Synthesis method of sulfonyl-containing indolo [1, 4] diazacycloheptanedione compound

Abstract

The invention discloses a synthesis method of a sulfonyl-containing indolo [1, 4] diazacycloheptanedione compound, and belongs to the technical field of organic chemistry. The method comprises the following steps: by taking N-alkyl-N-(2-(1H-indole-aryl) methacrylamide, aryl diazonium salt and a sulfur dioxide source as raw materials, carrying out heating reaction in a solvent under a catalyst-free condition, generating a sulfonyl free radical intermediate from the aryl diazonium salt and the sulfur dioxide source in situ, and carrying out free radical addition-cyclization reaction to obtain a target compound. According to the present invention, the method has characteristics of no catalyst, simple process, environmental protection, target product yield reaching up to 99%, strong substrate universality and strong functional group compatibility, and the synthesized compound has good in vitro proliferation inhibition activity on human colon cancer and breast cancer tumor cells, provides candidate molecules for anti-tumor drug research and development, and can easily achieve industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, specifically relating to a method for synthesizing compounds containing sulfonyl indolo[1,4] diazacyclic heptanediones. Background Technology

[0002] Sulfonyl-indolo[1,4]diazacyclic heptanediones are a class of organic compounds containing a sulfonyl group. These compounds can serve as active pharmaceutical ingredients and are expected to be used in the preparation of drugs for treating diseases related to abnormal kinase activity (such as tumors, inflammation, etc.). Their conventional synthetic method involves reacting the corresponding N-alkyl-N-(2-(1H-indolo-aryl)methacrylamide with sulfonyl chloride or sodium sulfinate under heating or light irradiation.

[0003] Sulfur dioxide insertion reaction is a novel organic synthesis strategy that has attracted widespread attention. Specifically, it involves "inserting" a molecule of sulfur dioxide into an organic chemical reaction to synthesize sulfonyl compounds. Its advantage lies in avoiding the use and preparation of strong acidic sulfonic acids or sulfonyl chlorides in traditional sulfonyl compound synthesis routes, and instead directly constructing the sulfonyl functional group in one step, which has the advantages of simplicity, efficiency, and environmental friendliness. In recent years, the existing synthetic methods for sulfonyl indolo[1,4]diazacyclic heptanedione compounds still rely on sulfonyl chloride compounds, which has certain limitations [(a) Y. Wang, X. Huang, J. Chen, J. Xu, and Q. Song, Org. Biomol. Chem., 2025, 23, 4349-4354.].

[0004] The method of this invention uses ethyl acetate as a green mixed solvent as the reaction medium, and diazonium salt, DABSO and N-alkyl-N-(2-(1H-indole-aryl)methacrylamide as raw materials. The reaction is carried out under heating conditions without a catalyst. The diazonium salt reacts with DABSO to generate a sulfonyl radical intermediate, and further reaction yields a sulfonyl indolo[1,4]diazacyclic heptanedione compound. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide a simple and efficient method for synthesizing sulfonyl indolo[1,4] diazacycloheptanone compounds.

[0006] To address the aforementioned technical problems, this invention provides a method for synthesizing sulfonyl indolo[1,4]diazacyclic heptanedione compounds. This method utilizes N-alkyl-N-(2-(1H-indolo-aryl)methacrylamide, an aryl diazonium salt, and a sulfur dioxide source in a solvent under catalyst-free and heating conditions to efficiently construct sulfonyl indolo[1,4]diazacyclic heptanedione compounds.

[0007] Specifically, the method of the present invention involves reacting N-alkyl-N-(2-(1H-indole-aryl)methacrylamide of formula (I) with an aryl diazonium salt and a sulfur dioxide source in a solvent under catalytic-free conditions. In the reaction, the aryl diazonium salt and the sulfur dioxide source generate a sulfonyl radical intermediate in situ. This intermediate first undergoes radical addition to the alkenyl group of the substrate, followed by radical cyclization, to obtain a sulfonyl indole[1,4]diazacyclic heptanedione compound of formula (II).

[0008] In the formula, R 1 It is selected from electron-withdrawing group I or electron-donating group I. Electron-withdrawing group I is selected from any one of the substituents of nitro, chlorine atom, bromine atom, trifluoromethyl, acyl, ester group, and carboxyl group. Electron-donating group I is selected from any one of the substituents of alkyl and alkoxy groups.

[0009] R 2 It is an electron-withdrawing group II or an electron-donating group II. The electron-withdrawing group II is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group. The electron-donating group II is selected from any one of the substituents of alkyl group and substituted amino group.

[0010] R 3 It is an electron-withdrawing group III or an electron-donating group III. The electron-withdrawing group III is selected from any one of the substituents of acyl, ester, and carboxyl groups, and the electron-donating group III is an alkyl group.

[0011] R 4 It is an electron-withdrawing group IV or an electron-donating group IV. The electron-withdrawing group IV is selected from any substituent of sulfonyl or acyl, and the electron-donating group IV is any type of alkyl group.

[0012] R 5 It is an electron-withdrawing group V or an electron-donating group V. The electron-withdrawing group V is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group. The electron-donating group V is selected from any one of the substituents of alkyl group and substituted amino group.

[0013] Ar is an aryl or heteroaryl group having an electron-withdrawing group VI or an electron-donating group VI. The electron-withdrawing group VI is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group. The electron-donating group VI is selected from any one of the substituents of alkyl group and substituted amino group.

[0014] As some embodiments of the present invention, the solvent used is selected from one of ethyl acetate, acetonitrile, dichloromethane, dichloroethane, toluene, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfone, and ethanol.

[0015] As a preferred embodiment of the present invention, the solvent used is ethyl acetate.

[0016] As some embodiments of the present invention, the sulfur dioxide source used is selected from one of DABSO, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium bisulfite, and sodium dithionite.

[0017] As a preferred embodiment of the present invention, DABSO is preferred as a sulfur dioxide source because it is inexpensive, efficient, and easy to process and separate. Using other sulfur dioxide sources will result in a certain decrease in reaction yield.

[0018] As a preferred embodiment of the present invention, when the electron-donating group I is an alkyl group, it is selected as a cyclic alkyl group or a chain alkyl group, that is, the electron-donating group I is selected from any one of the substituents of alkyl, cycloalkyl, and alkoxy groups.

[0019] As a preferred embodiment of the present invention, the electron-donating group III is a chain alkyl group.

[0020] As some embodiments of the present invention, the specific steps of the method of the present invention are as follows: S1. At room temperature, add N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt and sulfur dioxide source to a dry reaction vessel. After sealing the reaction vessel, purge with protective gas, then add solvent and place in a heating device at 30℃~50℃ and stir for 10h~25h. After the reaction is complete, obtain the reaction solution.

[0021] S2. Extract the reaction solution from step S1 with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use a mixture of petroleum ether and ethyl acetate as the mobile phase for column chromatography separation to obtain sulfonyl indolode[1,4]diazacyclic heptanedione compounds.

[0022] As a preferred embodiment of the present invention, the reaction vessel in step S1 is a test tube, and the protective gas is nitrogen, argon or helium.

[0023] As some embodiments of the present invention, in step S1, the molar ratio of the added N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt and sulfur dioxide source is 1:(1.0-2.5):(1.0-2.5).

[0024] As a preferred embodiment of the present invention, in step S1, the molar ratio of the added N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt, and sulfur dioxide source is 1:1.5:1.5. This results in a higher reaction yield.

[0025] As some embodiments of the present invention, in step S1, the reaction substrate N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt and sulfur dioxide source are dissolved in a solvent to prepare a solution with a reaction substrate concentration of 0.05 mol / L to 0.5 mol / L.

[0026] As a preferred embodiment of the present invention, in step S1, the mixture is placed in a heating device at 40°C and stirred for 18 hours.

[0027] As a preferred embodiment of the present invention, in step S1, TLC is used to monitor whether the reaction is complete, that is, TLC is used to monitor the reaction process, and the reaction is stopped after the reaction is complete.

[0028] As a preferred embodiment of the present invention, in step S2, the reaction solution is first quenched with water and then extracted with ethyl acetate.

[0029] As a preferred embodiment of the present invention, in step S2, the specific process of quenching the reaction solution with water is as follows: distilled water is added to the reaction solution, wherein the volume ratio of the distilled water to the reaction solution is 0.5:1 to 2:1, the solution is allowed to stand and separate into layers, and the organic phase is separated.

[0030] As some embodiments of the present invention, in step S2, the volume ratio of petroleum ether to ethyl acetate in the column chromatography mobile phase is 2:1 to 4:1.

[0031] As a preferred embodiment of the present invention, in step S2, the volume ratio of petroleum ether to ethyl acetate in the column chromatography mobile phase is 3:1.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The process is extremely simple and controllable, significantly reducing synthesis costs and scale-up barriers. This invention employs a catalytic-free reaction system, completely avoiding the use of metal catalysts and small organic molecule catalysts. This significantly reduces raw material costs and eliminates the quality control risks associated with metal residues in drug synthesis, eliminating the need for additional catalyst removal processes. Furthermore, this invention utilizes a three-component one-pot cascade reaction, generating a sulfonyl intermediate in situ from an aryl diazonium salt and a sulfur dioxide source, completing the free radical addition-cyclization reaction in one step to directly construct the fused polycyclic target framework. No intermediate separation and purification are required, resulting in a short and simple synthetic process. The reaction conditions are mild, requiring only 40°C for efficient operation, and the 30°C–50°C temperature range has no significant impact on the reaction yield. The wide reaction window and low requirements for production equipment make it easily scalable for industrial-scale production.

[0033] 2. Green and environmentally friendly, in line with the concept of green chemistry development. This invention preferentially uses ethyl acetate as the reaction solvent, which is a low-toxicity, easily recyclable, and environmentally friendly solvent. It replaces the highly toxic, difficult-to-degrade, and environmentally polluting organic solvents used in traditional synthetic routes, significantly improving environmental friendliness. Furthermore, this invention employs a sulfur dioxide insertion synthesis strategy, directly constructing sulfonyl functional groups in situ using sulfur dioxide sources such as DABSO. This completely avoids the preparation and use of strong acidic sulfonic acids and sulfonyl chlorides in traditional processes, greatly reducing the generation of acidic waste liquid and corrosive byproducts, lowering waste treatment costs and environmental pressure. Moreover, post-reaction processing only requires conventional extraction, drying, and column chromatography to obtain the high-purity target product, making the operation process green and simple.

[0034] 3. Excellent reaction efficiency, outstanding atom economy and selectivity. The synthetic route of this invention exhibits excellent chemoselectivity and regioselectivity. It allows for the precise and directional construction of an indole-7-membered lactam fused skeleton via a free radical tandem reaction, with no significant side reactions occurring. Under optimal conditions, the yield of the target product can reach 99%. Furthermore, this invention optimizes the reactant ratio. Using N-alkyl-N-(2-(1H-indole-aryl)methacrylamide substrate as a 1.0 equivalent, only 1.5 equivalents of DABSO and aryl diazonium salt are required for efficient conversion, resulting in high reactant utilization, good atom economy, and further reduced synthesis costs.

[0035] 4. It has broad substrate applicability and extremely strong functional group compatibility. The synthetic method of this invention has a wide range of substrate applicability and is compatible with a rich variety of substituents and skeletal structures: the R1-R5 substituents in the substrate can be adapted to various electron-withdrawing groups such as nitro, halogen, trifluoromethyl, acyl, ester, carboxyl, and sulfonyl groups, and can also be compatible with electron-donating groups such as chain / cyclic alkyl, alkoxy, and substituted amino groups; the aryl Ar can be extended to various structures such as substituted benzene rings and electron-rich / electron-deficient heteroaromatic rings. All of the above-mentioned substrates can be reacted smoothly to obtain the corresponding target products. The excellent functional group compatibility and substrate universality can rapidly construct a diverse library of sulfonyl indolo[1,4]diazacyclic heptanedione derivatives, providing an efficient and convenient synthetic route for the study of structure-activity relationships and drug activity screening of such compounds.

[0036] 5. The product has outstanding medicinal value and possesses broad potential for new drug development. The target compounds synthesized in this invention simultaneously contain three recognized important pharmacodynamic groups: an indole ring, a seven-membered lactam ring, and a sulfonyl group, possessing abundant structural modification sites and potential for medicinal chemical modification. Bioactivity tests confirmed that some of the synthesized products exhibited good antitumor activity against human colon cancer SW620 cells and human breast cancer MDA-MB-231 cells, providing novel candidate molecular scaffolds for the development of new antitumor drugs, and demonstrating extremely high medicinal chemical application value and promising prospects for new drug development. Attached Figure Description

[0037] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only one embodiment of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0038] Figure 1 The reaction formula is shown in Example 1 of this invention; Figure 2 The ¹H NMR spectrum of the product structure characterization in Example 1 of this invention is shown. Figure 3 The nuclear magnetic resonance carbon spectrum (¹³C NMR) of the product structure characterization in Example 1 of the present invention. Figure 4 The ¹H NMR spectrum of the product structure characterization in Example 2 of this invention is shown. Figure 5 The nuclear magnetic resonance carbon spectrum (¹³C NMR) of the product structure characterization in Example 2 of the present invention. Figure 6 The ¹H NMR spectrum of the product structure characterization in Example 3 of this invention is shown. Figure 7 The nuclear magnetic resonance carbon spectrum (¹³C NMR) of the product structure characterization in Example 3 of the present invention. Figure 8 The ¹H NMR spectrum of the product structure characterization in Example 4 of this invention is shown. Figure 9 The nuclear magnetic resonance carbon spectrum (¹³C NMR) of the product structure characterization in Example 4 of the present invention. Figure 10 The ¹H NMR spectrum of the product structure characterization in Example 5 of this invention is shown. Figure 11 The nuclear magnetic resonance carbon spectrum (¹³C NMR) of the product structure characterization in Example 5 of the present invention. Figure 12 This is a schematic diagram of the single-crystal structure of the product of Example 6 of the present invention; Figure 13 This is a bioactivity test diagram of the product of Example 31 of the present invention. Detailed Implementation

[0039] To make the technical means, creative features, objectives and effects of this invention easier to understand, the technical solutions in the specific embodiments of this invention are described clearly and completely below to further illustrate this invention. Obviously, the specific embodiments described are only a part of the embodiments of this invention, and not all of them.

[0040] Example 1: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , Yield 61%, specific steps are as follows: like Figure 1 As shown, at room temperature, 0.3 mmol of DABSO, 0.3 mmol of aryl diazonium salt, and 0.2 mmol of N-benzyl-N-(2-(1H-indole-phenyl)methacrylamide were added to a dry test tube. After stopping the test tube, 2 mL of ethyl acetate was added, and the tube was placed at 40°C. o The mixture was stirred in a heating apparatus for 18 hours. After the reaction was complete as monitored by TLC, the reaction solution was quenched with water and poured into 20 mL of water. It was then extracted with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the mobile phase. The resulting product was characterized as shown in the figure. Figure 2 , Figure 3The compound shown is 5-benzyl-7-(((4-(tert-butyl)phenyl)sulfonyl)methyl)-7-methyl-5H-benzo[2,3][1,4]diazaquinolino[1,7-a]indole-6(7H)-one (compound 3c).

[0041] Structural characterization of compound 3c: 1 H NMR(400 MHz, CDCl3) δ 7.68 - 7.63 (m, 1H), 7.42- 7.33 (m, 3H), 7.32 (s, 2H), 7.26 (s, 1H), 7.25 - 7.19 (m, 3H), 7.19 - 7.15(m, 2H), 7.07 - 6.96 (m, 3H), 6.88 - 6.80 (m, 2H), 6.67 (s, 1H), 5.31 (d,J=15.7 Hz, 1H), 4.87 (d,J= 15.7 Hz, 1H), 3.24 (d,J= 11.9 Hz, 2H), 2.18 (s, 3H), 1.25 (s, 9H). 13 C NMR(100 MHz, CDCl3) δ 169.2, 157.6, 140.3, 136.8, 136.8,136.0, 135.5, 132.9, 128.7, 128.4, 128.0, 127.2, 127.0, 126.7, HRMS(ESI) m / z Calcd for [C 35 H 34 [N2O3S, M+H] + : 563.2363, found:563.2361. Example 2: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , Yield 64%, specific steps are as follows: At room temperature, add 0.3 mmol of DABSO, 0.3 mmol of aryl diazonium salt, and 0.2 mmol of N-benzyl-N-(2-(1H-indole-phenyl)methacrylamide) to a dry test tube. After sealing the reaction tube, add 2 mL of ethyl acetate and place it at 40°C. oThe mixture was stirred in a heating apparatus for 18 hours. After complete reaction monitoring by TLC, the reaction solution was quenched with water and poured into 20 mL of water. It was then extracted with ethyl acetate, and the combined organic phases were washed twice with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and then separated by column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the mobile phase. The resulting product was characterized as shown below. Figure 4 , Figure 5 The methyl-4-[(5-phenyl-7-methyl-6-oxo-6,7-dihydro-5H-benzo[2,3][1,4]diazolo[1,7-a]indol-7-yl)methylsulfonyl]benzoate shown (compound 3g).

[0042] Structural characterization of compound 3g: 1 H NMR(400 MHz, CDCl3) δ 8.01 - 7.96 (m, 2H), 7.68- 7.62 (m, 1H), 7.59 - 7.53 (m, 2H), 7.50 - 7.39 (m, 3H),7.36 - 7.26 (m, 2H),7.24 - 7.18 (m, 2H), 7.09 - 6.96 (m, 3H), 6.89 - 6.83 (m, 2H), 6.64 (s, 1H), 5.37 (d,J= 15.7 Hz, 1H), 4.89 (d,J= 15.7 Hz, 1H), 3.93 (s, 3H), 3.22 (d,J=2.3 Hz, 2H), 2.14 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 169.0, 165.3, 143.8,140.2, 136.8, 136.0, 135.6, 134.8, 133.2, 130.1, 128.7, 128.4, 128.1, 127.2,127.1, 127.1, 126.8, 125.2, 124.6, 123.1, 121.5, 121.2, 110.6, 103.2, 59.08,54.0, 52.8, 45.7, 23.1.HRMS(ESI) m / z Calcd for [C 33 H 28 [N2O5S, M+H] + : 565.1792, found: 565.1799. Example 3: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , Yield 62%, specific steps are as follows: At room temperature, add 0.3 mmol of DABSO, 0.3 mmol of aryl diazonium salt, and 0.2 mmol of N-benzyl-N-(2-(1H-indole-phenyl)methacrylamide) to a dry test tube. After sealing the reaction tube, add 2 mL of ethyl acetate and place it at 40°C. o The mixture was stirred in a heating apparatus for 18 hours. After complete reaction monitoring by TLC, the reaction solution was quenched with water and poured into 20 mL of water. It was then extracted with ethyl acetate, and the combined organic phases were washed twice with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and then separated by column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the mobile phase. The resulting product was characterized as shown below. Figure 6 , Figure 7 The 5-benzyl-7-methyl-7-(quinoline-5-ylsulfonylmethyl)-5H-benzo[2,3][1,4]diazaquinoline-6(7H)-one (compound 3r) shown.

[0043] Structural characterization of compound 3r: 1 H NMR(400 MHz, CDCl3) δ 8.95 (d,J= 4.2 Hz, 1H), 8.53 (d,J= 8.8 Hz, 1H), 8.28 (d,J= 8.5 Hz, 1H), 7.98 (d,J= 7.4 Hz, 1H), 7.66(dd,J= 6.7, 2.6 Hz, 1H), 7.55 (t,J= 7.7 Hz, 1H), 7.36 (td,J= 7.7, 3.8 Hz,2H), 7.28 (d,J= 8.2 Hz, 1H), 7.20 (dd,J= 6.5, 2.9 Hz, 2H), 7.14 - 7.07 (m,2H), 7.07 - 6.99 (m, 3H), 6.94 (d,J= 7.7 Hz, 1H), 6.87 (d,J= 7.3 Hz, 2H), 6.69 (s, 1H), 5.27 (d,J= 15.7 Hz, 1H), 4.91 (d,J= 15.7 Hz, 1H), 3.49 (d,J=14.9 Hz, 1H), 3.37 (d,J= 14.9 Hz, 1H), 2.18 (s, 3H). 13C NMR(100 MHz, CDCl3) δ169.0, 151.1, 148.2, 140.0, 136.8, 136.6, 136.0, 135.7, 135.2, 132.8, 132.1,131.0, 128.7, 128.5, 127.8, 127.1, 126.9, 126.8, 126.5, 124.7, 124.5, 124.3,123.1, 123.0, 121.5, 121.2, 110.6, 103.5, 59.0, 54.3, 46.0, 23.5, 21.0.HRMS(ESI) m / z Calcd for [C 34 H 27 N3O3S, M+H] + : 558.1846, found: 558.1853. Example 4: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , Yield 42%, specific steps are as follows: At room temperature, add 0.3 mmol of DABSO, 0.3 mmol of aryl diazonium salt, and 0.2 mmol of N-benzyl-N-(2-(1H-indole-phenyl)methacrylamide) to a dry test tube. After sealing the reaction tube, add 2 mL of ethyl acetate and place it at 40°C. o The mixture was stirred in a heating apparatus for 18 hours. After complete reaction monitoring by TLC, the reaction solution was quenched with water and poured into 20 mL of water. It was then extracted with ethyl acetate, and the combined organic phases were washed twice with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and then separated by column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the mobile phase. The resulting product was characterized as shown below. Figure 8 , Figure 9 The compound shown is 5-benzyl-7-(((2,3-dihydrobenzofuran-5-yl)sulfonyl)methyl)-7-methyl-5H-benzo[2,3][1,4]diazaquinoline-6(7H)-one (compound 3n).

[0044] Structural characterization of compound 3n: 1H NMR (400 MHz, CDCl3) δ 7.71 - 7.63 (m, 1H), 7.39 (dd,J= 10.8, 6.7 Hz, 2H), 7.30 - 7.24 (m, 1H), 7.20 (m, 4H), 7.15 - 7.08 (m,2H), 7.03 (dt,J= 14.5, 7.0 Hz, 3H), 6.85 (d,J= 7.2 Hz, 2H), 6.69 - 6.61 (m,2H), 5.26 (d,J= 15.7 Hz, 1H), 4.91 (d,J= 15.7 Hz, 1H), 4.56 - 4.38 (m, 2H),3.34 - 3.15 (m, 2H), 2.95 - 2.77 (m, 1H), 2.65 - 2.51 (m, 1H), 2.18 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 169.2, 164.5, 140.2, 136.8, 135.9, 135.5, 132.7,131.2, 130.0, 128.8, 128.5, 128.4, 127.2, 127.0, 126.7, 126.6, 125.4, 124.7,122.8, 121.4, 121.2, 110.5, 109.3, 103.3, 72.5, 59.3, 54.2, 46.0, 28.4, 22.8.HRMS(ESI) m / z Calcd for [C 33 H 28 N₂O₄S, M+H] + : 549.1843, found: 549.1849. Example 5: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , Yield 67%, specific steps are as follows: At room temperature, add 0.3 mmol of DABSO, 0.3 mmol of aryl diazonium salt, and 0.2 mmol of N-benzyl-N-(2-(5-methoxy-1H-indol-1-yl)phenyl)methacrylamide to a dry test tube. After sealing the reaction tube, add 2 mL of ethyl acetate and place it at 40°C. oThe mixture was stirred in a heating apparatus (C) for 18 hours. After complete reaction monitoring by TLC, the reaction solution was quenched with water and poured into 20 mL of water. It was then extracted with ethyl acetate, and the combined organic phases were washed twice with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and then separated by column chromatography using a 3:1 mixture of petroleum ether and ethyl acetate as the mobile phase. The resulting product was characterized as shown below. Figure 10 , Figure 11 The compound shown is 5-benzyl-10-methoxy-7-methyl-7-((benzenesulfonyl)methyl)-5H-benzo[2,3][1,4]diazaquinolino[1,7-a]indole-6(7H)-one (compound 4a).

[0045] Structural characterization of compound 4a: 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.47 (m, 2H), 7.46 (d,J= 1.7 Hz, 2H), 7.36 - 7.30 (m, 2H), 7.30 - 7.26 (m, 3H), 7.24 - 7.18 (m,1H), 7.12 - 7.04 (m, 2H), 7.03 - 6.97 (m, 2H), 6.89 - 6.83 (m, 3H), 6.59 (s,1H), 5.37 (d,J= 15.7 Hz, 1H), 4.87 (d,J= 15.7 Hz, 1H), 3.92 - 3.86 (m, 3H),3.20 (d,J= 3.7 Hz (2H), 2.14 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 169.1, 155.1,140.8, 140.1, 136.8, 135.4, 133.6, 133.2, 131.1, 129.4, 129.0, 128.4, 128.0,127.0, 126.9, 126.9, 126.7, 125.0, 124.4, 113.1, 111.4, 102.8, 102.6, 59.2,55.8, 54.0, 45.8, 23.0. HRMS(ESI) m / z Calcd for [C 32 H 28 N₂O₄S, M+H] + : 537.1843, found: 587.1836. Example 6: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... , The yield was 97%. The specific synthesis method and process parameters were the same as in Example 1.

[0046] Example 7: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... , The yield was 99%. The specific synthesis method and process parameters were the same as in Example 1.

[0047] Example 8: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... , The yield was 60%. The specific synthesis method and process parameters were the same as in Example 1.

[0048] Example 9: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptanedione compound to synthesize... , The yield was 75%. The specific synthesis method and process parameters were the same as in Example 1.

[0049] Example 10: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , The yield was 72%. The specific synthesis method and process parameters were the same as in Example 1.

[0050] Example 11: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... , The yield was 90%. The specific synthesis method and process parameters were the same as in Example 1.

[0051] Example 12: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... , The yield was 73%. The specific synthesis method and process parameters were the same as in Example 1.

[0052] Example 13: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... , The yield was 69%. The specific synthesis method and process parameters were the same as in Example 1.

[0053] Example 14: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 64%. The specific synthesis method and process parameters were the same as in Example 1.

[0054] Example 15: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 82%. The specific synthesis method and process parameters were the same as in Example 1.

[0055] Example 16: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 54%. The specific synthesis method and process parameters were the same as in Example 1.

[0056] Example 17: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 51%. The specific synthesis method and process parameters were the same as in Example 1.

[0057] Example 18: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 56%. The specific synthesis method and process parameters were the same as in Example 1.

[0058] Example 19: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 84%. The specific synthesis method and process parameters were the same as in Example 1.

[0059] Example 20: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... The yield was 95%. The specific synthesis method and process parameters were the same as in Example 1.

[0060] Example 21: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 97%. The specific synthesis method and process parameters were the same as in Example 1.

[0061] Example 22: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 32%. The specific synthesis method and process parameters were the same as in Example 1.

[0062] Example 23: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 65%, and the specific synthesis method and process parameters were the same as in Example 1.

[0063] Example 24: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 42%. The specific synthesis method and process parameters were the same as in Example 1.

[0064] Example 25: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 99%. The specific synthesis method and process parameters were the same as in Example 1.

[0065] Example 26: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 95%. The specific synthesis method and process parameters were the same as in Example 1.

[0066] Example 27: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptadecone compounds to synthesize... The yield was 64%. The specific synthesis method and process parameters were the same as in Example 1.

[0067] Example 28: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 76%. The specific synthesis method and process parameters were the same as in Example 1.

[0068] Example 29: As shown in Table 1, this example uses a synthetic method for sulfonyl indolo[1,4]diazacyclic heptanedione compounds to synthesize... The yield was 53%. The specific synthesis method and process parameters were the same as in Example 1.

[0069] Example 30: As shown in Table 1, this example uses a synthetic method for a sulfonyl indolo[1,4]diazacyclic heptadecone compound to synthesize... The yield was 43%. The specific synthesis method and process parameters were the same as in Example 1.

[0070] Table 1. Substrate suitability assessment for each example Example Substrate diazonium salt product Yield Example 1 61% Example 2 64% Example 3 62% Example 4 42% Example 5 67% Example 6 97% Example 7 99% Example 8 60% Example 9 75% Example 10 73% Example 11 90% Example 12 73% Example 13 69% Example 14 64% Example 15 82% Example 16 54% Example 17 51% Example 18 56% Example 19 84% Example 20 95% Example 21 97% Example 22 32% Example 23 65% Example 24 42% Example 25 99% Example 26 95% Example 27 64% Example 28 76% Example 29 53% Example 30 43% Example 31: In this example, the MTT assay was used to determine the in vitro proliferation inhibitory activity of the compounds prepared in Examples 1-5 against human colon cancer cells (SW620) and human breast cancer cells (MDA-MB-231). SW620 cells and MDA-MB-231 cells in logarithmic growth phase were seeded in 96-well plates at a density of 5 × 10³ cells per well and cultured at 37°C in a 5% CO2 incubator for 24 hours. After cell attachment, different concentrations (0.1, 1, 10, 50, 100 μmol / L) of the products from Examples 1-5 were added, with three replicates for each concentration. A blank control group (culture medium only) and a negative control group (solvent added) were also included. After culturing for another 48 hours, 20 μL of MTT solution (5 mg / mL) was added to each well, and incubation continued for another 4 hours. After terminating the culture, aspirate the supernatant, add 150 μL of DMSO to each well, shake to dissolve the crystals, and measure the absorbance (OD value) of each well at 490 nm using a microplate reader. Calculate the cell inhibition rate and half-maximal inhibitory concentration (IC50). 50 ).

[0071] The in vitro antitumor activity test results of the products in Examples 1-5 against SW620 cells and MDA-MB-231 cells are as follows: Figure 13 As shown, by Figure 13 It can be known that: The products from Examples 1-5 all exhibited varying degrees of inhibitory effects on the proliferation of both types of tumor cells, showing a clear dose-dependent effect. Among them, the product from Example 3 showed the best activity, inhibiting the proliferation of SW620 cells at IC50 levels. 50 The value was 2.15 μmol / L, and the IC50 value for MDA-MB-231 cells was [value missing]. 50 The value was 4.86 μmol / L. The product of Example 2 also exhibited good inhibitory activity, showing an effect on the IC50 concentration of SW620 cells. 50 The value was 39.37 μmol / L, and the IC50 value for MDA-MB-231 cells was [value missing]. 50 The value was 4.81 μmol / L. These results indicate that the compounds of this invention exhibit good inhibitory activity against human colon cancer cells and breast cancer cells, and hold promise for use in the preparation of antitumor drugs.

[0072] The main technical features, basic principles, and related advantages of the present invention have been described above. It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the concept or basic characteristics of the invention. Therefore, the above-described embodiments should be considered exemplary and non-limiting in all respects. The scope of the present invention is defined by the appended claims rather than the foregoing description, and thus all variations falling within the meaning and scope of the equivalents of the claims are intended to be included within the present invention.

[0073] Furthermore, it should be understood that although this specification describes various embodiments, not every embodiment contains only one independent technical solution. This way of describing the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound, characterized in that: The method involves reacting N-alkyl-N-(2-(1H-indole-aryl)methacrylamide of formula (I) with an aryl diazonium salt and a sulfur dioxide source in a solvent under catalytic conditions. In the reaction, the aryl diazonium salt and the sulfur dioxide source generate a sulfonyl radical intermediate in situ. This intermediate is first radically added to the alkenyl group of the substrate, and then undergoes a radical cyclization reaction to obtain the sulfonyl indole[1,4]diazacyclic heptadecone compound of formula (II). In the formula, R 1 It is selected from electron-withdrawing group I or electron-donating group I. Electron-withdrawing group I is selected from any one of the substituents of nitro, chlorine atom, bromine atom, trifluoromethyl, acyl, ester group, and carboxyl group. Electron-donating group I is selected from any one of the substituents of alkyl and alkoxy groups. R 2 It is an electron-withdrawing group II or an electron-donating group II. The electron-withdrawing group II is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group. The electron-donating group II is selected from any one of the substituents of alkyl group and substituted amino group. R 3 It is an electron-withdrawing group III or an electron-donating group III, wherein the electron-withdrawing group III is selected from any one of the substituents of acyl, ester, and carboxyl groups, and the electron-donating group III is an alkyl group; R 4 It is an electron-withdrawing group IV or an electron-donating group IV, wherein the electron-withdrawing group IV is selected from any substituent of sulfonyl or acyl, and the electron-donating group IV is an alkyl group; R 5 It is an electron-withdrawing group V or an electron-donating group V, wherein the electron-withdrawing group V is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group, and the electron-donating group V is selected from any one of the substituents of alkyl and substituted amino groups; Ar is an aryl or heteroaryl group having an electron-withdrawing group VI or an electron-donating group VI. The electron-withdrawing group VI is selected from any one of the substituents of fluorine atom, chlorine atom, bromine atom, iodine atom, and acyl group. The electron-donating group VI is selected from any one of the substituents of alkyl group and substituted amino group.

2. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 1, characterized in that: The solvent is selected from one of ethyl acetate, acetonitrile, dichloromethane, dichloroethane, toluene, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfone, and ethanol.

3. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 2, characterized in that: The sulfur dioxide source is selected from one of DABSO, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium bisulfite, and sodium dithionite.

4. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 3, characterized in that: The solvent is ethyl acetate; the sulfur dioxide source is DABSO.

5. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 1, characterized in that: The electron-donating group I is selected from any one of the substituents: alkyl, cycloalkyl, and alkoxy. Electron-donating group III is a chain alkyl group.

6. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 1, characterized in that: The specific steps of this synthesis method are as follows: S1. At room temperature, add N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt and sulfur dioxide source to a dry reaction vessel. After sealing the reaction vessel, purge with protective gas, then add solvent and place in a heating device at 30℃~50℃ and stir for 10h~25h. After the reaction is complete, obtain the reaction solution. S2. Extract the reaction solution from step S1 with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and use a mixture of petroleum ether and ethyl acetate as the mobile phase for column chromatography separation to obtain sulfonyl indolode[1,4]diazacyclic heptanedione compounds.

7. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 6, characterized in that: In step S1, the molar ratio of the added N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt and sulfur dioxide source is 1:(1.0-2.5):(1.0-2.5).

8. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 7, characterized in that: In step S1, the molar ratio of the added N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt, and sulfur dioxide source is 1:1.5:1.5; The reaction vessel is a test tube; The protective gas is nitrogen, argon, or helium; The reaction substrates N-alkyl-N-(2-(1H-indole-aryl)methacrylamide, aryl diazonium salt, and sulfur dioxide source were dissolved in a solvent to prepare a solution with a reaction substrate concentration of 0.05 mol / L to 0.5 mol / L. Place in a 40℃ heating device and stir for 18 hours; The reaction process was monitored using TLC, and the reaction was stopped once it was complete.

9. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 6, characterized in that: In step S2, the reaction solution is first quenched with water and then extracted with ethyl acetate. The volume ratio of petroleum ether to ethyl acetate in the mobile phase for column chromatography separation is 2:1 to 4:

1.

10. The method for synthesizing a sulfonyl indolo[1,4]diazacyclic heptanedione compound according to claim 9, characterized in that: In step S2, the specific process of quenching the reaction solution with water is as follows: distilled water is added to the reaction solution, and the volume ratio of the distilled water to the reaction solution is 0.5:1 to 2:

1. The solution is allowed to stand and separate into layers to separate the organic phase. The volume ratio of petroleum ether to ethyl acetate in the mobile phase for column chromatography separation is 3:1.

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