A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative, preparation method and use thereof

Abstract

The present invention relates to the field of chemical technology, and in particular to a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative, a method for preparing the 1,2,4-triazolo[4,3-a]pyridine sulfone derivative compound, and use of the 1,2,4-triazolo[4,3-a]pyridine sulfone derivative in treating citrus Huanglongbing disease. The derivative is formed by combining a [1,2,4]triazolo[4,3-a]pyridine structure with a sulfone structure.

Description

Technical Field

[0001] The present invention relates to the field of chemical technology, and in particular to a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative, a method for preparing the 1,2,4-triazolo[4,3-a]pyridine sulfone derivative compound, and use of the 1,2,4-triazolo[4,3-a]pyridine sulfone derivative in treating citrus Huanglongbing disease. Background Art

[0002] Citrus Huanglongbing (HLB), also known as yellow tip disease, yellow wilt, and green fruit disease, is an immune-mediated disease caused by infection with Candidatus Liberobacterasiaticus (CLas), which has devastated the global citrus industry. 1,2,4-Triazolo[4,3-a]pyridine compounds possess excellent biological activity and are important lead structures in the design of antimicrobial agents. In 2011, Prakash et al. reported that a series of 1,2,4-triazolo[4,3-a]pyridine compounds exhibited excellent antibacterial activity against Bacillus subtilis. In 2014, Liu Xinghai et al. reported that a series of 1,2,4-triazolo[4,3-a]pyridine compounds exhibited excellent in vitro antibacterial activity against Sclerotinia sclerotiorum. Among them, at a concentration of 50 mg / L, the compound 3-(4-(tert-butyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine had 100% inhibitory activity against Sclerotinia sclerotiorum. The EC 50The concentration of 1,2,4-triazolo[4,3-a]pyridine derivatives was 11.13 mg / L, which is comparable to the antibacterial activity of the commercially available antibacterial agent tricyclazole (11.45 mg / L). In 2016, Mu Jinxia et al. reported a series of novel 1,2,4-triazolo[4,3-a]pyridine derivatives containing hydrazone structures. At a concentration of 100 mg / L, some of these compounds showed good antibacterial activity against tomato sclerotinia and Fusarium oxysporum. In 2017, Xu Fangzhou et al. reported a series of 1,2,4-triazolo[4,3-a]pyridine compounds that exhibited good in vitro antibacterial activity against wheat sheath blight and wheat root rot at a concentration of 50 mg / L. Among them, 8-chloro-3-((2-fluoro-5-(trifluoromethyl)benzyl)thio)-[1,2,4]triazolo[4,3-a]pyridine exhibited inhibitory activities of 70.9% and 67.3% against wheat sheath blight and wheat root rot, respectively. In 2019, Fan Zhijiang et al. reported a series of 1,2,4-triazolo[4,3-a]pyridinylquinazoline sulfide compounds that exhibited strong in vitro antibacterial activity against rice bacterial blight and citrus canker at a concentration of 100 mg / L. In vivo pot experiments demonstrated that the compound ethyl 4-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinazoline-2-carboxylate exhibited therapeutic and protective activities of 48.54% and 49.47%, respectively, against rice bacterial blight at a concentration of 200 mg / L, surpassing chlorothiazolinone (40.63% and 38.82%) and thiophanate-methyl (42.82% and 46.80%). Sulfone compounds exhibited excellent antibacterial activity against plant pathogens, with the sulfone group playing a key role in the antimicrobial target interaction. For example, in 2018, Li Pei et al. reported a series of 1,3,4-oxadiazole sulfone compounds containing a disulfone group. This series of compounds had good in vitro antibacterial activity against rice bacterial leaf blight and rice bacterial leaf streak fungus at a concentration of 100 mg / L. In vivo pot experiments showed that the compound 2-((4-chlorophenyl)sulfonyl)methyl-5-(methylsulfonyl)-1,3,4-oxadiazole can effectively alleviate the symptoms of rice bacterial leaf blight, with therapeutic activity and protective activity of 45.05% and 51.77%, respectively, which are better than the control agents chlorothalonil (37.80% and 43.31%) and thiophanate-methyl (39.89% and 44.70%). In 2021, Wei Chengqian et al. reported that a series of new oxadiazole sulfone compounds containing an amide group had good in vitro antibacterial activity against rice bacterial leaf blight and rice bacterial leaf streak fungus.In vivo pot experiments showed that the protective and therapeutic activities of the compound (E)-3-(4-fluorophenyl)-N-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl) acrylamide against rice bacterial leaf blight at a concentration of 200 mg / L were 43.2% and 44.5%, respectively, which were better than the control agents mesylate (34.1% and 32.6%) and thiophanate-methyl (33.0% and 30.2%). The protective and therapeutic activities against rice bacterial leaf spot were 53.6% and 51.7%, respectively, which were better than mesylate (26.4% and 24.4%) and thiophanate-methyl (30.2% and 28.6%). In 2022, Chen Yifang et al. (Chen Yifang, Luo Xin, Wang Yu, Xing Zhifu, Peng Ju, Chen Jixiang. Design, synthesis and antibacterial activity study of 1,3,4-oxadiazole sulfone compounds containing sulfonamide structure. Organic Chemistry, 2023, 43, 274-284.) reported a series of 1,3,4-oxadiazole sulfone compounds containing sulfonamide structure. Most of the compounds showed excellent in vitro antibacterial activity against rice bacterial leaf blight and rice bacterial leaf streak pathogen at a concentration of 100 mg / L. Among them, the compound 4-fluoro-N-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)methyl)benzenesulfonamide showed the best antibacterial activity, with EC50 values of 1.1 and 1.3 mg / L against Xanthomonas oryzae and Xanthomonas oryzae, respectively, significantly outperforming the control agents chlorothalonil (71.4 and 84.1 mg / L) and thiophanate-methyl (84.0 and 122.1 mg / L). This shows that [1,2,4]triazolo[4,3-a]pyridine and sulfone groups play an important role in the development of antimicrobial agents and are one of the key directions for the creation of new antimicrobial agents.

[0003] At present, there are no reports on the synthesis and anti-citrus Huanglongbing activity of [1,2,4]triazolo[4,3-a]pyridine sulfone compounds at home and abroad. Summary of the Invention

[0004] In view of the deficiencies in the prior art, the present invention provides a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative, a preparation method thereof and a use thereof.

[0005] This is achieved specifically through the following technical solutions:

[0006] A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative is prepared by combining a [1,2,4]triazolo[4,3-a]pyridine structure and a sulfone structure, and its structural formula is as follows:

[0007]

[0008] Among them, R 1 is substituted phenyl, substituted pyridyl, substituted furyl or substituted thienyl; R 2is methyl, ethyl or propyl.

[0009] Furthermore, the R 1 Selected from the following structural formula:

[0010]

[0011] Furthermore, a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative includes but is not limited to:

[0012] A1: 2-bromo-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0013] A2: 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0014] A3: 3-methyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0015] A4: N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide;

[0016] A5: N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide;

[0017] A6: N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide;

[0018] A7: 2-methoxy-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0019] A8: 2,6-dichloro-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0020] A9: 2-Fluoro-N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0021] A10: 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0022] A11: 2,5-dimethyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide;

[0023] A12: N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide;

[0024] A13: N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide;

[0025] A14: 2,6-difluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide;

[0026] A15: 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide.

[0027] The synthetic route of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative is as follows:

[0028]

[0029] A method for preparing a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative comprises the following steps:

[0030] The first step is the preparation of 2-hydrazine-5-nitropyridine (a):

[0031] Ethanol, 2-chloro-5-nitropyridine and 80% hydrazine hydrate were reacted at room temperature. The starting material disappeared after TLC detection. The product was directly filtered and the filter cake was compound a.

[0032] Step 2 Preparation of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0033] Compound a and potassium carbonate were stirred in anhydrous ethanol at a molar ratio of compound a: carbon disulfide: potassium carbonate = 1:1.5:1.5, and carbon disulfide was added. After reflux, the ethanol was removed by decompression. Water was added and the pH was adjusted to 4-5 with 1% hydrobromic acid to precipitate a yellow solid, which was filtered and dried to obtain compound b.

[0034] Step 3 Preparation of 3-(methyl / ethyl / propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1c-3c):

[0035] Compound b was dissolved in acetonitrile, K2CO3 was added with stirring, and then a halogenated alkane was added. After the reaction was refluxed at 85°C for 2 h, the acetonitrile was removed by desolventizing and then dissolved in ethyl acetate. The mixture was washed with saturated brine, extracted, dried over anhydrous magnesium sulfate, and filtered. After desolventizing and purification by chromatography, a brown solid was obtained after drying, which was compound 1c-3c.

[0036] Step 4 Preparation of 3-(methyl / ethyl / propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (1d-3d):

[0037] Compounds 1c-3c were dissolved in ethanol solution, ammonium chloride was added with stirring, and iron powder was added. After reflux at 90°C for 3 h, the iron residue was removed by filtration, and then extracted three times with ethyl acetate. After desolventizing under reduced pressure, the mixture was separated and purified by column chromatography. After drying, a green solid was obtained, which was compound 1d-3d.

[0038] Step 5: Preparation of intermediate 1e-15e:

[0039] Compounds 1d-3d were dissolved in dichloromethane at a molar ratio of 1d-3d: substituted acid chloride: triethylamine = 1:1.2:1.5. Triethylamine was added and stirred in an ice bath for 5 minutes. The substituted acid chloride was then slowly added dropwise and allowed to react for 1 hour. The reaction product was washed with saturated brine, desolvated under reduced pressure, and purified by column chromatography. After drying, a white / brown solid was obtained, which is compound 1e-15e.

[0040] Step 6 Preparation of Compounds A1-A15:

[0041] Compounds 1e-15e were dissolved in ethanol at a molar ratio of compound 1e-15e: ammonium molybdate: hydrogen peroxide = 1:0.1:20. Ammonium molybdate was dissolved in hydrogen peroxide and then slowly added dropwise to the reaction system. After stirring at room temperature for 24 h, ice water was added to precipitate a white / brown solid, which was filtered and dried to obtain the target products A1-A15.

[0042] A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative is used for preventing / controlling citrus Huanglongbing disease.

[0043] Application of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative in the preparation of a citrus Huanglongbing preventive preparation.

[0044] Application of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative in the preparation of a preparation for treating citrus Huanglongbing disease.

[0045] Beneficial effects:

[0046] The derivatives of the present invention have the advantages of simple preparation process, excellent reaction yield and low raw material cost.

[0047] The derivatives of the invention have excellent activity of inhibiting citrus Huanglongbing pathogenic bacteria. DETAILED DESCRIPTION

[0048] The specific embodiments of the present invention are further described in detail below, but the present invention is not limited to these embodiments. Any improvement or replacement based on the basic spirit of the present embodiment still falls within the scope of protection required by the claims of the present invention.

[0049] Example 1

[0050] The preparation method of 2-bromo-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A1) comprises the following steps:

[0051] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0052] 2-Chloro-5-nitropyridine (4.0 g, 25.23 mmol) was added to a 500 mL single-necked flask containing ethanol (250 mL). 80% hydrazine hydrate (3.79 g, 75.69 mmol) was dissolved in 50 mL of ethanol and slowly added dropwise to the reaction system. The reaction system gradually changed from white to yellow and a yellow solid slowly precipitated during the reaction. After stirring at room temperature for 12 h, compound a was directly filtered and dried to obtain a yellow solid with a mass of 3.6 g and a yield of 92.54%.

[0053] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0054] 2-Hydrazine-5-nitropyridine (3.6 g, 23.36 mmol) was added to a 50 mL three-necked flask containing 30 mL of anhydrous ethanol. Potassium carbonate (4.84 g, 35.04 mmol) was added and stirred thoroughly. Carbon disulfide (2.67 g, 35.04 mmol) was then added. The reaction system formed a yellow liquid and was heated under reflux at 80°C with stirring for 12 hours. After the reaction, the ethanol was removed by vacuum desolventization, and 20 mL of water was added for dissolution. 1% hydrobromic acid was slowly added dropwise to adjust the pH to 4-5. A yellow solid precipitated, which was filtered and dried. The weight was 2.0 g, with a yield of 43.67%.

[0055] (3) Synthesis of 3-(methylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1c):

[0056] 6-Nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (2 g, 10.19 mmol) was added to a 25 mL three-necked flask containing 10 mL of acetonitrile. Potassium carbonate (2.11 g, 15.29 mmol) was added and stirred thoroughly. Methyl iodide (1.74 g, 12.23 mmol) was then added and stirred at 85°C for 2 h. After the reaction, the acetonitrile was removed by decompression, and the mixture was dissolved in ethyl acetate (40 mL), washed with saturated brine (40 mL), extracted with ethyl acetate (40 mL x 2), dried over anhydrous magnesium sulfate, filtered, and decompressed. Purification by column chromatography (petroleum ether:ethyl acetate = 3:1) afforded 1.7 g of a white solid in a yield of 79.44%.

[0057] (4) Synthesis of 3-(methylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (1d):

[0058] 3-(Methylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1.7 g, 8.09 mmol) was added to a 50 mL three-necked flask containing 30 mL of ethanol / water (ethanol / water = 1 / 1). Ammonium chloride (2.16 g, 40.44 mmol) was added and stirred thoroughly. Reduced iron powder (1.35 g, 24.26 mmol) was then added and stirred under reflux at 90°C for 3 h. After the reaction, the iron filings were filtered to remove the residue. The product was extracted with ethyl acetate (40 mL x 3), dried over anhydrous magnesium sulfate, filtered, and desolvated under reduced pressure. The product was then purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1 g of a white solid in a yield of 68.49%.

[0059] (5) Synthesis of 2-bromo-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (1e):

[0060] 3-(Methylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (0.2 mg, 1.11 mmol) was added to a 25 mL single-necked flask containing 10 mL of dichloromethane. Triethylamine (0.17 g, 1.66 mmol) was added and stirred in an ice bath for 5 minutes. 2-Bromobenzoyl chloride (0.29 g, 1.33 mmol) was dissolved in 5 mL of dichloromethane and slowly added to the reaction system. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was washed with saturated brine (15 mL x 3). The solvent was removed under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 0.30 g of 2-bromo-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 74.43%.

[0061] (6) Synthesis of 2-bromo-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A1):

[0062] 2-Bromo-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.30 g, 0.86 mmol) was added to 4 mL of anhydrous ethanol in a 10 mL single-necked flask. Ammonium molybdate (0.10 g, 0.08 mmol) was dissolved in 30% hydrogen peroxide (0.56 g, 16.52 mmol) and slowly added dropwise to the reaction system. Solid precipitated during the reaction. After completion of the reaction, the reaction system was transferred to a 50 mL beaker and 10 mL of water was added. A large amount of white solid precipitated. The solid was filtered, rinsed with ethanol, and dried to obtain 0.24 g of 2-bromo-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 73.24%.

[0063] Physical and chemical properties of compound A1: white solid, melting point 97.5-98.8℃.

[0064] Example 2

[0065] The preparation method of 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A2) comprises the following steps:

[0066] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0067] The product was synthesized using the method and conditions described in Example 1(1).

[0068] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0069] The product was synthesized using the method and conditions described in Example 1(2).

[0070] (3) Synthesis of 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (2c):

[0071] The product was synthesized using the same method and conditions as in Example 1(3), except that bromoethane (1.33 g, 12.23 mmol) was added instead of iodomethane to obtain 1.8 g of 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine as a white solid in a yield of 78.60%.

[0072] (4) Synthesis of 3-(ethylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (2d):

[0073] The product was synthesized using the same method and conditions as in Example 1(4), except that 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1.8 g, 8.03 mmol) was added to obtain 1.1 g of 3-(ethylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine as a green solid in a yield of 70.51%.

[0074] (5) Synthesis of 3-methyl-N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (2e):

[0075] The product was synthesized using the same method and conditions as in Example 1(5), except that 3-(ethylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (0.2 mg, 1.03 mmol) was added to obtain 0.22 g of 3-methyl-N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 68.40%.

[0076] (6) Synthesis of 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A2):

[0077] The product was synthesized using the same method and conditions as in Example 1(6), except that 3-methyl-N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.22 g, 0.70 mmol) was added to obtain 0.18 g of 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 74.01%.

[0078] Physical and chemical properties of compound A2: white solid, melting point 175.2-177.0℃.

[0079] Example 3

[0080] The preparation method of 3-methyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A3) comprises the following steps:

[0081] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0082] The product was synthesized using the method and conditions described in Example 1(1).

[0083] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0084] The product was synthesized using the method and conditions described in Example 1(2).

[0085] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0086] The product was synthesized using the same method and conditions as in Example 1(3), except that bromopropane (1.50 g, 12.23 mmol) was added instead of iodomethane to obtain 1.8 g of 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine as a white solid in a yield of 74.07%.

[0087] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0088] The product was synthesized using the same method and conditions as in Example 1(4), except that 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1.8 g, 7.55 mmol) was added to obtain 1.0 g of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine as a green solid in a yield of 63.69%.

[0089] (5) Synthesis of 3-methyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (3e):

[0090] The product was synthesized using the same method and conditions as in Example 1(5), except that 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (0.2 mg, 0.96 mmol) was added to obtain 0.22 g of 3-methyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 70.19%.

[0091] (6) Synthesis of 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A3):

[0092] The product was synthesized using the same method and conditions as in Example 1(6), except that 3-methyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.22 g, 0.67 mmol) was added to obtain 0.18 g of 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 74.55%.

[0093] Physical and chemical properties of compound A3: white solid, melting point 186.6-188.6℃.

[0094] Example 4

[0095] The preparation method of N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (compound number A4) comprises the following steps:

[0096] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0097] The product was synthesized using the method and conditions described in Example 1(1).

[0098] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0099] The product was synthesized using the method and conditions described in Example 1(2).

[0100] (3) Synthesis of 3-(methylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1c):

[0101] The product was synthesized using the method and conditions described in Example 1(3).

[0102] (4) Synthesis of 3-(methylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (1d):

[0103] The product was synthesized using the method and conditions described in Example 1(4).

[0104] (5) Synthesis of N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (4e):

[0105] The product was synthesized using the same method and conditions as in Example 1(5), except that 2-nitro-4-trifluoromethylbenzoyl chloride (0.34 g, 1.33 mmol) was added to obtain 0.31 g of N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide in a yield of 70.31%.

[0106] (6) Synthesis of N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (A4):

[0107] The product was synthesized using the same method and conditions as in Example 1(6), except that N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (0.31 g, 0.78 mmol) was added to obtain 0.25 g of N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide in a yield of 74.64%.

[0108] Physical and chemical properties of compound A4: white solid, melting point 193.2-195.0℃.

[0109] Example 5

[0110] The preparation method of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (compound number A5) comprises the following steps:

[0111] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0112] The product was synthesized using the method and conditions described in Example 1(1).

[0113] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0114] The product was synthesized using the method and conditions described in Example 1(2).

[0115] (3) Synthesis of 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (2c):

[0116] The product was synthesized using the method and conditions described in Example 2(3).

[0117] (4) Synthesis of 3-(ethylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (2d):

[0118] The product was synthesized using the method and conditions described in Example 2(4).

[0119] (5) Synthesis of N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (5e):

[0120] The product was synthesized using the same method and conditions as in Example 2(5), except that 2-nitro-4-trifluoromethylbenzoyl chloride (0.31 g, 1.24 mmol) was added to obtain 0.32 g of N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide as a brown solid in a yield of 75.56%.

[0121] (6) Synthesis of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (A5):

[0122] The product was synthesized using the same method and conditions as in Example 2(6), except that N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (0.32 g, 0.78 mmol) was added to obtain 0.25 g of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide in a yield of 72.49%.

[0123] Physical and chemical properties of compound A5: white solid, melting point 193.2-195.0℃.

[0124] Example 6

[0125] The preparation method of N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (compound number A6) comprises the following steps:

[0126] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0127] The product was synthesized using the method and conditions described in Example 1(1).

[0128] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0129] The product was synthesized using the method and conditions described in Example 1(2).

[0130] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0131] The product was synthesized using the method and conditions described in Example 3(3).

[0132] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0133] The product was synthesized using the method and conditions described in Example 3(4).

[0134] (5) Synthesis of N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (6e):

[0135] The product was synthesized using the same method and conditions as in Example 3(5), except that 2-nitro-4-trifluoromethylbenzoyl chloride (0.29 g, 1.15 mmol) was added to obtain 0.30 g of N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide as a brown solid in a yield of 73.44%.

[0136] (6) Synthesis of N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (A6):

[0137] The product was synthesized using the same method and conditions as in Example 3(6), except that N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide (0.30 g, 0.71 mmol) was added to obtain 0.24 g of N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide in a yield of 74.40%.

[0138] Physical and chemical properties of compound A6: white solid, melting point 214.8-215.9℃.

[0139] Example 7

[0140] The preparation method of 2-methoxy-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A7) comprises the following steps:

[0141] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0142] The product was synthesized using the method and conditions described in Example 1(1).

[0143] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0144] The product was synthesized using the method and conditions described in Example 1(2).

[0145] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0146] The product was synthesized using the method and conditions described in Example 3(3).

[0147] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0148] The product was synthesized using the method and conditions described in Example 3(4).

[0149] (5) Synthesis of 2-methoxy-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (7e):

[0150] The product was synthesized using the same method and conditions as in Example 3(5), except that 2-methoxybenzoyl chloride (0.20 g, 1.15 mmol) was added to obtain 0.24 g of 2-methoxy-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 72.99%.

[0151] (6) Synthesis of 2-methoxy-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A7):

[0152] The product was synthesized using the same method and conditions as in Example 3(6), except that 2-methoxy-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.24 g, 0.70 mmol) was added to obtain 0.19 g of 2-methoxy-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 72.40%.

[0153] Physical and chemical properties of compound A7: white solid, melting point 181.9-183.8℃.

[0154] Example 8

[0155] The preparation method of 2,6-dichloro-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A8) comprises the following steps:

[0156] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0157] The product was synthesized using the method and conditions described in Example 1(1).

[0158] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0159] The product was synthesized using the method and conditions described in Example 1(2).

[0160] (3) Synthesis of 3-(methylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1c):

[0161] The product was synthesized using the method and conditions described in Example 1(3).

[0162] (4) Synthesis of 3-(methylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (1d):

[0163] The product was synthesized using the method and conditions described in Example 1(4).

[0164] (5) Synthesis of 2,6-dichloro-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (8e):

[0165] The product was synthesized using the same method and conditions as in Example 1(5), except that 2,6-dichlorobenzoyl chloride (0.28 g, 1.33 mmol) was added to obtain 0.29 g of 2,6-dichloro-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 73.99%.

[0166] (6) Synthesis of 2,6-dichloro-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A8):

[0167] The product was synthesized using the same method and conditions as in Example 1(6), except that 2,6-dichloro-N-(3-(methylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.29 g, 0.82 mmol) was added to obtain 0.24 g of 2,6-dichloro-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 75.88%.

[0168] Physical and chemical properties of compound A8: white solid, melting point 217.2-219.2℃.

[0169] Example 9

[0170] The preparation method of 2-fluoro-N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A9) comprises the following steps:

[0171] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0172] The product was synthesized using the method and conditions described in Example 1(1).

[0173] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0174] The product was synthesized using the method and conditions described in Example 1(2).

[0175] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0176] The product was synthesized using the method and conditions described in Example 3(3).

[0177] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0178] The product was synthesized using the method and conditions described in Example 3(4).

[0179] (5) Synthesis of 2-fluoro-N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (9e):

[0180] The product was synthesized using the same method and conditions as in Example 3(5), except that 2-fluorobenzoyl chloride (0.18 g, 1.15 mmol) was added to obtain 0.24 g of 2-fluoro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 75.65%.

[0181] (6) Synthesis of 2-fluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A9):

[0182] The product was synthesized using the same method and conditions as in Example 3(6), except that 2-fluoro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.24 g, 0.73 mmol) was added to obtain 0.19 g of 2-fluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 72.18%.

[0183] Physical and chemical properties of compound A9: white solid, melting point 140.5-142.5℃.

[0184] Example 10

[0185] The preparation method of 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A10) comprises the following steps:

[0186] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0187] The product was synthesized using the method and conditions described in Example 1(1).

[0188] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0189] The product was synthesized using the method and conditions described in Example 1(2).

[0190] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine) (3c):

[0191] The product was synthesized using the method and conditions described in Example 3(3).

[0192] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0193] The product was synthesized using the method and conditions described in Example 3(4).

[0194] (5) Synthesis of 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (10e):

[0195] The product was synthesized using the same method and conditions as in Example 3(5), except that 2-chlorobenzoyl chloride (0.20 g, 1.15 mmol) was added to obtain 0.25 g of 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 75.07%.

[0196] (6) Synthesis of 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A10):

[0197] The product was synthesized using the same method and conditions as in Example 3(6), except that 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.25 g, 0.72 mmol) was added to obtain 0.19 g of 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 69.58%.

[0198] Physical and chemical properties of compound A10: white solid, melting point 90.2-91.2°C.

[0199] Example 11

[0200] The preparation method of 2,5-dimethyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (compound number A11) comprises the following steps:

[0201] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0202] The product was synthesized using the method and conditions described in Example 1(1).

[0203] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0204] The product was synthesized using the method and conditions described in Example 1(2).

[0205] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0206] The product was synthesized using the method and conditions described in Example 3(3).

[0207] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0208] The product was synthesized using the method and conditions described in Example 3(4).

[0209] (5) Synthesis of 2,5-dimethyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (11e):

[0210] The product was synthesized using the same method and conditions as in Example 3(5), except that 2,5-dimethylbenzoyl chloride (0.20 g, 1.15 mmol) was added to obtain 0.24 g of 2,5-dimethyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as a brown solid in a yield of 72.06%.

[0211] (6) Synthesis of 2,5-dimethyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (A11):

[0212] The product was synthesized using the same method and conditions as in Example 3(6), except that 2,5-dimethyl-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide (0.24 g, 0.69 mmol) was added to obtain 0.18 g of 2,5-dimethyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide in a yield of 68.66%.

[0213] Physical and chemical properties of compound A11: white solid, melting point 107.8-109.8℃.

[0214] Example 12

[0215] The preparation method of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide (compound number A12) comprises the following steps:

[0216] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0217] The product was synthesized using the method and conditions described in Example 1(1).

[0218] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0219] The product was synthesized using the method and conditions described in Example 1(2).

[0220] (3) Synthesis of 3-(ethylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (2c):

[0221] The product was synthesized using the method and conditions described in Example 2(3).

[0222] (4) Synthesis of 3-(ethylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (2d):

[0223] The product was synthesized using the method and conditions described in Example 2(4).

[0224] (5) Synthesis of N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide (12e):

[0225] The product was synthesized using the same method and conditions as in Example 2(5), except that thiophene-2-carboxylic acid chloride (0.18 g, 1.24 mmol) was added to obtain 0.21 g of N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide as a brown solid in a yield of 67.01%.

[0226] (6) Synthesis of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide (A12):

[0227] The product was synthesized using the same method and conditions as in Example 2(6), except that N-(3-(ethylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide (0.21 g, 0.69 mmol) was added to obtain 0.15 g of N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide in a yield of 64.63%.

[0228] Physical and chemical properties of compound A12: white solid, melting point 195.7-197.5℃.

[0229] Example 13

[0230] The preparation method of N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide (compound number A13) comprises the following steps:

[0231] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0232] The product was synthesized using the method and conditions described in Example 1(1).

[0233] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0234] The product was synthesized using the method and conditions described in Example 1(2).

[0235] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0236] The product was synthesized using the method and conditions described in Example 3(3).

[0237] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0238] The product was synthesized using the method and conditions described in Example 3(4).

[0239] (5) Synthesis of N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide (13e):

[0240] The product was synthesized using the same method and conditions as in Example 3(5), except that furan-2-carbonyl chloride (0.15 g, 1.15 mmol) was added to obtain 0.21 g of N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide as a brown solid in a yield of 72.33%.

[0241] (6) Synthesis of N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide (A13):

[0242] The product was synthesized using the same method and conditions as in Example 3(6), except that N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide (0.21 g, 0.69 mmol) was added to obtain 0.15 g of N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide in a yield of 64.59%.

[0243] Physical and chemical properties of compound A13: white solid, melting point 162.3-163.3°C.

[0244] Example 14

[0245] A method for preparing 2,6-difluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (compound number A14) comprises the following steps:

[0246] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0247] The product was synthesized using the method and conditions described in Example 1(1).

[0248] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0249] The product was synthesized using the method and conditions described in Example 1(2).

[0250] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0251] The product was synthesized using the method and conditions described in Example 3(3).

[0252] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0253] The product was synthesized using the method and conditions described in Example 3(4).

[0254] (5) Synthesis of 2,6-difluoro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (14e):

[0255] The product was synthesized using the same method and conditions as in Example 3(5), except that 2,6-difluoronicotinoyl chloride (0.20 g, 1.15 mmol) was added to obtain 0.24 g of 2,6-difluoro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide as a brown solid in a yield of 71.54%.

[0256] (6) Synthesis of 2,6-difluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (A14):

[0257] The product was synthesized using the same method and conditions as in Example 3(6), except that 2,6-difluoro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (0.21 g, 0.69 mmol) was added to obtain 0.16 g of 2,6-difluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide in a yield of 61.07%.

[0258] Physical and chemical properties of compound A14: white solid, melting point 152.7-153.6°C.

[0259] Example 15

[0260] A method for preparing 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (compound number A15) comprises the following steps:

[0261] (1) Synthesis of 2-hydrazine-5-nitropyridine (a):

[0262] The product was synthesized using the method and conditions described in Example 1(1).

[0263] (2) Synthesis of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b):

[0264] The product was synthesized using the method and conditions described in Example 1(2).

[0265] (3) Synthesis of 3-(propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (3c):

[0266] The product was synthesized using the method and conditions described in Example 3(3).

[0267] (4) Synthesis of 3-(propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (3d):

[0268] The product was synthesized using the method and conditions described in Example 3(4).

[0269] (5) Synthesis of 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (15e):

[0270] The product was synthesized using the same method and conditions as in Example 3(5), except that 2-chloronicotinoyl chloride (0.20 g, 1.15 mmol) was added to obtain 0.23 g of 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide as a brown solid in a yield of 68.86%.

[0271] (6) Synthesis of 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (A15):

[0272] The product was synthesized using the same method and conditions as in Example 3(6), except that 2-chloro-N-(3-(propylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide (0.23 g, 0.66 mmol) was added to obtain 0.16 g of 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide in a yield of 63.75%.

[0273] Physical and chemical properties of compound A15: white solid, melting point 238.8-239.5℃.

[0274] H NMR spectra of synthesized 1,2,4-triazolo[4,3-a]pyridine sulfone derivatives ( 1 H NMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) data are shown in Tables 1 and 2, respectively.

[0275] Table 1 The target compounds obtained in Examples A1-A15 1 HNMR data

[0276]

[0277]

[0278]

[0279]

[0280] Table 2 The target compounds obtained in Examples A1-A15 13 C NMR data

[0281]

[0282]

[0283] Test Example: Semi-in vivo antibacterial activity test of Examples A1-A15 against citrus Huanglongbing

[0284] (1) Collecting diseased citrus branches

[0285] Diseased branches were collected in Longping Town, Luodian County, Guizhou Province, and those with similar growth and healthy and symmetrical leaves were selected as test plants.

[0286] (2) Anti-citrus Huanglongbing activity test

[0287] Each of the 15 compounds, A1-A15, was weighed and prepared at a concentration of 200 mg / L. Penicillin and streptomycin, commonly used antibiotic fungicides, were used as positive controls. Test plants were placed in 50 mL centrifuge tubes containing 10 mL of deionized water. Three branches were selected for each sample test, with triplicate replicates. Citrus leaves were evenly sprayed with a fast-acting rooting solution to maintain freshness. After air-drying, the right half of the leaf was evenly coated with the prepared solution using a brush as the treatment group. The left half was then coated with the same treatment solvent without the drug as the control group (CK). The leaves were then incubated in an artificial climate chamber (24°C, 95% RH, 12 h light, 12 h dark). After three days of incubation, the treated branches were removed, and three leaves were harvested from each branch. The left and right halves were collected, wrapped in tin foil, labeled, and quickly frozen in liquid nitrogen before being transferred to a -80°C freezer.Total RNA was extracted from citrus using Trizol, and its concentration and quality were determined using a ScanDrop2 Ultra micro-protein and nucleic acid analyzer. The RNA was then used as a template for reverse transcription into cDNA using reverse transcriptase. The reverse transcription procedure was as follows: 30°C for 10 min; 42°C for 60 min; 70°C for 15 min; and 4°C forever. PCR amplification was performed using the CLas detection primer pair optimized by Li et al. (forward primer 5'-TCGAGCGCGTATGCAATACG-3' and reverse primer 5'-GCGTTATCCCGTAGAAAAGGTA-3') (Li, WB; Hartung, JS; Levy, L. Quantitative real-time PCR for detection and identification of Candidatus Liberibacter species associated with citrus Huanglongbing.JMicrobiolMeth.2006,66,104-115.), using citrus actin (forward primer: 5'-GGTATTGCCGACCGTATGAG-3' and reverse primer: 5'-TGGAAGGTGCTGAGGGATG-3') (Huang, CY; Niu, DD; Kund, G.; Jones, M.; Albrecht, U.; Nguyen, L.; Bui, C.; Ramadugu, C.; Bowman, KD; Trumble, J.; Jin, HL Identification of citrus immune regulators involved in indefence against Huanglongbing using a new functional screening system.Plant Biotechnol. J.2020,19,757-766.) as the internal reference gene. Reaction conditions: 95°C for 2 min, 95°C for 20 s, 57°C for 30 s, 70°C for 30 s (40 cycles), with fluorescence readings taken at the end of each cycle at 57°C. Each sample was measured three times, and the average Cq value was calculated by 2. -△△Cq The relative expression levels of the CLas gene were obtained, and finally the therapeutic activity of the corresponding compounds against citrus Huanglongbing was calculated according to the relative expression levels of the genes (as shown in Table 3).

[0288] Table 3 Anti-citrus Huanglongbing activity

[0289]

[0290]

[0291] The activity test results in Table 3 show that most 1,2,4-triazolo[4,3-a]pyridinesulfone compounds have good activity against citrus Huanglongbing. Among them, compounds A1, A2, A3, A6, A7, A8, A9, A10, and A15 all have anti-citrus Huanglongbing activity greater than 60%. Compounds A7 and A9 have the highest activity against citrus Huanglongbing fungi, with anti-citrus Huanglongbing activity of 84.1% and 73.4%, respectively.

Claims

1. A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative, characterized in that: The structural formula of the derivative is as follows: Among them, R 1 Select any one of the following structural formulas: R 2 is methyl, ethyl or propyl.

2. A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative according to claim 1, characterized in that: The 1,2,4-triazolo[4,3-a]pyridine sulfone derivatives include but are not limited to: A1: 2-bromo-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A2: 3-methyl-N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A3: 3-methyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A4: N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide; A5: N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide; A6: N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-nitro-4-(trifluoromethyl)benzamide; A7: 2-methoxy-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A8: 2,6-dichloro-N-(3-(methylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A9: 2-Fluoro-N-(3-(propanesulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A10: 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A11: 2,5-dimethyl-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide; A12: N-(3-(ethylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carboxamide; A13: N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)furan-2-carboxamide; A14: 2,6-difluoro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide; A15: 2-chloro-N-(3-(propylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)nicotinamide.

3. The synthetic route of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative as claimed in claim 1 or 2 is as follows:

4. A method for preparing a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative according to any one of claims 1 or 2, comprising the following steps: The first step is the preparation of 2-hydrazine-5-nitropyridine (a): Ethanol, 2-chloro-5-nitropyridine and 80% hydrazine hydrate were reacted at room temperature. The starting material disappeared after TLC detection. The product was directly filtered and the filter cake was compound a. Step 2 Preparation of 6-nitro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (b): Compound a and potassium carbonate were stirred in anhydrous ethanol at a molar ratio of compound a: carbon disulfide: potassium carbonate = 1:1.5:1.5, and carbon disulfide was added. After reflux, the ethanol was removed by decompression. Water was added and the pH was adjusted to 4-5 with 1% hydrobromic acid to precipitate a yellow solid, which was filtered and dried to obtain compound b. Step 3 Preparation of 3-(methyl / ethyl / propylthio)-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (1c-3c): Compound b was dissolved in acetonitrile, K2CO3 was added with stirring, and then a halogenated alkane was added. After the reaction was refluxed at 85°C for 2 h, the acetonitrile was removed by desolventizing and then dissolved in ethyl acetate. The mixture was washed with saturated brine, extracted, dried over anhydrous magnesium sulfate, and filtered. After desolventizing and purification by chromatography, a brown solid was obtained after drying, which was compound 1c-3c. Step 4 Preparation of 3-(methyl / ethyl / propylthio)-6-amino-[1,2,4]triazolo[4,3-a]pyridine (1d-3d): Compounds 1c-3c were dissolved in ethanol solution, ammonium chloride was added with stirring, and iron powder was added. After reflux at 90°C for 3 h, the iron residue was removed by filtration, and then extracted three times with ethyl acetate. After desolventizing under reduced pressure, the mixture was separated and purified by column chromatography. After drying, a green solid was obtained, which was compound 1d-3d. Step 5: Preparation of intermediate 1e-15e: Compounds 1d-3d were dissolved in dichloromethane at a molar ratio of 1d-3d: substituted acid chloride: triethylamine = 1:1.2:1.

5. Triethylamine was added and stirred in an ice bath for 5 minutes. The substituted acid chloride was then slowly added dropwise and allowed to react for 1 hour. The reaction product was washed with saturated brine, desolvated under reduced pressure, and purified by column chromatography. After drying, a white / brown solid was obtained, which is compound 1e-15e. Step 6 Preparation of Compounds A1-A15: Compounds 1e-15e were dissolved in ethanol at a molar ratio of compound 1e-15e: ammonium molybdate: hydrogen peroxide = 1:0.1:

20. Ammonium molybdate was dissolved in hydrogen peroxide and then slowly added dropwise to the reaction system. After stirring at room temperature for 24 h, ice water was added to precipitate a white / brown solid, which was filtered and dried to obtain the target products A1-A15.

5. A 1,2,4-triazolo[4,3-a]pyridine sulfone derivative as claimed in claim 1 or 2 for use in preventing and controlling citrus Huanglongbing disease.

6. Use of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative as claimed in claim 1 or 2 in the preparation of a citrus Huanglongbing preventive preparation.

7. Use of a 1,2,4-triazolo[4,3-a]pyridine sulfone derivative as claimed in claim 1 or 2 in the preparation of a preparation for treating citrus Huanglongbing.

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