Preparation method and application of evodiamine analogue

Abstract

The invention relates to an evodiamine analogue as well as a preparation method and application thereof, and belongs to the field of organic chemistry. A target compound is synthesized through an intramolecular hydrogen borrowing reaction by taking a 2-indolyl quinazolinone derivative as a substrate and using a nickel-based catalyst. The method is simple in route, high in yield and low in production cost. When the concentration is 1 [mu] M / L, the inhibition effects of the target compounds 1k and 1o on the proliferation of in-vitro human colon cancer cells HCT-116 are superior to that of the medicine evodiamine, and the inhibition effects of the target compounds 1k and 1o on the proliferation of the in-vitro human colon cancer cells HCT-116 are equivalent to that of the medicine In addition, the inhibition effects of the compounds 1d, 1k and 1o on proliferation of in-vitro human bladder cancer cells T24 are better than those of evodiamine; it shows that part of target compounds have potential medicinal values.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and particularly relates to a molecular structure of evodiamine analog, a synthesis method thereof, and an evaluation of an inhibitory effect on proliferation of human cancer cells in vitro. BACKGROUND

[0002] Quinazolinones are an important class of nitrogen heterocycles. Quinazolinone skeleton is widely present in various natural products and bioactive molecules. As a key pharmacophore in drugs, it has important application value in drug molecule design. Evodiamine is a natural product containing quinazolinone skeleton, which is widely present in Evodia plants. Drug chemistry research has confirmed that evodiamine has various biological activities, including anti-inflammatory, anti-tumor, anti-obesity, anti-cardiovascular disease, anti-Alzheimer's disease, anti-microbial effects, etc. In addition, it also shows analgesic, body temperature regulation, anti-hypoxia, bronchial constriction and hormone secretion regulation activities. Due to the diverse biological activities and wide pharmacological effects of evodiamine and its analogs, they have important research value in the field of drug development. In recent years, structural modification of evodiamine analogs is a research hotspot in the field of medicinal chemistry. At present, the main synthesis method of evodiamine analogs is based on o-tolylmethylamine and other raw materials, which leads to insufficient structural diversity of evodiamine analogs. Therefore, it is urgent and has application prospect to develop a new method for constructing evodiamine skeleton. The generation of C-C and C-N bonds by borrowing hydrogen reaction is an important green synthesis strategy in organic chemistry. This kind of reaction uses alcohol compounds as alkylating agents, and the byproduct is only water, which has significant atom economy and environmental friendliness. In recent years, significant progress has been made in the study of transition metal-catalyzed borrowing hydrogen reaction, especially in the selective alkylation of indole C3 and N1 positions. The present application synthesizes a series of evodiamine analogs and their derivatives by using intramolecular borrowing hydrogen reaction strategy, and evaluates their in vitro anti-cancer activity. SUMMARY

[0003] The main content of the present application is to provide a method for synthesizing evodiamine analogs, which is briefly described as follows: using isatin anhydride and its derivatives, 1H-indole-2-carboxaldehyde and its derivatives, ethanolamine, propanolamine, dimethyl sulfate, etc. as raw materials, using nickel-based catalyst, and synthesizing target product by using intramolecular borrowing hydrogen reaction. The synthesis route is shown in the attached Figure 1The synthesis route of the evodiamine analogues is shown as follows: taking isatoic anhydride and its derivatives as raw materials, N-methyl isatoic anhydride and its derivatives (I) are synthesized; then, acylation reaction occurs between the N-methyl isatoic anhydride and ethanolamine or propanolamine to generate 2-(methylamino) benzamide derivatives (II); then, condensation reaction occurs between the 2-(methylamino) benzamide derivatives and 1H-indole-2-carboxaldehyde and its derivatives under acidic conditions to generate 2-indolyl quinazolinone derivatives (III); finally, intramolecular hydrogen transfer occurs under the catalysis of a nickel-based catalyst to generate the target compound (IV). R1 and R2 are F, Cl, Br, methyl and methoxy, etc.

[0004] The prepared evodiamine analogues are also evaluated for the effect of inhibiting the proliferation of human cancer cells in vitro. At a concentration of 1 μM / L, the inhibitory effect of compounds 1k and 1o on the proliferation of human colon cancer cells HCT-116 is better than that of evodiamine, and the inhibitory effect of 1d is equivalent to that of evodiamine; and the inhibitory effect of compounds 1d, 1k and 1o on the proliferation of human bladder cancer cells T24 is better than that of evodiamine.

[0005] The advantages of the present application are:

[0006] 1. The raw materials are easy to obtain, the synthesis method is simple, and a variety of evodiamine analogues and derivatives can be efficiently prepared.

[0007] 2. The inexpensive nickel-based catalyst is used to generate the target compound at a high yield.

[0008] 3. The byproduct of the reaction is only water, and the synthesis method is green and environmentally friendly.

[0009] 4. Some of the evodiamine analogues synthesized by the present application have a strong inhibitory effect on the cell proliferation of human cancer cells HCT-116 and T24 in vitro. BRIEF DESCRIPTION OF DRAWINGS

[0010] Figure 1 The synthesis route of the evodiamine analogues prepared by the present application. DETAILED DESCRIPTION

[0011] The present application will be described in detail below through specific examples. It should be particularly pointed out that the examples listed are only used to illustrate the technical solutions of the present application, and are not a limitation on the present application. The technical solutions of the present application can be adjusted, improved and combined in various ways according to actual needs without departing from the core idea of the present application.

[0012] In the following examples, 1 The internal standard for H NMR testing is tetramethylsilane (TMS).

[0013] Example 1:

[0014] The reaction steps are as follows:

[0015] 1 Synthesis of compound 1a

[0016]

[0017] Indigo anhydride (2 mmol, 324.1 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask in sequence. Dimethyl sulfate (2.6 mmol, 327.9 mg) was added slowly under ice-water bath condition. After stirring for 1 h, the reaction was continued at room temperature for 6 h, and the reaction progress was monitored by thin layer chromatography (TLC). After the reaction was completed, water (60 mL) was added slowly, and a cream-colored solid was obtained by filtration, which was washed with water and dried to give 264 mg of white solid compound 3a (yield 75%).

[0018] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added into a 100 mL round-bottom flask in sequence. Compound 3a (1 mmol, 176.1 mg) was added under ice-water bath condition. After stirring for 30 min, the reaction was continued at room temperature for 4 h, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 159.2 mg of white solid compound 4a (yield 82%).

[0019] Compound 4a (0.5 mmol, 97.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle in sequence. The reaction was stirred under heating for 24 h under nitrogen protection, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 120.5 mg of brown-yellow solid compound 5a (yield 75%).

[0020] Compound 5a (0.1 mmol, 32.1 mg), nickel phthalocyanine (0.01 mmol, 5.7 mg), cesium carbonate (0.2 mmol, 65.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle in sequence. The reaction was stirred at 160 °C under vacuum for 30 h, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction liquid was extracted with water and ethyl acetate, and the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 27.6 mg of white solid compound 1a (yield 91%). 1H NMR (500 MHz, DMSO-d6) δ = 7.65 (d, J = 8.0 Hz, 1H), 7.52 - 7.34 (m, 3H), 7.14 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.35 (d, J = 7.5 Hz, 2H), 4.75 - 4.71 (m, 1H), 4.22 - 4.19 (m, 1H), 4.03 - 3.99 (m, 1H), 3.64 - 3.60 (m, 1H), 3.26 (s, 3H) ppm.

[0021] 2 Synthesis of compound 1b

[0022]

[0023] Compound 6b was prepared according to the procedure described in Example 1, step 2, using compound 5b (0.5 mmol, 120.7 mg) and 2-aminopyridine (0.75 mmol, 80.6 mg). The reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 87.6 mg of compound 6b as a white solid (yield 68%).

[0024] Compound 7b was prepared according to the procedure described in Example 1, step 3, using compound 6b (0.5 mmol, 87.6 mg). The reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 87.6 mg of compound 7b as a white solid (yield 68%).

[0025] Compound 8b was prepared according to the procedure described in Example 1, step 4, using compound 7b (0.5 mmol, 87.6 mg). The reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 87.6 mg of compound 8b as a white solid (yield 68%).

[0026] Compound 5b (0.1 mmol, 35.5 mg), nickel bis(triphenylphosphine) dichloride (0.01 mmol, 7.0 mg), sodium carbonate (0.2 mmol, 21.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 150 °C for 30 h under vacuum condition, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 20.9 mg of compound 1b as a light yellow solid (yield 62%). 1 H NMR (500 MHz, CDC13) δ = 8.02 - 7.88 (m, 1H), 7.59 (s, 1H), 7.47 - 7.41 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.47 (s, 1H), 6.05 (s, 1H), 5.03 - 4.95 (m, 1H), 4.25 - 4.17 (m, 2H), 3.46 - 3.40 (m, 1H), 3.06 - 2.99 (m, 3H) ppm.

[0027] 3 Synthesis of compound 1c

[0028]

[0029] Compound 3c (1 mmol, 190.1 mg) was added into a 100 mL round-bottom flask under ice-water bath condition. After the reaction was stirred for 30 min, it was continued to react at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 189.3 mg of compound 4c as a white solid (yield 83%).

[0030] Compound 3c (1 mmol, 190.1 mg) was added into a 100 mL round-bottom flask under ice-water bath condition. After the reaction was stirred for 30 min, it was continued to react at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 189.3 mg of compound 4c as a white solid (yield 83%).

[0031] Compound 4c (0.5 mmol, 104.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle successively. The reaction was stirred under nitrogen protection for 24 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 120.7 mg of brown-yellow solid compound 5c (yield 68%).

[0032] Compound 5c (0.1 mmol, 33.5 mg), bis(triphenylphosphine) nickel dibromide (0.01 mmol, 7.4 mg), potassium carbonate (0.2 mmol, 27.6 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle successively. The reaction was stirred at 160°C under vacuum for 30 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 22.5 mg of light yellow solid compound 1c (yield 71%). 1 H NMR (500 MHz, CDC13) δ = 7.78 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.13 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 6.00 (s, 1H), 4.96 - 4.92 (m, 1H), 4.26 - 4.14 (m, 2H), 3.45 - 3.39 (m, 1H), 2.92 (s, 3H), 2.30 (s, 3H) ppm.

[0033] 4 Synthesis of compound 1d

[0034]

[0035] 5-Fluoro-phthalic anhydride (2 mmol, 362.2 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask successively. Dimethyl sulfate (2.6 mmol, 327.9 mg) was slowly added under ice-water bath conditions, and the reaction was stirred for 1 hour. Then the reaction was continued at room temperature for 5 hours, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was slowly added, and a cream-colored solid was obtained by filtration, washed with water and dried to obtain 283.2 mg of white solid compound 3d (yield 73%).

[0036] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added into a 100 mL round bottom flask successively. Compound 3d (1 mmol, 194.1 mg) was added under ice-water bath condition. After stirring for 30 min, the reaction was continued at room temperature for 4 h. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 178.2 mg of white solid compound 4d (yield 84%).

[0037] Compound 4d (0.5 mmol, 106.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle successively. The reaction was stirred under nitrogen protection for 24 h. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 110.2 mg of yellow solid compound 5d (yield 65%).

[0038] Compound 5d (0.1 mmol, 31.9 mg), ethylene glycol dimethyl ether nickel dibromide (0.01 mmol, 3.1 mg), sodium carbonate (0.2 mmol, 21.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle successively. The reaction was stirred at 140 °C under vacuum for 30 h. TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 25.1 mg of light yellow solid compound 1d (yield 78%). 1 H NMR (500 MHz, DMSO-d6) δ = 7.50 (d, J = 8.0 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.36 - 7.32 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.98 - 6.95 (m, 1H), 6.38 (s, 1H), 6.34 (s, 1H), 4.74 - 4.70 (m, 1H), 4.26 - 4.22 (m, 1H), 4.05 - 4.00 (m, 1H), 3.66 - 3.58 (m, 1H), 3.17 (s, 3H) ppm.

[0039] 5 Synthesis of compound 1e

[0040]

[0041] 5-Chloroindocyanine anhydride (2 mmol, 395.2 mg), potassium carbonate (2.4 mmol, 331.7 mg), and N,N-dimethylformamide (10 mL) were sequentially added to a 100 mL round-bottom flask. Dimethyl sulfate (2.6 mmol, 327.9 mg) was slowly added under ice-water bath conditions. After stirring for 1 hour, the reaction was continued at room temperature for 6 hours, with the reaction progress monitored by TLC. After the reaction was complete, water (60 mL) was slowly added, and the mixture was filtered to obtain a cream-colored solid. The solid was washed with water and dried to give 315 mg of a white solid, compound 3e (75% yield).

[0042] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added sequentially to a 100 mL round-bottom flask. Compound 3e (1 mmol, 210.0 mg) was added under ice-water bath conditions. The mixture was stirred for 30 minutes, then reacted at room temperature for 4 hours, monitored by TLC. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 187 mg of a white solid, compound 4e (yield 82%).

[0043] Compound 4e (0.5 mmol, 114.0 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL), and acetic acid (1 mL) were sequentially added to a 25 mL sealed reaction flask. The reaction was heated and stirred under nitrogen protection for 24 hours, and the reaction was monitored by TLC. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 120.7 mg of brownish-yellow solid compound 5e (yield 68%).

[0044] Compound 5e (0.1 mmol, 35.5 mg), tetraphenylporphyrin nickel (0.01 mmol, 6.7 mg), sodium carbonate (0.2 mmol, 21.2 mg), and N,N-dimethylformamide (1 mL) were sequentially added to a sealed reaction flask. The reaction was stirred at 140 °C under vacuum for 30 hours, and the reaction was monitored by TLC. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 23.6 mg of pale yellow solid compound 1e (yield 70%). 1H NMR (500 MHz, DMSO-d6) δ = 7.57 (d, J = 2.5 Hz, 1H), 7.48 (t, J = 6.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 4.75 - 4.71 (m, 1H), 4.23 - 4.20 (m, 1H), 4.04 - 3.98 (m, 1H), 3.66 - 3.60 (m, 1H), 3.27 (s, 3H) ppm.

[0045] 6 Synthesis of compound 1f

[0046]

[0047] Compound 4a (0.5 mmol, 97.1 mg), 6-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction vial successively. The reaction was stirred under nitrogen protection for 24 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 120.7 mg of brown-yellow solid compound 5f (yield 68%).

[0048] Compound 5f (0.1 mmol, 35.5 mg), nickel acetate (0.01 mmol, 1.8 mg), sodium carbonate (0.2 mmol, 21.0 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 150°C for 30 hours under vacuum, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 23.3 mg of light yellow solid compound 1f (yield 69%). 1 H NMR (500 MHz, CDCl3) δ = 7.97 - 7.95 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.47 (s, 1H), 6.05 (s, 1H), 5.01 - 4.96 (m, 1H), 4.24 - 4.18 (m, 2H), 3.47 - 3.40 (m, 1H), 3.05 (s, 3H) ppm.

[0049] 7Synthesis of compound 1g

[0050]

[0051] Compound 5g (0.1 mmol, 33.5 mg), bis(l,5-cyclooctadiene)nickel (0.01 mmol, 2.8 mg), potassium phosphate (0.2 mmol, 42.5 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube under vacuum. The reaction was stirred at 150 °C for 30 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 24.1 mg of compound 1g as a light yellow solid (yield 76%).

[0052] Compound 5g (0.1 mmol, 33.5 mg), bis(l,5-cyclooctadiene)nickel (0.01 mmol, 2.8 mg), potassium phosphate (0.2 mmol, 42.5 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube under vacuum. The reaction was stirred at 150 °C for 30 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 24.1 mg of compound 1g as a light yellow solid (yield 76%).

[0053] Compound 5g (0.1 mmol, 33.5 mg), bis(l,5-cyclooctadiene)nickel (0.01 mmol, 2.8 mg), potassium phosphate (0.2 mmol, 42.5 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube under vacuum. The reaction was stirred at 150 °C for 30 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 24.1 mg of compound 1g as a light yellow solid (yield 76%).

[0054] Compound 5g (0.1 mmol, 33.5 mg), bis(l,5-cyclooctadiene)nickel (0.01 mmol, 2.8 mg), potassium phosphate (0.2 mmol, 42.5 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube under vacuum. The reaction was stirred at 150 °C for 30 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 24.1 mg of compound 1g as a light yellow solid (yield 76%). 1H NMR (500 MHz, CDC13) δ = 7.79 (d, J = 2.0 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.37 - 7.30 (m, 1H), 7.29 - 7.24 (m, 2H), 7.16 - 7.12 (m, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 1.1 Hz, 1H), 6.02 (s, 1H), 4.97 - 4.93 (m, 1H), 4.28 - 4.15 (m, 2H), 3.46 - 3.40 (m, 1H), 2.93 (s, 3H), 2.30 (s, 3H) ppm.

[0055] 8 Synthesis of compound 1h

[0056]

[0057] Dimethylsulfate (2.6 mmol, 327.9 mg) was added slowly under ice water bath condition, after stirring for 1 hour, the reaction was continued at room temperature for 6 hours, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was added slowly, and a cream-colored solid was obtained by filtration, which was washed with water and dried to obtain 280.1 mg of white solid compound 3h (yield 68%).

[0058] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were sequentially added to a 100 mL round-bottom flask. Compound 3h (1 mmol, 206.1 mg) was added under ice water bath condition, after stirring for 30 minutes, the reaction was continued at room temperature for 4 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 201.7 mg of white solid compound 4h (yield 90%).

[0059] Compound 4h (0.5 mmol, 112.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL), and acetic acid (1 mL) were sequentially added to a 25 mL sealed tube reaction bottle. The reaction was stirred under heating for 24 hours under nitrogen protection, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 105.3 mg of brownish yellow solid compound 5h (yield 60%).

[0060] Compound 5h (0.1 mmol, 35.1 mg), tetrakis(triphenylphosphine)nickel (0.01 mmol, 11.0 mg), sodium bicarbonate (0.2 mmol, 16.8 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 140 °C for 30 h under vacuum condition, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 21.3 mg of compound 1h as a light yellow solid (yield 64%). 1 H NMR (500 MHz, DMSO-d6) δ = 7.68 - 7.60 (m, 1H), 7.48 - 7.38 (m, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.31 (s, H), 6.28 (s, H), 4.73 - 4.70 (m, 1H), 4.17 - 4.13 (m, 1H), 3.99 (d, J = 5.5 Hz, 1H), 3.81 (s, 3H), 3.64 - 3.54 (m, 1H), 3.25 (s, 3H) ppm.

[0061] 9Synthesis of compound 1i

[0062]

[0063] Compound 4i (1 mmol, 180.3 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask successively. Dimethyl sulfate (2.6 mmol, 327.9 mg) was added slowly under ice-water bath condition, and the reaction was stirred for 1 h. The reaction was continued at room temperature for 6 h, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was added slowly, and a cream-colored solid was obtained by filtration, which was washed with water and dried to give 298.7 mg of compound 3i as a white solid (yield 77%).

[0064] Compound 4i (1 mmol, 180.3 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask successively. Dimethyl sulfate (2.6 mmol, 327.9 mg) was added slowly under ice-water bath condition, and the reaction was stirred for 1 h. The reaction was continued at room temperature for 6 h, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was added slowly, and a cream-colored solid was obtained by filtration, which was washed with water and dried to give 298.7 mg of compound 3i as a white solid (yield 77%).

[0065] Compound 4i (0.5 mmol, 106.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle successively. The reaction was stirred under nitrogen protection for 24 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 118.7 mg of brown-yellow solid compound 5i (yield 70%).

[0066] Compound 5i (0.1 mmol, 33.9 mg), nickelocene (0.01 mmol, 1.9 mg), sodium carbonate (0.2 mmol, 21.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle successively. The reaction was stirred at 150°C under vacuum for 30 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 23.1 mg of light yellow solid compound 1i (yield 72%). 1 H NMR (500 MHz, DMSO-d6) δ = 7.69-7.65 (m, 1H), 7.50-7.41 (m, 2H), 7.28-7.26 (m, 1H), 6.94-6.87 (m, 2H), 6.76 (t, J = 7.5 Hz, 1H), 6.35 (d, J = 10.0 Hz, 2H), 4.75-4.71 (m, 1H), 4.19-4.16 (m, 1H), 4.01-3.95 (m, 1H), 3.64-3.58 (m, 1H), 3.26 (s, 3H) ppm.

[0067] 10 Synthesis of compound 1j

[0068]

[0069] 4-Chloro- indoxyl-9-anhydride (2 mmol, 395.2 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask successively. Dimethyl sulfate (2.6 mmol, 327.9 mg) was slowly added under ice water bath conditions, and the reaction was stirred for 1 hour. Then the reaction was continued at room temperature for 6 hours, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was slowly added, and a cream-colored solid was obtained by filtration, washed with water and dried to obtain 306.6 mg of white solid compound 3j (yield 73%).

[0070] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added into a 100 mL round bottom flask successively. Compound 3j (1 mmol, 210.0 mg) was added under ice-water bath condition. After stirring for 30 min, the reaction was continued at room temperature for 4 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 182.4 mg of white solid compound 4j (yield 80%).

[0071] Compound 4j (0.5 mmol, 114.0 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction flask successively. The reaction was stirred under nitrogen protection for 24 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 126.1 mg of brown-yellow solid compound 5j (yield 71%).

[0072] Compound 5j (0.1 mmol, 35.5 mg), nickel dichloride (0.01 mmol, 1.3 mg), potassium carbonate (0.2 mmol, 27.6 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction flask successively. The reaction was stirred at 140 °C for 30 h under vacuum condition. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 26.3 mg of light yellow solid compound 1j (yield 78%). 1 H NMR (500 MHz, DMSO-d6) δ = 7.65 (d, J = 7.5 Hz, 1H), 7.57 - 7.39 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 10.0 Hz, 2H), 4.74 - 4.70 (m, 1H), 4.21 (d, J = 11.0 Hz, 1H), 4.01 (s, 1H), 3.61 (s, 1H), 3.26 (s, 3H) ppm.

[0073] 11 Synthesis of compound 1k

[0074]

[0075] Compound 4a (0.5 mmol, 97.1 mg), 5-methoxy-lH-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle successively. The reaction was heated and stirred under nitrogen protection for 24 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 136.9 mg of brown-yellow solid compound 5k (yield 78%).

[0076] Compound 5k (0.1 mmol, 35.1 mg), bis(triphenylphosphine) nickel dichloride (0.01 mmol, 3.7 mg), potassium tert-butoxide (0.2 mmol, 22.4 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle successively. The reaction was stirred at 140°C under vacuum for 30 hours, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 30.0 mg of light yellow solid compound Ik (yield 90%). 1 H NMR (500 MHz, CDC13) δ = 7.95 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.96-6.87 (m, 2H), 6.47 (s, 1H), 6.05 (s, 1H), 5.00-4.96 (m, 1H), 4.26-4.18 (m, 2H), 3.46-3.40 (m, 1H), 3.05 (s, 3H) ppm.

[0077] 12 Synthesis of compound 11

[0078]

[0079] 4-methylisatoic anhydride (2 mmol, 354.3 mg), potassium carbonate (2.4 mmol, 331.7 mg) and N,N-dimethylformamide (10 mL) were added into a 100 mL round-bottom flask successively. Dimethyl sulfate (2.6 mmol, 327.9 mg) was slowly added under ice-water bath conditions, and the reaction was stirred for 1 hour. Then the reaction was continued at room temperature for 6 hours, and the reaction progress was monitored by TLC. After the reaction was completed, water (60 mL) was slowly added, and a cream-colored solid was obtained by filtration, washed with water and dried to obtain 285 mg of white solid compound 31 (yield 75%).

[0080] Acetonitrile (30 mL) and ethanolamine (1.5 mmol, 91.6 mg) were added into a 100 mL round bottom flask successively. Compound 3l (1 mmol, 190.2 mg) was added under ice-water bath condition. After stirring for 30 min, the reaction was continued at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 179 mg of white solid compound 4l (yield 86%).

[0081] Compound 4l (0.5 mmol, 104.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL), and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle successively. The reaction was stirred under nitrogen protection for 24 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 133.2 mg of brownish yellow solid compound 5l (yield 75%).

[0082] Compound 5l (0.1 mmol, 33.5 mg), nickel phthalocyanine (0.01 mmol, 5.7 mg), sodium tert-butoxide (0.2 mmol, 19.2 mg), and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle successively. The reaction was stirred at 150 °C under vacuum for 30 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 23.5 mg of light yellow solid compound 1l (yield 74%). 1 H NMR (500 MHz, CDC13) δ = 7.83 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.16-7.11 (m, 1H), 6.75-6.72 (m, 1H), 6.68 (s, 1H), 6.45 (s, 1H), 6.02 (s, 1H), 5.03-4.91 (m, 1H), 4.24-4.15 (m, 2H), 3.44-3.38 (m, 1H), 3.06 (s, 3H), 2.37 (s, 3H) ppm.

[0083] 13 Synthesis of compound 1m

[0084]

[0085] Compound 4a (0.5 mmol, 97.1 mg), 6-fluoro-lH-indole-2-carboxaldehyde (0.75 mmol, 122.4 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction vial successively. The reaction was stirred under nitrogen protection for 24 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 125.5 mg of brown yellow solid compound 5m (yield 74%).

[0086] Compound 5m (0.1 mmol, 33.9 mg), ethylene glycol dimethyl ether nickel dibromide (0.01 mmol, 3.1 mg), potassium carbonate (0.2 mmol, 27.6 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 140 °C under vacuum for 30 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 23.8 mg of light yellow solid compound Im (yield 74%). 1 H NMR (500 MHz, CDC13) δ = 7.95-7.93 (m, 1H), 7.46-7.42 (m, 1H), 7.16-7.12 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.94-6.87 (m, 2H), 6.81-6.78 (m, 1H), 6.53 (s, 1H), 6.03 (s, 1H), 5.04-4.98 (m, 1H), 4.24-4.15 (m, 2H), 3.47-3.40 (m, 1H), 3.10 (s, 3H) ppm.

[0087] 14 Synthesis of compound In

[0088]

[0089] Compound 4a (0.5 mmol, 97.1 mg), 6-fluoro-lH-indole-2-carboxaldehyde (0.75 mmol, 122.4 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction vial successively. The reaction was stirred under nitrogen protection for 24 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 125.5 mg of brown yellow solid compound 5m (yield 74%).

[0090] Compound 5n (0.1 mmol, 35.1 mg), bis(triphenylphosphine) nickel dichloride (0.01 mmol, 7.0 mg), potassium phosphate (0.2 mmol, 42.5 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube in turn. The reaction was stirred at 140 °C for 30 h under vacuum, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 28.3 mg of compound In as a light yellow solid (yield 85%). 1 H NMR (500 MHz, CDC13) δ = 7.97 - 7.90 (m, 1H), 7.44 - 7.39 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.85 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 6.5 Hz, 2H), 6.01 (s, 1H), 5.00 - 4.94 (m, 1H), 4.21 - 4.14 (m, 2H), 3.93 (s, 3H), 3.43 - 3.37 (m, 1H), 3.08 (s, 3H) ppm.

[0091] 15 Synthesis of compound lo

[0092]

[0093] Compound 4d (0.5 mmol, 106.1 mg), 5-methoxy-lH-indole-2-carboxaldehyde (0.75 mmol, 131.4 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube in turn. The reaction was stirred under nitrogen protection for 24 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 129.2 mg of compound 50 as a brownish yellow solid (yield 70%).

[0094] Compound 50 (0.1 mmol, 36.9 mg), tetraphenylporphyrin nickel (0.01 mmol, 6.7 mg), sodium carbonate (0.2 mmol, 21.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube in turn. The reaction was stirred at 150 °C for 30 h under vacuum, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to give 19.7 mg of compound lo as a light yellow solid (yield 56%). 1H NMR (500 MHz, CDC13) δ = 7.69 - 7.67 (m, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.46 (s, 1H), 6.01 (s, 1H), 4.92 - 4.88 (m, 1H), 4.25 - 4.21 (m, 1H), 4.16 - 4.11 (m, 1H), 3.84 (s, 3H), 3.47 - 3.41 (m, 1H), 2.85 (s, 3H) ppm.

[0095] 16 Synthesis of compound 1p

[0096]

[0097] Acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 112.7 mg) were added into a 100 mL round bottom flask in turn. Compound 3a (1 mmol, 176.1 mg) was added under ice water bath condition, after stirring for 30 minutes, the reaction was continued at room temperature for 4 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 170.6 mg of white solid compound 4p (yield 82%).

[0098] Compound 4p (0.5 mmol, 104.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle in turn. The reaction was stirred under nitrogen protection for 24 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 124 mg of brown yellow solid compound 5p (yield 74%).

[0099] Compound 5p (0.1 mmol, 33.5 mg), bis(1,5-cyclooctadiene)nickel (0.01 mmol, 2.8 mg), sodium bicarbonate (0.2 mmol, 16.8 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle in turn. The reaction was stirred at 150°C under vacuum for 30 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 19.0 mg of light yellow solid compound 1p (yield 60%). 1H NMR (500 MHz, DMSO-d6) δ = 7.59 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.77 (t, J = 7.5 Hz, 1H), 6.40 (s, 1H), 5.73 (s, 1H), 4.75 - 4.63 (m, 1H), 4.65 (d, J = 13.5 Hz, 1H), 4.21 - 4.12 (m, 1H), 3.35 (s, 1H), 3.24 (d, J = 13.0 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.67 - 1.56 (m, 1H) ppm.

[0100] 17 Synthesis of compound 1q

[0101]

[0102] Acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 112.7 mg) were added into a 100 mL round bottom flask in turn. Compound 3e (1 mmol, 210.0 mg) was added under ice water bath condition, after stirring for 30 minutes, the reaction was continued at room temperature for 4 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 181.6 mg white solid compound 4q (yield 75%).

[0103] Compound 4q (0.5 mmol, 121.0 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle in turn. The reaction was stirred under nitrogen protection for 24 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 129.2 mg brown yellow solid compound 5q (yield 70%).

[0104] Compound 5q (0.1 mmol, 36.9 mg), tetrakis(triphenylphosphine)nickel (0.01 mmol, 11.0 mg), potassium carbonate (0.2 mmol, 27.6 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle in turn. The reaction was stirred at 150 °C under vacuum for 30 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 15.4 mg light yellow solid compound 1q (yield 44%). 1H NMR (500 MHz, CDC13) δ = 7.81 (d, J = 2.5 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.28 (d, J = 8.5 Hz, 1H), 7.21 - 7.18 (m, 1H), 7.06 - 7.03 (m, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.92 (s, 1H), 5.84 (s, 1H), 5.02 - 4.94 (m, 1H), 4.73 - 4.62 (m, 1H), 4.08 - 4.03 (m, 1H), 3.18 (s, 3H), 3.08 - 3.02 (m, 1H), 2.14 - 2.07 (m, 1H), 2.00 - 1.96 (m, 1H) ppm.

[0105] 18 Synthesis of compound 1r

[0106]

[0107] Acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 112.7 mg) were added into a 100 mL round bottom flask in turn. Compound 3g (1 mmol, 190.1 mg) was added under ice water bath condition, after stirring for 30 minutes, the reaction was continued at room temperature for 4 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 184.4 mg white solid compound 4r (yield 83%).

[0108] Compound 4r (0.5 mmol, 111.1 mg), 1H-indole-2-carboxaldehyde (0.75 mmol, 108.9 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction bottle in turn. The reaction was stirred under nitrogen protection for 24 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 113.5 mg brown yellow solid compound 5r (yield 65%).

[0109] Compound 5r (0.1 mmol, 39.9 mg), nickel acetate (0.01 mmol, 1.8 mg), sodium carbonate (0.2 mmol, 21.2 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction bottle in turn. The reaction was stirred at 150°C under vacuum for 30 hours, TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 16.2 mg light yellow solid compound 1q (yield 49%). 1H NMR (500 MHz, CDC13) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.19 - 7.16 (m, 1H), 7.04 - 7.01 (m, 1H), 6.75 (d, J = 8.5 Hz, 1H), 5.95 (s, 1H), 5.81 (s, 1H), 5.02 - 4.97 (m, 1H), 4.68 - 4.63 (m, 1H), 4.09 - 4.03 (m, 1H), 3.16 (s, 3H), 3.07 - 2.99 (m, 1H), 2.27 (s, 3H), 2.12 - 1.94 (m, 2H) ppm.

[0110] 19 Synthesis of compound 1s

[0111]

[0112] Compound 4p (0.5 mmol, 104.1 mg), 5-methyl-lH-indole-2-carboxaldehyde (0.75 mmol, 119.4 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction vial successively. The reaction was stirred under nitrogen protection for 24 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 132.1 mg of brown yellow solid compound 5s (yield 75%).

[0113] Compound 5s (0.1 mmol, 39.9 mg), nickelocene (0.01 mmol, 1.9 mg), potassium tert-butoxide (0.2 mmol, 22.4 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 150°C under vacuum for 30 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 15.2 mg of white solid compound 1s (yield 46%). 1H NMR (500 MHz, CDC13) δ = 7.84 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.87 - 6.79 (m, 2H), 5.85 (s, 1H), 5.82 (s, 1H), 4.99 (d, J = 14.0 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.08 - 4.02 (m, 1H), 3.17 (s, 3H), 3.04 - 2.99 (m, 1H), 2.36 (s, 3H), 2.09 - 1.96 (m, 2H) ppm.

[0114] 20 Synthesis of compound 1t

[0115]

[0116] Compound 4p (0.5 mmol, 104.1 mg), 5-chloro-1H-indole-2-carboxaldehyde (0.75 mmol, 134.7 mg), ethanol (5 mL) and acetic acid (1 mL) were added into a 25 mL sealed tube reaction vial successively. The reaction was stirred under nitrogen protection for 24 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain 155.7 mg of brown-yellow solid compound 5t (yield 84%).

[0117] Compound 5t (0.1 mmol, 36.4 mg), nickel phthalocyanine (0.01 mmol, 5.7 mg), potassium carbonate (0.2 mmol, 27.6 mg) and N,N-dimethylformamide (1 mL) were added into a sealed tube reaction vial successively. The reaction was stirred at 150°C under vacuum for 30 hours, and TLC was used to monitor the reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 17.2 mg of light yellow solid compound 1t (yield 49%). 1H NMR (500 MHz, DMSO-d6) δ = 7.66 (s, 1H), 7.59 (d, J = 7.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 8.5 Hz, 1H), 6.96 - 6.92 (m, 2H), 6.77 (t, J = 7.5 Hz, 1H), 6.39 (s, 1H), 5.74 (d, J = 15 Hz, 1H), 4.78 - 4.71 (m, 1H), 4.66 - 4.60 (m, 1H), 4.19 - 4.12 (m, 1H), 3.27 - 3.19 (m, 1H), 3.18 (d, J = 4.5 Hz, 3H), 2.08 (t, J = 11.5 Hz, 1H), 1.66 - 1.58 (m, 1H) ppm.

[0118] The in vitro anti-tumor activity of the above target products was evaluated. The evaluation method was to test the inhibitory effect of the compounds on the cell proliferation of human colon cancer cells HCT-116 and human bladder cancer cells T24 by using CCK-8 reagent. The experimental results of some target compounds affecting the proliferation of human colon cancer cells HCT-116 at a concentration of 1 μM / L are shown in Table 1. The experimental results of some target compounds affecting the proliferation of human bladder cancer cells T24 at a concentration of 1 μM / L are shown in Table 2.

[0119] Table 1

[0120] Compound Cell survival rate (%) 1a 56.04±0.25 1d 24.67±1.13 1m 42.72±0.89 1e 106.60±0.88 1f 109.16±0.59 1g 99.77±0.17 1k 18.51±0.92 1o 17.88±0.46 1p 105.63±0.96 1r 107.35±0.46 Evodiamine 23.58±0.29

[0121] Table 2

[0122] Compound Cell survival rate (%) 1a 79.74±2.33 1d 15.84±0.55 1m 55.92±1.71 1e 85.48±0.69 1f 80.10±1.81 1g 83.42±1.34 1k 13.43±0.81 1o 11.82±1.23 1p 86.45±1.60 1r 93.35±2.45 Evodiamine 31.21±1.43

[0123] From the above test results, it can be seen that at a concentration of 1 μM / L, the inhibitory effect of compounds 1k and 1o on the proliferation of HCT-116 cells is better than that of evodiamine, and 1d is equivalent to evodiamine; and the inhibitory effect of compounds 1d, 1k and 1o on the proliferation of T24 cells is better than that of evodiamine; the anti-tumor effect is obvious, and has potential pharmaceutical value.

[0124] Although the present application has been described in detail with general description and specific embodiments above, it is simple and easy for those skilled in the art to make some modifications or improvements on the basis of the present application. Therefore, these modifications or improvements made on the basis of not deviating from the subject matter of the present application, all belong to the scope of protection claimed by the present application.

Claims

1. An eleutheroside analogue, characterized by a C-ring consisting of a piperazine unit or a diaza-7-membered ring, with the following general structural formula: ,in, R 1 and R 2 The following are the possible values: H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, amino, fluorine, chlorine, bromine, trifluoromethyl, and difluoromethyl.

2. The evodiamine analogue according to claim 1, characterized in that... R 1 and R 2 The following are possible values: H, methoxy, ethoxy, methyl, nitro, fluorine, chlorine, bromine, and trifluoromethyl.

3. The evodiamine analogue according to claim 1, characterized in that... R 1 H, methoxy, methyl, fluorine, chlorine, bromine; R 2 The components are H, methoxy, methyl, chlorine, and bromine.

4. The method for preparing any one of the evodiamine analogues according to claims 1, 2, and 3, characterized in that... The specific steps are as follows: (1) Using indomethacin anhydride and its derivatives as raw materials, N-methylindomethacin anhydride and its derivatives are reacted with dimethyl sulfate to generate N-methylindomethacin anhydride and its derivatives, the molecular structural formula of which is as follows: , where R 1 The following are the compounds: H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, and difluoromethyl. (2) Using the N-methylindosan anhydride and its derivatives prepared in (1) as raw materials, an acylation reaction is carried out with ethanolamine or 3-amino-1-propanol to obtain a 2-(methylamino)benzamide derivative, the molecular structure of which is as follows: , where R 1 The following are the compounds: H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, and difluoromethyl. (3) The 2-(methylamino)benzamide derivative prepared in step (2) undergoes a condensation reaction with 1H-indole-2-carboxaldehyde and its derivatives to generate a 2-indole-quinazolinone derivative, the molecular structure of which is as follows: , where R 1 and R 2 The following are compounds: H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, and difluoromethyl. (4) Under alkaline conditions, using a nickel-based catalyst, the 2-indolylquinazolinone derivative prepared in step (3) undergoes an intramolecular hydrogen-borrowing reaction to generate the target compound, evodiamine analogue and its derivatives, the molecular structural formula of which is as follows: , where R 1 and R 2 It is H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl.

5. The use of any of the evodiamine analogues described in claims 1–3 in the preparation of anticancer drugs.

6. The use of any of the evodiamine analogues according to claims 1–3 in the preparation of anti-colon cancer drugs.

7. The use of any of the evodiamine analogues according to claims 1–3 in the preparation of anti-bladder cancer drugs.

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