1, 2, 4-thiadiazole-containing amide derivative and preparation method and application thereof

Abstract

The invention relates to the technical field of chemistry, in particular to an amide derivative containing 1, 2, 4-thiadiazole, and further relates to a preparation method of the amide derivative containing 1, 2, 4-thiadiazole and application of the amide derivative containing 1, 2, 4-thiadiazole in the aspects of plant pathogenic bacterium resistance and nematicidal activity, and particularly relates to an amide derivative containing 1, 2, 4-thiadiazole, a preparation method of the amide derivative containing 1, 2, 4-thiadiazole and application of the amide derivative containing 1, 2, 4-thiadiazole in the aspects of plant pathogenic bacterium resistance and nematicidal activity. The amide derivative containing 1, 2, 4-thiadiazole has excellent antibacterial activity on three kinds of plant pathogenic bacteria, which shows that the amide derivative has a good application prospect in preparation of antibacterial agent drugs.

Description

Technical Field

[0001] The present invention relates to the field of chemical technology, and in particular to an amide derivative containing 1,2,4-thiadiazole, and also relates to a preparation method of the amide derivative containing 1,2,4-thiadiazole, and use of the amide derivative containing 1,2,4-thiadiazole in preventing and controlling anti-plant pathogenic bacteria and nematicidal activity. Background Art

[0002] Plant bacterial diseases cause a significant decrease in crop yield and quality (Mansfield J., Genin S., Magori S., Citovsky V., Sriariyanum M., Ronald P., Dow M., Verdier V., Beer SV, Machado MA, Toth I., Salmond G., Foster GD Top 10 plant pathogenic bacteria in molecular plant pathology [J]. Mol. Plant Pathol. 2012, 13, 614-629.), which greatly reduces global crop productivity and causes huge economic losses to agricultural production every year (Yi CF, Chen JX, Hu DY, Song B.A. First report about the screening, characterization, and fosmid library construction of Xanthomonas oryzae pv. oryzae strain with resistance to Fubianezuofeng [J]. Pestic. Biochem. Phys. 2020, 169, 104645.). Plant pathogenic nematodes are of various species, have a wide range of hosts, cause serious damage, are highly contagious and adaptable (Chen JX, Chen Y.Z., Gan XH, Song BJ, Hu D.Y., Song BA Synthesis, nematicidal evaluation, and 3D-QSAR analysis of novel 1,3,4-oxadiazole-cinnamic acid hybrids[J]. J. Agric. Food Chem. 2018, 66, 9616-9623.), and cause huge economic losses to the world every year (Wang GL, Chen XL, Deng YY, Li Z., Xu X.Y. Synthesis and nematicidal activities of 1,2,3–benzotriazin–4–one derivatives against Meloidogyne incognita[J]. J. Agric. Food Chem. 2015, 63, 6883–6889.).The 1,2,4-thiadiazole structure is a small nitrogen-containing heterocyclic molecule, and the derivatives containing the 1,2,4-thiadiazole structure have insecticidal (Yoshihisa O., Kazuo Y., Masafumi N., Miki A., Takashi M., Fumio M. Fipronil-Related Heterocyclic Compounds: Structure–Activity Relationships for Interaction with γ-Aminobutyric Acid-and Voltage-Gated Ion Channels and Insecticidal Action [J]. Pestic. Biochem. Physiol. 2000, 66, 92-104.) and antibacterial (Anton S., Marina T., Valentina K., Sergey B., Kirill G., Svetlana K., Nikolina S., Vladimir S., Elizaveta VR, Liudmila AKExternal oxidant-free and transitionmetal-free synthesis of 5-amino-1,2,4-thiadiazoles as promising antibacterials against ESKAPE pathogen strains[J].Mol.Divers.2023,27,651-666.) and other broad-spectrum activities, but their anti-plant bacteria and nematicide effects have not yet been reported.Amide compounds have good anti-plant pathogenic bacteria (Chen MH, Lu DW, Zhang X., Zhou ZY, Wang XB, ShuH. Synthesis of novel coumarin substituted amide derivatives and their antibacterial activities[J]. Chemical Papers. 2017, 71, 1579-1586.) and nematicidal activities (Chen JX, Yi CF, Wang SB, Wu SK, Li SY, Hu DY, Song BA Novel amide derivatives containing 1,3,4-thiadiazole moiety: Design, synthesis, nematocidal and antibacterial activities. Bioorg. Med. Chem. Lett. 2019, 29, 1203–1210.). In terms of nematode killing, the amide structure plays a key role in the SDH target (Xu QB, Zhao ZX, Liang PB, Wang S.M., Li F., Jin SH, Zhang J J. Identification of novel nematode succinate dehydrogenase inhibitors: Virtual screening based on ligand-pocket interactions [J]. Chem. Bio. Drug Des., 2023, 101, 9-23).For example, in 2020, Xiang J., Liu D., Chen JX, Hu DY, Song BADesign and synthesis of novel 1,3,4-oxadiazole sulfone compounds containing 3,4-dichloroisothiazolylamide moiety and evaluation of rice bacterial activity[J]. Pestic.Biochem.Physiol.2020,170,104695.) reported a series of novel 1,3,4-oxadiazole sulfone compounds with 1,3-dichloroisothiazoleamide as the part. The biological activity experiments showed that the compounds 3,4-dichloro-N-((5-(ethylsulfonyl)-1,3,4-oxadiazole-2-yl)methyl)isothiazole-5-carboxamide and 3,4-dichloro-N-((5-(propylsulfonyl)-1,3,4-oxadiazole-2-yl)methyl)isothiazole-5-carboxamide had good activity against rice bacterial blight pathogen, and their EC 50 They are 0.79 and 0.85 mg / L respectively; they also have good activity against bacterial leaf spot on rice, and their EC 50 2.21 and 1.12 mg / L respectively. The results of physiological and biochemical tests showed that the compound 3,4-dichloro-N-((5-(ethylsulfonyl)-1,3,4-oxazol-2-yl)methyl)isothiazole-5-carboxamide can affect the function of biofilm by inhibiting extracellular polysaccharides and increasing cell membrane permeability, thereby inhibiting bacterial growth. In 2021, Mou Honglan et al. (Mou HL, Shi J., Chen JX, Hu DYSynthesis, antibacterial activity and mechanism of newbutenolides derivatives containing an amide moiety[J]. Pestic. Biochem. Physiol. 2021, 178, 104913.) reported a series of new butenolide derivatives containing amide structures and evaluated their inhibitory activity. The results showed that the compound 2-((3-fluorobenzyl)(5-oxo-2,5-dihydrofuran-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)acetamide had good activity against Xanthomonas oryzae. 50The results of in vivo tests on rice showed that it showed good in vivo activity against rice bacterial leaf blight at 100 mg / L, with therapeutic and protective activities of 40.9% and 48.9%, respectively, which were better than those of chlorothalonil (31.2% and 31.4%). The results of mechanism studies showed that it may enhance the disease resistance of rice by increasing the activity of defense enzymes. Its protective activity against rice bacterial leaf blight may be closely related to oxidative phosphorylation and defense enzyme activity. In 2023, Wei Chengqian et al. (Wei, CQ; Huang, JJ; Luo, YQ; Wang, SB; Wu, SK; Xing, ZF; Chen, JX Novel amide derivatives containing an imidazo[1,2–a]pyridine moiety: Design, synthesis as potential nematicidal and antibacterial agents. Pestic. Biochem. Phys. 2021, 175, 104857.) reported new amide-containing imidazo[1,2-a]pyridine derivatives. The test results showed that the compound 8-chloro-N-(((5-(propylsulfone)-1,3,4-oxadiazol-2-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridinecarboxamide had a high LC-MS / MS activity against rice dry tip nematodes. 50 The compound 8-chloro-N-(3-(5-(decylsulfonyl)-1,3,4-oxadiazol-2-yl)propyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridinecarboxamide has good nematicidal activity against rice stem nematodes and Caenorhabditis elegans, LC 50 35.9 and 5.7 mg / L, respectively, which are better than the control drug thiazophos (45.4 and 77.2 mg / L). The mechanism results show that the compound 8-chloro-N-(3-(5-(decylsulfone)-1,3,4-oxadiazol-2-yl)propyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridinecarboxamide shows good inhibitory activity (71.1%) on acetylcholinesterase (AchE) of Caenorhabditis elegans at a concentration of 50 mg / L. Molecular docking shows that it has a good binding mode and binding energy with AChE, with a binding energy of -47.9 kcal / mol, which is better than the control drug thiazophos (-33.6 kcal / mol), which is consistent with the nematicidal activity test results. It can be seen that the splicing of 1,2,4-thiadiazole and amide structures plays an important role in the creation of antibacterial and nematicidal agents, indicating that it has good application prospects in the preparation of antibacterial and nematicidal drugs.

[0003] At present, there are no reports on the synthesis of amide derivatives containing 1,2,4-thiadiazole and their anti-plant pathogenic bacteria and nematicidal activities at home and abroad. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides an amide derivative containing 1,2,4-thiadiazole and a preparation method and use thereof.

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

[0006] An amide derivative containing 1,2,4-thiadiazole is prepared by combining an amide structure with a 1,2,4-thiadiazole structure, and its structural formula is as follows:

[0007]

[0008] Where n is 1 or 2; R 1 is methyl, ethyl, propyl, chloromethyl or chloroethyl; R 2 is 4-fluorophenyl, phenyl, 4-chlorophenyl or 4-bromophenyl.

[0009] Furthermore, the R 2 Selected from the following structural formula:

[0010]

[0011] Furthermore, an amide derivative containing 1,2,4-thiadiazole includes but is not limited to:

[0012] Z1: 4-fluoro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0013] Z2: N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0014] Z3: 4-chloro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0015] Z4: 4-bromo-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0016] Z5: N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide;

[0017] Z6: N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0018] Z7: 4-chloro-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0019] Z8: 4-bromo-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0020] Z9: 4-fluoro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0021] Z10: N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0022] Z11: 4-chloro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0023] Z12: 4-bromo-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0024] Z13: N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide;

[0025] Z14: N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0026] Z15: 4-chloro-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0027] Z16: 4-bromo-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0028] Z17: N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide;

[0029] Z18: N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0030] Z19: 4-chloro-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0031] Z20: 4-bromo-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide;

[0032] Z21: 4-fluoro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide;

[0033] Z22: N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide;

[0034] Z23: 4-chloro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide;

[0035] Z24: 4-bromo-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide.

[0036] The synthetic route of an amide derivative containing 1,2,4-thiadiazole is as follows:

[0037]

[0038] The preparation method of amide derivatives containing 1,2,4-thiadiazole comprises the following steps:

[0039] Preparation of the first intermediate oxime (a1-a2):

[0040] Dissolve aminoacetonitrile hydrochloride in dichloromethane, add triethylamine, add di-tert-butyl dicarbonate under ice bath conditions, react at room temperature for 16 hours, and detect the reaction on a plate. After the reaction is complete, add water and extract 2-3 times, combine the organic layers and distill under reduced pressure to obtain crude product a1-a2;

[0041] Preparation of the second intermediate (b1-b2):

[0042] Dissolve the intermediate a1-a2 in ethanol, add triethylamine first, stir for 30 minutes, add hydroxylamine hydrochloride, react at room temperature for 8 hours, and monitor the reaction with a plate. After the ethanol is distilled under reduced pressure, extract with water and ethyl acetate 2-3 times, combine the organic layers and distill under reduced pressure to obtain a white solid b1-b2;

[0043] Preparation of the third intermediate (c1-c2):

[0044] Dissolve KOH in ethanol and add CS 2 , stirred for 30 min, then added intermediate b1-b2, heated under reflux for 8 h, and tested the reaction on a plate. After the reaction was complete, the intermediate c1-c2 was obtained by vacuum distillation;

[0045] Preparation of the fourth step intermediate (d1-d6):

[0046] The above intermediate c was dissolved in acetonitrile and K 2 CO3 , then add R 1 X, heated under reflux for 2 h. Remove acetonitrile by decompression, and purify by column chromatography (PE / EA=3 / 1) to obtain intermediate d1-d6;

[0047] Preparation of the fifth intermediate (e1-e6):

[0048] Directly add CF to the above intermediates d1-d6 3 COOH, react at room temperature for 30 minutes, and detect the reaction on a spot plate. After the reaction is complete, trifluoroacetic acid is removed by vacuum distillation to obtain intermediates e1-e6;

[0049] Preparation of the sixth step intermediate (f1-f4):

[0050] Direct addition of SOCl to different benzoic acids 2 , add a few drops of DMF as a catalyst, heat to reflux for 6 hours, and monitor the reaction. 2 Remove to obtain intermediate f1-f4;

[0051] Preparation of the seventh intermediate (g1-g24):

[0052] Directly add dichloromethane to the intermediate e to dissolve it, add intermediate f under ice bath condition, react for 2 hours, and detect the reaction by spot plate. After the reaction is completed, purify it by column chromatography (PE / EA=2 / 1) to obtain intermediate g;

[0053] Step 8 Preparation of Compounds Z1-Z24:

[0054] Add a small amount of ethanol to the intermediate g to dissolve it, and add ammonium molybdate and H 2 O 2 The reagents were mixed, reacted for 6 hours, and the reaction was detected by spot plate. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered and washed with ethanol several times to obtain the target compounds Z1-Z24.

[0055] An amide derivative containing 1,2,4-thiadiazole is used to control plant pathogenic bacteria and nematodes.

[0056] The invention discloses an application of an amide derivative containing 1,2,4-thiadiazole in the preparation of an antibacterial agent for plant pathogenic bacteria and a nematode.

[0057] Beneficial effects:

[0058] The derivative of the invention has the advantages of simple preparation process, excellent reaction yield and low raw material cost.

[0059] The derivatives of the present invention have excellent inhibitory activity against plant pathogenic bacteria. DETAILED DESCRIPTION

[0060] The specific embodiments of the present invention are further described in detail below, but the present invention is not limited to these embodiments, and any improvement or substitution based on the basic spirit of the present embodiment still falls within the scope of protection required by the claims of the present invention.

[0061] Example 1

[0062] The preparation method of 4-fluoro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z1) comprises the following steps:

[0063] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0064] Aminoacetonitrile hydrochloride (22.2, 240 mmol) was added to a three-necked flask (500 mL) containing 150 mL of dichloromethane, followed by triethylamine (480 mmol). Finally, di-tert-butyl dicarbonate (264 mmol) was added at 0°C and reacted at room temperature for 16 h. After the reaction was completed, water was added and extracted twice, and the organic layers were combined and distilled under reduced pressure to obtain intermediate a1, with a mass of 32.78 g and a yield of 87.5%.

[0065] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0066] Intermediate a1 (32.78 g, 210 mmol) and triethylamine (630 mmol) were added to a round-bottom flask containing ethanol and stirred for 30 min. Hydroxylamine hydrochloride (420 mmol) was then added and reacted at room temperature for 8 h. After the reaction, the ethanol was distilled under reduced pressure, and water and ethyl acetate were added to extract twice. The organic layers were combined and distilled under reduced pressure to obtain intermediate b1. The mass was 34.02 g, and the yield was 85.7%.

[0067] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0068] KOH (360 mmol) was dissolved in 120 mL of ethanol and CS was slowly added. 2 (900 mmol), stirred for 30 min. Then, intermediate b1 (34.02 g, 180 mmol) was added, and heated under reflux for 10 h. After ethanol was distilled under reduced pressure, intermediate c1 was obtained, with a mass of 25.19 g and a yield of 60.5%.

[0069] (4) Synthesis of tert-butyl ((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d1):

[0070] Intermediate c (11.55 g, 50 mmol) and K 2 CO 3 (75 mmol) was dissolved in 100 mL of acetonitrile, followed by addition of iodomethane (75 mmol) and heating under reflux for 2 h. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate d1 with a mass of 7.15 g and a yield of 72.0%.

[0071] (5) Synthesis of (5-(methylthio)-1,2,4-thiadiazol-3-yl)methylamine (e1):

[0072] To intermediate d1 (7.15 g, 36 mmol) was added CF 3 COOH (180 mmol) was added and reacted at room temperature for 30 min. After the reaction was completed, trifluoroacetic acid was distilled off under reduced pressure to obtain intermediate e1 with a mass of 4.81 g and a yield of 92.1%.

[0073] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0074] 4-Fluoroformic acid (0.28 g, 2 mmol) and SOCl 2 (10 mmol) was added into a 100 mL round-bottom flask and heated under reflux for 6 h. 2 The intermediate f1 was removed by distillation under reduced pressure, with a mass of 0.25 g and a yield of 90.5%.

[0075] (7) Synthesis of 4-fluoro-N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g1):

[0076] Intermediate e1 (0.29 g, 1.8 mmol) and triethylamine (2.7 mmol) were dissolved in dichloromethane, and intermediate f1 was added at 0°C for 2 h. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate g1 with a mass of 0.21 g and a yield of 44.4%.

[0077] (8) Synthesis of 4-fluoro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z1):

[0078] Intermediate g1 (0.23 g, 0.8 mmol) was dissolved in 3 mL of ethanol, and ammonium molybdate (0.08 mmol) and H 2 O 2 (5.6 mmol) mixed reagents, reacted at room temperature for 8 h, added 20 mL of water to quench the reaction, filtered and washed with a small amount of ethanol to obtain the target compound Z1, a white solid of 0.20 g, with a yield of 83.6%.

[0079] Physical and chemical properties of compound Z1: white solid, melting point 133.5-134.8℃.

[0080] Example 2

[0081] The preparation method of N-((5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)methyl)benzamide (compound number Z2) comprises the following steps:

[0082] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0083] The product was synthesized using the method and conditions of Example 1(1).

[0084] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0085] The product was synthesized using the method and conditions of Example 1(2).

[0086] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0087] The product was synthesized using the method and conditions of Example 1(3).

[0088] (4) Synthesis of tert-butyl ((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d1):

[0089] The product was synthesized using the method and conditions of Example 1(4).

[0090] (5) Synthesis of (5-(methylthio)-1,2,4-thiadiazol-3-yl)methylamine (e1):

[0091] The product was synthesized using the method and conditions of Example 1(5).

[0092] (6) Synthesis of benzoyl chloride (f2):

[0093] The synthesis was carried out according to the method and conditions of Example 1 (6), except that benzoic acid (0.24 g, 2 mmol) was added to obtain 0.25 g of benzoyl chloride with a yield of 89.2%.

[0094] (7) Synthesis of N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g2):

[0095] The method and conditions of Example 1 (7) were used for synthesis, except that benzoyl chloride (0.25 g, 1.78 mmol) was added to obtain intermediate g2 with a mass of 0.17 g and a yield of 40.2%.

[0096] (8) Synthesis of N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z2):

[0097] The product was synthesized using the method and conditions of Example 1(8), except that N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.17 g, 0.72 mmol) and 0.15 g of N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide were added to give a white solid with a yield of 68.3%.

[0098] Physical and chemical properties of compound Z2: white solid, melting point 117.0-118.2℃.

[0099] Example 3

[0100] The preparation method of 4-chloro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z3) comprises the following steps:

[0101] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0102] The product was synthesized using the method and conditions of Example 1(1).

[0103] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0104] The product was synthesized using the method and conditions of Example 1(2).

[0105] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0106] The product was synthesized using the method and conditions of Example 1(3).

[0107] (4) Synthesis of tert-butyl ((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d1):

[0108] The product was synthesized using the method and conditions of Example 1(4).

[0109] (5) Synthesis of (5-(methylthio)-1,2,4-thiadiazol-3-yl)methylamine (e1):

[0110] The product was synthesized using the method and conditions of Example 1(5).

[0111] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0112] The method and conditions of Example 1(6) were used for synthesis, except that 4-chlorobenzoic acid (0.31 g, 2 mmol) was added to obtain 0.32 g of 4-chlorobenzoyl chloride with a yield of 91.5%.

[0113] (7) Synthesis of 4-chloro-N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g3):

[0114] The method and conditions of Example 1 (7) were used for synthesis, except that 4-chlorobenzoyl chloride (0.32 g, 1.83 mmol) was added to obtain intermediate g3 with a mass of 0.25 g and a yield of 46.2%.

[0115] (8) Synthesis of 4-chloro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z3):

[0116] The method and conditions of Example 1(8) were used for synthesis, except that 4-chloro-N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.25 g, 0.85 mmol) was added to obtain 0.20 g of 4-chloro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 72.1%.

[0117] Physical and chemical properties of compound Z3: white solid, melting point 159.2-160.5℃.

[0118] Example 4

[0119] The preparation method of 4-bromo-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z4) comprises the following steps:

[0120] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0121] The product was synthesized using the method and conditions of Example 1(1).

[0122] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0123] The product was synthesized using the method and conditions of Example 1(2).

[0124] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0125] The product was synthesized using the method and conditions of Example 1(3).

[0126] (4) Synthesis of tert-butyl ((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d1):

[0127] The product was synthesized using the method and conditions of Example 1(4).

[0128] (5) Synthesis of (5-(methylthio)-1,2,4-thiadiazol-3-yl)methylamine (e1):

[0129] The product was synthesized using the method and conditions of Example 1(5).

[0130] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0131] The synthesis was carried out according to the method and conditions of Example 1 (6), except that 4-bromobenzoic acid (0.40 g, 2 mmol) was added to obtain 0.40 g of 4-bromobenzoyl chloride with a yield of 92.0%.

[0132] (7) Synthesis of 4-bromo-N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g4):

[0133] The method and conditions of Example 1 (7) were used for synthesis, except that 4-bromobenzoyl chloride (0.40 g, 1.84 mmol) was added to obtain intermediate g4 with a mass of 0.32 g and a yield of 50.6%.

[0134] (8) Synthesis of 4-bromo-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z4):

[0135] The method and conditions of Example 3(4) were used for synthesis, except that 4-bromo-N-((5-(methylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.32 g, 0.93 mmol) was added to obtain 0.28 g of 4-bromo-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid, 80.5%.

[0136] Physical and chemical properties of compound Z4: white solid, melting point 175.9-177.2℃.

[0137] Example 5

[0138] The preparation method of N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (compound number Z5) comprises the following steps:

[0139] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0140] The product was synthesized using the method and conditions of Example 1(1).

[0141] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0142] The product was synthesized using the method and conditions of Example 1(2).

[0143] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0144] The product was synthesized using the method and conditions of Example 1(3).

[0145] (4) Synthesis of tert-butyl ((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d2):

[0146] The method and conditions of Example 1(4) were used for synthesis, except that ethyl bromide was added to obtain intermediate d2 with a mass of 8.21 g and a yield of 75.1%.

[0147] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e2):

[0148] The method and conditions of Example 1(5) were used for synthesis, except that tert-butyl((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate was added to obtain intermediate e2 with a mass of 5.12 g and a yield of 93.5%.

[0149] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0150] The product was synthesized using the method and conditions of Example 1(6).

[0151] (7) Synthesis of N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (g5):

[0152] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.32 g, 1.80 mmol) was added to obtain intermediate g5 with a mass of 0.33 g and a yield of 56.5%.

[0153] (8) Synthesis of N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (Z5):

[0154] The synthesis was carried out according to the method and conditions of Example 1(8), except that N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide was added to obtain 0.29 g of N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide as a white solid. The yield was 85.2%.

[0155] Physical and chemical properties of compound Z5: white solid, melting point 132.7-133.9℃.

[0156] Example 6

[0157] The preparation method of N-((5-(ethylsulfonyl)-1,2,4-thiadiazole-3-yl)methyl)benzamide (compound number Z6) comprises the following steps:

[0158] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

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

[0160] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0161] The product was synthesized using the method and conditions of Example 1(2).

[0162] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0163] The product was synthesized using the method and conditions of Example 1(3).

[0164] (4) Synthesis of tert-butyl ((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d2):

[0165] The product was synthesized using the method and conditions of Example 5(4).

[0166] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e2):

[0167] The product was synthesized using the method and conditions of Example 5(5).

[0168] (6) Synthesis of benzoyl chloride (f2):

[0169] The product was synthesized using the method and conditions of Example 2(6).

[0170] (7) Synthesis of N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g6):

[0171] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.32 g, 1.80 mmol) was added to obtain intermediate g6 with a mass of 0.30 g and a yield of 51.4%.

[0172] (8) Synthesis of N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z6):

[0173] The method and conditions of Example 1(8) were used for synthesis, except that N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.30 g, 0.93 mmol) was added to obtain 0.18 g of N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 62.9%.

[0174] Physical and chemical properties of compound Z6: white solid, melting point 110.9-112.0℃.

[0175] Example 7

[0176] The preparation method of 4-chloro-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z7) comprises the following steps:

[0177] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0178] The product was synthesized using the method and conditions of Example 1(1).

[0179] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0180] The product was synthesized using the method and conditions of Example 1(2).

[0181] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0182] The product was synthesized using the method and conditions of Example 1(3).

[0183] (4) Synthesis of tert-butyl ((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d2):

[0184] The product was synthesized using the method and conditions of Example 5(4).

[0185] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e2):

[0186] The product was synthesized using the method and conditions of Example 5(5).

[0187] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0188] The product was synthesized using the method and conditions of Example 3(6).

[0189] (7) Synthesis of 4-chloro-N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g7):

[0190] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.32 g, 1.80 mmol) was added to obtain intermediate g7 with a mass of 0.32 g and a yield of 54.8%.

[0191] (8) Synthesis of 4-chloro-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z7):

[0192] The method and conditions of Example 1(8) were used for synthesis, except that 4-chloro-N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.32 g, 0.99 mmol) was added to obtain 0.25 g of 4-chloro-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a yellow solid. The yield was 72.7%.

[0193] Physical and chemical properties of compound Z7: yellow solid, melting point 134.7-135.9℃.

[0194] Example 8

[0195] The preparation method of 4-bromo-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z8) comprises the following steps:

[0196] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0197] The product was synthesized using the method and conditions of Example 1(1).

[0198] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0199] The product was synthesized using the method and conditions of Example 1(2).

[0200] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0201] The product was synthesized using the method and conditions of Example 1(3).

[0202] (4) Synthesis of tert-butyl ((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d2):

[0203] The product was synthesized using the method and conditions of Example 5(4).

[0204] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e2):

[0205] The product was synthesized using the method and conditions of Example 5(5).

[0206] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0207] The product was synthesized using the method and conditions of Example 4(6).

[0208] (7) Synthesis of 4-bromo-N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g8):

[0209] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.32 g, 1.80 mmol) was added to obtain intermediate g7 with a mass of 0.34 g and a yield of 58.2%.

[0210] (8) Synthesis of 4-bromo-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z8):

[0211] The method and conditions of Example 1(8) were used for synthesis, except that 4-bromo-N-((5-(ethylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.34 g, 1.05 mmol) was added to obtain 0.33 g of 4-bromo-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 81.3%.

[0212] Physical and chemical properties of compound Z8: white solid, melting point 142.9-143.8℃.

[0213] Example 9

[0214] The preparation method of 4-fluoro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z9) comprises the following steps:

[0215] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0216] The product was synthesized using the method and conditions of Example 1(1).

[0217] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0218] The product was synthesized using the method and conditions of Example 1(2).

[0219] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0220] The product was synthesized using the method and conditions of Example 1(3).

[0221] (4) Synthesis of tert-butyl ((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d3):

[0222] The method and conditions of Example 1(4) were used for synthesis, except that bromopropane was added to obtain intermediate d3 with a mass of 8.10 g and a yield of 71.8%.

[0223] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e3):

[0224] The method and conditions of Example 1(5) were used for synthesis, except that tert-butyl ((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate was added to obtain intermediate e3 with a mass of 4.92 g and a yield of 91.6%.

[0225] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0226] The product was synthesized using the method and conditions of Example 1(6).

[0227] (7) Synthesis of 4-fluoro-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g9):

[0228] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.33 g, 1.75 mmol) was added to obtain intermediate g9 with a mass of 0.27 g and a yield of 50.2%.

[0229] (8) Synthesis of 4-fluoro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z9):

[0230] The method and conditions of Example 1(8) were used for synthesis, except that 4-fluoro-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.27 g, 0.88 mmol) was added to obtain 0.25 g of 4-fluoro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 83.4%.

[0231] Physical and chemical properties of compound Z9: white solid, melting point 132.7-134.1℃.

[0232] Example 10

[0233] The preparation method of N-((5-(propylsulfonyl)-1,2,4-thiadiazole-3-yl)methyl)benzamide (compound number Z10) comprises the following steps:

[0234] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0235] The product was synthesized using the method and conditions of Example 1(1).

[0236] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0237] The product was synthesized using the method and conditions of Example 1(2).

[0238] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0239] The product was synthesized using the method and conditions of Example 1(3).

[0240] (4) Synthesis of tert-butyl ((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d3):

[0241] The product was synthesized using the method and conditions of Example 9(4).

[0242] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e3):

[0243] The product was synthesized using the method and conditions of Example 9(5).

[0244] (6) Synthesis of benzoyl chloride (f2):

[0245] The product was synthesized using the method and conditions of Example 2(6).

[0246] (7) Synthesis of N-((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g10):

[0247] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.33 g, 1.75 mmol) was added to obtain intermediate g10 with a mass of 0.30 g and a yield of 55.8%.

[0248] (8) Synthesis of N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z10):

[0249] The method and conditions of Example 1(8) were used for synthesis, except that N-((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.30 g, 0.98 mmol) was added to obtain 0.21 g of N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 65.5%.

[0250] Physical and chemical properties of compound Z10: white solid, melting point 103.3-104.6℃.

[0251] Embodiment 11

[0252] The preparation method of 4-chloro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z11) comprises the following steps:

[0253] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0254] The product was synthesized using the method and conditions of Example 1(1).

[0255] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0256] The product was synthesized using the method and conditions of Example 1(2).

[0257] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0258] The product was synthesized using the method and conditions of Example 1(3).

[0259] (4) Synthesis of tert-butyl ((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d3):

[0260] The product was synthesized using the method and conditions of Example 9(4).

[0261] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e3):

[0262] The product was synthesized using the method and conditions of Example 9(5).

[0263] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0264] The product was synthesized using the method and conditions of Example 3(6).

[0265] (7) Synthesis of 4-chloro-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g11):

[0266] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.33 g, 1.75 mmol) was added to obtain intermediate g11 with a mass of 0.32 g and a yield of 59.5%.

[0267] (8) Synthesis of 4-chloro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z11):

[0268] The method and conditions of Example 1(8) were used to synthesize the product, except that 4-chloro-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.32 g, 1.04 mmol) was added to obtain 0.29 g of 4-chloro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 77.2%.

[0269] Physical and chemical properties of compound Z11: white solid, melting point 148.3-150.1℃.

[0270] Example 12

[0271] The preparation method of 4-bromo-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z12) comprises the following steps:

[0272] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0273] The product was synthesized using the method and conditions of Example 1(1).

[0274] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0275] The product was synthesized using the method and conditions of Example 1(2).

[0276] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0277] The product was synthesized using the method and conditions of Example 1(3).

[0278] (4) Synthesis of tert-butyl ((5-(propylthio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d3):

[0279] The product was synthesized using the method and conditions of Example 9(4).

[0280] (5) Synthesis of (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (e3):

[0281] The product was synthesized using the method and conditions of Example 9(5).

[0282] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0283] The product was synthesized using the method and conditions of Example 4(6).

[0284] (7) Synthesis of 4-bromo-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g12):

[0285] The method and conditions of Example 1(7) were used for synthesis, except that (5-(ethylthio)-1,2,4-thiadiazol-3-yl)methylamine (0.33 g, 1.75 mmol) was added to obtain intermediate g12 with a mass of 0.30 g and a yield of 55.8%.

[0286] (8) Synthesis of 4-bromo-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z12):

[0287] The synthesis was carried out according to the method and conditions of Example 1(8), except that 4-bromo-N-((5-propylthio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.30 g, 0.98 mmol) was added to obtain 0.32 g of 4-bromo-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 81.8%.

[0288] Physical and chemical properties of compound Z12: white solid, melting point 147.2-148.3℃.

[0289] Embodiment 13

[0290] The preparation method of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (compound number Z13) comprises the following steps:

[0291] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0292] The product was synthesized using the method and conditions of Example 1(1).

[0293] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0294] The product was synthesized using the method and conditions of Example 1(2).

[0295] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0296] The product was synthesized using the method and conditions of Example 1(3).

[0297] (4) Synthesis of tert-butyl ((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d4):

[0298] The method and conditions of Example 1(4) were used for synthesis, except that bromochloromethane was added to obtain intermediate d4 with a mass of 7.68 g and a yield of 68.9%.

[0299] (5) Synthesis of (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (e4):

[0300] The method and conditions of Example 1(5) were used for synthesis, except that tert-butyl((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate was added to obtain intermediate e4 with a mass of 4.76 g and a yield of 88.3%.

[0301] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0302] The product was synthesized using the method and conditions of Example 1(6).

[0303] (7) Synthesis of N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (g13):

[0304] The method and conditions of Example 1(7) were used for synthesis, except that (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (0.36 g, 1.83 mmol) was added to obtain intermediate g13 with a mass of 0.34 g and a yield of 59.2%.

[0305] (8) Synthesis of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (Z13):

[0306] The method and conditions of Example 1(8) were used to synthesize the product, except that N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (0.34 g, 1.08 mmol) was added to obtain 0.31 g of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide as a white solid. The yield was 82.1%.

[0307] Physical and chemical properties of compound Z13: white solid, melting point 122.7-123.9℃.

[0308] Embodiment 14

[0309] The preparation method of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z14) comprises the following steps:

[0310] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0311] The product was synthesized using the method and conditions of Example 1(1).

[0312] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0313] The product was synthesized using the method and conditions of Example 1(2).

[0314] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0315] The product was synthesized using the method and conditions of Example 1(3).

[0316] (4) Synthesis of tert-butyl ((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d4):

[0317] The product was synthesized using the method and conditions of Example 13(4).

[0318] (5) Synthesis of (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (e4):

[0319] The product was synthesized using the method and conditions of Example 13(5).

[0320] (6) Synthesis of benzoyl chloride (f2):

[0321] The product was synthesized using the method and conditions of Example 2(6).

[0322] (7) Synthesis of N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g14):

[0323] The synthesis was carried out according to the method and conditions of Example 1 (7), except that (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (0.36 g, 1.83 mmol) was added to obtain intermediate g14 with a mass of 0.30 g and a yield of 52.2%.

[0324] (8) Synthesis of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z14):

[0325] The method and conditions of Example 1(8) were used for synthesis, except that N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.30 g, 0.96 mmol) was added to obtain 0.22 g of N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 70.1%.

[0326] Physical and chemical properties of compound Z14: white solid, melting point 123.7-124.4℃.

[0327] Embodiment 15

[0328] The preparation method of 4-chloro-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z15) comprises the following steps:

[0329] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0330] The product was synthesized using the method and conditions of Example 1(1).

[0331] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0332] The product was synthesized using the method and conditions of Example 1(2).

[0333] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0334] The product was synthesized using the method and conditions of Example 1(3).

[0335] (4) Synthesis of tert-butyl ((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d4):

[0336] The product was synthesized using the method and conditions of Example 13(4).

[0337] (5) Synthesis of (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (e4):

[0338] The product was synthesized using the method and conditions of Example 13(5).

[0339] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0340] The product was synthesized using the method and conditions of Example 3(6).

[0341] (7) Synthesis of 4-chloro-N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g15):

[0342] The method and conditions of Example 1(7) were used for synthesis, except that (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (0.36 g, 1.83 mmol) was added to obtain intermediate g15 with a mass of 0.35 g and a yield of 60.9%.

[0343] (8) Synthesis of 4-chloro-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z15):

[0344] The method and conditions for synthesis were the same as in Example 1 (8), except that 4-chloro-N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.35 g, 1.11 mmol) was added to obtain 0.33 g of 4-chloro-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 80.6%.

[0345] Physical and chemical properties of compound Z15: white solid, melting point 144.3-145.3℃.

[0346] Example 16

[0347] The preparation method of 4-bromo-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z16) comprises the following steps:

[0348] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0349] The product was synthesized using the method and conditions of Example 1(1).

[0350] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0351] The product was synthesized using the method and conditions of Example 1(2).

[0352] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0353] The product was synthesized using the method and conditions of Example 1(3).

[0354] (4) Synthesis of tert-butyl ((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d4):

[0355] The product was synthesized using the method and conditions of Example 13(4).

[0356] (5) Synthesis of (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (e4):

[0357] The product was synthesized using the method and conditions of Example 13(5).

[0358] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0359] The product was synthesized using the method and conditions of Example 4(6).

[0360] (7) Synthesis of 4-bromo-N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g16):

[0361] The method and conditions of Example 1(7) were used for synthesis, except that (5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methylamine (0.36 g, 1.83 mmol) was added to obtain intermediate g16 with a mass of 0.32 g and a yield of 55.7%.

[0362] (8) Synthesis of 4-bromo-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z16):

[0363] The method and conditions of Example 1(8) were used to synthesize the product, except that 4-bromo-N-((5-((chloromethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.32 g, 1.02 mmol) was added to obtain 0.34 g of 4-bromo-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 81.5%.

[0364] Physical and chemical properties of compound Z16: white solid, melting point 134.2-135.8℃.

[0365] Embodiment 17

[0366] The preparation method of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (compound number Z17) comprises the following steps:

[0367] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0368] The product was synthesized using the method and conditions of Example 1(1).

[0369] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0370] The product was synthesized using the method and conditions of Example 1(2).

[0371] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0372] The product was synthesized using the method and conditions of Example 1(3).

[0373] (4) Synthesis of tert-butyl ((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d5):

[0374] The method and conditions of Example 1(4) were used for synthesis, except that bromochloromethane was added to obtain intermediate d5 with a mass of 7.96 g and a yield of 71.5%.

[0375] (5) Synthesis of (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (e5):

[0376] The method and conditions of Example 1(5) were used for synthesis, except that tert-butyl((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate was added to obtain intermediate e4 with a mass of 4.98 g and a yield of 89.7%.

[0377] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0378] The product was synthesized using the method and conditions of Example 1(6).

[0379] (7) Synthesis of N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (g17):

[0380] The method and conditions of Example 1(7) were used for synthesis, except that (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (0.36 g, 1.72 mmol) was added to obtain intermediate g17 with a mass of 0.29 g and a yield of 51.6%.

[0381] (8) Synthesis of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (Z17):

[0382] The synthesis was carried out according to the method and conditions of Example 1(8), except that N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide (0.36 g, 0.89 mmol) was added to obtain 0.26 g of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide as a white solid. The yield was 78.8%.

[0383] Physical and chemical properties of compound Z17: white solid, melting point 122.3-123.1℃.

[0384] Embodiment 18

[0385] The preparation method of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z18) comprises the following steps:

[0386] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0387] The product was synthesized using the method and conditions of Example 1(1).

[0388] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0389] The product was synthesized using the method and conditions of Example 1(2).

[0390] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0391] The product was synthesized using the method and conditions of Example 1(3).

[0392] (4) Synthesis of tert-butyl ((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d5):

[0393] The product was synthesized using the method and conditions of Example 17(4).

[0394] (5) Synthesis of (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (e5):

[0395] The product was synthesized using the method and conditions of Example 17(5).

[0396] (6) Synthesis of benzoyl chloride (f2):

[0397] The product was synthesized using the method and conditions of Example 2(6).

[0398] (7) Synthesis of N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g18):

[0399] The method and conditions of Example 1(7) were used for synthesis, except that (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (0.36 g, 1.72 mmol) was added to obtain intermediate g18 with a mass of 0.27 g and a yield of 48.0%.

[0400] (8) Synthesis of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z18):

[0401] The synthesis was carried out according to the method and conditions of Example 1(8), except that N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.27 g, 0.83 mmol) was added to obtain 0.18 g of N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 62.1%.

[0402] Physical and chemical properties of compound Z18: white solid, melting point 124.0-125.1℃.

[0403] Embodiment 19

[0404] The preparation method of 4-chloro-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z19) comprises the following steps:

[0405] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0406] The product was synthesized using the method and conditions of Example 1(1).

[0407] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0408] The product was synthesized using the method and conditions of Example 1(2).

[0409] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0410] The product was synthesized using the method and conditions of Example 1(3).

[0411] (4) Synthesis of tert-butyl ((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d5):

[0412] The product was synthesized using the method and conditions of Example 17(4).

[0413] (5) Synthesis of (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (e5):

[0414] The product was synthesized using the method and conditions of Example 17(5).

[0415] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0416] The product was synthesized using the method and conditions of Example 3(6).

[0417] (7) Synthesis of 4-chloro-N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g19):

[0418] The synthesis was carried out according to the method and conditions of Example 1(7), except that (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (0.36 g, 1.72 mmol) was added to obtain intermediate g19 with a mass of 0.32 g and a yield of 56.9%.

[0419] (8) Synthesis of 4-chloro-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z19):

[0420] The synthesis was carried out according to the method and conditions of Example 1(8), except that 4-chloro-N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.32 g, 0.98 mmol) was added to obtain 0.28 g of 4-chloro-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 74.4%.

[0421] Physical and chemical properties of compound Z19: white solid, melting point 149.7-151.0℃.

[0422] Embodiment 20

[0423] The preparation method of 4-bromo-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (compound number Z20) comprises the following steps:

[0424] (1) Synthesis of tert-butyl (cyanomethyl) carbamate (a1):

[0425] The product was synthesized using the method and conditions of Example 1(1).

[0426] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b1):

[0427] The product was synthesized using the method and conditions of Example 1(2).

[0428] (3) Synthesis of tert-butyl ((5-mercapto-1,2,4-thiadiazol-3-yl)methyl)carbamate (c1):

[0429] The product was synthesized using the method and conditions of Example 1(3).

[0430] (4) Synthesis of tert-butyl ((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)carbamate (d5):

[0431] The product was synthesized using the method and conditions of Example 17(4).

[0432] (5) Synthesis of (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (e5):

[0433] The product was synthesized using the method and conditions of Example 17(5).

[0434] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0435] The product was synthesized using the method and conditions of Example 4(6).

[0436] (7) Synthesis of 4-bromo-N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (g20):

[0437] The synthesis was carried out according to the method and conditions of Example 1(7), except that (5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methanamine (0.36 g, 1.72 mmol) was added to obtain intermediate g20 with a mass of 0.33 g and a yield of 58.7%.

[0438] (8) Synthesis of 4-bromo-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide (Z20):

[0439] The method and conditions of Example 1(8) were used to synthesize the product, except that 4-bromo-N-((5-((2-chloroethyl)thio)-1,2,4-thiadiazol-3-yl)methyl)benzamide (0.33 g, 1.01 mmol) was added to obtain 0.34 g of 4-bromo-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide as a white solid. The yield was 79.1%.

[0440] Physical and chemical properties of compound Z20: white solid, melting point 155.6-156.6℃.

[0441] Embodiment 21

[0442] The preparation method of 4-fluoro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (compound number Z21) comprises the following steps:

[0443] (1) Synthesis of tert-butyl (2-cyanoethyl) carbamate (a2):

[0444] The same method and conditions as in Example 1(1) were used for synthesis, except that aminopropionitrile hydrochloride (10.65 g, 100 mmol) was added to produce 14.48 g of tert-butyl (2-cyanoethyl)carbamate (a2) as a yellow liquid with a yield of 85.2%.

[0445] (2) Synthesis of tert-butyl (Z)-(3-amino-3-(hydroxyimino)propyl)carbamate (b2):

[0446] The synthesis was carried out according to the method and conditions of Example 1(2), except that tert-butyl (2-cyanoethyl)carbamate (14.48 g, 85.2 mmol) was added to produce tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b2) 14.21 g of white solid with a yield of 82.1%.

[0447] (3) Synthesis of tert-butyl (2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate (c2):

[0448] The synthesis was carried out according to the method and conditions of Example 1(3), except that tert-butyl (Z)-(3-amino-3-(hydroxyimino)propyl)carbamate (14.21 g, 69.95 mmol) was added to produce 11.96 g of tert-butyl (2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate (c2) as a white solid. The yield was 65.5%.

[0449] (4) Synthesis of tert-butyl (2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)carbamate (d6):

[0450] The method and conditions of Example 1(4) were used for synthesis, except that tert-butyl(2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate was added to obtain intermediate d6 with a mass of 9.55 g and a yield of 75.8%.

[0451] (5) Synthesis of 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (e6):

[0452] The method and conditions of Example 1(5) were used for synthesis, except that tert-butyl (2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)carbamate was added to obtain intermediate e6 with a mass of 5.27 g and a yield of 86.5%.

[0453] (6) Synthesis of 4-fluorobenzoyl chloride (f1):

[0454] The product was synthesized using the method and conditions of Example 1(6).

[0455] (7) Synthesis of 4-fluoro-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (g21):

[0456] The method and conditions of Example 1(7) were used for synthesis, except that 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (0.32 g, 1.81 mmol) was added to obtain intermediate g21 with a mass of 0.33 g and a yield of 62.1%.

[0457] (8) Synthesis of 4-fluoro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (Z21):

[0458] The synthesis was carried out according to the method and conditions of Example 1(8), except that 4-fluoro-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (0.33 g, 1.12 mmol) was added to obtain 0.32 g of 4-fluoro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide as a white solid. The yield was 87.9%.

[0459] Physical and chemical properties of compound Z21: white solid, melting point 149.0-150.1℃.

[0460] Embodiment 22

[0461] The preparation method of N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (compound number Z22) comprises the following steps:

[0462] (1) Synthesis of tert-butyl (2-cyanoethyl) carbamate (a2):

[0463] The product was synthesized using the method and conditions of Example 21(1).

[0464] (2) Synthesis of tert-butyl (Z)-(3-amino-3-(hydroxyimino)propyl)carbamate (b2):

[0465] The product was synthesized using the method and conditions of Example 21(2).

[0466] (3) Synthesis of tert-butyl (2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate (c2):

[0467] The product was synthesized using the method and conditions of Example 21(3).

[0468] (4) Synthesis of tert-butyl (2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)carbamate (d6):

[0469] The product was synthesized using the method and conditions of Example 21(4).

[0470] (5) Synthesis of 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (e6):

[0471] Synthesized using the method and conditions of Example 21(5).

[0472] (6) Synthesis of benzoyl chloride (f2):

[0473] The product was synthesized using the method and conditions of Example 2(6).

[0474] (7) Synthesis of N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (g22):

[0475] The method and conditions of Example 1(7) were used for synthesis, except that 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (0.32 g, 1.81 mmol) was added to obtain intermediate g22 with a mass of 0.27 g and a yield of 50.8%.

[0476] (8) Synthesis of N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (Z22):

[0477] The synthesis was carried out according to the method and conditions of Example 1(8), except that N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (0.27 g, 0.92 mmol) was added to obtain 0.22 g of N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide as a white solid. The yield was 78.5%.

[0478] Physical and chemical properties of compound Z22: white solid, melting point 128.8-129.4℃.

[0479] Embodiment 23

[0480] The preparation method of 4-chloro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (compound number Z23) comprises the following steps:

[0481] (1) Synthesis of tert-butyl (2-cyanoethyl) carbamate (a2):

[0482] The product was synthesized using the method and conditions of Example 21(1).

[0483] (2) Synthesis of tert-butyl (Z)-(3-amino-3-(hydroxyimino)propyl)carbamate (b2):

[0484] The product was synthesized using the method and conditions of Example 21(2).

[0485] (3) Synthesis of tert-butyl (2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate (c2):

[0486] The product was synthesized using the method and conditions of Example 21(3).

[0487] (4) Synthesis of tert-butyl (2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)carbamate (d6):

[0488] The product was synthesized using the method and conditions of Example 21(4).

[0489] (5) Synthesis of 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (e6):

[0490] Synthesized using the method and conditions of Example 21(5).

[0491] (6) Synthesis of 4-chlorobenzoyl chloride (f3):

[0492] The product was synthesized using the method and conditions of Example 3(6).

[0493] (7) Synthesis of 4-chloro-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (g23):

[0494] The method and conditions of Example 1(7) were used for synthesis, except that 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (0.32 g, 1.81 mmol) was added to obtain intermediate g23 with a mass of 0.31 g and a yield of 58.3%.

[0495] (8) Synthesis of 4-chloro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (Z23):

[0496] The method and conditions of Example 1(8) were used for synthesis, except that 4-chloro-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (0.31 g, 1.06 mmol) was added to obtain 0.31 g of 4-chloro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide as a white solid. The yield was 85.7%.

[0497] Physical and chemical properties of compound Z23: white solid, melting point 132.5-133.6℃.

[0498] Embodiment 24

[0499] The preparation method of 4-bromo-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (compound number Z24) comprises the following steps:

[0500] (1) Synthesis of tert-butyl (2-cyanoethyl) carbamate (a2):

[0501] The product was synthesized using the method and conditions of Example 21(1).

[0502] (2) Synthesis of tert-butyl (Z)-(3-amino-3-(hydroxyimino)propyl)carbamate (b2):

[0503] The product was synthesized using the method and conditions of Example 21(2).

[0504] (3) Synthesis of tert-butyl (2-(5-mercapto-1,2,4-thiadiazol-3-yl)ethyl)carbamate (c2):

[0505] The product was synthesized using the method and conditions of Example 21(3).

[0506] (4) Synthesis of tert-butyl (2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)carbamate (d6):

[0507] The product was synthesized using the method and conditions of Example 21(4).

[0508] (5) Synthesis of 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (e6):

[0509] Synthesized using the method and conditions of Example 21(5).

[0510] (6) Synthesis of 4-bromobenzoyl chloride (f4):

[0511] The product was synthesized using the method and conditions of Example 4(6).

[0512] (7) Synthesis of 4-bromo-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (g24):

[0513] The method and conditions of Example 1(7) were used for synthesis, except that 2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)acetic acid-1-amine (0.32 g, 1.81 mmol) was added to obtain intermediate g24 with a mass of 0.35 g and a yield of 65.8%.

[0514] (8) Synthesis of 4-bromo-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (Z24):

[0515] The method and conditions of Example 1(8) were used for synthesis, except that 4-bromo-N-(2-(5-(methylthio)-1,2,4-thiadiazol-3-yl)ethyl)benzamide (0.35 g, 1.19 mmol) was added to obtain 0.41 g of 4-bromo-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide as a white solid. The yield was 88.3%.

[0516] Physical and chemical properties of compound Z24: white solid, melting point 148.6-149.9℃.

[0517] The H NMR spectra of the synthesized amide derivatives containing 1,2,4-thiadiazole ( 1 H NMR) and carbon nuclear magnetic resonance spectroscopy ( 13 C NMR) data are shown in Tables 1 and 2, respectively.

[0518] Table 1 Example Z1-Z24 obtained target compounds 1 HNMR data

[0519]

[0520]

[0521]

[0522]

[0523] Table 2 The target compounds obtained in Examples Z1-Z24 13 C NMR data

[0524]

[0525]

[0526] Test example: Antibacterial activity test of Examples Z1-Z24 against plant pathogenic bacteria

[0527] The bactericidal activity was determined by the following method:

[0528] (1) Test materials: pipette tips (specifications: 5 mL, 1 mL, 200 μL), 15 mL centrifuge tubes, secondary water, 2 mL PE tubes, NB culture medium, all need to be sterilized. NB culture medium is prepared according to the following proportions: 3 g beef peptone, 5 g peptone, 1 g yeast powder, 10 g glucose, 1 L secondary water. Dispense into test tubes (4 mL / tube), pH 7.0-7.2.

[0529] (2) Operation steps:

[0530] 1. Weigh a certain amount (5 mg) of the compound to be tested, and then dissolve it with a corresponding volume (100 μL) of DMSO. Prepare a 5% solution system, dilute it to the required concentration in proportion, and dilute it to 4 mL with 0.1% Tween-20 solution.

[0531] 2. Use a pipette to draw 1 mL of the mixed solution of drug and Tween and add it to the test tube containing culture medium.

[0532] 3. Use a pipette to aspirate 200 μL of the mixed solution (culture solution), measure its OD value using a 96-well plate, and record it.

[0533] 4. Add 40 μL of bacterial solution of tobacco solanacearum or rice bacterial leaf blight pathogen into each test tube.

[0534] 5. Place in a shaker and set the shaker to 28°C and 180 rpm.

[0535] 6. After 24h-36h (CK OD value is 0.6-0.8), measure its OD value and record it, then calculate its inhibition rate. Corrected OD value = OD value of bacterial culture medium - sterile culture medium

[0536] OD value inhibition rate % = (corrected control culture medium bacterial solution OD value - corrected toxic culture medium OD value) / corrected control culture medium bacterial solution OD value * 100

[0537] Table 3 Activity of compounds Z1-Z24 against plant pathogenic bacteria

[0538]

[0539]

[0540] Taking Xanthoceras oryzae (Xoo), Xanthoceras oryzae (Xoc) and Psa as research objects, the antibacterial activity of amide compounds Z1-Z24 containing 1,2,4-thiadiazole against Xoo, Xoc and Psa at concentrations of 100 and 50 mg / L was tested. From the activity test results in Table 3, it can be seen that compounds Z1-Z24 showed excellent antibacterial activity against Xoo and Xoc at concentrations of 100 and 50 mg / L, and the inhibition rates of all compounds were greater than 77.5%. In particular, compound Z4 had an inhibition rate of 100% against Xoo and Xoc at concentrations of 100 and 50 mg / L. Most compounds also showed good activity against Psa, such as compounds Z1, Z2, Z3, Z4, Z6, Z7, Z10, Z13, Z14 and Z15, whose inhibition rates at a concentration of 50 mg / L were all greater than 80%.

[0541] Test example: In vivo activity test of Example Z4 against rice bacterial blight

[0542] The method of the in vivo test of rice bacterial blight is as follows:

[0543] Compound Z4 was dissolved in DMSO and prepared into a 200 mg / L test solution with 0.2% Tween-80 solution. In the protective activity, the test solution was evenly sprayed on healthy rice leaves. After 24 hours, the rice leaf blight pathogen was inoculated at about 2-3 cm from the top of the rice leaf using the leaf cutting method. In the therapeutic activity, the rice leaf blight pathogen was inoculated using the same method. After 24 hours, the solution was evenly sprayed on the rice leaves. After 14 days of spraying, the length of the lesions on the rice leaves was measured, and the protective and therapeutic activities were calculated using the disease index.

[0544] Table 4. In vivo activity of compound Z4 against rice bacterial blight at 200 mg / L

[0545]

[0546] Note: Control means negative control

[0547] We used the leaf clipping method to test the therapeutic and protective activities of compound Z4 against rice bacterial blight. The results are shown in Table 4. At a treatment concentration of 200 mg / L, the therapeutic and protective activities of compound Z4 against rice bacterial blight were 44.93% and 49.42%, respectively.

[0548] Test Example: Nematicidal Activity Test of Examples Z1-Z24 against Plant Parasitic Nematodes

[0549] The method used for the determination of nematicidal activity is as follows:

[0550] Nematodes were raised with Botrytis cinerea and cultured in a dark environment at 27°C for 7 days. The cultured nematodes on the bacterial plate were rinsed with deionized water, and the 2nd-instar pine nematodes were collected for the initial screening experiment. The compounds were prepared at concentrations of 100 mg / L and 50 mg / L, and the in vitro nematicidal activity against pine nematodes was tested. The nematicides Fluopyram and were used as positive controls. The negative control (CK) was a solution without the test compound. The in vitro nematicidal activity of the target compound against pine nematodes was determined by the immersion method.

[0551] Table 5. In vitro nematicidal activity of compounds Z1-Z24 against pine wood nematodes

[0552]

[0553]

[0554] Taking pine wood nematodes as the research object, the nematicidal activity of amide compounds Z1-Z24 containing 1,2,4-thiadiazole against pine wood nematodes at concentrations of 100 and 50 mg / L was tested. From the activity test results in Table 5, it can be seen that compounds Z3, Z13, Z17 and Z21 showed certain nematicidal activity against pine wood nematodes at concentrations of 100 and 50 mg / L.

Claims

1. An amide derivative containing 1,2,4-thiadiazole, characterized in that: The derivative structural formula is as follows: Where n is 1 or 2; R 1 is methyl, ethyl, propyl, chloromethyl or chloroethyl; R 2 is 4-fluorophenyl, phenyl, 4-chlorophenyl or 4-bromophenyl.

2. An amide derivative containing 1,2,4-thiadiazole as claimed in claim 1, characterized in that: The R 2 Select from any one of the following structural formulas:

3. An amide derivative containing 1,2,4-thiadiazole as claimed in claim 1, characterized in that: The amide derivatives containing 1,2,4-thiadiazole include but are not limited to: Z1: 4-fluoro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z2: N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z3: 4-chloro-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z4: 4-bromo-N-((5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z5: N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide; Z6: N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z7: 4-chloro-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z8: 4-bromo-N-((5-(ethylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z9: 4-fluoro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z10: N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z11: 4-chloro-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z12: 4-bromo-N-((5-(propylsulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z13: N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide; Z14: N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z15: 4-chloro-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z16: 4-bromo-N-((5-((chloromethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z17: N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)-4-fluorobenzamide; Z18: N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z19: 4-chloro-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z20: 4-bromo-N-((5-((2-chloroethyl)sulfonyl)-1,2,4-thiadiazol-3-yl)methyl)benzamide; Z21: 4-fluoro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide; Z22: N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide; Z23: 4-chloro-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide; Z24: 4-bromo-N-(2-(5-(methylsulfonyl)-1,2,4-thiadiazol-3-yl)ethyl)benzamide.

4. The synthetic route of an amide derivative containing 1,2,4-thiadiazole as claimed in any one of claims 1 to 3 is as follows:

5. A method for preparing an amide derivative containing 1,2,4-thiadiazole as claimed in any one of claims 1 to 3, comprising the following steps: Preparation of the first intermediate oxime (a1-a2): Dissolve aminoacetonitrile hydrochloride in dichloromethane, add triethylamine, add di-tert-butyl dicarbonate under ice bath condition, react for 16 hours at room temperature, and detect the reaction by spot plate; after the reaction, add water and extract 2-3 times, combine the organic layers and distill under reduced pressure to obtain crude product a1-a2; Preparation of the second intermediate (b1-b2): Dissolve the intermediate a1-a2 in ethanol, add triethylamine first, stir for 30 minutes, add hydroxylamine hydrochloride, react at room temperature for 8 hours, and monitor the reaction with a plate; distill the ethanol under reduced pressure, extract with water and ethyl acetate 2-3 times, combine the organic layers and distill under reduced pressure to obtain a white solid b1-b2; Preparation of the third intermediate (c1-c2): Dissolve KOH in ethanol, add CS2, stir for 30 min, then add intermediate b1-b2, heat and reflux for 8 h, and detect the reaction on a plate; after the reaction is complete, distill under reduced pressure to obtain intermediate c1-c2; Preparation of the fourth step intermediate (d1-d6): The intermediate c was dissolved in acetonitrile, K2CO3 was added, and then R 1 X, heated to reflux for 2 h; desolventized to remove acetonitrile, and purified by column chromatography (PE / EA=3 / 1) to obtain intermediate d1-d6; Preparation of the fifth intermediate (e1-e6): Directly add CF3COOH to the intermediates d1-d6, react at room temperature for 30 minutes, and detect the reaction on a plate; after the reaction is complete, remove trifluoroacetic acid by vacuum distillation to obtain intermediates e1-e6; Preparation of the sixth step intermediate (f1-f4): Directly add SOCl2 to different benzoic acids, add a few drops of DMF as a catalyst, heat and reflux for 6 hours, and monitor the reaction on a plate; remove SOCl2 by vacuum distillation to obtain intermediates f1-f4; Preparation of the seventh intermediate (g1-g24): Directly add dichloromethane to the intermediate e to dissolve it, add the intermediate f under ice bath conditions, react for 2 hours, and detect the reaction by spot plate; after the reaction is completed, purify it by column chromatography (PE / EA=2 / 1) to obtain the intermediate g; Step 8 Preparation of Compounds Z1-Z24: Directly add a small amount of ethanol to the intermediate g to dissolve it, add a mixed reagent of ammonium molybdate and H2O2 at room temperature, react for 6 hours, and detect the reaction on a spot plate; after the reaction is completed, add water to quench the reaction, filter and wash with ethanol several times to obtain the target compounds Z1-Z24.

6. An amide derivative containing 1,2,4-thiadiazole as claimed in any one of claims 1 to 3 for controlling plant pathogenic bacteria and nematodes.

7. Use of an amide derivative containing 1,2,4-thiadiazole as claimed in any one of claims 1 to 3 in the preparation of antibacterial agents for plant pathogenic bacteria and nematicides.

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