3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds, methods of preparation and uses thereof

Abstract

The application discloses a 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound in the field of organic chemical synthesis technology, and a structural formula is as follows: when preparing the compound, a beta-4'-methyl indole aryl ethylene, an alkyl or aryl sulfonyl chloride and a solvent are sequentially added into a Schlenk tube provided with a stirring rod, and the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound is prepared by one-pot method under the condition of constant temperature and organic photocatalysis. The method has mild conditions and does not need to add an oxidant, and provides a green and efficient preparation method for the 1,3,4,5-tetrahydrobenzo[cd]-indole compound modified by a sulfonyl group. Meanwhile, it is verified that the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound has certain anti-hepatoma activity, and can be applied to the preparation of an anti-hepatoma drug.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound, its preparation method, and its application. Background Technology

[0002] 1,3,4,5-Tetrahydrobenzo[cd]-indole, a compound with a unique structure, has shown great potential in drug development. Nicergoline, used to treat cerebrovascular diseases, methysergide, used to prevent migraines, and metoclopramide, with its anxiolytic and sedative effects, are all closely related to the 1,3,4,5-tetrahydrobenzo[cd]-indole structure. Meanwhile, the sulfonyl group, as a common synthetic intermediate, can significantly improve the solubility and biocompatibility of compounds; introducing a sulfonyl group into drug molecules can enhance their pharmacokinetic properties. Given the unique structure and importance of 1,3,4,5-tetrahydrobenzo[cd]-indole and the sulfonyl group, developing an efficient and practical synthetic method for sulfonyl-modified 1,3,4,5-tetrahydrobenzo[cd]-indole compounds is of great significance for the discovery of drug lead compounds and the development of new drugs. Currently, acid-catalyzed cyclization is one of the main methods for constructing polycyclic indole structures (Organic Letters, 2019, 21, 1574-1577). However, these methods typically suffer from problems such as high temperature and strong acid, narrow substrate range, and environmental pollution. Alternatively, 1,3,4,5-tetrahydrobenzo[cd]indole compounds can be constructed by reductive amination of suitable ketones with amines (CN1036566A, J.Am.Chem.Soc., 2006, 128, 4946–4947). However, the preparation of ketone precursors is complex, requiring multiple steps and demanding reaction conditions, which limits the synthesis of diverse products and related industrial applications to some extent. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention presents a one-step method for preparing 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds under organic photocatalytic synthesis conditions.

[0004] One objective of this invention is to provide a 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound with the following structural formula:

[0005]

[0006] Ar is 4-methylphenyl, biphenyl, 2-naphthyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl;

[0007] R is methyl, ethyl, propyl, cyclopropyl, phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, biphenyl, 2-naphthyl, 2-thienyl, 2-furanyl, or 2-benzofuranyl;

[0008] R' is hydrogen, methyl, or benzyl.

[0009] A second objective of this invention is to provide a method for preparing 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds. The method involves sequentially adding β-4'-methylindole arylethylene, alkyl or arylsulfonyl chloride, and a solvent to a reaction vessel, and preparing 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds in a one-pot reaction under isothermal organic photocatalytic conditions. The general reaction formula is shown below:

[0010]

[0011] The working principle and beneficial effects of this invention: This invention innovatively uses β-4'-methylindole arylethylene and alkyl or arylsulfonyl chlorides as raw materials, and obtains 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds through organic photocatalytic synthesis and subsequent purification. This reaction fully utilizes the EDA complex (electron donor-acceptor complex) to develop a novel reaction mode for synthesizing structurally novel and diverse 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds.

[0012] Furthermore, the molar ratio of each substance in the reaction is: β-4'-methylindolylethylene:sulfonyl chloride = 1:0.5-5, preferably 1:1.5.

[0013] Furthermore, the solvent is selected from one or more of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, toluene, dimethyl sulfoxide, methanol, 1,4-dioxane, or N,N-dimethylformamide, preferably ethyl acetate.

[0014] Furthermore, in the above scheme, the light source is selected from violet light, which is selected from violet light (5-50W), blue light (5-50W), white light (5-50W) and red light (5-50W), and is preferably violet light (40W).

[0015] Furthermore, the temperature used is 0–60°C, preferably 25°C; the reaction time is 0.5–24 h, preferably 12 h; the gas atmosphere is selected from air, argon, nitrogen and oxygen, preferably argon; the separation and purification method is selected from column chromatography and recrystallization, preferably column chromatography.

[0016] A third objective of this invention is to provide the application of C-3 benzylated indole compounds in the preparation of anti-hepatocellular carcinoma drugs. Verification has shown that the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds possess certain anti-cancer (human hepatocellular carcinoma SMMC-7721 cells) drug activity.

[0017] This invention utilizes β-4'-methylindole arylethylene, alkyl or arylsulfonyl chlorides as starting materials to prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds in one step under organic photocatalytic synthesis conditions. This method features readily available starting materials, mild reaction conditions, no need for metal or oxidizing agents, and easy derivatization and transformation of the product, providing a green and efficient synthetic route for 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds. Attached Figure Description

[0018] Figure 1 The attached figure shows a single crystal of compound 1f prepared in Example 6;

[0019] Figure 2 Compound 1a prepared in Example 1 1 H NMR spectrum;

[0020] Figure 3 Compound 1a prepared in Example 1 13 C NMR spectrum;

[0021] Figure 4 Compound 1b prepared in Example 2 1 H NMR spectrum;

[0022] Figure 5 Compound 1b prepared in Example 2 13 C NMR spectrum;

[0023] Figure 6 Compound 1d prepared in Example 4 1 H NMR spectrum;

[0024] Figure 7Compound 1d prepared in Example 4 13 C NMR spectrum;

[0025] Figure 8 Compound 1e prepared in Example 5 1 H NMR spectrum;

[0026] Figure 9 Compound 1e prepared in Example 5 13 C NMR spectrum;

[0027] Figure 10 Compound 1f prepared in Example 6 1 H NMR spectrum;

[0028] Figure 11 Compound 1f prepared in Example 6 13 C NMR spectrum;

[0029] Figure 12 1g of the compound prepared in Example 7 1 H NMR spectrum;

[0030] Figure 13 1g of the compound prepared in Example 7 13 C NMR spectrum;

[0031] Figure 14 Compound 1i prepared in Example 9 1 H NMR spectrum;

[0032] Figure 15 Compound 1i prepared in Example 9 13 C NMR spectrum;

[0033] Figure 16 Compound 1j prepared in Example 10 1 H NMR spectrum;

[0034] Figure 17 Compound 1j prepared in Example 10 13 C NMR spectrum;

[0035] Figure 18 Compound 1k prepared in Example 11 1 H NMR spectrum;

[0036] Figure 19 Compound 1k prepared in Example 11 13 C NMR spectrum;

[0037] Figure 20This is a schematic diagram illustrating the inhibitory effect of some compounds on the proliferation of human liver cancer cells (SMMC-7721 cells). Detailed Implementation

[0038] The following detailed description illustrates the specific implementation method:

[0039] Example 1:

[0040] Using 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole as an olefin substrate and 3-methylbenzenesulfonyl chloride as a sulfonating agent, compound 1a (reaction formula 1) of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole was prepared.

[0041]

[0042] 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole (0.2 mmol, 1.0 equiv.) and 3-methylbenzenesulfonyl chloride (0.3 mmol, 1.5 equiv.) were added to a 25 mL Schlenk tube equipped with a stir bar. The Schlenk tube was evacuated and re-primed with argon three times. Subsequently, ultra-dry ethyl acetate (EA) (2.0 mL, 0.1 M) was added to the Schlenk tube under argon protection. The reaction mixture was sealed and placed in a fan-cooled environment at room temperature with stirring under ultraviolet light for 12 h. After the reaction was completed, the reaction was monitored by thin-layer chromatography (TLC). The crude product was concentrated under reduced pressure and then subjected to column chromatography (petroleum ether and ethyl acetate as eluents, petroleum ether / ethyl acetate = 15:1-5:1) to give a dark green solid 1a (dr>20:1, 52.6 mg, 61%).

[0043] The detection data for product 1a are as follows:

[0044] mp: 82.5-83.8℃

[0045] 1 H NMR (400MHz, CDCl3) δ7.27(d,J=7.9Hz,2H),7.10(t,J=7.6Hz,1H),6.99–6.93(m,3H),6.81(d,J=7.3Hz,1H),6.78(d,J=7.8Hz,2H),6. 71(d,J=8.1Hz,2H),6.48(s,1H),4.97(d,J=2.6Hz,1H),3.74(s,4H),3.62(s,3H),3.52–3.45(m,1H),3.38–3.30(m,1H),2.23(s,3H).

[0046] 13 C NMR (101MHz, CDCl3) δ158.4,143.2,135.3,134.7,134.2,129.1,128.1,127.9,126.6, 126.2,124.4,122.6,116.1,113.8,111.4,106.8,68.8,55.2,38.6,32.7,25.0,21.4.

[0047] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 26 H 25 O3NS,454.1447.Found:454.1445.

[0048] Example 2:

[0049] Prepare compound 1b (reaction formula 2) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0050]

[0051] In Example 1, 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole, and 3-methylbenzenesulfonyl chloride was replaced with 4-methylbenzenesulfonyl chloride. Other conditions were the same as in Example 1, and the dark green solid 1b (dr>20:1, 38.3 mg, 39%) was finally obtained.

[0052] The detection data for product 1b are as follows:

[0053] mp: 178.4-179.5℃

[0054] 1 H NMR (400MHz, CDCl3) δ7.25(d,J=8.3Hz,2H),7.14–7.09(m,1H),6.97(d,J=8.2Hz,1H),6.84(d,J=7.0Hz,1H),6.80(d,J=8.0Hz,2H),6.4 5(s,1H),6.25(s,2H),4.88(d,J=5.0Hz,1H),3.85–3.82(m,1H),3.80(s,3H),3.66(s,6H),3.63(s,3H),3.54–3.47(m,2H),2.23(s,3H).

[0055] 13C NMR (101MHz, CDCl3) δ153.2,143.4,138.5,136.8,135.5,134.4,128.11,128.09,126.7,126. 4,124.7,122.8,116.4,112.1,107.1,105.4,68.5,60.9,56.2,40.7,32.9,29.8,25.8,21.5.

[0056] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 27 H 27 O5NS,514.1659.Found:514.1658.

[0057] Example 3:

[0058] Prepare compound 1c (reaction formula 3) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0059]

[0060] In Example 1, 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(5-benzo[d][1,3]dioxolane)allyl)-1-methyl-indole, and 3-methylbenzenesulfonyl chloride was replaced with hydroiodic acid. Other conditions were the same as in Example 1, and a dark green oily liquid 1c (18.1 mg, 31%) was finally obtained.

[0061] The 1c test data of the product are as follows:

[0062] 1 H NMR (400MHz, CDCl3) δ7.23–7.18(m,1H),7.15(d,J=8.0Hz,1H),6.90(d,J=6.6Hz,1H),6.79(s,3H),6.58(s,1 H),5.96(s,2H),4.21(d,J=6.5Hz,1H),3.76(s,3H),3.09–2.97(m,2H),2.33–2.26(m,1H),2.13–2.05(m,1H).

[0063] 13C NMR (101MHz, CDCl3) δ147.6,146.0,140.1,135.0,132.0,127.7,123.3,122. 4,121.0,116.4,115.5,108.4,108.1,106.5,100.9,40.1,34.6,32.9,27.0.

[0064] HRMS(ESI,Q-TOF)m / z:[M+H + ]Calcd for C 19 H 18 O2N, 292.1332. Found: 292.1337.

[0065] Example 4:

[0066] Prepare compound 1d of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole (reaction formula 4).

[0067]

[0068] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with cyclopropylsulfonyl chloride, and other conditions were the same as in Example 1, resulting in a dark green solid 1d (dr>20:1, 31.3 mg, 41%).

[0069] The product's 1-day detection data are as follows:

[0070] mp:166.1-167.0℃

[0071] 1 H NMR (400MHz, CDCl3) δ7.25–7.20(m,1H),7.20–7.13(m,3H),6.95(d,J=6.5Hz,1H),6.83(d,J=8.7Hz,2H),6.64(s,1H),4.95(d,J=5.0Hz,1 H),3.79(s,3H),3.77(s,3H),3.68–3.64(m,1H),3.52–3.44(m,2H),1.27–1.18(m,1H),0.98–0.92(m,1H),0.84(m,1H),0.33–0.21(m,2H).

[0072] 13C NMR (101MHz, CDCl3) δ158.8,135.4,134.6,129.6,127.3,127.2,124.5,12 3.0,116.3,114.1,112.7,107.4,68.4,55.4,39.6,33.1,29.5,25.4,5.0.

[0073] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 22 H 23 O3NS, 404.1291. Found: 404.1295.

[0074] Example 5:

[0075] Prepare compound 1e (reaction formula 5) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0076]

[0077] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with morpholinesulfonyl chloride, and other conditions were the same as in Example 1, finally yielding a dark green solid 1e (dr>20:1, 19.6 mg, 23%).

[0078] The detection data for product 1e are as follows:

[0079] mp: 172.1-173.4℃

[0080] 1 H NMR (400MHz, CDCl3) δ7.23(d,J=3.5Hz,2H),7.01(d,J=8.6Hz,2H),6.94–6.90(m,1H),6.79(d,J=8.6Hz,2H),6.71(s,1H),4 .94(d,J=2.6Hz,1H),3.80(s,3H),3.77(s,4H),3.48–3.41(m,1H),3.34–3.27(m,1H),3.11–3.02(m,4H),2.63–2.48(m,4H).

[0081] 13 C NMR (101MHz, CDCl3) δ158.6,136.3,134.6,129.0,126.9,126.8,124.2,12 3.2,116.2,114.0,111.6,107.7,67.8,66.6,55.4,45.9,38.8,33.2,25.3.

[0082] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 23 H 26 O4N2S,449.1505.Found:449.1507.

[0083] Example 6:

[0084] Prepare compound 1f (reaction formula 6) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0085]

[0086] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with 4-cyanophenylsulfonyl chloride, and other conditions were the same as in Example 1, finally yielding a dark green solid 1f (dr>20:1, 52.2 mg, 59%).

[0087] The product 1f detection data are as follows:

[0088] mp: 194.5-194.7℃

[0089] 1 H NMR (400MHz, CDCl3) δ7.39(d,J=8.3Hz,2H),7.14–7.06(m,3H),6.99–6.90(m,3H),6.81(d,J=7.0Hz,1H),6.72(d, J=8.6Hz,2H),6.55(s,1H),5.03(d,J=2.1Hz,1H),3.74(s,4H),3.64(s,3H),3.57–3.48(m,1H),3.37–3.28(m,1H).

[0090] 13 C NMR (101MHz, CDCl3) δ158.6,141.5,134.7,134.1,129.9,129.0,128.2,126.5,125.6,1 24.6,122.9,117.3,116.7,115.3,113.9,110.3,107.31,69.7,55.3,38.5,32.8,24.4.

[0091] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 26 H 22 O3N2S,465.1243.Found:465.1245.

[0092] Product 1f single crystal, such as Figure 1 As shown, the specific data is as follows:

[0093]

[0094]

[0095] Example 7:

[0096] Prepare 1 g of the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound with the following structural formula (Reaction Formula 7).

[0097]

[0098] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with 4-nitrophenylsulfonyl chloride, and other conditions were the same as in Example 1, finally yielding 1g of dark green solid (dr>20:1, 44.4mg, 48%).

[0099] The detection data for 1g of product are as follows:

[0100] mp: 147.5-148.6℃

[0101] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=8.0Hz,2H),7.45(d,J=8.1Hz,2H),7.07(t,J=7.6Hz,1H),6.95(d,J=8.1Hz,2H),6.83–6.77(m ,2H),6.73(d,J=8.0Hz,2H),6.60(s,1H),5.09–5.05(m,1H),3.74(s,4H),3.60(s,3H),3.55–3.49(m,1H),3.37–3.28(m,1H).

[0102] 13 C NMR (101MHz, CDCl3) δ158.7,149.4,142.6,134.8,134.1,129.1,128.8,126.6,125 .7,124.7,123.0,121.0,116.9,114.0,110.3,107.2,69.9,55.3,38.5,32.8,24.4.

[0103] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 25 H 22O5N2S,485.1142.Found:485.1142.

[0104] Example 8:

[0105] Prepare 1h and 1h' (reaction formula 8) of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds with the following structural formula.

[0106]

[0107] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with thienylsulfonyl chloride, and other conditions were the same as in Example 1. The final product was a dark green solid 1h (dr>20:1, 47.4 mg, 56%) + 1h' (dr>20:1, 23.7 mg, 28%).

[0108] The product detection data after 1 hour are as follows:

[0109] mp: 144.3–145.7℃

[0110] 1 H NMR(400MHz, CDCl3) δ7.35(d,J=4.9Hz,1H),7.17–7.12(m,1H),7.07–6.98(m,4H),6.85(d,J=7.0Hz,1H),6.76(d,J=8.6Hz,2H),6.69 –6.63(m,1H),6.54(s,1H),5.01(d,J=3.9Hz,1H),3.87–3.82(m,1H),3.77(s,3H),3.68(s,3H),3.59–3.52(m,1H),3.45–3.38(m,1H).

[0111] 13 C NMR (101MHz, CDCl3) δ158.6,139.0,135.4,134.52,134.47,133.5,129.2,126.8 ,126.1,124.6,122.8,116.3,112.0,111.6,107.3,69.9,55.4,39.0,32.9,25.5.

[0112] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 23 H 21 O3NS2,446.0855.Found:446.0854.

[0113] The product detection data after 1 hour are as follows:

[0114] mp: 218.0-218.9℃

[0115] 1 H NMR (400MHz, CDCl3) δ7.70–7.65(m,1H),7.64–7.59(m,1H),7.13(d,J=8.3Hz, 1H),7.09(d,J=3.0Hz,1H),7.07–7.03(m,1H),6.93(d,J=8.6Hz,2H),6.75(d,J =8.7Hz,2H),6.70(d,J=8.4Hz,1H),6.41(d,J=2.6Hz,1H),5.00(d,J=5.9Hz,1H ),4.19–4.12(m,1H),3.83–3.77(m,3H),3.77–3.72(m,4H),3.69–3.62(m,1H).

[0116] 13 C NMR (101MHz, CDCl3) δ158.5,139.1,136.5,136.1,134.8,134.5,134.3,130.8,129 .5,129.1,127.8,124.5,118.5,114.0,109.2,99.0,73.7,55.3,52.3,33.3,32.4.

[0117] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 23 H 21 O3NS2,446.0855.Found:446.0851.

[0118] Example 9:

[0119] Prepare compound 1i of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole with the following structural formula (reaction formula 9).

[0120]

[0121] The product 1i was obtained by replacing 3-methylbenzenesulfonyl chloride in Example 1 with benzofuranylsulfonyl chloride, with other conditions the same as in Example 1, and finally obtaining dark green solid 1i (dr>20:1, 54.2 mg, 59%).

[0122] The detection data for product 1i are as follows:

[0123] mp: 163.4-164.5℃

[0124] 1 H NMR(400MHz, CDCl3)δ7.22(d,J=8.4Hz,1H),7.11–7.06(m,1H),7.02(s,1H),6.97( d,J=8.1Hz,3H),6.82(d,J=7.0Hz,1H),6.72(d,J=8.6Hz,2H),6.49(s,1H),6.30(d, J=8.4Hz,1H),4.98(d,J=3.2Hz,1H),4.51(t,J=8.8Hz,2H),3.75(s,3H),3.73–3.6 8(m,1H),3.65(s,3H),3.54–3.47(m,1H),3.38–3.30(m,1H),2.91(t,J=8.8Hz,2H).

[0125] 13 C NMR (101MHz, CDCl3) δ163.7,158.4,135.5,134.3,130.0,129.1,129.0,126.6,126.5,126.4,12 5.5,124.4,122.7,116.2,113.8,111.5,107.7,106.8,72.2,69.1,55.3,38.8,32.8,28.6,25.0.

[0126] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 27 H 25 O4NS,482.1397.Found:482.1397.

[0127] Example 10:

[0128] Prepare compound 1j (reaction formula 10) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0129]

[0130] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with benzo[d]thiazole-5-sulfonyl chloride, and other conditions were the same as in Example 1, finally yielding a dark green solid 1j (dr>20:1, 38.9 mg, 41%).

[0131] The detection data for product 1j are as follows:

[0132] mp:199.0-199.4℃

[0133] 1H NMR(400MHz, CDCl3)δ9.08(s,1H),7.88(d,J=1.4Hz,1H),7.61(d,J=8.6Hz,1H),7.50–7.47(m,1H),6.97–6.91(m,3H),6.80(d,J=7.0Hz,1H) ,6.69–6.64(m,3H),6.45(s,1H),5.05(d,J=3.1Hz,1H),3.82–3.78(m ,1H),3.70(s,3H),3.61–3.54(m,1H),3.41(s,3H),3.39–3.33(m,1H).

[0134] 13 C NMR (101MHz, CDCl3) δ158.6,157.8,155.3,135.1,134.9,134.1,132.2,129.2,126.5,126.0, 125.8,124.3,123.4,123.0,121.9,116.5,113.9,111.1,107.3,69.8,55.3,38.9,32.6,24.9.

[0135] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 26 H 22 O3N2S2,497.0964.Found:497.0963.

[0136] Example 11:

[0137] Prepare compound 1k of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole with the following structural formula (reaction formula 11).

[0138]

[0139] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with phenylsulfonyl chloride, and other conditions were the same as in Example 1, finally yielding a dark green solid 1k (dr>20:1, 49.3 mg, 59%).

[0140] The 1k detection data for the product are as follows:

[0141] mp: 140.3-141.2℃

[0142] 1H NMR (400MHz, CDCl3) δ7.40(d,J=7.5Hz,2H),7.25–7.20(m,1H),7.13–7.07(m,1H),7.03–6.93(m,5H),6.83(d,J=6.8Hz,1H) ,6.71(d,J=8.1Hz,2H),6.48(s,1H),4.99(d,J=1.4Hz,1H),3.75(s,4H),3.62(s,3H),3.55–3.48(m,1H),3.40–3.33(m,1H).

[0143] 13 C NMR (101MHz, CDCl3) δ158.5,138.1,135.2,134.3,132.4,129.2,128.2,127.4,126 .7,126.2,124.4,122.7,116.3,113.9,111.5,107.3,69.1,55.3,38.8,32.8,25.1.

[0144] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 25 H 23 O3NS,440.1291.Found:440.1293.

[0145] Example 12:

[0146] Prepare compound 11 of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole (reaction formula 12).

[0147]

[0148] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with dimethylaminosulfonyl chloride, and other conditions were the same as in Example 1, resulting in 1L of dark green solid (dr>20:1, 22.3mg, 29%).

[0149] The test data for product 1L are as follows:

[0150] mp: 102.4-104.2℃

[0151] 1H NMR (400MHz, CDCl3) δ7.21(d,J=6.1Hz,2H),7.05(d,J=8.6Hz,2H),6.93(d,J=5.8Hz,1H),6.80(d,J=8.7Hz,2H),6.65(s,1 H),4.91(d,J=3.8Hz,1H),3.84–3.81(m,1H),3.78(s,3H),3.78(s,3H),3.49–3.42(m,1H),3.37–3.30(m,1H),2.15(s,6H).

[0152] 13 C NMR (101MHz, CDCl3) δ158.5,136.2,134.6,129.1,127.3,126.7,124.4,123.0,116.2,114.0,112.4,107.4,67.5,55.4,39.3,36.9,33.1,25.9.

[0153] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 21 H 24 O3N2S,407.1400.Found:407.1403.

[0154] Example 13:

[0155] Prepare compound 1m of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole (reaction formula 13).

[0156]

[0157] The 3-methylbenzenesulfonyl chloride in Example 1 was replaced with 4-fluorophenylsulfonyl chloride, and other conditions were the same as in Example 1, finally yielding a dark green solid 1m (dr>20:1, 47.9 mg, 55%).

[0158] The 1-minute product test data are as follows:

[0159] mp: 149.4-150.5℃

[0160] 1H NMR (400MHz, CDCl3) δ7.36–7.29(m,2H),7.10(t,J=7.6Hz,1H),6.99–6.93(m,3H),6.81(d,J=7.0Hz,1H),6.73(d,J=8.4Hz,2H),6.56(d ,J=8.5Hz,2H),6.52(s,1H),5.01(d,J=2.3Hz,1H),3.75(s,3H),3.73–3.69(m,1H),3.63(s,3H),3.55–3.47(m,1H),3.37–3.30(m,1H).

[0161] 13 C NMR (101MHz, CDCl3) δ 164.9 (d, J = 254.8Hz), 158.6, 135.2, 134.3, 133.6 (d, J = 3.1Hz), 130.8 (d, J = 9.7Hz), 129. 1,126.6,126.0,124.5,122.9,116.5,114.1(d,J=22.6Hz),114.0,110.9,107.2,69.4,55.4,38.7,32.8,24.8.

[0162] 19 F NMR (376MHz, CDCl3) δ-105.50.

[0163] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 25 H 22 O3FNS,458.1197.Found:458.1196.

[0164] Example 14:

[0165] Prepare compound 1n (reaction formula 14) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0166]

[0167] In Example 2, 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(4-methoxyphenyl)allyl)-1-benzyl-indole, and other conditions were the same as in Example 2. The final product was a dark green solid 1n (dr>20:1, 53.8 mg, 53%).

[0168] The detection data for product 1n are as follows:

[0169] mp: 76.6-77.6℃

[0170] 1 H NMR(400MHz, CDCl3)δ7.36–7.27(m,5H),7.14(d,J=6.8Hz,2H),7.07–7.02( m,1H),6.98(d,J=8.5Hz,2H),6.95(d,J=8.3Hz,1H),6.81–6.75(m,3H),6.7 2(d,J=8.7Hz,2H),6.62(s,1H),5.14(s,2H),5.00(d,J=4.0Hz,1H),3.81–3 .77(m,1H),3.76(s,3H),3.52–3.45(m,1H),3.41–3.34(m,1H),2.21(s,3H).

[0171] 13 C NMR (101MHz, CDCl3) δ158.4,143.3,137.5,135.2,134.9,133.9,129.1,128.8,128.21,128.17,127.7 ,127.1,126.8,126.4,123.7,122.7,116.5,113.8,112.4,107.3,68.7,55.2,50.3,38.9,25.2,21.4.

[0172] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 32 H 29 O3NS,530.1760.Found:530.1760.

[0173] Example 15:

[0174] Prepare compound 1o of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole with the following structural formula (reaction formula 15).

[0175]

[0176] In Example 2, 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(4-methoxyphenyl)allyl)-1H-indole, and other conditions were the same as in Example 2. The final product was a dark green oily liquid 1o (dr>20:1, 32.6 mg, 39%).

[0177] The detection data for product 1O are as follows:

[0178] 1 H NMR (400MHz, DMSO-d6) δ10.68(d,J=1.2Hz,1H),7.29(d,J=8.2Hz,2H),7.03–6.94(m,3H),6.91(t,J=7.6Hz,1H),6.77(d,J=8.6Hz,2H),6.68(d, J=7.0Hz,1H),6.64(d,J=8.8Hz,3H),4.64(d,J=4.5Hz,1H),3.87–3.81( m,1H),3.60(s,3H),3.26–3.19(m,1H),3.17–3.10(m,1H),2.19(s,3H).

[0179] 13 C NMR(101MHz,DMSO-d6)δ157.9,143.3,135.2,135.0,133.2,128.9,128.6,127.8126 .0,125.6,121.9,120.4,115.5,113.7,112.0,109.0,66.7,55.0,38.5,24.9,21.0.

[0180] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 25 H 23 O3NS,440.1291.Found:440.1293.

[0181] Example 16:

[0182] Prepare 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compound 1p (reaction formula 16) with the following structural formula.

[0183]

[0184] In Example 2, 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(3,4-dimethoxyphenyl)allyl)-1-methyl-indole, and other conditions were the same as in Example 2. The final product was a dark green solid 1p (dr>20:1, 49.9 mg, 54%).

[0185] The detection data for product 1p are as follows:

[0186] mp: 78.9-81.2℃

[0187] 1 H NMR (400MHz, CDCl3) δ7.26–7.23(m,2H),7.11(t,J=7.5Hz,1H),6.96(d,J=8.7H z,1H),6.82(d,J=7.1Hz,1H),6.78(d,J=7.8Hz,2H),6.65–6.59(m,2H),6.51(d, J=8.2Hz,1H),6.47(s,1H),4.92(d,J=4.4Hz,1H),3.88–3.86(m,1H),3.82(s,3H ),3.72(s,3H),3.64(s,3H),3.53–3.46(m,1H),3.45–3.38(m,1H),2.23(s,3H).

[0188] 13 C NMR (101MHz, CDCl3) δ149.0,148.1,143.3,135.5,135.2,134.4,128.2,128.0,126.8,126.5,12 4.5,122.8,120.7,116.3,112.0,111.1,110.9,107.0,68.8,56.0,55.9,39.7,32.9,25.5,21.5.

[0189] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 27 H 27 O4NS,484.1553.Found:484.1554.

[0190] Example 17:

[0191] Prepare compound 1q (reaction formula 17) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0192]

[0193] In Example 2, 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(4-dimethylaminophenyl)allyl)-1-methyl-indole, and other conditions were the same as in Example 2. The final product was a dark green solid 1q (dr>20:1, 28.5 mg, 32%).

[0194] The 1q test data for the product are as follows:

[0195] mp: 184.5-185.5℃

[0196] 1 H NMR (400MHz, CDCl3) δ7.26 (d, J = 8.2 Hz, 2H), 7.12–7.07 (m, 1H), 6.94 (d, J = 8. 2Hz,1H),6.91(d,J=8.6Hz,2H),6.80(d,J=7.0Hz,1H),6.76(d,J=8.0Hz,2H), 6.56(d,J=8.5Hz,2H),6.50(s,1H),4.94(d,J=3.4Hz,1H),3.75–3.70(m,1H), 3.63(s,3H),3.51–3.43(m,1H),3.39–3.31(m,1H),2.89(s,6H),2.22(s,3H).

[0197] 13 C NMR (101MHz, CDCl3) δ149.5,143.1,135.0,134.3,128.8,128.2,127.9,126.9,126 .5,124.4,122.6,116.2,112.7,111.8,106.8,69.1,40.8,38.6,32.8,25.1,21.5.

[0198] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 27 H 28 O2N2S,467.1764.Found:467.1762.

[0199] Example 18:

[0200] Prepare compound 1r (reaction formula 18) of the following structural formula: 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole.

[0201]

[0202] In Example 2, 4-(2E)-(3-(3,4,5-trimethoxyphenyl)allyl)-1-methyl-indole was replaced with 4-(2E)-(3-(5-benzo[d][1,3]dioxolane)allyl)-1-methyl-indole, and other conditions were the same as in Example 2. The final product was a dark green solid 1r (dr>20:1, 55.2 mg, 62%).

[0203] The product 1r test data are as follows:

[0204] mp: 151.9-152.4℃

[0205] 1 H NMR (400MHz, CDCl3) δ7.27(d,J=7.8Hz,2H),7.09(t,J=7.6Hz,1H),6.95(d,J=8.1Hz,1H),6.84–6.77(m,3H),6.61(dd,J=21.0,7.8Hz,2H),6.49(s, 1H),6.43(s,1H),5.86(d,J=7.3Hz,2H),4.91(d,J=3.3Hz,1H),3.73–3.6 8(m,1H),3.63(s,3H),3.51–3.44(m,1H),3.40–3.32(m,1H),2.24(s,3H).

[0206] 13 C NMR (101MHz, CDCl3) δ147.7,146.4,143.3,137.1,134.9,134.3,128.2,128.0,126.6,126.2, 124.4,122.7,121.6,116.3,111.5,108.4,108.1,106.9,101.0,68.8,39.4,32.8,25.2,21.5.

[0207] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for NaC 26 H 23 O4NS,468.1240.Found:468.1245.

[0208] Antitumor activity verification experiment:

[0209] The 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds prepared in the examples were selected, and their in vitro antitumor activity was tested using human liver cancer cells (SMMC-7721 cells) as receptors by the CCK-8 assay.

[0210] The activity test process is illustrated using compound 1a from Example 1 as an example: (1) Collect logarithmic phase cells, adjust the cell suspension concentration, add 100 μL to each well, and plate the cells to be tested at a density of 5000 cells / well; (2) 5% Incubate with CO2 at 37°C until the cell monolayer covers the bottom of the 96-well plate. Then add compound 1a at different concentrations (0.015μM, 0.045μM, 0.137μM, 0.411μM, 1.234μM, 3.703μM, 11.111μM, 33.333μM, 100.000μM) in triplicate. (3) Incubate with 5% CO2 at 37°C for 48 hours and observe under an inverted microscope. (4) Add 10μL CCK-8 solution to each well and continue culturing for 1-4 hours. (5) When the solution in the 96-well plate gradually turns orange-red and a significant color change occurs, measure the color using an automated microplate reader at OD450. (5) Simultaneously set up zeroing wells (culture medium, CCK-8 solution), positive control wells (cells, cisplatin dissolution medium of the same concentration, culture medium, CCK-8 solution), and blank control wells (no drug added, only cells, culture medium and CCK-8 solution); (6) Plot the cell survival rate (%) against the logarithmically transformed drug concentration (e.g., log (drug concentration), and use nonlinear regression curve fitting (GraphPad Prism) to obtain the IC50 value of compound 1a; (7) The tumor inhibition experiments of 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds and their cisplatin prepared in other examples were performed in a similar manner as above.

[0211] Table 2 shows the inhibitory effects of some of the compounds in the examples on the proliferation of human liver cancer cells (SMMC-7721 cells).

[0212] compound Human liver cancer cells (SMMC-7721 cells) [IC50 (μM)] Example 1 Compound 1a 50.35 Example 2 Compound 1b 30.70 Example 3 Compound 1c 27.89 Example 4 Compound 1d 50.61 Example 5 Compound 1e 47.97 Cisplatin 12.36

[0213] like Figure 20 As shown, the results indicate that the 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[cd]-indole compounds prepared in this invention have a certain inhibitory effect on human liver cancer cells.

[0214] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific structures and characteristics is not elaborated upon here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the structure of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[ cd ]-Indole compounds, characterized in that, Its structural formula is as follows: ， Ar is 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3-methyl-4-methoxyphenyl or 2,3-dihydrobenzofuran-5-yl; R is methyl, ethyl, propyl, or cyclopropyl; R' is hydrogen or methyl.

2. The method for preparing the compound according to claim 1, characterized in that: use β Using 4'-methylindolylarylethylene and alkyl or arylsulfonyl chloride as raw materials, 3-aryl-4-sulfonyl-1,3,4,5-tetrahydrobenzo[ cd Indole compounds, the reaction formula is as follows: 。 3. The preparation method according to claim 2, characterized in that: The molar ratio of each substance in the reaction: β -4'-Methylindolylethylene:alkyl or arylsulfonyl = 1:0.5-5.

4. The preparation method according to claim 3, characterized in that: Solvents selected from ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, toluene, dimethyl sulfoxide, methanol, 1,4-dioxane, or... N , N - One or more of dimethylformamides.

5. The preparation method according to claim 4, characterized in that: The light source is selected from 5~50 W of violet, blue, white or red light.

6. The preparation method according to claim 5, characterized in that: The temperature used is 0–60 ℃.

7. The preparation method according to claim 6, characterized in that: The reaction time is 0.5–24 h.

8. The preparation method according to claim 7, characterized in that: The gas atmosphere is selected from air, argon, nitrogen, and oxygen.

9. The preparation method according to claim 8, characterized in that: The separation and purification methods are selected from column chromatography or recrystallization.

10. The use of the compound according to claim 1 in the preparation of an anti-hepatocellular carcinoma drug.

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