CN117800977A

CN117800977A - Preparation method and application of 2, 3-condensed quinazolinone compound

Info

Publication number: CN117800977A
Application number: CN202311796863.XA
Authority: CN
Inventors: 孔翔飞; 周超; 王桂霞; 冯柯; 王良风
Original assignee: Guilin University of Technology
Current assignee: Guilin University of Technology
Priority date: 2023-12-25
Filing date: 2023-12-25
Publication date: 2024-04-02

Abstract

The invention relates to a 2, 3-condensed quinazolinone derivative, a preparation method and application thereof, wherein the 2, 3-quinazolinone derivative is synthesized by a simple method, the yield is high, the production cost is low, when the concentration of LPS is 1 mu m, the release inhibition capability of compounds 1e and 1f is better than that of anti-inflammatory drugs indomethacin and rutaecarpine when the concentration of LPS is 1 mu m, 1g and 1q are equivalent to indomethacin, and 1w and 1m are equivalent to rutaecarpine; the cytoxic effect of the compounds 1e,1f,1g,1q and 1m with stronger NO release inhibiting ability on RAW264.7 cells is lower than that of anti-inflammatory drugs indomethacin and rutaecarpine; has obvious anti-inflammatory effect and low toxicity. Can be prepared into anti-inflammatory medicaments in various dosage forms, and has high medical value and wide market prospect.

Description

Preparation method and application of 2, 3-condensed quinazolinone compound

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a 2, 3-condensed quinazolinone compound, a preparation method and application thereof.

Background

Quinazolinones are an important class of nitrogen-containing heterocyclic compounds that are widely found in a variety of natural products and drug molecules. Has the functions of anti-inflammatory, anti-tumor, anticonvulsant, tranquilization, depressurization, vasodilation, bacteriostasis and the like, and has great development potential in the pharmaceutical and medical fields. It was found that quinazolinones substituted at both the C2 and N3 positions have anticancer properties. The core structural unit of the quinazolinone derivative contains oxygen atoms and nitrogen atoms, and can also coordinate with metal ions to generate a complex. In addition, the molecular structure of the fluorescent probe is a large conjugated system, has stronger fluorescence performance, and can be used for preparing fluorescent molecular probes. The hydrogen reaction, also called automatic transfer of hydrogen, is a novel organic synthesis method integrating oxidation reaction and hydrogenation reduction reaction. The hydrogen-assisted reaction is derived from a metal-catalyzed dehydrogenation reaction, in which a hydrogen donor molecule with lower reactivity is temporarily converted into an intermediate with higher reactivity (for example, alkane is converted into alkene, alcohol is converted into aldehyde or ketone, and amine is converted into imine) under metal catalysis, and the intermediate with higher reactivity is further reacted to obtain a compound containing double bonds such as c= C, C =n, and then the compound is reduced by metal hydride generated in the dehydrogenation step to generate single bonds such as C-C, C-N respectively. The reaction typically uses an alcohol or amine as the alkylating agent, producing water or ammonia, respectively, as the only by-product. Therefore, from the aspects of chemical synthesis and green environmental protection, the hydrogen-borrowing reaction has the characteristics of high efficiency, green, cleanness and the like, and is widely paid attention to people.

Disclosure of Invention

The invention aims to provide a 2, 3-condensed quinazolinone compound with good anti-inflammatory effect and low toxicity, and a preparation method and application thereof. The main synthesis steps are as follows: reacting isatoic anhydride serving as a raw material with 3-amino-1-propanol and the like to synthesize 3- (3-hydroxypropyl) -2- (1H-indol-2-yl) quinazoline-4 (3H) -ketone, and then reacting with hydrogen in molecules to generate a 2, 3-condensed quinazolinone compound. The synthetic route is shown in figure 1.

The invention also provides application of the 2, 3-condensed quinazolinone compound in preparing anti-inflammatory drugs.

According to the invention, a simple method is used for synthesizing a 2, 3-condensed quinazolinone derivative, when the concentration of LPS is 1 mu g/mL and the concentration of LPS is 5 mu m, the release inhibition capacity of compounds 1e and 1f is better than that of anti-inflammatory drugs indomethacin and rutaecarpine, 1g and 1q are equivalent to that of indomethacin, and 1w and 1m are equivalent to that of rutaecarpine; the cytoxic effect of the compounds 1e,1f,1g,1q and 1m with stronger NO release inhibiting ability on the mouse macrophage RAW264.7 is lower than that of the anti-inflammatory drugs indomethacin and rutaecarpine; the anti-inflammatory effect is obvious, the toxicity is small, and the test results of part of the compounds are shown in figures 2 and 3. The composition can be used for preparing anti-inflammatory medicaments in various dosage forms, and has high medical value and wide market prospect.

The invention has the advantages that:

1. the raw materials selected by the scheme are easy to obtain, and various 2, 3-condensed quinazolinone compounds are easy to prepare.

2. The proposal adopts alcohol as alkylating agent, only produces byproduct water, and has the characteristics of green and high atom economy.

3. The 2, 3-condensed quinazolinone compound synthesized by the scheme has obvious anti-inflammatory effect and low toxicity, and can be used for preparing anti-inflammatory drugs in various dosage forms.

Drawings

FIG. 1 is a reaction scheme for preparing 2, 3-fused quinazolinone compounds of the present invention

FIG. 2 partial Compound action NO Release from RAW264.7 cells

FIG. 3 survival of RAW264.7 cells with partial Compound

Detailed Description

Any feature disclosed in this specification (including any accompanying claims, abstract) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. That is, each feature is one example only of a generic series of equivalent or similar features, unless expressly stated otherwise.

In the embodiments to be described below, ¹ the internal standard at the time of H NMR testing was Tetramethylsilane (TMS).

Example 1:

the reaction steps are as follows:

1. synthesis of Compound 1a

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 6-methyl isatoic anhydride 2a (1 mmol,177.2 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at ambient temperature for 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), 110.2. 110.2 mg yellow oily compound 3a (yield 53%).

Under electromagnetic stirring, compound 3a (0.6 mmol,124.3 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) are sequentially added into a 100 mL round bottom flask, after reaction at normal temperature under the protection of nitrogen for 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the condition of ice water bath, the reaction is carried out again for 0.5H, then the ice water bath is removed for continuous reaction for 4H, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to afford 185 mg as a tan powder compound 4a (93% yield).

Under electromagnetic stirring, compound 4a (0.3 mmol,100 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos, 0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) were added to a vial, the reaction was sealed at 165℃for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), to give 45.4. 45.4 mg yellow powdery compound 1a (yield 48%). ¹ H NMR （500 MHz，DMSO） δ 7.68 （t，J = 8.5 Hz， 3H），7.54 （d，J = 8.5 Hz，1H），7.30 （t，J = 8.0 Hz，2H），7.13 （d，J = 13.0 Hz，2H），4.44 （t，J = 7.0 Hz，2H），4.01 （t，J = 7.0 Hz，2H），2.84 （s，3H），2.31–2.26 （m，2H）。

2. Synthesis of Compound 1b

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 3-methylindole anhydride 2b (1 mmol,177.2 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at ambient temperature for 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 151.6 mg as yellow powder compound 3b (yield 73%).

Under electromagnetic stirring, compound 3b (0.6 mmol,124.3 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) were sequentially added to a 100 mL round bottom flask, after reaction at room temperature under nitrogen protection of 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) was added under ice water bath, the reaction was again carried out for 0.5H, then the ice water bath was removed to continue the reaction for 4H, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 170.8 mg as a brown powder compound 4b (yield 85%).

Under electromagnetic stirring, compound 4b (0.3 mmol,100 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) were added into a tube-sealed reaction flask, the reaction was sealed at 165℃for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1) to give 60 mg as yellow powder compound 1b (yield 63%). ¹ H NMR （500 MHz，DMSO） δ 8.03 （d，J = 8.0 Hz，1H），7.72–7.66 （m，3H），7.43 （t，J = 7.5 Hz，1H），7.30 （t，J = 7.5 Hz，1H），7.18 （s，1H），7.13 （t，J = 7.5 Hz，1H），4.44 （t，J = 7.0 Hz，2H），4.06 （t，J = 6.5 Hz，2H），2.58 （s，3H），2.32–2.27 （m，2H）。

3. Synthesis of Compound 1c

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 3-methoxyisatoic anhydride 2c (1 mmol,0.1932 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at ambient temperature for 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), giving 207 mg as yellow oily compound 3c (93% yield).

Under electromagnetic stirring, compound 3c (0.6 mmol,133.9 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) were sequentially added to a 100 mL round bottom flask, after reaction at room temperature under nitrogen protection of 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) was added under ice water bath, the reaction was again carried out for 0.5H, then the ice water bath was removed to continue the reaction for 4H, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), to give 184.6 mg as a brown powder compound 4c (yield 88%).

Compound 4c (0.3 mmol, 7. 104.7 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N-dimethylformamide (2 mL) were added in sequence to a tube-sealed reaction flask under electromagnetic stirring, the reaction was sealed at 165 ℃ for 24 h, and the crude product was purified by column chromatography over silica gel (eluent: V _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), to give 37.7. 37.7 mg as a tan powder compound 1c (yield 38%). ¹ H NMR （500 MHz，DMSO） δ 7.74 （d，J = 8.0 Hz，1H），7.71 （d，J = 8.0 Hz，1H），7.67 （d，J = 8.5 Hz，1H），7.49 （t，J = 8.0 Hz，1H），7.40 （d，J = 8.0 Hz，1H），7.30 （t，J = 7.5 Hz，1H），7.13 （d，J = 6.5 Hz，2H），4.43 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），3.94 （s，3H），2.31–2.26 （m，2H）。

4. Synthesis of Compound 1d

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) are added into a 100 mL round bottom flask in sequence under electromagnetic stirring, 4- (trifluoromethyl) isatoic anhydride 2d (1 mmol,231.1 mg) is slowly added under the ice-water bath condition, the ice-water bath is removed after 30 min, the reaction is carried out at normal temperature 4h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 185.7. 185.7 mg as a white powder compound 3d (yield 71%).

Under electromagnetic stirring, adding 3d (0.6 mmol,157.3 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), to give 188.1. 188.1 mg as a brown powder compound 4d (yield 81%).

Under electromagnetic stirring, adding 4d (0.3 mmol,116.2 mg), ruthenium (0.015 mmol,14.4 mg) tri (triphenylphosphine) chloride, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent): V _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 46 mg as a tan powder compound 1d (41% yield). ¹ H NMR （500 MHz，DMSO） δ 8.38 （d，J = 8.5 Hz，1H），8.06 （s，1H），7.85 （d，J = 8.5 Hz，1H），7.73–7.68 （m，2H），7.32 （t，J = 7.5 Hz，1H），7.21 （s，1H），7.14 （t，J = 7.5 Hz，1H），4.49 （t，J = 6.5 Hz，2H），4.07 （t，J = 6.5 Hz，2H），2.34–2.29 （m，2H）。

5. Synthesis of Compound 1e

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 5-methylidene anhydride 2e (1 mmol,231.1 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at room temperature for 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 185.7. 185.7 mg as a white powder compound 3e (yield 71%).

Under electromagnetic stirring, sequentially adding 3e (0.6 mmol,157.3 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 188.1. 188.1 mg as brown powder compound 4e (yield 81%).

Compound 4e (0.3 mmol,116.2 mg), ruthenium (0.015 mmol,14.4 mg) tris (triphenylphosphine) chloride, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) were sequentially stirred electromagneticallyAdding N, N-dimethylformamide (2 mL) into a tube-sealed reaction bottle, sealing at 165 deg.C for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 46 mg as a tan powder compound 1e (41% yield). ¹ H NMR （500 MHz，DMSO） δ 8.38 （d，J = 8.5 Hz，1H），8.06 （s，1H），7.85 （d，J = 8.5 Hz，1H），7.73–7.68 （m，2H），7.32 （t，J = 7.5 Hz，1H），7.21 （s，1H），7.14 （t，J = 7.5 Hz，1H），4.49 （t，J = 6.5 Hz，2H），4.07 （t，J = 6.5 Hz，2H），2.34–2.29 （m，2H）。

6. Synthesis of Compound 1f

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 5-methoxyisatoic anhydride 2f (1 mmol, 193.2 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at ambient temperature for 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 188.26 mg as a white powder compound 3f (yield 84%).

Under electromagnetic stirring, sequentially adding 3f (0.6 mmol,133.9 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 129 mg as brown powder compound 4f (yield 72%).

Compound 4f (0.3 mmol,104.7 mg), tris (triphenylphosphine) was sequentially stirred electromagnetically) Ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) are added into a tube-sealing reaction bottle, the reaction is sealed at 165 ℃ for 24 h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 54.6. 54.6 mg as a tan powder compound 1f (55% yield). ¹ H NMR （500 MHz，DMSO） δ 7.71–7.65 （m，3H），7.57 （d，J = 3.0 Hz，1H），7.47–7.45 （m，1H），7.29 （t，J = 7.5 Hz，1H），7.14–7.09 （m，2H），4.43 （t，J = 7.0 Hz，2H），4.06 （t，J = 6.5 Hz，2H），3.90 （s，3H），2.31–2.26 （m，2H）。

7. Synthesis of Compound 1g

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) are added into a 100 mL round bottom flask in sequence under electromagnetic stirring, 2g (1 mmol, 181.1 mg) of 5-fluoroisatoic anhydride is slowly added under the ice-water bath condition, the ice-water bath is removed after 30 min, the reaction is carried out at normal temperature for 4h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 161.1. 161.1 mg as yellow powder compound 3g (yield 76%).

Under electromagnetic stirring, 3g (0.6 mmol,127.3 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) are sequentially added into a 100 mL round bottom flask, after reaction at normal temperature under the protection of nitrogen for 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the ice-water bath condition, the reaction is carried out again for 0.5H, then the ice water bath is removed for continuing the reaction for 4H, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), to give 196.2. 196.2 mg brown powdery compound 4g (yield 97%).

Under electromagnetic stirring, 4g (0.3 mmol,101.1 mg) of the compound, ruthenium (0.015 mmol,14.4 mg) chloride, 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) are added into a tube-sealing reaction bottle in sequence, the mixture is subjected to a sealed reaction at 165 ℃ for 24 h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 56.5. 56.5 mg tan powder compound 1g (yield 59%). ¹ H NMR （500 MHz，DMSO） δ 8.13 （s，1H），7.88 （d，J = 8.5 Hz，1H），7.76 （d，J = 8.5 Hz，1H），7.73–7.64 （m，2H），7.31 （t，J = 8.0 Hz，1H），7.18 （s，1H），7.13 （t，J = 7.5 Hz，1H），4.46 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），2.33–2.27 （m，2H）。

8. Synthesis of Compound 1h

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 5-chloroisatoic anhydride (1 mmol,197.6 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at ambient temperature 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 148 mg as yellow crystalline compound 3h (yield 65%).

Under electromagnetic stirring, sequentially adding 3H (0.6 mmol,136.8 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (washingStripping agent V _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 192.8 mg as a brown powder compound 4h (91% yield).

Under electromagnetic stirring, adding the compound 4h (0.3 mmol,105.9 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 42.2. 42.2 mg as a tan powder compound 1h (42% yield). ¹ H NMR （500 MHz，DMSO） δ 11.07 （s，1H），7.83 （s，1H），7.62 （d，J = 7.0 Hz，1H），7.47 （d，J = 7.5 Hz，1H），7.36 （d，J = 8.0 Hz，1H），7.12 （t，J = 7.5 Hz，1H），7.02 （d，J = 8.0 Hz，2H），6.18 （s，1H），4.70–4.53 （m，1H），3.36 （s，3H），3.24–3.21 （m，1H），2.95 （s, 3H）。

9. Synthesis of Compound 1i

Under electromagnetic stirring, compound 3f (0.6 mmol,136.8 mg), 5-methoxy-1H-indole-2-carbaldehyde (0.9 mmol,157.6 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) are added into a 100 mL round bottom flask, after reaction at normal temperature under the protection of nitrogen gas of 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the condition of ice water bath, the reaction is carried out again for 0.5H, then the ice water bath is removed for continuous reaction for 4H, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 213 mg as a tan powder compound 4i (94% yield).

Compound 4i (0.3 mmol,113.8 mg), tris (triphenylphosphine) ruthenium chloride (0) was sequentially stirred electromagnetically015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) were added to a tube-sealed reaction flask, the reaction was sealed at 165℃for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 35.5. 35.5 mg tan powder compound 1i (33% yield) was obtained. ¹ H NMR （500 MHz，DMSO） δ 7.69 （d，J = 9.0 Hz，1H），7.62–7.51 （m，2H），7.47–7.44 （m，1H），7.15 （s，1H），7.02 （s，1H），6.93 （d，J = 9.0 Hz，1H），4.38 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），3.90 （s，3H），3.79 （s，3H），2.30–2.25 （m，2H）。

10. Synthesis of Compound 1j

Under electromagnetic stirring, compound 3e (0.6 mmol,124.9 mg), 5-methoxy-1H-indole-2-carbaldehyde (0.9 mmol,157.6 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) are sequentially added into a 100 mL round bottom flask, after reaction at normal temperature under the protection of nitrogen gas of 4H, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the ice-water bath condition, the reaction is carried out again for 0.5H, then the ice-water bath is removed for continuous reaction for 4H, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 187.4. 187.4 mg as a tan powder compound 4j (86% yield).

Under electromagnetic stirring, adding the compound 4j (0.3 mmol,108.9 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle in turn, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloro-sMethane} : V _{Petroleum ether} =3:1) to give 33 mg as a tan powder compound 1j (33% yield). ¹ H NMR （500 MHz，DMSO） δ 7.98 （s，1H），7.67 （d，J = 8.5 Hz，1H），7.63 （d，J = 8.0 Hz，1H），7.58 （d，J = 9.0 Hz，1H），7.16 （s，1H），7.04 （s，1H），6.94 （d，J = 9.0 Hz，1H），4.39 （t，J = 7.0 Hz，2H），4.04 （t，J = 6.5 Hz，2H），3.79 （s，3H），2.48 （s，3H），2.27 （t，J = 6.5 Hz，2H）。

11. Synthesis of Compound 1k

Under electromagnetic stirring, sequentially adding 3f (0.6 mmol,133.9 mg), 6-chloro-1H-indole-2-carbaldehyde (0.9 mmol,161.6 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 202 mg as a tan powder compound 4k (87% yield).

Under electromagnetic stirring, adding the compound 4k (0.3 mmol,108.9 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle in turn, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1) to give 57 mg as a tan powder compound 1k (yield 52%). ¹ H NMR （500 MHz，DMSO） δ 7.86 （s，1H），7.69 （d，J = 8.5 Hz，2H），7.57 （d，J = 3.0 Hz，1H），7.47–7.45 （m，1H），7.12 （d，J = 6.5 Hz，2H），4.43 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），3.90 （s，3H），2.30–2.25 （m，2H）。

12. Synthesis of Compound 1l

Under electromagnetic stirring, sequentially adding 3e (0.6 mmol,124.9 mg), 6-chloro-1H-indole-2-carbaldehyde (0.9 mmol,161.6 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), to give 196 mg as a tan powder compound 4l (89% yield).

Under electromagnetic stirring, adding 4l (0.3 mmol,110.1 mg), ruthenium (0.015 mmol,14.4 mg) tri (triphenylphosphine) chloride, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), giving 60.7. 60.7 mg as a tan powder compound 1l (58% yield). ¹ H NMR （500 MHz，DMSO） δ 7.99 （s，1H），7.87 （s，1H），7.74–7.66 （m，2H），7.64 （d，J = 8.0 Hz，1H），7.19–7.08 （m，2H），4.44 （t，J = 7.0 Hz，2H），4.04（t，J = 6.5 Hz, 2H），2.48（s，3H），2.29–2.25（m，2H）。

13. Synthesis of Compound 1m

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) are added into a 100 mL round bottom flask in sequence under electromagnetic stirring, isatoic anhydride 2m (1 mmol,163 mg) is slowly added under the ice water bath condition, the ice water bath is removed after 30 min, the reaction is carried out at normal temperature 4h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), giving 155.3. 155.3 mg as a white powder compound 3m (88% yield).

Under electromagnetic stirring, adding 3m (0.6 mmol,116.5 mg), 6-chloro-1H-indole-2-carbaldehyde (0.9 mmol,161.6 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), to give 184.3. 184.3 mg as a tan powder compound 4m (yield 87%).

Under electromagnetic stirring, adding 4m (0.3 mmol,105.9 mg), ruthenium (0.015 mmol,14.4 mg) tri (triphenylphosphine) chloride, 4, 5-bis (diphenylphosphine) -9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), to give 61.3. 61.3 mg as a tan powder compound 1m (yield 61%). ¹ H NMR （500 MHz，DMSO） δ 7.99 （s，1H），7.87 （s，1H），7.74–7.66 （m，2H），7.64 （d，J = 8.0 Hz，1H），7.19–7.08 （m，2H），4.44 （t，J = 7.0 Hz，2H），4.04 （t，J = 6.5 Hz，2H），2.48 （s，3H），2.29–2.25 （m，2H）。

14. Synthesis of Compound 1n

Under electromagnetic stirring, adding 3m (0.6 mmol,116.5 mg), 6-bromo-1H-indole-2-carbaldehyde (0.9 mmol,200 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at room temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 197.73 mg as a tan powder compound 4n (83% yield).

Under electromagnetic stirring, adding the compound 4N (0.3 mmol,119.1 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle in turn, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 48.9. 48.9 mg tan powder compound 1n (53% yield) was obtained. ¹ H NMR （500 MHz，DMSO） δ 8.20 （d，J = 8.0 Hz，1H），8.02 （s，1H），7.86 （t，J = 7.5 Hz，1H），7.74 （d，J = 8.0 Hz，1H），7.66 （d，J = 8.5 Hz，1H），7.57 （t，J = 7.5 Hz，1H），7.25 （d，J = 8.5 Hz，1H），7.18 （s，1H），4.46 （s，2H），4.05 （t，J = 6.5 Hz，2H），2.31–2.27 （m，2H）。

15. Synthesis of Compound 1o

Compound 3e (0.6 mmol,124.9 mg), 5-methyl-1H-indole-2-carbaldehyde (0.9 mmol, 14) was successively stirred electromagnetically3.2 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg), tetrahydrofuran (30 mL) are added into a 100 mL round bottom flask, after 4h reaction at normal temperature under the protection of nitrogen, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the ice water bath condition, 0.5 h reaction is carried out again, then the ice water bath is removed to continue the reaction for 4h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), giving 183.3. 183.3 mg as a tan powder compound 4o (88% yield).

Under electromagnetic stirring, adding 4o (0.3 mmol,104.1 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 54.3 mg as a tan powder compound 1o (55% yield). ¹ H NMR （500 MHz，DMSO） δ 7.98 （s，1H），7.67 （d，J = 8.0 Hz，1H），7.63 （d，J = 8.0 Hz，1H），7.55 （d，J = 8.5 Hz，1H），7.45 （s，1H），7.12 （d，J = 8.5 Hz，1H），7.04 （s，1H），4.39 （t，J = 7.0 Hz，2H），4.03 （t，J = 6.5 Hz，2H），2.48 （s，3H），2.40 （s，3H），2.29–2.24 （m，2H）。

16. Synthesis of Compound 1p

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added to a 100 mL round bottom flask in sequence under electromagnetic stirring, 4-methyl isatoic anhydride 2p (1 mmol,177.2 mg) was slowly added under ice-water bath conditions, the ice-water bath was removed after 30 min, the reaction was performed at room temperature, 4h was performed, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), yielding 176.9 mg whiteCompound 3p was a coloured powder (85% yield).

Under electromagnetic stirring, sequentially adding 3p (0.6 mmol,124.9 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 181.9 mg as a tan powder compound 4p (91% yield).

Under electromagnetic stirring, compound 4p (0.3 mmol,100 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) were added to a tube-sealed reaction flask, the reaction was sealed at 165℃for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 38.8. 38.8 mg tan powder compound 1p (41% yield) was obtained. ¹ H NMR （500 MHz，DMSO） δ 8.08 （d，J = 8.0 Hz，1H），7.71–7.67 （m，2H），7.55 （s，1H），7.39 （d，J = 8.0 Hz，1H），7.30 （t，J = 7.5 Hz，1H），7.14 （d，J = 9.5 Hz，2H），4.44 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），2.49 （s，3H），2.32–2.26 （m，2H）。

17. Synthesis of Compound 1q

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 mmol,0.2 mL) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, 4-chloroisatoic anhydride 2q (1 mmol,197 mg) was slowly added under ice water bath conditions, the ice water bath was removed after 30 min,normal temperature reaction 4h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3) to give 187 mg as a white powder compound 3q (yield 82%).

Under electromagnetic stirring, sequentially adding 3q (0.6 mmol,136.8 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round-bottomed flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 197 mg as a tan powder compound 4q (93% yield).

Under electromagnetic stirring, adding 4q (0.3 mmol,106 mg), ruthenium (0.015 mmol,14.4 mg) tri (triphenylphosphine) chloride, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealed reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), to give 49.4. 49.4 mg as a tan powder compound 1q (yield 49%). ¹ H NMR （500 MHz，DMSO） δ 8.17 （d，J = 8.5 Hz，1H），7.78 （d，J = 2.0 Hz，1H），7.71–7.67 （m，2H），7.59–7.56 （m，1H），7.31 （t，J = 7.5 Hz，1H），7.18 （s，1H），7.13 （t，J = 7.5 Hz，1H），4.46 （t，J = 7.0 Hz，2H），4.04 （t，J = 6.5 Hz，2H），2.29 （t，J = 6.5 Hz，2H）。

18. Synthesis of Compound 1r

Acetonitrile (30 mL), 3-amino-1-propanol (1.5 m) were sequentially stirred electromagneticallymol, 0.2. 0.2 mL) was added to a 100 mL round bottom flask, 4-methoxyisatoic anhydride 2r (1 mmol,193 mg) was slowly added under ice water bath conditions, the ice water bath was removed after 30 min, the reaction was performed at ambient temperature 4h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:3), to give 197 mg as a white powder compound 3r (yield 88%).

Under electromagnetic stirring, sequentially adding 3r (0.6 mmol,134.5 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 169.7. 169.7 mg as a tan powder compound 4r (yield 81%).

Under electromagnetic stirring, adding the compound 4r (0.3 mmol,105 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealed reaction bottle in sequence, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), giving 37.7. 37.7 mg as a tan powder compound 1r (38% yield). ¹ H NMR （500 MHz，DMSO） δ 8.10 （t，J = 10.0 Hz，1H），7.73–7.67 （m，2H），7.30 （t，J = 8.0 Hz，1H），7.21–7.09 （m，4H），4.44 （t，J = 8.5 Hz，2H），4.03 （t，J = 8.5 Hz，2H），3.96–3.88 （m，3H），2.33–2.23 （m，2H）。

19. Synthesis of Compound 1s

Under electromagnetic stirring, adding 3m (0.6 mmol,116.5 mg), 4-methoxy-1H-indole-2-carbaldehyde (0.9 mmol,157.7 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition after reacting at normal temperature of 4H, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 190.63 mg as a tan powder compound 4s (91% yield).

Under electromagnetic stirring, adding the compound 4s (0.3 mmol,104.7 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle in turn, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 54.6. 54.6 mg as a tan powder compound 1s (yield 55%). ¹ H NMR （500 MHz，DMSO） δ 8.20 （d，J = 8.0 Hz，1H），8.02 （s，1H），7.86 （t，J = 7.5 Hz，1H），7.74 （d，J = 8.0 Hz，1H），7.66 （d，J = 8.5 Hz，1H），7.57 （t，J = 7.5 Hz，1H），7.25 （d，J = 8.5 Hz，1H），7.18 （s，1H），4.46 （s，2H），4.05 （t，J = 6.5 Hz，2H），2.31–2.27 （m，2H）。

20. Synthesis of Compound 1t

Compound 3m (0.6 mmol,116.5 mg), 5-methoxy-1H-indole-2-carbaldehyde (0.9 mmol,157.7 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg), tetrahydrofuran (3)0.0 mL) is added into a 100 mL round bottom flask, after 4h of normal temperature reaction under the protection of nitrogen, 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) is added under the ice-water bath condition to react again with 0.5 h, then the ice-water bath is removed to continue the reaction for 4h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2) to give 196.92 mg as a tan powder compound 4t (94% yield).

Under electromagnetic stirring, adding the compound 4t (0.3 mmol,104.7 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle in sequence, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), to give 51.7. 51.7 mg as a tan powder compound 1t (yield 52%). ¹ H NMR （500 MHz，DMSO） δ 8.19 （d，J = 8.0 Hz，1H），7.85 （t，J = 7.5 Hz，1H），7.73 （d，J = 8.0 Hz，1H），7.59–7.54 （m，2H），7.17 （s，1H），7.07 （s，1H），6.95 （d，J = 9.0 Hz，1H），4.41 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），3.79 （s，3H），2.31–2.26 （m，2H）。

21. Synthesis of Compound 1u

Under electromagnetic stirring, sequentially adding 3m (0.6 mmol,116.5 mg), 5-chloro-1H-indole-2-carbaldehyde (0.9 mmol,161.1 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), 182.2. 182.2 mg as a tan powder compound 4u (86% yield).

Under electromagnetic stirring, adding 4u (0.3 mmol,105.9 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg) and N, N-dimethylformamide (2 mL) into a tube-sealing reaction bottle, sealing at 165 ℃ for reaction 24 h, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 58.3 mg as a tan powder compound 1u (58% yield). ¹ H NMR （500 MHz，DMSO） δ 8.19 （d，J = 8.0 Hz，1H），7.86 （t，J = 7.5 Hz，1H），7.80–7.68 （m，3H），7.57 （t，J = 7.5 Hz，1H），7.30 （d，J = 9.0 Hz，1H），7.15 （s，1H），4.46 （t，J = 7.0 Hz，2H），4.05 （t，J = 6.5 Hz，2H），2.31–2.26 （m，2H）。

22. Synthesis of Compound 1v

Under electromagnetic stirring, sequentially adding 3m (0.6 mmol,116.5 mg), 5-methyl-1H-indole-2-carbaldehyde (0.9 mmol,143.2 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuing to react for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), giving 178 mg as a tan powder compound 4v (89% yield).

Under electromagnetic stirring, compound 4v (0.3 mmol,100 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethyloxaAnthracene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) are added into a tube-sealed reaction flask, the reaction is sealed at 165 ℃ for 24 h, and the crude product is purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 49.2. 49.2 mg tan powder compound 1v (yield 52%). ¹ H NMR （500 MHz，DMSO） δ 8.19 （d，J = 8.0 Hz，1H），7.85 （t，J = 7.5 Hz，1H），7.73 （d，J = 8.0 Hz，1H），7.56 （d，J = 7.5 Hz，2H），7.47 （s，1H），7.13 （d，J = 8.5 Hz，1H），7.07 （s，1H），4.41 （t，J = 7.0 Hz，2H），4.04 （t，J = 6.5 Hz，2H），2.40 （s，3H），2.30–2.25 （m，2H）。

22. Synthesis of Compound 1w

Under electromagnetic stirring, sequentially adding 3m (0.6 mmol,116.5 mg), 1H-indole-2-carbaldehyde (0.9 mmol,130.5 mg), anhydrous magnesium sulfate (1.32 mmol,158.9 mg), paratoluenesulfonic acid hydrate (0.12 mmol,22.8 mg) and tetrahydrofuran (30 mL) into a 100 mL round bottom flask, reacting at normal temperature under nitrogen protection for 4H, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.48 mmol,108.9 mg) under ice water bath condition, reacting again for 0.5H, removing ice water bath, continuously reacting for 4H, purifying the crude product by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _Methanol =200:2), giving 172 mg as a tan powder compound 4w (80% yield).

Under electromagnetic stirring, compound 4w (0.3 mmol,95.7 mg), tris (triphenylphosphine) ruthenium chloride (0.015 mmol,14.4 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.03 mmol,17.4 mg), cesium carbonate (0.6 mmol,195.5 mg), N, N-dimethylformamide (2 mL) were added to a tube-sealed reaction flask, the reaction was sealed at 165℃for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V) _{Dichloromethane (dichloromethane)} : V _{Petroleum ether} =3:1), 53 is obtainedmg of compound 1w as a tan powder (59% yield). ¹ H NMR （500 MHz，DMSO） δ 8.20 （d，J = 6.5 Hz，1H），7.86 （t，J = 7.0 Hz，1H），7.74 （d，J = 8.0 Hz，1H），7.67–7.71 （m，2H），7.56 （t，J = 7.5 Hz，1H），7.30 （t，J = 8.0 Hz，1H），7.17 （s，1H），7.13 （t，J = 7.5 Hz，1H），4.45 （t，J = 7.0 Hz，2H），4.06 （t，J = 6.5 Hz，2H），2.30 （t，J = 6.5 Hz，2H）。

Part of the above target products were tested for anti-inflammatory activity. Anti-inflammatory activity was determined by determining the inhibition of Lipopolysaccharide (LPS) -induced release of mouse macrophage RAW264.7 NO by the compound using the Griess method. The results of the experiment for inhibiting lipopolysaccharide-induced release of NO by mouse macrophage RAW264.7 with a part of the target compounds are shown in Table 1. The effect of the target compound on RAW264.7 cell viability at a concentration of 5 μm is shown in table 2.

TABLE 1

TABLE 2

From the above test results, when the concentration of LPS is 1 μg/mL, the release inhibition ability of the compounds 1e and 1f is better than that of the anti-inflammatory drugs indomethacin and rutaecarpine, while 1g and 1q are equivalent to that of indomethacin and 1w and 1m are equivalent to rutaecarpine; the cytoxic effect of the compounds 1e,1f,1g,1q and 1m with stronger NO release inhibiting ability on RAW264.7 cells is lower than that of anti-inflammatory drugs indomethacin and rutaecarpine; has obvious anti-inflammatory effect and low toxicity.

While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims

1. A2, 3-condensed quinazolinone compound is characterized in that the C2 and N3 positions of the compound on quinazolinone are simultaneously substituted, and the structural general formula is as follows:wherein R is ¹ Or R is ² Can be H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl and difluoromethyl.

2.2, 3-fused quinazolinone compound according to claim 1, characterized in that R ¹ Or R is ² Can be H, methoxy, ethoxy, methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl.

3.2, 3-fused quinazolinone compound according to claim 1, characterized in that R ¹ Can be H, methoxy, methyl, fluorine, chlorine, trifluoromethyl; r is R ² Can be H, methoxy, methyl, chlorine and bromine.

4. A process for the preparation of a 2, 3-fused quinazolinone compound according to any of claims 1-3, characterized by the specific steps of:

(1) Isatoic anhydride is used as a raw material to react with 1-amino-3-propanol to generate 2-amino-N- (3-hydroxypropyl) benzamide, and the molecular structural formula is as follows:wherein R is ¹ =h, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl;

(2) Reacting the 2-amino-N- (3-hydroxypropyl) benzamide prepared in step (1) with 1H-indole-2-carbaldehyde to produce 3- (3-hydroxypropyl) -2- (1H-indol-2-yl) quinazolin-4 (3H) schemeA ketone having the molecular structural formula:wherein R is ¹ = R ² =h, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl;

(3) Catalyzing the 3- (3-hydroxypropyl) -2- (1H-indol-2-yl) quinazolin-4 (3H) -one prepared in step (2) with tris (triphenylphosphine) ruthenium chloride to produce a 2, 3-fused quinazolinone compound having the following molecular structural formula:wherein R is ¹ = R ² =h, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl.

5. Use of a 2, 3-fused quinazolinone compound according to any of claims 1-3 for the preparation of an anti-inflammatory agent.