A flexible arylformamide derivative containing 1,2,4-oxadiazole, its preparation method and uses

Abstract

The present invention belongs to the fields of chemical engineering and pesticides, and particularly relates to a flexible arylformamide derivative containing 1,2,4-oxadiazole, a preparation method thereof and uses thereof. By introducing a flexible arylformamide fragment at the 3-position of 1,2,4-oxadiazole directly connected to a benzene ring or a pyridine ring, the present invention synthesizes a series of flexible arylformamide derivatives containing 1,2,4-oxadiazole, which are proved by experiments to exhibit excellent in vitro nematicidal activities against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor. The preparation method of the present invention has the advantages of simple synthesis process, high reaction yield and low raw material cost, etc.

Description

Technical Field

[0001] The present invention belongs to the fields of chemical engineering and pesticides, and particularly relates to a flexible arylformamide derivative containing 1,2,4-oxadiazole, and a preparation method and use thereof. Background Art

[0002] Plant parasitic nematodes are pathogenic nematodes that pose a serious threat to the sustainable development of agriculture, characterized by strong concealment, rapid transmission, and severe harm. 1,2,4-Oxadiazole compounds are an important class of heterocyclic compounds and are widely used in the field of drug design and synthesis. In 2014, Monsanto developed a new 1,2,4-oxadiazole nematicide, Tioxazafen, which has broad-spectrum nematicidal activity against cyst nematodes and root-knot nematodes in plants such as corn, soybean, and cotton (Slomczynska, U.; South, M.; Bunkers, G.; Edgecomb, D.; Wyse-Pester, D.; Selness, S.; Ding, Y.; Christiansen, J.; Ediger, K.; Miller, W.; Charumilind, P.; Hartmann, G.; Williams, J.; Dimmic, M.; Shortt, B.; Haakenson, W.; Wideman, A.; Crawford, M.; Hresko, M.; Mc, Carte, J. Tioxazafen: A New Broad-Spectrum Seed Treatment Nematicide [C] Abstracts of Papers, 2Acs National Meeting & Exposition, San Francisco, Ca, United States, August. 2014.). Since then, research on the creation of nematicides has continued to focus on the 1,2,4-oxadiazole core ring. For example, in 2020, Zhu et al. designed and synthesized a series of novel 1,2,4-oxadiazole derivatives by introducing a 1,3,4-oxa(thio)diazole sulfide structure at the 5-position of 1,2,4-oxadiazole. The results of nematicidal activity tests showed that the compound with the best activity had a 63.3% toxicity against Meloidogyne incognita at a concentration of 100 mg / L, far lower than 100% of the commercial drug fluopyram (Zhu, L.Z.; Zeng, H.N.; Liu, D.; Fu, Y.; Wu, Q.; Song, B.A.; Gan, X.H. Design, synthesis, and biological activity of novel 1,2,4-oxadiazole derivatives. BMC Chem. 2020, 14, 68.) In 2022, Liu et al. designed and synthesized a series of 1,2,4-oxadiazole thioethers containing 1,3,4-thiadiazole amide structures by introducing a 1,3,4-thiadiazole thioether structure at the 2-position of 1,2,4-oxadiazole. The results of the bioactivity test showed that the compound with the best activity had a nematicidal activity of 60.1% against Meloidogyne incognita at a concentration of 200 mg / L, while the commercial drug fluopyram was 100% (Liu, D.; Wang, Z. X.; Zhou, J. J.; Gan, X. H. Design, synthesis and nematocidal activity of novel 1,2,4-oxadiazole derivatives with a 1,3,4-thiadiazole amide moiety. Phosphorus, Sulfur, and Silicon and the Related Elements 2022, 197, 934–942); In 2022, Liu et al. designed and synthesized a series of formamide compounds containing 1,2,4-oxadiazole. The results of the nematocidal activity test showed that the compound with the best activity had a nematicidal activity of 24.8% against Meloidogyne incognita at a concentration of 50 mg / L, far lower than 100% of fluopyram (Liu, D.; Luo, L.; Wang, Z. X.; Ma, X. Y.; Gan, X. H. Design, Synthesis and Antifungal / Nematicidal Activity of Novel 1,2,4-Oxadiazole Derivatives Containing Amide Fragments. Int. J. Mol. Sci. 2022, 23, 1596.); In the same year, Luo et al. introduced a flexible oxygen ether structure containing chalcone at the 5-position of 1,2,4-oxadiazole and designed and synthesized a series of chalcone compounds containing 1,2,4-oxadiazole units. The results of the nematocidal activity test showed that the compound with the best activity had an LC50 value against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor... 50They were 35.5, 44.7, and 30.2 mg / L, respectively (Luo, L.; Liu, D.; Lan, S. C.; Gan, X. H. Design, Synthesis, and Biological Activity of Novel Chalcone Derivatives Containing an 1,2,4-Oxadiazole Moiety. Front. Chem. 2022, 10, 943062.). Although there have been studies on the nematicidal activity of 1,2,4-oxadiazolecarboxamides, unfortunately, the nematicidal activity of these compounds against nematodes is much lower than that of commercial drugs and they do not have the commercial value of being developed into nematicides.

[0003] For another example, the patent with publication number CN114213403B discloses 1,2,4-oxadiazole-5-carboxamide derivatives and their applications in anti-plant fungal and anti-nematode aspects. However, the product yield of this scheme is low, and the yields of most compounds cannot reach 60%, and the inhibition rates against Bursaphelenchus xylophilus and Aphelenchoides besseyi are still not ideal.

[0004] For yet another example, the patent with publication number CN115093377B discloses a halogenoalkyl-containing 1,2,4-oxadiazole derivative and its preparation method and application. Although the yields of these compounds have increased, their nematicidal activity against Bursaphelenchus xylophilus is average, and their nematicidal activity against Aphelenchoides besseyi and Ditylenchus destructor is poor. They do not have high nematicidal activity and broad-spectrum properties, and their application value is limited. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides a flexible arylcarboxamide derivative containing 1,2,4-oxadiazole with excellent nematicidal activity against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor, and its preparation method and application.

[0006] Specifically, it is achieved through the following technical solutions:

[0007] The first object of the present invention is to provide: a flexible arylcarboxamide derivative containing 1,2,4-oxadiazole, whose structural general formula is as formula (I):

[0008]

[0009] Wherein, R 1 is any one or two of fluorine, chlorine, bromine, iodine, trifluoromethyl, or nitro; R 2 is a substituted phenyl, substituted pyridyl, substituted furyl, or substituted thienyl, and the substitution means substitution by fluorine, chlorine, bromine, trifluoromethyl, or nitro groups; X is CH or N.

[0010] In the present invention, R 1 represents substitution at any position on the benzene ring or pyridine ring.

[0011] Furthermore, the flexible arylformamide derivative containing 1,2,4-oxadiazole is any one of the following compounds:

[0012] A1: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2,4-dichlorobenzamide;

[0013] A2: N-((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide;

[0014] A3: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide;

[0015] A4: N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide;

[0016] A5: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0017] A6: N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0018] A7: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide;

[0019] A8: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide;

[0020] A9: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide;

[0021] A10: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide;

[0022] A11: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide;

[0023] A12: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide;

[0024] A13: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide;

[0025] A14: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide;

[0026] A15: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)thiophene-2-carboxamide;

[0027] A16: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-5-chlorothiophene-2-carboxamide;

[0028] A17: N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide;

[0029] A18: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0030] A19: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide;

[0031] A20: N-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0032] A21: N-((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0033] A22: N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0034] A23: N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide;

[0035] A24: N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide;

[0036] A25: N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide;

[0037] A26: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-bromopyridine-3-carboxamide;

[0038] A27: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoropyridine-3-carboxamide;

[0039] A28: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluorobenzamide;

[0040] A29: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chlorobenzamide;

[0041] A30: N-((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide.

[0042] The second object of the present invention is to provide: A preparation method of a flexible arylformamide derivative containing 1,2,4-oxadiazole, and the synthetic route of the derivative is:

[0043]

[0044] wherein 1c to 9c and 1f to 11f are respectively:

[0045]

[0046] Furthermore, a preparation method of a flexible arylformamide derivative containing 1,2,4-oxadiazole includes the following steps:

[0047] The first step: Preparation of tert-butyl (cyanomethyl)carbamate (a)

[0048] According to the molar ratio of aminoacetonitrile hydrochloride: di-tert-butyl dicarbonate: triethylamine = 1:1.1:2.3, aminoacetonitrile hydrochloride and triethylamine were fully stirred in dichloromethane. The reaction system was a white milky liquid. Under an ice bath, di-tert-butyl dicarbonate diluted with dichloromethane was added dropwise thereto. A large amount of bubbles were generated, and the white floccules gradually disappeared. The reaction system was a colorless or light white liquid; after stirring for 2 h under an ice bath, it was transferred to room temperature and stirred for 10 h; washed with saturated brine, extracted with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate a, which was a light yellow oily liquid;

[0049] Step 2: Preparation of (Z)-(2-amino-2-(hydroxyimino)ethyl) carbamic acid tert-butyl ester (b)

[0050] According to the molar ratio of intermediate a: hydroxylamine hydrochloride: triethylamine = 1:1.2:1.5, hydroxylamine hydrochloride and triethylamine were fully stirred in absolute ethanol. The reaction system was a colorless liquid. After adding intermediate a dropwise thereto, the reaction system was a light yellow transparent liquid, and the reaction was stirred at room temperature for 6 h; after the reaction was completed, the ethanol was removed by solvent removal under reduced pressure. The residue was successively washed with saturated brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate b, which was a white solid;

[0051] Step 3: Preparation of intermediates 1d - 9d

[0052] According to the molar ratio of intermediate b: substituted arylcarbonyl chloride 1c - 9c: triethylamine = 1:1.1:3, (Z)-(2-amino-2-(hydroxyimino)ethyl) carbamic acid tert-butyl ester (b) and triethylamine were fully stirred in toluene, and then substituted arylcarbonyl chloride 1c - 10c diluted with toluene was added dropwise thereto. The temperature was raised to reflux (110 °C) and the reaction was carried out for 6 - 10 h. The system was black, and the reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove toluene. The residue was dissolved in ethyl acetate, washed with saturated brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure, followed by column chromatography separation and purification to obtain intermediates 1d - 9d, which were white to yellow solids;

[0053] Step 4: Preparation of intermediates 1e - 9e

[0054] The intermediates 1d - 9d obtained in the previous step were dissolved in a mixed solution of dichloromethane and trifluoroacetic acid and stirred well. A large amount of bubbles were generated, and the reaction was carried out at room temperature for 0.5 - 1 h. The reaction process was monitored by TLC. After the reaction was completed, trifluoroacetic acid was removed by solvent removal under reduced pressure. The residue was dried and did not require further purification and was directly used for the next step;

[0055] Step 5: Preparation of compounds A1 - A30

[0056] According to the molar ratio of intermediate 1e - 9e: substituted arylcarbonyl chloride 1f - 11f: triethylamine = 1:1.1:1.5, intermediate 1e - 9e and triethylamine were stirred well in dichloromethane. While under ice bath, the substituted arylcarbonyl chloride 1f - 11f diluted with dichloromethane was added dropwise thereto. After stirring for half an hour under ice bath, the mixture was transferred to room temperature for reaction for 2 - 4 h, and the reaction process was monitored by TLC. After the reaction was completed, saturated brine was added for washing and extraction with dichloromethane. After solvent removal under reduced pressure, column chromatography was carried out for separation and purification to obtain compounds A1 - A30, which were white to brown solids.

[0057] In the third step, the elution reagent used in the column chromatography was petroleum ether: ethyl acetate = 5:1 - 3:1.

[0058] In the fourth step, the mixed solution of dichloromethane and trifluoroacetic acid was formed by mixing dichloromethane and trifluoroacetic acid in an equal volume ratio.

[0059] In the fifth step, the elution reagent used in the column chromatography was petroleum ether: ethyl acetate = 3:1 - 1:1.

[0060] The third object of the present invention is to provide: an application of a flexible arylformamide derivative containing 1,2,4 - oxadiazole in the preparation of a drug for preventing and treating Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor.

[0061] Beneficial effects:

[0062] By introducing a flexible arylformamide fragment at the 3 - position of 1,2,4 - oxadiazole directly connected to a benzene ring or a pyridine ring, the present invention synthesizes a series of flexible arylformamide derivatives containing 1,2,4 - oxadiazole, which are proved by experiments to exhibit excellent in vitro nematicidal activity against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor.

[0063] The preparation method of the present invention has the advantages of simple synthesis process, high reaction yield, and low raw material cost. Specific embodiments

[0064] The following further details the specific embodiments of the present invention, but the present invention is not limited to these embodiments. Any improvement or substitution based on the basic spirit of this embodiment still belongs to the scope protected by the claims of the present invention.

[0065] Example 1

[0066] A preparation method of N - ((5 - (2 - chloro - 4 - (trifluoromethyl)phenyl)-1,2,4 - oxadiazol - 3 - yl)methyl)-2,4 - dichlorobenzamide (compound number A1) includes the following steps:

[0067] (1) Synthesis of (cyanomethyl)carbamic acid tert - butyl ester (a):

[0068] Add aminoacetonitrile hydrochloride (5.0 g, 54.04 mmol) to a 250 mL single-necked flask containing dichloromethane (100 mL), add triethylamine (13.12 g, 129.69 mmol) and stir well. The reaction system is a white milky liquid. Dropwise add di-tert-butyl dicarbonate (11.79 g, 54.04 mmol) dissolved in dichloromethane to it under an ice bath. A large amount of bubbles are generated and the white floccules gradually disappear. The reaction system becomes a colorless or light white liquid. After stirring for 2 hours under the ice bath, transfer it to room temperature and stir for 10 hours. Add saturated brine for washing and extract with dichloromethane (40 mL × 3). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure to obtain intermediate a, which is a light yellow oily liquid with a mass of 7.74 g and a yield of 91.74%.

[0069] (2) Synthesis of (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamic acid tert-butyl ester (b):

[0070] Add hydroxylamine hydrochloride (4.13 g, 59.47 mmol) to a 100 mL single-necked flask containing 50 mL of absolute ethanol, add triethylamine (7.52 g, 74.34 mmol) and stir well. The reaction system is a colorless liquid. After dropwise adding intermediate a (7.74 g, 49.56 mmol) to it, the reaction system becomes a light yellow transparent liquid. Stir and react at room temperature for 6 hours. After the reaction is completed, remove the ethanol under reduced pressure. Dissolve the residue in ethyl acetate and successively carry out washing with saturated brine (50 mL), extraction with ethyl acetate (40 mL × 3), drying over anhydrous magnesium sulfate, filtering, and removing the solvent under reduced pressure to obtain intermediate b, which is a white solid with a mass of 7.86 g and a yield of 83.83%.

[0071] (3) Synthesis of ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamic acid tert-butyl ester

[0072] tert-Butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (1.42 g, 7.50 mmol) was added to a 50 mL three-necked flask containing toluene (20 mL). Triethylamine (2.28 g, 22.51 mmol) was added and stirred well. 2-Chloro-4-(trifluoromethyl)benzoyl chloride (2.00 g, 8.23 mmol) diluted with dichloromethane was added dropwise to the above system. The temperature was raised to reflux the reaction system. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 4:1). After the starting material spot disappeared, the reaction was stopped. Toluene was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL), extracted with ethyl acetate (40 mL × 3) successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 1.15 g of a white solid with a yield of 51.48%.

[0073] (4) Synthesis of (4)(5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0074] ((5-(2-Chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamic acid tert-butyl ester (1.15 g, 3.04 mmol) and 8 mL of dichloromethane solution containing trifluoroacetic acid (volume ratio of trifluoroacetic acid to dichloromethane = 1:1) were added to a 50 mL single-necked flask and stirred well. A large number of bubbles were generated in the system. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 4:1). After the starting material spot disappeared, the reaction was stopped. The solvent was removed by evaporation under reduced pressure. After drying, 0.83 g of a white solid was obtained with a crude yield of 98.46%. The product was used directly in the next step without further purification.

[0075] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2,4-dichlorobenzamide (A1):

[0076] Add (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.54 mmol), triethylamine (82.01 mg, 0.81 mmol) and 20 mL of dichloromethane to a 50 mL single-necked flask and stir well. Dropwise add 2,4-dichlorobenzoyl chloride (0.12 g, 0.59 mmol) diluted with dichloromethane under an ice bath. After stirring for half an hour, transfer the reaction to room temperature and monitor the reaction progress by TLC (petroleum ether:ethyl acetate = 3:1). After the starting material spot disappears, stop the reaction, add saturated brine (50 mL) for washing, extract with dichloromethane (40 mL × 3), remove the solvent under reduced pressure and then perform column chromatography separation and purification (petroleum ether:ethyl acetate = 3:1) to obtain 0.16 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2,4-dichlorobenzamide, with a yield of 66.67%.

[0077] Physical and chemical properties of compound A1: white solid, melting point 129 - 130 °C.

[0078] Example 2

[0079] Preparation method of N-((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (compound number A2), comprising the following steps:

[0080] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0081] Synthesize according to the method and conditions of Example 1(1).

[0082] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0083] Synthesize according to the method and conditions of Example 1(2).

[0084] (3) Synthesis of tert-butyl ((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0085] Synthesize according to the method and conditions of Example 1(3), with the difference that 2,4-dichlorobenzoyl chloride (1.83 g, 8.72 mmol) is added to obtain 1.21 g of tert-butyl ((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate, which is a white solid with a yield of 44.21%.

[0086] (4) Synthesis of (5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0087] Synthesized according to the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (1.21 g, 3.52 mmol) was added, and 0.83 g of (5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a white solid with a yield of 96.58%.

[0088] (5) Synthesis of N-((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (A2):

[0089] Synthesized according to the method and conditions of Example 1(5), with the difference that (5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.61 mmol) and 3-chloro-5-(trifluoromethyl)pyridine-2-carbonyl chloride (0.16 g, 0.67 mmol) were added, and 0.15 g of N-((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide was obtained with a yield of 54.12%.

[0090] Physical and chemical properties of compound A2: White solid, melting point 152 - 153 °C.

[0091] Example 3

[0092] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide (compound number A3), comprising the following steps:

[0093] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a): The same as step (1) in Example 1.

[0094] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b): The same as step (2) in Example 1.

[0095] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0096] Synthesized according to the method and conditions of Example 1(3).

[0097] (4) Synthesis of (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0098] Synthesized according to the method and conditions of Example 1(4).

[0099] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide (A3):

[0100] Synthesized according to the method and conditions of Example 1(5), with the difference that 4-(trifluoromethyl)nicotinoyl chloride (0.12 g, 0.59 mmol) was added, and 0.14 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide was obtained, with a yield of 56.32%.

[0101] Physical and chemical properties of compound A3: White solid, melting point 156 - 157 °C.

[0102] Example 4

[0103] Preparation method of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (compound number A4), comprising the following steps:

[0104] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0105] Synthesized according to the method and conditions of Example 1(1).

[0106] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0107] Synthesized according to the method and conditions of Example 1(2).

[0108] (3) Synthesis of tert-butyl ((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0109] Synthesized according to the method and conditions of Example 1(3), with the difference that 3-chloro-5-(trifluoromethyl)picolinoyl chloride (1.99 g, 8.14 mmol) was added, and 1.08 g of tert-butyl ((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate was obtained as a white solid, with a yield of 38.74%.

[0110] (4) Synthesis of (5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methanamine:

[0111] Synthesized according to the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (1.08 g, 2.85 mmol) was added, to obtain 0.77 g of (5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methanamine as a white solid, with a yield of 97.36%.

[0112] (5) Synthesis of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (A4):

[0113] Synthesized according to the method and conditions of Example 1(5), with the difference that (5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.59 mmol), 2-chloronicotinoyl chloride (0.10 g, 0.59 mmol) and triethylamine (81.72 mg, 0.81 mmol) were added, to obtain 0.14 g of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide, with a yield of 62.67%.

[0114] Physical and chemical properties of compound A4: White solid, melting point 156 - 157 °C.

[0115] Example 5

[0116] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound number A5), comprising the following steps:

[0117] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0118] Synthesized according to the method and conditions of Example 1(1).

[0119] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0120] Synthesized according to the method and conditions of Example 1(2).

[0121] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0122] Synthesized according to the method and conditions of Example 1(3).

[0123] (4) Synthesis of (4-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)amine:

[0124] Synthesized according to the method and conditions of Example 1(4).

[0125] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A5):

[0126] Synthesized according to the method and conditions of Example 1(5), with the difference that 2-(trifluoromethyl)benzoyl chloride (0.12 g, 0.59 mmol) was added, and 0.18 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide was obtained, with a yield of 73.68%.

[0127] Physical and chemical properties of compound A5: White solid, melting point 134 - 135 °C.

[0128] Example 6

[0129] Preparation method of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound number A6), comprising the following steps:

[0130] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0131] Synthesized according to the method and conditions of Example 1(1).

[0132] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0133] Synthesized according to the method and conditions of Example 1(2).

[0134] (3) Synthesis of tert-butyl ((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0135] Synthesized according to the method and conditions of Example 4(3).

[0136] (4) Synthesis of (5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methylamine:

[0137] Synthesized according to the method and conditions of Example 4(4).

[0138] (5) Synthesis of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A6):

[0139] Synthesized according to the method and conditions of Example 1(5), with the difference that 2-(trifluoromethyl)benzoyl chloride (0.12 g, 0.59 mmol) was added, obtaining 0.19 g of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide, with a yield of 78.34%.

[0140] Physical and chemical properties of compound A6: White solid, melting point 146 - 147 °C.

[0141] Example 7

[0142] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (compound number A7), comprising the following steps:

[0143] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0144] Synthesized according to the method and conditions of Example 1(1).

[0145] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0146] Synthesized according to the method and conditions of Example 1(2).

[0147] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0148] Synthesized according to the method and conditions of Example 1(3).

[0149] (4) Synthesis of (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0150] Synthesized according to the method and conditions of Example 1(4).

[0151] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (A3):

[0152] Synthesized according to the method and conditions of Example 1(5), with the difference that 2-chloronicotinoyl chloride (0.10 g, 0.59 mmol) was added, and 0.14 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide was obtained, with a yield of 63.44%.

[0153] Physical and chemical properties of Compound A7: white solid, melting point 123 - 124 °C.

[0154] Example 8

[0155] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (Compound No. A8), comprising the following steps:

[0156] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0157] Synthesized according to the method and conditions of Example 1(1).

[0158] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0159] Synthesized according to the method and conditions of Example 1(2).

[0160] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0161] Synthesized according to the method and conditions of Example 1(3), with the difference that 2-fluoro-4-(trifluoromethyl)benzoyl chloride (1.84 g, 8.14 mmol) was added, and 1.02 g of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate was obtained as a white solid, with a yield of 52.74%.

[0162] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0163] Synthesized according to the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (1.02 g, 0.39 mmol) was added, and 0.72 g of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a white solid, with a yield of 97.64%.

[0164] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (A8):

[0165] Synthesized according to the method and conditions of Example 1(5), with the difference that (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methylamine (0.15 g, 0.57 mmol) and 2-chloronicotinoyl chloride (0.11 g, 0.63 mmol) were added to obtain 0.15 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide, with a yield of 66.48%.

[0166] Physical and chemical properties of compound A8: White solid, melting point 119 - 120 °C.

[0167] Example 9

[0168] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (compound number A9), comprising the following steps:

[0169] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0170] Synthesized according to the method and conditions of Example 1(1).

[0171] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0172] Synthesized according to the method and conditions of Example 1(2).

[0173] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0174] Synthesized according to the method and conditions of Example 1(3).

[0175] (4) Synthesis of (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methylamine:

[0176] Synthesized according to the method and conditions of Example 1(4).

[0177] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (A9):

[0178] Synthesized by the method and conditions of Example 1(5), except that 3-chloro-5-(trifluoromethyl)picolyl chloride (0.15 g, 0.59 mmol) was added to obtain 0.14 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide, with a yield of 53.74%.

[0179] Physical and chemical properties of Compound A9: white solid, melting point 120 - 121 °C.

[0180] Example 10

[0181] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (Compound No. A10), comprising the following steps:

[0182] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0183] Synthesized by the method and conditions of Example 1(1).

[0184] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0185] Synthesized by the method and conditions of Example 1(2).

[0186] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0187] Synthesized by the method and conditions of Example 8(3).

[0188] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0189] Synthesized by the method and conditions of Example 8(4).

[0190] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide (A10):

[0191] Synthesized according to the method and conditions of Example 8(5), with the difference that 3-chloro-5-(trifluoromethyl)picolyl chloride (0.15 g, 0.63 mmol) was added, to obtain 0.15 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3-chloro-5-(trifluoromethyl)pyridine-2-carboxamide, with a yield of 57.52%.

[0192] Physical and chemical properties of Compound A10: White solid, melting point 126 - 127 °C.

[0193] Example 11

[0194] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide (Compound No. A11), comprising the following steps:

[0195] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0196] Synthesized according to the method and conditions of Example 1(1).

[0197] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0198] Synthesized according to the method and conditions of Example 1(2).

[0199] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0200] Synthesized according to the method and conditions of Example 1(3).

[0201] (4) Synthesis of (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0202] Synthesized according to the method and conditions of Example 1(4).

[0203] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide (A11):

[0204] Synthesized according to the method and conditions of Example 1(5), with the difference that 3,5-dichloropicolinoyl chloride (0.15 g, 0.54 mmol) was added, to obtain 0.14 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide, with a yield of 57.58%.

[0205] Physical and chemical properties of Compound A11: white solid, melting point 102 - 103 °C.

[0206] Example 12

[0207] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide (Compound No. A12), comprising the following steps:

[0208] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0209] Synthesized according to the method and conditions of Example 1(1).

[0210] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0211] Synthesized according to the method and conditions of Example 1(2).

[0212] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0213] Synthesized according to the method and conditions of Example 8(3).

[0214] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0215] Synthesized according to the method and conditions of Example 8(4).

[0216] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide (A12):

[0217] Synthesized according to the method and conditions of Example 8(5), with the difference that 3,5-dichloropicolinoyl chloride (0.13 g, 0.63 mmol) was added, and 0.13 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-3,5-dichloropyridine-2-carboxamide was obtained, with a yield of 52.39%.

[0218] Physical and chemical properties of Compound A12: white solid, melting point 105 - 106 °C.

[0219] Example 13

[0220] Preparation method of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide (Compound No. A13), comprising the following steps:

[0221] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0222] Synthesized according to the method and conditions of Example 1(1).

[0223] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0224] Synthesized according to the method and conditions of Example 1(2).

[0225] (3) Synthesis of tert-butyl ((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0226] Synthesized according to the method and conditions of Example 1(3).

[0227] (4) Synthesis of (5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0228] Synthesized according to the method and conditions of Example 1(4).

[0229] (5) Synthesis of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide (A13):

[0230] Synthesized according to the method and conditions of Example 1(5), except that 2-(trifluoromethyl)nicotinoyl chloride (0.12 g, 0.59 mmol) was added to obtain 0.16 g of N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide, with a yield of 66.17%.

[0231] Physical and chemical properties of Compound A13: White solid, melting point 169-170 °C.

[0232] Example 14

[0233] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide (Compound No. A14), comprising the following steps:

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

[0235] Synthesized according to the method and conditions of Example 1(1).

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

[0237] Synthesized according to the method and conditions of Example 1(2).

[0238] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0239] Synthesized according to the method and conditions of Example 8(3).

[0240] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0241] Synthesized according to the method and conditions of Example 8(4).

[0242] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide (A14):

[0243] Synthesized according to the method and conditions of Example 8(5), except that 4-(trifluoromethyl)nicotinoyl chloride (0.13 g, 0.63 mmol) was added, and 0.16 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(trifluoromethyl)pyridine-3-carboxamide was obtained, with a yield of 60.27%.

[0244] Physical and chemical properties of compound A14: yellow solid, melting point 160 - 161 °C.

[0245] Example 15

[0246] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)thiophene-2-carboxamide (compound number A15), comprising the following steps:

[0247] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0248] Synthesized according to the method and conditions of Example 1(1).

[0249] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0250] Synthesized according to the method and conditions of Example 1(2).

[0251] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0252] Synthesized according to the method and conditions of Example 8(3).

[0253] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0254] Synthesized according to the method and conditions of Example 8(4).

[0255] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)thiophene-2-carboxamide (A15):

[0256] Synthesized according to the method and conditions of Example 8(5), except that thiophene-2-carbonyl chloride (0.09 g, 0.63 mmol) was added to obtain 0.13 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)thiophene-2-carboxamide, with a yield of 63.54%.

[0257] Physical and chemical properties of compound A15: White solid, melting point 116 - 117 °C.

[0258] Example 16

[0259] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-5-chlorothiophene-2-carboxamide (compound number A16), comprising the following steps:

[0260] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0261] Synthesized according to the method and conditions of Example 1(1).

[0262] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0263] Synthesized according to the method and conditions of Example 1(2).

[0264] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0265] Synthesized according to the method and conditions of Example 8(3).

[0266] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0267] Synthesized according to the method and conditions of Example 8(4).

[0268] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-5-chlorothiophene-2-carboxamide (A16):

[0269] Synthesized according to the method and conditions of Example 8(5), except that 5-chlorothiophene-2-carbonyl chloride (0.11 g, 0.63 mmol) was added, and 0.14 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-5-chlorothiophene-2-carboxamide was obtained with a yield of 59.61%.

[0270] Physical and chemical properties of compound A16: White solid, melting point 138 - 139 °C.

[0271] Example 17

[0272] Preparation method of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide (compound numbered A17), comprising the following steps:

[0273] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0274] Synthesized according to the method and conditions of Example 1(1).

[0275] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0276] Synthesized according to the method and conditions of Example 1(2).

[0277] (3) Synthesis of tert-butyl ((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0278] Synthesized according to the method and conditions of Example 4(3).

[0279] (4) Synthesis of (5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methanamine:

[0280] Synthesized according to the method and conditions of Example 4(4).

[0281] (5) Synthesis of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide (A17):

[0282] Synthesized according to the method and conditions of Example 1(5), with the difference that 2-fluoro-4-(trifluoromethyl)benzoyl chloride (0.11 g, 0.59 mmol) was added, and 0.16 g of N-((5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide was obtained, with a yield of 64.21%.

[0283] Physical and chemical properties of compound A17: White solid, melting point 173 - 174 °C.

[0284] Example 18

[0285] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound number A18), comprising the following steps:

[0286] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0287] Synthesized according to the method and conditions of Example 1(1).

[0288] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0289] Synthesized according to the method and conditions of Example 1(2).

[0290] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0291] Synthesized according to the method and conditions of Example 8(3).

[0292] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0293] Synthesized according to the method and conditions of Example 8(4).

[0294] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A18):

[0295] Synthesized according to the method and conditions of Example 8(5), with the difference that 5-chlorothiophene-2-carbonyl chloride (0.11 g, 0.63 mmol) was added to obtain 0.19 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide, with a yield of 78.63%.

[0296] Physical and chemical properties of compound A18: yellow solid, melting point 149-150 °C.

[0297] Example 19

[0298] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide (compound number A19), comprising the following steps:

[0299] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0300] Synthesized according to the method and conditions of Example 1(1).

[0301] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0302] Synthesized according to the method and conditions of Example 1(2).

[0303] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0304] Synthesized according to the method and conditions of Example 8(3).

[0305] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0306] Synthesized according to the method and conditions of Example 8(4).

[0307] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide (A19):

[0308] Synthesized according to the method and conditions of Example 8(5), with the difference that 2-(trifluoromethyl)nicotinoyl chloride (0.11 g, 0.63 mmol) was added to obtain 0.17 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)pyridine-3-carboxamide, with a yield of 70.47%.

[0309] Physical and chemical properties of Compound A19: light purple solid, melting point 156 - 157 °C.

[0310] Example 20

[0311] Preparation method of N-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (Compound No. A20), comprising the following steps:

[0312] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0313] Synthesized according to the method and conditions of Example 1(1).

[0314] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0315] Synthesized according to the method and conditions of Example 1(2).

[0316] (3) Synthesis of tert-butyl ((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0317] Synthesized according to the method and conditions of Example 1(3), with the difference that 2-(trifluoromethyl)-4-fluorobenzoyl chloride (1.84 g, 8.14 mmol) was added, and 0.91 g of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate was obtained as a white solid, with a yield of 47.15%.

[0318] (4) Synthesis of (5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0319] Synthesized according to the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (0.91 g, 2.52 mmol) was added, and 0.63 g of (5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a white solid, with a yield of 96.37%.

[0320] (5) Synthesis of N-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A20):

[0321] Synthesized by the method and conditions of Example 1(5), with the difference that (5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.63 mmol) and 2-(trifluoromethyl)benzoyl chloride (0.11 g, 0.63 mmol) were added to obtain 0.20 g of N-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide, with a yield of 82.19%.

[0322] Physical and chemical properties of Compound A20: white solid, melting point 144 - 145 °C.

[0323] Example 21

[0324] Preparation method of N-((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (Compound No. A21), comprising the following steps:

[0325] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0326] Synthesized by the method and conditions of Example 1(1).

[0327] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0328] Synthesized by the method and conditions of Example 1(2).

[0329] (3) Synthesis of tert-butyl ((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0330] Synthesized by the method and conditions of Example 1(3), with the difference that 2,4-bis(trifluoromethyl)benzoyl chloride (2.25 g, 8.14 mmol) was added to obtain 0.70 g of tert-butyl ((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate, which is a white solid, with a yield of 36.48%.

[0331] (4) Synthesis of (5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0332] Synthesized by the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (0.70 g, 1.70 mmol) was added, and 0.49 g of (5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a white solid, with a yield of 93.57%.

[0333] (5) Synthesis of N-((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A21):

[0334] Synthesized by the method and conditions of Example 1(5), with the difference that (5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.48 mmol) and 2-(trifluoromethyl)benzoyl chloride (0.10 g, 0.53 mmol) were added, and 0.18 g of N-((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide was obtained, with a yield of 77.45%.

[0335] Physical and chemical properties of compound A21: Light yellow solid, melting point 106 - 107 °C.

[0336] Example 22

[0337] N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound number A22):

[0338] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0339] Synthesized by the method and conditions of Example 1(1).

[0340] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0341] Synthesized by the method and conditions of Example 1(2).

[0342] (3) Synthesis of tert-butyl ((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0343] Synthesized according to the method and conditions of Example 1(3), with the difference that 2-bromo-4-(trifluoromethyl)benzoyl chloride (1.00 g, 5.28 mmol) was added, and 0.63 g of tert-butyl ((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate was obtained as a yellow solid with a yield of 38.55%.

[0344] (4) Synthesis of (5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0345] Synthesized according to the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (0.63 g, 1.49 mmol) was added, and 0.42 g of (5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a yellow solid with a yield of 87.39%.

[0346] (5) Synthesis of N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A22):

[0347] Synthesized according to the method and conditions of Example 1(5), with the difference that (5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.46 mmol) and 2-(trifluoromethyl)benzoyl chloride (0.09 g, 0.51 mmol) were added, and 0.18 g of N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide was obtained with a yield of 81.14%.

[0348] Physicochemical properties of compound A22: yellow solid, melting point 131 - 132 °C.

[0349] Example 23

[0350] N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (compound number A23):

[0351] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0352] Synthesized according to the method and conditions of Example 1(1).

[0353] (2) Synthesis of (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0354] Synthesized according to the method and conditions of Example 1(2).

[0355] (3)Synthesis of tert-butyl ((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0356] Synthesized according to the method and conditions of Example 22(3).

[0357] (4)Synthesis of (5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0358] Synthesized according to the method and conditions of Example 22(4).

[0359] (5)Synthesis of N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (A23):

[0360] Synthesized according to the method and conditions of Example 22(5), except that 2-nicotinoyl chloride (0.09 g, 0.51 mmol) was added to obtain 0.14 g of N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide, with a yield of 67.35%.

[0361] Physical and chemical properties of compound A23: Brown solid, melting point 132 - 133 °C.

[0362] Example 24

[0363] Preparation method of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (compound number A24), comprising the following steps:

[0364] (1)Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0365] Synthesized according to the method and conditions of Example 1(1).

[0366] (2)Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0367] Synthesized according to the method and conditions of Example 1(2).

[0368] (3)Synthesis of tert-butyl ((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0369] Synthesized by the method and conditions of Example 1(3), with the difference that 2-nitro-4-(trifluoromethyl)benzoyl chloride (1.20 g, 1.77 mmol) was added, to obtain 1.08 g of tert-butyl ((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate as a white solid, with a yield of 53.17%.

[0370] (4) Synthesis of (5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0371] Synthesized by the method and conditions of Example 1(4), with the difference that tert-butyl ((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (1.08 g, 2.78 mmol) was added, to obtain 0.74 g of (5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine as a white solid, with a yield of 92.27%.

[0372] (5) Synthesis of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A24):

[0373] Synthesized by the method and conditions of Example 1(5), with the difference that (5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine (0.15 g, 0.52 mmol) and 2-(trifluoromethyl)benzoyl chloride (0.10 g, 0.57 mmol) were added, to obtain 0.20 g of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide, with a yield of 83.64%.

[0374] Physical and chemical properties of compound A24: White solid, melting point 124 - 125 °C.

[0375] Example 25

[0376] Preparation method of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (compound number A25), comprising the following steps:

[0377] (1) Synthesis of (cyanomethyl)carbamic acid tert-butyl ester (a):

[0378] Synthesized by the method and conditions of Example 1(1).

[0379] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0380] Synthesized according to the method and conditions in Example 1(2).

[0381] (3) Synthesis of tert-butyl ((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0382] Synthesized according to the method and conditions in Example 24(3).

[0383] (4) Synthesis of (5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0384] Synthesized according to the method and conditions in Example 24(4).

[0385] (5) Synthesis of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide (A25):

[0386] Synthesized according to the method and conditions in Example 24(5), with the difference that 2-chloronicotinoyl chloride (0.10 g, 0.57 mmol) was added to obtain 0.19 g of N-((5-(2-nitro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide, with a yield of 86.22%.

[0387] Physical and chemical properties of compound A25: White solid, melting point 131 - 132 °C.

[0388] Example 26

[0389] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-bromopyridine-3-carboxamide (compound number A26), comprising the following steps:

[0390] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0391] Synthesized according to the method and conditions in Example 1(1).

[0392] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0393] Synthesized according to the method and conditions in Example 1(2).

[0394] (3)Synthesis of tert-Butyl ((5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0395] Synthesized according to the method and conditions of Example 8(3).

[0396] (4)Synthesis of (5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0397] Synthesized according to the method and conditions of Example 8(4).

[0398] (5)Synthesis of N-((5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-bromopyridine-3-carboxamide (A26):

[0399] Synthesized according to the method and conditions of Example 8(5), except that 2-bromonicotinoyl chloride (0.11 g, 0.63 mmol) was added, and 0.19 g of N-((5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-bromopyridine-3-carboxamide was obtained with a yield of 76.71%.

[0400] Physical and chemical properties of compound A26: White solid, melting point 119 - 120 °C.

[0401] Example 27

[0402] Preparation method of N-((5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoropyridine-3-carboxamide (compound number A27), comprising the following steps:

[0403] (1)Synthesis of tert-Butyl (cyanomethyl)carbamate (a):

[0404] Synthesized according to the method and conditions of Example 1(1).

[0405] (2)Synthesis of tert-Butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0406] Synthesized according to the method and conditions of Example 1(2).

[0407] (3)Synthesis of tert-Butyl ((5-(2-Fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0408] Synthesized according to the method and conditions of Example 8(3).

[0409] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0410] Synthesized according to the method and conditions of Example 8(4).

[0411] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoropyridine-3-carboxamide (A27):

[0412] Synthesized according to the method and conditions of Example 8(5), with the difference that 2-fluoronicotinoyl chloride (0.10 g, 0.63 mmol) was added, and 0.13 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluoropyridine-3-carboxamide was obtained, with a yield of 58.94%.

[0413] Physical and chemical properties of compound A27: White solid, melting point 110 - 111 °C.

[0414] Example 28

[0415] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluorobenzamide (compound number A28), comprising the following steps:

[0416] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0417] Synthesized according to the method and conditions of Example 1(1).

[0418] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0419] Synthesized according to the method and conditions of Example 1(2).

[0420] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0421] Synthesized according to the method and conditions of Example 8(3).

[0422] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0423] Synthesized according to the method and conditions of Example 8(4).

[0424] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluorobenzamide (A28):

[0425] Synthesized according to the method and conditions of Example 8(5), with the difference that 2-fluorobenzoyl chloride (0.10 g, 0.63 mmol) was added, and 0.17 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-fluorobenzamide was obtained, with a yield of 77.53%.

[0426] Physical and chemical properties of compound A28: White solid, melting point 75 - 76 °C.

[0427] Example 29

[0428] Preparation method of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chlorobenzamide (compound number A29), comprising the following steps:

[0429] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0430] Synthesized according to the method and conditions of Example 1(1).

[0431] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0432] Synthesized according to the method and conditions of Example 1(2).

[0433] (3) Synthesis of tert-butyl ((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0434] Synthesized according to the method and conditions of Example 8(3).

[0435] (4) Synthesis of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0436] Synthesized according to the method and conditions of Example 8(4).

[0437] (5) Synthesis of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chlorobenzamide (A29):

[0438] Synthesized according to the method and conditions of Example 8(5), except that 2-chlorobenzoyl chloride (0.12 g, 0.57 mmol) was added, and 0.19 g of N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chlorobenzamide was obtained with a yield of 82.97%.

[0439] Physical and chemical properties of Compound A29: White solid, melting point 105-106 °C.

[0440] Example 30

[0441] Preparation method of N-((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (Compound No. A30), comprising the following steps:

[0442] (1) Synthesis of tert-butyl (cyanomethyl)carbamate (a):

[0443] Synthesized according to the method and conditions of Example 1(1).

[0444] (2) Synthesis of tert-butyl (Z)-(2-amino-2-(hydroxyimino)ethyl)carbamate (b):

[0445] Synthesized according to the method and conditions of Example 1(2).

[0446] (3) Synthesis of tert-butyl ((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate:

[0447] Synthesized according to the method and conditions of Example 1(3), except that 2-iodo-4-(trifluoromethyl)benzoyl chloride (2.72 g, 8.14 mmol) was added, and 1.36 g of tert-butyl ((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate was obtained as a white solid with a yield of 38.58%.

[0448] (4) Synthesis of (5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine:

[0449] Synthesized according to the method and conditions of Example 1(4), except that tert-butyl ((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)carbamate (1.36 g, 2.89 mmol) was added, and 1.01 g of (5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methanamine was obtained as a white solid with a yield of 94.17%.

[0450] Synthesis of N-((5-(2-Iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide (A30):

[0451] Synthesized according to the method and conditions of Example 8(5), with the difference that 2-(trifluoromethyl)benzoyl chloride (0.09 g, 0.45 mmol) was added, and 0.18 g of N-((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide was obtained, with a yield of 80.37%.

[0452] Physicochemical properties of compound A30: White solid, melting point 135 - 136 °C.

[0453] 1H nuclear magnetic resonance spectra ( 1 1H NMR) and 13C nuclear magnetic resonance spectra ( 13 13C NMR) of the synthesized flexible arylformamide derivatives containing 1,2,4-oxadiazole are shown in Table 1 and Table 2 respectively.

[0454] Table 1 1H NMR data of the compounds prepared in Examples 1 - 30

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] Table 2 13C NMR data of the compounds prepared in Examples 1 - 30 13 13C NMR data

[0464]

[0465]

[0466]

[0467] Test example: In vitro nematicidal activity test of the compounds prepared in Examples 1 - 30 against second-instar Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor

[0468] (1) Cultivation of nematodes

[0469] On the basis of the reported method (Rajasekharan, S.K.; Lee, J-H.; Ravichandran, V.; Lee, J. Assessments of iodoindoles and abamectin as inducers of methuosis in pinewood nematode, Bursaphelenchus xylophilus. Sci. Rep. 2017, 7, 6803.), the cultivation method was further optimized to obtain second-stage larvae. The pinewood nematodes were inoculated onto the cultivated Botrytis cinerea, and after culturing in the dark at 27 °C in a biochemical incubator for 5 - 7 days, 2 - 3 Petri dishes covered with pinewood nematodes were taken, and the pinewood nematodes were washed out with deionized water, then transferred to a 5 mL centrifuge tube and centrifuged for 5 minutes (6000 rpm / min), and the supernatant was discarded. Then the concentrated pinewood nematodes were inoculated onto a new Petri dish of Botrytis cinerea. After culturing for 24 hours, the pinewood nematodes and eggs in the culture medium were washed into a glass Petri dish with deionized water and left to stand for 2 hours, and the pinewood nematode eggs would adsorb onto the glass Petri dish. Then the water was slowly poured out, and the Petri dish was slowly washed with deionized water 1 - 2 times, and then deionized water was added to completely immerse the eggs. Finally, it was placed in a biochemical incubator at 27 °C for 24 hours to collect the second-stage larvae. The same method was used to obtain Aphelenchoides besseyi and Ditylenchus destructor.

[0470] (2) Nematicidal activity test

[0471] The test compound was first fully dissolved in DMSO and then diluted with a 1% aqueous solution of Tween 80 to a test solution of the required concentration. The immersion method (Wei, C.Q,; Huang, J.J.; Luo, Y.Q.; Wang, S.B.; Wu, S.K.; Xing, Z.F.; Chen, J.X. 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) was used to determine the in vitro nematicidal activity of the compound against pinewood nematodes, Aphelenchoides besseyi and Ditylenchus destructor. At five different concentration gradients, the median lethal concentration (LC 50)。Commercial Tioxazafen was used as the positive control, and the test solution without the compound was used as the negative control (CK). Each treatment had three replicates, and the experiment was repeated three times. The results were expressed as the mean ± deviation. The mortality and corrected mortality of the nematodes were calculated using the following formulas (when the mortality of the CK group was less than 5%, there was no corrected mortality):

[0472] Mortality (%) = Number of dead nematodes in the treatment group / Total number of nematodes in the treatment group × 100

[0473] Corrected mortality (%) = (Mortality of the treatment group (%) - Mortality of the blank group (%)) / (100 - Mortality of the blank group (%)) × 100

[0474] (3) In vitro nematicidal activity of the compounds prepared in Examples 1 - 30

[0475] The initial screening concentrations were selected as 200 and 100 mg / L, and the immersion method was used to determine the in vitro nematicidal activity of all target compounds against second - instar Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor for 72 hours. The nematicidal activities of some compounds are shown in Table 3. From the results, it can be seen that the toxicidal activities of Compounds A5, A18, A20, A21, A22, and A30 against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor were all 100% at the concentrations of 200 and 100 mg / L, which were significantly better than the control agent Tioxazafen (53.17% and 51.63%, 90.04% and 81.74%, 86.25% and 82.57%).

[0476] Table 3 In vitro nematicidal activity of the compounds prepared in Examples 1 - 30 against second - instar Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor (72h)

[0477]

[0478]

[0479] The target compounds with better initial screening activities were selected to further determine their median lethal concentrations (LC 50 ) against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor. The results are shown in Table 4. From the test results, it can be seen that the LC 50 values of Compounds A5, A18, A20, A21, and A22 against the above three nematodes were all close to or less than 3 mg / L, and among them, the LC 50 values against Ditylenchus destructor were all less than 2 mg / L, which were all significantly better than the control agent Tioxazafen (105.53, 48.95, and 74.95 mg / L).

[0480] Table 4 LC 50 values of the selected compounds against second - instar Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor (72h)

[0481]

[0482]

Claims

1. A flexible arylformamide derivative containing 1,2,4-oxadiazole, characterized in that, Any one selected from the following compounds: A5: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide; A7: N-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide; A8: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide; A18: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide; A20: N-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide; A21: N-((5-(2,4-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide; A22: N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide; A23: N-((5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chloropyridine-3-carboxamide; A29: N-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-chlorobenzamide; A30: N-((5-(2-iodo-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-(trifluoromethyl)benzamide.

2. Use of a flexible arylformamide derivative containing 1,2,4-oxadiazole as described in claim 1 in the preparation of a drug for preventing and treating Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor.

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