

Example 14:

a process for the preparation of 5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (14) comprising the steps of:

2-methyl-1- (2-phenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 76 percent.¹H NMR(400MHz,CDCl₃)δ8.44(d,J＝7.8Hz,1H),8.31–8.19(m,1H),7.75(t,J＝11.4Hz,1H),7.40–7.29(m,7H),7.22–7.14(m,2H),7.12(d,J＝7.9Hz,1H),4.57–4.32(m,1H),4.10–3.83(m,1H),1.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.61,148.21,142.82,138.75,136.14,132.38,130.45,130.30,128.36,127.99,127.49,126.59,125.66,125.25,125.05,124.75,122.51,121.84,118.83,114.80,63.55,45.94,30.16.HRMS(ESI):Calcd for C₂₃H₁₉N₂O₃S[M+H]⁺403.1117,found 403.1109。

Example 15:

a preparation method of 5-butyl-5- ((phenylsulfonyl) methyl) benzo [4,5] imidazo [2, 1-alpha ] isoquinoline-6- (5H) -ketone (15) comprises the following steps:

dissolving 2-butyl-1- (2-phenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring at 100 ℃ for reaction for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 45 percent.¹H NMR(400MHz,CDCl₃)δ8.46(d,J＝7.0Hz,1H),8.31–8.21(m,1H),7.85–7.69(m,1H),7.43–7.28(m,6H),7.24–7.15(m,2H),7.08(d,J＝7.9Hz,1H),4.45(d,J＝14.7Hz,1H),4.05(m,J＝14.7Hz,1H),2.28–2.08(m,1H),1.88–1.68(m,1H),1.05–0.91(m,2H),0.87–0.74(m,2H),0.64–0.53(t,J＝7.6Hz,3H).¹³C NMR(101MHz,CDCl₃)δ169.36,148.32,142.59,138.79,134.78,132.30,130.40,130.14,127.96,127.49,126.53,125.35,125.10,124.79,123.33,118.74,114.85,64.12,50.01,43.40,24.18,21.26,12.43.HRMS(ESI):Calcd for C₂₆H₂₅N₂O₃S[M+H]⁺445.1587,found 445.1585。

Example 16:

a process for the preparation of 5-benzyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (16) comprising the steps of:

dissolving 2-benzyl-1- (2-phenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring at 100 ℃ for reaction for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 52 percent.¹H NMR(500MHz,CDCl₃)δ8.28–8.13(m,2H),7.61(dd,J＝5.8,3.0Hz,1H),7.44(d,J＝7.5Hz,2H),7.40–7.20(m,8H),6.81(t,J＝7.4Hz,1H),6.68(t,J＝7.7Hz,2H),6.32(t,J＝22.6Hz,2H),4.69(d,J＝14.7Hz,1H),4.11(t,J＝14.7Hz,1H),3.34(t,J＝18.0Hz,1H),3.04(d,J＝12.6Hz,1H).¹³C NMR(126MHz,CDCl₃)δ168.70,147.79,139.0,133.76,132.47,131.08,129.87,128.15,128.0,127.58,126.85,126.77,126.67,126.14,124.92,124.84,124.57,123.68,118.62,114.47,62.50,51.95,49.48.¹³C NMR(126MHz,CDCl₃)δ168.70,147.79,139.00,133.76,132.47,131.08,129.87,128.15,128.0,127.58,126.85,126.77,126.67,126.14,124.92,124.84,124.57,123.68,118.62,114.47,62.50,51.95,49.48.HRMS(ESI):Calcd for C₂₉H₂₃N₂O₃S[M+H]⁺479.1430,found 479.1400。

Example 17:

a process for the preparation of 3, 5-dimethyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (17) comprising the steps of:

2-methyl-1- (2-p-methylphenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 72 percent.¹H NMR(500MHz,CDCl₃)δ8.35–8.24(m,2H),7.75–7.74(m,1H),7.45–7.26(m,5H),7.20–7.13(m,3H),6.77(s,1H),4.49(d,J＝14.9Hz,1H),3.95(d,J＝14.9Hz,1H),2.08(s,3H),1.64(d,J＝49.1Hz,3H).¹³C NMR(126MHz,CDCl₃)δ170.76,149.44,143.94,141.98,139.92,136.97,133.31,131.47,129.61,128.85,127.53,127.19,126.17,126.00,125.58,120.36,119.77,115.80,64.56,46.86,31.15,21.65.HRMS(ESI):Calcd for C₂₄H₂₁N₂O₃S[M+H]⁺417.1274,found 417.1271。

Example 18:

a process for the preparation of 3-methoxy-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (18) comprising the steps of:

2-methyl-1- (2-p-methoxyphenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to obtain an oily substance.

The specific results are as follows:

yield: 74 percent.¹H NMR(400MHz,CDCl₃)δ8.44–8.28(m,1H),8.28(s,1H),7.85–7.64(m,1H),7.41–7.30(m,5H),7.23(d,J＝8.0Hz,2H),6.89(dd,J＝8.8,2.4Hz,1H),6.51(d,J＝2.4Hz,1H),4.50(d,J＝14.8Hz,1H),4.00–3.79(m,1H),3.64(s,3H),1.59(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.58,160.99,148.35,142.99,138.88,137.99,132.24,130.37,127.89,127.11,126.59,124.93,124.26,118.42,114.72,114.65,113.38,111.25,63.53,54.35,46.08,30.29.HRMS(ESI):Calcd for C₂₄H₂₁N₂O₄S[M+H]⁺433.1223,found 433.1212。

Example 19:

a process for the preparation of 3-tert-butyl-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (19), comprising the following steps:

2-methyl-1- (2-p-tert-butylphenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 73 percent.¹H NMR(400MHz,CDCl₃)δ8.34(d,J＝8.3Hz,1H),8.27–8.22(m,1H),7.76–7.71(m,1H),7.43–7.25(m,7H),7.15(dd,J＝9.4,7.9Hz,2H),4.51(d,J＝14.8Hz,1H),4.00(d,J＝14.8Hz,1H),1.63(s,3H),1.18(s,9H).¹³C NMR(101MHz,CDCl₃)δ169.89,154.09,148.39,142.95,138.84,135.98,132.47,130.42,127.90,126.70,125.00,124.93,124.48,122.28,119.23,118.66,114.72,63.86,46.20,34.12,30.40,29.98.HRMS(ESI):Calcd for C₂₇H₂₇N₂O₃S[M+H]⁺459.1743,found 459.1710。

Example 20:

a process for the preparation of 3-benzyloxy-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (20) by the following steps:

2-methyl-1- (2-p-benzyloxyphenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after completion of the reaction, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: and 69 percent.¹H NMR(400MHz,CDCl₃)δ8.35(d,J＝8.7Hz,1H),8.26–8.16(m,1H),7.78–7.64(m,1H),7.40–7.27(m,10H),7.19(dd,J＝9.5,5.9Hz,2H),7.01–6.89(m,1H),6.56(t,J＝10.8Hz,1H),4.82(q,J＝11.2Hz,2H),4.45(d,J＝18.3Hz,1H),3.87(d,J＝18.3Hz,1H),1.56(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.56,160.22,148.31,142.98,138.90,138.02,134.77,132.25,130.37,127.90,127.74,127.42,127.08,126.58,124.93,124.28,118.43,114.94,114.66,114.11,112.09,69.20,63.56,46.05,30.16.HRMS(ESI):Calcd for C₃₀H₂₅N₂O₄S[M+H]⁺509.1536,found 509.1536。

Example 21:

a process for the preparation of 3-bromo-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (21) comprising the steps of:

2-methyl-1- (2-p-bromophenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-phenylbenzenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after completion of the reaction, the solvent was removed by quenching, extraction, drying, distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oily substance.

The specific results are as follows:

yield: 51 percent.¹H NMR(400MHz,CDCl₃)δ8.33–8.24(m,2H),7.77–7.75(m,1H),7.48–7.45(m,1H),7.43–7.35(m,5H),7.26(t,J＝7.8Hz,2H),7.14(d,J＝1.6Hz,1H),4.48(d,J＝14.9Hz,1H),3.90(d,J＝14.9Hz,1H),1.59(s,3H).¹³C NMR(101MHz,CDCl₃)δ168.87,147.34,142.81,138.58,137.73,133.36,132.88,130.96,130.43,128.96,128.40,128.10,127.21,126.57,126.31,125.23,125.07,124.92,121.01,118.93,114.84,63.33,45.82,29.86.HRMS(ESI):Calcd for C₂₃H₁₈BrN₂O₃S[M+H]⁺481.0222,found 481.0251。

Example 22:

a process for the preparation of 3-fluoro-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (22) comprising the steps of:

2-methyl-1- (2-p-fluorophenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE, the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily matter.

The specific results are as follows:

yield: 53 percent.¹H NMR(400MHz,CDCl₃)δ8.44(dd,J＝8.8,5.7Hz,1H),8.28–8.20(m,1H),7.80–7.67(m,1H),7.44–7.33(m,5H),7.25(t,J＝7.7Hz,2H),7.07(td,J＝8.6,2.4Hz,1H),6.79(dd,J＝9.5,2.4Hz,1H),4.45(d,J＝14.8Hz,1H),4.01(d,J＝14.8Hz,1H),1.67(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.07,165.66,163.13,148.47,143.86,139.90,139.82,139.70,133.71,131.40,129.12,128.79,128.70,127.54,126.18,125.84,119.85,119.45,119.42,116.71,116.49,115.79,113.96,113.72,64.40,47.12,31.06.HRMS(ESI):Calcd for C₂₃H₁₈FN₂O₃S[M+H]⁺421.1023,found 421.1021。

Example 23:

a process for the preparation of 1-fluoro-5-methyl-5- ((phenylsulfo) methyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (23) comprising the steps of:

dissolving 2-methyl-1- (o-fluorophenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-phenyl benzene sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring for reaction at 100 ℃ for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily matter.

The specific results are as follows:

yield: 41 percent.¹H NMR(400MHz,CDCl₃)δ8.32–8.20(m,1H),7.95–7.83(m,1H),7.45(t,J＝7.2Hz,2H),7.42–7.34(m,3H),7.24(dd,J＝15.0,7.7Hz,3H),7.14(dd,J＝10.5,8.4Hz,1H),7.04(d,J＝7.8Hz,1H),4.50(d,J＝14.7Hz,1H),4.00(dd,J＝36.8,10.9Hz,1H),1.62(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.02,160.79,158.18,144.44,144.36,143.17,138.75,138.68,132.60,130.98,130.89,129.43,128.08,126.60,125.26,125.12,121.74,121.70,119.64,115.49,115.27,114.69,111.34,111.24,63.54,45.96,30.47.HRMS(ESI):Calcd for C₂₃H₁₈FN₂O₃S[M+H]⁺421.1023,found 421.0998。

Example 24:

a process for the preparation of 5-methyl-5- (p-methylbenzenesulfonyl) benzo [4,5] imidazo [2, 1-alpha ] isoquinolin-6- (5H) -one (24) comprising the steps of:

2-methyl-1- (phenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-p-toluene-p-toluenesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) are dissolved in 3 ml of DCE, the mixture is heated and stirred at 100 ℃ for reaction for 10 hours, after the reaction is finished, the solvent is removed by quenching, extraction, drying and reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain oily matter.

The specific results are as follows:

yield: 78 percent.¹H NMR(400MHz,CDCl₃)δ8.44(d,J＝7.8Hz,1H),8.18(d,J＝7.3Hz,1H),7.72(t,J＝20.2Hz,1H),7.37(tt,J＝20.2,7.5Hz,4H),7.22(d,J＝8.2Hz,3H),6.85(t,J＝40.5Hz,2H),4.48(d,J＝14.7Hz,1H),4.07–3.64(d,J＝14.7Hz,1H),2.11(s,3H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.44,148.21,143.83,142.81,136.16,135.07,130.44,130.32,128.46,127.43,126.89,125.97,125.17,125.00,124.68,121.80,118.83,114.74,63.45,45.88,30.54,20.29.HRMS(ESI):Calcd for C₂₄H₂₁N₂O₃S[M+H]⁺417.1274,found 417.1265。

Example 25:

a process for the preparation of 5-methyl-5- (p-fluorophenylsulphonyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (25) comprising the steps of:

dissolving 2-methyl-1- (phenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-p-fluorophenyl sulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring for reaction at 100 ℃ for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain oily substance.

The specific results are as follows:

yield: 52 percent.¹H NMR(500MHz,CDCl₃)δ8.45(dd,J＝7.9,1.1Hz,1H),8.29–8.19(m,1H),7.82–7.71(m,1H),7.42–7.33(m,5H),7.29–7.23(m,1H),7.12(dd,J＝17.2,7.6Hz,1H),6.91–6.82(m,2H),4.46(t,J＝25.1Hz,1H),4.02–3.85(m,1H),1.63(s,3H).¹³C NMR(126MHz,CDCl₃)δ180.94,169.52,165.58,163.53,148.09,142.88,136.09,134.77,130.41,130.31,129.59,129.52,127.56,125.62,125.31,125.15,124.87,121.95,118.92,115.37,115.19,114.72,63.70,45.95,30.14.HRMS(ESI):Calcd for C₂₃H₁₈FN₂O₃S[M+H]⁺421.1023,found 421.1017。

Example 26:

a process for the preparation of 5-methyl-5- (methylsulfonyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (26) comprising the steps of:

2-methyl-1- (phenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-methylmethanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after the reaction was completed, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was separated by silica gel column chromatography to give an oil.

The specific results are as follows:

yield: and 69 percent.¹H NMR(400MHz,CDCl₃)δ8.49(d,J＝7.8Hz,1H),8.33–8.18(m,1H),7.81–7.71(m,1H),7.59–7.42(m,3H),7.37(p,J＝7.4Hz,2H),4.33(d,J＝14.8Hz,1H),3.87(d,J＝14.8Hz,1H),2.39(s,3H),1.68(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.89,148.16,142.97,136.97,130.72,130.42,127.75,125.77,125.07,125.02,124.82,122.07,118.97,114.65,62.23,46.14,42.87,29.79.HRMS(ESI):Calcd for C₁₈H₁₇N₂O₃S[M+H]⁺341.0961,found 341.0954。

Example 27:

a process for the preparation of 3-benzyloxy-5-methyl-5- (methylsulfonyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (27) by the following steps:

2-methyl-1- (p-benzyloxyphenyl-1H-benzo [ d ] imidazol-1-yl) propenyl-1-one (0.1mmol), S-methylmethanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) were dissolved in 3 ml of DCE, and the mixture was heated and stirred at 100 ℃ for 10 hours, after completion of the reaction, the solvent was removed by quenching, extraction, drying and distillation under reduced pressure, and the residue was chromatographed on a silica gel column to give an oily substance.

The specific results are as follows:

yield: 71 percent.¹H NMR(400MHz,CDCl₃)δ8.48(d,J＝8.7Hz,1H),8.34–8.27(m,1H),7.81–7.75(m,1H),7.40(tdd,J＝14.0,11.2,7.1Hz,7H),7.17(dd,J＝8.8,2.2Hz,1H),7.05(d,J＝2.1Hz,1H),5.32–5.04(m,2H),4.35(d,J＝14.8Hz,1H),3.75(t,J＝35.0Hz,1H),2.48(s,3H),1.69(s,3H).¹³C NMR(101MHz,CDCl₃)δ170.88,161.54,149.31,144.05,140.07,135.95,131.34,128.86,128.75,128.52,127.68,126.01,125.38,119.59,115.99,115.54,115.21,112.93,70.51,63.24,47.33,43.83,30.95.HRMS(ESI):Calcd for C₂₅H₂₃N₂O₄S[M+H]⁺447.1379,found 447.1369。

Example 28:

a process for the preparation of 1-fluoro-5-methyl-5- (methylsulfonyl) benzo [4,5] imidazo [2,1- α ] isoquinolin-6- (5H) -one (28) comprising the steps of:

dissolving 2-methyl-1- (o-fluorophenyl-1H-benzo [ d ] imidazole-1-yl) propenyl-1-ketone (0.1mmol), S-methyl methanesulfonate (0.1mmol), TBPB (0.3mmol) and copper bromide (0.01mmol) in 3 ml of DCE, heating and stirring at 100 ℃ for reaction for 10 hours, after the reaction is finished, quenching, extracting, drying, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain an oily substance.

The specific results are as follows:

yield: 56 percent.¹H NMR(400MHz,CDCl₃)δ8.33–8.23(m,1H),7.90–7.84(m,1H),7.52(td,J＝8.1,5.2Hz,1H),7.42–7.37(m,2H),7.31–7.21(m,2H),4.40(d,J＝14.7Hz,1H),4.09–3.71(d,J＝14.7Hz,,1H),2.78(s,3H),1.70(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.50,158.45,143.29,143.26,139.68,131.45,131.35,129.38,125.31,125.17,120.88,120.84,119.76,115.77,115.56,114.48,61.83,46.40,43.27,30.29.HRMS(ESI):Calcd for C₁₈H₁₆FN₂O₃S[M+H]⁺359.0866,found 359.0859.

Pharmacological experiment-MTT method

The MTT method is also called MTT colorimetry, and is a method for detecting cell survival and growth. The detection principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline Formazan (Formazan) and can be deposited in cells, but dead cells do not have the function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured by enzyme linked immunosorbent detector at 540nm or 720nm wavelength, which can indirectly reflect living cell number. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely applied to activity detection of some bioactive factors, large-scale screening of anti-tumor drugs, cytotoxicity test, tumor radiosensitivity determination and the like. It features high sensitivity and economy.

The experimental method comprises the following steps: tumor cell strains in logarithmic growth phase, including human cervical cancer cell strain (Hela), human gastric cancer cell (MGC803) and human bladder cancer cell (T24), are inoculated to a 96-well plate according to 4000 cells/well. 5-Fluorouracil was used as a positive control, compound concentrations up to 100. mu.g/mL, 5-fold gradient dilutions, total 5 concentrations, three duplicate wells per concentration. After the compound acts on the cells for 72 hours, the culture solution is discarded, 100 microliters of precooled 10% trichloroacetic acid (TCA) solution is added into each hole to fix the cells, the cells are placed in a refrigerator at 4 ℃ for 1 hour, each hole of the culture solution is washed for five times by deionized water, the trichloroacetic acid solution is removed, after the cells are dried in the air, 50 microliters of SRB solution (4mg/mL) prepared by 1% acetic acid is added into each hole, the cells are placed for 20 minutes at room temperature, the liquid in each hole is discarded and then washed for five times by 1% acetic acid, unbound SRB dye is washed and then dried in the air, 100 microliters of 10mM Tris-base (trihydroxymethylaminomethane) solution with the pH of 10.5 is added into each hole to be dissolved, the plates are shaken for 5 minutes, and the OD value is measured under the wavelength of 515nm by an enzyme reader.

Determination of IC of the Compound₅₀The values are shown in Table 1:

TABLE 1

As can be seen from Table 1, the sulfonated indolo [2,1-a ] isoquinoline compounds and benzimidazolo [2,1-a ] isoquinoline-6 (5H) ketone compounds obtained by utilizing the free radical reaction show better activity of inhibiting the proliferation of tumor cells. Among them, compound 21 showed better activity for inhibiting Hela, MGC803 and T24 cell lines than the positive control 5-fluorouracil.

The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.