Benzimidazole derivatives, preparation methods and applications thereof, and agricultural fungicides

Abstract

The present invention provides a benzimidazole derivative, a preparation method and application thereof, and an agricultural fungicide, and belongs to the technical field of agricultural chemistry. The present invention provides a benzimidazole derivative having a structure shown in Formula I, and provides a salt, a hydrate or a solvate thereof that is acceptable for agricultural production. The benzimidazole derivative provided by the present invention has a novel structure, has extremely high selective antibacterial activity against plant pathogenic oomycetes, and has a selective broad-spectrum antibiotic activity against plant pathogenic fungi, has a novel mechanism of action, has no cross-resistance with other types of fungicides, can be used to prevent and control plant diseases, and can be specifically used to prevent and control plant oomycete diseases such as vegetables, fruits, grain crops, oil crops, garden crops and Chinese medicinal materials, and also treat fungal diseases, especially has a good chemical protection effect and systemic therapeutic effect on drug-resistant crop diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural chemistry, and in particular to benzimidazole derivatives, preparation methods and applications thereof, and agricultural fungicides. Background Art

[0002] With the high-yield and high-quality production of agricultural products, the occurrence and harm of various crop diseases have become more serious, especially Phytophthora, Downy Mildew and Pythium in the Peronosporales, which are important plant pathogens. They have the characteristics of sudden harm with a wide host range and strong epidemicity, and often cause significant losses in the production of fruits, vegetables, grain and oil crops.

[0003] Crop disease prevention and control in modern agricultural production is inseparable from the use of safe, efficient, and low-toxic selective fungicides. Among them, fungicides for the prevention and control of oomycete diseases, especially blight and downy mildew, account for more than 22% of the fungicide market share, and fungicides account for about 3 / 4 of the fungicide market. However, the rapid genetic variation and huge reproductive capacity of pathogenic microorganisms and other biological characteristics can easily lead to the emergence of high-level drug-resistant pathogen groups in production soon after the application of various selective fungicides, often resulting in the sudden failure of fungicide control. The epidemic of drug-resistant diseases often catches prevention and control off guard, and if the dosage is blindly increased, not only will the disease not be effectively controlled, but it will also easily cause pesticide residues and pesticide damage.

[0004] Therefore, the management of fungicide resistance requires the continuous discovery of safe, highly effective and selective new fungicides that specifically bind to target proteins. In 2014, DuPont developed a piperidinyl thiazole isoxazoline fungicide, fluthiazolylpyrone, whose chemical name is 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one. This fungicide only exhibits extremely high antibacterial activity against downy mildew and phytophthora in plant pathogenic oomycetes, and also exhibits good antibacterial activity against pythium, but has almost no biological activity against plant pathogenic fungi. Summary of the invention

[0005] The purpose of the present invention is to provide a benzimidazole derivative, a preparation method and application thereof, and an agricultural fungicide. The benzimidazole derivative provided by the present invention has a novel structure, has extremely high selective antibacterial activity against plant pathogenic oomycetes, and has selective broad-spectrum antibiotic activity against plant pathogenic fungi.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a benzimidazole derivative, and a salt, hydrate or solvate thereof acceptable for agricultural production, characterized in that the benzimidazole derivative has a structure shown in Formula I:

[0008]

[0009] Among them, R 1 , R 2 , R 3 With R 4 Independently selected from -H, -C n H 2n+1 、-CH 2 Cl, -CH 2 Br, -CHF 2 , -CF 3 , cyclopropyl, -OC n H 2n+1 , -SC n H 2n+1 、-OCHF 2 、-OCF 3 ,-COOC n H 2n+1 , -NHCOOC n H 2n+1 、-NHCOC n H 2n+1 , -OH, -NH 2 、-NO 2 、-SH、-SO 3 H, -CN or a halogen group, and R, R 1 , R 2 , R 3 With R 4 Not at the same time -H;

[0010] R 5 Selected from -H, -C n H 2n+1 , -CHF 2 , -CF 3 , cyclopropyl, -OC n H 2n+1 , -SC n H 2n+1 、-SO 2 C n H 2n+1 、-OCHF 2 、-OCF 3 , -OH, -NH 2 、-NO 2 , -SH, -CN or a halogen group;

[0011] n is a positive integer from 1 to 4;

[0012] m is a positive integer from 1 to 5.

[0013] Preferably, the R is selected from -H, -CH3 , -C 2 H 5 、-nC 3 H 7 、-iC 3 H 7 、-CH 2 Cl, -CH 2 Br, -CHF 2 , -CF 3 , cyclopropyl, -OCH 3 、-OC 2 H 5 、-OnC 3 H 7 、-OiC 3 H 7 、-SCH 3 , -SC 2 H 5 、-SnC 3 H 7 、-SiC 3 H 7 、-COOCH 3 ,-COOC 2 H 5 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -NH 2 、-NO 2 、-SH、-SO 3 H, -CN or a halogen group;

[0014] R 1 , R 2 , R 3 With R 4 Independently selected from -H, -CH 3 , -C 2 H 5 、-nC 3 H 7 、-iC 3 H 7 , -CHF 2 , -CF 3 , cyclopropyl, -OCH 3 、-OC 2 H 5 、-OnC 3 H 7 、-OiC 3 H 7 、-OCHF 2 、-OCF 3 、-COOCH 3,-COOC 2 H 5 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -NH 2 、-NO 2 、-SH、-SO 3 H, -CN or a halogen group, and R, R 1 , R 2 , R 3 With R 4 Not at the same time -H;

[0015] R 5 is selected from -H, -Cl, -Br, -F or -I;

[0016] m is a positive integer from 1 to 3.

[0017] Preferably, the R is selected from -H, -CH 3 , -C 2 H 5 , -CHF 2 , -CF 3 、-OC 2 H 5 、-SCH 3 、-COOCH 3 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -Cl, -Br or -F;

[0018] R 1 , R 2 , R 3 With R 4 Independently selected from -H, -CH 3 , -CF 3 、-OCH 3 、-OCF 3 、-NO 2 , -Cl, -Br or -F, and R, R 1 , R 2 , R 3 With R 4 Not at the same time -H;

[0019] (R 5 ) m It is a 2,6-difluoro group.

[0020] Preferably, the benzimidazole derivative is selected from 2-(2-chloro-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-bromo-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-(difluoromethyl)-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, -1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-methoxy-2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-fluoro-2 -hydroxy-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-hydroxy-6-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-hydroxy-6-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one -(2-ethyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(methylthio)-1H-benzimidazol-1-yl)ethan-1-one, 2-(2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one,1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-bromo-2-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-bromo-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one -1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethoxy-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5,6-dimethyl-1H-benzimidazol-1-yl)ethan-1-one, 2-(6-chloro-4- methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one,1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-nitro-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-(trifluoromethoxy)-1H-benzimidazol-1-yl)ethan-1-one oxazol-1-yl)ethan-1-one, 2-(5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl) 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carboxylic acid methyl ester, 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carboxylic acid methyl ester, -4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carbamic acid methyl ester or N-(1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-yl)acetamide.

[0021] The present invention provides a method for preparing the benzimidazole derivatives described in the above technical scheme, comprising the following steps:

[0022] Mixing compound II, compound III, an acid-binding agent and an organic solvent to carry out a substitution reaction to obtain a benzimidazole derivative having a structure shown in formula I;

[0023] The structural formula of the compound II is shown in Formula II, and the structural formula of the compound III is shown in Formula III:

[0024]

[0025] Among them, R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined in formula I, and X is a halogen group.

[0026] The present invention provides the use of the benzimidazole derivatives described in the above technical solution, and their salts, hydrates or solvates acceptable for agricultural production in preventing and controlling plant diseases.

[0027] Preferably, the plant disease is a disease caused by a plant pathogenic oomycete or a plant pathogenic fungus of the order Peronosporales.

[0028] Preferably, the plant disease is a disease caused by Phytophthora, Sclerophthora, Sclerospora, Plasmopara, Peronophythora, Pseudoperonospora, Peronospora, Bremia, Paraperonosporora, Albugo, Pythium, Magnaporthe, Rhizoctonia, Fusarium, Botrytis or Colletotrichum.

[0029] The present invention provides the use of the benzimidazole derivatives described in the above technical solution, and their salts, hydrates or solvates acceptable for agricultural production as agricultural fungicides.

[0030] The present invention provides an agricultural fungicide, comprising an active ingredient and auxiliary materials; the active ingredient comprises at least one of the benzimidazole derivatives described in the above technical solution, and salts, hydrates and solvates thereof acceptable for agricultural production.

[0031] The present invention provides a benzimidazole derivative, and a salt, hydrate or solvate thereof acceptable for agricultural production, characterized in that the benzimidazole derivative has a structure shown in Formula I. The benzimidazole derivative provided by the present invention has a novel structure, has extremely high selective antibacterial activity against plant pathogenic oomycetes, and has a selective broad-spectrum antibiotic activity against plant pathogenic fungi, has a novel mechanism of action, has no cross-resistance with other types of fungicides, can be used for preventing and controlling plant diseases, and can be specifically used for preventing and controlling plant oomycete diseases and fungal diseases of vegetables, fruits, grain crops, oil crops, garden crops and Chinese medicinal materials, and has a good chemical protection effect and systemic therapeutic effect on drug-resistant crop diseases. DETAILED DESCRIPTION

[0032] The present invention provides a benzimidazole derivative, and a salt, hydrate or solvate thereof acceptable for agricultural production. The benzimidazole derivative has a structure shown in Formula I:

[0033]

[0034] Among them, R 1 , R2 , R 3 With R 4 Independently selected from -H, -C n H 2n+1 、-CH 2 Cl, -CH 2 Br, -CHF 2 , -CF 3 , cyclopropyl, -OC n H 2n+1 , -SC n H 2n+1 、-OCHF 2 、-OCF 3 ,-COOC n H 2n+1 , -NHCOOC n H 2n+1 、-NHCOC n H 2n+1 , -OH, -NH 2 、-NO 2 、-SH、-SO 3 H, -CN or a halogen group, and R, R 1 , R 2 , R 3 With R 4 Not at the same time -H;

[0035] R 5 Selected from -H, -C n H 2n+1 , -CHF 2 , -CF 3 , cyclopropyl, -OC n H 2n+1 , -SC n H 2n+1 、-SO 2 C n H 2n+1 、-OCHF 2 、-OCF 3 , -OH, -NH 2 、-NO 2 , -SH, -CN or a halogen group;

[0036] n is a positive integer from 1 to 4; m is a positive integer from 1 to 5.

[0037] The present invention is based on the demand for sustainable and green development of major crop disease prevention and control technologies, and conducts research on the structural biology of drug-sensitive target proteins of plant pathogens, proposing a theory that drug-target interactions are specific and accurate. Using Fusarium graminearum, which causes wheat fusarium head blight, as the material, the structural differentiation characteristics of drug-sensitive oxysterol-binding proteins of plant pathogenic fungi and plant pathogenic oomycetes were studied and analyzed. Through a large number of drug-target affinity studies and analyses, it was found that replacing the pyrazole heterocycle in the fluthiazolinone molecule with a benzimidazole heterocycle can improve the antibacterial activity against fruit and vegetable gray mold and Fusarium graminearum, but the antibacterial activity against oomycetes decreased by more than 1,000 times. In order to improve the antibacterial activity against oomycetes and fungi, the present invention introduces various electron-donating groups or electron-withdrawing groups through substitution and structural optimization of H on the benzimidazole heterocycle, designs and synthesizes a series of targeted oxysterol binding protein inhibitors, screens compounds with antibacterial or anti-disease activity against representative plant pathogenic oomycetes and fungi, and obtains a novel antibacterial compound of the piperidinylthiazole isoxazoline type containing a benzimidazole derivative structure with extremely high antibacterial activity against plant pathogenic oomycetes and good antifungal activity. The benzimidazole derivatives provided by the present invention are described in detail below.

[0038] In the present invention, the R is preferably -H, -CH 3 , -C 2 H 5 、-nC 3 H 7 、-iC 3 H 7 、-CH 2 Cl, -CH 2 Br, -CHF 2 , -CF 3 , cyclopropyl, -OCH 3 、-OC 2 H 5 、-OnC 3 H 7 、-OiC 3 H 7 、-SCH 3 , -SC 2 H 5 、-SnC 3 H 7 、-SiC 3 H 7 、-COOCH 3 ,-COOC 2 H 5 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -NH 2 、-NO 2 、-SH、-SO3 H, -CN or a halogen group, wherein the halogen group preferably includes -Cl, -Br, -F or -I; and R is more preferably -H, -CH 3 , -C 2 H 5 , -CHF 2 , -CF 3 、-OC 2 H 5 、-SCH 3 、-COOCH 3 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -Cl or -Br.

[0039] In the present invention, the R 1 , R 2 , R 3 With R 4 Preferably, they are independently -H, -CH 3 , -C 2 H 5 、-nC 3 H 7 、-iC 3 H 7 、-CH 2 Cl, -CH 2 Br, -CHF 2 , -CF 3 , cyclopropyl, -OCH 3 、-OC 2 H 5 、-OnC 3 H 7 、-OiC 3 H 7 、-OCHF 2 、-OCF 3 、-COOCH 3 ,-COOC 2 H 5 、-NHCOOCH 3 、-NHCOCH 3 , -OH, -NH 2 、-NO 2 、-SH、-SO 3 H, -CN or a halogen group, wherein the halogen group preferably includes -Cl, -Br, -F or -I; 1 , R 2 , R 3 With R 4 More preferably, they are independently -H, -CH 3 , -CF 3、-OCH 3 、-OCF 3 、-NO 2 , -Cl, -Br or -F; and R, R 1 , R 2 , R 3 With R 4 Not at the same time -H.

[0040] In the present invention, the R 5 Preferred are -H, -CH 3 , -C 2 H 5 、-nC 3 H 7 、-iC 3 H 7 , -CHF 2 , -CF 3 , cyclopropyl, -OCH 3 、-OC 2 H 5 、-OnC 3 H 7 、-OiC 3 H 7 、-OCHF 2 、-OCF 3 、-SO 2 CH 3 , -OH, -NH 2 、-NO 2 , -SH, -CN or a halogen group, wherein the halogen group preferably includes -Cl, -Br, -F or -I; and more preferably R 5 Preferred is -H, -Cl, -Br, -F or -I.

[0041] The n described in the present invention is preferably 1, 2, 3 or 4. The m described in the present invention is preferably 1, 2, 3, 4 or 5.

[0042] In the present invention, the (R 5 ) m Specifically, it may be a 2,6-difluoro group.

[0043] In the present invention, the benzimidazole derivative is preferably 2-(2-chloro-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-bromo-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-(difluoromethyl)-1H-benzimidazole-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-methoxy-2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-methoxy-2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one -2-hydroxy-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-hydroxy-6-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-methyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)- 2-(2-ethyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(methylthio)-1H-benzimidazol-1-yl)ethan-1-one, 2-(2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one,1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-bromo-2-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-bromo-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one -1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethoxy-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5,6-dimethyl-1H-benzimidazol-1-yl)ethan-1-one, 2-(6-chloro-4- methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one,1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-nitro-1H-benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-(trifluoromethoxy)-1H-benzimidazol-1-yl)ethan-1-one oxazol-1-yl)ethan-1-one, 2-(5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl) 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carboxylic acid methyl ester, 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carboxylic acid methyl ester, -4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carbamic acid methyl ester or N-(1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-yl)acetamide.

[0044] The present invention provides a method for preparing the benzimidazole derivatives described in the above technical scheme, comprising the following steps:

[0045] Mixing compound II, compound III, an acid-binding agent and an organic solvent to carry out a substitution reaction to obtain a benzimidazole derivative having a structure shown in formula I;

[0046] The structural formula of the compound II is shown in Formula II, and the structural formula of the compound III is shown in Formula III:

[0047]

[0048] Among them, R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined in formula I, and X is a halogen group.

[0049] In the present invention, unless otherwise specified, the raw materials used are commercially available products known to those skilled in the art or prepared using methods known to those skilled in the art. Wherein the compound II used in the present invention is synthesized according to the method reported in the literature (Pesticide Biochemistry and Physiology, 2020, 169: 104673 or Bioorganic & Medicinal Chemistry Letters, 2016, 26 (12): 2965-2973), compound III, acid binding agent and organic solvent are all products currently sold on the market, such as 2- (trifluoromethyl) benzimidazole sold by Shanghai Bid Pharmaceutical Technology Co., Ltd. under the trade name 2- (trifluoromethyl) benzimidazole, potassium carbonate sold by Nanjing Crystal Chemical Technology Co., Ltd. under the trade name potassium carbonate, and acetonitrile sold by Beijing Mai Ruida Technology Co., Ltd. under the trade name acetonitrile.

[0050] The present invention uses compound II and compound III as reaction raw materials to prepare a benzimidazole derivative having a structure shown in formula I, wherein X in compound II is preferably -Cl, -Br or -I, more preferably -Cl or -Br. In the present invention, the acid binding agent is preferably pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, more preferably potassium carbonate, cesium carbonate or sodium hydride. In the present invention, the molar ratio of compound II, compound III to the acid binding agent is preferably 1:1-1.2:1-3, more preferably 1:1-1.1:1.1-2. In the present invention, if the molar ratio of compound II to compound III is greater than 1:1, compound II will have a surplus, post-processing is difficult, and the synthesis cost is increased; if the molar ratio of compound II to compound III is less than 1:1.2, the product yield cannot be further improved, and the synthesis cost is also increased; if the molar ratio of the acid binding agent to compound II is less than 1:1, the reaction is insufficient and the product yield decreases; if the molar ratio of the acid binding agent to compound II is greater than 3:1, the product yield cannot be further improved, and the synthesis cost increases. Therefore, it is appropriate for the present invention to limit the molar ratio of the compound II, compound III and the acid binding agent to the above range. In the present invention, the organic solvent is preferably methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or pyridine, more preferably acetonitrile or tetrahydrofuran; the present invention does not specifically limit the amount of the organic solvent, as long as it can ensure that the reaction proceeds smoothly.

[0051] The present invention preferably mixes compound II, compound III and an acid binding agent in an organic solvent, and then performs the substitution reaction. In the present invention, the substitution reaction is preferably performed under reflux conditions, and the reflux temperature is preferably 60 to 120°C; the substitution reaction time is preferably 0.1 to 72 hours, more preferably 1 to 48 hours, and further preferably 4 to 24 hours; if the substitution reaction time is shorter than 0.1 hours, the reaction will not be thorough, and the product yield will decrease; if the substitution reaction time is longer than 72 hours, the product yield will not be further increased, and the synthesis cost will also increase; the substitution reaction is preferably performed under stirring conditions.

[0052] After the substitution reaction, the present invention preferably cools the obtained substitution product system, then removes the solvent by reduced pressure distillation to obtain a product mixture; the product mixture is mixed with water and an extractant for extraction, and the extract phase is collected and washed and dried in sequence to obtain a crude product; the crude product is recrystallized or separated by column chromatography to obtain a benzimidazole derivative having a structure shown in Formula I. The post-treatment method involved after the substitution reaction is described in detail below.

[0053] The present invention cools the substitution product system, and then removes the solvent by reduced pressure distillation to obtain a product mixture. In the present invention, the pressure of the reduced pressure distillation is preferably 0.1-100 kPa, more preferably 0.5-95 kPa, and further preferably 1-90 kPa; the temperature is preferably 30-100 ° C, more preferably 35-90 ° C, and more preferably 40-85 ° C. In the present invention, when the reduced pressure distillation temperature is within the above range, if the reduced pressure distillation pressure is lower than 0.1 KPa, it exceeds the actual need for distillation to remove the solvent; if the reduced pressure distillation pressure is higher than 100 KPa, it is difficult to distill the solvent; when the reduced pressure distillation pressure is within the above range, if the reduced pressure distillation temperature is lower than 30 ° C, it is difficult to distill the solvent; if the reduced pressure distillation temperature is higher than 100 ° C, it exceeds the actual need for distillation to remove the solvent. In the present invention, the solvent content in the product mixture is preferably less than 1.0 wt%; the solvent content in the product mixture is preferably obtained by analysis and detection according to the national standard analysis method, such as the acetonitrile content is obtained by gas chromatography analysis according to SH / T 1627.2-1996 standard. In the embodiments of the present invention, the reduced pressure distillation is performed using a rotary evaporator; the rotary evaporator is a product currently sold on the market, such as a product sold by Tokyo Rikaki Co., Ltd. under the trade name N-1100S-WD rotary evaporator.

[0054] After obtaining the product mixture, the present invention mixes the product mixture with water and an extractant for extraction, and collects the extract phase. The present invention preferably mixes the product mixture with water to obtain a product mixture aqueous solution, and then mixes the product mixture aqueous solution with an extractant for extraction. In the present invention, the extractant is preferably ether, ethyl acetate, dichloromethane, chloroform or carbon tetrachloride. In the present invention, the mass ratio of the product mixture to water is preferably 1:1-50, more preferably 1:5-40, and further preferably 1:10-33; the volume ratio of the product mixture aqueous solution to the extractant is preferably 1:0.1-5.0, more preferably 1:0.2-4.0, and further preferably 1:0.5-3.0; the number of extractions is preferably 2-4 times; the extract phases obtained after each extraction are combined to obtain a combined extract phase. In the present invention, the main purpose of adding water to the product mixture is to dissolve and remove impurities soluble in water. It is undesirable to add water in an amount exceeding the above range, because the mass ratio of the product mixture to water is greater than 1:1, and the purpose of dissolving and removing water-soluble impurities cannot be achieved, and if the mass ratio of the product mixture to water is less than 1:5.0, water will be wasted. In the present invention, if the volume ratio of the product mixture aqueous solution to the extractant is greater than 1:0.1, the reaction product cannot be effectively dissolved and extracted; if the volume ratio of the product mixture aqueous solution to the extractant is less than 1:5.0, the difficulty of post-processing is increased, and the processing cost is increased.

[0055] After obtaining the combined extract phase, the present invention sequentially washes and dries the combined extract phase to obtain a crude product. In the present invention, the washing liquid used for the washing is preferably 0.1 to 5.0 mol / L HCl solution, saturated NaHCO 3 solution and distilled water; the volume ratio of the combined extract phase to the washing liquid used for each washing is preferably 1:0.5-2.0; the number of washings with the HCl solution is preferably 2-4 times, the main function of which is to remove the residual compound III and the acid binding agent; the saturated NaHCO 3 The number of times of solution washing is preferably 2 to 4 times, the main function of which is to remove residual HCl; the number of times of washing with distilled water is preferably based on washing until neutrality. In the present invention, the desiccant used for drying is preferably anhydrous Na 2 SO 4; After the drying, the present invention preferably filters the obtained material, collects the feed liquid and performs reduced pressure distillation to remove the solvent to obtain a crude product. In the present invention, the pressure of the reduced pressure distillation is preferably 0.1-100 kPa, more preferably 0.5-95 kPa, and further preferably 1-90 kPa; the temperature is preferably 30-100 ° C, more preferably 38-90 ° C, and more preferably 46-80 ° C. In the present invention, when the reduced pressure distillation temperature is within the above range, if the reduced pressure distillation pressure is lower than 0.1 kPa, it exceeds the actual need for distillation to remove the solvent; if the reduced pressure distillation pressure is higher than 100 kPa, it is difficult to distill the solvent; when the reduced pressure distillation pressure is within the above range, if the reduced pressure distillation temperature is lower than 30 ° C, it is difficult to distill the solvent; if the reduced pressure distillation temperature is higher than 100 ° C, it exceeds the actual need for distillation to remove the solvent. In the present invention, the solvent content in the crude product is preferably 1.0 wt% or less.

[0056] After obtaining the crude product, the present invention performs recrystallization or column chromatography separation on the crude product to obtain a benzimidazole derivative having a structure shown in Formula I. The crude product of the present invention is specifically a solid crude product or a liquid crude product; when the crude product is a solid crude product, the present invention can perform recrystallization on the solid crude product, or mix the solid crude product with a dissolving agent to obtain a dissolving solution, and then perform column chromatography separation on the dissolving solution; when the crude product is a liquid crude product, the present invention preferably performs column chromatography separation on the liquid crude product. In the present invention, the recrystallization agent used for the recrystallization is preferably a mixed reagent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 100:0 to 100; after the recrystallization, it is preferred to further include filtering, collecting the filter cake for drying, so as to obtain a benzimidazole derivative having a structure shown in Formula I. In the present invention, the amount ratio of the solid crude product to the dissolving agent is preferably 1g:1 to 20mL; the dissolving agent is preferably ethyl acetate. In the present invention, the eluent used for the column chromatography separation is preferably a mixed reagent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 100:0 to 100; the column chromatography separation is preferably carried out under a pressure of 0.1 to 5.0 MPa. In the present invention, after the column chromatography separation, it is preferred to further include: removing the solvent from the obtained eluent by vacuum distillation to obtain a benzimidazole derivative having a structure shown in Formula I; the optional conditions for the vacuum distillation are preferably consistent with the optional conditions for the vacuum distillation described in the above technical solution, and will not be repeated here. The benzimidazole derivative provided in the present invention is specifically a crystal, a block solid, a powdery solid or an oily liquid in colors such as white, yellow, brownish yellow, brown, etc.

[0057] The present invention provides the use of the benzimidazole derivatives described in the above technical scheme, and their salts, hydrates or solvates acceptable in agricultural production in the prevention and treatment of plant diseases. The benzimidazole derivatives provided by the present invention have a novel structure, and not only have extremely high biological activity against plant pathogenic oomycetes and certain antibacterial activity against plant pathogenic fungi, but are also safe for plants and adaptable to the environment; they are selective when used for the prevention and treatment of diseases of crops and garden crops, and are in line with the development direction of new targeted fungicides that are safe, efficient, low-toxic, low-residue, and compatible with the environment, and meet the requirements of ensuring environmental ecological safety; at the same time, they have no cross-resistance with existing fungicides, and can be used in combination with a variety of fungicides to prevent and treat drug-resistant diseases, especially to solve the problem that there is no drug to treat multiple drug-resistant diseases; in addition, they have high antibacterial activity, long lasting effect, small amount per unit area, low cost of use, long suitable medication time, high input-output ratio, good economic benefits, and meet the requirements of modern agricultural development.

[0058] In the present invention, the plant disease is preferably a disease caused by a plant pathogenic oomycete or a plant pathogenic fungus of the Peronosporales order; the plant disease is more preferably a disease caused by a plant pathogenic oomycete or a plant pathogenic fungus of the genus Phytophthora, Sclerophthora, Sclerospora, Plasmopara, Peronophythora, Pseudoperonospora, Peronospora, Bremia, Pasilespora, raperonospora), Albugo, Pythium, Magnaporthe, Rhizoctonia, Fusarium, Botrytis or Colletotrichum, for example, including but not limited to one or more of potato late blight, tomato late blight, pepper blight, soybean blight, litchi blight, cucumber downy mildew, vegetable downy mildew, grape downy mildew, rice blast, rice sheath blight, wheat fusarium or fruit and vegetable gray mold, sclerotinia and anthracnose.

[0059] The present invention refers to the literature such as "Pesticide Bioassay" (China Agriculture Press, 2013, Beijing) edited by Shen Jinliang, and uses the plant pathogenic bacteria materials stored and temporarily collected in the laboratory to determine the biological activities of the benzimidazole derivatives provided by the present invention against Phytophthora infestans (causing late blight of potatoes and tomatoes), Phytophthora capsici (causing a variety of fruit and vegetable blights), grape downy mildew and cucumber downy mildew, as well as rice blast, rice sheath blight, wheat fusarium, fruit and vegetable gray mold, strawberry anthracnose, grape anthracnose and rapeseed sclerotinia. Specifically, the benzimidazole derivatives of the present invention are dissolved in dimethyl sulfoxide (DMSO) or methanol to obtain a pharmaceutical mother solution with a concentration of 10 mg / mL or 1 mg / mL, and then the pharmaceutical mother solution is diluted with sterile water to a concentration of 1000 μg / mL, 100 μg / mL and 10 μg / mL of pharmaceutical solution, and then the pharmaceutical solution is added to a potato dextrose agar (PDA) medium or a lima bean medium cooled to a temperature of 45°C, and evenly mixed to prepare the benzimidazole derivatives with final concentrations of 100 μg / mL, 10 μg / mL and 1 μg / mL, respectively, and the antibacterial activity of the test pathogens is preliminarily screened. Subsequently, according to the activity of the initially screened benzimidazole derivatives and the sensitivity of the pathogens, a series of drug-containing culture media with final concentrations of 20 μg / mL, 5 μg / mL, 1.25 μg / mL, or 0.2 μg / mL, 0.04 μg / mL, 0.008 μg / mL, or 0.1 μg / mL, 0.05 μg / mL, 0.025 μg / mL, 0.0125 μg / mL, 0.00625 μg / mL, 0.0031 μg / mL were prepared. At the same time, a culture medium without benzimidazole derivatives but containing an equal amount of solvent was prepared as a blank control, and the test plant pathogens Phytophthora infestans, Phytophthora capsici, Rice blast fungus, Rice sheath blight, Gibberella fusca, Botrytis cinerea, Colletotrichum sclerotiorum, and Sclerotinia sclerotiorum were inoculated. Cultivate at an appropriate temperature, and when the bacterial colonies on the control culture plate grow close to the edge of the culture dish (φ90mm or 50mm), measure the minimum inhibitory concentration (MIC) or the inhibitory concentration (EC 50 ), the MIC value was evaluated based on the lowest concentration that completely prevented growth on the test drug-containing plates, or the concentration of the drug that inhibited growth by 50% on the initial screening drug-containing plates, to evaluate the effective mid-range concentration range of the compound to inhibit growth.

[0060] When the biological activity is determined in vivo, the benzimidazole derivatives provided by the present invention are processed into preparations, diluted with water to a final concentration of 500 μg / mL, 250 μg / mL, 50 μg / mL, 10 μg / mL, and 2 μg / mL of the liquid, and the potted plant seedlings are sprayed until the liquid is about to flow, or the roots are irrigated with soil or mixed with seeds at the seedling stage, and then pathogens are inoculated to determine the preventive effect of the benzimidazole derivatives on plant diseases; or the benzimidazole derivatives are used for treatment 24 hours after the pathogens are inoculated to determine the therapeutic effect.

[0061] In the present invention, the preparation of the pathogenic oomycete inoculum is to collect grape or cucumber downy mildew diseased leaves, rinse them with tap water, place them on wet filter paper in a glass culture dish with a diameter of 15 cm, cover them, and culture them in the dark at 18°C ​​for 24 hours, then wash the sporangium with 4°C tap water, and prepare 10 4 / mL of sporangium suspension, or culture potato infestation blight, pepper phytophthora or aphaniderma on CMA medium at 20°C, pick mycelium from the edge of the colony after 3 days and inoculate it in Petri liquid culture medium for 2-3 days, filter with gauze and centrifuge at 1000r / min for 5min, collect sporangium and resuspend it with sterile water and adjust the sporangium concentration to 1×10 5 / mL, and a sporangium suspension is obtained, which is used for the drip or spray inoculation, soil irrigation or soil inoculation or seed inoculation of potted seedlings treated with benzimidazole derivatives and untreated controls in the efficacy determination of the present invention, and cultured in a greenhouse until the crop seedlings (control) not treated with benzimidazole derivatives are fully diseased, and the biological activity of each benzimidazole derivative in preventing and controlling plant diseases is investigated and analyzed.

[0062] In the present invention, the preparation of the pathogenic fungus inoculum is to culture the pathogenic fungus on a solid culture medium plate or in a liquid culture medium using a plant pathology method, collect spores, and prepare 10 5 / mL of conidia suspension was used for inoculation.

[0063] The benzimidazole derivatives of the present invention have no cross-resistance with existing oomyceticides such as propamocarb of carbamates, cymoxanil of aliphatic families, metalaxyl of benzamides, fosetyl-aluminum of organophosphorus families, azoxystrobin and oxadiazine of methoxyacrylates, oxadiazine of carboxylic acid amides, and benzamides, as well as various existing fungicides, but have cross-resistance with the OSBPIs oomycetic agent fluthiazolpyruvate. The benzimidazole derivatives of the present invention are mixed with the above-mentioned oomycetic agents for use to prevent and control plant oomycetic diseases that have developed drug resistance.

[0064] In the present invention, the antibacterial activity of the benzimidazole derivatives against the point mutants of oxysterol binding protein (OSBP) is greatly reduced, indicating that the target of the compounds is oxysterol binding protein, which is consistent with the goal of molecular design.

[0065] The present invention has found that the antifungal activity of benzimidazole derivatives against pathogenic fungi of rice, wheat, fruit trees and vegetables is structure-dependent. Some of these compounds show good control effects on rice blast, wheat head blight and gray mold of fruits and vegetables, while others require higher doses to show antifungal activity. However, the antifungal activity of these compounds is significantly higher than that of fluthiazolinone with the same mode of action, and there is no cross-resistance with existing fungicides.

[0066] The present invention provides the use of the benzimidazole derivatives, their salts, hydrates or solvates acceptable for agricultural production as agricultural fungicides described in the above technical scheme. In the present invention, the agricultural fungicide specifically includes active ingredients and adjuvants; the active ingredients include at least one of the benzimidazole derivatives, their salts, hydrates and solvates acceptable for agricultural production described in the above technical scheme. In the present invention, the adjuvants are preferably adjuvants acceptable for agricultural production, and more preferably include one or more of carriers, solvents, cosolvents, surfactants, dispersants, emulsifiers, wetting agents, suspending agents, thickeners, stabilizers, defoamers, antifreeze agents and synergists. The content of the active ingredient in the agricultural fungicide of the present invention is preferably 0.1-99.9wt%. In the present invention, the dosage form of the agricultural fungicide preferably includes mother powder, mother liquid, emulsifiable concentrate, suspension, water, water emulsion, microemulsion, powder, wettable powder, soluble powder, granules, water-dispersible granules, oil, smoke agent or bait. In the present invention, the benzimidazole derivatives in the present invention can be processed into any of the above-mentioned dosage forms according to actual needs using auxiliary materials and existing pesticide production technology, such as wettable powder (WP), suspension concentrate (SC) or water dispersible granules (WG), and then the biological activity of the benzimidazole derivatives can be determined according to the above method. The biological activity against other plant pathogenic oomycetes and fungi can also be determined by a similar method. For example, the antibacterial activity against other plant pathogens can be determined according to "Pesticide Formulation Processing and Management" (Edited by Shen Jinliang, China Agriculture Press, 2002, Beijing), "Pesticide Formulation" (Edited by Wang Kaiyun, China Agriculture Press, 2002, Beijing) or "Pesticide Bioassay" (Edited by Shen Jinliang, China Agriculture Press, 2013, Beijing).

[0067] The present invention provides an agricultural fungicide, comprising an active ingredient and an auxiliary material; the active ingredient comprises at least one of the benzimidazole derivatives described in the above technical solution, and salts, hydrates and solvates thereof acceptable for agricultural production. In the present invention, the active ingredient content, auxiliary material types and dosage forms in the agricultural fungicide are preferably consistent with those in the above technical solution, and are not described in detail herein.

[0068] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0069] In the following examples of the present invention, the yield of the method for preparing benzimidazole derivatives in the present invention is calculated according to the following calculation formula: Yield = (the number of moles of the benzimidazole derivative having the structure shown in Formula I / the number of moles of Compound II) × 100%.

[0070] Example 1: Preparation of 2-(2-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A1)

[0071]

[0072] 0.02 mol of compound II (X is Cl, (R 5 ) m 0.022 mol of 2-chloro-1H-benzimidazole (compound III) and 0.03 mol of potassium carbonate were mixed evenly in 30 mL of acetonitrile, and heated under reflux reaction for 7.8 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled and distilled using a rotary evaporator at a pressure of 28 kPa and a temperature of 55° C. to a solvent content of 0.5 wt % to obtain a product mixture;

[0073] According to the mass ratio of the product mixture to water of 1:22, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to ethyl acetate of 1:2.0, ethyl acetate was added to the product mixture aqueous solution for extraction, and the extraction was performed 3 times in total, and the obtained extract phases were combined to obtain a combined extraction phase; according to the volume ratio of the combined extraction phase to a 1.0 mol / L HCl solution of 1:1.2, a 1.0 mol / L HCl solution was added to the combined extraction phase for washing, and the washing was performed 3 times in total; then, the combined extraction phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:1.2, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4The filtrate was dried, filtered, and then distilled under reduced pressure using a rotary evaporator at a pressure of 52 kPa and a temperature of 60° C. to a solvent content of 0.8 wt %, to obtain a solid crude product; a mixed reagent prepared by using petroleum ether and ethyl acetate in a volume ratio of 100:20 was used as a recrystallization reagent, and the solid crude product was recrystallized in the recrystallization reagent at room temperature, and then the filter cake was collected by filtration, and dried in an oven at 46° C. to a solvent content of 0.2 wt %, to obtain a light yellow solid powder, which is compound A1, with a yield of 82%. The nuclear magnetic resonance data of compound A1 are as follows:

[0074] 1 H NMR (500 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.61(d,J=7.9 Hz,1H,ArH),7.58(d,J=7.8Hz,1H,ArH),7.51(quintet,J=8.4 Hz,1H,PhH),7.29-7.22(m,2H,ArH),7.17(t,J=8.5 Hz,2H,PhH),6.02(dd,J=12.0,8.7 Hz,1H,OCH),5.42-5.30(m,2H,COCH 2 ),4.36(d,J=12.8 Hz,1H,CH 2 N), 4.12(d, J=13.1 Hz, 1H, CH 2 N),3.91(dd,J=17.3,12.1 Hz,1H,OCCH 2 ),3.53(dd,J=17.2,8.7 Hz,1H,OCCH 2 ),3.46-3.40(m,1H,CH),3.27(t,J=12.2Hz,1H,CH 2 N), 2.87(t, J=12.1 Hz, 1H, CH 2 N), 2.20(d, J=12.7Hz,1H,CH 2 ),2.11(d,J=12.5Hz,1H,CH 2 ),1.91(qd,J=11.3,4.3 Hz,1H,CH 2 ),1.58(qd,J=11.3,4.1Hz,1H,CH 2 ).

[0075] The minimum inhibitory concentrations (MIC) of compound A1 prepared in this example on the mycelial growth of pepper phytophthora, infestans and downy mildew on the drug-containing culture medium plate were 0.1 μg / mL, 0.01 μg / mL and 0.1 μg / mL, respectively; the effective inhibitory concentration (EC) of compound A1 on the mycelial growth of strawberry anthracnose, fruit and vegetable gray mold, rice blast and wheat fusarium was 0.1 μg / mL, 0.01 μg / mL and 0.1 μg / mL, respectively. 50 ) were 25μg / mL, 10μg / mL, 15μg / mL and 25μg / mL respectively.

[0076] Example 2: Preparation of 2-(2-bromo-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A2)

[0077]

[0078] 0.01 mol of compound II (X is Cl, (R 5 ) m 0.01 mol of 2-bromo-1H-benzimidazole (compound III) and 0.02 mol of potassium carbonate were mixed evenly in 15 mL of acetonitrile, and heated under reflux for 6.9 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled and distilled using a rotary evaporator at a pressure of 34 kPa and a temperature of 68° C. to a solvent content of 0.5 wt % to obtain a product mixture;

[0079] According to the mass ratio of the product mixture to water of 1:33, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to dichloromethane of 1:1.0, dichloromethane was added to the product mixture aqueous solution for extraction, and the extractions were performed twice, and the obtained extract phases were combined to obtain a combined extraction phase; according to the volume ratio of the combined extraction phase to a 0.8 mol / L HCl solution of 1:1.2, 0.8 mol / L HCl solution was added to the combined extraction phase for washing, and the washing was performed three times; then, the combined extraction phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:1.0, and saturated NaHCO 3 The solution was washed twice, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4After drying, filtering, collecting the filtrate, using a rotary evaporator under a pressure of 42 kPa and a temperature of 35 ° C, the filtrate was decompressed and distilled to a solvent content of 0.6 wt% to obtain a viscous liquid crude product; the viscous liquid crude product was separated by a silica gel chromatography column (the silica gel used was 300 mesh silica gel, the eluent used was a mixed reagent prepared by petroleum ether and ethyl acetate in a volume ratio of 100:5, and the separation was performed under a pressure of 0.1 MPa), the eluate was collected, and the filtrate was decompressed and distilled to a solvent content of less than or equal to 0.6 wt% using a rotary evaporator under a pressure of 70 kPa and a temperature of 60 ° C to obtain a light yellow powder solid, which is compound A2, and the yield is 88%. The nuclear magnetic resonance data of the compound A2 are as follows:

[0080] 1 H NMR (500 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.60(t,J=8.3Hz,2H,ArH),7.54-7.47(m,1H,PhH),7.28-7 .14(m,4H,2ArH+2PhH),6.02(dd,J=11.8,8.7Hz,1H,OCH),5.39-5.26(m,2H,COCH 2 ),4.36(d,J=12.8Hz,1H,CH 2 N), 4.15(d, J=13.1Hz,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.3,9.4Hz,1H,OCCH 2 ),3.47-3.36(m,2H,CH+CH 2 N), 2.87(t, J=12.0Hz,1H,CH 2 N), 2.21(d, J=11.9Hz,1H,CH 2 ),2.12(d,J=12.2Hz,1H,CH 2 ),1.91(qd,J=12.4,3.2Hz,1H,CH 2 ),1.59(qd,J=12.4,3.3Hz,1H,CH 2 ).

[0081] The MICs of compound A2 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate were 0.1 μg / mL, 0.2 μg / mL and 0.2 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe oryzae and Botrytis cinerea were 0.1 μg / mL, 0.2 μg / mL and 0.2 μg / mL, respectively. 5015μg / mL and 10μg / mL respectively.

[0082] Example 3: Preparation of 2-(2-(difluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A3)

[0083]

[0084] 0.015 mol of compound II (X is Cl, (R 5 ) m 0.016 mol of 2-(difluoromethyl)-1H-benzimidazole (compound III) and 0.022 mol of potassium carbonate were mixed evenly in 22 mL of acetonitrile, and heated under reflux for 12.2 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled, and distilled using a rotary evaporator at a pressure of 58 kPa and a temperature of 76° C. to a solvent content of 0.9 wt %, to obtain a product mixture;

[0085] According to the mass ratio of the product mixture to water of 1:18, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to ethyl acetate of 1:1.5, ethyl acetate was added to the product mixture aqueous solution for extraction, and the extraction was performed 4 times in total, and the obtained extract phases were combined to obtain a combined extract phase; according to the volume ratio of the combined extract phase to a 1.2 mol / L HCl solution of 1:0.8, a 1.2 mol / L HCl solution was added to the combined extract phase for washing, and the washing was performed 3 times in total; then, the combined extract phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:0.9, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4After drying, filtering, collecting the filtrate, using a rotary evaporator under a pressure of 58 kPa and a temperature of 62 ° C, distilling under reduced pressure to a solvent content of 0.9 wt% to obtain a solid crude product; the solid crude product was mixed with ethyl acetate in a ratio of 1 g: 1 mL, and the resulting solution was separated by a silica gel chromatography column (the silica gel used was 400 mesh silica gel, and the eluent used was a mixed reagent prepared by a volume ratio of petroleum ether and ethyl acetate of 100: 100, and the separation was performed under a pressure of 1.3 MPa), collecting the eluate, and using a rotary evaporator under a pressure of 28 kPa and a temperature of 54 ° C. Distilling under reduced pressure to a solvent content of less than or equal to 0.9 wt%, a white powder solid was obtained, which is compound A3, and the yield is 91%. The nuclear magnetic resonance data of the compound A3 are as follows:

[0086] 1 HNMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.75(d,J=8.0Hz,1H,ArH),7.66(d,J=8.1Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.43-7.29(m,3H,CHF 2 +2ArH),7.17(t,J=8.6Hz,2H,PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.52-5.40(m,2H,COCH 2 ),4.35(d,J=12.9Hz,1H,CH 2 N), 4.12(d, J=14.0Hz,1H,CH 2 N),3.92(dd,J=17.3,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.4,8.6Hz,1H,OCCH 2 ),3.44(tt,J=11.4,3.7Hz,1H,CH),3.36(t,J=11.8Hz,1H,CH 2 N), 2.86(t, J=11.4Hz,1H,CH 2 N), 2.21(d, J=12.8Hz,1H,CH 2 ),2.11(d,J=12.0Hz,1H,CH 2 ),1.90(qd,J=12.4,2.6Hz,1H,CH 2 ),1.59(qd,J=11.8,3.5Hz,1H,CH 2 ).

[0087] The MIC of compound A3 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate was 0.1 μg / mL; the EC of compound A3 on the mycelial growth of Gibberella zeae and Magnaporthe oryzae was 50 Example 4: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A4)

[0088]

[0089] 0.025 mol of compound II (X is Cl, (R 5 ) m 0.026 mol of 2-(trifluoromethyl)-1H-benzimidazole (compound III) and 0.05 mol of cesium carbonate were mixed evenly in 40 mL of acetonitrile, and heated under reflux reaction for 20.41 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled, and distilled using a rotary evaporator at a pressure of 72 kPa and a temperature of 70° C. to a solvent content of 0.7 wt %, to obtain a product mixture;

[0090] According to the mass ratio of the product mixture to water of 1:25, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to chloroform of 1:1.2, chloroform was added to the product mixture aqueous solution for extraction, and the extraction was performed 3 times in total, and the obtained extract phases were combined to obtain a combined extraction phase; according to the volume ratio of the combined extraction phase to a 0.5 mol / L HCl solution of 1:1.5, a 0.5 mol / L HCl solution was added to the combined extraction phase for washing, and the washing was performed 3 times in total; then, the combined extraction phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:1.8, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4The mixture was dried, filtered, and the filtrate was collected. The mixture was distilled under reduced pressure using a rotary evaporator at a pressure of 70 kPa and a temperature of 50° C. until the solvent content was 0.5 wt % to obtain a solid crude product. A mixed reagent prepared by using petroleum ether and ethyl acetate in a volume ratio of 100:100 was used as a recrystallization reagent. The solid crude product was recrystallized in the recrystallization reagent at room temperature. The filter cake was then collected by filtration and dried in an oven at 74° C. until the solvent content was 0.3 wt % to obtain a white powdery solid, which was compound A4, with a yield of 80%. The nuclear magnetic resonance data of compound A4 are as follows:

[0091] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.83(d,J=8.1 Hz,1H,ArH),7.77(d,J=8.2Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.46(t,J=7.6 Hz,1H,ArH),7.38(t,J=8.0 Hz,1H,ArH),7.17(t,J=8.4 Hz,2H,PhH),6.02(dd,J=12.0,8.6 Hz,1H,OCH),5.58-5.46(m,2H,COCH 2 ),4.34(d,J=13.2Hz,1H,CH 2 N), 4.13(d, J=13.6 Hz, 1H, CH 2 N),3.92(dd,J=17.2,12.1 Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6 Hz,1H,OCCH 2 ),3.44(tt,J=11.3,3.97 Hz,1H,CH),3.36(t,J=12.6 Hz,1H,CH 2 N), 2.88(t, J=11.4 Hz, 1H, CH 2 N), 2.21(d, J=11.3 Hz, 1H, CH 2 ),2.11(d,J=12.4 Hz,1H,CH 2 ),1.88(qd,J=11.8,2.4Hz,1H,CH 2 ),1.56(qd,J=12.3,3.2 Hz,1H,CH 2 ).

[0092] The MICs of compound A4 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plates were 0.025 μg / mL, 0.008 μg / mL and 0.10 μg / mL, respectively; the EC for the mycelial growth of Colletotrichum granatum was 0.010 μg / mL. 50 The EC value for mycelial growth of rice blast fungus and rice sheath blight fungus was 7.6 μg / mL. 50 28μg / mL and 20μg / mL respectively.

[0093] Example 5: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-methoxy-2-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A5)

[0094]

[0095] 0.012 mol of compound II (X is Br, (R 5 ) m 0.013 mol of 6-methoxy-2-(trifluoromethyl)-1H-benzimidazole (compound III) and 0.02 mol of cesium carbonate were mixed evenly in 30 mL of tetrahydrofuran, and heated under reflux for 30.1 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled, and distilled using a rotary evaporator at a pressure of 52 kPa and a temperature of 60° C. to a solvent content of 0.5 wt %, to obtain a product mixture;

[0096] According to the mass ratio of the product mixture to water being 1:10, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to carbon tetrachloride being 1:3.0, carbon tetrachloride was added to the product mixture aqueous solution for extraction, and the extraction was performed 3 times in total, and the obtained extract phases were combined to obtain a combined extract phase; according to the volume ratio of the combined extract phase to a 0.1 mol / L HCl solution being 1:2.0, a 0.1 mol / L HCl solution was added to the combined extract phase for washing, and the washing was performed 3 times in total; then, the combined extract phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:2.0, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4After drying, filtering, collecting the filtrate, using a rotary evaporator under a pressure of 82 kPa and a temperature of 64 ° C, distilling under reduced pressure to a solvent content of 0.8 wt% to obtain a viscous liquid crude product; the viscous liquid crude product was separated by a silica gel chromatography column (the silica gel used was 100 mesh silica gel, the eluent used was a mixed reagent prepared by petroleum ether and ethyl acetate in a volume ratio of 100:2, and the separation was performed under a pressure of 3.9 MPa), collecting the eluate, using a rotary evaporator under a pressure of 82 kPa and a temperature of 72 ° C, distilling under reduced pressure to a solvent content of less than or equal to 0.8 wt%, to obtain a white powder solid, which is compound A5, with a yield of 78%. The nuclear magnetic resonance data of the compound A5 are as follows:

[0097] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.67(dd,J=15.5,8.9Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.30(dd,J=8.5,2.3Hz,1H,ArH),7.17(t,J=8.5Hz,2H, PhH),7.09(dd,J=9.0,2.3Hz,0.5H,ArH),6.99(dd,J=8.9,2.3Hz,0.5H,ArH),6.02(dd,J=12.1,8.6Hz,1H,OCH),5.54-5.41(m,2H,COCH 2 ),4.34(d,J=13.3Hz,1H,CH 2 N),4.12(br,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.82(d,J=5.2Hz,3H,OCH 3 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.48-3.32(m,2H,CH+CH 2 N), 2.88(br,1H,CH 2 N), 2.21(t, J=11.3Hz,1H,CH 2 ),2.11(d,J=13.2Hz,1H,CH 2 ),1.86(q,J=11.8,Hz,1H,CH 2 ),1.55(qd,J=12.2,3.5Hz,1H,CH 2 ).

[0098] The MICs of compound A5 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.5 μg / mL, 0.1 μg / mL and 1.0 μg / mL, respectively; the ECs for the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.1 μg / mL and 1.0 μg / mL, respectively. 50 It is 10~20μg / mL.

[0099] Example 6: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-fluoro-2-hydroxy-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A6)

[0100]

[0101] 0.1 mol of compound II (X is Cl, (R 5 ) m 2,6-difluoro-1,4-difluoro-2,4-difluoro-2,4-difluoro-1 ...

[0102] According to the mass ratio of the product mixture to water being 1:15, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to carbon tetrachloride being 1:1.9, carbon tetrachloride was added to the product mixture aqueous solution for extraction, and the extraction was performed 4 times in total, and the obtained extract phases were combined to obtain a combined extract phase; according to the volume ratio of the combined extract phase to a 1.0 mol / L HCl solution being 1:1.2, a 1.0 mol / L HCl solution was added to the combined extract phase for washing, and the washing was performed 3 times in total; then, the combined extract phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:1.5, and saturated NaHCO 3 The solution was washed twice, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4After drying, filtering, collecting the filtrate, using a rotary evaporator under a pressure of 0.1 kPa and a temperature of 30°C, distilling under reduced pressure to a solvent content of 0.9 wt% to obtain a liquid crude product; the liquid crude product was separated by a silica gel chromatography column (the silica gel used was 600 mesh silica gel, the eluent used was a mixed reagent prepared by petroleum ether and ethyl acetate in a volume ratio of 100:32, and the separation was performed under a pressure of 2.6 MPa), collecting the eluate, and using a rotary evaporator under a pressure of 0.1 kPa and a temperature of 30°C, distilling under reduced pressure to a solvent content of less than or equal to 0.9 wt%, to obtain a white powdery solid, which is compound A6, with a yield of 85%. The nuclear magnetic resonance data of the compound A6 are as follows:

[0103] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.33,11.26(s,s,1H,OH),8.04(s,1H,ThH),7.54-7.47(m,1H,PhH),7.35(t,J=8.8Hz,1H, ArH),7.25-7.15(m,4H,2ArH+2PhH),6.01(dd,J=12.0,8.7Hz,1H,OCH),4.93-4.78(m,2H,COCH 2 ),4.35(d,J=12.2Hz,1H,CH 2 N), 4.08(d, J=13.0Hz,1H,CH 2 N),3.91(dd,J=17.1,12.1Hz,1H,OCCH 2 ),3.54(dd,J=17.2,8.5Hz,1H,OCCH 2 ),3.40(tt,J=11.6,4.1Hz,1H,CH),3.31(t,J=12.1Hz,1H,CH 2 N), 2.83(t, J=12.0Hz,1H,CH 2 N),2.13(dd,J=27.6,12.8Hz,2H,CH 2 ),1.85(qd,J=12.2,3.0Hz,1H,CH 2 ),1.57(qd,J=12.5,3.6Hz,1H,CH 2 ).

[0104] The MICs of compound A6 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 5.0 μg / mL, 1.0 μg / mL and 5.0 μg / mL, respectively; the ECs for the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 1.0 μg / mL and 1.0 μg / mL, respectively. 50 It is 10~20μg / mL.

[0105] Example 7: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-hydroxy-6-(trifluoromethyl)-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A7)

[0106]

[0107] 0.13 mol of compound II (X is Cl, (R 5 ) m 0.14 mol of 2-hydroxy-6-(trifluoromethyl)-1H-benzimidazole (compound III) and 0.2 mol of potassium carbonate were mixed evenly in 150 mL of tetrahydrofuran, and heated under reflux for reaction for 8.0 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled, and distilled using a rotary evaporator at a pressure of 0.1 kPa and a temperature of 40° C. to a solvent content of 0.6 wt %, to obtain a product mixture;

[0108] According to the mass ratio of the product mixture to water being 1:50, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to diethyl ether being 1:0.1, diethyl ether was added to the product mixture aqueous solution for extraction, and the extraction was performed 4 times in total, and the obtained extract phases were combined to obtain a combined extract phase; according to the volume ratio of the combined extract phase to a 2.0 mol / L HCl solution being 1:0.5, a 2.0 mol / L HCl solution was added to the combined extract phase for washing, and the washing was performed 3 times in total; then, the combined extract phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:0.5, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4The filtrate was dried, filtered, and collected. The filtrate was distilled under reduced pressure using a rotary evaporator at a pressure of 45 kPa and a temperature of 30° C. until the solvent content was 0.7 wt % to obtain a solid crude product. A mixed reagent prepared by using petroleum ether and ethyl acetate in a volume ratio of 100:5 was used as a recrystallization reagent. The solid crude product was recrystallized in the recrystallization reagent at room temperature. The filter cake was then collected by filtration and dried in an oven at 30° C. until the solvent content was less than or equal to 0.1 wt % to obtain a white powdery solid, which was compound A7, with a yield of 86%. The nuclear magnetic resonance data of compound A7 are as follows:

[0109] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.03,10.90(s,s,1H,OH),8.04(s,1H,ThH),7.54-7.46(m,1H,PhH),7.19-6.75(m,5H,3ArH+2PhH),6.01(dd,J=12.0,8.7 Hz,1H,OCH),4.82-4.68(m,2H,COCH 2 ),4.36(d,J=12.6 Hz,1H,CH 2 N), 4.06(d, J=12.3 Hz, 1H, CH 2 N),3.91(dd,J=17.2,12.2 Hz,1H,OCCH 2 ),3.54(dd,J=17.3,8.6 Hz,1H,OCCH 2 ),3.40(tt,J=11.9,4.0 Hz,1H,CH),3.29(t,J=12.7 Hz,1H,CH 2 N), 2.82(t, J=12.2 Hz, 1H, CH 2 N),2.13(dd,J=24.1,12.7 Hz,2H,CH 2 ),1.85(q,J=12.2 Hz,1H,CH 2 ),1.63-1.51(m,1H,CH 2 ).

[0110] The MIC of compound A7 prepared in this example on the growth of mycelium of pepper phytophthora, infestans and downy mildew on the drug-containing culture medium plate was 1.0-5.0 μg / mL; the EC of compound A7 on the growth of wheat fusarium, rice blast, fruit and vegetable gray mold and strawberry anthracnose was 1.0-5.0 μg / mL. 50 It is 10~20μg / mL.

[0111] Example 8: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-methyl-1H-benzoimidazol-1-yl)ethan-1-one (abbreviated as Compound A8)

[0112]

[0113] 0.014 mol of compound II (X is Br, (R 5 ) m 0.015 mol of 2-methyl-1H-benzimidazole (compound III) and 0.019 mol of sodium hydride were mixed evenly in 35 mL of acetonitrile, and heated under reflux reaction for 9.9 hours under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled and distilled using a rotary evaporator at a pressure of 70 kPa and a temperature of 65° C. to a solvent content of 0.7 wt %, to obtain a product mixture;

[0114] According to the mass ratio of the product mixture to water of 1:26, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to ethyl acetate of 1:1.0, ethyl acetate was added to the product mixture aqueous solution for extraction, and the extraction was performed twice, and the obtained extract phases were combined to obtain a combined extraction phase; according to the volume ratio of the combined extraction phase to a 0.9 mol / L HCl solution of 1:1.0, 0.9 mol / L HCl solution was added to the combined extraction phase for washing, and the washing was performed three times; then, the combined extraction phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:0.8, and saturated NaHCO 3 The solution was washed 4 times in total, and then washed with distilled water in the same way until neutral, and the neutral combined extract was washed with anhydrous Na 2 SO 4After drying, filtering, collecting the filtrate, using a rotary evaporator at a pressure of 100 kPa and a temperature of 70°C, distilling under reduced pressure to a solvent content of 0.7 wt% to obtain a solid crude product; the solid crude product was mixed with ethyl acetate at a ratio of 1 g: 20 mL, and the resulting solution was separated by a silica gel chromatography column (the silica gel used was 500 mesh silica gel, and the eluent used was a mixed reagent prepared by petroleum ether and ethyl acetate at a volume ratio of 100: 70, and the separation was performed under a pressure of 5.0 MPa), collecting the eluate, and using a rotary evaporator at a pressure of 100 kPa and a temperature of 70°C, distilling under reduced pressure to a solvent content of less than or equal to 0.7 wt%, to obtain a light yellow powdery solid, which is compound A8, and the yield is 75%. The nuclear magnetic resonance data of the compound A8 are as follows:

[0115] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.54-7.41(m,3H,2ArH+1PhH),7.20-7.10(m,4H,2ArH+2PhH),6.02(dd,J=12.1,8.6Hz,1H,OCH),5.34-5.21(m,2H,OCCH 2 ),4.38(d,J=13.2Hz,1H,CH 2 N), 4.13(d, J=13.0Hz,1H,CH 2 N),3.92(dd,J=17.4,12.2Hz,1H,OCCH 2 ),3.55(dd,J=16.2,8.8Hz,1H,OCCH 2 ),3.43(tt,J=11.5,3.6Hz,1H,CH),3.38(t,J=12.1Hz,1H,CH 2 N), 2.86(t, J=12.2Hz,1H,CH 2 N), 2.41(s,3H,ArCH 3 ),2.21(d,J=12.6Hz,1H,CH 2 ),2.11(d,J=12.2Hz,1H,CH 2 ),1.92(qd,J=12.0,3.5Hz,1H,CH 2 ),1.59(qd,J=12.0,3.5Hz,1H,CH 2 ).

[0116] The MICs of compound A8 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plates were 0.02 μg / mL, 0.01 μg / mL and 0.5 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe oryzae and Sheath blight of rice were 0.01 μg / mL, 0.01 μg / mL and 0.5 μg / mL, respectively. 50 40μg / mL and 35μg / mL respectively.

[0117] Example 9: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethyl-1H-benzoimidazol-1-yl)ethan-1-one (abbreviated as Compound A9)

[0118]

[0119] 0.05 mol of compound II (X is Cl, (R 5 ) m 0.054 mol of 2-ethyl-1H-benzimidazole (III) and 0.08 mol of potassium carbonate were mixed evenly in 65 mL of acetonitrile, and heated under reflux for 24.0 h under stirring conditions using a heating reflux device; after the reaction, the obtained product system was cooled, and distilled using a rotary evaporator at a pressure of 44 kPa and a temperature of 72° C. to a solvent content of 0.8 wt %, to obtain a product mixture;

[0120] According to the mass ratio of the product mixture to water being 1:30, water was added to the product mixture to obtain a product mixture aqueous solution; according to the volume ratio of the product mixture aqueous solution to ethyl acetate being 1:0.5, ethyl acetate was added to the product mixture aqueous solution for extraction, and the extraction was performed 3 times in total, and the obtained extract phases were combined to obtain a combined extract phase; according to the volume ratio of the combined extract phase to a 0.5 mol / L HCl solution being 1:1.5, a 0.5 mol / L HCl solution was added to the combined extract phase for washing, and the washing was performed 3 times in total; then, the combined extract phase was mixed with saturated NaHCO 3 The volume ratio of the solution was 1:1.5, and saturated NaHCO 3 The solution was washed for 3 times, and then washed with distilled water in the same way until neutral. The neutral combined extract was washed with anhydrous Na 2 SO 4The filtrate was dried, filtered, and collected. The filtrate was distilled under reduced pressure using a rotary evaporator at a pressure of 100 kPa and a temperature of 40° C. until the solvent content was 0.6 wt % to obtain a solid crude product. A mixed reagent prepared by using petroleum ether and ethyl acetate in a volume ratio of 100:50 was used as a recrystallization reagent. The solid crude product was recrystallized in the recrystallization reagent at room temperature. The filter cake was then collected by filtration and dried in an oven at 100° C. until the solvent content was less than or equal to 0.3 wt % to obtain a light yellow powdery solid, which was compound A9, with a yield of 78%. The nuclear magnetic resonance data of compound A9 are as follows:

[0121] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.57-7.40(m,3H,2ArH+1PhH),7.19-7.11(m,4H,2ArH+2PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.34-5.21(m,2H,OCCH 2 ),4.37(d,J=13.1Hz,1H,CH 2 N), 4.14(d, J=13.5Hz,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.46-3.32(m,2H,CH+CH 2 N), 2.85(t, J=12.2Hz,1H,CH 2 N), 2.74(q, J = 7.5 Hz, 2H, ArCH 2 ),2.20(d,J=13.5Hz,1H,CH 2 ),2.11(d,J=12.6Hz,1H,CH 2 ),1.91(qd,J=12.0,3.4Hz,1H,CH 2 ),1.60(qd,J=12.0,3.4Hz,1H,CH 2 ),1.30(t,J=7.4Hz,3H,CH 3 ).

[0122] The MICs of compound A9 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plates were 0.1 μg / mL, 0.08 μg / mL and 0.5 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe oryzae and Sheath blight of rice were50 42μg / mL and 23μg / mL respectively.

[0123] Example 10: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(methylthio)-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A10)

[0124]

[0125] The method of Example 6 was used, except that the compound III used in this example was 2-(methylthio)-1H-benzimidazole; the final prepared compound A10 was a light yellow powdery solid with a yield of 83%. The NMR data of the compound A10 are as follows:

[0126] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.56-7.41m,3H,2ArH+1PhH),7.19-7.13(m,4H,2ArH+2PhH),6.01(dd,J=12.0,8.6Hz,1H,OCH),5.25-5.19(m,2H,OCCH 2 ),4.36(d,J=13.6Hz,1H,CH 2 N), 4.14(d, J=13.6Hz,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.2,8.6Hz,1H,OCCH 2 ),3.46-3.31(m,2H,CH+CH 2 N), 2.86(t, J=12.2Hz,1H,CH 2 N), 2.68(s,3H,SCH 3 ),2.19(d,J=13.3Hz,1H,CH 2 ),2.11(d,J=12.9Hz,1H,CH 2 ),1.88(qd,J=12.7,2.3Hz,1H,CH 2 ),1.58(qd,J=12.7,4.6Hz,1H,CH 2 ).

[0127] The MICs of compound A10 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.02 μg / mL, 0.01 μg / mL and 0.5 μg / mL, respectively, and the EC values ​​for the mycelial growth of Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.01 μg / mL and 0.5 μg / mL, respectively. 50 It is 10~20μg / mL.

[0128] Example 11: Preparation of 2-(2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A11)

[0129]

[0130] The method of Example 5 was used, except that the compound III used in this example was 2-chloro-6-(trifluoromethyl)-1H-benzimidazole; the final prepared compound A11 was a white powdery solid with a yield of 78%. The NMR data of the compound A11 are as follows:

[0131] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.17,8.16(s+s,1H,ArH),8.05(s,1H,ThH),7.83(t,J=8.5Hz,1H,ArH),7.65,7.58(d+d,J=8.6,8.6Hz,1H,Ar H),7.54-7.47(m,1H,PhH),7.17(t,J=8.5Hz,2H,PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.55-5.40(m,2H,OCCH 2 ),4.35(d,J=12.8Hz,1H,CH 2 N), 4.10(br,1H,CH 2 N),3.91(dd,J=17.2,12.3Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.46-3.37(m,2H,CH+CH 2 N), 2.89(t, J=12.9Hz,1H,CH 2 N), 2.22(d, J=9.9Hz,1H,CH 2 ),2.12(d,J=13.2Hz,1H,CH 2),1.93(qd,J=11.8,3.5Hz,1H,CH 2 ),1.59(qd,J=12.0,3.5Hz,1H,CH 2 ).

[0132] The MICs of compound A11 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.02 μg / mL, 0.01 μg / mL and 0.5 μg / mL, respectively; the ECs for the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.01 μg / mL and 0.5 μg / mL, respectively. 50 It is 10~20μg / mL.

[0133] Example 12: Preparation of 2-(2-chloro-6-fluoro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A12)

[0134]

[0135] The method of Example 1 was used, except that the compound III used in this example was 2-chloro-6-fluoro-1H-benzimidazole; the final prepared compound A12 was a white powdery solid with a yield of 82%. The NMR data of the compound A12 are as follows:

[0136] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.64-7.44(m,3H,2ArH+1PhH),7.20-7.07(m,3H,1ArH+2PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.44-5.27(m,2H,OCCH 2 ),4.35(d,J=12.5Hz,1H,CH 2 N), 4.09(br,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.47-3.35(m,2H,CH+CH 2 N), 2.87(t, J=12.3Hz,1H,CH 2 N), 2.20(d, J=9.5Hz,1H,CH 2),2.11(d,J=12.1Hz,1H,CH 2 ),1.98-1.86(m,1H,CH 2 ),1.64-1.54(m,1H,CH 2 ).

[0137] The MICs of compound A12 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate were 0.005 μg / mL, 0.005 μg / mL and 0.025 μg / mL, respectively; the EC values ​​for the mycelial growth of Pythium aphanidermatum, Magnaporthe oryzae and Sheath blight of rice were 0.01 μg / mL, 0.02 μg / mL and 0.03 μg / mL, respectively. 50 The EC value for the mycelial growth of fruit and vegetable gray mold, grape anthracnose and wheat fusarium is 5-10 μg / mL. 50 They were 6.5μg / mL, 12.2μg / mL and 10.4μg / mL respectively.

[0138] Example 13: Preparation of 2-(5-bromo-2-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A13)

[0139]

[0140] The method of Example 9 was used, except that the compound III used in this example was 5-bromo-2-chloro-1H-benzimidazole; the final prepared compound A13 was a white powdery solid with a yield of 75%. The NMR data of the compound A13 are as follows:

[0141] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(d,J=1.4Hz,1H,ThH),7.97,7.83(d+d,J=1.7,1.8Hz,1H,ArH),7.61-7.38(m,3H,2Ar H+1PhH),7.17(t,J=8.5Hz,2H,PhH),6.01(dd,J=12.0,8.5Hz,1H,OCH),5.45-5.31(m,2H,OCCH 2 ),4.35(d,J=12.1Hz,1H,CH 2 N), 4.08(br,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.1,8.6Hz,1H,OCCH2 ),3.46-3.32(m,2H,CH+CH 2 N), 2.87(t, J=12.7Hz,1H,CH 2 N), 2.20(d, J=10.9Hz,1H,CH 2 ),2.11(d,J=12.4Hz,1H,CH 2 ),1.98-1.86(m,1H,CH 2 ),1.65-1.53(m,1H,CH 2 ).

[0142] The MICs of compound A13 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate were 0.1 μg / mL, 0.1 μg / mL and 0.5 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe oryzae and Sheath blight of rice were 50 Both are 10μg / mL.

[0143] Example 14: Preparation of 2-(2-chloro-5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A14)

[0144]

[0145] The method of Example 6 was used, except that the compound III used in this example was 2-chloro-5-methoxy-1H-benzimidazole; the final prepared compound A14 was a yellow powdery solid with a yield of 73%. The NMR data of the compound A14 are as follows:

[0146] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.54-7.45(m,2H,1ArH+1PhH),7.19-7.14(m,3H,1ArH+2PhH) ,6.92-6.83(m,1H,ArH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.38-5.24(m,2H,OCCH 2 ),4.36(d,J=10.3Hz,1H,CH 2 N), 4.11(d, J=10.8Hz,1H,CH 2 N),3.91(dd,J=17.3,12.1Hz,1H,OCCH 2),3.79(d,J=3.4Hz,3H,OCH 3 ),3.55(dd,J=17.4,8.6Hz,1H,OCCH 2 ),3.47-3.31(m,2H,CH+CH 2 N), 2.90-2.83(m,1H,CH 2 N), 2.20(br,1H,CH 2 ),2.11(d,J=12.5Hz,1H,CH 2 ),1.90(q,J=11.4Hz,1H,CH 2 ),1.58(q,J=12.1Hz,1H,CH 2 ).

[0147] The MIC of compound A14 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate was 0.5-2.0 μg / mL; the EC of compound A14 on the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. was 0.5-2.0 μg / mL. 50 15~35μg / mL.

[0148] Example 15: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-fluoro-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A15)

[0149]

[0150] The method of Example 9 was used, except that the compound III used in this example was 5-fluoro-1H-benzimidazole; the final prepared compound A15 was a yellow powdery solid with a yield of 75%. The NMR data of the compound A15 are as follows:

[0151] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.18,8.13(s+s,1H,ArH),8.04(d,J=0.7Hz,1H,ThH),7.66-7.43(m,3H,2ArH+1PhH),7.17(t,J =8.5Hz,2H,PhH),7.14-7.01(m,1H,ArH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.41-5.27(m,2H,OCCH 2 ),4.38(d,J=13.2Hz,1H,CH 2N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.46-3.29(m,2H,CH+CH 2 N), 2.85(t, J=12.0Hz,1H,CH 2 N), 2.18(d, J=12.5Hz,1H,CH 2 ),2.10(d,J=12.1Hz,1H,CH 2 ),1.95-1.84(m,1H,CH 2 ),1.66-1.54(m,1H,CH 2 ).

[0152] The MICs of compound A15 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.1 μg / mL, 0.1 μg / mL and 0.2 μg / mL, respectively; the ECs for the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.1 μg / mL, 0.1 μg / mL and 0.2 μg / mL, respectively; 50 It is 19~39μg / mL.

[0153] Example 16: Preparation of 2-(5-chloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A16)

[0154]

[0155] The method of Example 6 was used, except that the compound III used in this example was 5-chloro-1H-benzimidazole; the final prepared compound A16 was a yellow powdery solid with a yield of 85%. The NMR data of the compound A16 are as follows:

[0156] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.23,8.21(s+s,1H,ArH),8.04(d,J=1.3Hz,1H,ThH),7.74-7.44(m,3H,2ArH+1PhH), 7.29-7.15(m,3H,1ArH+2PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.43-5.31(m,2H,OCCH 2),4.38(d,J=13.0Hz,1H,CH 2 N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.46-3.29(m,2H,CH+CH 2 N), 2.85(t, J=12.7Hz,1H,CH 2 N), 2.18(d, J=12.5Hz,1H,CH 2 ),2.10(d,J=12.9Hz,1H,CH 2 ),1.96-1.85(m,1H,CH 2 ),1.67-1.54(m,1H,CH 2 ).

[0157] The MICs of compound A16 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora personiae on the drug-containing culture medium plates were 0.5 μg / mL, 0.2 μg / mL and 2.5 μg / mL, respectively; the ECs for the mycelial growth of Gibberella fusca, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.1 μg / mL, 0.2 μg / mL and 2.5 μg / mL, respectively. 50 20~30μg / mL.

[0158] Example 17: Preparation of 2-(5-bromo-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A17)

[0159]

[0160] The method of Example 9 was used, except that the compound III used in this example was 5-bromo-1H-benzimidazole; the final prepared compound A17 was a yellow powdery solid with a yield of 77%. The compound NMR data of the compound A17 are as follows:

[0161] 1 H NMR (400 MHz, DMSO-d 6)δ:8.18,8.15(s+s,1H,ArH),8.04(d,J=1.4Hz,1H,ThH),7.85(dd,J=5.5,1.8Hz,1H,ArH),7.61-7.31(m ,3H,2ArH+1PhH),7.17(t,J=8.5Hz,2H,PhH),,6.02(dd,J=12.0,8.5Hz,1H,OCH),5.42-5.31(m,2H,OCCH 2 ),4.38(d,J=12.8Hz,1H,CH 2 N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.2,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.46-3.29(m,2H,CH+CH 2 N), 2.85(t, J=12.8Hz,1H,CH 2 N), 2.18(d, J=13.6Hz,1H,CH 2 ),2.10(d,J=13.2Hz,1H,CH 2 ),2.01-1.84(m,1H,CH 2 ),1.66-1.50(m,1H,CH 2 ).

[0162] The MICs of compound A17 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.5 μg / mL, 0.2 μg / mL and 1.0 μg / mL, respectively; the ECs for the mycelial growth of Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea and Colletotrichum spp. were 0.1 μg / mL, 0.2 μg / mL and 1.0 μg / mL, respectively. 50 It is 15~39μg / mL.

[0163] Example 18: Preparation of 2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A18)

[0164]

[0165] The method of Example 6 was used, except that the compound III used in this example was 6-bromo-2-methyl-1H-benzimidazole; the final prepared compound A18 was a yellow powdery solid with a yield of 82%. The NMR data of the compound A18 are as follows:

[0166] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(d,J=1.4Hz,1H,ThH),7.78(d,J=1.6Hz,0.5H,ArH),+7.69(d,J=1.8Hz,0.5H,ArH),7.54-7.44(m,2H,1ArH+ 1PhH),7.31-7.24(m,1H,ArH),7.17(t,J=8.5Hz,2H,PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.37-5.24(m,2H,OCCH 2 ),4.37(d,J=12.4Hz,1H,CH 2 N), 4.08(t, J=11.6Hz,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.2,8.6Hz,1H,OCCH 2 ),3.46-3.31(m,2H,CH+CH 2 N), 2.86(t, J=12.8Hz,1H,CH 2 N), 2.40(d, J=7.2Hz, 3H, ArCH 3 ),2.20(d,J=13.7Hz,1H,CH 2 ),2.11(d,J=12.5Hz,1H,CH 2 ),2.01-1.87(m,1H,CH 2 ),1.66-1.54(m,1H,CH 2 ).

[0167] The MIC of compound A18 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 1.0-10.0 μg / mL; the EC of compound A18 on the mycelial growth of Colletotrichum spp. and Gibberella spp. was 1.0-10.0 μg / mL. 50 Both are 10μg / mL.

[0168] Example 19: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethoxy-1H-benzoimidazol-1-yl)-ethan-1-one (abbreviated as Compound A19)

[0169]

[0170] The method of Example 6 was used, except that the compound III used in this example was 2-ethoxy-1H-benzimidazole; the final prepared compound A19 was a yellow solid with a yield of 79%. The NMR data of the compound A19 are as follows:

[0171] 1 HNMR (400 MHz, DMSO-d 6 )δ:8.04(s,1H,ThH),7.54-7.47(m,1H,PhH),7.40-7.36(m,1H,ArH),7.30-7.26(m,1H,ArH),7.17(t ,J=8.5Hz,2H,PhH),7.09-7.02(m,2H,ArH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.08-4.93(m,2H,OCCH 2 ),4.50(q,J=7.0Hz,2H,OCH 2 ),4.36(d,J=13.0Hz,1H,CH 2 N), 4.09(d, J=13.6Hz,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.54(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.41(tt,J=11.4,3.6Hz,1H,CH),3.32(t,J=11.9Hz,1H,CH 2 N), 2.84(t, J=12.0Hz,1H,CH 2 N), 2.16(d, J=12.9Hz,1H,CH 2 ),2.09(d,J=11.1Hz,1H,CH 2 ),1.89-1.79(m,1H,CH 2 ),1.62-1.51(m,1H,CH 2 ),1.36(t,J=7.1Hz,3H,CH 3 ).

[0172] The MIC of compound A19 prepared in this example for the growth of mycelia of pepper Phytophthora on the drug-containing medium plate was 1.5 μg / mL, and the MIC for the growth of mycelia of Phytophthora infestans and Phytophthora persicae was less than 0.1 μg / mL; the EC for the growth of mycelia of rice blast fungus and rice sheath blight fungus was 2.1 μg / mL. 50 Less than 10μg / mL.

[0173] Example 20: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-1H-benzoimidazol-1-yl)-ethan-1-one (abbreviated as Compound A20)

[0174]

[0175] The method of Example 9 was used, except that the compound III used in this example was 5-methyl-1H-benzimidazole; the final prepared compound A20 was a yellow powdery solid with a yield of 79%. The NMR data of the compound A20 are as follows:

[0176] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.04,8.03(s+s,2H,ThH+ArH),7.54-7.29(m,3H,2ArH+1PhH),7.17(t,J=8.5Hz,2H,PhH) ,7.02(dd,J=15.4,8.6Hz,1H,ArH),6.01(dd,J=12.0,8.6Hz,1H,OCH),5.35-5.23(m,2H,OCCH 2 ),4.39(d,J=12.9Hz,1H,CH 2 N), 4.09(d, J=13.2Hz,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.5Hz,1H,OCCH 2 ),3.46-3.29(m,2H,CH+CH 2 N), 2.84(t, J=12.4Hz,1H,CH 2 N), 2.41(d, J=4.1Hz,3H,ArCH 3 ),2.17(d,J=12.9Hz,1H,CH 2 ),2.09(d,J=12.9Hz,1H,CH 2 ),1.93-1.82(m,1H,CH 2 ),1.65-1.54(m,1H,CH 2 ).

[0177] The MIC of compound A20 prepared in this example on the mycelial growth of Phytophthora capsici on the drug-containing medium plate was 2.5 μg / mL, and the MIC of compound A20 on the mycelial growth of Phytophthora infestans and Phytophthora personiae was 1.0-5.0 μg / mL; the MIC of compound A20 on the mycelial growth of Pyricularia oryzae and Sheath blight was 2.5 μg / mL, and the MIC of compound A20 on the mycelial growth of Pyricularia oryzae and Sheath blight was 1.0-5.0 μg / mL. 50 Less than 10μg / mL.

[0178] Example 21: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5,6-dimethyl-1H-benzoimidazol-1-yl)-ethan-1-one (abbreviated as Compound A21)

[0179]

[0180] The method of Example 9 was used, except that the compound III used in this example was 5,6-dimethyl-1H-benzimidazole; the final prepared compound A21 was a yellow solid with a yield of 71%. The nuclear magnetic resonance data of the compound A21 are as follows:

[0181] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.04(s,1H,ThH),7.96(s,1H,ArH),7.54-7.46(m,1H,APhH),7.40(s,1H,ArH),7.25(s,1 H, ArH),7.17(t,J=8.5Hz,2H,PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.32-5.20(m,2H,OCCH 2 ),4.38(d,J=13.3Hz,1H,CH 2 N), 4.09(d, J=13.7Hz,1H,CH 2 N),3.91(dd,J=17.2,12.2Hz,1H,OCCH 2 ),3.54(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.42(tt,J=11.4,3.6Hz,1H,CH),3.36-3.29(m,1H,CH 2 N), 2.84(t, J=12.0Hz,1H,CH 2 N), 2.31(s,3H,ArCH 3 ),2.30(s,3H,ArCH 3 ),2.17(d,J=12.6Hz,1H,CH 2),2.09(d,J=13.1Hz,1H,CH 2 ),1.91-1.83(m,1H,CH 2 ),1.59(qd,J=12.2,3.6Hz,1H,CH 2 ).

[0182] The MIC of compound A21 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 0.1-2.0 μg / mL; the EC of compound A21 on the mycelial growth of Pyricularia oryzae and Sheath blight was 50 Less than 10μg / mL.

[0183] Example 22: Preparation of 2-(6-chloro-4-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A22)

[0184]

[0185] The method of Example 9 was used, except that the compound III used in this example was 6-chloro-4-methyl-1H-benzimidazole; the final prepared compound A22 was a yellow solid with a yield of 72%. The NMR data of the compound A22 are as follows:

[0186] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.11(s,1H,ArH),8.05(s,1H,ThH),7.54-7.47(m,2H,1ArH+1PhH),7.17(t,J=8.5H z,2H,PhH),7.05(s,1H,ArH),6.02(dd,J=12.0,8.5Hz,1H,OCH),5.38-5.27(m,2H,OCCH 2 ),4.38(d,J=12.7Hz,1H,CH 2 N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.4,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.4,8.6Hz,1H,OCCH 2 ),3.46-3.28(m,2H,CH+CH 2 N), 2.85(t, J=12.3Hz,1H,CH 2 N), 2.53(s,3H,ArCH3 ),2.19(d,J=14.1Hz,1H,CH 2 ),2.10(d,J=12.0Hz,1H,CH 2 ),1.96-1.86(m,1H,CH 2 ),1.61(qd,J=11.7,2.6Hz,1H,CH 2 ).

[0187] The MIC of compound A22 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 0.5-10.0 μg / mL; the EC of compound A22 on the mycelial growth of Pyricularia oryzae was 50 It is 10μg / mL.

[0188] Example 23: Preparation of 2-(5,6-dichloro-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-ethan-1-one (abbreviated as Compound A23)

[0189]

[0190] The method of Example 6 was used, except that the compound III used in this example was 5,6-dichloro-1H-benzimidazole; the final prepared compound A23 was a yellow solid with a yield of 78%. The NMR data of the compound A23 are as follows:

[0191] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.25(s,1H,ArH),8.05(s,1H,ThH),7.98(s,1H,ArH),7.94(s,1H,ArH),7.54-7.47(m,1H ,PhH),7.17(t,J=8.5Hz,2H,PhH),6.01(dd,J=12.0,8.5Hz,1H,OCH),5.42-5.32(m,2H,OCCH 2 ),4.38(d,J=12.9Hz,1H,CH 2 N), 4.04(br,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2 ),3.43(tt,J=11.4,3.8Hz,1H,CH),2.32(t,J=11.6Hz,1H,CH2 N), 2.85(t, J=12.3Hz,1H,CH 2 N), 2.19(d, J=12.9Hz,1H,CH 2 ),2.11(d,J=14.3Hz,1H,CH 2 ),1.98-1.88(m,1H,CH 2 ),1.62(qd,J=11.9,3.4Hz,1H,CH 2 ).

[0192] The MIC of compound A23 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 0.5-10.0 μg / mL; the EC of compound A23 on the mycelial growth of Pyricularia oryzae was 50 Less than 10μg / mL.

[0193] Example 24: Preparation of 2-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-ethan-1-one (abbreviated as Compound A24)

[0194]

[0195] The method of Example 6 was used, except that the compound III used in this example was 5,6-dichloro-2-methyl-1H-benzimidazole; the final prepared compound A24 was a yellow solid with a yield of 83%. The NMR data of the compound A24 are as follows:

[0196] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.90(s,1H,ArH),7.78(s,1H,ArH),7.54-7.47(m,1H,PhH),7 .17(t,J=8.5Hz,2H,PhH),6.01(dd,J=12.0,8.5Hz,1H,OCH),5.38-5.26(m,2H,OCCH 2 ),4.37(d,J=13.3Hz,1H,CH 2 N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.1,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.3,8.6Hz,1H,OCCH 2),3.46-3.30(m,2H,CH+CH 2 N), 2.86(t, J=12.0Hz,1H,CH 2 N), 2.41(s,3H,ArCH 3 ),2.20(d,J=12.3Hz,1H,CH 2 ),2.11(d,J=12.0Hz,1H,CH 2 ),1.99-1.90(m,1H,CH 2 ),1.61(qd,J=11.8,3.6Hz,1H,CH 2 ).

[0197] The MIC of compound A24 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 0.5-10.0 μg / mL; the EC of compound A24 on the mycelial growth of Pyricularia oryzae was 50 Less than 10μg / mL.

[0198] Example 25: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-nitro-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A25)

[0199]

[0200] The method of Example 9 was used, except that the compound III used in this example was 5-nitro-1H-benzimidazole; the final prepared compound A25 was a yellow powdery solid with a yield of 82%. The NMR data of the compound A25 are as follows:

[0201] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.68,8.56(d+d,J=2.1,2.1Hz,1H,ArH),8.49,8.44(s+s,1H,ArH),8.20-8.10(m,1H,ThH),8.05(s,1H,ArH),7.85,7.78(d+d,J =8.9,9.0Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.17(t,J=8.5Hz,2H,PhH),6.02(dd,J=12.0,8.6Hz,1H,OCH),5.59-5.43(m,2H,OCCH 2 ),4.38(d,J=12.8Hz,1H,CH 2N), 4.06(d, J=13.7Hz,,1H,CH 2 N),3.91(dd,J=17.3,12.2Hz,1H,OCCH 2 ),3.55(dd,J=17.4,8.5Hz,1H,OCCH 2 ),3.47-3.31(m,2H,CH+CH 2 N), 2.87(t, J=13.1Hz,1H,CH 2 N), 2.20(d, J=12.4Hz,1H,CH 2 ),2.11(d,J=11.7Hz,1H,CH 2 ),2.01-1.88(m,1H,CH 2 ),1.67-1.57(m,1H,CH 2 ).

[0202] The MIC of compound A25 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 1.0-20.0 μg / mL; the EC of compound A25 on the mycelial growth of Pyricularia oryzae was 50 Less than 10μg / mL.

[0203] Example 26: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-(trifluoromethoxy)-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A26)

[0204]

[0205] The method of Example 9 was used, except that the compound III used in this example was 5-(trifluoromethoxy)-1H-benzimidazole; the final prepared compound A26 was a yellow powdery solid with a yield of 76%. The NMR data of the compound A26 are as follows:

[0206] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.26,8.24(s+s,1H,ArH),8.05(s,1H,ThH),7.75-7.62(m,2H,ArH),7.54-7.47(m,1H,Ph H),7.26-7.15(m,3H,1ArH+2PhH),6.02(dd,J=12.0,8.5Hz,1H,OCH),5.45-5.34(m,2H,OCCH 2),4.38(d,J=13.0Hz,1H,CH 2 N), 4.06(br,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.2,8.6Hz,1H,OCCH 2 ),3.47-3.30(m,2H,CH+CH 2 N), 2.85(t, J=12.2Hz,1H,CH 2 N), 2.19(d, J=11.9Hz,1H,CH 2 ),2.10(d,J=12.5Hz,1H,CH 2 ),1.96-1.85(m,1H,CH 2 ),1.60(qd,J=12.2,3.3Hz,1H,CH 2 ).

[0207] The MIC of compound A26 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 1.0-10.0 μg / mL; the EC of compound A26 on the mycelial growth of Pyricularia oryzae was 50 It is 7.5μg / mL.

[0208] Example 27: Preparation of 2-(5-methoxy-1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A27)

[0209]

[0210] The method of Example 9 was used, except that the compound III used in this example was 5-methoxy-1H-benzimidazole; the final prepared compound A27 was a yellow powdery solid with a yield of 83%. The NMR data of the compound A27 are as follows:

[0211] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.08,8.01(s+s,1H,ArH),8.04(s,1H,ThH),7.54-7.38(m,2H,ArH),7.19-7.08(m,3H ,ArH),6.88-6.80(m,1H,ArH),6.02(dd,J=11.9,8.7Hz,1H,OCH),5.35-5.24(m,2H,OCCH2 ),4.39(d,J=11.4Hz,1H,CH 2 N), 4.09(d, J=11.3Hz,1H,CH 2 N),3.91(dd,J=17.3,12.3Hz,1H,OCCH 2 ),3.78(s,3H,OCH 3 ),3.54(dd,J=17.2,12.2Hz,1H,OCCH 2 ),3.48-3.36(m,2H,CH+CH 2 N), 2.85(t, J=12.5Hz,1H,CH 2 N), 2.21-2.08 (br, 2H, CH 2 ),1.93-1.83(m,1H,CH 2 ),1.65-1.54(m,1H,CH 2 ).

[0212] The MIC of compound A27 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Phytophthora persicae on the drug-containing culture medium plate was 1.0-10.0 μg / mL; the EC of compound A27 on the mycelial growth of Pyricularia oryzae was 50 Less than 10μg / mL.

[0213] Example 28: Preparation of 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-fluoro-1H-benzimidazol-1-yl)ethan-1-one (abbreviated as Compound A28)

[0214]

[0215] The method of Example 9 was used, except that the compound III used in this example was 2-fluoro-1H-benzimidazole; the final prepared compound A28 was a light yellow powdery solid with a yield of 88%. The NMR data of the compound A28 are as follows:

[0216] 1 H NMR (400 MHz, DMSO-d 6)δ:8.05(s,1H,ThH),7.62(d,J=8.0Hz,1H,ArH),7.59(d,J=7.9Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.2 8-7.21(m,2H,PhH),7.17(t,J=8.5Hz,2H,ArH),6.01(dd,J=12.0,8.7Hz,1H,OCH),5.44-5.32(m,2H,COCH 2 ),4.36(d,J=12.8Hz,1H,CH 2 N), 4.13(d, J=13.1Hz,1H,CH 2 N),3.91(dd,J=17.3,12.1Hz,1H,OCCH 2 ),3.54(dd,J=17.2,8.9Hz,1H,OCCH 2 ),3.46-3.34(m,2H,CH+CH 2 N), 2.87(t, J=12.1Hz,1H,CH 2 N), 2.20(d, J=12.3Hz,1H,CH 2 ),2.11(d,J=12.3Hz,1H,CH 2 ),1.91(qd,J=12.3,4.0Hz,1H,CH 2 ),1.58(qd,J=11.3,4.1Hz,1H,CH 2 ).

[0217] The MICs of compound A28 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora were 0.008 μg / mL, 0.005 μg / mL and 0.08 μg / mL respectively on the drug-containing culture medium plate; the ECs of compound A28 on the mycelial growth of Pyricularia oryzae, Botrytis cinerea and Sclerotinia sclerotiorum were 0.01 μg / mL, 0.02 μg / mL and 0.08 μg / mL respectively. 50 It is 10.5~17.5μg / mL.

[0218] Example 29: Preparation of 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carboxylic acid methyl ester (abbreviated as Compound A29)

[0219]

[0220] The method of Example 9 was used, except that the compound III used in this example was 1H-benzimidazole-2-carboxylic acid methyl ester; the final prepared compound A29 was a light yellow powdery solid with a yield of 85%. The NMR data of the compound A29 are as follows:

[0221] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H,ThH),7.54-7.47(m,1H,ArH),7.38-7.34(m,1H,ArH),7.29-7.24(m,1H,ArH),7.17(t ,J=8.5Hz,2H,ArH),7.15-7.36(m,2H,ArH),6.01(dd,J=12.1,8.6Hz,1H,OCH),5.09-4.91(m,2H,OCCH 2 ),4.38(d,J=13.1Hz,1H,CH 2 N), 4.08(d, J=13.2Hz,1H,CH 2 N), 3.98(s,3H,OCH 3 ),3.91(dd,J=17.1,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.1,8.6Hz,1H,OCCH 2 ),3.45-3.34(m,2H,CH+CH 2 N), 2.84(t, J=12.3Hz,1H,CH 2 N), 2.17(d, J=12.5Hz,1H,CH 2 ),2.10(d,J=11.6Hz,1H,CH 2 ),1.80-1.71(m,1H,CH 2 ),1.60-1.49(m,1H,CH 2 ).

[0222] The MICs of compound A29 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plates were 0.1 μg / mL, 0.05 μg / mL and 1.0 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe oryzae and Botrytis cinerea were 0.1 μg / mL, 0.05 μg / mL and 1.0 μg / mL, respectively. 50 They are 1.25μg / mL and 0.5μg / mL respectively.

[0223] Example 30: Preparation of 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazole-2-carbamic acid methyl ester (abbreviated as Compound A30)

[0224]

[0225] The method of Example 9 was used, except that the compound III used in this example was 1H-benzimidazole-2-carbamic acid methyl ester; the final prepared compound A30 was a light yellow powdery solid with a yield of 89%. The NMR data of the compound A30 are as follows:

[0226] 1 H NMR (400 MHz, DMSO-d 6 )δ:12.68(s,1H,NH),8.04(s,1H,ThH),7.54-7.47(m,1H,ArH),7.45-7.39(m,1H,ArH),7.35-7.28(m,1H,ArH) ,7.17(t,J=8.5Hz,2H,ArH),7.06-7.26(m,2H,ArH),6.02(dd,J=12.1,8.6Hz,1H,OCH),5.07-4.92(m,2H,OCCH 2 ),4.36(d,J=12.3Hz,1H,CH 2 N), 4.09(d, J=13.5Hz,1H,CH 2 N),3.91(dd,J=17.3,12.1Hz,1H,OCCH 2 ),3.86(s,3H,OCH 3 ),3.54(dd,J=17.2,8.6Hz,1H,OCCH 2 ),3.48-3.35(m,2H,CH+CH 2 N), 2.84(t, J=12.2Hz,1H,CH 2 N), 2.17(d, J=12.2Hz,1H,CH 2 ),2.10(d,J=11.6Hz,1H,CH 2 ),1.85-1.74(m,1H,CH 2 ),1.62-1.52(m,1H,CH 2 ).

[0227] The MICs of compound A30 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora were 0.008 μg / mL, 0.05 μg / mL and 0.08 μg / mL respectively on the drug-containing culture medium plate; the ECs of compound A30 on the mycelial growth of Botrytis cinerea and Sclerotinia sclerotiorum were 0.01 μg / mL, 0.05 μg / mL and 0.08 μg / mL respectively. 50 0.5μg / mL and 2.5μg / mL respectively.

[0228] Example 31: Preparation of N-(1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-benzimidazol-2-yl)acetamide (abbreviated as Compound A31)

[0229]

[0230] The method of Example 9 was used, except that the compound III used in this example was N-(1H-benzimidazol-2-yl)acetamide; the final prepared compound A31 was a light yellow powdery solid with a yield of 80%. The NMR data of the compound A31 are as follows:

[0231] 1 H NMR (400 MHz, DMSO-d 6 )δ:13.20(s,1H,NH),8.04(s,1H,ThH),7.54-7.47(m,1H,ArH),7.41-7.28(m,2H,ArH),7.17(t,J= 8.5Hz,2H,ArH),7.11-7.31(m,2H,ArH),6.01(dd,J=12.2,8.6Hz,1H,OCH),5.08-4.93(m,2H,OCCH 2 ),4.38(d,J=13.0Hz,1H,CH 2 N), 4.10(d, J=13.5Hz,1H,CH 2 N),3.91(dd,J=17.2,12.1Hz,1H,OCCH 2 ),3.53(dd,J=17.1,8.6Hz,1H,OCCH 2 ),3.40(tt,J=11.8,3.5Hz,1H,CH),3.31(t,J=11.8Hz,1H,CH 2 N), 2.84(t, J=12.2Hz,1H,CH 2 N), 2.65(s,3H,CH 3 ),2.17(d,J=12.3Hz,1H,CH 2),2.10(d,J=12.1Hz,1H,CH 2 ),1.88-1.76(m,1H,CH 2 ),1.61-1.50(m,1H,CH 2 ).

[0232] The MICs of compound A31 prepared in this example on the mycelial growth of Phytophthora capsici, Phytophthora infestans and Downy Phytophthora on the drug-containing culture medium plate were 0.01 μg / mL, 0.01 μg / mL and 0.1 μg / mL, respectively; the ECs for the mycelial growth of Magnaporthe grisea and Sclerotinia sclerotiorum were 0.01 μg / mL, 0.01 μg / mL and 0.1 μg / mL, respectively. 50 1.20 and 0.52 μg / mL respectively.

[0233] Comparative Example 1: Preparation of 2-(1H-benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one (abbreviated as Compound A32)

[0234]

[0235] The method of Example 9 was used, except that the compound III used in this example was 1H-benzimidazole; the final prepared compound A32 was a white powdery solid with a yield of 90%. The NMR data of the compound A32 are as follows:

[0236] 1 HNMR (400 MHz, DMSO-d 6 )δ:8.12(s,1H,ArH),8.04(s,1H,ThH),7.64(d,J=7.7Hz,1H,ArH),7.54-7.47(m,1H,PhH),7.28-7.21(m ,2H,PhH+ArH),7.24-7.15(m,4H,2PhH+2ArH),6.02(dd,J=12.0,8.5Hz,1H,OCH),5.40-5.28(m,2H,COCH 2 ),4.39(d,J=13.3Hz,1H,CH 2 N), 4.10(d, J=13.7Hz,1H,CH 2 N),3.91(dd,J=17.4,12.1Hz,1H,OCCH 2 ),3.55(dd,J=17.4,8.6Hz,1H,OCCH 2 ),3.42(tt,J=11.4,3.6Hz,1H,CH),3.32(t,J=10.5Hz,1H,CH2 N), 2.85(t, J=12.0Hz,1H,CH 2 N), 2.18(d, J=13.5Hz,1H,CH 2 ),2.10(d,J=12.0Hz,1H,CH 2 ),1.94-1.84(m,1H,CH 2 ),1.60(qd,J=12.1,3.2Hz,1H,CH 2 ).

[0237] The MIC of compound A32 prepared in this comparative example on the drug-containing culture medium plate against the mycelial growth of pepper phytophthora, infestation phytophthora and downy mildew was greater than 200.0 μg / mL, and the EC of compound A32 on the mycelial growth of rice blast, rice sheath blight, fruit and vegetable gray mold, rapeseed sclerotinia and grape anthracnose was greater than 200.0 μg / mL. 50 Greater than 100.0 μg / mL; compared with the control agent fluthiazolin, the antibacterial activity of compound A32 is very low.

[0238] The preliminary screening results of the in vitro activity of the above compounds show that, compared with the benzimidazole derivatives in Comparative Example 1, the antibacterial activity of the benzimidazole derivatives provided by the present invention against several plant pathogenic oomycetes and fungi tested is significantly improved to varying degrees, and the activity and the selective activity against oomycetes and fungi are related to the molecular structure of the compound. The present invention selects some of the benzimidazole derivatives with higher preliminary screening activity to be processed into preparations, further conducts in vivo efficacy tests on some common diseases on plant tissues or plant seedlings, and compares with currently commonly used fungicides, which are described in detail below.

[0239] Formulation Example 1: Preparation of wettable powder (10 wt% WP or 30 wt% WP)

[0240] According to the effective content of the intended processed preparation, measured by the weight of the effective ingredient, weigh 10% of the weight of the formulation of a benzimidazole derivative (with a particle size of 300 mesh), 85% of a carrier (specifically light calcium carbonate) and 5% of a surfactant (specifically sodium lignin sulfonate) to obtain a mixture for preparing a 10% wettable powder of the effective ingredient; weigh 30% of the weight of the formulation of a benzimidazole derivative (with a particle size of 200 mesh), 58% of a carrier (specifically white carbon black) and 12% of a surfactant (specifically 8% sodium lignin sulfonate and 4% peregal) to obtain a mixture for preparing a 30% wettable powder of the effective ingredient;

[0241] The above two kinds of mixtures were respectively subjected to air flow milling and sieving in sequence, and the mixtures passing 44 μm were collected to obtain 10 wt% WP or 30 wt% WP, respectively.

[0242] The sample quality was tested according to the GB / T 14825-1993 standard method. The results showed that the time for the 10wt% WP or 30wt% WP sample to reach wetness was less than 2 minutes, the suspension rate was greater than 70% after being stirred and left to stand for 1 hour, and the pH value was 6.8-7.2.

[0243] Dosage Form Example 2: Preparation of Suspension (0.1wt% SC, 0.3wt% SC, 0.5wt% SC, 1wt% SC or 5wt% SC)

[0244] According to the effective content of the preparation to be processed, measured by weight of the effective ingredient, weigh 0.1% of a benzimidazole derivative (with a particle size of 300 mesh), 0.2% of a wetting agent (specifically, peregrin), 0.3% of a dispersing suspending agent (specifically, lakai powder), 0.2% of a viscosity increasing agent (specifically, xanthan gum), 0.3% of a stabilizer (specifically, bentonite), 3% of an antifreeze agent (specifically, polyethylene glycol 400), and 0.1% of a defoaming agent (specifically, lauric acid), accounting for the weight of the dosage form, and add water to 100% to obtain a suspension concentrate with an effective ingredient content of 0.1%, i.e., a mixture of 0.1wt% SC;

[0245] Weigh 0.3% of a benzimidazole derivative (with a particle size of 300 mesh), 0.5% of a water-soluble wetting agent (specifically Peregrin), 0.5% of a dispersing suspending agent (specifically dispersant NNO), 0.2% of a viscosity increasing agent (specifically xanthan gum), 0.3% of a stabilizer (specifically diatomaceous earth), 3% of an antifreeze agent (specifically ethylene glycol 400), and 0.1% of a defoaming agent (specifically lauric acid) based on the weight of the dosage form, add water to 100%, and obtain a suspension concentrate having an active ingredient content of 0.3%, i.e., a mixture of 0.3wt% SC;

[0246] Weigh 0.5% of the weight of the dosage form of a benzimidazole derivative (particle size 300 mesh), 1.0% of a water-soluble wetting agent (specifically Peregrin), 1.0% of a dispersing and suspending agent (specifically Nongru 11 # ), 0.2% of a viscosity enhancer (specifically dextrin), 0.5% of a stabilizer (specifically magnesium aluminum silicate), 3% of an antifreeze agent (specifically polyethylene glycol 400), and 0.1% of a defoaming agent (specifically silicone), and adding water to 100% to obtain a suspension concentrate having an active ingredient content of 0.5%, i.e., a mixture of 0.5wt% SC;

[0247] Weigh 1% of a benzimidazole derivative (with a particle size of 300 mesh), 1.5% of a water-soluble wetting agent (specifically Periga), 2.0% of a dispersing suspending agent (specifically Lakai powder), 0.2% of a viscosity increasing agent (specifically xanthan gum), 0.5% of a stabilizer (specifically bentonite), 3% of an antifreeze agent (specifically polyethylene glycol 400), and 0.2% of a defoaming agent (specifically lauric acid) based on the weight of the dosage form, and add water to 100% to obtain a suspension concentrate having an active ingredient content of 1%, i.e., a mixture of 1wt% SC;

[0248] Weigh 5% of the weight of the dosage form of a benzimidazole derivative (with a particle size of 300 mesh), 3% of a water-soluble wetting agent (specifically, Periga), 3% of a dispersing suspending agent (specifically, Lakai powder), 0.8% of a viscosity increasing agent (specifically, dextrin), 0.6% of a stabilizer (specifically, bentonite), 3% of an antifreeze agent (specifically, ethylene glycol 400), and 0.2% of a defoaming agent (specifically, silicone), and add water to 100% to obtain a suspension concentrate with an active ingredient content of 5%, i.e., a mixture of 5wt% SC;

[0249] The above five mixtures were mixed and prepared into slurries, and then ground by a sand mill for 3 to 4 times. Finally, the pH value, fluidity and wettability were adjusted to obtain 0.1wt% SC, 0.3wt% SC, 0.5wt% SC, 1wt% SC or 5wt% SC with different active ingredient contents.

[0250] The sample quality was tested according to the NY / T4014-2021 standard method. The results showed that the relative error of the active ingredient content was ±0.1~0.5%, there was no stratification and precipitation after being placed indoors for 30 days, and it could maintain a stable suspension state when diluted with water. The effective suspension rate after standing still for 1 hour was greater than 90%.

[0251] Dosage Form Example 3: Preparation of Water Dispersible Granules (3wt% WG, 10wt% WG or 20wt% WG)

[0252] According to the effective content of the preparation to be processed, based on the weight of the effective ingredient, 3% of the weight of the dosage form of benzimidazole derivatives (with a particle size of 300 mesh), 1% of calcium dodecylbenzenesulfonate, 2% of PO-EO-block polyether, 3% of urea, 20% of disintegrants (specifically ammonium sulfate and sucrose in a mass ratio of 3:1), and 71% of carriers (specifically kaolin) were weighed to prepare a water-dispersible granule with an effective ingredient content of 3%, i.e., a mixture of 3wt% WG; 10% of the weight of the dosage form of benzimidazole derivatives (with a particle size of 200 mesh), 5% of naphthalenesulfonate dispersants GY-D10, 2 % of sodium butylbenzenesulfonate, 3% of urea, 15% of a disintegrant (specifically potassium sulfate and sodium chloride in a mass ratio of 4:1), and 65% of a carrier (specifically bentonite) to obtain a mixture of 10% water-dispersible granules with an active ingredient content of 10%, i.e., 10wt% WG; 20% of a benzimidazole derivative (with a particle size of 100 mesh), 10% of calcium lignin sulfonate, 2% of a dispersant NNO, 3% of ammonium sulfate, 2% of polyethylene glycol, and 63% of a carrier (specifically clay) accounting for 20% of the weight of the dosage form are weighed separately to obtain a mixture of 20% water-dispersible granules with an active ingredient content of 20%, i.e., 20wt% WG.

[0253] The above three kinds of mixtures were respectively pulverized by air flow, and the mixtures with particle sizes below 10 μm were collected and successively granulated by extrusion and dried to obtain 3wt% WG, 10wt% WG or 20wt% WG with different active ingredient contents.

[0254] The sample quality was tested according to the HG / T 4463-2012 standard method. The results showed that the time for the above three types of 3wt% WG, 10wt% WG or 20wt% WG to reach wet disintegration was less than 2min, the suspension rate after standing for 1h after stirring was greater than 70%, and the pH value was 6.8-7.2.

[0255] Efficacy Test Example 1

[0256] In this example, a test on the control of potato late blight and pepper blight by benzimidazole derivatives was conducted, as follows:

[0257] A. Test compounds: Compounds A32, A1, A4, A12 and A28 were processed into 10 wt% wettable powders (WP) according to the aforementioned method; compounds A8, A14 and A19 were processed into 30 wt% wettable powders (WP) according to the aforementioned method; the control test sample was Zengwei Green Win 10 wt% dispersible oil suspension (fluthiazolinone) sold by Corteva.

[0258] B. Greenhouse pot test conditions: Potato seedlings and pepper seedlings at the 4-5 leaf stage, one plant per pot; cultured in a glass solar greenhouse at a temperature of 15-25°C.

[0259] C. Test methods:

[0260] I. Preparation of test solutions: Weigh the wettable powders of the compounds of the present invention respectively, dilute with water to the active ingredient of the compounds at 50 mg / L, 10 mg / L and 2 mg / L (the same below), and prepare three treatment concentration solutions.

[0261] II. Test operation method: Spray 3 pots of potato seedlings and pepper seedlings with 3 treatment concentrations of each compound using a throat sprayer until the leaves are flowing with the liquid. After 24 hours, 10 μL of the prepared sporangium suspension of potato late blight (Phytophthora infestans) and pepper phytophthora (P. capsici) were dripped on the leaves, and a total of 30 leaflets were inoculated (10 leaves were inoculated for each pot of seedlings). When the bacterial solution was about to dry, the pots were placed in a greenhouse and covered with plastic cloth. They were cultured in a dark environment for 24 hours, and then the plastic cloth was removed and continued to be cultured (protective effect determination); or after inoculation, the dark environment was moisturized for 24 hours and then sprayed with the drug. After drying, the pots were placed in a greenhouse at 15-25°C for culture (curative effect determination). The number and length of lesions were investigated for 7 days after inoculation, and the control effect was calculated by the following formula: Control effect % = [1-(treatment lesion length ÷ blank control lesion length)] × 100%.

[0262] D. Test results: are listed in Table 1 and Table 2. The results listed in Table 1 and Table 2 clearly show that the benzimidazole derivatives provided by the present invention have good preventive and therapeutic effects on potato late blight and pepper blight, and the preventive effect on potato late blight is higher than that on pepper blight, and the protective effect is higher than the therapeutic effect, which is similar to the effect of Zengwei Luying, the best control agent currently used in production. There are certain differences in activity between different compounds, especially compound A19 has obvious selectivity in the activity of preventing and controlling potato late blight and pepper blight.

[0263] Table 1 The protective effect of benzimidazole derivatives on potato late blight and pepper blight (%)

[0264]

[0265] Table 2 The therapeutic effect of benzimidazole derivatives on the prevention and control of potato late blight and pepper blight (%)

[0266]

[0267] Efficacy Test Example 2

[0268] In this example, benzimidazole derivatives were tested for controlling grape downy mildew and cucumber downy mildew, as follows:

[0269] A. Test compounds: Compounds A2, A4, A5, A6, A10 and A15 were processed into 1 wt% suspension concentrate (SC) according to the aforementioned method; compounds A17, A23, A26, A27 and A29 were processed into 5 wt% suspension concentrate (SC) according to the aforementioned method; the control test sample was a 50 wt% enoylmorph suspension concentrate (SC) sold by Qingdao Xiaofeng Biotechnology Co., Ltd.

[0270] B. Greenhouse potted test conditions: 5-leaf cucumber seedlings (variety: Xintai Mici) and grape seedlings with a vine length of about 1.5 meters (variety: Rose Fragrance), one plant per pot; cultured in a glass solar greenhouse at a temperature of 20-30°C.

[0271] C. Test methods:

[0272] I. Preparation of test solutions: Weigh the suspensions of the above compounds respectively, dilute them with water to 50 mg / L, 10 mg / L and 2 mg / L, and prepare solutions of three treatment concentrations.

[0273] II. Test operation method: Spray 4 cucumber seedlings and 3 grape seedlings with 3 concentrations of each compound using a throat sprayer until the leaves have liquid flowing. After 24 hours, drip 10 μL of the prepared sporangium suspension of cucumber downy mildew and grape downy mildew, respectively, and inoculate 15 leaves in total (one inoculation point on both sides of the vein of each leaf, a total of 30 inoculation points). After drying, place the pots in a greenhouse and cover them with plastic cloth to keep them moist in the dark for 24 hours, then remove the plastic cloth and continue to cultivate for 7 days. Investigate the length of the lesions and calculate the control effect by the following formula: Control effect % = [1-(treatment lesion length ÷ blank control lesion length)] × 100%.

[0274] D. Test results: are listed in Table 3. The results listed in Table 3 clearly show that the benzimidazole derivatives provided by the present invention have good preventive effects on grape downy mildew and cucumber downy mildew, and there are certain differences in activity between different compounds. The preventive effect on grape downy mildew is higher than that on cucumber downy mildew, among which A2, A4, A10 and A15 are significantly better than the most commonly used control agent dimethomorph in current production, and the dosage is only 1 / 10 to 1 / 50 or lower, such as compound A4.

[0275] Table 3 Experimental effect of benzimidazole derivatives on the prevention and treatment of grape downy mildew and cucumber downy mildew (%)

[0276]

[0277] Efficacy Test Example 3

[0278] In this example, a benzimidazole derivative soil treatment experiment was conducted to control damping-off disease of tomatoes and peppers, as follows:

[0279] A. Test drug sample: Prepare the test drug sample according to the above method:

[0280] (1) 10 wt% A1 wettable powder (WP); (2) 10 wt% A4 wettable powder (WP); (3) 10 wt% A12 wettable powder (WP); (4) 30 wt% A8 wettable powder (WP); (5) 1 wt% A2 suspension concentrate (SC); (6) 1 wt% A10 suspension concentrate (SC); (7) 5 wt% A19 suspension concentrate (SC); (8) 3 wt% A18 water dispersible granules (WG);

[0281] The control agent was a 98 wt % soluble powder of carbendazim produced by Beijing Beinong Lvheng Technology Development Co., Ltd. purchased online.

[0282] B. Greenhouse pot test method: Take natural soil from the vegetable fields in the suburbs of Nanjing, crush and mix it, first mix part of the fine soil with the test preparation at 0.1g of the effective ingredient of the compound per kilogram of soil, and then mix it with the soil until the final drug content per kilogram of soil is 50mg and 10mg. The final drug content of the control agent, carbendazim, is set at 50mg / kg. The water content is measured by kneading it into a ball with your hands and letting it loose when you put it down. Put the treated soil into a 50×30cm plastic pot, sow tomato and pepper seeds respectively, and cultivate them in a glass greenhouse under sunlight and 15-25℃. Check the diseased plant rate after 15 days. The prevention effect is calculated by the following formula: Prevention effect % = [1-(treated diseased plant rate ÷ diseased plant rate of blank control)] × 100%.

[0283] C. Test results: are listed in Table 4. As can be seen from Table 4, soil treatment with the benzimidazole derivative provided by the present invention has a significant control effect on tomato and pepper seedling diseases, and is better than the commonly used soil treatment agent oxadipazole, and the dosage is only 1 / 5 of the control agent. The isolates of the diseased seedlings treated with the control were identified as Phytophthora spp. accounting for 78.66%, Pythium spp. accounting for 6.31%, and Rhizoctonia spp. accounting for 15.03%.

[0284] Table 4 Experimental effect of benzimidazole derivatives on the prevention and treatment of tomato and pepper damping-off disease (%)

[0285]

[0286]

[0287] Efficacy Test Example 4

[0288] In this example, a test on the control of rice sheath blight by benzimidazole derivatives was carried out, as follows:

[0289] A. Test drug sample: Prepare the test drug sample according to the above method:

[0290] (1) 30 wt% A4 wettable powder (WP); (2) 30 wt% A12 wettable powder (WP); (3) 1 wt% A2 suspension concentrate (SC); (4) 5 wt% A3 suspension concentrate (SC); (5) 5 wt% A11 suspension concentrate (SC); (6) 3 wt% A13 water dispersible granules (WG); (7) 3 wt% A16 water dispersible granules (WG); (8) 10 wt% A18 water dispersible granules (WG); (9) 10 wt% A20 water dispersible granules (WG); (10) 20 wt% A22 water dispersible granules (WG);

[0291] The control agents were the 10 wt % dispersible oil suspension concentrate of Zengwei Green Win (fluthiazolinone) sold by Corteva and the 24 wt % thiothiazide suspension concentrate (SC) produced by Dow AgroSciences.

[0292] B. Greenhouse pot test conditions: Rice seedlings were planted in 4 holes in pots with a diameter of 25 cm and cultivated in a glass greenhouse under sunlight and 20-35℃. The 5-leaf stage was used for the test.

[0293] C. Test methods:

[0294] I. Preparation of drug solutions: Add water to the test drug samples listed in A to prepare two drug solutions with active ingredient contents of 500 mg / L and 250 mg / L respectively.

[0295] II. Test operation method: One day before spraying, inoculate the leaf sheaths of rice seedlings at the 5-leaf stage with a 3mm diameter mycelium block of rice sheath blight fungus Rhizoctoniasolani, inoculate 10 plants per pot, and wrap with absorbent cotton to keep moist overnight; spray 10 pots with each test agent sample, spray each time until droplets are about to roll off the leaf sheaths and leaves, and set spray water treatment as a blank control. After drying, place in a greenhouse for cultivation, check the length of the inoculated leaf sheath lesions after 7 days, and calculate the control effect. The calculation method is shown in Example 1 of the efficacy test.

[0296] D. Test results: listed in Table 5. The results listed in Table 5 show that the 10 benzimidazole derivatives provided by the present invention have different degrees of control effects on rice sheath blight, and the control effect of high-concentration liquid is better than that of low-concentration treatment, while the Zengwei Green Win 10% dispersible oil suspension with the same action mode has no control effect, indicating that the benzimidazole derivatives provided by the present invention have control effects on rice sheath blight caused by fungi.

[0297] Table 5 Test results of benzimidazole derivatives for controlling sheath blight of potted rice

[0298]

[0299]

[0300] Efficacy Test Example 5

[0301] In this example, a benzimidazole derivative seed treatment experiment for preventing and controlling soybean root rot was conducted, as follows:

[0302] A. Test drug sample: Prepare the test drug sample according to the above method:

[0303] (1) 0.1wt% A4 suspension (SC); (2) 0.1wt% A7 suspension (SC); (3) 0.1wt% A9 suspension (SC); (4) 0.1wt% A11 suspension (SC); (5) 0.1wt% A12 suspension (SC); (6) 0.3wt% A21 suspension (SC); (7) 0.3wt% A22 suspension (SC); (8) 0.5wt% A23 suspension (SC); (9) 0.5wt% A24 suspension (SC); (10) 1wt% A25 suspension (SC);

[0304] The control agent is a 62.5 wt% fludioxonil-SMC suspension seed coating agent (SC) commercially available from Syngenta.

[0305] B. Test methods:

[0306] I. Preparation of drug solution: Prepare 1 mL of drug solution with 10 mg and 100 mg of the active ingredient per 10 kg of seeds.

[0307] II. Seed treatment: Mix 1 mL of the above-prepared solution with 33 g of seeds respectively. After drying, take 100 full seeds and sow them in a plastic pot. At the same time, set up seeds mixed with clean water as a control.

[0308] III. Soil inoculation: Refer to the sporangium culture method of Phytophthora infestans to prepare 10 5 / mL soybean Phytophthora sojae sporangium suspension. 10mL of sporangium suspension was mixed with 3kg of nutrient soil (plant growth medium) and inoculated into 50×30cm plastic pots. 100 seeds of each treatment were sown in each pot and cultured in a glass solar greenhouse at a temperature of 20-35℃ until the 3-leaf stage.

[0309] C. Results Investigation and Analysis:

[0310] Soybean seedlings were pulled out when they reached the 3-leaf stage, and the number of dead seedlings and diseased plants with brown spots at the base of the stems was checked. The protection effect was calculated according to the following formula: Protection effect (%) = [1-(disease rate of treated plants ÷ disease rate of blank control)] × 100%.

[0311] The test results are listed in Table 6. The results listed in Table 6 clearly show that the 10 benzimidazole derivatives provided by the present invention, when used for seed dressing at a dosage 10 times lower than that of the control agent, all have excellent preventive effects on soybean root rot caused by Phytophthora, and are positively correlated with the treatment concentration.

[0312] Table 6 Test results of benzimidazole derivatives for preventing and controlling potted soybean root rot

[0313]

[0314]

[0315] Efficacy Test Example 6

[0316] In this example, a field test of the efficacy of benzimidazole derivatives in controlling rice blast was conducted, as follows:

[0317] A. Test drug sample: Prepare the test drug sample according to the above method:

[0318] (1) 30 wt% A32 wettable powder (WP); (2) 30 wt% A4 wettable powder (WP); (3) 30 wt% A12 wettable powder (WP); (4) 1 wt% A2 suspension concentrate (SC); (5) 5 wt% A3 suspension concentrate (SC); (6) 10 wt% A20 water dispersible granules (WG); (7) 10 wt% A30 water dispersible granules (WG); (8) 10 wt% A31 water dispersible granules (WG);

[0319] The control agents were 10 wt% dispersible oil suspension concentrate of Zengwei Green Win (fluthiazolinone) and 40 wt% rice blast-butyl wettable powder (WP) sold by Corteva.

[0320] B. Experimental location, rice variety and growth period:

[0321] The test site was set up in Qiancang Community, Xiongzhou Street, Liuhe District, Nanjing City. The rice variety Sujing 4699, which is susceptible to rice blast, was cultivated and pesticides were sprayed during the heading stage for prevention and control.

[0322] C. Test methods:

[0323] I. Preparation of drug solutions: Add water to the test drug samples listed in A to prepare two drug solutions with active ingredient contents of 500 mg / L and 250 mg / L respectively.

[0324] II. Test operation method: Draw a 20 square meter plot for each dose treatment, with 3 replicates, spray 30 kg of liquid per mu in the evening of the heading period, and spray the second time 7 days later. 14 days after the second spray, sample 5 points to investigate the incidence of ear neck blight in 300 ears. The calculation method of control effect is as follows: control effect % = [1-(treatment diseased plant rate ÷ blank control diseased plant rate)] × 100%.

[0325] D. Test results: The test results are listed in Table 7. The field test results show that the benzimidazole derivatives provided by the present invention have good control effects on rice blast when sprayed at the rice heading stage. The control effects of a few compounds are similar to those of the commonly used rice blast, and their field effects are better than expected based on the results of indoor in vitro tests. However, Zengwei Luying, which has the same mode of action, has almost no control effect on rice blast. R and R 1 ~R 4 The benzimidazole-containing piperidinyl thiazole isoxazoline compounds (i.e., compound A32) all have an in vitro activity against Phytophthora infestans and Phytophthora capsici that is 100 times lower than that of fluthiazolinone, and also have a low efficacy against rice blast.

[0326] Table 7 Field test results of benzimidazole derivatives for controlling rice blast

[0327]

[0328]

[0329] Cross-resistance assay example

[0330] In this example, the mycelial growth inhibition rate of benzimidazole derivatives against Phytophthora capsici (parent) and its known oxysterol binding protein point mutants was determined, and the cross-resistance pattern and molecular target of different agents were analyzed. The test strain was kindly provided by Professor Liu Xili of Northwest Agriculture and Forestry University (references for strain and mutant background: J. Agric. Food Chem. 2021, 69, 3827-3835; Front. Microbiol. 2016, 7: 615), and the specific test methods and results are as follows:

[0331] A. Test agent samples: Representative compounds of benzimidazole derivatives A1, A2, A4, A28, and fluthiazolin with the same mode of action, and other fungicides with different modes of action, such as oxazolidinone, cymoxanil, mefenamic acid, and azoxystrobin.

[0332] B. Test methods:

[0333] I. Preparation of drug solution and drug-containing culture medium plate: Dissolve the compounds listed in Table 8 and other original drugs in methanol to prepare 10 mg / mL drug stock solution, add the drug stock solution into lima bean agar medium melted at about 45°C with a pipette to an effective final concentration of 5 μg / mL, pour into a 90 mm diameter culture dish, cool to prepare drug-containing plates, and set up control plates without drug addition.

[0334] II. Experimental operation method: Prepare a 5mm diameter mycelium block from the colony edge of the susceptible parent of Capsicum frutescens and the target oxysterol binding protein point mutant strain cultured on lima bean medium plates, transfer it to the center of each drug-containing plate with the mycelium facing up, and then culture it in a 25℃ incubator for 5 days, and measure the colony growth diameter.

[0335] The inhibition rate was calculated as follows: inhibition rate % = [1-(colony growth diameter of treated group ÷ colony growth diameter of blank control group)] × 100%.

[0336] C. Test results: The test results are listed in Table 8. The test results show that the inhibitory activity of the benzimidazole derivatives provided by the present invention on the mycelial growth of two sensitive parent strains of Phytophthora capsici is higher than or equal to that of fluthiazolinone with the same action mode, but the growth inhibition rate of strains with different mutants of oxysterol binding protein is lower, and these mutants show resistance to the compounds of the present invention and cross-resistance to fluthiazolinone, but have no cross-resistance to dimethomorph, cymoxanil, oxadipamide, and azoxystrobin with different action modes, which also indicates that the target of the benzimidazole derivatives of the present invention is oxysterol binding protein.

[0337] Table 8 Determination of cross-resistance between benzimidazole derivatives and fungicides with different modes of action

[0338]

[0339] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A benzimidazole derivative or an agriculturally acceptable salt thereof, characterized in that: The benzimidazole derivative has a structure shown in Formula I: Formula I; wherein R is selected from -H, -CH3, -C2H5, -CHF2, -CF3, -OC2H5, -SCH3, -COOCH3, -NHCOOCH3, -NHCOCH3, -OH, -Cl, -Br or -F; R1, R2, R3 and R4 are independently selected from -H, -CH3, -CF3, -OCH3, -OCF3, -NO2, -Cl, -Br or -F, and R, R1, R2, R3 and R4 are not -H at the same time; (R5) m It is a 2,6-difluoro group.

2. The benzimidazole derivative or an agriculturally acceptable salt thereof according to claim 1, characterized in that: The benzimidazole derivative is selected from 2-(2-chloro-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-bromo-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-(difluoromethyl)-1 H 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(trifluoromethyl)-1-one H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-methoxy-2-(trifluoromethyl)-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(6-fluoro-2-hydroxy-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-hydroxy-6-(trifluoromethyl)-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-methyl-1 H -benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethyl-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-(methylthio)-1 H -benzimidazol-1-yl)ethan-1-one, 2-(2-chloro-6-(trifluoromethyl)-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-6-fluoro-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-bromo-2-chloro-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(2-chloro-5-methoxy-1 H -benzoimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-fluoro-1 H -Benzimidazol-1-yl)ethan-1-one, 2-(5-chloro-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5-bromo-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(6-bromo-2-methyl-1 H -benzoimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-ethoxy-1 H -benzimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-methyl-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5,6-dimethyl-1 H -benzimidazol-1-yl)ethan-1-one, 2-(6-chloro-4-methyl-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-1 H -benzimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(5,6-dichloro-2-methyl-1 H -benzoimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-nitro-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(5-(trifluoromethoxy)-1 H -benzimidazol-1-yl)ethan-1-one, 2-(5-methoxy-1 H -benzoimidazol-1-yl)-1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)ethan-1-one, 1-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-(2-fluoro-1 H -benzoimidazol-1-yl)ethan-1-one, 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1 H -Methyl benzimidazole-2-carboxylate, 1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1 H -Methyl benzimidazole-2-carbamate or N -(1-(2-(4-(4-(5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)-1 H -benzoimidazol-2-yl)acetamide.

3. The method for preparing the benzimidazole derivative according to claim 1 or 2, characterized in that: The following steps are involved: Mixing compound II, compound III, an acid-binding agent and an organic solvent to carry out a substitution reaction to obtain a benzimidazole derivative having a structure shown in formula I; The structural formula of the compound II is shown in Formula II, and the structural formula of the compound III is shown in Formula III: Formula II; Formula III; Where R, R1, R2, R3, R4 and (R5) m As defined in formula I, X is a halogen group.

4. Use of the benzimidazole derivative or its agriculturally acceptable salt according to claim 1 or 2 in preventing and controlling plant diseases, wherein the plant disease is Peronosporales ( Peronosporales ) Diseases caused by plant pathogenic oomycetes or plant pathogenic fungi.

5. The use according to claim 4, characterized in that: The plant disease is Phytophthora ( Phytophthora ), Phytophthora spp. Sclerophthora ), Peronospora spp. Sclerospora ), Peronospora spp. Plasmopara ), Downy Phytophthora spp. Peronophythora )、Pseudoceromyces( Pseudoperonospora ), Downy Mildew ( Peronospora ), Peronospora spp. Bremia ), Parasitic Peronospora ( Paraperonospora )、Albugo Albugo ), Pythium Pythium ), Pyricularia Magnaporthe ), Rhizoctonia spp. Rhizoctonia ), Fusarium ( Fusarium ), Botrytis cinerea ( Botrytis ) or Colletotrichum spp. Colletotrichum ) caused by diseases.

6. Use of the benzimidazole derivative according to claim 1 or 2 or its agriculturally acceptable salt in the preparation of agricultural fungicides.

7. An agricultural fungicide, characterized in that: It comprises active ingredients and auxiliary materials; the active ingredients comprise at least one of the benzimidazole derivatives according to claim 1 or 2 and salts thereof acceptable for agricultural production.

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