An oxadiazole sulfamide compound containing a pyrazole structure, a preparation method and application thereof

Abstract

The application provides an oxadiazole sulfamide compound containing a pyrazole structure and a preparation method and application thereof, and relates to the fields of chemical technology and pesticide technology. A series of oxadiazole sulfamide compounds containing a pyrazole structure are synthesized by taking 4,4-difluoroacetyl acetic acid ethyl ester as a raw material, and the prepared compound can effectively prevent and treat plant bacterial diseases (rice bacterial leaf blight, rice bacterial leaf streak, citrus canker or kiwi canker) or plant fungal diseases (tomato gray mold, wheat scab, rice sheath blight or rapeseed sclerotinia disease).

Description

Technical Field

[0001] This invention relates to the fields of chemical technology and pesticide technology, and in particular to an oxadiazole sulfonamide compound containing a pyrazole structure, its preparation method and application. Background Technology

[0002] Rice bacterial blight caused by the Gram-negative bacterium *Xanthomonas oryzae* pv. *Oryzae Xoo* can reduce rice yield by up to 50%. Other diseases include bacterial leaf streak in rice caused by *Xanthomonas oryzaepv. oryzicola Xoc*, citrus canker caused by *Xanthomonas axonopodis* pv. *citri Xac*, kiwifruit canker caused by *Pseudomonas syringae* pv. *actinidiae Psa*, gray mold in tomatoes caused by *Botrytis cinerea* Pers Bc, Fusarium graminearum Fg in wheat, and *Rhizoctonia solani*. Rice sheath blight caused by *Rhizoctonia solani* and rapeseed sclerotinia rot caused by *Sclerotinia sclerotiorum* are notorious agricultural diseases worldwide. Once infected, they are difficult to control, causing severe yield and economic losses to crops. Plant bacterial and fungal diseases are characterized by rapid onset, high damage, and wide distribution. To date, there are no effective chemical agents or other control methods, causing enormous losses to agricultural production. There is an urgent need to develop effective agents for their control.

[0003] Therefore, finding a highly efficient and environmentally friendly chemical agent to combat bacterial or fungal diseases in plants is an urgent problem to be solved in the field of plant protection. Summary of the Invention

[0004] The purpose of this invention is to provide an oxadiazole sulfonamide compound containing a pyrazole structure, its preparation method, and its application, in order to solve the problems existing in the prior art and provide a compound with significant and green resistance to bacterial or fungal diseases of plants.

[0005] To achieve the above objectives, the present invention provides the following solution:

[0006] One of the technical solutions of this invention is to provide an oxadiazole sulfonamide compound containing a pyrazole structure, having the structure shown in general formula A:

[0007]

[0008] R is selected from ethyl, propyl, cyclopropy, isopropyl, phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-Br-phenyl, 2-NO2-phenyl, 3-F- phenyl, 3-Cl-phenyl, 3-Br-phenyl, 3-NO2-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-Br-phenyl, 4-NO2-phenyl, 4-CF 3-phenyl, 4-CH3-phenyl, 4-OCH3-phenyl, 4-CN-phenyl, 4-C(CH3)3-phenyl, 2-thienyl, 5-chlorothienyl, 4-3,5 - Any one of dimethylisoxazolyl, 2-naphthyl, 2,4,6-triisopropylbenzenyl, mesityl, 4-1-methyl-1H-pyrazolyl.

[0009] The second technical solution of the present invention provides a method for preparing the above-mentioned oxadiazole sulfonamide compounds containing a pyrazole structure, comprising the following steps:

[0010] (1) Ethyl 4,4-difluoroacetoacetate and CH(OEt)3 were refluxed in Ac2O solution for 7 h, separated and purified to obtain intermediate 1;

[0011]

[0012] (2) The intermediate 1 was added to a methylhydrazine EtOAc solution at 5-10℃, and then heated under reflux for 3 hours. The mixture was then extracted and concentrated to obtain intermediate 2.

[0013]

[0014] (3) The intermediate 2 and LiOH·H2O were heated under reflux in THF / H2O (4:1) solution for 3 hours, cooled to room temperature, acidified (pH value adjusted to 4-5 with HCl), separated and purified to obtain intermediate 3;

[0015]

[0016] (4) Dissolve the intermediate 3 and react it with tert-butoxycarbonylhydrazine at room temperature, then separate and purify to obtain intermediate 4;

[0017]

[0018] Preferably, the system after intermediate 3 is dissolved also contains the catalyst carbodiimide hydrochloride (EDCl), N,N-diisopropylethylamine (DIEA) and 1-hydroxybenzotriazole (HOBt);

[0019] (5) Dissolve the intermediate 4, add trifluoroacetic acid at 0°C, react at room temperature, separate and purify to obtain intermediate 5;

[0020]

[0021] (6) Dissolve the intermediate 5, add potassium hydroxide, add carbon disulfide at 0°C, then reflux at 85°C, acidify with concentrated hydrochloric acid, filter and dry to obtain intermediate 6.

[0022]

[0023] (7) Dissolve anhydrous piperazine, add sulfonyl chloride compounds, react at 0°C, separate and purify to obtain intermediate 7 (sulfonyl piperazine compounds);

[0024]

[0025] (8) Dissolve intermediate 7, add bromoacetyl bromide, react at 0°C, and stir for 10 minutes until the solid is completely dissolved. Dissolve bromoacetyl bromide in dry dioxane and add it dropwise to the above solution. Continue stirring at room temperature for 5 hours. Separate and purify to obtain intermediate 8 (2-bromo-1-(4-sulfonylpiperazin-1-yl)ethyl-1-one compound);

[0026]

[0027] (9) Dissolve the intermediate 8, add the intermediate 6 and potassium carbonate, react at room temperature, separate and purify to obtain the target compound A;

[0028]

[0029] R is selected from ethyl, propyl, cyclopropy, isopropyl, phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-Br-phenyl, 2-NO2-phenyl, 3-F- phenyl, 3-Cl-phenyl, 3-Br-phenyl, 3-NO2-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-Br-phenyl, 4-NO2-phenyl, 4-CF 3-phenyl, 4-CH3-phenyl, 4-OCH3-phenyl, 4-CN-phenyl, 4-C(CH3)3-phenyl, 2-thienyl, 5-chlorothienyl, 4-3,5 - Any one of dimethylisoxazolyl, 2-naphthyl, 2,4,6-triisopropylbenzenyl, mesityl, 4-1-methyl-1H-pyrazolyl.

[0030] The third technical solution of the present invention provides a composition containing the above-mentioned oxadiazole sulfonamide compound with a pyrazole structure.

[0031] The composition may also include agricultural adjuvants, fungicides, or insecticides.

[0032] The fourth technical solution of the present invention provides the application of the above-mentioned oxadiazole sulfonamide compounds or compositions containing pyrazole structures in the prevention and control of bacterial and / or fungal plant diseases;

[0033] The bacterial diseases of the plants are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker or kiwifruit canker; the fungal diseases of the plants are tomato gray mold, wheat scab, rice sheath blight or rapeseed sclerotinia rot.

[0034] As a further preferred embodiment of the present invention, the effective concentration of the oxadiazole sulfonamide compound containing the pyrazole structure is 0 μg / mL-100 μg / mL, and is not 0 μg / mL.

[0035] Fifth technical solution of the present invention: providing the application of the above-mentioned pyrazole-containing oxadiazole sulfonamide compounds or compositions in the preparation of antibacterial and / or antifungal drugs;

[0036] The plant bacteria are *Bacillus oryzae*, *Bacillus streak*, *Citrus canker*, or *Actinidia kiwifruit*; the plant fungi are *Gray mold*, *Fusarium graminearum*, *Rhizoctonia solani*, or *Sclerotinia sclerotiorum*.

[0037] The sixth technical solution of the present invention: provides a method for preventing and controlling plant bacterial diseases and / or plant fungal diseases, wherein the oxadiazole sulfonamide compound containing the pyrazole structure or the composition is applied to the harmful substances or the living environment of the plant bacterial diseases and / or plant fungal diseases;

[0038] The bacterial diseases of the plants are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker or kiwifruit canker; the fungal diseases of the plants are tomato gray mold, wheat scab, rice sheath blight or rapeseed sclerotinia rot.

[0039] As a further preferred embodiment of the present invention, the effective concentration of the oxadiazole sulfonamide compound containing the pyrazole structure is 0 μg / mL-100 μg / mL, and is not 0 μg / mL.

[0040] The oxadiazole sulfonamide compounds containing pyrazole structures of this invention have certain inhibitory effects on citrus canker, kiwifruit canker, wheat scab, rapeseed sclerotinia, and rice sheath blight in agricultural pests and diseases. They also have good inhibitory effects on rice bacterial blight, rice bacterial leaf streak, and tomato gray mold. They can be used to prepare agents against plant bacteria and fungi.

[0041] The present invention discloses the following technical effects:

[0042] This invention synthesizes a series of oxadiazole sulfonamide compounds containing pyrazole structures using ethyl 4,4-difluoroacetoacetate as a raw material. The prepared compounds can effectively control bacterial diseases of plants (bacterial leaf blight of rice, bacterial leaf streak of rice, citrus canker or kiwifruit canker) or fungal diseases of plants (gray mold of tomato, scab of wheat, sheath blight of rice or sclerotinia rot of rapeseed). Detailed Implementation

[0043] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0044] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0045] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0046] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0047] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0048] The compounds of the present invention are numbered as shown in Table 1:

[0049] Table 1

[0050]

[0051]

[0052] Example 1

[0053] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(ethylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A1) includes the following steps:

[0054] (1) Ethyl 4,4-difluoroacetoacetate (16.6 g, 0.1 mol, 1 equivalent) and CH(OEt)3 (29.6 g, 0.2 mol, 2 equivalents) were stirred and refluxed in Ac2O (30.6 g, 0.3 mol, 3 equivalents) solution for 7 hours. The solvent was removed under vacuum to give intermediate 1 (2-(ethoxymethylene)-4,4-difluoroacetoacetate), yield 79%;

[0055] (2) Ethyl 2-(ethoxymethylene)-4,4-difluoroacetoacetate (9.1 g, 0.04 mol) was added dropwise to a solution of methylhydrazine (1.9 g, 0.04 mol) in 50 mL of EtOAc, stirred at 5 °C. The mixture was heated under reflux for 3 hours. Then, 100 mL of water was added to quench the reaction, and the mixture was extracted with 200 mL of EtOAc. The organic layer was washed with brine, dried, and concentrated to give the solid intermediate 2 (ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate), yield 97%.

[0056] (3) Intermediate 2 (ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid) (0.37 g, 1.8 mmol, 1 equivalent) and LiOH·H2O (1.0 g, 3.6 mmol, 2 equivalent) were heated under reflux for 3 hours in a THF / H2O solution (4:1, 10 mL). TLC showed that the reaction was complete, and then the mixture was cooled to room temperature. The pH of the mixture was adjusted to 4-5 by adding 2N HCl, resulting in a large amount of white solid precipitate. The precipitate was filtered off and dried in air to give intermediate 3 (3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid) in 100% yield;

[0057] (4) Intermediate 3 (3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid) (2.0 g, 11.4 mmol, 1 equivalent), catalyst carbodiimide hydrochloride (EDCl) (1.5 g, 11.4 mmol, 1 equivalent), N,N-diisopropylethylamine (DIEA) (2.8 mL, 11.4 mmol, 1 equivalent) and 1-hydroxybenzotriazole (HOBt) (1.5 g, 11.4 mmol, 1 equivalent) were stirred in 50 mL of dichloromethane solution until the solid dissolved. Finally, tert-butoxycarbonylhydrazine (BOC-hydrazine) (1.5 g, 11.4 mmol, 1 equivalent) was added, and the reaction was carried out at room temperature. After separation and purification, intermediate 4 (2-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester) was obtained with a yield of 90%.

[0058] (5) Trifluoroacetic acid (7.3 mL, 95.33 mmol, 32 equivalents) was added dropwise to a CH2Cl2 (30 mL) solution of intermediate 4 (2-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester) (0.8668 g, 2.986 mmol, 1 equivalent) under stirring at 0 °C. The mixture was stirred at 20 °C for 4 hours, then dissolved under reduced pressure and recrystallized to obtain intermediate 5 (3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonylhydrazine), with a yield of 97%.

[0059] (6) Intermediate 5(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbazide) (9.5 g, 50 mmol, 1 equivalent) and KOH (3.4 g, 60 mmol, 1.2 equivalent) were dissolved in 10 mL of anhydrous ethanol and stirred at 0 °C for 15 minutes. Then CS2 (4.6 g, 60 mmol, 1.2 equivalent) was added dropwise. The mixture was refluxed at 85 °C for 8 hours. The ethanol was removed by vacuum concentration. The residue was dissolved in ice water, acidified with concentrated hydrochloric acid, filtered and dried to obtain intermediate 6(5-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)-1,3,4-oxadiazole-2-thiol), yield 40%.

[0060] (7) At 0 °C, ethylsulfonyl chloride (1.43 g, 10 mmol, 1 equivalent) was added in a single batch to anhydrous piperazine (5.17 g, 60 mmol, 6 equivalent) in CH2Cl2 (100 mL, 0.1 M). The reaction mixture was stirred at 0 °C for 30 minutes, diluted with CH2Cl2 (200 mL), quenched by adding saturated NaHCO3 (aqueous solution) (50 mL), washed with brine (50 mL), dried (Na2SO4), and concentrated under vacuum to obtain the crude product. The crude product was recrystallized from anhydrous ethanol to obtain pure intermediate 7 (ethylsulfonyl piperazine) in 98% yield.

[0061] (8) At 0 °C, ethylsulfonylpiperazine (2.0 g, 11.2 mmol, 1.0 equivalent) and 16 mL of 1,4-dioxane were added sequentially to a 50 mL flask and stirred until the solid was completely dissolved. Bromoacetyl bromide (2.94 g, 14.56 mmol, 1.3 equivalent) was dissolved in 3 mL of dry dioxane and added dropwise to the above solution. Stirring was continued at room temperature for 5 hours. Finally, the reaction mixture was poured into ice water, and the solid precipitated to give intermediate 8 (2-bromo-1-(4-(ethylsulfonyl)piperazin-1-yl)ethyl-1-one), yield 100%.

[0062] (9) At room temperature, add intermediate 6(5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole-2-thiol) (0.770 g, 3.1 mmol, 1 equivalent), anhydrous potassium carbonate (0.643 g, 4.65 mmol, 1.5 equivalent), and intermediate 8(2-bromo-1-(4-(ethylsulfonyl)piperazin-1-yl)ethyl-1-one) (1.3 g, 3.41 mmol) to a 50 mL flask sequentially. The reaction was carried out with 1 mol (1.1 equivalents) and DMF (30 mL), monitored by TLC. After stirring for 4 hours, the reaction was completed. The mixture was poured into ice water, and a solid precipitated out. After filtration and drying, column chromatography yielded the target compound 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(ethylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A1), a white solid with a yield of 19%.

[0063] Example 2

[0064] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(propylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A2) includes the following steps:

[0065] Steps (1)-(6) are the same as in Example 1;

[0066] (7) Synthesis of intermediate 7 (propylsulfonylpiperazine): as in step (7) of Example 1, except that propylsulfonyl chloride is used as the raw material, with a yield of 98%.

[0067] (8) Synthesis of intermediate 8 (2-bromo-1-(4-(propylsulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that propylsulfonylpiperazine is used as the starting material and the yield is 100%.

[0068] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(propylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A2): as in step (9) of Example 1, except that 2-bromo-1-(4-(propylsulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 32%.

[0069] Example 3

[0070] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A3) includes the following steps:

[0071] Steps (1)-(6) are the same as in Example 1;

[0072] (7) Synthesis of intermediate 7 (cyclopropylsulfonylpiperazine): as in step (7) of Example 1, except that cyclopropylsulfonyl chloride is used as the raw material and the yield is 98%.

[0073] (8) Synthesis of intermediate 8 (2-bromo-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that cyclopropylsulfonylpiperazine is used as the starting material and the yield is 100%.

[0074] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A3): as in step (9) of Example 1, except that 2-bromo-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 25%.

[0075] Example 4

[0076] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(isopropylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A4) includes the following steps:

[0077] Steps (1)-(6) are the same as in Example 1;

[0078] (7) Synthesis of intermediate 7 (isopropylsulfonylpiperazine): as in step (7) of Example 1, except that isopropylsulfonyl chloride is used as the raw material and the yield is 98%.

[0079] (8) Synthesis of intermediate 8 (2-bromo-1-(4-(isopropylsulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that propylsulfonylpiperazine is used as the starting material and the yield is 100%.

[0080] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(isopropylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A4): as in step (9) of Example 1, except that 2-bromo-1-(4-(isopropylsulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 52%.

[0081] Example 5

[0082] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(benzenesulfonyl)piperazin-1-yl)ethyl-1-one (compound number A5) includes the following steps:

[0083] Steps (1)-(6) are the same as in Example 1;

[0084] (7) Synthesis of intermediate 7 (phenylsulfonylpiperazine): as in step (7) of Example 1, except that phenylsulfonyl chloride is used as the raw material and the yield is 98%.

[0085] (8) Synthesis of intermediate 8 (2-bromo-1-(4-(phenylsulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that phenylsulfonylpiperazine is used as the starting material, with a yield of 100%;

[0086] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(phenylsulfonyl)piperazin-1-yl)ethyl-1-one (compound number A5): as in step (9) of Example 1, except that 2-bromo-1-(4-(phenylsulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 63%.

[0087] Example 6

[0088] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A6) includes the following steps:

[0089] Steps (1)-(6) are the same as in Example 1;

[0090] (7) Synthesis of intermediate 7 (1-((2-fluorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 2-fluorophenylsulfonyl chloride is used as the raw material, with a yield of 98%.

[0091] (8) Synthesis of intermediate 8(2-bromo-1-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 2-fluorophenylsulfonylpiperazine is used as the starting material and the yield is 100%.

[0092] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A6): as in step (9) of Example 1, except that 2-bromo-1-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 76%.

[0093] Example 7

[0094] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A7) includes the following steps:

[0095] Steps (1)-(6) are the same as in Example 1;

[0096] (7) Synthesis of intermediate 7 (1-((2-chlorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 2-chlorophenylsulfonyl chloride is used as the raw material and the yield is 98%.

[0097] (8) Synthesis of intermediate 8(2-bromo-1-(4-(2-chlorophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((2-chlorophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0098] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A7): as in step (9) of Example 1, except that 2-bromo-1-(4-(2-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 76%.

[0099] Example 8

[0100] The synthesis of 1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A8) includes the following steps:

[0101] Steps (1)-(6) are the same as in Example 1;

[0102] (7) Synthesis of intermediate 7 (1-((2-bromophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 2-bromophenylsulfonyl chloride is used as the starting material, with a yield of 98%.

[0103] (8) Synthesis of intermediate 8(2-bromo-1-((2-bromophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((2-bromophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0104] (9) Synthesis of 1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A8): As in step (9) of Example 1, except that 2-bromo-1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 44%.

[0105] Example 9

[0106] The synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((2-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A9) includes the following steps:

[0107] Steps (1)-(6) are the same as in Example 1;

[0108] (7) Synthesis of intermediate 7 (1-((2-(nitro)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 2-(nitro)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0109] (8) Synthesis of intermediate 8(2-bromo-1-(4-((2-(nitro)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((2-(nitro)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0110] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-diazol-2-yl)thio)-1-(4-((2-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A9): As in step (9) of Example 1, except that 2-bromo-1-(4-(2-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 80%.

[0111] Example 10

[0112] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 10 The process includes the following steps:

[0113] Steps (1)-(6) are the same as in Example 1;

[0114] (7) Synthesis of intermediate 7 (1-((3-fluorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 3-fluorophenylsulfonyl chloride is used as the raw material and the yield is 98%.

[0115] (8) Synthesis of intermediate 8(2-bromo-11-((3-fluorophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((3-fluorophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0116] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3-fluorophenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 10 Synthesis: as in step (9) of Example 1, except that 2-bromo-11-((3-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 39%.

[0117] Example 11

[0118] Synthesis of 1-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 11 The process includes the following steps:

[0119] Steps (1)-(6) are the same as in Example 1;

[0120] (7) Synthesis of intermediate 7 (1-((3-chlorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 3-chlorophenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0121] (8) Synthesis of intermediate 8(2-bromo-1-((3-chlorophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((3-chlorophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0122] (9) Synthesis of 1-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 11 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((3-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 67%.

[0123] Example 12

[0124] Synthesis of 1-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 12 This includes the following steps:

[0125] Steps (1)-(6) are the same as in Example 1;

[0126] (7) Synthesis of intermediate 7 (1-((3-bromophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 3-bromophenylsulfonyl chloride is used as the starting material, with a yield of 98%.

[0127] (8) Synthesis of intermediate 8(2-bromo-1-(4-((3-bromophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((3-bromophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0128] (9) Synthesis of 1-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 12 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 41%.

[0129] Example 13

[0130] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 13 This includes the following steps:

[0131] Steps (1)-(6) are the same as in Example 1;

[0132] (7) Synthesis of intermediate 7 (1-((3-(nitro)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 3-(nitro)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0133] (8) Synthesis of intermediate 8(2-bromo-1-(4-((3-(nitro)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((3-(nitro)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0134] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3-(nitro)phenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 13 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((3-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 91%.

[0135] Example 14

[0136] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 14 This includes the following steps:

[0137] Steps (1)-(6) are the same as in Example 1;

[0138] (7) Synthesis of intermediate 7 (1-((4-fluorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-fluorophenylsulfonyl chloride is used as the raw material and the yield is 98%.

[0139] (8) Synthesis of intermediate 8(2-bromo-1-((4-fluorophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-fluorophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0140] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 14 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 16%.

[0141] Example 15

[0142] Synthesis of 1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 15 The process includes the following steps:

[0143] Steps (1)-(6) are the same as in Example 1;

[0144] (7) Synthesis of intermediate 7 (1-((4-chlorophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-chlorophenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0145] (8) Synthesis of intermediate 8(2-bromo-1-(4-((4-fluorophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-chlorophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0146] (9) Synthesis of 1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 15 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 36%.

[0147] Example 16

[0148] Synthesis of 1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 16 The process includes the following steps:

[0149] Steps (1)-(6) are the same as in Example 1;

[0150] (7) Synthesis of intermediate 7 (1-((4-bromophenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-bromophenylsulfonyl chloride is used as the starting material, with a yield of 98%.

[0151] (8) Synthesis of intermediate 8(2-bromo-1-((4-bromophenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-bromophenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0152] (9) Synthesis of 1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 16 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((4-bromophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 75%.

[0153] Example 17

[0154] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 17 This includes the following steps:

[0155] Steps (1)-(6) are the same as in Example 1;

[0156] (7) Synthesis of intermediate 7 (1-((4-(nitro)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(nitro)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0157] (8) Synthesis of intermediate 8(2-bromo-1-((4-(nitro)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-(nitro)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0158] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(nitro)phenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 17 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((4-(nitro)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 23%.

[0159] Example 18

[0160] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 18 This includes the following steps:

[0161] Steps (1)-(6) are the same as in Example 1;

[0162] (7) Synthesis of intermediate 7 (1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(trifluoromethyl)phenylsulfonyl chloride is used as the starting material, with a yield of 98%.

[0163] (8) Synthesis of intermediate 8(2-bromo-1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-(trifluoromethyl)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0164] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 18 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(((4-trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 45%.

[0165] Example 19

[0166] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-((4-(methyl)phenyl)sulfonylpiperazin-1-yl)ethyl-1-one (compound number A) 19 This includes the following steps:

[0167] Steps (1)-(6) are the same as in Example 1;

[0168] (7) Synthesis of intermediate 7(1-((4-(methyl))phenylsulfonyl)piperazine: as in step (7) of Example 1, except that 4-(methyl)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0169] (8) Synthesis of intermediate 8(2-bromo-1-((4-(methyl)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-(4-toluenesulfonyl)piperazine is used as the starting material and the yield is 100%.

[0170] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-((4-(methyl)phenyl)sulfonylpiperazin-1-yl)acetoone (compound number A) 19 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((4-(methyl)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 85%.

[0171] Example 20

[0172] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(methoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 20 The process includes the following steps:

[0173] Steps (1)-(6) are the same as in Example 1;

[0174] (7) Synthesis of intermediate 7 (1-((4-(methoxy)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(methoxy)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0175] (8) Synthesis of intermediate 8(2-bromo-1-((4-(methoxy)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-(methoxy)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0176] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(methoxy)phenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A)20 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-((4-(methoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 17%.

[0177] Example 21

[0178] Synthesis of 4-((4-(2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)acetyl)piperazin-1-yl)sulfonyl)benzyl nitrile (compound number A) 21 The process includes the following steps:

[0179] Steps (1)-(6) are the same as in Example 1;

[0180] (7) Synthesis of intermediate 7 (1-((4-(cyano)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(cyano)phenylsulfonyl chloride is used as the starting material and the yield is 98%.

[0181] (8) Synthesis of intermediate 8(4-((4-(2-bromoacetyl)piperazine-1-yl)sulfonyl)benzyl nitrile): as in step (8) of Example 1, except that 1-((4-(cyano)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0182] (9) Synthesis of 4-((4-(2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)acetyl)piperazin-1-yl)sulfonyl)benzyl nitrile (compound number A) 21 Synthesis of ) as in step (9) of Example 1, except that 4-((4-(2-bromoacetyl)piperazine-1-yl)sulfonyl)benzyl nitrile was used as the starting material, with a yield of 47%.

[0183] Example 22

[0184] Synthesis of 1-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 22 The process includes the following steps:

[0185] Steps (1)-(6) are the same as in Example 1;

[0186] (7) Synthesis of intermediate 7 (1-((4-(tert-butyl)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(tert-butyl)phenylsulfonyl chloride is used as the starting material, with a yield of 98%.

[0187] (8) Synthesis of intermediate 8(2-bromo-1-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-(tert-butyl)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0188] (9) Synthesis of 1-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 22 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 63%.

[0189] Example 23

[0190] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((thiophen-2-yl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 23 The process includes the following steps:

[0191] Steps (1)-(6) are the same as in Example 1;

[0192] (7) Synthesis of intermediate 7 (1-((thiophen-2-yl)sulfonyl)piperazine): as in step (7) of Example 1, except that thiophen-2-sulfonyl chloride is used as the raw material and the yield is 98%.

[0193] (8) Synthesis of intermediate 8(2-bromo-1-(4-((thiophen-2-yl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that (1-(thiophen-2-yl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0194] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((thiophen-2-yl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 23 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((thiophen-2-yl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 51%.

[0195] Example 24

[0196] Synthesis of 1-(4-((5-chlorothiophene-2-yl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 24 The process includes the following steps:

[0197] Steps (1)-(6) are the same as in Example 1;

[0198] (7) Synthesis of intermediate 7 (1-(4-((5-chlorothiophen-2-yl)sulfonyl)piperazine): as in step (7) of Example 1, except that 5-chlorothiophen-2-sulfonyl chloride is used as the starting material, with a yield of 98%.

[0199] (8) Synthesis of intermediate 8(2-bromo-1-(4-(((5-chlorothiophen-2-yl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-(4-((5-chlorothiophen-2-yl)sulfonyl)piperazine was used as the starting material and the yield was 100%;

[0200] (9) Synthesis of 1-(4-((5-chlorothiophene-2-yl)sulfonyl)piperazin-1-yl)-2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethyl-1-one (compound number A) 24 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-(((5-chlorothiophen-2-yl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 16%.

[0201] Example 25

[0202] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3,5-dimethylisooxazol-4-yl)sulfonyl)piperazin-1-yl)acet-1-one (compound number A) 25 The process includes the following steps:

[0203] Steps (1)-(6) are the same as in Example 1;

[0204] (7) Synthesis of intermediate 7 (1-(4-((3,5-dimethylisoxazole-4-yl)sulfonyl)piperazine): as in step (7) of Example 1, except that 3,5-dimethylisoxazole-4-sulfonyl chloride was used as the starting material, with a yield of 98%.

[0205] (8) Synthesis of intermediate 8(2-bromo-1-(4-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-(4-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperazine was used as the starting material, with a yield of 100%;

[0206] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((3,5-dimethylisooxazol-4-yl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 25 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 99%.

[0207] Example 26

[0208] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(naphthyl-2-yl)phenyl)sulfonyl)piperazin-1-yl)acet-1-one (compound number A) 26 The process includes the following steps:

[0209] Steps (1)-(6) are the same as in Example 1;

[0210] (7) Synthesis of intermediate 7 (1-((4-(naphthyl-2-yl)phenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-(naphthyl-2-yl)benzenesulfonyl chloride was used as the starting material, with a yield of 98%.

[0211] (8) Synthesis of intermediate 8(2-bromo-1-(4-((4-(naphth-2-yl)phenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((4-(naphth-2-yl)phenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%;

[0212] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((4-(naphthyl-2-yl)phenyl)sulfonyl)piperazin-1-yl)acet-1-one (compound number A) 26 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((4-(naphth-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 44%.

[0213] Example 27

[0214] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((2,4,6-triisopropylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one (compound number A) 27 The process includes the following steps:

[0215] Steps (1)-(6) are the same as in Example 1;

[0216] (7) Synthesis of intermediate 7 (1-((2,4,6-triisopropylphenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that 2,4,6-triisopropylphenylsulfonyl chloride was used as the starting material, with a yield of 98%.

[0217] (8) Synthesis of intermediate 8(2-bromo-1-(4-((2,4,6-triisopropylphenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-((2,4,6-triisopropylphenyl)sulfonyl)piperazine was used as the starting material and the yield was 100%.

[0218] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((2,4,6-triisopropylphenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 27 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((2,4,6-triisopropylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 62%.

[0219] Example 28

[0220] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((trimethylphenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 28 The process includes the following steps:

[0221] Steps (1)-(6) are the same as in Example 1;

[0222] (7) Synthesis of intermediate 7 (1-((trimethylphenyl)sulfonyl)piperazine): as in step (7) of Example 1, except that trimethylphenylsulfonyl chloride is used as the raw material and the yield is 98%.

[0223] (8) Synthesis of intermediate 8(2-bromo-1-(4-((trimethylphenyl)sulfonyl)piperazine-1-yl)ethyl-1-one): as in step (8) of Example 1, except that 1-(trimethylphenyl)sulfonyl)piperazine is used as the starting material and the yield is 100%.

[0224] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((trimethylphenyl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 28 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((trimethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 75%.

[0225] Example 29

[0226] Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)acet-1-one (compound number A) 29 The process includes the following steps:

[0227] Steps (1)-(6) are the same as in Example 1;

[0228] (7) Synthesis of intermediate 7 (4-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperazine): as in step (7) of Example 1, except that 4-((1-methyl-1H-pyrazole-4-yl)sulfonyl chloride was used as the starting material, with a yield of 98%.

[0229] (8) Synthesis of intermediate 8(2-bromo-1-(4-(((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazine-1-yl)ethyl-1-one)): as in step (8) of Example 1, except that 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazine was used as the starting material and the yield was 100%;

[0230] (9) Synthesis of 2-((5-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)acetoone (compound number A) 29 Synthesis of ) as in step (9) of Example 1, except that 2-bromo-1-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)ethyl-1-one was used as the starting material, with a yield of 31%.

[0231] The physicochemical properties and high-resolution mass spectrometry data of oxadiazole sulfonamide compounds containing pyrazole structures are shown in Table 2, and the proton nuclear magnetic resonance spectra are also shown. 1 H NMR and carbon spectroscopy 13 The C NMR data are shown in Table 3.

[0232] Table 2. Physicochemical properties of the target compounds and their high-resolution mass spectrometry (HRMS) analysis data.

[0233]

[0234]

[0235] Table 3. 1H NMR spectra of the target compounds ( 1 H NMR and carbon spectrum data ( 13 (C NMR)

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242] Example 1 for efficacy verification: The activity of the target compound in in vitro inhibiting the botrytis cinerea of ​​tomato, scab of wheat, sheath blight of rice, and sclerotinia sclerotinia of rape was tested. The test results are shown in Table 4.

[0243] Using the target compound as the agent, the synthesized target compound and the commercial drugs pyraclostrobin and fluopyram were added to potato solid agar (PDA) medium to prepare PDA solid agar medium with final concentrations of 100 μg / mL and 0 μg / mL of the agent, respectively. Tomato gray mold mycelial discs with a diameter of 0.5 cm were inoculated in the center of the two PDA solid agar medium concentrations, with the 0 μg / mL concentration serving as the control group. The above-mentioned inoculum-containing mediums were statically cultured in a 28℃ constant temperature climate chamber for 2-7 days until the colony diameter of the blank control reached 50-60 mm. The colony diameter was measured, with each colony measured twice vertically, and the average value was recorded in the original experimental record book. The activity tests for wheat scab, rice sheath blight, and rapeseed sclerotinia were conducted in the same manner, and the results are shown in Table 4.

[0244] The formula for calculating the inhibition rate of a compound is as follows:

[0245] Compound inhibition rate (%) = [(colony diameter of control group - colony diameter of treatment group) / (colony diameter of control group - 0.5)] × 100.

[0246] Table 4. Antimicrobial activity (%) of the target compounds against *Botrytis cinerea* (Bc), *Fusarium graminearum* (Fg), *Rhizoctonia solani* (Rs), and *Sclerotinia sclerotiorum* (Ss). a

[0247]

[0248] Note: a Mean ± standard mean deviation.

[0249] The in vitro antifungal activity and structure-activity relationship analysis are shown in Table 4. Compound A 17 A 22 and A 24 At 100 μg / mL, the inhibition rate against *Botrytis cinerea* (Bc) of tomato was over 70%, which was superior to the control azoxystrobin (34.3%). At 100 μg / mL, the antibacterial activity of the target compound against *Botrytis cinerea* of tomato showed significant differences: (1) The antibacterial activity differed significantly when the R substituent was different: A 22 (88.2%, R=4-C(CH3)3-phenyl)>A 24 (87.6%, R=5-chlorothienyl)>A 17 (78.7%, R=4-NO2-phenyl)>A3 (54.3%, R=Cyclopropyl)>A 20 (47.3%, R = 4-OCH3-phenyl) > A 26 (35.7%, R = 2-naphthyl) > A 14 (34.9%, R=4-F-phenyl)>Azoxystrobin (34.3%); (2) When the position of the R-substituted benzene ring substituent is different, the antibacterial activity is significantly different: for example, A 17 (78.7%, R = 4-NO2-phenyl) > A 13 (34.6%, R = 3-NO2-phenyl) > A9 (19.0%, R = 2-NO2-phenyl). In summary, the antifungal activity of the compounds is significantly influenced by factors such as the substituent R and the position of the R group on the benzene ring.

[0250] Example 2: The activity of the target compound in in vitro inhibiting rice bacterial blight, rice bacterial leaf streak, citrus canker, and kiwifruit canker was tested. The test results are shown in Table 5.

[0251] Using the target compound as the agent, the synthesized target compound and commercial drugs thiabendazole, tebuconazole, and thiabendazole zinc were added to NB liquid medium to prepare NB liquid medium with final concentrations of 100 μg / mL, 50 μg / mL, and 0 μg / mL of the agent, respectively. 40 μL of rice bacterial blight fungus (Xoo) was added to each of the three concentrations of NB liquid medium, with the 0 μg / mL group serving as the control. The bacterial cultures were cultured in a constant temperature shaker at 28℃ and 180 rpm for 24–48 h until the logarithmic growth phase, and the OD value was measured using a microplate reader. 595 The value is the OD value of the bacterial solution. Simultaneously, the OD values ​​of the culture media without the three bacterial agents were measured and deducted as background absorbance during calculation. The activity tests for *Bacterium streakum* of rice, *Bacterium citrus*, and *Bacterium kiwifruit* were conducted in the same manner, and the results are shown in Table 5.

[0252] Calculating the inhibition rate of a compound requires correcting for the background OD value generated by the NB liquid culture medium itself. The formulas for calculating the corrected OD value and the inhibition rate are as follows:

[0253] Corrected OD value = OD value of liquid culture medium containing bacteria - OD value of untreated culture medium

[0254] Compound inhibition rate (%) = [(corrected OD value of control group bacterial solution - corrected OD value of drug-containing bacterial solution) / corrected OD value of control group bacterial solution] × 100.

[0255] Table 5. Antibacterial activity (%) of the target compounds against *Xoo* (bacterial blight of rice), *Xoc* (bacterial leaf streak of rice), *Xac* (citrus canker), and *Psa* (kiwifruit canker). a

[0256]

[0257]

[0258] Note: a Mean ± standard mean deviation.

[0259] In vitro antibacterial activity and structure-activity relationship analysis are shown in Table 5. Compounds A5 and A 10 A 12 A 14 A 23 A 24 A 26 and A 27 At 100 μg / mL, the inhibition rate against rice bacterial blight pathogen (Xoo) was over 60%, especially A. 23At 100 μg / mL, the inhibition rate was 100%, comparable to the control drug thiabendazole (100%). At 50 μg / mL, the inhibition rate was 90.7%, superior to the control drug thiabendazole (84.5%). Compounds A7 and A8, at 100 μg / mL, showed a 100% inhibition rate against rice bacterial leaf streak (Xoc), comparable to the control drugs thiabendazole (100%) and thiamethoxam (100%). Compounds A5, A6, A7, A8, A9, and A... 10 A 12 A 14 A 15 A 16 A 23 A 24 A 26 A 27 and A 29 Several compounds, at a concentration of 50 μg / mL, showed inhibition rates of over 50% against rice bacterial leaf streak (Xoc), superior to the control drug tebuconazole (33.2%). Compounds A7 and A... 24 and A 26 At 100 μg / mL, the compound showed an inhibition rate against *Actinidia kiwifruit* causal agent comparable to the control drug thiabendazole (77.6%), and superior to tebuconazole (52.8%). Compound A 23 At 100 μg / mL, the inhibition rate against *Citrus canker* was comparable to that of the control drugs thiabendazole copper and thiamethoxam zinc, and superior to that of the control drug tebuconazole. Compound A 23 and A 27 At 50 μg / mL, the inhibition rate against *Citrus canker* was superior to that of tebuconazole. At 100 μg / mL, the antibacterial activity of the target compounds against *Bacillus streakus* of rice was significantly different: (1) The antibacterial activity was significantly different when the R substituent was different: thiamethoxam zinc (100%) = thiamethoxam copper (100%) = A7 (100%), = 2-Cl-phenyl) = A8 (100%), R = 2-Br-phenyl) > A 26 (95.8%, R=2-naphthyl)>A5 (89.8%, R=Phenyl)>A 11 (88.5%, R = 3-Cl-phenyl) > A 10 (87.0%, R = 3-F-phenyl) > A 23 (85.1%, R = 2-thienyl) > A 12 (78.8%, R = 3-Br-phenyl) > A 17 (78.0%, R = 4-NO2-phenyl) > A 24 (77.7%, R=5-chlorothienyl)>A 19(75.7%, R = 4-CH3-phenyl) > A 29 (73.3%, R=4-1-methyl-1H-pyrazolyl)>A9 (67.9%, R=2-NO2-phenyl)>A 18 (67.2%, R = 4-CF3-phenyl) > A 14 (66.8%, R = 4-F-phenyl) > A 16 (63.1%, R = 4-Br-phenyl) > A 15 (62.7%, R = 4-Cl-phenyl) > A 21 (61.0%, R = 4-CN-phenyl) > tebuconazole (55.9%); (2) When the position of the R-substituted benzene ring substituent is different, the antibacterial activity is significantly different: for example, A7 (100%, R = 2-Cl-phenyl) > A 11 (88.5%, R = 3-Cl-phenyl) > A 15 (62.7%, R = 4-Cl-phenyl). In summary, the antibacterial activity of the compound is greatly affected by factors such as the substituent R and the position of the R group on the benzene ring.

[0260] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. An oxadiazole sulfonamide compound containing a pyrazole structure, characterized in that, It has the structure shown in general formula A: ； R is selected from any one of ethyl, propyl, cyclopropyl, isopropyl, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-tert-butylphenyl, 2-thienyl, 5-chlorothienyl, 4-(3,5-dimethylisoxazolyl), 2-naphthyl, 2,4,6-triisopropylphenyl, mesityleneyl, and 4-(1-methyl-1H-pyrazolyl).

2. The method for preparing the oxadiazole sulfonamide compound containing a pyrazole structure as described in claim 1, characterized in that, Includes the following steps: (1) Ethyl 4,4-difluoroacetoacetate and CH(OEt)3 were refluxed in Ac2O solution, separated and purified to obtain intermediate 1; ； (2) The intermediate 1 was added to a methylhydrazine EtOAc solution at 5-10℃, and then heated under reflux to react, extracted, concentrated, and obtained intermediate 2. ； (3) The intermediate 2 and LiOH·H2O were heated and refluxed in THF / H2O solution, acidified, separated and purified to obtain intermediate 3; ； (4) Dissolve the intermediate 3 and react it with tert-butoxycarbonylhydrazine at room temperature, then separate and purify to obtain intermediate 4; ； (5) Dissolve the intermediate 4, add trifluoroacetic acid at 0°C, react at room temperature, separate and purify to obtain intermediate 5; ； (6) Dissolve the intermediate 5, add potassium hydroxide, add carbon disulfide at 0°C, then reflux at 85°C, acidify with concentrated hydrochloric acid, filter and dry to obtain intermediate 6. ； (7) Dissolve anhydrous piperazine, add sulfonyl chloride compounds, react at 0°C, separate and purify to obtain intermediate 7; ； (8) Dissolve the intermediate 7, add bromoacetyl bromide, react at room temperature, separate and purify to obtain intermediate 8; ； (9) Dissolve the intermediate 8, add the intermediate 6 and potassium carbonate, react at room temperature, separate and purify to obtain the target compound A; ； R is selected from any one of ethyl, propyl, cyclopropyl, isopropyl, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-tert-butylphenyl, 2-thienyl, 5-chlorothienyl, 4-(3,5-dimethylisoxazolyl), 2-naphthyl, 2,4,6-triisopropylphenyl, mesityleneyl, and 4-(1-methyl-1H-pyrazolyl).

3. A composition, characterized in that, The oxadiazole sulfonamide compound containing the pyrazole structure as described in claim 1.

4. The use of the pyrazole-containing oxadiazole sulfonamide compound of claim 1 or the composition of claim 3 in the prevention and control of bacterial and / or fungal plant diseases; The bacterial diseases of the plants are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker or kiwifruit canker; the fungal diseases of the plants are tomato gray mold, wheat scab, rice sheath blight or rapeseed sclerotinia rot.

5. The application according to claim 4, characterized in that, The effective concentration of the pyrazole-containing oxadiazole sulfonamide compound is 0. µ g / mL-100 µ g / mL, and not 0 µ g / mL.

6. The use of the pyrazole-containing oxadiazole sulfonamide compound of claim 1 or the composition of claim 3 in the preparation of antibacterial and / or antifungal drugs; The plant bacteria are *Bacillus oryzae*, *Bacillus streak*, *Citrus canker*, or *Actinidia kiwifruit*; the plant fungi are *Gray mold*, *Fusarium graminearum*, *Rhizoctonia solani*, or *Sclerotinia sclerotiorum*.

7. A method for preventing and controlling bacterial and / or fungal plant diseases, characterized in that, The oxadiazole sulfonamide compound containing the pyrazole structure of claim 1 or the composition of claim 3 is applied to the harmful substances or their habitats of the plant bacterial diseases and / or plant fungal diseases; The bacterial diseases of the plants are rice bacterial leaf blight, rice bacterial leaf streak, citrus canker or kiwifruit canker; the fungal diseases of the plants are tomato gray mold, wheat scab, rice sheath blight or rapeseed sclerotinia rot.

8. The method as described in claim 7, characterized in that, The effective concentration of the pyrazole-containing oxadiazole sulfonamide compound is 0. µ g / mL-100 µ g / mL, and not 0 µ g / mL.

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