A method for synthesizing a benzimidazopyrimidine compound

Abstract

The application discloses a kind of synthesis method of benzimidazopyrimidine compound, belong to organic synthesis technical field.The technical scheme of the application is as follows: aromatic aldehyde compound, 2-amino benzimidazole compound and triethylamine are dissolved in solvent, then catalyst and 2,2,6,6-tetramethylpiperidine-1-oxyl radical are added, and then the target product benzimidazopyrimidine compound is prepared by reacting at 100-140 DEG C.The synthesis process of the application is simple and efficient, and the benzimidazopyrimidine compound is prepared by one-pot tandem reaction without transition metal catalyst.The operation is simple, the raw material is simple, the reaction condition is mild, the substrate is widely applicable, and the production cost is greatly reduced by using triethylamine as raw material.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to the synthesis of benzimidazole-pyrimidine compounds, specifically to a method for synthesizing benzimidazole-pyrimidine compounds. Background Technology

[0002] Studies have shown that benzimidazolidine compounds are an important class of nitrogen-containing fused tricyclic compounds, and their derivatives possess a variety of biological activities, such as ubiquitin-specific proteinase 5 (USP5) inhibitors [Bioorg. Chem. 2023,136, 106462.], X chromosome bone marrow tyrosine (BMX) kinase inhibitors [Eur. J. Med. Chem. 2023,258, 115610.], anti-inflammatory [Bioorg. Med. Chem. 2008, 16, 6344–6352.], and antimalarial [J. Med. Chem. 2011, 54, 4581–4589.]. Furthermore, benzo[4,5]imidazo[1,2-a]pyrimidine, as a conjugated planar fused benzimidazole skeleton, possesses excellent photophysical properties and can be used as a PET tracer for tau protein pathology [J. Alzheimer's Dis. 2012, 31, 601–612.]. Benzimidazole-pyrimidine compounds have shown significant application value in biological and pharmaceutical fields, but the traditional synthetic methods reported in the literature mainly rely on the condensation reaction of 2-aminobenzimidazole with a carbonyl-containing bifunctional reagent. In recent years, the three-component cyclization reaction of 2-aminobenzimidazole with aromatic aldehydes, ketones, or alkynes to synthesize benzimidazole-pyrimidine compounds has attracted increasing attention. However, these methods suffer from drawbacks such as the use of corrosive and toxic reagents, expensive catalysts, harsh reaction conditions, cumbersome post-processing, and low yields, which significantly limit their application in practical production. Therefore, researching and developing methods for synthesizing benzimidazole-pyrimidine compounds using inexpensive and safe reagents and through simple operating procedures is not only of theoretical significance but also of important application value. Summary of the Invention

[0003] The technical problem solved by this invention is to provide a method for synthesizing benzimidazole-pyrimidine compounds. This method starts from simple raw materials and obtains the target product benzimidazole-pyrimidine compounds in one step through a one-pot series reaction. It has the advantages of simple operation, mild reaction conditions, wide range of applicable substrates, and suitability for industrial production.

[0004] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing benzimidazole-pyrimidine compounds, the specific synthesis steps of which are as follows: aromatic aldehyde compound 1, 2-aminobenzimidazole compound 2, and triethylamine are dissolved in a solvent, then a catalyst and 2,2,6,6-tetramethylpiperidine-1-oxy radical are added, and then the reaction is carried out at 100-140℃ to obtain the target product benzimidazole-pyrimidine compound 3. The reaction equation in this synthesis method is as follows: Where R 1 It can be phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, furanyl, thiophene, 3-pyridyl, 4-pyridyl, benzofuranyl, benzothiophene, N -Methylindolyl or quinolinyl, wherein the substituted phenyl group is 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,4-dichlorophenyl, 3,4,5-trimethoxyphenyl, or a monosubstituted phenyl group, wherein the substituent on the monosubstituted phenyl ring is methyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl ester, or nitro; R 2 It is methyl, fluorine, or chlorine; R 3 It is a bromine or methyl ester group; the catalyst is hydroiodic acid, acetic acid, benzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid monohydrate.

[0005] More preferably, the solvent is acetonitrile, 1,4-dioxane, or dimethyl sulfoxide (DMSO). N , N Dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), chlorobenzene, or toluene.

[0006] Further preferably, the molar ratio of the aromatic aldehyde compound 1, the 2-aminobenzimidazole compound 2, the triethylamine, the catalyst, and the 2,2,6,6-tetramethylpiperidine-1-oxygen radical is 5:5:15:1:15, and the ratio of aromatic aldehyde compound 1 to solvent is 1 mmol:4 mL.

[0007] More preferably, the benzimidazole-pyrimidine compound is one of the following compounds: Compared with existing technologies, this invention has the following advantages and beneficial effects: 1. The synthesis process of this invention is a one-pot series reaction, which is simple and efficient, while avoiding resource waste and environmental pollution caused by pre-preparation processes; 2. The raw materials of this invention are inexpensive, readily available, or easy to prepare; 3. The reaction conditions of this invention are simple, the operation is convenient, the yield is high, and it has good application prospects; 4. The substrates of this invention have a wide range of applicability and good functional group tolerance. Therefore, this invention provides an economical and practical new method for the synthesis of benzimidazole pyrimidine compounds. Detailed Implementation

[0008] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0009] Example 1 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (114.1 mg, 93%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.81 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.74–7.69 (m, 1H), 7.66 (t, J = 7.6Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 4.4 Hz, 1H), 6.70 (d,J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.0, 151.6, 149.6, 144.7, 132.1, 131.1, 129.4, 128.2, 127.2, 126.1,121.4, 120.4, 114.8, 107.9; HRMS (ESI): m / z [M + H] + calcd for C 16 H 12 N3:246.1026; found: 246.1028.

[0010] Example 2 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and 1,4-dioxane (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (92 mg, 75%).

[0011] Example 3 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and dimethyl sulfoxide (2 mL) were added. The mixture was then stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (96.7 mg, 78%).

[0012] Example 4 Add benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol) to a 35 mL reaction flask. N , N 2 mL of dimethylformamide was added and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (98.1 mg, 80%).

[0013] Example 5 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and 1-methyl-2-pyrrolidone (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (100.6 mg, 82%).

[0014] Example 6 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and chlorobenzene (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (101.8 mg, 83%).

[0015] Example 7 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and toluene (2 mL) were added. The mixture was then stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (104.2 mg, 85%).

[0016] Example 8 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), acetic acid (6 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask and stirred in a 130 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (98.1 mg, 80%).

[0017] Example 9 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), benzoic acid (12.2 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (104.2 mg, 85%).

[0018] Example 10 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), trifluoroacetic acid (11.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask and stirred in a 130 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (106.7 mg, 87%).

[0019] Example 11 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), trifluoromethanesulfonic acid (15 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask and stirred in a 130 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (106.7 mg, 87%).

[0020] Example 12 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask and stirred in a 130 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (109.2 mg, 89%).

[0021] Example 13 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask and stirred in a 130 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (35.6 mg, 29%).

[0022] Example 14 Benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask, and the mixture was stirred in a metal bath at 140 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (112.8 mg, 92%).

[0023] Example 15 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 120 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (110.4 mg, 90%).

[0024] Example 16 In a 35 mL reaction flask, benzaldehyde 1a (53.1 mg, 0.5 mmol), 2-aminobenzimidazole 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a 100 °C metal bath for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3a (55.2 mg, 45%).

[0025] Example 17 In a 35 mL reaction flask, 1b (60 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3b (119.3 mg, 92%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.47 (q, J = 8.4 Hz, 5H), 7.09–7.04 (m, 1H), 6.80 (d, J =8.4 Hz, 1H), 6.73 (d, J = 4.4 Hz, 1H), 2.55 (s, 3H); 13 C NMR (100 MHz, CDCl3): d(ppm) 155.0, 151.7, 149.9, 144.7, 141.5, 130.0, 129.2, 128.1, 127.3, 126.0,121.2, 120.3, 114.9, 108.0, 21.6; HRMS (ESI): m / z [M+H] + calcd for C 17 H 14 N3:260.1182; found: 260.1182.

[0026] Example 18 In a 35 mL reaction flask, 1c (74.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3c (133.6 mg, 93%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.78 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.53–7.45 (m, 5H), 7.09–7.04 (m, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H), 3.16–3.05 (m, 1H), 1.40 (s, 3H), 1.38 (s, 3H); 13 C NMR (100 MHz, CDCl3): d(ppm) 154.9, 152.4, 151.7, 149.9, 144.7, 129.5,128.1, 127.4, 127.3, 126.0, 121.2, 120.3, 114.9, 108.0, 34.2, 23.9; HRMS(ESI): m / z [M + H] + calcd for C 19 H 18 N3: 288.1495; found: 288.1496.

[0027] Example 19 In a 35 mL reaction flask, 1d (81.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3d (137.1 mg, 91%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.69–7.62 (m, 2H), 7.56–7.51 (m, 2H), 7.50–7.45 (m,1H), 7.10–7.04 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 4.4 Hz, 1H), 1.46 (s, 9H); 13 C NMR (100 MHz, CDCl3): d(ppm) 154.9, 154.8, 151.7, 149.9, 144.7,129.2, 127.9, 127.3, 126.2, 126.0, 121.2, 120.3, 114.9, 108.0, 35.1, 31.3;HRMS (ESI): m / z [M + H] + calcd for C 20 H 20 N3: 302.1652; found: 302.1653.

[0028] Example 20 In a 35 mL reaction flask, 1e (68.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3e (126.6 mg, 92%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.60–7.51 (m, 2H), 7.51–7.45 (m, 1H), 7.20–7.12 (m,2H), 7.11–7.05 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H), 3.97(s, 3H); 13 C NMR (100 MHz, CDCl3): d(ppm) 161.7, 155.0, 151.8, 149.8, 144.6,129.7, 127.3, 126.1, 124.3, 121.3, 120.3, 114.9, 114.7, 108.1, 55.5; HRMS(ESI): m / z [M+H] + calcd for C 17 H 14 N3O: 276.1131; found: 276.1133. 3e is an inhibitor of ubiquitin-specific protein 5 (USP5) [Bioorg. Chem. 2023, 136, 106462.].

[0029] Example 21 In a 35 mL reaction flask, 1f (70.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3f (130.2 mg, 90%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.55–7.45 (m, 3H), 7.13 (d, J = 8.8 Hz, 2H), 7.08 (t, J =8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 4.19 (q, J = 6.8Hz, 2H), 1.52 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d (ppm) 161.1, 154.9,151.8, 149.8, 144.7, 129.7, 127.3, 126.0, 124.0, 121.2, 120.3, 115.1, 114.9,108.0, 63.8, 14.7; HRMS (ESI): m / z [M + H] + calcd for C 18 H 16 N3O: 290.1288; found: 290.1288.

[0030] Example 22 1 g (62.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give 3 g (114.5 mg, 87%) of a yellow solid. The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.8, 5.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 8.4 Hz, 2H), 7.09 (t, J = 8.0 Hz, 1H), 6.78–6.70 (m, 2H); 13 C NMR (100MHz, CDCl3): d(ppm) 165.5, 162.9, 154.9, 151.5, 148.6, 144.7, 130.5, 130.4,128.2, 128.1, 127.1, 126.2, 121.5, 120.6, 116.9, 116.7, 114.5, 108.1; HRMS(ESI): m / z [M + H] + calcd for C 16 H 11 FN3: 264.0932; found: 264.0930.

[0031] Example 23 In a 35 mL reaction flask, 1h (62.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3h (124.5 mg, 89%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.78 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.68–7.63 (m, 2H), 7.60–7.55 (m, 2H), 7.52–7.47 (m,1H), 7.14–7.08 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d(ppm) 154.9, 151.4, 148.3, 144.7, 137.5, 130.4, 129.8,129.7, 127.0, 126.3, 121.6, 120.6, 114.6, 108.0; HRMS (ESI): m / z [M + H] + calcd for C 16 H 11 ClN3: 280.0636; found: 280.0639.

[0032] Example 24 In a 35 mL reaction flask, 1i (92.5 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a brown solid product 3i (141 mg, 87%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.78 (d, J = 4.0 Hz, 1H), 8.00(d, J = 8.0 Hz, 1H), 7.85–7.78 (m, 2H), 7.53–7.47 (m, 3H), 7.14–7.09 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 4.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm)154.8, 151.4, 148.3, 144.7, 132.7, 130.9, 129.8, 127.0, 126.3, 125.7, 121.6,120.6, 114.6, 108.0; HRMS (ESI): m / z [M + H] +calcd for C 16 H 11 BrN3: 324.0131; found: 324.0130.

[0033] Example 25 In a 35 mL reaction flask, 1j (87.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3j (133.1 mg, 85%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.82 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.55–7.47 (m, 1H), 7.15–7.08 (m, 1H), 6.76 (d, J = 4.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.8, 151.3, 147.8, 144.7, 135.5, 133.4,133.1, 128.9, 126.9, 126.6, 126.5(2), 126.4(8), 126.4, 126.38, 124.9, 122.2,121.8, 120.8, 114.3, 108.1; HRMS (ESI): m / z [M + H] + calcd for C 17 H 11F3N3:314.0900; found: 314.0904.

[0034] Example 26 In a 35 mL reaction flask, 1k (65.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3k (114.9 mg, 85%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 3H), 7.81 (d, J = 8.0 Hz, 2H), 7.52–7.48 (m, 1H), 7.13–7.09(m, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.6, 151.0, 147.0, 144.6, 136.0, 133.1, 129.2, 126.6, 126.3,121.8, 120.7, 117.5, 115.1, 114.0, 107.9; HRMS (ESI): m / z [M + Na] + calcd forC 17 H 10 N4Na: 293.0798; found: 293.0792.

[0035] Example 27 In a 35 mL reaction flask, 1 L (82.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give 3 L (136.5 mg, 90%) of a yellow solid. The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.82 (d, J = 4.0 Hz, 1H), 8.33 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.74–7.68 (m, 2H), 7.51–7.47(m, 1H), 7.09–7.04 (m, 1H), 6.78 (d, J = 4.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 166.0, 154.8, 151.3, 148.3,144.7, 136.1, 132.6, 130.6, 128.4, 127.0, 126.3, 121.7, 120.6, 114.5, 107.9,52.6; HRMS (ESI): m / z [M + H] + calcd for C 18 H 14 N3O2: 304.1081; found: 304.1077.

[0036] Example 28 In a 35 mL reaction flask, 1m (60.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3m (112.8 mg, 87%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.80 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.56–7.46 (m, 3H), 7.38 (d, J = 6.8 Hz, 2H), 7.06 (t, J =8.0 Hz, 1H), 6.79–6.68 (m, 2H), 2.49 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm)155.0, 151.6, 149.9, 144.7, 139.5, 132.0, 131.8, 129.3, 128.6, 127.3, 126.1,125.2, 121.3, 120.4, 114.9, 107.8, 21.5; HRMS (ESI): m / z [M + H] + calcd forC 17 H 14 N3: 260.1182; found: 260.1183.

[0037] Example 29 In a 35 mL reaction flask, 1n (68.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3n (117 mg, 85%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.80 (d, J = 4.0 Hz, 1H), 8.00(d, J = 8.0 Hz, 1H), 7.59–7.54 (m, 1H), 7.51–7.46 (m, 1H), 7.25–7.21 (m, 1H),7.16 (d, J = 7.6 Hz, 1H), 7.11–7.05 (m, 2H), 6.80–6.75 (m, 2H), 3.87 (s, 3H); 13 CNMR (100 MHz, CDCl3): d (ppm) 160.2, 154.9, 151.6, 149.4, 144.7, 133.2, 130.7,127.2, 126.1, 121.4, 120.4, 120.3, 116.8, 114.9, 113.4, 107.7, 55.5; HRMS(ESI): m / z [M + H] + calcd for C 17 H 14 N3O: 276.1131; found: 276.1130.

[0038] Example 30 In a 35 mL reaction flask, 1o (92.5 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3o (136.2 mg, 84%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.82 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.88–7.83 (m, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.56–7.49(m, 3H), 7.15–7.10 (m, 1H), 6.79–6.73 (m, 2H); 13 C NMR (100 MHz, CDCl3): d (ppm)154.9, 151.4, 147.7, 144.8, 134.3, 133.9, 131.2, 130.9, 127.0, 126.9, 126.3,123.4, 121.8, 120.7, 114.5, 108.0; HRMS (ESI): m / z [M + H] + calcd forC 16 H 11 BrN3: 324.0131; found: 324.0133.

[0039] Example 31 In a 35 mL reaction flask, 1p (75.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3p (117.6 mg, 81%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.84 (d, J = 4.0 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.06–7.97 (m, 2H), 7.91 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 4.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.8, 151.2, 148.7,146.5, 144.7, 134.2, 133.5, 130.8, 126.8, 126.5, 125.9, 123.6, 122.0, 121.0,114.0, 108.3; HRMS (ESI): m / z [M + H] + calcd for C 16 H 11 N4O2: 291.0877; found: 291.0880.

[0040] Example 32 In a 35 mL reaction flask, 1q (60.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3q (110.2 mg, 85%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 4.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.58–7.52 (m, 1H), 7.43–7.37 (m, 3H), 7.33–7.29 (m,1H), 6.99–6.94 (m, 1H), 6.69 (d, J = 4.0 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 1.97(s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.1, 151.3, 149.4, 144.6, 136.5,131.7, 131.1, 130.9, 128.6, 127.3, 127.0, 126.2, 121.9, 120.3, 113.8, 107.5,19.0; HRMS (ESI): m / z [M + H] + calcd for C 17 H 14 N3: 260.1182; found: 260.1182.

[0041] Example 33 In a 35 mL reaction flask, 1r (68.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3r (114.3 mg, 83%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.41(d, J = 7.2 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.05 (t, J =7.6 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H); 13 CNMR (100 MHz, CDCl3): d (ppm) 156.0, 153.7, 150.3, 146.3, 143.3, 131.7, 128.9,126.6, 124.7, 120.3, 120.2, 119.9, 118.8, 112.9, 110.1, 107.3, 54.5; HRMS(ESI): m / z [M + H] + calcd for C 17 H 14 N3O: 276.1131; found: 276.1133.

[0042] Example 34 In a 35 mL reaction flask, 1S (62.1 mg, 0.5 mmol), 2A (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3S (111.9 mg, 80%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.87 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 3.6 Hz, 2H), 7.61–7.56 (m, 1H), 7.54–7.47(m, 2H), 7.09 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 4.0 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.9, 151.2, 146.5, 144.6, 133.6, 132.5,131.3, 130.5, 130.4, 127.9, 127.2, 126.2, 122.0, 120.5, 113.7, 108.0; HRMS(ESI): m / z [M + H] + calcd for C 16 H 11 ClN3: 280.0636; found: 280.0634.

[0043] Example 35 In a 35 mL reaction flask, 1t (67.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give 3t (117.5 mg, 86%) as a brown solid. The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.36–7.30 (m, 2H), 7.07 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 4.0Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.0,151.8, 150.1, 144.7, 140.1, 138.0, 130.5, 129.6, 129.1, 127.3, 126.0, 125.5,121.2, 120.3, 115.0, 107.9, 20.0, 19.9; HRMS (ESI): m / z [M + H] + calcd forC 18 H 16 N3: 274.1339; found: 274.1338.

[0044] Example 36 In a 35 mL reaction flask, 1u (83.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a brown solid product 3u (136.6 mg, 84%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.78 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.52–7.46 (m, 1H), 7.19 (dd, J = 8.0, 2.0 Hz, 1H),7.14–7.05 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H), 3.88 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.9, 151.7, 151.2, 149.6,149.5, 144.7, 127.2, 126.1, 124.3, 121.3, 121.1, 120.3, 115.0, 111.5, 110.8,108.0, 56.2, 56.1; HRMS (ESI): m / z [M + H] + calcd for C 18 H 16 N3O2: 306.1237; found: 306.1238.

[0045] Example 37 In a 35 mL reaction flask, 1v (87.5 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3v (114.7 mg, 73%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H),7.54–7.48 (m, 2H), 7.16–7.11 (m, 1H), 6.76 (d, J = 4.0 Hz, 1H), 6.56 (d, J = 8.4Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.5, 150.8, 145.1, 144.3, 137.9,134.3, 131.2, 130.2, 129.5, 128.2, 126.8, 126.1, 122.0, 120.3, 113.3, 108.0;HRMS (ESI): m / z [M + Na] + calcd for C 16 H9Cl2N3Na: 336.0066; found: 336.0068.

[0046] Example 38 In a 35 mL reaction flask, 1w (98.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3w (137.5 mg, 82%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.79 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.87(d, J = 8.4 Hz, 1H), 6.80 (s, 2H), 6.78 (d, J = 4.0 Hz, 1H), 4.02 (s, 3H), 3.88(s, 6H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.9, 154.0, 151.6, 149.4, 144.7,140.1, 127.1, 126.2, 121.5, 120.4, 115.0, 107.7, 105.2, 61.2, 56.4; HRMS(ESI): m / z [M+H] + calcd for C 19 H 18 N3O3: 336.1343; found: 336.1344.

[0047] Example 39 In a 35 mL reaction flask, 1x (78.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3x (135.9 mg, 92%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.88 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.73–7.68 (m, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.35 (dd, J =12.8, 7.6 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 4.0 Hz, 1H), 6.79 (t, J =8.0 Hz, 1H), 6.00 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.6,151.1, 148.0, 144.3, 133.0, 131.1, 130.0, 129.1, 128.5, 127.6, 126.9, 126.8,126.7, 125.6, 125.2, 123.8, 121.3, 119.8, 114.2, 108.5; HRMS (ESI): m / z [M +H] + calcd for C20 H 14 N3: 296.1182; found: 296.1185.

[0048] Example 40 In a 35 mL reaction flask, 1y (78.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a brown solid product 3y (138.8 mg, 94%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.83 (d, J = 4.4 Hz, 1H),8.15–8.08 (m, 2H), 8.05–7.96 (m, 3H), 7.72–7.61 (m, 3H), 7.46 (t, J = 8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 4.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.0, 151.6, 149.7, 144.7, 134.1, 133.0,129.3, 129.2, 128.6, 128.3, 128.1(0), 128.0(8), 127.5, 127.3, 126.1, 124.6,121.4, 120.4, 114.9, 108.3; HRMS (ESI): m / z [M + H] + calcd for C 20 H 14 N3:296.1182; found: 296.1186.

[0049] Example 41 In a 35 mL reaction flask, 1z (48 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the mixture was evaporated to dryness and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a brown oily product 3z (52.9 mg, 45%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.78 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.56–7.52 (m, 1H), 7.29–7.23(m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 6.77 (dd, J = 3.2, 1.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.2,151.2, 144.8, 144.4, 144.2, 138.3, 126.9, 126.0, 121.6, 120.2, 114.1, 114.0,112.2, 107.8; HRMS (ESI): m / z [M + Na] + calcd for C 14 H9N3NaO: 258.0638; found: 258.0636.

[0050] Example 42 In a 35 mL reaction flask, 1aa (56.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the mixture was evaporated to dryness and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3aa (109.3 mg, 87%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.75 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 4.8, 0.8 Hz, 1H), 7.52–7.47 (m, 2H), 7.34(dd, J = 4.8, 3.6 Hz, 1H), 7.16–7.10 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 4.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.3, 151.4, 144.5, 142.7,131.3, 129.8, 129.3, 128.0, 127.1, 126.1, 121.5, 120.3, 114.5, 109.6; HRMS(ESI): m / z [M + H] + calcd for C 14 H 10 N3S: 252.0590; found: 252.0586.

[0051] Example 43 In a 35 mL reaction flask, 1ab (53.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3ab (108.4 mg, 88%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.98 (dd, J = 4.8, 1.6 Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.06–8.02 (m, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.66 (dd, J = 7.6, 4.8 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H),7.12–7.07 (m, 1H), 6.78 (d, J = 4.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H); 13 C NMR (100MHz, CDCl3): d (ppm) 154.7, 152.2, 151.1, 148.6, 146.0, 144.6, 135.9, 128.3,126.9, 126.3, 123.8, 121.8, 120.6, 114.2, 108.5; HRMS (ESI): m / z [M + H] + calcd for C 15 H 11 N4: 247.0978; found: 247.0976.

[0052] Example 44 In a 35 mL reaction flask, 1ac (53.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (ethyl acetate) to give a yellow solid product 3ac (70.2 mg, 57%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.98 (dd, J = 4.4, 1.6 Hz, 2H), 8.78 (d, J =4.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 4.4, 1.6 Hz, 2H), 7.52–7.48(m, 1H), 7.13–7.08 (m, 1H), 6.76 (d, J = 4.4 Hz, 1H), 6.75 (s, 1H); 13 C NMR (100MHz, CDCl3): d (ppm) 154.6, 151.0, 150.9, 146.2, 144.6, 139.5, 126.6, 126.3,122.5, 121.8, 120.7, 114.2, 107.7; HRMS (ESI): m / z [M + H] + calcd for C 15 H 11 N4:247.0978; found: 247.0982.

[0053] Example 45 In a 35 mL reaction flask, 1ad (73.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3ad (89.9 mg, 63%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.83 (d, J = 4.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56–7.51 (m, 2H), 7.46–7.41 (m, 2H), 7.28 (d, J = 9.2 Hz, 1H), 7.23–7.19 (m, 1H), 7.08 (d, J = 4.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.1, 154.3, 151.3,146.0, 144.7, 138.3, 127.3, 127.1, 127.0, 126.3, 124.3, 122.3, 122.0, 120.6,114.3, 112.1, 110.5, 108.7; HRMS (ESI): m / z [M + H] + calcd for C 18 H 12 N3O:286.0975; found: 286.0978.

[0054] Example 46 In a 35 mL reaction flask, 1ae (81.1 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3ae (129.6 mg, 86%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.46 (t, J = 7.2Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30–7.23 (m, 2H), 6.91 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 4.0 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm)154.3, 151.0, 144.2, 143.5, 139.4, 136.2, 128.6, 127.2, 126.6, 125.7, 125.4,125.2, 122.8, 122.1, 121.3, 119.8, 114.2, 108.7; HRMS (ESI): m / z [M + H] + calcd for C 18 H 12 N3S: 302.0746; found: 302.0740.

[0055] Example 47 In a 35 mL reaction flask, 1af (79.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3af (77.6 mg, 52%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.71 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.46–7.41 (m,1H), 7.39–7.35 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16–7.11 (m, 2H), 6.98–6.93(m, 1H), 6.81 (d, J = 4.4 Hz, 1H), 4.00 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm)154.5, 152.3, 145.0, 144.7, 136.9, 129.6, 127.6, 125.9, 125.8, 123.3, 121.4,120.7, 120.5, 119.9, 115.4, 110.3, 108.9, 107.2, 33.5; HRMS (ESI): m / z [M +H] + calcd for C 19 H 15 N4: 299.1291; found: 299.1296.

[0056] Example 48 1 ag (78.6 mg, 0.5 mmol), 2a (66.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added to a 35 mL reaction flask, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give 3 ag (131.9 mg, 89%) of a yellow solid. The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 9.12 (d, J = 4.0 Hz, 1H), 8.78 (t, J = 3.2 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.17(s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.0, 4.0Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.4, 151.9,150.8, 148.2, 148.1, 144.1, 136.2, 130.3, 129.5, 127.9, 127.6, 126.5, 125.6,122.0, 121.0, 119.8, 114.1, 107.8; HRMS (ESI): m / z [M + H] + calcd for C 19 H13 N4:297.1135; found: 297.1134.

[0057] Example 49 In a 35 mL reaction flask, 1a (53.1 mg, 0.5 mmol), 2b (80.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3ah (127.1 mg, 93%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.73 (d, J = 4.0 Hz, 1H),7.74 (s, 1H), 7.72–7.68 (m, 1H), 7.67–7.63 (m, 2H), 7.60–7.56 (m, 2H), 6.70(d, J = 4.0 Hz, 1H), 6.43 (s, 1H), 2.38 (s, 3H), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 153.9, 151.3, 149.1, 143.5, 135.7, 132.3, 131.0, 130.7, 129.2,128.2, 125.6, 120.1, 114.7, 107.5, 20.7, 20.6; HRMS (ESI): m / z [M + H] + calcdfor C 18 H 16 N3: 274.1339; found: 274.1336.

[0058] Example 50 In a 35 mL reaction flask, 1a (53.1 mg, 0.5 mmol), 2c (84.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product 3ai (128 mg, 91%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.77 (d, J = 2.8 Hz, 1H),7.79–7.65 (m, 4H), 7.61 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 3.2 Hz, 1H), 6.51–6.40(m, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 154.8, 152.3, 151.1, 150.9, 148.9,148.6, 148.4, 147.4, 147.2, 144.9, 144.8, 140.5, 140.4, 131.4, 131.0, 129.5,127.9, 121.9, 121.8, 108.1, 106.9, 106.7, 102.9, 102.6; HRMS (ESI): m / z [M +H] + calcd for C 16 H 10 F2N3: 282.0837; found: 282.0838.

[0059] Example 51 In a 35 mL reaction flask, 1a (53.1 mg, 0.5 mmol), 2d (101 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product 3aj (141.4 mg, 90%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.80 (d, J = 4.0 Hz, 1H),8.00 (s, 1H), 7.79–7.74 (m, 1H), 7.71 (t, J = 7.6 Hz, 2H), 7.63–7.59 (m, 2H), 6.82 (d, J = 4.0 Hz, 1H), 6.74 (s, 1H); 13 C NMR (100 MHz, CDCl3): d (ppm) 155.8,152.3, 149.4, 143.6, 131.5, 130.9, 130.2, 129.5, 127.8, 125.9, 124.9, 120.9,115.9, 108.4; HRMS (ESI): m / z [M + H] + calcd for C 16 H 10 Cl2N3: 314.0246; found: 314.0251.

[0060] Example 52 In a 35 mL reaction flask, 1a (53.1 mg, 0.5 mmol), 2e (106 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give a yellow solid product 3ak (141 mg, 87%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, DMSO- d 6): d (ppm) 8.92 (d, J = 4.4 Hz, 1H), 7.73 (dd, J = 14.4, 7.2 Hz, 6H), 7.10 (d, J = 4.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, DMSO- d 6): d (ppm) 156.7, 151.3,149.8, 142.5, 131.6, 131.2, 129.4, 128.4, 128.3, 127.6, 121.8, 114.0, 112.3,109.1; HRMS (ESI): m / z [M + H] + calcd for C 16 H 11 BrN3: 324.0131; found: 324.0126.

[0061] Example 53 In a 35 mL reaction flask, 1a (53.1 mg, 0.5 mmol), 2f (95.6 mg, 0.5 mmol), triethylamine (151.8 mg, 1.5 mmol), hydroiodic acid (57%, 22.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxo radical (234.4 mg, 1.5 mmol), and acetonitrile (2 mL) were added, and the mixture was stirred in a metal bath at 130 °C for 15 h. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and separated by silica gel column chromatography (ethyl acetate) to give a yellow solid product 3al (127.4 mg, 84%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl3): d (ppm) 8.86 (d, J = 4.0 Hz, 1H), 8.19 (dd, J = 7.6,0.8 Hz, 1H), 7.76–7.71 (m, 1H), 7.71–7.66 (m, 2H), 7.61 (dd, J = 8.0, 1.2 Hz,2H), 7.12–7.07 (m, 1H), 6.90 (dd, J = 7.6, 1.2 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 4.10 (s, 3H); 13 C NMR (100 MHz, CDCl3): d (ppm) 166.9, 155.9, 152.6, 149.6,143.5, 131.7, 131.3, 129.6, 129.3, 128.5, 128.1, 121.6, 120.4, 119.1, 108.7,52.5; HRMS (ESI): m / z [M + H] + calcd for C 18 H 14 N3O2: 304.1081; found: 304.1082.

[0062] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are only illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and modifications fall within the protection scope of the present invention.

Claims

1. A method for synthesizing benzimidazole-pyrimidine compounds, characterized in that: The specific synthetic steps are as follows: Aromatic aldehyde compound 1, 2-aminobenzimidazole compound 2, and triethylamine are dissolved in a solvent, then a catalyst and 2,2,6,6-tetramethylpiperidine-1-oxy radical are added, and then the mixture is reacted at 100-140℃ to obtain the target product benzimidazole-pyrimidine compound 3. The reaction equation in this synthetic method is as follows: Where R 1 It can be phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, furanyl, thiophene, 3-pyridyl, 4-pyridyl, benzofuranyl, benzothiophene, N -Methylindolyl or quinolinyl, wherein the substituted phenyl group is 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,4-dichlorophenyl, 3,4,5-trimethoxyphenyl, or a monosubstituted phenyl group, wherein the substituent on the monosubstituted phenyl ring is methyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl ester, or nitro; R 2 It is methyl, fluorine, or chlorine; R 3 It is a bromine or methyl ester group; the catalyst is hydroiodic acid, acetic acid, benzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid monohydrate.

2. The method for synthesizing benzimidazole-pyrimidine compounds according to claim 1, characterized in that: The solvent is acetonitrile, 1,4-dioxane, dimethyl sulfoxide, N , N Dimethylformamide, 1-methyl-2-pyrrolidone, chlorobenzene or toluene.

3. The method for synthesizing benzimidazole-pyrimidine compounds according to claim 1, characterized in that: The molar ratio of aromatic aldehyde 1, 2-aminobenzimidazole 2, triethylamine, catalyst and 2,2,6,6-tetramethylpiperidine-1-oxygen radical is 5:5:15:1:15, and the ratio of aromatic aldehyde 1 to solvent is 1 mmol:4 mL.

4. The method for synthesizing benzimidazole-pyrimidine compounds according to claim 1, characterized in that: The benzimidazole-pyrimidine compound is one of the following compounds: 。

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