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

Abstract

A 2,3-fused quinazolinone derivative, its preparation method, and application are disclosed. A 2,3-quinazolinone derivative was synthesized using a simple method with high yield and low production cost. At a concentration of 5 µM and an LPS concentration of 1 µg / mL, compounds 1e and 1f exhibited superior NO release inhibition compared to the anti-inflammatory drugs indomethacin and evodiamine, while compounds 1g and 1q were comparable to indomethacin, and compounds 1w and 1m were comparable to evodiamine. Compounds 1e, 1f, 1g, 1q, and 1m, which exhibited strong NO release inhibition, exhibited less cytotoxicity against RAW264.7 cells than the anti-inflammatory drugs indomethacin and evodiamine. The derivative exhibited significant anti-inflammatory effects and low toxicity. The derivative can be formulated into various dosage forms of anti-inflammatory drugs, possessing high medical value and broad market prospects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a 2,3-fused quinazolinone compound, a preparation method and application thereof. Background Art

[0002] Quinazolinones are an important class of nitrogen-containing heterocyclic compounds, found in a wide variety of natural products and pharmaceutical molecules. They exhibit anti-inflammatory, antitumor, anticonvulsant, sedative, antihypertensive, vasodilatory, and antibacterial properties, showing great potential in the pharmaceutical and medical fields. Studies have shown that quinazolinones substituted at both the C2 and N3 positions exhibit anticancer properties. Quinazolinone derivatives contain oxygen and nitrogen atoms in their core structural units and can form complexes with metal ions. Furthermore, their large conjugated molecular structures exhibit strong fluorescence, making them useful for the preparation of fluorescent molecular probes. The hydrogen borrowing reaction, also known as hydrogen autotransfer, is a novel organic synthesis method that combines oxidation and hydrogenation reduction reactions. Hydrogen borrowing reactions are derived from metal-catalyzed dehydrogenation reactions. Under metal catalysis, less reactive hydrogen donor molecules are temporarily converted into more reactive intermediates (e.g., alkanes to alkenes, alcohols to aldehydes or ketones, and amines to imines). The more reactive intermediates further react to form compounds containing double bonds, such as C=C and C=N. These compounds are then reduced by the metal hydride produced in the dehydrogenation step to form single bonds, such as C=C and C=N, respectively. These reactions typically use alcohols or amines as alkylating agents, producing water or ammonia as the sole byproduct, respectively. Therefore, from the perspectives of chemical synthesis and environmental protection, hydrogen borrowing reactions have attracted widespread attention due to their high efficiency, greenness, and cleanliness. Summary of the Invention

[0003] The present invention aims to provide a 2,3-fused quinazolinone compound with excellent anti-inflammatory effects and low toxicity, as well as its preparation method and application. The main synthesis steps are as follows: isatoic anhydride is used as a raw material, reacted with 3-amino-1-propanol and the like to synthesize 3-(3-hydroxypropyl)-2-(1H-indol-2-yl)quinazolin-4(3H)-one, and then an intramolecular hydrogen-borrowing reaction is used to generate the 2,3-fused quinazolinone compound. The synthesis route is shown in the attached figure. Figure 1 shown.

[0004] The present invention also provides an application of a 2,3-fused quinazolinone compound in the preparation of anti-inflammatory drugs.

[0005] The present invention synthesized a 2,3-fused quinazolinone derivative using a simple method. When the concentration was 5 μM and the LPS concentration was 1 μg / mL, compounds 1e and 1f had better NO release inhibition abilities than the anti-inflammatory drugs indomethacin and evodiamine, while compounds 1g and 1q were comparable to indomethacin, and compounds 1w and 1m were comparable to evodiamine. Compounds 1e, 1f, 1g, 1q, and 1m, which had stronger NO release inhibition abilities, had lower cytotoxic effects on mouse macrophage RAW264.7 cells than the anti-inflammatory drugs indomethacin and evodiamine. The compounds had significant anti-inflammatory effects and minimal toxicity. The test results of some compounds are shown in the attached figure. Figure 2 and Figure 3 As shown. Therefore, it can be used to prepare anti-inflammatory drugs in various dosage forms, which has high medical value and broad market prospects.

[0006] The advantages of the present invention are:

[0007] 1. The raw materials used in this scheme are readily available and can be used to easily prepare a variety of 2,3-fused quinazolinone compounds.

[0008] 2. This scheme uses alcohol as an alkylating agent and only produces water as a by-product, which is green and highly atom-economical.

[0009] 3. The 2,3-fused quinazolinone compound synthesized in this scheme has obvious anti-inflammatory effect and low toxicity, and can be used to prepare anti-inflammatory drugs in various dosage forms. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The reaction formula for preparing the 2,3-fused quinazolinone compound of the present invention is

[0011] Figure 2 NO release in RAW264.7 cells under the action of some compounds

[0012] Figure 3 Survival rate of RAW264.7 cells under the action of some compounds DETAILED DESCRIPTION

[0013] Any feature disclosed in this specification (including any appended claims and abstract), unless otherwise stated, may be replaced by other equivalent or similar features. In other words, unless otherwise stated, each feature is only an example of a series of equivalent or similar features.

[0014] In the following examples, 1 Tetramethylsilane (TMS) was used as the internal standard in H NMR measurements.

[0015] Example 1:

[0016] The reaction steps are as follows:

[0017] 1 Synthesis of compound 1a

[0018]

[0019] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 6-Methylisatoic anhydride 2a (1 mmol, 177.2 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), affording 110.2 mg of compound 3a as a yellow oil (yield 53%).

[0020] Under electromagnetic stirring, compound 3a (0.6 mmol, 124.3 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 185 mg of brown powder compound 4a (yield 93%).

[0021] 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165°C for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 45.4 mg of yellow powder compound 1a (yield 48%). 1H 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).

[0022] 2 Synthesis of compound 1b

[0023]

[0024] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 3-Methylisatoic anhydride 2b (1 mmol, 177.2 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), affording 151.6 mg of yellow powdered compound 3b (yield 73%).

[0025] Under electromagnetic stirring, compound 3b (0.6 mmol, 124.3 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 170.8 mg of brown powdered compound 4b (yield 85%).

[0026] 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 60 mg of 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).

[0027] 3. Synthesis of compound 1c

[0028]

[0029] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 3-Methoxyisatoic anhydride 2c (1 mmol, 0.1932 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 =200:3), affording 207 mg of yellow oily compound 3c (yield 93%).

[0030] Under electromagnetic stirring, compound 3c (0.6 mmol, 133.9 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 184.6 mg of brown powdered compound 4c (yield 88%).

[0031] Under electromagnetic stirring, compound 4c (0.3 mmol, 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 37.7 mg of brown-yellow 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 = 7.0Hz, 2H), 4.05 (t, J = 6.5 Hz, 2H), 3.94 (s, 3H), 2.31–2.26 (m,2H).

[0032] 4 Synthesis of compound 1d

[0033]

[0034] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 4-(trifluoromethyl)isatoic anhydride 2d (1 mmol, 231.1 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 3), affording 185.7 mg of white powdered compound 3d (yield 71%).

[0035] Under electromagnetic stirring, compound 3d (0.6 mmol, 157.3 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 188.1 mg of brown powdered compound 4d (yield 81%).

[0036] Under electromagnetic stirring, compound 4d (0.3 mmol, 116.2 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 46 mg of brown-yellow powder compound 1d (yield 41%). 1H 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).

[0037] 5. Synthesis of compound 1e

[0038]

[0039] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 5-Methylisatoic anhydride 2e (1 mmol, 231.1 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), affording 185.7 mg of white powdered compound 3e (yield 71%).

[0040] Under electromagnetic stirring, compound 3e (0.6 mmol, 157.3 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 188.1 mg of brown powdered compound 4e (yield 81%).

[0041] Under electromagnetic stirring, compound 4e (0.3 mmol, 116.2 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 46 mg of brown-yellow powder compound 1e (yield 41%). 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).

[0042] 6 Synthesis of compound 1f

[0043]

[0044] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 5-Methoxyisatoic anhydride 2f (1 mmol, 193.2 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 =200: 3), affording 188.26 mg of white powdered compound 3f (yield 84%).

[0045] Under electromagnetic stirring, compound 3f (0.6 mmol, 133.9 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 129 mg of brown powdered compound 4f (yield 72%).

[0046] Under electromagnetic stirring, compound 4f (0.3 mmol, 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 54.6 mg of brown-yellow powder compound 1f (yield 55%). 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).

[0047] 7 Synthesis of compound 1g

[0048]

[0049] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 5-fluoroisatidic anhydride 2 g (1 mmol, 181.1 mg) was slowly added under ice-water bath conditions. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), to obtain 161.1 mg of yellow powder compound 3g (yield 76%).

[0050] Under electromagnetic stirring, compound 3g (0.6 mmol, 127.3 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 196.2 mg of brown powder compound 4g (yield 97%).

[0051] Under electromagnetic stirring, compound 4g (0.3 mmol, 101.1 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 56.5 mg of brown-yellow powder compound 1g (yield 59%). 1H 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).

[0052] 8 Synthesis of compound 1h

[0053]

[0054] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 5-chloroisatoic anhydride (1 mmol, 197.6 mg) was slowly added under ice-water bath conditions for 2 h. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 3), to obtain 148 mg of yellow crystalline compound 3h (yield 65%).

[0055] Under electromagnetic stirring, compound 3h (0.6 mmol, 136.8 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 192.8 mg of brown powder compound 4h (yield 91%).

[0056] Under electromagnetic stirring, compound 4h (0.3 mmol, 105.9 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 42.2 mg of brown powder compound 1h (yield 42%). 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).

[0057] 9 Synthesis of compound 1i

[0058]

[0059] 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 213 mg of brown-yellow powder compound 4i (yield 94%).

[0060] Under electromagnetic stirring, compound 4i (0.3 mmol, 113.8 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 35.5 mg of brown-yellow powder compound 1i (yield 33%). 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).

[0061] 10 Synthesis of compound 1j

[0062]

[0063] 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:2), affording 187.4 mg of brownish-yellow powder compound 4j (yield 86%).

[0064] Under electromagnetic stirring, compound 4j (0.3 mmol, 108.9 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 33 mg of brown-yellow powder compound 1j (yield 33%). 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).

[0065] 11 Synthesis of compound 1k

[0066]

[0067] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature under nitrogen protection for 4 h. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 202 mg of brown-yellow powder compound 4k (yield 87%).

[0068] Under electromagnetic stirring, compound 4k (0.3 mmol, 108.9 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 57 mg of brown-yellow 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).

[0069] 12 Synthesis of compound 11

[0070]

[0071] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 196 mg of brown-yellow powder compound 41 (yield 89%).

[0072] Under electromagnetic stirring, compound 4l (0.3 mmol, 110.1 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 60.7 mg of brown powder compound 11 (yield 58%). 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).

[0073] 13 Synthesis of compound 1m

[0074]

[0075] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. In an ice-water bath, 2 mL of isatoic anhydride (1 mmol, 163 mg) was slowly added. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 3), to obtain 155.3 mg of white powder compound 3m (yield 88%).

[0076] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 184.3 mg of brown powder compound 4m (yield 87%).

[0077] Under electromagnetic stirring, compound 4m (0.3 mmol, 105.9 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 61.3 mg of brown-yellow 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).

[0078] 14 Synthesis of compound 1n

[0079]

[0080] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 197.73 mg of brown-yellow powder compound 4n (yield 83%).

[0081] Under electromagnetic stirring, compound 4n (0.3 mmol, 119.1 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 48.9 mg of brown-yellow powder compound 1n (yield 53%). 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).

[0082] 15 Synthesis of compound 1o

[0083]

[0084] Under electromagnetic stirring, compound 3e (0.6 mmol, 124.9 mg), 5-methyl-1H-indole-2-carbaldehyde (0.9 mmol, 143.2 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), affording 183.3 mg of brown-yellow powder compound 4o (yield 88%).

[0085] Under electromagnetic stirring, compound 4o (0.3 mmol, 104.1 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 54.3 mg of brown powder compound 1o (yield 55%). 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).

[0086] 16 Synthesis of compound 1p

[0087]

[0088] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 4-Methylisatoic anhydride 2p (1 mmol, 177.2 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), affording 176.9 mg of white powdered compound 3p (yield 85%).

[0089] Under electromagnetic stirring, compound 3p (0.6 mmol, 124.9 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 181.9 mg of brown powder compound 4p (yield 91%).

[0090] 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 38.8 mg of brown-yellow powder compound 1p (yield 41%). 1H 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).

[0091] 17 Synthesis of compound 1q

[0092]

[0093] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 4-chloroisatoic anhydride 2q (1 mmol, 197 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 3), affording 187 mg of compound 3q as a white powder (yield 82%).

[0094] Under electromagnetic stirring, compound 3q (0.6 mmol, 136.8 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 197 mg of brown-yellow powder compound 4q (yield 93%).

[0095] Under electromagnetic stirring, compound 4q (0.3 mmol, 106 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 49.4 mg of brown 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).

[0096] 18 Synthesis of compound 1r

[0097]

[0098] Under electromagnetic stirring, acetonitrile (30 mL) and 3-amino-1-propanol (1.5 mmol, 0.2 mL) were added to a 100 mL round-bottom flask in sequence. 4-Methoxyisatoic anhydride 2r (1 mmol, 193 mg) was slowly added in an ice-water bath. After 30 min, the ice-water bath was removed and the reaction was carried out at room temperature for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200:3), affording 197 mg of white powdered compound 3r (yield 88%).

[0099] Under electromagnetic stirring, compound 3r (0.6 mmol, 134.5 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for another 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 169.7 mg of brown powder compound 4r (yield 81%).

[0100] Under electromagnetic stirring, 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 37.7 mg of brown powder compound 1r (yield 38%). 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).

[0101] 19 Synthesis of compound 1s

[0102]

[0103] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 190.63 mg of brown powder compound 4s (yield 91%).

[0104] Under electromagnetic stirring, compound 4s (0.3 mmol, 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 54.6 mg of brown-yellow 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).

[0105] 20 Synthesis of compound 1t

[0106]

[0107] Under electromagnetic stirring, 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 196.92 mg of brown powder compound 4t (yield 94%).

[0108] Under electromagnetic stirring, compound 4t (0.3 mmol, 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 51.7 mg of brown 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).

[0109] 21 Synthesis of compound 1u

[0110]

[0111] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 182.2 mg of brown powder compound 4u (yield 86%).

[0112] Under electromagnetic stirring, compound 4u (0.3 mmol, 105.9 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) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 58.3 mg of brown powder compound 1u (yield 58%). 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).

[0113] 22 Synthesis of compound 1v

[0114]

[0115] Under electromagnetic stirring, compound 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), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 178 mg of brown-yellow powder compound 4v (yield 89%).

[0116] 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-dimethylxanthene (0.03 mmol, 17.4 mg), cesium carbonate (0.6 mmol, 195.5 mg), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 49.2 mg of brown-yellow 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).

[0117] 22 Synthesis of compound 1w

[0118]

[0119] Under electromagnetic stirring, compound 3m (0.6 mmol, 116.5 mg), 1H-indole-2-carboxaldehyde (0.9 mmol, 130.5 mg), anhydrous magnesium sulfate (1.32 mmol, 158.9 mg), p-toluenesulfonic acid hydrate (0.12 mmol, 22.8 mg), and tetrahydrofuran (30 mL) were added to a 100 mL round-bottom flask in sequence. The mixture was reacted at room temperature for 4 h under nitrogen protection. 2,3-Dichloro-5,6-dicyanobenzoquinone (0.48 mmol, 108.9 mg) was then added in an ice-water bath and the reaction was continued for another 0.5 h. The ice-water bath was then removed and the reaction was continued for 4 h. The crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 甲醇 = 200: 2), to obtain 172 mg of brown powder compound 4w (yield 80%).

[0120] 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), and N,N-dimethylformamide (2 mL) were added to a sealed reaction bottle in sequence. The reaction was sealed at 165 °C for 24 h, and the crude product was purified by silica gel column chromatography (eluent: V 二氯甲烷 : V 石油醚 = 3: 1), to obtain 53 mg of brown-yellow powder compound 1w (yield 59%). 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 = 7.0Hz, 2H), 4.06 (t, J = 6.5 Hz, 2H), 2.30 (t, J = 6.5 Hz, 2H).

[0121] The anti-inflammatory activity of some of the target products was tested. The Griess assay was used to determine the inhibitory effect of the compounds on lipopolysaccharide (LPS)-induced NO release from RAW264.7 mouse macrophages. The results of the experiments on the inhibition of LPS-induced NO release by some of the target compounds in RAW264.7 mouse macrophages are shown in Table 1. The effects of the target compounds on RAW264.7 cell viability at a concentration of 5 μM are shown in Table 2.

[0122] Table 1

[0123]

[0124] Table 2

[0125]

[0126] The above test results show that when the concentration is 5 μM and the LPS concentration is 1 μg / mL, compounds 1e and 1f have better ability to inhibit NO release than the anti-inflammatory drugs indomethacin and evodiamine, while 1g and 1q are comparable to indomethacin, and 1w and 1m are comparable to evodiamine. The cytotoxic effects of compounds 1e, 1f, 1g, 1q, and 1m, which have stronger ability to inhibit NO release, on RAW264.7 cells are lower than those of the anti-inflammatory drugs indomethacin and evodiamine; they have obvious anti-inflammatory effects and low toxicity.

[0127] Although the present invention has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A 2,3-fused quinazolinone compound, characterized in that Its general structural formula is: , where R 1 and R 2 is selected from H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl; and R 1 and R 2 Not H at the same time.

2. The 2,3-fused quinazolinone compound according to claim 1, characterized in that R 1 or R 2 is H, methoxy, ethoxy, methyl, ethyl, fluorine, chlorine, bromine, or trifluoromethyl; and R 1 and R 2 Not H at the same time.

3. The 2,3-fused quinazolinone compound according to claim 1, characterized in that R 1 is H, methoxy, methyl, fluorine, chlorine, or trifluoromethyl; R 2 is H, methoxy, methyl, chlorine, or bromine; and R 1 and R 2 Not H at the same time.

4. The method for preparing a 2,3-fused quinazolinone compound according to any one of claims 1 to 3, characterized in that The specific steps are: (1) Using isatoic anhydride compounds as raw materials, they react with 3-amino-1-propanol to generate 2-amino-N-(3-hydroxypropyl)benzamide compounds, the molecular structure of which is as follows: , where R 1 is H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl; (2) The 2-amino-N-(3-hydroxypropyl)benzamide compound prepared in step (1) reacts with a 1H-indole-2-carboxaldehyde compound to generate a 3-(3-hydroxypropyl)-2-(1H-indol-2-yl)quinazoline-4(3H)-one compound, the molecular structure of which is as follows: , where R 1 and R 2 Selected from H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl; (3) The 3-(3-hydroxypropyl)-2-(1H-indol-2-yl)quinazolin-4(3H)-one compound prepared in step (2) is catalyzed by tris(triphenylphosphine)ruthenium chloride to generate a 2,3-fused quinazolinone compound, the molecular structure of which is as follows: , where R 1 and R 2 is selected from H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl; and R 1 and R 2 Not H at the same time.

5. Use of a 2,3-fused quinazolinone compound according to any one of claims 1 to 3 in the preparation of anti-inflammatory drugs.

Images