An oxadiazole compound, a preparation method and application thereof

Abstract

The compound shown in the formula (I) has good activity to various pathogenic bacteria in agriculture or other fields. Moreover, the compound can obtain good prevention and treatment effect at a very low dose, and thus can be used for preparing a fungicide. In addition, the compound has simple preparation steps and high yield, and thus has good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of bactericide technology, specifically relating to an oxadiazole compound, its preparation method, and its uses. Background Technology

[0002] In agriculture, with the increasing severity of disease resistance problems, farmers need to increase pesticide use, leading to higher pesticide residues and environmental pollution. There is a need to develop new pesticide varieties with the aim of reducing the amount of active ingredients used, while maintaining effectiveness at least equal to or better than existing known compounds.

[0003] WO2013 / 008162 discloses that oxadiazole compounds have histone deacetylase 4 (HDAC4) inhibitory activity and their use in medicine.

[0004] WO2017 / 102006 discloses oxadiazole compounds represented by the following general formula and their use in controlling plant pathogenic fungi.

[0005]

[0006] However, the bioactivity of the aforementioned compounds still needs further improvement. The inventors conducted in-depth research to discover bactericides with superior performance. Summary of the Invention

[0007] To further develop high-performance bactericides, this invention provides a compound containing an oxadiazole or a pharmaceutically acceptable salt thereof, as shown in formula (I).

[0008]

[0009] Among them, R1, R2, R3, and R4 may be the same or different, and each is independently selected from hydrogen, halogen or C1-C4 alkyl;

[0010] R5 is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl-C1-C4 alkyl;

[0011] R6 is selected from hydrogen or C1-C4 alkyl;

[0012] R7 and R8 may be the same or different, and each is independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0013] X is selected from O or CR a R b ;

[0014] R a R b They may be the same or different, and each is independently selected from hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl;

[0015] Q is selected from unsubstituted or arbitrarily assigned to one, two or more Rs. s1 The following groups are substituted: C3-C6 cycloalkyl C1-C4 alkyl, C1-C4 alkoxycarbonyl C1-C4 alkyl, C1-C4 alkyl-NHC(O)-C1-C4 alkyl or cyanoC1-C4 alkyl;

[0016] Each R s1 They may be the same or different, and are independently selected from the following groups: halogen, cyano or C1-C4 alkyl.

[0017] According to embodiments of the present invention, R1, R2, R3, and R4 may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, or methyl.

[0018] According to an embodiment of the present invention, R1 and R2 are hydrogen, R3 is selected from H, F or methyl, and R4 is selected from hydrogen or fluorine.

[0019] According to an embodiment of the present invention, R5 is selected from hydrogen or methyl.

[0020] According to an embodiment of the present invention, R6 is selected from hydrogen, methyl, or ethyl.

[0021] According to embodiments of the present invention, R7 and R8 may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl.

[0022] According to an embodiment of the present invention, R7 is selected from hydrogen or methyl, and R8 is selected from hydrogen or methyl.

[0023] According to an embodiment of the present invention, X is selected from O or CH2.

[0024] According to an embodiment of the present invention, R s1 It is selected from fluorine, chlorine, bromine, cyano, methyl or ethyl.

[0025] According to an embodiment of the present invention, Q is selected from C3-C6 cycloalkyl or C1-C4 alkyl or is formed by one or more R. s1 Substituted C3-C6 cycloalkyl and C1-C4 alkyl.

[0026] According to an embodiment of the present invention, Q is selected from C1-C4 alkoxycarbonyl C1-C4 alkyl or is formed by one or more R s1 Substituted C1-C4 alkoxycarbonyl C1-C4 alkyl.

[0027] According to an embodiment of the present invention, Q is selected from C1-C4 alkyl-NHC(O)-C1-C4 alkyl or is formed by one or more R. s1 Substituted C1-C4 alkyl-NHC(O)-C1-C4 alkyl.

[0028] According to an embodiment of the present invention, Q is selected from cyanoC1-C4 alkyl or is formed by one or more R atoms. s1 Substituted cyano C1-C4 alkyl groups.

[0029] According to an embodiment of the present invention, Q is selected from...

[0030]

[0031] As an example, the compound of formula (I) is selected from the following compounds:

[0032]

[0033] Table 1

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] To reduce the length of the specification, exemplary groups and / or compounds of the present invention are described in the form of the above tables.

[0046] This invention also provides a method for preparing compounds of formula (I) as described above or pharmaceutically acceptable salts thereof, the method comprising:

[0047] Method 1

[0048]

[0049] Compounds of general formula (III) and general formula (II) are subjected to amide coupling transformation to obtain compound of general formula (I).

[0050] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine.

[0051] According to an embodiment of the present invention, the solvent may be selected from one, two or more of N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, etc.

[0052] According to an embodiment of the present invention, the coupling agent may be selected from one, two or more of DCC, PyBOP, EDCI, HOBt, HATU, HBTU, etc.

[0053] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 120°C.

[0054] According to embodiments of the present invention, the reaction may be carried out with reference to the methods described in patent documents Valeur, E.; Bradley, M. Chem. Soc. Rev. [Chemical Review] (2009), 38, 606 and Chinchilla, R., Najera, C. Chem. Soc. Rev. [Chemical Review] (2011), 40, 5084 or other similar methods.

[0055] Method 2

[0056]

[0057] Step 1: Preparation of compounds of general formula (IV)

[0058] Using conventional methods, the -OH group of the carboxylic acid functional group of compound III is converted into a leaving group L1 (such as a chloride group) to obtain compound IV.

[0059] According to an embodiment of the present invention, the chlorinating agent may be selected from thionyl chloride, oxalyl chloride, carbonyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, triphosgene, etc.

[0060] According to an embodiment of the present invention, the solvent may be selected from one, two or more of haloalkane solvents, aromatic solvents, etc., for example, selected from one, two or more of dichloromethane, 1,2-dichloroethane, toluene, etc.

[0061] According to an embodiment of the present invention, the reaction temperature is preferably -10 to 100°C.

[0062] Step 2: Preparation of compounds of general formula (I)

[0063] Compound of general formula I is prepared by reacting compound of general formula IV with compound of general formula II in a suitable solvent.

[0064] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine; or inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide.

[0065] According to an embodiment of the present invention, the solvent may be selected from one, two or more of haloalkane solvents, aromatic solvents, ester solvents, etc., for example, selected from one, two or more of dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, etc.

[0066] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 150°C.

[0067] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in patent document CN 109068652 A or other similar methods.

[0068] Method 3

[0069]

[0070] L2 and L3 are selected from leaving groups, such as hydroxyl groups and halogens;

[0071] Step 1: Preparation of compounds of general formula VII

[0072] Compound of general formula VIII is reacted with (Boc)2O in a suitable solvent to prepare compound of general formula VII.

[0073] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be an organic base or an inorganic base; for example, one, two or more of triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, etc.

[0074] According to an embodiment of the present invention, the solvent may be selected from one, two, or more of acetonitrile, tetrahydrofuran, dichloromethane, water, etc.

[0075] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0076] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in patent document Chem. Pharm. Bull. 2002, 50(4) 554-557 or other similar methods.

[0077] Step 2: Preparation of compound of general formula VI

[0078] Compounds of general formula VII can be reacted to prepare compounds of general formula VI;

[0079] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, potassium tert-butoxide, and sodium tert-butoxide, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0080] According to an embodiment of the present invention, the solvent may be selected from one, two or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, etc.

[0081] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0082] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in patent document CN 108368099 A or other similar methods.

[0083] Step 3: Preparation of compound of general formula V

[0084] Compounds of general formula VI can be reacted to prepare compounds of general formula V;

[0085] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, potassium tert-butoxide, and sodium tert-butoxide, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0086] According to an embodiment of the present invention, the solvent may be selected from one, two or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, etc.

[0087] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0088] According to an embodiment of the present invention, the reaction may be carried out with reference to the methods described in patent documents WO 2011 / 146335 A1, Banerjee,s. et al., organic & biomolecular Chemistry (2013), 11(37), 6307, or other similar methods.

[0089] Step 4: Preparation of Compounds of General Formula II

[0090] Compound of general formula V is deprotected in a suitable solvent in the presence of an acid to give compound of general formula II.

[0091] According to an embodiment of the present invention, the solvent may be selected from one, two, or more of ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, etc.

[0092] According to an embodiment of the present invention, the acid may be selected from one or two of trifluoroacetic acid, hydrochloric acid, etc.

[0093] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0094] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in patent document CN 117069673 A or other similar methods.

[0095] Method 4

[0096]

[0097] L2 and L3 are selected from leaving groups, such as hydroxyl groups and halogens;

[0098] Step 1: Preparation of compounds of general formula IX

[0099] Compound of general formula VIII is reacted with CBzCl in a suitable solvent to prepare compound of general formula IX.

[0100] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be an organic base or an inorganic base; for example, one, two or more of triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.

[0101] According to an embodiment of the present invention, the solvent may be selected from one, two, or more of acetonitrile, tetrahydrofuran, dichloromethane, water, etc.

[0102] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0103] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in the patent document Kim, Myoung Goo et al., Journal of Antibiotics 56.32(2003):160 or other similar methods.

[0104] Step 2: Preparation of compound of general formula X

[0105] Compound of general formula IX can be reacted to prepare compound of general formula X;

[0106] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, potassium tert-butoxide, and sodium tert-butoxide, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0107] According to an embodiment of the present invention, the solvent may be selected from one, two or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, etc.

[0108] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0109] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in patent document CN 108368099 A or other similar methods.

[0110] Step 3: Preparation of compounds of general formula XI

[0111] Compounds of general formula X can be reacted to prepare compounds of general formula XI;

[0112] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, potassium tert-butoxide, and sodium tert-butoxide, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0113] According to an embodiment of the present invention, the solvent may be selected from one, two or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, etc.

[0114] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0115] According to an embodiment of the present invention, the reaction may be carried out with reference to the methods described in patent documents WO 2011 / 146335 A1, Banerjee,s. et al., organic & biomolecular Chemistry (2013), 11(37), 6307, or other similar methods.

[0116] Step 4: Preparation of Compounds of General Formula II

[0117] Compounds of general formula XI are prepared by hydrogenation to release the benzoyl carbamate group, thus yielding compounds of general formula II.

[0118] According to an embodiment of the present invention, the solvent may be selected from one, two or more of methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, etc.

[0119] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0120] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in the patent document Kim, Myoung Goo et al., Journal of Antibiotics 56.32(2003):160 or other similar methods.

[0121] Method 5

[0122]

[0123] Step 1: Preparation of compound of general formula XII

[0124] Compound of general formula XIII can be prepared by reacting it with hydroxylamine hydrochloride salt in a suitable solvent in the presence of a base;

[0125] According to an embodiment of the present invention, the base may be selected from organic bases such as triethylamine and pyridine, or from one, two, or more inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide.

[0126] According to an embodiment of the present invention, the solvent may be selected from one, two or more of alcohols, ethers, water, etc., for example, selected from one, two or more of water, methanol, ethanol, tetrahydrofuran, etc.

[0127] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 150°C.

[0128] According to an embodiment of the present invention, the reaction may be carried out with reference to the method described in the patent document Kitamura, S. et al. Chem. Pharm. Bull. (2001), 49, 268 or other similar methods.

[0129] Step 2: Preparation of Compounds of Formula IV

[0130] Compounds of general formula XII can be reacted with TFAA in a suitable solvent to prepare compounds of general formula III;

[0131] According to an embodiment of the present invention, the reaction can be carried out in the presence of a base; the base may be selected from one, two or more of organic bases such as triethylamine, pyridine, and N,N-diisopropylethylamine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide.

[0132] According to an embodiment of the present invention, the solvent may be selected from one, two or more of haloalkane solvents, ether solvents, etc., for example, selected from one, two or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, etc.

[0133] According to an embodiment of the present invention, the reaction temperature is preferably 0 to 100°C.

[0134] According to an embodiment of the present invention, the reaction can be referred to in patent documents WO 2013 / 008162 A1 and WO

[0135] The method described in 2013 / 080120A1 or other similar methods shall be used.

[0136] Compounds of general formulas VIII, XIII, and X, as well as other conventional raw materials and reagents, are usually commercially available or can be prepared in-house using conventional methods.

[0137] The preparation method of the present invention can be adapted to the appropriate reaction conditions and the selection of raw materials in each case. For example, in a one-step reaction, only one substituent can be replaced with another substituent according to the present invention, or multiple substituents can be replaced with other substituents according to the present invention in the same reaction step.

[0138] If the compounds cannot be obtained via the above route, they can be prepared by deriving other compounds of formula (I) or by conventionally changing the synthetic route.

[0139] The reaction mixture is post-processed in a conventional manner, such as by mixing with water, phase separation, and purification of the crude product by chromatography, for example, on alumina or silica gel.

[0140] This invention also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in formula (I), which can be prepared by known methods. For example, a pharmaceutically acceptable acid addition salt of the compound shown in (I) can be obtained by treating it with a suitable acid. The preparation method is as follows: the compound shown in formula (I) is reacted with an acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, malic acid, or citric acid, etc.) in a solvent such as water, ether, or toluene, to readily obtain a pharmaceutically acceptable salt of the compound shown in formula (I).

[0141] The above preparation method can obtain a mixture of isomers of the compound shown in formula (I). If pure isomers are required, they can be separated by conventional methods such as crystallization or chromatography.

[0142] Unless otherwise specified, all of the above reactions can be conveniently carried out at atmospheric pressure or at the pressure of the reaction itself.

[0143] The present invention also provides the use of at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a fungicide for use in agriculture or other fields.

[0144] The present invention also provides the use of at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof as a fungicide for use in agriculture or other fields.

[0145] The present invention also provides a composition comprising at least one of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0146] The present invention also provides the use of the composition as a fungicide in agriculture or other fields.

[0147] The present invention also provides the use of the composition in the preparation of bactericides.

[0148] According to an embodiment of the present invention, the fungus may be a fungus, such as a plant pathogen.

[0149] The present invention also provides a method for controlling pathogens, such as plant pathogens, comprising applying an effective amount of at least one of the compounds represented by formula (I) or a pharmaceutically acceptable salt thereof, or applying the composition to the growth medium of the plant pathogen.

[0150] According to an embodiment of the present invention, the plant can be a crop, such as corn, rice, or peanut.

[0151] According to an embodiment of the present invention, the plant diseases caused by the pathogen can be selected from corn rust, rice blast, and peanut white mold.

[0152] The examples of diseases mentioned below are only used to illustrate the present invention, and are by no means limiting the present invention.

[0153] The compound shown in formula (I) can be used to control the following diseases or their corresponding pathogens: Oomycete diseases, such as downy mildew (downy mildew of cucumber, rapeseed, soybean, beet, sugarcane, tobacco, pea, loofah, winter melon, cantaloupe, Chinese cabbage, spinach, radish, grape, and onion), and white rust (white rust of rapeseed and Chinese cabbage). Damping-off (rapeseed damping-off, tobacco damping-off, tomato damping-off, pepper damping-off, eggplant damping-off, cucumber damping-off, cotton seedling damping-off), cottony rot (pepper cottony rot, loofah cottony rot, winter melon cottony rot), blight (broad bean blight, cucumber blight, pumpkin blight, winter melon blight, watermelon blight, cantaloupe blight, pepper blight, leek blight, garlic blight, cotton blight), late blight (potato late blight, tomato late blight), etc.Deuteromycete diseases, such as wilt (sweet potato wilt, cotton wilt, sesame wilt, castor bean wilt, tomato wilt, bean wilt, cucumber wilt, loofah wilt, pumpkin wilt, winter melon wilt, watermelon wilt, cantaloupe wilt, pepper wilt, broad bean wilt, rapeseed wilt, soybean wilt), root rot (pepper root rot, eggplant root rot, bean root rot, cucumber root rot, bitter gourd root rot, cotton black root rot, broad bean root rot), damping-off (cotton seedling damping-off, sesame damping-off, pepper damping-off, cucumber damping-off, cabbage damping-off), anthracnose (sorghum anthracnose, cotton anthracnose, kenaf anthracnose, jute anthracnose, flax anthracnose, tobacco anthracnose, mulberry anthracnose). Anthracnose (including diseases such as anthracnose of peppers, eggplants, beans, cucumbers, bitter melons, zucchini, winter melons, watermelons, cantaloupes, and lychees); Verticillium wilt (including cotton, sunflowers, tomatoes, peppers, and eggplants); Black spot (including zucchini, winter melons, and cantaloupes); Gray mold (including cotton boll mold, kenaf gray mold, tomato gray mold, pepper gray mold, bean gray mold, celery gray mold, spinach gray mold, and kiwifruit gray mold); Brown spot (including cotton brown spot, jute brown spot, beet brown spot, peanut brown spot, pepper brown spot, winter melon brown spot, soybean brown spot, sunflower brown spot, and pea brown spot). Spot disease (broad bean brown spot), black spot (flax false black spot, rapeseed black spot, sesame black spot, sunflower black spot, castor bean black spot, tomato black spot, pepper black spot, eggplant black spot, green bean black spot, cucumber black spot, celery black spot, carrot black rot, carrot black spot, apple black spot, peanut black spot), leaf spot (tomato leaf spot, pepper leaf spot, celery leaf spot), early blight (tomato early blight, pepper early blight, eggplant early blight, potato early blight, celery early blight), ring spot (soybean ring spot, sesame ring spot, green bean ring spot), leaf blight (sesame leaf blight, sunflower leaf blight, watermelon leaf blight, melon leaf blight), stem base rot (tomato stem base rot, vegetable leaf blight). Bean stem base rot), and others (corn round spot, kenaf waist break, rice blast, chestnut black sheath disease, sugarcane eye spot, cotton boll aspergillosis, peanut crown rot, soybean stem blight, soybean black spot, melon large leaf spot, peanut net spot, tea red leaf spot, pepper white star disease, winter melon leaf spot, celery black rot, spinach heart rot, kenaf leaf mold, kenaf spot, jute stem spot, soybean purple spot, sesame leaf spot, castor bean gray spot, tea brown leaf spot, eggplant brown round star disease, common bean red spot, bitter gourd white spot, watermelon spot, jute blight, sunflower root and stem rot, common bean anthracnose, soybean target spot, eggplant scab leaf spot, cucumber target spot, tomato leaf mold, eggplant leaf mold, broad bean red spot, etc.);Basidiomycete diseases, such as rust (wheat stripe rust, wheat stem rust, wheat leaf rust, flower rust, sunflower rust, sugarcane rust, leek rust, onion rust, chestnut rust, soybean rust), smut (corn silk smut, corn smut, sorghum silk smut, sorghum loose smut, sorghum sturdy smut, sorghum pillar smut, chestnut smut, sugarcane smut, bean rust), and others (such as wheat sheath blight, rice sheath blight, etc.); ascomycete diseases, such as powdery mildew (wheat powdery mildew, rapeseed powdery mildew, sesame powdery mildew, etc.). Powdery mildew in sunflowers, beets, eggplants, peas, loofahs, pumpkins, zucchini, winter melons, cantaloupes, grapes, and broad beans; sclerotinia stem rot in flax, rapeseed, soybeans, peanuts, tobacco, peppers, eggplants, beans, peas, cucumbers, bitter melons, winter melons, watermelons, and celery; and black spot in apples and pears.

[0154] Due to their positive properties, the above compounds can be advantageously used to protect important crops, livestock and breeding stock in agriculture and horticulture, as well as environments frequented by humans, from pathogens.

[0155] To achieve the desired effect, the amount of compound used varies depending on various factors, such as the compound used, the crop being protected, the type of pest, the degree of infection, climatic conditions, the application method, and the formulation used.

[0156] The selection of dosage forms or compositional components described herein should be consistent with the physical properties of the active ingredient, the method of application, and environmental factors such as soil type, humidity, and temperature.

[0157] The dosage forms include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and / or suspensions), etc., which may optionally be thickened into a gel. The dosage forms also include solids such as powders, granules, tablets, pills, films, etc., which may be water-dispersible (“wettable”) or water-soluble. The active ingredient may be microencapsulated and re-formed into a suspension or solid dosage form; alternatively, the entire dosage form of the active ingredient may be encapsulated. Encapsulation can control or delay the release of the active ingredient. Sprayable formulations can be diluted in a suitable medium, with a spray volume of approximately one hundred to several hundred liters per hectare. High-concentration compositions are primarily used as intermediates for further processing.

[0158] Typical solid diluents are described in Watkins et al., *Handbook of Insecticide Dust Diluents and Carriers*, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, *Solvents Guide*, 2nd Ed., Interscience, New York, 1950. McCutcheon's *Detergents and Emulsifiers Annual*, Allured Publ. Corp., Ridgewood, New Jersey, and *Sisely and Wood, Encyclopedia of Surface Active Agents*, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended applications. All formulations may contain small amounts of additives to reduce foaming, prevent clumping, prevent corrosion, inhibit microbial growth, etc., or thickeners to increase viscosity.

[0159] Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, sulfonated dialkyl succinate, alkyl sulfates, alkylbenzene sulfonates, organosilanes, N,N-dialkyl taurate, lignin sulfonates, naphthalene sulfonates with aldehyde condensates, polycarboxylate esters, and polyoxyethylene / polyoxypropylene block copolymers.

[0160] Solid diluents include, for example, clays such as bentonite, montmorillonite, magnesia and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium sulfate; liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfone, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffin, alkylbenzene, alkylnaphthalene, olive oil, castor oil, linseed oil, tung oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and cocoa butter, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, dodecyl alcohol and tetrahydrofuran alcohol.

[0161] Solutions, including emulsifiable concentrates, can be prepared by simply mixing the components. Powders and fine powders can be prepared by mixing or, typically, by grinding in a hammer mill or hydraulic mill. Suspensions are generally prepared by wet milling, for example, by the method described in US 3060084. Granules and pellets are prepared by spraying the active ingredient onto freshly made granular carriers or by granulation techniques. See Browning, “Agglomeration,” Chemical Engineering, December 4, 1967, 147-48; Perry’s Chemical Engineer’s Handbook, 4th Ed., McGraw-Hill, New York, 1963, 8-57; and WO 9113546. The preparation of pills is described in US 4172714; water-dispersible and water-soluble granules are prepared according to methods in US 4144050, US3920442, and DE 3246493; tablets are prepared according to methods in US 5180587, US 5232701, and US5208030. Films can be prepared according to methods in GB2095558 and US 3299566.

[0162] More information on the processing can be found in US 3235361, column 6, line 16 to column 7, line 19, and Examples 10-41; US3309192, column 5, line 43 to column 7, line 62, and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167, and 169-182; US2891855, column 3, line 66 to column 5, line 17, and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York 1961, 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.

[0163] In this article, for certain applications of the composition, such as in agriculture, one, two or more other fungicides, insecticides, acaricides, herbicides, plant growth regulators or fertilizers may be added to the composition of the present invention, thereby producing additional advantages and effects.

[0164] Beneficial effects

[0165] The compounds represented by formula (I) of this invention exhibit excellent activity against a variety of pathogens in agriculture or other fields. Furthermore, these compounds achieve good control effects at very low doses, and therefore can be used to prepare fungicides.

[0166] Furthermore, the preparation steps of the compounds of this invention are simple and the yield is high, thus they have good application prospects.

[0167] Terminology Definitions and Explanations

[0168] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0169] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0170] The numerical ranges described in this application specification and claims, when the numerical range can only be "integers", should be understood to include the two endpoints of the range and every integer within the range. For example, "1-5" should be understood to include every integer of 1, 2, 3, 4, and 5.

[0171] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0172] Term "C" 1- "C4 alkyl" should be understood as representing a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 4 carbon atoms, preferably C4. 1- C3 alkyl. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl.

[0173] The above refers to the term "alkyl", such as "C". 1- The definition of "C4 alkyl" also applies to compounds containing "C". 1- Other terms for "C4 alkyl", such as the term "C 1- C4 alkoxy", C 1- C4 haloalkyl", C 1- "C4 haloalkoxy", "C1-C4 alkoxycarbonyl", "C1-C4 alkylcarbonyl", etc.

[0174] The term "C3-C6 cycloalkyl" should be understood to refer to a saturated monocyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0175] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid and free base of the specified compound and has no adverse effects in biological or other respects. The compounds in this application also include pharmaceutically acceptable salts, such as nitrates, hydrochlorides, sulfates, or phosphates. A pharmaceutically acceptable salt is defined as a salt formed by converting a base group in the parent compound into its salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts containing base groups such as amine (amino) groups. The pharmaceutically acceptable salts of this application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Detailed Implementation

[0176] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0177] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0178] The following methods are used for LC-MS analysis:

[0179] Column: Agilent ZORBAX SB-C18 150mm×4.6mm, 5μm (inner diameter);

[0180] Detection wavelength: 254nm;

[0181] Flow rate: 0.8 mL / min;

[0182] Column temperature: 30℃;

[0183] Gradient elution conditions:

[0184] Time (min) Acetonitrile (%) 0.1% formic acid aqueous solution (%) 0.00 50 50 5.00 50 50 15.00 90 10 20.00 90 10

[0185] Synthesis Examples

[0186] Example 1: N-(2-(cyclopropylmethyl)-3-oxoisoxazolidine-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (Compound 1)

[0187]

[0188] First step reaction: 4-(N'-hydroxycarbamoyl)benzoic acid

[0189] 10 g (68.0 mmol) of 4-cyanobenzoic acid, 9.45 g (136 mmol) of 50% hydroxylamine hydrochloride aqueous solution, and 0.1 g (0.68 mmol) of 8-hydroxyquinoline were each dissolved in 80 mL of ethanol. 14.10 g (102 mmol) of K₂CO₃ solution was added dropwise at room temperature. After no more bubbles were produced, the mixture was heated under reflux for 4 h. The solvent ethanol was removed under reduced pressure, and 1 M hydrochloric acid was added to the concentrated solution to adjust the pH to 4. A solid precipitated out; this solid was filtered and washed with water. The product was dried in an oven to obtain 11.64 g of product, with a yield of 95%.

[0190] LC / MS[M+H] + =181.06, [M+Na] + =203.04, [M+K] + =210.01.

[0191] Second step reaction: 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid

[0192] 10 g (55.5 mmol) of 4-(N'-hydroxycarbamoyl)benzoic acid was dissolved in 100 mL of THF. At 0 °C, 14.00 g (66.6 mmol) of a THF solution of trifluoroacetic anhydride was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 5.5 h. THF was removed under reduced pressure, water was added to the concentrate, and the mixture was stirred for 15 min. The mixture was filtered, and the solid was washed with water. The product was dried in an oven to obtain 6.88 g of product, with a yield of 48%.

[0193] LC / MS[M+H] + =259.04, [M+Na] + =281.02, [M+K] + =296.99.

[0194] Third step reaction: 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl chloride

[0195] 1 g (3.87 mmol) of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid, 1.38 g (7.74 mmol) of thionyl chloride, and 1 drop of DMF were dissolved separately in 10 mL of dichloroethane. The mixture was heated under reflux for 2 h. The solution was concentrated under reduced pressure to give 1.05 g of product, with a yield of 99%.

[0196] LC / MS[M+H] + =277.00, [M+Na] + =298.98, [M+K]+ =314.95.

[0197] Fourth step reaction: Methyl 3-(4-chlorophenyl)-3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoylamino)propionate

[0198] 0.31 g (1.97 mmol) of 4-amino-2-(cyclopropylmethyl)isoxazolidine-3-one and 0.22 g (2.17 mmol) were dissolved separately in dichloromethane. A solution of 0.60 g (2.17 mmol) of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl chloride in dichloromethane was added dropwise at 0 °C. The reaction mixture was then allowed to react at room temperature for 5 h. Water was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:6) to give 0.33 g of the product, in 42% yield.

[0199] LC / MS[M+H] + =397.11, [M+Na] + =419.09, [M+K] + =435.06.

[0200] 1 H NMR (400MHz, DMSO-d6): δ9.27(d,1H),8.21(d,2H),8.11(d,2H),5.13(q,1H), 4.64(t,1H),4.13(m,1H),3.42(m,2H),1.07(m,1H),0.51(m,2H),0.28(m,2H).

[0201] Example 2: 4-Amino-2-(cyclopropylmethyl)isoxazolidine-3-one hydrochloride

[0202]

[0203] Step 1 reaction: (3-oxoisoxazolidine-4-yl)tert-butyl carbamate

[0204] 2 g (19.60 mmol) of cycloserine was added to a mixture of 30 ml THF and 10 ml water. 4.70 g (21.55 mmol) of (Boc)₂O and 2.38 g (23.50 mmol) of triethylamine were added at room temperature. The reaction mixture was kept at this temperature for 12 h. The solution was concentrated under reduced pressure, and hydrochloric acid was added to adjust the pH to 2–3. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was slurried with petroleum ether to give 3.43 g of the product, with a yield of 86.6%.

[0205] LC / MS[M+H] + =203.11, [M+Na] + =225.09, [M+K] + =241.06.

[0206] Second step reaction: (2-(cyclopropylmethyl)-3-oxoisoxazolidine-4-yl)tert-butyl carbamate

[0207] 1.0 g (4.94 mmol) of (3-oxoisoxazolidine-4-yl) tert-butyl carbamate and 0.12 g (5.94 mmol) of NaH were added sequentially to 10 mL of DMF, and the reaction was carried out at room temperature for 1 h. Then, 0.36 g of (bromomethyl)cyclopropane was added, and the reaction was maintained at this temperature for 4 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with 15 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:6) to give 0.62 g of the product, in 49% yield.

[0208] LC / MS[M+H] + =257.15, [M+Na] + =279.13, [M+K] + =295.10.

[0209] Step 3: 4-Amino-2-(cyclopropylmethyl)isoxazolidine-3-one hydrochloride

[0210] 0.6 g (2.34 mmol) of tert-butyl 2-(cyclopropylmethyl)-3-oxoisoxazolidine-4-yl)carbamate was dissolved in 5 mL of 1,4-dioxane, and 2.3 mL (23.4 mmol) of concentrated hydrochloric acid was added dropwise at room temperature. The reaction was maintained at this temperature for 18 h. The solvent was removed under reduced pressure, and 10 mL of toluene was added to the concentrate. The mixture was concentrated under reduced pressure, and this process was repeated three times. The product was thoroughly dried to obtain 0.34 g of the final product. The yield was 76%.

[0211] LC / MS[M+H] + =193.08, [M+Na] + =215.06, [M+K] + =231.03.

[0212] Example 3: Ethyl 2-(4-amino-3-oxoisoxazolidine-2-yl)ethyl acetate

[0213]

[0214] Step 1 reaction: (3-oxoisoxazolidine-4-yl)carbamate benzyl ester

[0215] At 0°C, 2 g (19.60 mmol) of cycloserine, 3.68 g (21.55 mmol) of benzyl chloroformate, and 0.86 g (21.55 mmol) of sodium hydroxide were added sequentially to 30 ml of THF. The mixture was reacted at room temperature for 3 h. THF was removed under reduced pressure. Water was added to the concentrate, and the mixture was extracted with EA. The concentrate was washed with saturated NaHCO3 aqueous solution and saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4.58 g, which was used directly in the next step.

[0216] LC / MS[M+H] + =237.09, [M+Na] + =259.07, [M+K] + =275.04.

[0217] Second step reaction: ethyl 2-(4-((benzyloxy)carbonyl)amino)-3-oxoisoxazolidine-2-yl)ethyl acetate

[0218] 2 g (8.47 mmol) of (3-oxoisoxazolidine-4-yl) benzyl carbamate and 1.05 g (9.31 mmol) of t-BuOK were dissolved in 10 mL of DMF and reacted at room temperature for 1 h. Then, 1.70 g (10.16 mmol) of ethyl 2-bromoacetate was added dropwise, and the reaction was continued at room temperature for 8 h. Water was added to the concentrate, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:3) to give 1.07 g of the product, yield 39.19%.

[0219] LC / MS[M+H] + =323.13, [M+Na] + =345.11, [M+K] + =361.08.

[0220] Third step reaction: ethyl 2-(4-amino-3-oxoisoxazolidine-2-yl)acetate

[0221] 1 g (3.10 mmol) of ethyl 2-(4-((benzyloxy)carbonyl)amino)-3-oxoisoxazolidine-2-yl) was dissolved in 20 ml of methanol, 0.3 g of palladium on carbon was added, and a hydrogen atmosphere was provided using a hydrogen balloon. The mixture was kept at room temperature for 1 h, filtered, and concentrated to obtain 0.43 g of product, with a yield of 74%.

[0222] LC / MS[M+H] + =189.09, [M+Na] + =211.07, [M+K] + =227.04.

[0223] Example 4: Ethyl 2-(3-oxo-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoylamino)isoxazolidine-2-yl)acetate (compound 6)

[0224]

[0225] 0.50 g (1.94 mmol) of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid, 1.51 g (2.91 mmol) of PyBop, and 0.39 g (2.52 mmol) of triethylamine were dissolved in dichloromethane and stirred at room temperature for 30 min. Then, 0.36 g (1.94 mmol) of 2-(4-amino-3-oxoisoxazolidine-2-yl)ethyl acetate was added, and the mixture was stirred for another 5 h. The solution was concentrated under reduced pressure and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:2) to give 0.17 g of the product, with a yield of 20.48%.

[0226] LC / MS[M+H] + =429.10, [M+Na] + =451.08, [M+K] + =467.05.

[0227] 1 H NMR (400MHz, DMSO-d6): δ9.14(d,1H),8.18(d,2H),7.95(d,2H),4.54(t,1H),4.16-4.20(m,4H),4.06(q,2H),1.21(t,3H).

[0228] Example 5: N-(2-(cyanomethyl)-3-oxoisoxazolidine-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (compound 12)

[0229] 0.50 g (1.94 mmol) of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid, 1.51 g (2.91 mmol) of PyBop, and 0.39 g (2.52 mmol) of triethylamine were dissolved in dichloromethane and stirred at room temperature for 30 min. Then, 0.27 g (1.94 mmol) of 2-(4-amino-3-oxoisoxazolidine-2-yl)acetonitrile was added, and the mixture was stirred for another 6 h. The solution was concentrated under reduced pressure and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:2) to give 0.17 g of the product, with a yield of 20.48%.

[0230] LC / MS[M+H] + =382.08, [M+Na] +=404.06, [M+K] + =420.03.

[0231] 1 H NMR (400MHz, DMSO-d6): δ9.08(d,1H),8.10(d,2H),7.85(d,2H),5.15(t,1H),4.83(s,2H),4.64(t,1H),4.13(m,1H).

[0232] Example 6: N-(2-(2-(ethylamino)-2-oxoethyl)-3-oxoisoxazolidine-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (Compound 11)

[0233]

[0234] Step 1 reaction: 2-(3-oxo-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoylamino)isoxazolidine-2-yl)acetic acid

[0235] 1 g (2.33 mmol) of ethyl 2-(3-oxo-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoylamino)isoxazolidine-2-yl) was dissolved in 5 ml of ethanol. 2.5 ml of 2N LiOH solution was slowly added dropwise at 0 °C, maintaining pH 12, and the reaction was maintained at this temperature for 2 h. Hydrochloric acid was then added dropwise under an ice-water bath until the pH reached 2–3, causing a solid to precipitate. The solid was filtered, washed with water, and dried to give 0.89 g of a white product, with a yield of 95.70%.

[0236] LC / MS[M+H] + =401.07, [M+Na] + =423.05, [M+K] + =439.02.

[0237] Second step reaction: N-(2-(2-(ethylamino)-2-oxoethyl)-3-oxoisooxazolidine-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide

[0238] 0.50 g (1.25 mmol) of 2-(3-oxo-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoylamino)isoxazolidine-2-yl)acetic acid, 0.98 g (1.88 mmol) of PyBop, and 0.25 g (2.50 mmol) of triethylamine were dissolved in dichloromethane. The reaction mixture was stirred at room temperature for 30 min, and then 0.07 g (1.40 mmol) of ethylamine was added, followed by stirring for another 6 h. Water was added to the concentrate, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = 1:3) to give 0.18 g of the product, with a yield of 33.96%.

[0239] LC / MS[M+H] + =428.12, [M+Na] + =450.10, [M+K] + =466.07.

[0240] 1 H NMR (400MHz, DMSO-d6): δ9.08(d,1H),8.10(d,2H),7.85(d,2H),6.96(s,1H), 5.02(t,1H),4.44(m,1H),4.29(m,2H),4.19(t,1H),3.20(q,2H),1.19(t,3H).

[0241] Other compounds of the present invention were synthesized using the method described above.

[0242] Characterization data for other fractional (I) compounds are shown in Table 2 below:

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] Formulation Examples

[0268] In the following examples, all percentages are by weight, and all dosage forms were prepared using conventional methods.

[0269] Example 7:

[0270] This embodiment uses the compound obtained in the above embodiment to prepare a wettable powder, specifically using the following raw material composition ratio:

[0271] Compound 25 60.0%, dodecylphenol polyethoxylated glycol ether 4.0%, sodium lignosulfonate 5.0%, sodium aluminosilicate 6.0%, montmorillonite (calcined) 25.0%.

[0272] Example 8:

[0273] This embodiment uses the compound obtained in the above embodiment to prepare granules, specifically using the following raw material composition ratio:

[0274] Compound 33 10.0%, other components are sodium dodecyl sulfate 2%, calcium lignosulfonate 6%, potassium chloride 10%, polydimethylsiloxane 1%, and soluble starch to make up to 100%.

[0275] Example 9:

[0276] This embodiment uses the compound obtained in the above embodiment to prepare extruded pellets, specifically using the following raw material composition ratio:

[0277] Compound 71 25.0%, anhydrous calcium sulfate 10.0%, crude lignin sulfonate calcium 5.0%, sodium alkyl naphthalene sulfonate 1.0%, calcium / magnesium bentonite 59.0%.

[0278] Example 10:

[0279] This embodiment uses the compound obtained in the above embodiment to prepare an emulsifiable concentrate, specifically using the following raw material composition ratio:

[0280] Compound 103 25.0%, solvent 150 60%, PEG400 5%, Rhodacal 70 / B 3%, RhodameenRAM / 7 7%.

[0281] Example 11:

[0282] This embodiment uses the compound obtained in the above embodiment to prepare an aqueous suspension, specifically using the following raw material composition ratio:

[0283] Compound 116 30.0%, POE polystyrene phenyl ether sulfate 5.0%, xanthan gum 0.5%, polyethylene glycol 5%, triethanolamine 1%, sorbitol 0.5%, water to 100.0%.

[0284] Bioactivity assay

[0285] The compounds of this invention exhibit excellent activity against a variety of pathogens in the agricultural field.

[0286] Example 12:

[0287] 1. Bactericidal activity assay

[0288] The compounds of this invention were tested for in vivo protection against various fungal diseases of plants. The results of the fungicidal activity assays are shown in the following examples.

[0289] 1.1 In vivo protective activity assay

[0290] The determination method is as follows: A live pot test method is used. The sample of the compound to be tested is dissolved in a small amount of solvent (the type of solvent is such as acetone, methanol, DMF, etc., and the solvent is selected according to its solubility in the sample; the volume ratio of solvent to spray volume is equal to or less than 0.05), and diluted with water containing 0.1% Tween 80 to prepare the test solution of the required concentration. The test solution is sprayed onto the diseased host plants (standard potted seedlings cultivated in a greenhouse) using a crop sprayer. Disease inoculation is carried out 24 hours later. Based on the characteristics of the disease, diseased plants requiring temperature and humidity control are inoculated and placed in an artificial climate chamber for cultivation. After the disease has fully infected the plants, they are transferred to a greenhouse for cultivation. Diseased plants not requiring humidity control are directly inoculated and cultivated in the greenhouse. The disease control effect of the compound is evaluated after the control group has fully developed the disease (usually one week). Disease indices for each treatment are investigated at different levels, and the control effect is calculated according to the following formula.

[0291] Prevention and control effect = (Control disease index - Treatment disease index) ÷ Control disease index × 100%

[0292] (1) The test results of the efficacy of some compounds against corn rust are as follows:

[0293] Compounds with a control efficacy of over 80% against corn rust at a dosage of 10 ppm include: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 4 3, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168.

[0294] Compounds with a control efficacy of over 80% against corn rust at a dosage of 1 ppm include: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 36, 37, 38, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 56, 57, 58, 59, 60, 66, 67, 68, 69, 70, 71, 72, 73, 74, 80, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 99, 100, 101, 102, 103, 1 04, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 13 6, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168.

[0295] The compounds that have a control efficacy of over 80% against corn rust at a dose of 0.2 ppm are: 1, 2, 3, 5, 6, 7, 12, 53, 66, 68, 86, 92, 93, 107, and 133.

[0296] (2) The results of the test on the efficacy of the compound against rice blast are as follows:

[0297] The compounds that have a control efficacy of over 80% against rice blast at a dose of 100 ppm are: 1, 2, 3, 4, 5, 7, 9, 12, 27, 42, 47, 73, 86, 90, 111, 124, 133, 138, 140, 146, 156, and 160.

[0298] Compounds with a control efficacy of over 80% against rice blast at a dose of 10 ppm include: 1, 2, 3, 4, 5, 9, 12, 86, and 133.

[0299] (3) The results of the test on the efficacy of the compound against peanut white mold are as follows:

[0300] The compounds that have a control efficacy of over 80% against peanut white mold at a dose of 100 ppm are: 1, 2, 3, 4, 5, 7, 12, 27, 47, 77, 86, 121, 133, 138, 141, and 160.

[0301] The compounds that have a control efficacy of over 80% against peanut white mold at a dose of 10 ppm are: 1, 2, 3, 5, 12, 77, 86, 121, and 133.

[0302] 2. Test results of exemplary embodiment compounds and control reagents

[0303] This embodiment included an activity comparison test between the exemplary compound and the control agent (compounds CK1, CK2, and CK3). The test results are shown in Tables 3 and 4 below.

[0304]

[0305] Table 3

[0306]

[0307]

[0308] Table 4

[0309]

[0310] In addition to the compounds listed in the table above, the compounds of other exemplary embodiments of the present invention exhibit superior pathogen control activity compared to the control agents. Therefore, the compounds of formula (I) of the present invention demonstrate excellent activity against a variety of pathogens in the agricultural field.

[0311] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. A compound containing an oxadiazole or a pharmaceutically acceptable salt thereof, as shown in formula (I), in, R1, R2, R3, and R4 may be the same or different, and each is independently selected from hydrogen, halogen, or C1-C4 alkyl. R5 is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl-C1-C4 alkyl; R6 is selected from hydrogen or C1-C4 alkyl; R7 and R8 may be the same or different, and each is independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; X is selected from O or CR a R b ; R a R b They may be the same or different, and each is independently selected from hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; Q is selected from unsubstituted or arbitrarily assigned to one, two or more Rs. s1 The following groups are substituted: C3-C6 cycloalkyl C1-C4 alkyl, C1-C4 alkoxycarbonyl C1-C4 alkyl, C1-C4 alkyl-NHC(O)-C1-C4 alkyl or cyanoC1-C4 alkyl; Each R s1 They may be the same or different, and are independently selected from the following groups: halogen, cyano or C1-C4 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R1, R2, R3, and R4 may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, or methyl. Preferably, R1 and R2 are hydrogen, R3 is selected from H, F or methyl, and R4 is selected from hydrogen or fluorine.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R5 is selected from hydrogen or methyl; Preferably, R6 is selected from hydrogen, methyl, or ethyl; Preferably, R7 and R8 may be the same or different, and each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl; Preferably, R7 is selected from hydrogen or methyl, and R8 is selected from hydrogen or methyl.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, X is selected from O or CH2; Preferably, R s1 It is selected from fluorine, chlorine, bromine, cyano, methyl or ethyl.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, Q is selected from C3-C6 cycloalkyl or C1-C4 alkyl or is composed of one or more R. s1 Substituted C3-C6 cycloalkyl and C1-C4 alkyl; Preferably, Q is selected from C1-C4 alkoxycarbonyl C1-C4 alkyl or is surrounded by one or more R s1 Substituted C1-C4 alkoxycarbonyl C1-C4 alkyl; Preferably, Q is selected from C1-C4 alkyl-NHC(O)-C1-C4 alkyl or is formed by one or more R atoms. s1 Substituted C1-C4 alkyl-NHC(O)-C1-C4 alkyl; Preferably, Q is selected from cyano C1-C4 alkyl or is surrounded by one or more R atoms. s1 Substituted cyano C1-C4 alkyl groups; Preferably, Q is selected from 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that, The compound or its pharmaceutically acceptable salt has the structure described below. 。 7. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the preparation method comprises at least one of the following methods: Method 1, Method 2, Method 3, Method 4, or Method 5: Method 1 Method 2 L1 is selected from leaving groups, such as halogens (e.g., chloride groups); Method 3 L2 and L3 are selected from leaving groups, such as hydroxyl groups and halogens; Method 4 L2 and L3 are selected from leaving groups, such as hydroxyl groups and halogens; Method 5 in, R1, R2, R3, R4, R5, R6, R7, R8, Q, and X each have the definition as described in any one of claims 1-6.

8. A composition comprising at least one of the compounds of any one of claims 1-6 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. The use of at least one of the compounds of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the composition of claim 8, in the preparation of a bactericide; Preferably, the fungus is a fungus, such as a plant pathogen; Preferably, the plant can be a crop, such as corn, rice, or peanut; Preferably, the plant diseases caused by the pathogen can be selected from corn rust, rice blast, and peanut white mold.

10. A method for controlling pathogens, such as plant pathogens, comprising applying an effective amount of at least one of the compounds of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the composition of claim 8, to the growth medium of the plant pathogen.

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