Process for the preparation of pyrazoline-1,3,4-oxadiazole thioacetamide derivatives and their use as insecticides

Abstract

The application discloses a pyrazoline-1,3,4-oxadiazole thioacetamide compound with a novel structure, a preparation method of the compound and application of the compound as an agricultural insecticide, and a structure of the compound is shown in a general formula I. 1 H, acetyl, C1-C3 alkyl; R 2 is selected from H, halogen, halogenated alkyl, nitro, methyl, and can be single or multiple on the benzene ring at any position; and Z is selected from C1-C10 alkylamine, C1-C4 halogenated alkylamine and substituted arylamine. The compound shown in the general formula I has the effect of preventing and treating agricultural pests, and can be used for preventing and treating agricultural major pests such as Plutella xylostella and Spodoptera exigua.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemicals, specifically relating to a method for preparing pyrazoline-1,3,4-oxadiazole thioacetamide by cyclizing 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiol with potassium hydroxide and carbon disulfide, and its application as an agricultural insecticide. Background Technology

[0002] In the development of green pesticides, amide compounds are widely present in the chemical structures of various pesticides. Some commercially available pesticides, such as the insecticides fleroranar, aforanar, loteranar, fipronil, phthalamide, and bromonitrile diacetamide, all contain amide structures. Therefore, amide insecticides have excellent commercial prospects. To discover new pesticide compounds, the inventors introduced amide fragments with excellent biological activity into their skeletons, obtaining a novel class of compounds represented by Formula I, and found that they control pests caused by agricultural pests. Therefore, this invention discloses a class of novel pyrazoline-1,3,4-oxadiazole thioacetamide compounds, their preparation methods, applications, and applications as agricultural insecticides. Therefore, the study of synthetic methods for amide derivatives is a direction of great interest, and a large number of literature reports have been published (J. Agric. Food Chem, 2010, 58(5), 2736-2740; Organic Letters, 2014, 16, 5772; Angewandte Chemie-International Edition, 2016, 55, 5327; Bioorganic, Letters, 2017, S0960894X17308478; Pest Manag Sci, 2012, 68: 801–810; J. Agric. Food Chem, 2013, 61, 8730-8736; J. Agric. Food Chem, 2013, 61, 5483-5493; Journal of the American Chemical Society, 2010, 132, 28; Rsc Advances). 2016,6,78307-78310;Green Chemistry,2015,17,1113-1119;Asian Journal of Organic Chemistry,2015,4,438-441;ChemicalCommunications,2014,50,9533-9535;European Journal of Organic Chemistry, 2014, 7174-7183; J. Agric. Food Chem, 2022, 70, 12651-12662...etc.).

[0003] In addition, derivatives containing pyrazoline rings and 1,3,4-oxadiazole rings have always been an important research subject. They are not only important intermediates in organic synthesis, but also insecticides, antibacterial agents, and plant growth regulators with excellent activity. There have been many reports on the application of pyrazoline ring and 1,3,4-oxadiazole ring (Bioorg.Med.Chem,17(2009)4241-4256; J.Agric.Food.Chem,2022,70.8,2510-2519; European Journal of Medicinal Chemistry,92(2015)342-352; J.Agric.Food.Chem,2022 70(11),3435-3446; European Journal of Medicinal Chemistry,112(2016)270-279; J.Agric.Food.Chem,2019,67(13),3535-3545).

[0004] In order to discover compounds with good agricultural biological activity, this invention utilizes the theory of isosteric biomass and the principle of skeletal transition to splice and modify the active fragments of the pyrazoline ring and the 1,3,4-oxadiazole ring, thereby obtaining a series of pyrazoline-1,3,4-oxadiazole thioacetamide derivatives with good insecticidal activity. Summary of the Invention

[0005] One of the objectives of this invention is to provide a pyrazoline-1,3,4-oxadiazole thioacetamide derivative and its application as an agricultural insecticide, the general formula of which is shown in I:

[0006]

[0007] In general formula I, R 1 The radical is selected from H, acetyl, C1-C3 alkyl; R is selected from H, halogen, haloalkyl, nitro, methyl, and can be substituted at any position on the benzene ring, either singly or in multiples; Z is selected from C1-C10 alkylamine, C1-C4 haloalkylamine, substituted aromatic amine.

[0008] Furthermore, in general formula I, R 1 Choose H and acetyl groups; R 2 It is selected from H, halogen, haloalkyl, and can be substituted at any position on the benzene ring, one or more; Z is selected from methylamino, dimethylamino, ethylamino, n-propylamino, n-butylamino, cyclopropylamino, cyclopentanamino, cyclohexylamino, 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino, and substituted aromatic amino groups.

[0009] Furthermore, in general formula I, R 1=H;R 2 Selected from H, 3,5-2Cl, 3,5-2Cl-4-CF 3、 3-Cl-4-CF3; Z is selected from methylamino, dimethylamino, ethylamino, n-propylamino, n-butylamino, cyclopropylamino, cyclopentanamino, cyclohexylamino, 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino, and substituted aniline groups.

[0010] Furthermore, in general formula I, R 1 =H;R 2 3,5-2Cl; Z is selected from methylamino, dimethylamino, ethylamino, n-propylamino, n-butylamino, cyclopropylamino, cyclopentanamino, cyclohexylamino, 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino, and substituted aniline groups.

[0011] Based on the above, further optimization is performed, in general formula I, R 1 =H;R 2 3,5-2Cl; Z is selected from dimethylamino, ethylamino, n-propylamino, n-butylamino, cyclopropylamino, cyclopentanamino, cyclohexylamino, 2,2-difluoroethylamino, 2,2,2-trifluoroethylamino, aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-fluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 3,4-dimethylaniline, 2-methyl-3-chloroaniline, 2-methyl-4-chloroaniline, 2-nitro-5-chloro- Aniline, 3-fluoro-4-nitro-aniline, 2-chloro-4-fluoro-aniline, 3-chloro-4-fluoro-aniline, 2,4-difluoro-aniline, 2,6-difluoro-aniline, 3,5-difluoro-aniline, 3-trifluoromethoxy-aniline, 2-trifluoromethyl-aniline, 3-trifluoromethyl-aniline, 4-trifluoromethyl-aniline, 3-fluoro-4-bromo-aniline, 2-nitro-aniline, 3-nitro-aniline, 4-nitro-aniline, 3-methoxy-5-trifluoromethyl-aniline.

[0012] The preparation method of the pyrazoline-1,3,4-oxadiazole thioacetamide derivative of the present invention includes the following steps.

[0013]

[0014] The specific steps are as follows: (1) Add substituted-5-(3,3,3-trifluoro-1-propen-2-yl)benzene, dry dichloromethane, add ethyl diazonium acetate solution and triethylamine dropwise, heat to reflux, after the reaction is complete, evaporate to dryness, extract with ethyl acetate to obtain ethyl pyrazoline carboxylate derivative 5-(substituted phenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-carboxylate, anhydrous ethanol, add triethylamine dropwise, add acetyl chloride dropwise under ice bath conditions, heat to room temperature and then heat to reflux, after the reaction is complete, evaporate to dryness, extract with ethyl acetate to obtain substituted 1-acetyl-5-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-3-carboxylate ethyl ester, and then add the substituted 1-acetyl-5-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-3-carboxylate. -5-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester is stirred with hydrazine hydrate at room temperature for 3-4 hours to obtain substituted 1-acetyl-5-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylhydrazine, which is then reacted with carbon disulfide under alkaline conditions to close the ring, thus obtaining substituted 1-(3-(5-mercapto-1,3,4-oxadiazol-2-yl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)ethyl-1-one; (2) substituted -5-(3,3,3-trifluoro-1-propen-2-yl)benzene is added, dichloromethane is dried, and ethyl diazonium acetate solution and triethylamine are added dropwise. After reflux and complete reaction, the mixture was evaporated to dryness and extracted with ethyl acetate to obtain ethyl 5-(substituted phenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylate, a pyrazoline carboxylate derivative. Anhydrous ethanol was added, followed by the dropwise addition of triethylamine and then a bromine-substituted alkyl group. The mixture was heated to reflux and complete reaction. After reflux and complete reaction, the mixture was evaporated to dryness and extracted with ethyl acetate to obtain alkyl-substituted 5-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylate. This alkyl-substituted 5-phenyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylate was then stirred with hydrazine hydrate at room temperature for 3-4 hours to obtain alkyl-substituted 5-(substituted phenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylhydrazine. Subsequently, under alkaline conditions, it reacted with carbon disulfide to close the ring, yielding the desired product. (2) 5-(5-(substituted phenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiol with alkyl substitution; (3) Chloroacetyl chloride is reacted with Z ammonia to obtain the corresponding chloroacetamide, and then reacted with substituted 1-(3-(5-mercapto-1,3,4-oxadiazole-2-yl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl) ethyl-1-one and substituted 5-(5-(substituted phenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiol under alkaline conditions to obtain the derivative shown in general formula 1.

[0015] The compound of this invention can be used to control a variety of agricultural pests such as diamondback moth, armyworm, cotton bollworm, corn borer, fall armyworm, aphid, and rice planthopper, and is particularly effective against diamondback moth and fall armyworm.

[0016] The innovation of this invention lies in the fact that, for the first time, a pyrazoline-1,3,4-oxadiazole thioacetamide derivative was constructed through a substitution method in 1,3,4-oxadiazole thioacetamide compounds, with excellent yields. Furthermore, the reaction process is relatively clean and environmentally friendly. In addition to generating pyrazoline-1,3,4-oxadiazole thioacetamide, the byproduct (5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiol) can also be used as a raw material, thereby achieving recycling and improving atom economy.

[0017] In addition, a series of pyrazoline-1,3,4-oxadiazole thioacetamide derivatives with good insecticidal activity were obtained. Experiments showed that some compounds were significantly effective against diamondback moth and fall armyworm. For example, compounds 15, 16, 17, 21, 22, 25, 27, 28, 29, 30, 31, and 34 showed a 100% lethality against diamondback moth at concentrations above 100 ppm, comparable to the control agent Fluralaner; they show promise as insecticides for controlling the agricultural pest diamondback moth. Similarly, compounds 15, 17, and 31 showed a 100% lethality against fall armyworm at a concentration of 200 ppm, comparable to the control Fluralaner; they also show promise as insecticides for controlling the agricultural pest fall armyworm.

[0018] The specific technical solutions of the present invention will be further described in detail below through specific embodiments: The preparation methods of the compounds of Formula I of the present invention will be specifically illustrated through some typical compound preparation examples. These examples are only for illustrating the preparation methods of the present invention and are not intended to limit the compounds of the present invention. The preparation methods of derivatives related to the present invention other than those in the examples can be performed by reference. For further explanation, more physicochemical data of related compounds are listed after the examples. Detailed Implementation

[0019] Example 1: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-ethylacetamide:

[0020] Step 1: Preparation of ethyl 1-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylate (intermediate 1): In a 50 mL single-necked flask, add 3.5 mL (41.49 mmol) of 1,3-dichloro-5-(3,3,3-trifluoro-1-propen-2-yl)benzene, 15 mL of dry dichloromethane, and dropwise add 2 mL of ethyl diazonium acetate (45.64 mmol, 1.2 eq). Then add 8 mL of triethylamine and heat to reflux for 24 hours. After the reaction is complete, evaporate to dryness, add 50 mL of ethyl acetate, wash three times with water, and wash once with saturated ammonium chloride. Combine the organic phases. After solvent removal under reduced pressure, give 7 g of white solid, yield 90%.

[0021]

[0022] Step 2: Add 6.0 g of ethyl 1-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylate and 2.5 mL of hydrazine hydrate (50.8 mmol) to a 50 mL single-necked flask, and stir at room temperature for 3-4 hours. After the reaction is complete, evaporate to dryness, add 50 mL of ethyl acetate, wash three times with water, and wash once with saturated sodium bicarbonate. Combine the organic phases. After solvent removal under reduced pressure, recrystallize from anhydrous ethanol, filter, and wash the filter cake with n-hexane to give 5.4 g of white solid, yield 86%.

[0023]

[0024] Step 3: In a 50 mL single-necked flask, add 5.2 g (14.66 mmol) of 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-3-carboxylhydrazide (intermediate 2) dissolved in 25 mL of anhydrous methanol. Then, add 1.72 g (30.78 mmol) of potassium hydroxide dissolved in 15 mL of anhydrous methanol dropwise to the reaction flask, followed by 2.23 mL (29.32 mmol) of carbon disulfide. Heat to 120 °C and reflux with stirring for 7-8 h. After the reaction is complete, evaporate to dryness, add 50 mL of ethyl acetate, wash three times with water, and wash once with saturated sodium bicarbonate. Combine the organic phases. After desolvation under reduced pressure, recrystallize from anhydrous ethanol, filter, and wash the filter cake with a small amount of petroleum ether to give 5.0 g of yellow solid, which is thiol intermediate 3, with a yield of 88%.

[0025]

[0026] Step 4: Add ethylamine to a 50mL single-necked flask, add 15mL of dry dichloroethane, place in an ice-salt bath and stir to cool, then slowly add acetyl chloride dropwise. After 20 minutes, remove the ice bath, heat to room temperature, and the reaction is complete after 2-3 hours. After evaporating the dichloroethane, wash with petroleum ether 2-3 times to obtain solid intermediate 4 for later use.

[0027]

[0028] Step 5: 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K₂CO₃ were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-ethylacetamide was added, and the mixture was stirred at room temperature for 10 min. The temperature was then raised to 110 °C, and the reaction was monitored by TLC. After 5 hours, the reaction was stopped, and column chromatography (dichloromethane:methanol = 100:1) was performed to remove the solvent, yielding the target compound in 82% yield as a white solid. The reaction route and physicochemical data of the product are as follows:

[0029]

[0030] mp187.1-188.4℃. 1 H NMR (400MHz, CDCl3) δ7.39 (dt, J=2.6, 1.8Hz, 1H, Ar-H), 7.31 (dd, J=4.4, 1.1Hz, 2H, Ar-H), 4.23 (d, J=7. 1Hz,1H),3.80(dd,J=18.3,1.1Hz,1H),3.36(s,1H),3.32–3.26(m,1H),1.67(s,2H),1.32–1.22(m,3H); 13 C NMR(101MHz,Chloroform-d)δ162.36,157.56,145.23,139.66,139.49,135.43,129.18(d, J=4.3Hz),125.37,72.38(d,J=28.3Hz),62.46,40.51,29.48,14.14.HRMS(ESI)m / z:calcd forC 16 H 14 Cl2F3N5O2S:([MH] - ):467.0197,found:465.0476.

[0031] Example 2: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-propylacetamide

[0032] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is n-propylamine. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0033]

[0034] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-propylacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 80% yield as a white solid; mp 180.2-181.4 °C. 1 H NMR(500MHz,DMSO)δ7.69(d,J=1.8Hz,1H,Ar-H),7.66(d,J=1.5Hz,2H,Ar-H),4.05(s,2H),3.87(s ,1H),3.71(d,J=18.0Hz,1H),3.02(d,J=7.0Hz,2H),1.40(d,J=7.1Hz,2H),0.82(t,J=7.4Hz,3H); 13 C NMR(126MHz,Methanol-d4)δ157.92,144.83,141.88,136.65,130.22,128.83,1 27.44,114.96,70.15,44.92,42.76,31.52,23.49,11.67.HRMS(ESI)m / z:calcd for C 17 H 16 Cl2F3N5O2S:([MH] - ):481.0354,found:480.0279.

[0035] Example 3: Preparation of N-butyl-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0036] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is n-butylamine. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0037]

[0038] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of N-butyl-2-chloroacetamide was added, and the mixture was stirred at room temperature for 10 min. The temperature was then raised to 110 °C, and the reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 79% yield as a white solid; mp 172.3-173.2 °C. 1 H NMR NMR(500MHz,DMSO-d6)δ7.73–7.68(m,3H,Ar-H),4.06(s,2H),3.88(s,1H),3.74(d,J=18.1Hz, 1H), 3.06 (t, J = 6.9Hz, 2H), 1.36 (d, J = 7.6Hz, 2H), 1.25 (d, J = 7.6Hz, 2H), 0.83 (t, J = 7.3Hz, 3H); 13 C NMR(101MHz,Chloroform-d)δ170.78,157.68,157.27,144.77,139.92,135.75,129.51,12 5.79,72.79(q,J=28.4Hz),43.54,40.96,33.11,29.07,20.08,13.78.HRMS(ESI)m / z:calcd for C 18 H 18 Cl2F3N5O2S:([MH] - ):495.0510,found:494.0436.

[0039] Example 4: Preparation of N-cyclopropyl-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0040] The methods for steps one through four are the same as in Example 1, except that in step four, cyclopropylamine is used. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0041]

[0042] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-cyclopropylacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 76% yield as a white solid; mp 182.1-183.2 °C. 1 H NMR(500MHz,DMSO-d6)δ7.71(t,J=1.9Hz,1H,Ar-H),7.69(d,J=1.9Hz,2H,Ar-H),4.02(s,2H),3.94–3 .87(m,1H),3.74(d,J=18.1Hz,1H),2.64–2.59(m,1H),0.62(td,J=7.0,4.7Hz,2H),0.43–0.38(m,2H); 13 C NMR (126MHz, DMSO-d6) δ166.99, 163.98, 160.20, 140.08, 134.63, 133.31 (d, J = 23.5Hz), 129.08, 126.68,72.50,35.86(d,J=5.4Hz),22.71(d,J=16.8Hz),5.73(d,J=2.9Hz).HRMS(ESI)m / z:calcd for C 17 H 14 Cl2F3N5O2S:([MH] - ):479.0197,found:480.0270.

[0043] Example 5: Preparation of N-cyclopentyl-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0044] The methods for steps one through four are the same as in Example 1, except that in step four, cyclopentylamine is used. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0045]

[0046] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-cyclopentylacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 66% yield as a white solid; mp 186.1-187.2 °C. 1 H NMR(500MHz,DMSO-d6)δ6.95(t,J=1.8Hz,1H,Ar-H),6.92(d,J=1.8Hz,2H,Ar-H),3.28(s,2H),3.23–3.18(m,1H),3.14 (d,J=18.2Hz,1H),2.98(d,J=18.0Hz,1H),1.05–0.98(m,2H),0.88–0.83(m,2H),0.76–0.69(m,2H),0.65–0.56(m,2H); 13 C NMR(126MHz,DMSO-d6)δ165.27(d,J=10.8Hz),164.11,160.28,140.19,134.73,133.46,129 .14,126.73,72.68(d,J=27.8Hz),50.99,47.74,36.12,32.32,23.56.HRMS(ESI)m / z:calcd for C 19 H 18 Cl2F3N5O2S:([MH] - ):507.0510,found:506.0426.

[0047] Example 6: Preparation of N-cyclohexyl-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0048] The methods for steps one through four are the same as in Example 1, except that in step four, cyclohexylamine is used. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0049]

[0050] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-cyclohexylacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 66% yield as a white solid; mp 192.1-193.2 °C. 1 H NMR (500MHz, DMSO-d6) δ7.72(s,1H,Ar-H),7.68(d,J=1.8Hz,2H,Ar-H),4.04(s,2H),3.89(d,J=18.1Hz,1H),3.73(d,J=18.0Hz ,1H),1.70(d,J=4.1Hz,2H),1.64(d,J=3.9Hz,2H),1.52(dt,J=13.0,3.8Hz,2H),1.22(t,J=3.1Hz,2H),1.12(d,J=3.1Hz,2H); 13 C NMR(126MHz,DMSO-d6)δ164.82,164.07,160.27,140.17,134.71,133.45,129.14,12 6.72,72.68(d,J=27.8Hz),36.16,32.35,29.81,25.31,24.56.HRMS(ESI)m / z:calcd for C 19 H 18 Cl2F3N5O2S:([MH] - ):521.0667,found:520.0583.

[0051] Example 7: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(difluoromethyl)acetamide

[0052] The methods for steps one through four are the same as in Example 1, except that in step four, cyclopentylamine is used. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0053]

[0054] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2,2-difluoroethyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 74% yield as a white solid; mp 169.1-170.3 °C. 1 H NMR(400MHz,Chloroform-d)δ7.41(t,J=1.8Hz,1H,Ar-H),7.32(dd,J=1.8,0.8Hz,2H,Ar-H),6.90–6 .82(m,1H),6.72(s,1H,NH),4.07–3.88(m,2H),3.83(d,J=18.4Hz,1H),3.34(dt,J=18.3,1.1Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ160.87,145.10,139.83,135.87,129.61,128.11, 125.70,125.31,73.03(d,J=28.3Hz),40.90,40.72,40.37.HRMS(ESI)m / z:calcd forC 16 H 12 Cl2F5N5O2S:([MH]-):503.0009,found:501.9951.

[0055] Example 8: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(trifluoromethyl)acetamide

[0056] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2,2,2-trifluoroethylamine. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0057]

[0058] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 75% yield as a white solid; mp 175.2-176.4 °C. 1 H NMR(500MHz,DMSO-d6)δ6.73(t,J=1.8Hz,1H,Ar-H),6.70(d,J=1.8Hz,2H,Ar-H),3.1 9(s,2H),2.96(d,J=9.6Hz,2H),2.92(dd,J=17.3,2.3Hz,1H),2.76(d,J=18.3Hz,1H); 13 C NMR(126MHz,DMSO-d6)δ166.95,163.63,160.18,140.01,134.55,133.24,128.95,126.54,72.51(q,J=27.8Hz),35.32.HRMS(ESI)m / z:calcd for C 16 H 12 Cl2F5N5O2S:([MH] - ):520.9915,found:519.9831.

[0059] Example 9: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N,N-dimethylacetamide

[0060] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is N,N-dimethylmethylamine. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0061]

[0062] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N,N-dimethylacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 68% yield as a white solid; mp 165.1-166.3 °C. 1 H NMR(500MHz,DMSO-d6)δ7.68(t,J=1.8Hz,1H,Ar-H),7.65(d,J=1.9Hz,2H,Ar-H),4.46( s,2H),3.86(dd,J=18.1,1.5Hz,1H),3.70(d,J=18.0Hz,1H),2.99(s,3H),2.82(s,3H); 13 C NMR (126MHz, DMSO-d6) δ165.93, 164.29, 160.03, 140.09 (d, J = 6.1Hz), 134.60, 133. 45,129.07,126.68,72.56(d,J=27.6Hz),37.23,37.03,35.45.HRMS(ESI)m / z:calcd for C 16 H 14 Cl2F5N5O2S:([M+Na) + ):467.0197,found:490.0078.

[0063] Example 10: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-phenylacetamide

[0064] The methods for steps one through four are the same as in Example 1, except that in step four, aniline is used as the amine. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0065]

[0066] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-phenylacetamide was added, and the mixture was stirred at room temperature for 10 min. The temperature was then raised to 110 °C, and the reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 81% yield as a white solid; mp 185.1-186.2 °C. 1 H NMR(500MHz,DMSO-d6)δ10.42(s,1H,NH),9.97(s,1H,NH),7.67(d,J=1.9Hz,2H,Ar-H),7.58–7.54(m,2H,Ar-H) ,7.33–7.27(m,2H,Ar-H),7.08–7.04(m,1H,Ar-H),4.33(s,2H),3.88(d,J=18.0Hz,1H),3.72(d,J=18.0Hz,1H); 13 CNMR(126MHz,DMSO-d6)δ164.62,163.79,160.16,140.03,138.64,134.53,132.92,128.89(d, J=12.9Hz),126.53,123.67,119.17,72.55(q,J=27.5Hz),36.92.29.81.HRMS(ESI)m / z:calcd for C 16 H 12 Cl2F3N5O2S:([MH] - ):515.0197,found:514.0113.

[0067] Example 11: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(o-tolyl)acetamide

[0068] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-methyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0069]

[0070] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-o-tolueneacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 83% yield as a white solid; mp 187.1-188.3 °C. 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),7.42(s,1H),7.36(d,J=5.4Hz,3H),7.17(dd,J=16.4,8.7H z,2H),6.93(d,J=7.5Hz,1H),4.03(d,J=6.7Hz,2H),3.97(s,1H),3.53(d,J=17.8Hz,1H),2.32(s,3H); 13 C NMR(101MHz,Chloroform-d)δ166.55,165.07,160.53,139.41,139.15,137.44,135.97,135.58,129.77,12 8.98,125.75(d,J=6.2Hz),120.63,117.15,72.76(q,J=28.5Hz),41.51,36.34,21.59.HRMS(ESI)m / z:calcd for C 21 H 16 Cl2F3N5O2S:([MH]-):529.0354,found:528.0720.

[0071] Example 12: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(m-tolyl)acetamide

[0072] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-methyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0073]

[0074] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-m-tolueneacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 85% yield as a white solid; mp 183.2-184.3 °C. 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H,NH),7.42(s,1H,Ar-H),7.36(d,J=5.4Hz,3H,Ar-H),7.22–7.1 1(m,2H),6.93(d,J=7.5Hz,1H),4.03(d,J=6.7Hz,2H),3.97(s,1H),3.53(d,J=17.8Hz,1H),2.32(s,3H); 13 C NMR(101MHz,Chloroform-d)δ166.55,165.07,160.53,139.41,139.15,137.44,135.97,135.58,129.77,12 8.98,125.75(d,J=6.2Hz),120.63,117.15,72.76(q,J=28.5Hz),36.34,27.03,21.59.HRMS(ESI)m / z:calcd for C 21 H 16 Cl2F3N5O2S:([MH] - ):529.0354,found:528.0270.

[0075] Example 13: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(p-tolyl)acetamide

[0076] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 4-methyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0077]

[0078] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-p-tolueneacetamide was added. The mixture was stirred at room temperature for 10 min, and then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 87% yield as a white solid; mp 95-96 °C. 1 H NMR(500MHz,Chloroform-D)δ8.32(t,J=1.8Hz,1H),8.25(d,J=7.8Hz,1H),7.60–7.54(m,1H),7.40(t,J=7.9Hz,1H),6.96(s,1H ),3.88–3.78(m,1H),1.97(dd,J=12.5,3.5Hz,2H),1.80–1.73(m,2H),1.67–1.62(m,1H),1.45–1.36(m,2H),1.31–1.19(m,3H). 13 C NMR (126MHz, Chloroform-D) δ186.80,160.29,135.00,134.75,134.26,131.16,129.84,129.49,48.69,32.76,25.48,24.81.HR-MS(ESI):Calculated forC 14 H 16 ClNO2[M+H] + :266.09423,found:266.09393.

[0079] Example 14: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(2-fluorophenyl)acetamide

[0080] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0081]

[0082] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2-fluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 60% yield as a white solid; mp 196.2-197.3 °C. 1 H NMR(500MHz,DMSO-d6)δ10.50(d,J=3.0Hz,1H,NH),7.73(dd,J=3.1,1.6Hz,1H,Ar-H),7.68–7.63(m,3H,Ar-H),7.56–7.51(m,1H,Ar-H),7.47 –7.40(m,1H,Ar-H),7.36(d,J=7.4Hz,1H,Ar-H),4.32(d,J=17.4Hz,1H),4.22(dd,J=17.3,1.2Hz,1H),3.66–3.60(m,1H),3.50–3.42(m,1H); 13 C NMR (126MHz, DMSO-d6) δ170.89,161.22,160.29,157.66,156.24,140.51,134.48,131.47,130.82,128.90 ,126.59,125.19,122.21(d,J=13.1Hz),116.65,72.31(q,J=28.0Hz),32.81,29.86.HRMS(ESI)m / z:calcd for C 20 H 13 Cl2F4N5O2S:([M+Na) + ):533.6103,found:555.9986.

[0083] Example 15: Preparation of N-(2-chlorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0084] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-chloro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0085]

[0086] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2-chlorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 82% yield as a white solid; mp 190.1-191.4 °C. 1 H NMR(500MHz,DMSO-d6)δ9.73(s,1H,NH),9.08(s,1H,NH),6.87(t,J=2.1Hz,1H,Ar-H),6.81–6.76(m,3H,Ar-H),6.51(ddd,J=8.3,2.0,1.0Hz, 1H, Ar-H), 6.43 (t, J = 8.1Hz, 1H, Ar-H), 6.21 (ddd, J = 8.0, 2.1, 1.0Hz, 1H, Ar-H), 3.44 (s, 2H), 2.99 (d, J = 18.0Hz, 1H), 2.83 (d, J = 18.0Hz, 1H); 13 C NMR(126MHz,DMSO-d6)δ167.97,165.87,141.80,135.77,129.00,128.43,126.45–125.01(m),122.01,12 0.30(d,J=12.1Hz),120.10,118.85,112.02,110.02,109.14,75.18,66.11,20.46.HRMS(ESI)m / z:calcd for C 20 H 13 Cl3F3N5O2S:([MH]-):548.9808,found:547.9723.

[0087] Example 16: Preparation of N-(3-chlorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0088] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-chloro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0089]

[0090] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-chlorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 87% yield as a white solid; mp 193.3-194.4 °C. 1 H NMR (500MHz, DMSO-d6) δ10.64(s,1H,NH),9.99(s,1H,NH),7.77(t,J=2.0Hz,1H,Ar-H),7.69(dd,J=6.6,1.8Hz,3H,Ar-H),7.42(dt,J=8 .3,1.2Hz,1H,Ar-H),7.34(t,J=8.1Hz,1H,Ar-H),7.14–7.10(m,1H,Ar-H),4.35(s,2H),3.90(d,J=18.0Hz,1H),3.74(d,J=18.0Hz,1H); 13 C NMR(126MHz,DMSO-d6)δ165.18,163.75,160.26,140.07(d,J=4.9Hz),134.57,133.27,133.10,130.65,129.01,1 26.61,125.07(d,J=285.9Hz),123.48,118.68,117.61,72.61(q,J=27.8Hz),36.93,29.08.HRMS(ESI)m / z:calcd for C 20 H 13 Cl3F3N5O2S:([MH] - ):548.9808,found:547.9723.

[0091] Example 17: Preparation of N-(4-chlorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0092] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 4-chloro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0093]

[0094] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(4-chlorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 87% yield as a white solid; mp 195.1-196.3 °C. 1 H NMR (500MHz, DMSO-d6) δ10.58(s,1H,NH),9.99(s,1H,NH),7.73(t,J=1.8Hz,1H,Ar-H),7.69(d,J=1.8Hz,2H,Ar-H ),7.62–7.57(m,2H,Ar-H),7.39–7.35(m,2H,Ar-H),4.34(s,2H),3.89(d,J=18.1Hz,1H),3.74(d,J=18.1Hz,1H); 13 C NMR(126MHz,DMSO-d6)δ164.93,163.78,160.24,140.05,137.63,134.56,133.13,129.04,128.87, 127.33,126.62,126.20,123.93,120.78,72.61(q,J=27.6Hz),36.91.29.89.HRMS(ESI)m / z:calcd for C 20 H 13 Cl3F3N5O2S:([MH]-):548.9808,found:547.9723.

[0095] Example 18: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(3,4-dimethylphenyl)acetamide

[0096] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3,4-di-methyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0097]

[0098] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K₂CO₃ were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3,4-dimethylphenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 81% yield as a white solid; mp 183.0-184.2 °C. 1H NMR(500MHz,Chloroform-d)δ8.89(s,1H,NH),7.41(t,J=1.8Hz,1H,Ar-H),7.38–7.35(m,3H,Ar-H),7.24(s,1H,Ar-H 13C NMR(126MHz,Chloroform-d)δ166.13,164.68,160.23,139.19,137.19,135.64,135.10,134.92,133.15,129 .81,129.45,125.49,121.13,117.37,72.49(q,J=28.4Hz),41.15,36.15,19.70,19.09.HRMS(ESI)m / z:calcd forC22H18Cl2F3N5O2S:([M+Na]+):543.0510,found:566.0393.

[0099] Example 19: Preparation of N-(3-chloro-2-methylphenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0100] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-methyl-3-chloro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0101]

[0102] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-chloro-2-methylphenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 68% yield as a white solid; mp 175.2-176.3 °C. 1 H NMR(500MHz,DMSO-d6)δ10.50(s,1H,NH),9.55(s,1H,NH),7.72(q,J=1.9Hz,1H ,Ar-H),7.65(s,2H,Ar-H),7.49(d,J=2.5Hz,1H,Ar-H),7.39(dd,J=8.5,2.4Hz, 1H, Ar-H), 7.28 (d, J=8.4Hz, 1H, Ar-H), 4.26 (dd, J=17.2, 2.0Hz, 1H), 4.20–4.1 5(m,1H),3.63(d,J=18.4Hz,1H),3.44(d,J=18.5Hz,1H),2.16(d,J=1.9Hz,3H); 13 C NMR (126MHz, DMSO-d6) δ171.23,162.38,157.77,142.26,140.49,138.68,134.48,133.66,133.02,130.5 7(d,J=14.6Hz),128.90,126.89,126.58,72.32(q,J=28.4Hz),32.87,29.81,16.97.HRMS(ESI)m / z:calcd for C 21 H 15 Cl3F3N5O2S:([M+Na) + ):562.9964,found:585.9839.

[0103] Example 20: Preparation of N-(4-chloro-2-methylphenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0104] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-methyl-4-chloro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0105]

[0106] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(4-chloro-2-methylphenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 70% yield as a white solid; mp 178.2-179.3 °C. 1 H NMR(500MHz,DMSO-d6)δ10.50(s,1H,NH),9.55(s,1H,NH),7.72(t,J=2.0Hz,1H, Ar-H),7.65(s,2H,Ar-H),7.49(d,J=2.5Hz,1H,Ar-H),7.40(dt,J=8.5,2.2Hz,1H ,Ar-H),7.28(d,J=8.4Hz,1H,Ar-H),4.26(dd,J=17.2,2.0Hz,1H),4.18(d,J=17 .2Hz,1H),3.63(d,J=18.6Hz,1H),3.45(d,J=18.6Hz,1H),2.16(d,J=2.0Hz,3H); 13 C NMR (126MHz, DMSO-d6) δ171.24,162.38,157.77,142.26,140.49,138.69,134.49,133.66,133.02,130.5 7(d,J=14.7Hz),128.91,126.89,126.59,72.32(q,J=28.3Hz),32.87,29.82,16.97.HRMS(ESI)m / z:calcd forC 21 H 15Cl3F3N5O2S:([M+Na) + ):562.9964,found:585.9844.

[0107] Example 21: Preparation of N-(5-chloro-2-nitrophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0108] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-chloro-5-nitro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0109]

[0110] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(5-chloro-2-nitrophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 86% yield as a white solid; mp 198.1-199.3 °C. 1 H NMR (500MHz, DMSO-d6) δ10.85(s,1H,NH),9.99(s,1H,NH),8.05(d,J=8.9Hz,1H,Ar-H),7.89(d,J=2.3Hz,1H,Ar-H),7.73(t,J=1.8Hz, 1H, Ar-H), 7.69 (d, J = 1.8Hz, 2H, Ar-H), 7.47 (dd, J = 8.9, 2.3Hz, 1H, Ar-H), 4.37 (s, 2H), 3.89 (d, J = 18.1Hz, 1H), 3.74 (d, J = 18.0Hz, 1H); 13C NMR(126MHz,DMSO-d6)δ165.89,163.34,160.34,140.09(d,J=9.9Hz),138.56,134.56,133.05,132.43,1 29.04,127.19,126.62,125.43,124.24,82.87–75.03(q,J=28.3Hz),36.34.29.82.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F3N6O4S:([M+Na) + ):593.9658,found:616.9549.

[0111] Example 22: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(5-fluoro-2-nitrophenyl)acetamide

[0112] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-fluoro-4-nitro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0113]

[0114] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-fluoro-4-nitrophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 85% yield as a white solid; mp 188.2-189.4 °C. 1H NMR(500MHz,DMSO-d6)δ8.48(dd,J=6.8,2.8Hz,1H,NH),7.82(ddd,J=9.1,3.9,2.7Hz,1H,Ar-H),7.63(d,J=1.8Hz,1H,Ar-H), 7.61(d,J=1.8Hz,3H,Ar-H),7.48(dd,J=11.1,9.1Hz,1H,Ar-H),4.30(s,2H),3.88(d,J=18.0Hz,1H),3.67(d,J=18.0Hz,1H); 13 C NMR (126MHz, DMSO-d6) δ166.03, 164.38, 160.90, 151.37 (d, J = 259.0Hz), 140.68, 137.04 (d, J = 8.1Hz), 135.85, 135. 24,133.85,129.46,127.00,119.42(d,J=21.8Hz),116.25,73.09(q,J=27.8Hz),37.05,30.16.HRMS(ESI)m / z:calcd for C 20 H 12 Cl2F4N6O4S:([M+Na) + ):577.9954,found:600.9841.

[0115] Example 23: Preparation of N-(2-chloro-4-fluorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0116] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-chloro-4-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0117]

[0118] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2-chloro-4-fluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 81% yield as a white solid; mp 178.2-179.4 °C. 1 H NMR (400MHz, Chloroform-d) δ7.43(d,J=1.8Hz,2H,Ar-H),7.35(s,2H,Ar-H),7.08(s,2H,Ar-H),3.86(d,J=17.7Hz,2H),3.43(s,1H),2.96(d,J=29.9Hz,1H); 13 C NMR (126MHz, Chloroform-d) δ 166.69, 165.37, 160.67, 139.33, 138.31 (d, J = 10.2Hz), 136.02, 135.41, 133.50, 129. 83,125.70,116.41(d,J=3.5Hz),108.57,108.35,103.86(d,J=21.1Hz),72.91,41.49,36.14.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):566.9713,found:589.9596.

[0119] Example 24: Preparation of N-(3-chloro-4-fluorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0120] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-chloro-4-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0121]

[0122] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-chloro-4-fluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 82% yield as a white solid; mp 182.2-183.4 °C. 1 H NMR(400MHz,Chloroform-d)δ7.43(s,1H,Ar-H),7.35(d,J=1.8Hz,3H,Ar-H),7.08(s,2H,Ar-H),3.86(d,J=17.7Hz,2H),3.43(s,1H),2.96(d,J=29.8Hz,1H); 13 C NMR(126MHz,Chloroform-d)δ166.69,165.37,160.67,139.33,138.31(d,J=10.2Hz),136.02,135.41,133.50,12 9.83,125.70,116.41(d,J=3.5Hz),108.57,108.35,72.79(q,J=28.9Hz),41.49,36.14.HRMS(ESI)m / z:calcdfor C 20 H 12 Cl3F4N5O2S:([M+Na) + ):566.9713,found:589.9606.

[0123] Example 25: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(2,4-di-fluorophenyl)acetamide

[0124] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2,4-di-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0125]

[0126] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2,4-di-fluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 84% yield as a white solid; mp 192.2-193.4 °C. 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H,NH),9.98(s,1H,NH),7.69(s,2H,Ar-H),7.56(d,J=8.1Hz,1H,Ar-H),7.32(q, J=7.8,6.1Hz,2H,Ar-H),7.08(d,J=7.1Hz,1H,Ar-H),4.34(s,2H),3.89(d,J=17.9Hz,1H),3.74(d,J=18.1Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ164.69,163.80,160.19,140.03,138.66,134.53,133.12,128.98(d,J=8 .9Hz),126.60,123.75,119.36,119.20,72.59(q,J=27.8Hz),43.65,36.94.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):551.0009,found:573.9890.

[0127] Example 26: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(2,6-di-fluorophenyl)acetamide

[0128] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2,6-di-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0129]

[0130] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2,6-difluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 8% yield as a white solid; mp 195.1-196.4 °C. 1 H NMR(500MHz,DMSO-d6)δ10.17(s,1H,NH),9.93(s,1H,NH),8.18(s,2H,Ar-H),7.61(d,J=1.8Hz,2H,Ar- H),7.56(s,1H,Ar-H),7.05(s,1H,Ar-H),4.34(s,2H),3.86(d,J=17.9Hz,1H),3.66(d,J=18.1Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ164.69,163.80,160.19,159.12,140.03,138.66,134.53,133.12,128.98(d, J=8.9Hz),126.60,123.75,119.36,119.20,72.59(q,J=27.8Hz),43.65,36.94.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):551.0009,found:573.9893.

[0131] Example 27: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(3,5-difluorophenyl)acetamide

[0132] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3,5-di-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0133]

[0134] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K₂CO₃ were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3,5-difluorophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 83% yield as a white solid; mp 198.1-199.4 °C. 1H⁺ NMR (400MHz, DMSO-d6) δ10.25(s,1H,NH),9.99(s,1H,NH),7.86–7.80(m,1H,Ar-H),7.73(t,J=1.8Hz,1H,Ar-H),7.69(d,J=1.8Hz,2H,Ar-H),7.33( ddd,J=11.1,9.0,2.9Hz,1H,Ar-H),7.07(dddd,J=9.6,8.4,2.9,1.4Hz,1H,Ar-H),4.37(s,2H),3.90(d,J=18.1Hz,1H),3.75(d,J=18.1Hz,1H); 13C NMR(101MHz,DMSO-d6)δ165.44,163.67,160.25,158.70(dd,J=244.2,11.5Hz),1 53.88(dd,J=248.7,12.5Hz),140.04,134.55,133.11,129.02,126.60,125.40(d d,J=9.6,2.9Hz),122.27(dd,J=12.0,3.7Hz),111.29(dd,J=21.9,3.6Hz),104.3 1(dd,J=26.8,23.9Hz),72.61(q,J=27.8Hz),36.31.29.81.HRMS(ESI)m / z:calcd for C20H12Cl3F4N5O2S:([M+Na]+):551.0009,found:573.9892.

[0135] Example 28: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(4-(trifluoromethoxy)phenyl)acetamide

[0136] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 4-trifluoromethoxy-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0137]

[0138] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(4-(trifluoromethoxy)phenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 79% yield as a white solid; mp 188.2-189.4 °C. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H,NH),7.55–7.52(m,2H,Ar-H),7.48(s,1H,Ar-H),7.41(t,J=1.8Hz,1H,Ar-H) ,7.37(d,J=1.8Hz,2H,Ar-H),7.14(t,J=1.1Hz,1H,Ar-H),4.07(s,2H),3.98(d,J=17.8Hz,1H),3.53(d,J=17.7Hz,1H); 13 C NMR(126MHz,Chloroform-d)δ166.42,165.41,160.64,145.72,139.38,136.17,135.94,135. 11,129.75,125.73,121.87,121.25,72.82(q,J=28.5Hz),41.37,36.25.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):599.0020,found:621.9900.

[0139] Example 29: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(2-(trifluoromethyl)phenyl)acetamide

[0140] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-trifluoromethyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0141]

[0142] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2-(trifluoromethyl)phenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 87% yield as a white solid; mp 196.2-197.4 °C. 1 H NMR(500MHz,DMSO-d6)δ10.06(s,1H,NH),9.98(s,1H,NH),7.72(d,J=7.7Hz,1H,Ar-H),7.67(d,J=2.6Hz,4H,Ar-H),7 .51(d,J=8.0Hz,1H,Ar-H),7.45(d,J=7.7Hz,1H,Ar-H),4.33(s,2H),3.89(d,J=18.0Hz,1H),3.73(d,J=18.0Hz,1H); 13 C NMR (126MHz, DMSO-d6) δ166.08,163.57,160.21,140.03,134.78,134.53,133.04,132.86,129.82 ,128.93,127.00,126.51,126.31,82.61–72.47(q,J=28.5Hz),35.99.29.81.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):583.0071,found:605.9952.

[0143] Example 30: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(3-(trifluoromethyl)phenyl)acetamide

[0144] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-trifluoromethyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0145]

[0146] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-(trifluoromethyl)phenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 90% yield as a white solid; mp 203.2-204.3 °C. 1 H NMR (400MHz, Chloroform-d) δ9.34 (s, 1H, NH), 7.83 (t, J=1.9Hz, 1H, Ar-H), 7.69 (dt, J=8.1, 1.7Hz, 1H, Ar-H), 7.41 (q, J=1. 6Hz,1H,Ar-H),7.36(d,J=1.9Hz,3H,Ar-H),7.31(s,1H,Ar-H),4.06(s,2H),3.99(d,J=17.9Hz,1H),3.54(d,J=17.9Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ166.48,165.52,160.65,139.36,138.08,135.96,135.30,131.51(q,J=32.6Hz),129.73(d,J= 8.3Hz),125.72,123.10,121.47(d,J=3.9Hz),116.77(d,J=3.9Hz),72.80(q,J=28.4Hz),41.43,36.28.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([MH] - ):583.0071,found:581.9987.

[0147] Example 31: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(4-(trifluoromethyl)phenyl)acetamide

[0148] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 4-trifluoromethyl-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0149]

[0150] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(4-(trifluoromethyl)phenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 84% yield as a white solid; mp 193.2-194.3 °C. 1 H NMR(500MHz,Chloroform-d)δ9.44(s,1H,NH),7.62(d,J=8.4Hz,2H,Ar-H),7.55–7.49(m,2H, Ar-H),7.41–7.36(m,1H,Ar-H),4.08(s,2H),3.98(d,J=17.8Hz,1H),3.54(d,J=17.8Hz,1H); 13 C NMR(126MHz,Chloroform-d)δ166.16,165.33,160.45,140.33,139.11,135.67,134.75,129.49,126.10 (d,J=3.9Hz),125.48,123.51,122.71,119.40,72.58(q,J=28.5Hz),41.09,36.07.HRMS(ESI)m / z:calcd for C 20 H 12 Cl3F4N5O2S:([M+Na) + ):583.0071,found:605.9953.

[0151] Example 32: Preparation of N-(4-bromo-3-fluorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0152] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-fluoro-4-bromo-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0153]

[0154] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of N-(4-bromo-3-fluorophenyl)-2-chloroacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 82% yield as a white solid; mp 187.2-188.3 °C. 1 H NMR(500MHz,Chloroform-d)δ9.35(s,1H,NH),7.59(dd,J=10.4,2.4Hz,1H,Ar-H),7.45–7.41(m,2H ,Ar-H),7.36(d,J=1.8Hz,2H,Ar-H),7.11(s,1H,Ar-H),4.03–3.97(m,3H),3.54(d,J=17.9Hz,1H); 13 C NMR(126MHz,Chloroform-d)δ166.69,165.37,160.67,139.33,138.31(d,J=10.2Hz),136.02,135.41,133.50,129.83,125.7 0,116.41(d,J=3.5Hz),108.46(d,J=27.3Hz),103.86(d,J=21.1Hz),72.79(q,J=28.9Hz),41.49,36.14.HRMS(ESI)m / z:calcd forC 20 H 11 BrCl2F4N5O2S:([M+Na] + ):610.9208,found:633.9090.

[0155] Example 33: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(2-nitrophenyl)acetamide

[0156] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 2-nitro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0157]

[0158] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K₂CO₃ were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(2-nitrophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 67% yield as a white solid; mp 179.1-180.3 °C. 1H⁺ NMR(500MHz,Chloroform-d)δ11.05(s,1H,NH),8.69(dd,J=8.5,1.3Hz,1H,Ar-H),8.20(dd,J=8.4,1.5Hz,1H,Ar-H),7.66(d,J=1.4Hz,1H,Ar -H),7.42(t,J=1.7Hz,1H,Ar-H),7.35(d,J=1.7Hz,2H,Ar-H),6.98(s,1H,Ar-H),4.22(s,2H),3.99(d,J=17.7Hz,1H),3.53(d,J=17.9Hz,1H); 13 C NMR (126MHz, Chloroform-d) δ 165.42, 164.56, 160.63, 139.47, 135.99 (d, J = 9.7Hz), 133.87, 129. 74,125.94,125.73,124.36,122.72,72.79(q,J=28.9Hz),36.99,29.84.HRMS(ESI)m / z:calcdfor C 20 H 13 Cl2F3N6O4S:([M+Na) + ):560.0048,found:582.9931.

[0159] Example 34: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(3-nitrophenyl)acetamide

[0160] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-nitro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0161]

[0162] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K₂CO₃ were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(3-nitrophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 72% yield as a white solid; mp 183.1-184.3 °C. 1H⁺ NMR(500MHz,Chloroform-d)δ11.05(s,1H,NH),8.69(dd,J=8.3,1.3Hz,1H,Ar-H),8.20(dd,J=8.3,1.6Hz,1H,Ar-H),7.69–7.64(m,1H,Ar-H) 13C NMR(126MHz,Chloroform-d)δ165.42,164.56,160.63,139.47,137.12.136.03,135.95,133.87,12 9.74,125.94,125.73,124.36,122.72,72.79(q,J=28.9Hz),36.99,29.84.HRMS(ESI)m / z:calcdfor C20H13Cl2F3N6O4S:([MH]-):560.0048,found:558.9988.

[0163] Example 35: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(4-nitrophenyl)acetamide

[0164] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 4-nitro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0165]

[0166] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-(4-nitrophenyl)acetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 76% yield as a white solid; mp 186.1-187.4 °C. 1 H NMR(500MHz,Chloroform-d)δ9.44(s,1H,NH),7.62(d,J=8.5Hz,2H,Ar-H),7.52(s,1H,Ar-H),7.42–7.3 9(m,1H,Ar-H),7.37(d,J=1.8Hz,2H,Ar-H),4.08(s,2H),3.98(d,J=17.9Hz,1H),3.54(d,J=17.8Hz,1H); 13 C NMR (126MHz, DMSO-d6) δ167.97,165.87,141.80,135.77,128.43,126.15–125.75(m),124.14–122.78(m),122. 01,120.30(d,J=12.1Hz),120.09,112.02,109.14,70.65(q,J=1139.7Hz),45.71,20.46.HRMS(ESI)m / z:calcd for C 20 H 13 Cl2F3N6O4S:([M+Na) + ):560.0048,found:582.9927.

[0167] Example 36: Preparation of 2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)-N-(3-methoxy-5-(trifluoromethyl)phenyl)acetamide

[0168] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-trifluoromethyl-5-trifluoromethoxy-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0169]

[0170] 2 mmol of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-thiol and 2 mmol of K2CO3 were added to a 15 mL reaction tube equipped with a stir bar. 5 mL of acetonitrile was added, and the mixture was stirred for 5 min. Then, 1 mmol of 2-chloro-N-o-tolueneacetamide was added. The mixture was stirred at room temperature for 10 min, then heated to 110 °C. The reaction was monitored by TLC. After 5-6 hours, the reaction was stopped, and the solution was removed by column chromatography (dichloromethane:methanol = 100:1). The target compound was obtained in 74% yield as a white solid; mp 193.1-194.3 °C. 1 H NMR(500MHz,Chloroform-d)δ9.24(s,1H,NH),7.45(t,J=2.2Hz,1H,Ar-H),7.42(t,J=1.8Hz,1H,Ar-H),7.36(d,J=1.8Hz,2H,Ar-H ),7.09(s,1H,Ar-H),6.88(t,J=2.0Hz,1H,Ar-H),5.30(s,1H,NH),4.03(s,2H),3.99(s,1H),3.82(s,3H),3.55(d,J=17.9Hz,1H); 13 C NMR (126MHz, Chloroform-d) δ 166.55, 165.46, 160.64, 160.46, 139.32 (d, J = 9.0Hz), 136.00, 135.56, 132.31 (d, J = 32.5Hz), 129. 80,125.71,123.21(d,J=144.2Hz),109.15–108.78(m),107.29,72.78(q,J=28.6Hz),55.81,41.50,36.28.HRMS(ESI)m / z:calcd for C 22 H 15Cl2F6N5O3S:([M+Na) + ):613.0177,found:636.0056.

[0171] Example 37: Activity Test Against Diamondback Moth

[0172] Freshly prepared cabbage discs were immersed in a solution containing the compound for 30 seconds, air-dried, and placed in petri dishes lined with filter paper. Fifteen third-instar diamondback moths were then carefully transferred to the petri dishes. The petri dishes were stored in an incubator at 26°C and 85% relative humidity, with a light / dark ratio of 16:8. The mortality rate was assessed after 3 days. Each activity test was repeated three times (15 larvae per test). The larvae's body was gently touched. If it could not crawl normally, it was considered dead.

[0173] Corrected lethality rate = XY / X × 100

[0174] Where X represents the percentage of total live larvae, and Y represents the percentage of surviving larvae after treatment in the petri dish. Data on the antidiarrheal activity of some compounds in Formula I are shown in Table 1.

[0175] Table 1 shows the anti-diarrheal activity data of some compounds in Formula I.

[0176]

[0177] As shown in Table 1, some of the Formula I compounds provided by this invention exhibit certain insecticidal activity against the tested diamondback moth. In particular, some compounds show significant control efficacy against both diamondback moth and fall armyworm. For example, compounds 15, 16, 17, 21, 22, 25, 27, 28, 29, 30, 31, and 34 show a 100% lethality against diamondback moth at concentrations above 100 ppm, comparable to the control agent Fluralaner; thus, they show promise as insecticides for controlling the agricultural pest diamondback moth.

[0178] Example 38: Activity test against fall armyworm

[0179] A 5000 mg / L stock solution of the target compound was prepared by dissolving it in dimethyl sulfoxide (DMSO) and serially diluted to different concentrations with 0.05% (w / v) Triton X-100. Equal volumes of DMSO and 0.05% (w / v) Triton X-100 were added to a blank. Artificial feed was added to 24-well plates, and after the feed cooled and solidified, 100 μL of the target compound solution was added to the surface of the feed. After drying at room temperature, third-instar larvae were transferred to each well. Each concentration was replicated three times (24 larvae per replicate). Finally, the 24-well plates were stored in an incubator at 26°C and 85% relative humidity with a light / dark ratio of 16:8. Larval mortality was recorded at 48 hours. Larvae were considered dead if they could not crawl normally when gently touched with a needle.

[0180] Corrected lethality (%) = (TC) × 100 / (100% - C)

[0181] Where T represents the mortality rate in the test compound group and C represents the mortality rate in the blank control group. All these parameters are expressed as a percentage.

[0182] Table 2 shows the activity data of some compounds in Formula I for *Pteris vittata* in *Pteris vittata*.

[0183]

[0184] As can be seen from Table 2, some of the Formula I compounds provided by this invention have certain insecticidal activity against the tested fall armyworm. For example, compounds 15, 17, and 31 showed a 100% lethality against fall armyworm at a concentration of 200 ppm, comparable to the control Fluralaner; they show promise as insecticides for controlling the agricultural pest fall armyworm.

Claims

1. A pyrazoline-1,3,4-oxadiazole thioacetamide derivative, characterized in that: The general formula of the derivatives is shown in I: ， In general formula I, R 1 For H; R 2 Selected from H, halogens, 3,5-2Cl-4-CF 3、 3-Cl-4-CF3, nitro, methyl, and may be substituted singly or in more than one position on the benzene ring; Z is selected from aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-fluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 3,4-dimethylaniline, 2-methyl-3-chloroaniline, 2-methyl-4-chloroaniline, 2-nitro-5-chloroaniline, 3-fluoro-4-nitro-aniline, 2-chloro-4-fluoroaniline, 3-chloro- 4-Fluoro-aniline, 2,4-difluoro-aniline, 2,6-difluoro-aniline, 3,5-difluoro-aniline, 3-trifluoromethoxy-aniline, 2-trifluoromethyl-aniline, 3-trifluoromethyl-aniline, 4-trifluoromethyl-aniline, 3-fluoro-4-bromo-aniline, 2-nitro-aniline, 3-nitro-aniline, 4-nitro-aniline, 3-methoxy-5-trifluoromethyl-aniline.

2. The pyrazoline-1,3,4-oxadiazole thioacetamide derivative according to claim 1, characterized in that... In general formula I, R 1 = H;R 2 Selected from H, 3,5-2Cl, 3,5-2Cl-4-CF 3、 3-Cl-4-CF3; Z is selected from aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-fluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 3,4-dimethylaniline, 2-methyl-3-chloroaniline, 2-methyl-4-chloroaniline, 2-nitro-5-chloroaniline, 3-fluoro-4-nitroaniline, 2-chloro-4-fluoroaniline, 3-chloro- 4-Fluoro-aniline, 2,4-difluoro-aniline, 2,6-difluoro-aniline, 3,5-difluoro-aniline, 3-trifluoromethoxy-aniline, 2-trifluoromethyl-aniline, 3-trifluoromethyl-aniline, 4-trifluoromethyl-aniline, 3-fluoro-4-bromo-aniline, 2-nitro-aniline, 3-nitro-aniline, 4-nitro-aniline, 3-methoxy-5-trifluoromethyl-aniline.

3. The method for preparing the pyrazoline-1,3,4-oxadiazole thioacetamide derivative according to any one of claims 1-2, characterized in that: Includes the following steps: R 1 For H; R 2 Selected from H, halogens, 3,5-2Cl-4-CF 3、 3-Cl-4-CF3, nitro, methyl, and may be substituted singly or in more than one position on the benzene ring; Z is selected from aniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2-fluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 3,4-dimethylaniline, 2-methyl-3-chloroaniline, 2-methyl-4-chloroaniline, 2-nitro-5-chloroaniline, 3-fluoro-4-nitro-aniline, 2-chloro-4-fluoroaniline, 3-chloro- 4-Fluoro-aniline, 2,4-difluoro-aniline, 2,6-difluoro-aniline, 3,5-difluoro-aniline, 3-trifluoromethoxy-aniline, 2-trifluoromethyl-aniline, 3-trifluoromethyl-aniline, 4-trifluoromethyl-aniline, 3-fluoro-4-bromo-aniline, 2-nitro-aniline, 3-nitro-aniline, 4-nitro-aniline, 3-methoxy-5-trifluoromethyl-aniline.

4. The application of the derivative as described in any one of claims 1-2 in the preparation of an insecticide for controlling agricultural pests, wherein the agricultural pest is diamondback moth or fall armyworm.

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