Oxime ether derivatives containing heterocyclic amide, preparation method thereof, agricultural fungicide and application

Abstract

The present application relates to the field of agrochemical technology, in particular to oxime ether derivatives containing heterocyclic amide and its preparation method, agricultural fungicide and application, the oxime ether derivatives containing heterocyclic amide have the structure shown in formula I:;Wherein, M is selected from one of substituted oxygen-containing five-membered heterocycle, substituted sulfur-containing five-membered heterocycle;Substituted oxygen-containing five-membered heterocycle, substituted sulfur-containing five-membered heterocycle is the hydrogen atom on oxygen-containing five-membered heterocycle, sulfur-containing five-membered heterocycle is replaced by substituent group, the number of substituent group is 1-3, wherein at least one substituent group is halogen, and the substituent group includes 1-3 of H, F, Cl, Br, I, C1-C4 alkyl.The oxime ether derivatives containing heterocyclic amide provided by the present application can efficiently and selectively inhibit the growth of plant pathogenic oomycetes, and also has certain antifungal and antibacterial activity, and has no cross resistance with known mechanism fungicides, and can be used for preventing and treating stubborn diseases resistant to conventional agents.

Description

Technical Field

[0001] This invention relates to the field of agricultural chemistry, and in particular to oxime ether derivatives containing heterocyclic amides, their preparation methods, agricultural fungicides, and their applications. Background Technology

[0002] With the deepening and development of molecular biology research, people have increasingly realized that the differences in drug sensitivity among different species are related to the specificity of their cells and drug target protein structures, as well as the level of drug metabolism (inactivation or deactivation) in the host. Furthermore, the effectiveness in controlling diseases is also related to the drug delivery method and route. In recent years, based on fundamental research in pathological mechanisms and chemical biology, the creation of safe and efficient targeted drugs has developed at an unprecedented pace, providing new weapons for the treatment of many malignant human diseases.

[0003] In agriculture, the pursuit of high-quality, high-yield modern agricultural production methods has made plant disease control increasingly important. The pathogenic microorganisms that cause plant diseases are diverse, reproduce and mutate rapidly, often causing sudden and devastating losses to agricultural production. Chemical control using fungicides has always been the primary emergency measure for controlling the spread of major crop diseases both domestically and internationally.

[0004] However, with the widespread and long-term use of safe and efficient selective fungicides, the problem of pesticide resistance has become increasingly prominent. For example, almost all selective fungicides currently used to control oomycete diseases, such as benzamides, carboxylic amides, methoxyacrylates, and oxysterol-binding protein inhibitors (OSBPIs), as well as those used to control fungal diseases, including benzimidazoles, DMIs, QoIs, and SDHIs, have shown varying degrees of resistance in field or laboratory conditions. The emergence of pesticide resistance has significantly shortened the lifespan of pesticides, posing a severe challenge to the control of major crop diseases. Therefore, the discovery of lead compounds and novel fungicides with new mechanisms of action and high safety and efficiency is an urgent need for controlling pesticide resistance and ensuring sustainable and green prevention and control of major plant diseases.

[0005] The cell wall of a pathogen is the first barrier for drug penetration into cells, and its composition has a decisive influence on drug absorption and activity. The main components of fungal cell walls are highly hydrophobic chitin and small amounts of β-glucan and mannan; oomycete cell walls are composed of cellulose and β-1,4-glucan; while bacterial cell walls are mainly composed of lipopeptidose. The physicochemical properties of the cell walls of these three types of pathogens differ significantly, and this difference provides the possibility for designing and creating patentable, selective antibacterial drugs.

[0006] By rationally combining different active groups and optimizing their molecular structure, a crucial strategy for discovering lead compounds with novel mechanisms of action or creating new fungicides with improved antibacterial spectrum and activity is emerging. Oxime ether structures are important pharmacophores in many molecules with agricultural or medical bioactivity. In the field of fungicides, there are already successfully marketed products containing oxime ether structures, such as Trifloxystrobin, but these are primarily used for controlling fungal diseases. Summary of the Invention

[0007] The purpose of this invention is to provide antibacterial lead compounds containing heterocyclic amide oxime ether derivatives, their molecular preparation methods with optimized structures, agricultural fungicides, and applications. The provided heterocyclic amide oxime ether derivatives can efficiently and selectively inhibit the growth of plant pathogenic oomycetes, while also possessing certain antifungal and antibacterial activities. Furthermore, they exhibit no cross-resistance with existing fungicides with different mechanisms of action, are easily absorbed and translocated by plants, and can be used to control stubborn diseases that have developed resistance to conventional pesticides.

[0008] To achieve the above objectives, the present invention provides an oxime ether derivative containing a heterocyclic amide, characterized in that it has the structure shown in Formula I: ; M is selected from one of the substituted oxygen-containing five-membered heterocycles and the substituted sulfur-containing five-membered heterocycles; The hydrogen atoms on the oxygen-containing five-membered heterocycle are replaced by substituent groups, the sulfur-containing five-membered heterocycle is replaced by an oxygen-containing five-membered heterocycle, and the number of substituent groups is 1 to 3, of which at least one substituent group is a halogen. The substituent groups include 1 to 3 of the following: H, F, Cl, Br, I, and C1 to C4 alkyl groups.

[0009] Preferably, the oxygen-containing five-membered heterocycle is selected from one or more of furan-2-yl, furan-3-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, and 1,3,4-oxadiazol-2-yl; The sulfur-containing five-membered heterocycle is selected from one or more of thiophene-2-yl, thiophene-3-yl, thiazolyl-4-yl, thiazolyl-5-yl, isothiazol-4-yl, isothiazol-5-yl, and 1,3,4-thiadiazol-2-yl.

[0010] The preparation method of the above-mentioned heterocyclic amide-containing oxime ether derivative includes the following steps: mixing compound II, compound III, catalyst and organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; The structural formula of compound II is shown in Formula II, and the structural formula of compound III is shown in Formula III: ; ; Wherein, R is a C1~C4 alkyl group; M is selected from one of the following: substituted oxygen-containing five-membered heterocycles or substituted sulfur-containing five-membered heterocycles. The catalyst is selected from one of the following: alkaline catalyst, metal catalyst, and aluminum catalyst; the organic solvent is selected from one of the following: benzene, toluene, and xylene.

[0011] The preparation method of the above-mentioned heterocyclic amide-containing oxime ether derivative includes the following steps: mixing compound II, compound IV, catalyst and organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; The structural formula of compound IV is shown in Formula IV: ; Wherein, M is selected from one of the substituted oxygen-containing five-membered heterocycles or the substituted sulfur-containing five-membered heterocycles; The catalyst is selected from Lewis acid catalysts, organic catalysts, condensation catalysts, triphenylphosphine catalytic systems, and DMAP catalytic systems. The organic solvent is selected from DMF, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

[0012] The method for preparing the above-mentioned heterocyclic amide-containing oxime ether derivative includes the following steps: mixing compound II, compound V, an acid-binding agent, and an organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; compound V is shown in formula V: ; Wherein, M is selected from one of the substituted oxygen-containing five-membered heterocycles or the substituted sulfur-containing five-membered heterocycles; The acid-binding agent is an organic or inorganic base, and the organic solvent is selected from one of DMF, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

[0013] Agricultural fungicides include one of the following: heterocyclic amide oxime ether derivatives, agriculturally acceptable salts thereof, their hydrates, and their solvates; the heterocyclic amide oxime ether derivatives include (Z) isomers, (E) isomers, or mixtures of (Z) and (E) isomers.

[0014] The above-mentioned agricultural fungicides are used in the prevention and control of plant oomycete diseases and plant fungal diseases. Plant oomycete diseases are caused by oomycete pathogens of the order Peronomycetes, while plant fungal diseases are caused by basidiomycetes, ascomycetes, or deuteromycetes.

[0015] The beneficial effects of this invention are: (1) The heterocyclic amide-containing oxime ether derivatives provided by the present invention are composed of four parts: tetrazolium, oxime ether, pyridine amide and substituted oxygen-containing five-membered heterocycle or substituted sulfur-containing five-membered heterocycle. At least one halogen is substituted for the oxygen-containing five-membered heterocycle or sulfur-containing five-membered heterocycle, which greatly improves the antibacterial activity. At the same time, the present invention provides three methods for preparing heterocyclic amide-containing oxime ether derivatives, which respectively use formate esters, formic acid and formyl chloride containing oxygen-containing five-membered heterocycles or sulfur-containing five-membered heterocycles as raw materials. The synthesis methods are simple and convenient to operate.

[0016] (2) The heterocyclic amide-containing oxime ether derivatives of the present invention have the effect on downymildew and Phytophthora in plant pathogenic oomycetes. Phytophthora ) and Pythium ( Pythium All showed highly effective inhibitory activity against Rhizoctonia solani, a plant pathogenic fungus. Rhizoctonia Fusarium ( ) Fusarium ), Pyreosporium ( Pyricularia ), gray mold ( Botrytis ) and Alternaria ( Alternaria It also exhibits selective antibacterial activity, and a few compounds also show good antibacterial activity against plant pathogenic bacteria.

[0017] (3) The heterocyclic amide-containing oxime ether derivative provided by this invention has a novel structure. It not only has extremely high biological activity against a variety of plant pathogens, but also facilitates plant absorption and translocation, is safe for plants, and is adaptable to the environment. When used for the prevention and control of diseases in agricultural and garden crops, it is selective and conforms to the development direction of new targeted fungicides that are safe, efficient, low toxic, low in residue, and environmentally compatible, and meets the requirements for ensuring environmental and ecological safety. At the same time, it does not have cross-resistance with existing fungicides and can be used in combination with a variety of fungicides to prevent and control drug-resistant diseases. In particular, it can solve the problem of no drug available for multidrug-resistant diseases. In addition, it has high antibacterial activity, long duration of action, low dosage per unit area, low cost of use, long suitable application time, high input-output ratio, and good economic benefits, which meet the requirements of modern agricultural development.

[0018] The technical solution of the present invention will be further described in detail below through embodiments. Detailed Implementation

[0019] This invention provides oxime ether derivatives containing heterocyclic amides, characterized in that they have the structure shown in Formula I: ; M is selected from one of the substituted oxygen-containing five-membered heterocycles and the substituted sulfur-containing five-membered heterocycles; The hydrogen atoms on the oxygen-containing five-membered heterocycle are replaced by substituent groups, the sulfur-containing five-membered heterocycle is replaced by an oxygen-containing five-membered heterocycle, and the number of substituent groups is 1 to 3, of which at least one substituent group is a halogen. The substituent groups include 1 to 3 of the following: H, F, Cl, Br, I, and C1 to C4 alkyl groups.

[0020] More preferably, the five-membered heterocycle containing oxygen is replaced, the five-membered heterocycle containing sulfur is replaced with an oxygen-containing five-membered heterocycle, and the hydrogen atoms on the sulfur-containing five-membered heterocycle are replaced by substituents. The number of substituents is 1 to 2, of which at least one substituent is a halogen. The substituents include 1 to 2 types of H, F, Cl, Br, and methyl. Preferably, the oxygen-containing five-membered heterocycle is selected from one of furan-2-yl, furan-3-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, and 1,3,4-oxadiazol-2-yl; the sulfur-containing five-membered heterocycle is selected from one of thiophene-2-yl, thiophene-3-yl, thiazolyl-4-yl, thiazolyl-5-yl, isothiazol-4-yl, isothiazol-5-yl, and 1,3,4-thiadiazol-2-yl.

[0021] More preferably, the oxygen-containing five-membered heterocycle is selected from one of furan-2-yl, oxazol-5-yl, and isoxazol-5-yl; The sulfur-containing five-membered heterocycle is selected from one of thien-2-yl, thien-3-yl, thiazolyl-4-yl, thiazolyl-5-yl, isothiazol-5-yl, and 1,3,4-thiadiazol-2-yl.

[0022] In some specific embodiments of the present invention, the oxime ether derivative containing heterocyclic amides is selected from one of the following compounds: ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A1); ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A2); ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A3); ( Z )-4,5-dibromo-N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A4); ( Z )-3-Fluoro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A5); ( Z )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A6); ( Z )-4-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A7); ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A8); ( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A9); ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A10); ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A11); ( Z)-4,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A12); ( Z )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A13); ( Z )-3-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A14); ( Z )-4-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A15); ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A16); ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A17); ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A18); ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide (abbreviated as compound A19); ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide (abbreviated as compound A20); ( Z )-2,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A21); ( Z )-2,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A22); ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)oxazol-5-carboxamide (abbreviated as compound A23); ( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isoxazole-5-carboxamide (abbreviated as compound A24); ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A25); ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A26); ( Z )-2,5-dichloro- N -(6-(((((1-methyl-1) H-Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A27); ( Z )-2,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A28); ( Z )-2-chloro-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A29); ( Z )-2-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A30); ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-5-carboxamide (abbreviated as compound A31); ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-5-carboxamide (abbreviated as compound A32); ( Z )-2-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-5-carboxamide (abbreviated as compound A33); ( Z )-2-bromo-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-5-carboxamide (abbreviated as compound A34); ( Z )-3,4-dichloro-N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide (abbreviated as compound A35); ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (abbreviated as compound A36); ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (abbreviated as compound A37); ( Z / E )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A38); ( Z / E )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A39); ( Z / E )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A40); ( Z / E )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A41); ( Z / E )-3,4-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide (abbreviated as compound A42).

[0023] The heterocyclic amide-containing oxime ether derivatives of the present invention have at least one halogen substituted for an oxygen-containing five-membered heterocycle or a sulfur-containing five-membered heterocycle. The halogen, as an electron-withdrawing group, optimizes the lipid-water partition coefficient of the structure, which not only enables it to better penetrate the cell wall of pathogens and increase the binding force with target proteins, but also enables it to be better absorbed by plants and transported in plants, resulting in better disease control effects on plants. Meanwhile, the halogens on the oxygen-containing or sulfur-containing five-membered heterocycles interact with the target protein through halogen bonds, exhibiting highly directional non-covalent interactions. Coupled with hydrophobic filling, dipole matching, and unique halogen bond-π interactions, this significantly enhances binding affinity and selectivity. Consequently, the oxime ether derivatives of the heterocyclic amides of this invention (such as compounds A1 to A42) exhibit significantly higher bactericidal activity than compounds without substitution of the oxygen-containing or sulfur-containing five-membered heterocycles or those substituted with alkyl groups such as methyl groups (such as compounds A43 to A47). This gives the oxime ether derivatives of the heterocyclic amides of this invention a clear advantage over derivatives without halogen substitution on the oxygen-containing or sulfur-containing five-membered heterocycles.

[0024] The present invention also provides a method for preparing the above-mentioned heterocyclic amide-containing oxime ether derivative, comprising the following steps: mixing compound II, compound III, catalyst and organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; The structural formula of compound II is shown in Formula II, and the structural formula of compound III is shown in Formula III: ; ; Wherein, R is a C1~C4 alkyl group, preferably methyl or ethyl; M is selected from one of the substituted oxygen-containing five-membered heterocycles or the substituted sulfur-containing five-membered heterocycles.

[0025] Preferably, the catalyst is selected from one of the following: an alkaline catalyst, a metal catalyst, and an aluminum catalyst, and the organic solvent is selected from one of the following: benzene, toluene, and xylene.

[0026] More preferably, the catalyst is selected from one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium di(trimethylsilyl)amino, butyllithium, lithium chloride, cobalt chloride, copper sulfate, trimethylaluminum, triethylaluminum, and dimethylaminoaluminum, and even more preferably trimethylaluminum.

[0027] A further preferred organic solvent is toluene.

[0028] The present invention also provides a second method for preparing the above-mentioned heterocyclic amide-containing oxime ether derivative, comprising the following steps: mixing compound II, compound IV, catalyst and organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; The structural formula of compound IV is shown in Formula IV: ; M is selected from either a substituted oxygen-containing five-membered heterocycle or a substituted sulfur-containing five-membered heterocycle.

[0029] Preferably, the catalyst is selected from Lewis acid catalysts, organic catalysts, condensation catalysts, triphenylphosphine catalytic systems, and DMAP catalytic systems, and the organic solvent is selected from DMF, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

[0030] More preferably, the catalyst is selected from one or more of zinc chloride, zinc sulfate, titanium tetrachloride, ammonia-borane, DCC, EDCI, DIC, HOBT, HATU, HCTU, CDI, and DMAP.

[0031] More preferably, the organic solvent is selected from one or more of DMF, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and toluene.

[0032] This invention also provides a third method for preparing the above-mentioned heterocyclic amide-containing oxime ether derivative, comprising the following steps: mixing compound II, compound V, an acid-binding agent, and an organic solvent, and carrying out an amidation reaction to obtain the heterocyclic amide-containing oxime ether derivative; compound V is shown in formula V: ; M is selected from either a substituted oxygen-containing five-membered heterocycle or a substituted sulfur-containing five-membered heterocycle.

[0033] Preferably, the acid-binding agent is an organic or inorganic base, and the organic solvent is selected from one of DMF, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

[0034] More preferably, the acid-binding agent is selected from one of triethylamine, pyridine, DMAP, DIPEA, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.

[0035] Preferably, the acid-binding agent is selected from triethylamine or potassium carbonate.

[0036] Preferably, the organic solvent is selected from one of dichloromethane, chloroform, acetonitrile, and tetrahydrofuran.

[0037] More preferably, the preparation step of compound II in this invention is as follows: compound VII and compound VIII are synthesized into compound VI in the presence of an acid-binding agent and an organic solvent, and compound VI is hydrolyzed to prepare compound II; the structural formulas of compounds VI, VII, and VIII are shown in formulas VI, VII, and VIII, respectively: , , .

[0038] The preparation of compound VII was carried out in accordance with the methods described in [Monatshefte fuer Chemie (2021), 152(1), 121-135] and [Bioorganic & Medicinal Chemistry Letters (2021), 34, 127762]. Compound VIII was prepared according to the methods described in [Bioorganic & Medicinal Chemistry (2006), 14(10), 3563-3570] and [ACS Medicinal Chemistry Letters (2025), 16(4), 651-659]. The acid-binding agent is selected from organic and inorganic bases; preferably triethylamine, pyridine, DMAP, DIPEA, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide; further preferably triethylamine, potassium carbonate, and cesium carbonate.

[0039] The organic solvent is selected from DMF, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene, with dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, and toluene being preferred; and dichloromethane, chloroform, acetonitrile, and tetrahydrofuran being even more preferred.

[0040] Hydrolysis can be carried out in an aqueous solution of an alkali or an aqueous solution of an acid, preferably in an aqueous solution of hydrochloric acid.

[0041] Agricultural fungicides include one of the above-mentioned heterocyclic amide-containing oxime ether derivatives, agriculturally acceptable salts thereof, their hydrates, and their solvates, wherein the heterocyclic amide-containing oxime ether derivatives include (Z) isomers, (E) isomers, or mixtures of (Z) and (E) isomers.

[0042] Furthermore, the agricultural fungicide further includes excipients. These excipients are preferably those acceptable for agricultural production, and more preferably include one or more of the following: carrier, solvent, co-solvent, surfactant, dispersant, emulsifier, wetting agent, suspending agent, thickener, stabilizer, defoamer, antifreeze, and synergist. Any excipients available in the prior art are acceptable, and this invention does not impose further limitations.

[0043] More preferably, the content of the active ingredient in the agricultural fungicide of the present invention is preferably 0.1~99.9 wt%. In the present invention, the formulation of the agricultural fungicide preferably includes one of the following: mother powder, mother liquor, emulsifiable concentrate, suspension concentrate, aqueous solution, water emulsion, microemulsion, powder, wettable powder, soluble powder, granules, water-dispersible granules, oil, fumigant, and bait.

[0044] The above-mentioned agricultural fungicides are used in the prevention and control of plant oomycete diseases and plant fungal diseases. Plant oomycete diseases are caused by oomycete pathogens of the order Peronomycetes, while plant fungal diseases are caused by basidiomycetes, ascomycetes, or deuteromycetes.

[0045] More preferably, the plant pathogenic oomycetes of the order Peronomycetes include the genus Phytophthora ( Phytophthora Phytophthora ( ) Sclerophthora ), genus *Peronospora* ( Sclerospora ), genus *Peronospora* ( Plasmopara ), Phytophthora ( Peronophythia ), genus *Pseudomonas* Downy mildew ), genus *Peronospora* Downy mildew ), genus *Peronospora* ( Bremia ), genus *Peronospora* ( Downy mildew ), White Rust ( Albugo ), Pythium ( Pythium One or more of the following.

[0046] The preferred basidiomycete is Rhizoctonia solani (…). Rhizoctonia The ascomycetes are Fusarium ( ); Fusarium ), gray mold ( Botrytis ) and Pyreospora ( Pyricularia ).

[0047] The present invention will be further described below with reference to embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0048] Compound II in all embodiments of this invention was prepared by the following steps: (1) Compound VII (10 mmol), compound VIII (10 mmol) and cesium carbonate (30 mmol) were added to acetonitrile (50 mL) and stirred. The reaction mixture was heated to reflux and the reaction progress was monitored by thin-layer chromatography until the starting material disappeared. After the reaction was completed, the mixture was filtered, the filtrate was collected, and the mixture was distilled under reduced pressure. 20 mL of ethyl acetate was added to dissolve the filtrate, and the mixture was washed with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was collected. The mixture was distilled under reduced pressure and recrystallized with ethanol to obtain compound VI in 90% yield.

[0049] .

[0050] (2) Compound VI (0.05 mol) was added to 25 mL of methanol and stirred. 15 mL of 10% HCl (hydrochloric acid) solution was slowly added dropwise. The reaction mixture was heated to reflux and the reaction progress was monitored by thin-layer chromatography until the starting material disappeared. After the reaction was completed, methanol was removed by vacuum distillation. The mixture was diluted with 20 mL of ethyl acetate and extracted. It was washed with saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and recrystallized with ethanol to obtain compound II with a yield of 72%.

[0051] .

[0052] Referring to literature such as "Pesticide Bioassay" edited by Shen Jinliang (China Agriculture Press, 2013, Beijing), and using plant pathogen materials preserved and temporarily collected in our laboratory, the bioactivity of the heterocyclic amide-containing oxime ether derivatives of this invention against pathogenic Phytophthora (causing late blight of potato and tomato), Phytophthora capsici (causing blight of various fruits and vegetables), Phytophthora lychee, Pythium spp. of melons, Pythium spp. of grapes, Pythium spp. of cucumbers, rice sheath blight, rice blast fungus, wheat scab, strawberry gray mold, and potato early blight fungus was determined.

[0053] Specifically, the heterocyclic amide-containing oxime ether derivatives obtained in Examples 1-39 of this invention were dissolved in dimethyl sulfoxide (DMSO) or methanol to obtain a stock solution with a concentration of 1000 μg / mL. The stock solution was then added to potato dextrose agar (PDA) medium, lima bean medium, or NA medium cooled to 45°C, mixed thoroughly, and then diluted with a drug-free medium to a series of proportionally proportional drug-containing mediums with final concentrations of 2.5 μg / mL and 0.25 μg / mL, 0.025 μg / mL, 0.0025 μg / mL, 0.00025 μg / mL, or 1 μg / mL, 0.1 μg / mL, 0.01 μg / mL, 0.001 μg / mL, and 0.0001 μg / mL of the heterocyclic amide-containing oxime ether derivatives. Simultaneously, a culture medium containing an equal amount of solvent but without the heterocyclic amide-containing oxime ether derivatives was prepared as a blank control. PDA medium was inoculated with *Rhizoctonia solani*, *Bacillus oryzae*, *Fusarium graminearum*, and *Botrytis cinerea*. Lima bean medium was inoculated with *Phytophthora indicum*, *Phytophthora capsici*, *Phytophthora lychee*, and *Pythium spp.*. NA medium was inoculated with *Bacillus bacterial blight*. The cultures were incubated at appropriate temperatures. When the fungal or oomycete colonies on the blank control plates reached near the edge of the petri dish (90 mm or 50 mm), the minimum inhibitory concentration (MIC) was measured, or the median inhibitory concentration (EC) was calculated based on the inhibition rate at a series of concentrations. 50The activity of bacteria was determined based on colonies inoculated on NA plates using streak plating.

[0054] Example 1 preparation( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A1) includes the following steps: 0.0105 mol of compound III (methyl 5-chlorofuran-2-carboxylate) and 0.01 mol of compound II were added to 20 mL of toluene. 0.01 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 5 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 100 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL, divided twice), and washed with saturated brine (50 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, v / v ratio 1:2) to give a white solid powder, compound A1, in 78% yield. The NMR data of compound A1 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.58 (s, 1H, NH), 8.23 ​​(d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.27 (d, J = 4.2 Hz, 1H, Fur-H), 7.06 (d, J = 7.5Hz, 1H, PyH), 6.39 (d, J = 3.5 Hz, 1H, Fur-H), 5.32 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0055] The compound A1 prepared in this embodiment strongly inhibited the mycelial growth of plant pathogenic oomycetes on drug-containing culture plates. The minimum inhibitory concentration (MIC) against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, *Phytophthora citrinum*, and *Phytophthora lychee* was less than 0.1 μg / mL, and the effective median concentration (EC50) for inhibiting mycelial growth was also less than 0.1 μg / mL. 50 The concentration was 0.0001-0.0008 μg / mL. It inhibited the EC50 of *Agropyron regiatum* and *Bacillus thuringiensis*. 50 The concentration is 5~25 μg / mL.

[0056] Example 2 preparation( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A2) includes the following steps: 0.01 mol of compound III (methyl 4-bromofuran-2-carboxylate) and 0.01 mol of compound II were added to 20 mL of toluene. 0.01 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 4 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 100 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL, divided twice), and washed with saturated brine (50 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, volume ratio 1:2) to give a yellow powdery solid, compound A2, in 82% yield. The NMR data of compound A2 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.65 (s, 1H, NH), 8.22 (d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.56 (s, 1H, Fur-H), 7.52-7.50 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.30 (s, 1H, Fur-H),7.07 (d, J= 7.4 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0057] The compound A2 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.002 to 0.0075 μg / mL. It inhibited the EC50 of Fusarium graminearum, the causal agent of wheat scab, and rice blast fungus. 50 Less than 25 μg / mL.

[0058] Example 3 preparation( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A3) includes the following steps: 0.021 mol of compound III (methyl 5-bromofuran-2-carboxylate) and 0.02 mol of compound II were added to 50 mL of toluene. 0.02 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 6 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 150 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (80 mL, divided twice), and washed with saturated brine (80 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and recrystallized from ethanol to give a pale yellow oily liquid, compound A3, with a yield of 72%. The NMR data of compound A3 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.70 (s, 1H, NH), 8.24 (d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.24 (d, J = 3.6 Hz, 1H, Fur-H), 7.07 (d, J= 7.5Hz, 1H, PyH), 6.53 (d, J = 3.6 Hz, 1H, Fur-H), 5.32 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0059] The compound A3 prepared in this embodiment showed a MIC value of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates; EC50... 50 The values ​​were all 0.0001-0.0005 μg / mL; EC50 against the growth of rice bacterial blight pathogens. 50 It is 0.1 μg / mL.

[0060] Example 4 preparation( Z )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A4) includes the following steps: 0.016 mol of compound III (ethyl 4,5-dibromofuran-2-carboxylate) and 0.015 mol of compound II were added to 30 mL of toluene. 0.015 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 4.5 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 120 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (60 mL, divided twice), and washed with saturated brine (60 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, v / v ratio 1:5) to obtain a yellow powdery solid, compound A4, with a yield of 85%. The NMR data of compound A4 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.60 (s, 1H, NH), 8.21 (d, J = 8.3 Hz, 1H, PyH), 7.76 (t, J= 7.9 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H,PhH), 7.40-7.36 (m, 2H, PhH), 7.30 (s, 1H, Fur-H), 7.08 (d, J = 7.5 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0061] The compound A4 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.00025 to 0.001 μg / mL.

[0062] Example 5 preparation( Z )-3-Fluoro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A5) includes the following steps: 0.0102 mol of compound III (methyl 3-fluorothiophene-2-carboxylate) and 0.01 mol of compound II were added to 20 mL of toluene. 0.01 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 5.5 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 100 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL, divided twice), and washed with saturated brine (50 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, v / v ratio 1:4) to give a yellow oily liquid, compound A5, in 76% yield. The NMR data of compound A5 are as follows: 1 H-NMR (400 MHz, CDCl3) d 8.65 (d, J = 9.6 Hz, 1H, NH), 8.21 (d, J = 8.3Hz, 1H, PyH), 7.74 (t, J= 7.8 Hz, 1H, PyH), 7.53-7.50 (m, 3H, Thi-H+2PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.05 (d, J = 7.5 Hz, 1H, PyH), 6.93 (d, J = 5.5 Hz, 1H, Thi-H), 5.31 (s, 2H, OCH2), 4.04 (s, 3H, NCH3).

[0063] The compound A5 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC5... 50 The concentration ranges from 0.001 to 0.0075 μg / mL.

[0064] Example 6 preparation( Z )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A6) includes the following steps: 0.01 mol of compound IV (3-chlorothiophene-2-carboxylic acid), 0.01 mol of compound II, 0.01 mol of DCC, and 0.01 mol of DMAP were added to 20 mL of LDM. The mixture was stirred and reacted at room temperature. The reaction progress was monitored by thin-layer chromatography, and the reaction was completed after 24 h. The mixture was filtered, and the solvent was removed by vacuum distillation. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL, divided into two portions). The extracts were washed with saturated brine (50 mL, divided into two portions), and the organic extracts were combined. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, volume ratio 1:5) to give a white powdery solid, which was compound A6, with a yield of 78%. The NMR data of compound A6 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.33 (s, 1H, NH), 8.23 ​​(d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 7.8 Hz, 1H, PyH), 7.58 (d, J= 5.3 Hz, 1H, Thi-H), 7.53-7.51(m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.08-7.06 (m,2H, Thi-H+PyH), 5.32 (s, 2H, OCH2), 4.03 (s, 3H, NCH3).

[0065] The compound A6 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration was 0.001-0.05 μg / mL. It exhibited high activity against the pathogenic bacteria causing rice bacterial blight, with an EC value of [missing value]. 50 It is 0.01 μg / mL.

[0066] Example 7 preparation( Z )-4-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A7) includes the following steps: 0.0103 mol of compound V (4-chlorothiophene-2-formyl chloride), 0.01 mol of compound II, and 0.02 mol of triethylamine were added to 20 mL of dichloromethane and stirred. The mixture was reacted at room temperature, and the reaction progress was monitored by thin-layer chromatography. The reaction was completed after 3 h. The mixture was washed with water (50 mL, divided twice). The organic phase was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluting solvent: ethyl acetate + petroleum ether, v / v ratio 1:6) to obtain a yellow powdery solid, compound A7, in 80% yield. The NMR data of compound A7 are as follows: 1 H-NMR (400 MHz, CDCl3) d 8.46 (br, 1H, NH), 8.20 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.61 (s, 1H, Thi-H), 7.51 (d, J= 7.2 Hz,2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 3H, Thi-H+2PhH), 7.05 (d, J =7.5 Hz, 1H, PyH), 6.93 (d, J = 5.5 Hz, 1H, Thi-H), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0067] The compound A7 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.00075 to 0.001 μg / mL. It exhibited extremely high activity against the pathogenic bacteria causing rice bacterial blight, with an EC value of [missing value]. 50 It is 0.001 μg / mL.

[0068] Example 8 preparation( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A8) includes the following steps: 0.0101 mol of compound III (methyl 5-chlorothiophene-2-carboxylate) and 0.01 mol of compound II were added to 20 mL of toluene. 0.01 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 5 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 100 mL of 1 M hydrochloric acid aqueous solution, extracted with ethyl acetate (50 mL, divided twice), and washed with saturated brine (50 mL, divided twice). The organic extracts were combined, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate + petroleum ether, v / v ratio 1:8) to give a yellow powdery solid, compound A8, with a yield of 81%. The NMR data of compound A8 are as follows: 1 H-NMR (400 MHz, CDCl3) d 8.46 (br, 1H, NH), 8.20 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J= 7.9 Hz, 1H, PyH), 7.61 (s, 1H, Thi-H), 7.51 (d, J = 7.2 Hz,2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 3H, Thi-H+2PhH), 7.05 (d, J =7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0069] The compound A8 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration is 0.0005-0.001 μg / mL.

[0070] Example 9 preparation( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A9) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 3-bromothiophene-2-carboxylate; a white powdery solid, compound A9, was finally prepared with a yield of 84%. The NMR data of compound A9 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.42 (s, 1H, NH), 8.23 ​​(d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.56 (d, J = 5.3 Hz, 1H, Thi-H), 7.53-7.51(m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.12 (d, J = 5.3Hz, 1H, Thi-H), 7.07 (d, J= 7.5 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.02 (s, 3H, NCH3).

[0071] The compound A9 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.2 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates; EC50... 50 The concentration is 0.005-0.05 μg / mL.

[0072] Example 10 preparation( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A10) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4-bromothiophene-2-carboxylate; the final product is a yellow powdery solid, compound A10, with a yield of 79%. The NMR data of compound A10 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.47 (s, 1H, NH), 8.20 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.65 (d, J = 1.0 Hz, 1H, Thi-H), 7.53-7.51(m, 3H, 2PhH+Thi-H), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.05 (d, J = 7.4 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0073] The compound A10 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration is 0.0005-0.001 μg / mL.

[0074] Example 11 preparation( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A11) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 5-bromothiophene-2-carboxylate; the final product is a light yellow powdery solid, compound A11, with a yield of 70%. The NMR data of compound A11 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.40 (s, 1H, NH), 8.19 (d, J = 8.3 Hz, 1H, PyH), 7.74 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.50 (m, 3H, Thi-H+PhH), 7.47-7.44(m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.13 (d, J = 4.0 Hz, 1H, Thi-H), 7.04 (d, J = 7.4 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0075] The compound A11 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.001 to 0.0075 μg / mL.

[0076] Example 12 preparation( Z )-4,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A12) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4,5-dichlorothiophene-2-carboxylate; the final compound A12 is a light yellow powder solid with a yield of 75%. The NMR data of compound A12 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.50 (s, 1H, NH), 8.16 (d, J = 8.2 Hz, 1H, PyH), 7.74 (t, J = 7.8 Hz, 1H, PyH), 7.58 (s, 1H, Thi-H), 7.52-7.50 (m, 2H,PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.04 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0077] The compound A12 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.001 to 0.05 μg / mL.

[0078] Example 13 preparation( Z )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A13) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4,5-dibromothiophene-2-carboxylate; the final compound A13 was a white powder solid with a yield of 78%. The NMR data of compound A13 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.48 (s, 1H, NH), 8.16 (d, J = 8.2 Hz, 1H, PyH), 7.74 (t, J= 7.9 Hz, 1H, PyH), 7.58 (s, 1H, Thi-H), 7.52-7.50 (m, 2H,PhH), 7.48-7.44 (m, 1H, PhH), 7.41-7.37 (m, 2H, PhH), 7.04 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0079] The MIC (micronizable concentration) of compound A13 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.01 to 0.075 μg / mL.

[0080] Example 14 preparation( Z )-3-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A14) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 3-chloro-4-methylthiophene-2-carboxylate; the final compound A14 is a yellow powder solid with a yield of 80%. The NMR data of compound A14 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.37 (br, 1H, NH), 8.24 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.53-7.51 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.43-7.36 (m, 2H, PhH), 7.30 (d, J = 0.9 Hz, 1H, Thi-H), 7.06 (d, J = 7.4Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.03 (s, 3H, NCH3), 2.28 (d, J= 0.8 Hz, 3H, Thi-CH3).

[0081] The MICs (micronization limits) of compound A14 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture plates were 0.25 μg / mL, 0.1 μg / mL, 0.25 μg / m, and 0.5 μg / m, respectively; EC (expiratory value) 50 The concentration was 0.0006-0.01 μg / mL.

[0082] Example 15 preparation( Z )-4-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A15) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4-bromo-5-methylthiophene-2-carboxylate; the final compound A15 was a yellow powder solid with a yield of 71%. The NMR data of compound A15 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.35 (s, 1H, NH), 8.19 (d, J = 8.3 Hz, 1H, PyH), 7.73 (t, J = 7.9 Hz, 1H, PyH), 7.55 (s, 1H, Thi-H), 7.52-7.50 (m, 2H,PhH), 7.47-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.04 (d, J = 7.5 Hz, 1H, PyH), 5.29 (s, 2H, OCH2), 3.99 (s, 3H, NCH3), 2.47 (s, 3H, Thi-CH3).

[0083] The compound A15 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.001 to 0.025 μg / mL.

[0084] Example 16 preparation( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A16) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-chlorothiophene-3-carboxylate; the final compound A16 is a pale yellow powder solid with a yield of 78%. The NMR data of compound A16 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.84 (s, 1H, NH), 8.26 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.47 (d, J = 5.9 Hz,1H, Thi-H), 7.45-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.17 (d, J = 5.8Hz, 1H, Thi-H), 7.06 (d, J = 7.5 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0085] The MIC (micronizable concentration) of compound A16 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration is 0.01-0.05 μg / mL.

[0086] Example 17 preparation( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A17) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 5-chlorothiophene-3-carboxylate; the final compound A17 was a yellow powder solid with a yield of 85%. The NMR data of compound A17 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.42 (s, 1H, NH), 8.22 (d, J = 8.3 Hz, 1H, PyH), 7.89 (d, J = 1.7 Hz, 1H, Thi-H), 7.74 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.50(m, 2H, PhH), 7.48-7.43 (m, 1H, PhH), 7.41 (d, J = 1.8 Hz, 1H, Thi-H), 7.40-7.36 (m, 2H, PhH), 7.03 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 3.99 (s, 3H, NCH3).

[0087] The MICs (micronization limits) of compound A17 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates were 1, 0.1, 0.1, and 0.1 μg / mL, respectively; EC (expiratory values) were also observed. 50 The concentration ranges from 0.001 to 0.005 μg / mL.

[0088] Example 18 preparation( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A18) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-bromothiophene-3-carboxylate; the final compound A18 was a pale yellow powder with a yield of 88%. The NMR data for compound A18 are as follows: 1 H-NMR (400 MHz, CDCl3) d: 8.79 (s, 1H, NH), 8.26 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.53-7.51 (m, 2H, PhH), 7.47-7.43 (m, 2H,PhH+Thi-H), 7.40-7.36 (m, 2H, PhH), 7.32 (d, J = 5.8 Hz, 1H, Thi-H), 7.06 (d, J =7.4 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0089] The compound A18 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture plates; EC50... 50 The concentration ranges from 0.001 to 0.0075 μg / mL.

[0090] Example 19 preparation( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A19) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4-bromothiophene-3-carboxylate; the final compound A19 was a yellow powder solid with a yield of 76%. The NMR data of compound A19 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.97 (s, 1H, NH), 8.27 (d, J = 8.3 Hz, 1H, PyH), 8.18 (d, J = 3.7 Hz, 1H, Thi-H), 7.76 (t, J= 7.9 Hz, 1H, PyH), 7.53-7.51(m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.41-7.36 (m, 3H, 2PhH+Thi-H), 7.06 (d, J = 7.5 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0091] The MICs (micronization limits) of compound A19 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates were 0.25, 0.1, 0.1, and 0.1 μg / mL, respectively; EC (excessive saturation) was 0.1 μg / mL. 50 The concentration ranged from 0.0025 to 0.075 μg / mL.

[0092] Example 20 preparation( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A20) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 5-bromothiophene-3-carboxylate; the final compound A20 is a pale yellow powder solid with a yield of 80%. The NMR data of compound A20 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.38 (s, 1H, NH), 8.22 (d, J = 8.3 Hz, 1H, PyH), 8.00 (d, J = 1.6 Hz, 1H, Thi-H), 7.74 (t, J = 8.0 Hz, 1H, PyH), 7.54-7.50(m, 3H, 2PhH+Thi-H), 7.46-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.04 (d, J = 7.4 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0093] The compound A20 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration is 0.0001-0.001 μg / mL.

[0094] Example 21 preparation( Z )-2,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A21) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2,5-dichlorothiophene-3-carboxylate; the final compound A21 is a yellow oily liquid with a yield of 79%. The NMR data of compound A21 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.77 (br, 1H, NH), 8.21 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H,PhH), 7.40-7.36 (m, 2H, PhH), 7.31 (s, 1H, Thi-H), 7.07 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0095] The compound A21 prepared in this embodiment showed MICs of 1, 1, and 2.5 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora virosa* on drug-containing culture medium plates, respectively; EC50... 50 The concentration ranges from 0.05 to 0.125 μg / mL.

[0096] Example 22 preparation( Z )-2,5-dibromo- N -(6-(((((1-methyl-1) H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-3-carboxamide (abbreviated as compound A22) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2,5-dibromothiophene-3-carboxylate; the final compound A22 was a yellow powder solid with a yield of 79%. The NMR data of compound A22 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.70 (s, 1H, NH), 8.21 (d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.47-7.43 (m, 2H,PhH+Thi-H), 7.40-7.36 (m, 2H, PhH), 7.06 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0097] The MIC (micronizable concentration) of compound A22 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.005 to 0.025 μg / mL.

[0098] Example 23 preparation( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)oxazol-5-carboxamide (abbreviated as compound A23) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 4-bromooxazol-5-carboxylate; the final compound A23 was a white solid with a yield of 73%. The NMR data for compound A23 are as follows: 1 H-NMR (400 MHz, CDCl3) d: 9.69 (br, 1H, NH), 8.24 (d, J = 8.3 Hz, 1H, PyH), 7.98 (s, 1H, Oxa-H), 7.77 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H,PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.09 (d, J = 7.5 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0099] The MIC (micronizable concentration) of compound A23 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.005 to 0.125 μg / mL.

[0100] Example 24 preparation( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isoxazole-5-carboxamide (abbreviated as compound A24) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 3-bromoisoxazole-5-carboxylate; the final compound A24 is a yellow solid with a yield of 72%. The NMR data of compound A24 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.82 (s, 1H, NH), 8.19 (d, J = 8.3 Hz, 1H, PyH), 7.79 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44 (m, 1H,PhH), 7.41-7.37 (m, 2H, PhH), 7.12 (s, 1H, Isoxaz-H), 7.11 (d, J= 7.4 Hz, 1H, PyH), 5.33 (s, 2H, OCH2), 4.02 (s, 3H, NCH3).

[0101] The MIC (micronizable concentration) of compound A24 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration is 0.005-0.01 μg / mL.

[0102] Example 25 preparation( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A25) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-chlorothiazol-4-carboxylate; the final compound A25 is a white powder solid with a yield of 82%. The NMR data of compound A25 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.51 (s, 1H, NH), 8.26 (d, J = 8.2 Hz, 1H, PyH), 8.15 (s, 1H, Thi-H), 7.76 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.51 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.06 (d, J = 7.4 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.04 (s, 3H, NCH3).

[0103] The MICs (micronization limits) of compound A25 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates were 0.5, 0.5, 0.5, and 0.1 μg / mL, respectively; EC (excessive saturation) was [not specified]. 50 The concentration is 0.0005-0.001 μg / mL.

[0104] Example 26 preparation( Z)-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A26) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-bromothiazole-4-carboxylate; the final compound A26 is a light yellow powder solid with a yield of 89%. The NMR data of compound A26 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.55 (s, 1H, NH), 8.27 (d, J = 8.2 Hz, 1H, PyH), 8.20 (s, 1H, Thi-H), 7.76 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.51 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.07 (d, J = 7.5 Hz, 1H, PyH), 5.33 (s, 2H, OCH2), 4.04 (s, 3H, NCH3).

[0105] The compound A26 prepared in this embodiment had a MIC of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.0025 to 0.0075 μg / mL.

[0106] Example 27 preparation( Z )-2,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A27) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is ethyl 2,5-dichlorothiazol-4-carboxylate; the final compound A27 was a white powder solid with a yield of 85%. The NMR data of compound A27 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.47 (br, 1H, NH), 8.26 (d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.48 (m, 2H, PhH), 7.46-7.42 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 7.07 (d, J = 7.5 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.03 (s, 3H, NCH3).

[0107] The MIC (micronizable concentration) of compound A27 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.001 to 0.015 μg / mL.

[0108] Example 28 preparation( Z )-2,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A28) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2,5-dibromothiazol-4-carboxylate; the final compound A28 was a yellow powder solid with a yield of 89%. The NMR data of compound A28 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.59 (s, 1H, NH), 8.28 (d, J = 8.4 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.07 (d, J= 7.4 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.03 (s, 3H, NCH3).

[0109] The MIC (micronizable concentration) of compound A28 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration is 0.0005-0.001 μg / mL.

[0110] Example 29 preparation( Z )-2-chloro-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A29) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is ethyl 2-chloro-5-methylthiazol-4-carboxylate; the final compound A29 is a light yellow powder solid with a yield of 77%. The NMR data of compound A29 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.60 (s, 1H, NH), 8.24 (d, J = 8.2 Hz, 1H, PyH), 7.73 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.04 (d, J = 7.5 Hz, 1H, PyH), 5.32 (s, 2H,OCH2), 4.04 (s, 3H, NCH3), 2.84 (s, 3H, Thi-CH3).

[0111] The compound A29 prepared in this embodiment had a MIC of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.001 to 0.025 μg / mL. It exhibited low activity against the tested plant pathogenic fungi and inhibited the EC50 of rice bacterial blight pathogens. 50 It is 0.25 μg / mL.

[0112] Example 30 preparation( Z )-2-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-4-carboxamide (abbreviated as compound A30) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-bromo-5-methylthiazolyl-4-carboxylate; the final compound A30 is a light yellow powder solid with a yield of 90%. The NMR data of compound A30 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.63 (s, 1H, NH), 8.24 (d, J = 8.3 Hz, 1H, PyH), 7.74 (t, J = 7.9 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.46-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.04 (d, J = 7.4 Hz, 1H, PyH), 5.32 (s, 2H,OCH2), 4.04 (s, 3H, NCH3), 2.84 (s, 3H, Thi-CH3).

[0113] The compound A30 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture plates; EC50... 50 The concentrations were 0.01, 0.0005, 0.0005, and 0.0005 μg / mL, respectively. The EC50 values ​​for the tested plant pathogenic fungi and rice bacterial blight pathogens were... 50 Less than 10 μg / mL.

[0114] Example 31 preparation( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide (abbreviated as compound A31) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-chlorothiazol-5-carboxylate; the final compound A31 was a white solid with a yield of 70%. The NMR data of compound A31 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.62 (s, 1H, NH), 8.22 (s, 1H, Thi-H), 8.14(d, J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.05 (d, J = 7.5 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0115] The compound A31 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentrations were 0.0025, 0.0025, 0.0025, and 0.0005 μg / mL, respectively.

[0116] Example 32 preparation( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide (abbreviated as compound A32) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-bromothiazol-5-carboxylate; the final compound A32 was a white solid with a yield of 87%. The NMR data of compound A32 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.66 (s, 1H, NH), 8.22 (s, 1H, Thi-H), 8.14(d,J = 8.3 Hz, 1H, PyH), 7.75 (t, J = 7.8 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.05 (d, J = 7.5 Hz, 1H, PyH), 5.31 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0117] The MIC (micronizable concentration) of compound A32 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.0001 to 0.0025 μg / mL.

[0118] Example 33 preparation( Z )-2-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide (abbreviated as compound A33) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 2-chloro-4-methylthiazolyl-5-carboxylate; the final compound A33 was a pale yellow powder with a yield of 82%. The NMR data for compound A33 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.15-8.13 (m, 2H, NH+PyH), 7.75 (t, J = 7.8Hz, 1H, PyH), 7.51-7.49 (m, 2H, PhH), 7.47-7.44 (m, 1H, PhH), 7.40-7.36 (m,2H, PhH), 7.06 (d, J = 7.5 Hz, 1H, PyH), 5.29 (s, 2H, OCH2), 4.00 (s, 3H, NCH3), 2.75 (s, 3H, Thi-CH3).

[0119] The MIC (micronizable concentration) of compound A33 prepared in this embodiment against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lichrysogenum* on drug-containing culture medium plates was 1 μg / mL; EC (excessive MIC) 50 The concentration ranges from 0.0001 to 0.0005 μg / mL.

[0120] Example 34 preparation( Z )-2-bromo-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide (abbreviated as compound A34) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is ethyl 2-bromo-4-methylthiazol-5-carboxylate; the final compound A34 is a brown oily substance with a yield of 79%. The NMR data of compound A34 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.15-8.13 (m, 2H, NH+PyH), 7.75 (t, J = 7.8Hz, 1H, PyH), 7.52-7.49 (m, 2H, PhH), 7.46-7.44 (m, 1H, PhH), 7.40-7.37 (m,2H, PhH), 7.06 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3), 2.75 (s, 3H, Thi-CH3).

[0121] The compound A34 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.001 to 0.05 μg / mL.

[0122] Example 35 preparation( Z )-3,4-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide (abbreviated as compound A35) includes the following steps: Referring to Example 6, the difference is that compound IV used in this example is 3,4-dichloroisothiazol-5-carboxylic acid; the final compound A35 was a white powder solid with a yield of 86%. The NMR data of compound A35 are as follows: 1 H-NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H, NH), 8.19 (d, J = 8.2 Hz, 1H, PyH), 7.79 (t, J = 7.8 Hz, 1H, PyH), 7.51 (d, J = 7.4 Hz, 2H, PhH), 7.48-7.37 (m,3H, ArH), 7.13 (d, J = 7.6 Hz, 1H, PyH), 5.34 (s, 2H, OCH2), 4.02 (s, 3H, NCH3).

[0123] The compound A35 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.1 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.00025 to 0.0005 μg / mL.

[0124] Example 36 preparation( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (abbreviated as compound A36) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 5-chloro-1,3,4-thiadiazole-2-carboxylate; the final compound A36 is a light yellow powder solid with a yield of 80%. The NMR data of compound A36 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.50 (s, 1H, NH), 8.17 (d, J = 8.2 Hz, 1H, PyH), 7.79 (t,J = 7.8 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.47-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.11 (d, J = 7.6 Hz, 1H, PyH), 5.34 (s, 2H, OCH2), 4.03 (s, 3H, NCH3).

[0125] The compound A36 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.5 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.025 to 0.075 μg / mL.

[0126] Example 37 preparation( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (abbreviated as compound A37) includes the following steps: Referring to Example 1, the difference is that compound III used in this example is methyl 5-bromo-1,3,4-thiadiazole-2-carboxylate; the final compound A37 was a light yellow powder with a yield of 78%. The NMR data for compound A37 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.52 (s, 1H, NH), 8.18 (d, J = 8.2 Hz, 1H, PyH), 7.79 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.47-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.11 (d, J = 7.6 Hz, 1H, PyH), 5.33 (s, 2H, OCH2), 4.04 (s, 3H, NCH3).

[0127] The compound A37 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.5 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.0025 to 0.075 μg / mL.

[0128] Example 38 preparation( Z / E )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A38) includes the following steps: and Compound A38 0.02 mol of compound III (methyl 5-bromofuran-2-carboxylate) and 0.02 mol of compound II were added to 50 mL of toluene. 0.02 mol of trimethylaluminum solution was slowly injected into the reaction flask using a syringe. The mixture was stirred and heated at 60 °C. The reaction progress was monitored by thin-layer chromatography. After 10 h, the reaction was complete, yielding the reaction mixture. The reaction mixture was cooled to room temperature, quenched with 150 mL of 1 M hydrochloric acid aqueous solution, and extracted with ethyl acetate (80 mL, divided twice). The extracts were washed with saturated brine (80 mL, divided twice), and the organic extracts were combined. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and without further purification, yielded a yellow oily liquid, compound A38, in 91% yield. The NMR data of compound A38 are as follows: Z -Isomer: 1 H-NMR (400 MHz, CDCl3) d : 8.70 (s, 1H, NH), 8.24 (d, J = 8.2Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43(m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.24 (d, J = 3.6 Hz, 1H, Fur-H), 7.07 (d, J = 7.5 Hz, 1H, PyH), 6.53 (d, J= 3.6 Hz, 1H, Fur-H), 5.32 (s, 2H, OCH2), 4.01 (s, 3H, NCH3).

[0129] E -Isomer: 1 H-NMR (400 MHz, CDCl3) d : 8.70 (s, 1H, NH), 8.26 (d, J = 8.2Hz, 1H, PyH), 7.74 (t, J = 8.0 Hz, 1H, PyH), 7.65-7.62 (m, 2H, PhH), 7.52-7.50(m, 3H, PhH), 7.23 (d, J = 3.6 Hz, 1H, Fur-H), 7.11 (d, J = 7.6 Hz, 1H, PyH), 6.50 (d, J = 3.5 Hz, 1H, Fur-H), 5.35 (s, 2H, OCH2), 4.12 (s, 3H, NCH3).

[0130] The compound A38 prepared in this embodiment showed a MIC value of 0.25 μg / mL on drug-containing culture medium plates against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee*. EC 50 The values ​​were all 0.00025-0.001 μg / mL; EC50 against the growth of rice bacterial blight pathogens. 50 It is 0.2 μg / mL.

[0131] Example 39 preparation( Z / E )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A39) includes the following steps: and Compound A39 Referring to Example 38, the difference from Example 38 is that compound III used in this example is methyl 3-chlorothiophene-2-carboxylate; the final product is a white powdery solid, compound A39, with a yield of 87%. The NMR data of compound A39 are as follows: Z -Isomeric:1 H-NMR (400 MHz, CDCl3) d : 9.33 (s, 1H, NH), 8.23 ​​(d, J = 8.2Hz, 1H, PyH), 7.75 (t, J = 7.8 Hz, 1H, PyH), 7.58 (d, J = 5.3 Hz, 1H, Thi-H), 7.53-7.51 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.08-7.06 (m, 2H, Thi-H+PyH), 5.32 (s, 2H, OCH2), 4.03 (s, 3H, NCH3).

[0132] E -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 9.36 (s, 1H, NH), 8.25 (d, J = 8.2Hz, 1H, PyH), 7.76 (t, J = 7.8 Hz, 1H, PyH), 7.67-7.64 (m, 2H, 7.67-7.64), 7.58(d, J = 5.3 Hz, 1H, Thi-H), 7.52-7.50 (m, 3H, PhH), 7.10-7.07 (m, 2H, Thi-H+PyH), 5.36 (s, 2H, OCH2), 4.13 (s, 3H, NCH3).

[0133] The compound A39 prepared in this embodiment had a MIC of 0.5 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.0025 to 0.075 μg / mL. It exhibited high activity against the pathogenic bacteria causing rice bacterial blight, with an EC value of [missing value]. 50 It is 0.025 μg / mL.

[0134] Example 40 preparation( Z / E )-4,5-dibromo- N -(6-(((((1-methyl-1) H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A40) includes the following steps: and Compound A40 Referring to Example 38, the difference is that compound III used in this example is methyl 4,5-dibromothiophene-2-carboxylate; the final product is a light yellow powdery solid, compound A40, with a yield of 93%. The NMR data of compound A40 are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 8.48 (s, 1H, NH), 8.16 (d, J = 8.2Hz, 1H, PyH), 7.74 (t, J = 7.9 Hz, 1H, PyH), 7.58 (s, 1H, Thi-H), 7.52-7.50 (m,2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.41-7.37 (m, 2H, PhH), 7.04 (d, J = 7.5 Hz, 1H, PyH), 5.30 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0135] E -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 8.48 (s, 1H, NH), 8.19 (d, J = 8.6Hz, 1H, PyH), 7.78 (t, J = 8.4 Hz, 1H, PyH), 7.64-7.62 (m, 2H, PhH), 7.58 (s,1H, Thi-H), 7.52-7.49 (m, 3H, PhH), , 7.11 (d, J = 7.4 Hz, 1H, PyH), 5.32 (s, 2H, OCH2), 4.11 (s, 3H, NCH3).

[0136] The compound A40 prepared in this embodiment had a MIC of 2.5 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora licheniformis* on drug-containing culture medium plates; EC50... 50 The concentration ranges from 0.012 to 0.08 μg / mL.

[0137] Example 41 preparation( Z / E )-2-bromo- N -(6-(((((1-methyl-1H-tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide (abbreviated as compound A41) includes the following steps: and Compound A41 Referring to Example 38, the difference is that compound III used in this example is methyl 2-bromothiazol-4-carboxylate; the final product is a yellow powdery solid, compound A41, with a yield of 89%. The NMR data of compound A41 are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 9.55 (s, 1H, NH), 8.27 (d, J = 8.2Hz, 1H, PyH), 8.20 (s, 1H, Thi-H), 7.76 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.51(m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.07 (d, J = 7.5Hz, 1H, PyH), 5.33 (s, 2H, OCH2), 4.04 (s, 3H, NCH3).

[0138] E -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 9.59 (s, 1H, NH), 8.27 (d, J = 8.2Hz, 1H, PyH), 8.20 (s, 1H, Thi-H), 7.76 (t, J= 7.8 Hz, 1H, PyH), 7.66-7.63 (m,2H, PhH), 7.51-7.43 (m, 3H, PhH), 7.10 (d, J = 7.4 Hz, 1H, PyH), 5.35 (s, 2H, OCH2), 4.14 (s, 3H, NCH3).

[0139] The compound A41 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.2 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration ranged from 0.003 to 0.009 μg / mL.

[0140] Example 42 preparation( Z / E )-3,4-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide (abbreviated as compound A42) includes the following steps: and Compound A42 Referring to Example 38, the difference from Example 38 is that compound III used in this example is methyl 3,4-dichloroisothiazol-5-carboxylate; the final product is a light yellow powdery solid, compound A42, with a yield of 95%. The NMR data of compound A42 are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) d : 9.10 (s, 1H, NH), 8.19 (d, J = 8.2Hz, 1H, PyH), 7.79 (t, J = 7.8 Hz, 1H, PyH), 7.51 (d, J = 7.4 Hz, 2H, PhH), 7.48-7.37 (m, 3H, ArH), 7.13 (d, J = 7.6 Hz, 1H, PyH), 5.34 (s, 2H, OCH2), 4.02 (s, 3H, NCH3).

[0141] E -Isomeric: 1H-NMR (400 MHz, CDCl3) d : 9.14 (s, 1H, NH), 8.20-8.16 (m, 1H,PyH), 7.82-7.78 (m, 1H, PyH), 7.66-7.63 (m, 2H, PhH), 7.51-7.49 (m, 3H, ArH), 7.17 (d, J = 7.5 Hz, 1H, PyH), 5.37 (s, 2H, OCH2), 4.12 (s, 3H, NCH3).

[0142] The compound A42 prepared in this embodiment showed a minimum inhibitory concentration (MIC) of 0.25 μg / mL against the mycelial growth of *Pythium spp.*, *Phytophthora capsici*, *Phytophthora virosa*, and *Phytophthora lychee* on drug-containing culture medium plates; EC50... 50 The concentration is 0.0005-0.001 μg / mL.

[0143] Comparative Example 1 preparation( Z )-2,4-Dimethyl- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)oxazol-5-carboxamide (abbreviated as compound A43) includes the following steps: Compound A43 Referring to Example 1, the difference is that compound III used in this example is methyl 2,4-dimethyloxazol-5-carboxylate; the final compound A43 was a white powder solid with a yield of 75%. The NMR data of compound A43 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.47 (s, 1H, NH), 8.23 ​​(d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 8.0 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.06 (d, J= 7.4 Hz, 1H, PyH), 5.31 (s, 2H,OCH2), 3.99 (s, 3H, NCH3), 2.54 (s, 3H, Oxa-CH3), 2.53 (s, 3H, Oxa-CH3).

[0144] The halogen-free compound A43 prepared in this comparative example had a MIC greater than 50.0 μg / mL against the mycelial growth of Phytophthora capsici, Phytophthora virosa, and Phytophthora perfringens on drug-containing culture medium plates; compared with the compounds in Examples 1-42 of this invention, compound A43 had very low antibacterial activity.

[0145] Comparative Example 2 preparation( Z )-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (abbreviated as compound A44) includes the following steps: Compound A44 Referring to Example 1, the difference is that compound III used in this example is methyl 5-methyl-1,3,4-thiadiazole-2-carboxylate; the final compound A44 is a white powder solid with a yield of 77%. The NMR data of compound A44 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 9.61 (s, 1H, NH), 8.20 (d, J = 8.3 Hz, 1H, PyH), 7.78 (t, J = 7.8 Hz, 1H, PyH), 7.53-7.51 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.09 (d, J = 7.5 Hz, 1H, PyH), 5.33 (s, 2H,OCH2), 4.04 (s, 3H, NCH3), 2.89 (s, 3H, Thiad-CH3). The compound A44 prepared in this comparative example had a MIC greater than 50.0 μg / mL against the mycelial growth of Phytophthora capsici, Phytophthora virosa, and Phytophthora perfringens on drug-containing culture medium plates; compared with the compounds in Examples 1-42 of this invention, compound A44 had very low antibacterial activity.

[0146] Comparative Example 3 preparation( Z )- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A45) includes the following steps: Compound A45 Referring to Example 1, the difference is that compound III used in this example is ethyl furan-2-carboxylate; the final compound A45 is a white powder solid with a yield of 81%. The NMR data of compound A45 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.69 (s, 1H, NH), 8.24 (d, J = 8.2 Hz, 1H, PyH), 7.73 (t, J = 8.1 Hz, 1H, PyH), 7.55-7.50 (m, 3H, 2PhH+Fur-H), 7.48-7.43(m, 1H, PhH), 7.41-7.37 (m, 2H, PhH), 7.31 (d, J = 4.2 Hz, 1H, Fur-H), 7.05 (d, J = 7.5 Hz, 1H, PyH), 6.59 (d, J = 3.5 Hz, 1H, Fur-H), 5.32 (s, 2H, OCH2), 4.00 (s, 3H, NCH3).

[0147] The compound A45 prepared in this comparative example had a MIC greater than 50.0 μg / mL against the mycelial growth of Phytophthora capsici, Phytophthora virosa, and Phytophthora perfringens on drug-containing culture medium plates; compared with the compounds in Examples 1-42 of this invention, compound A45 had very low antibacterial activity.

[0148] Comparative Example 4 preparation( Z )-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide (abbreviated as compound A46) includes the following steps: Compound A46 Referring to Example 1, the difference is that compound III used in this example is methyl 5-methylfuran-2-carboxylate; the final compound A46 was a white powder solid with a yield of 71%. The NMR data of compound A46 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.69 (s, 1H, NH), 8.23 ​​(d, J = 8.2Hz, 1H, PyH), 7.74 (t, J = 8.1 Hz, 1H, PyH), 7.53-7.50 (m, 3H, 2PhH), 7.48-7.43(m, 1H, PhH), 7.41-7.38 (m, 2H, PhH), 7.15 (d, J = 3.4 Hz, 1H, Fur-H), 7.05 (d, J = 7.5 Hz, 1H, PyH), 6.15 (d, J = 3.4 Hz, 1H, Fur-H), 5.31 (s, 2H, OCH2), 4.02(s, 3H, NCH3), 2.33(s, Fur-CH3).

[0149] The compound A46 prepared in this comparative example had a MIC greater than 50.0 μg / mL against the mycelial growth of Phytophthora capsici, Phytophthora virosa, and Phytophthora perfringens on drug-containing culture medium plates; compared with the compounds in Examples A1-A42 of this invention, compound A46 had very low antibacterial activity.

[0150] Comparative Example 5 preparation( Z )-3-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophen-2-carboxamide (abbreviated as compound A47) includes the following steps: Compound A47 Referring to Example 1, the difference is that compound III used in this example is ethyl 3-methylthiophene-2-carboxylate; a light yellow powdery solid, compound A47, was obtained with a yield of 77%. The NMR data of compound A47 are as follows: 1 H-NMR (400 MHz, CDCl3) d : 8.89 (s, 1H, NH), 8.21 (d, J = 8.2 Hz, 1H, PyH), 7.75 (t, J = 7.9 Hz, 1H, PyH), 7.52-7.49 (m, 2H, PhH), 7.49-7.43 (m, 2H,PhH+Thi-H), 7.41-7.37 (m, 2H, PhH), 7.05 (d, J = 7.5 Hz, 1H, PyH), 7.00 (d, J =5.0 Hz, 1H, Thi-H), 5.34 (s, 2H, OCH2), 4.02 (s, 3H, NCH3), 2.68 (s, Thi-CH3).

[0151] The compound A47 prepared in this comparative example had a MIC greater than 100.0 μg / mL against the mycelial growth of Phytophthora capsici, Phytophthora virosa, and Phytophthora perfringens on drug-containing culture medium plates; compared with the compounds in Examples A1-A42 of this invention, compound A47 had very low antibacterial activity.

[0152] Application Example 1 Preparation of wettable powder (WP): Based on the effective content of the formulation to be processed, weigh 15% by weight of heterocyclic amide oxime ether derivatives (particle size of 300 mesh, selected from compounds A1, A2, A6, A7, A8, A12, A39, and comparative compound A43), 80% by weight of carrier (light calcium carbonate), and 5% by weight of surfactant (sodium lignosulfonate) to obtain a mixture of wettable powders with an effective content of 15%. The mixture is then subjected to air jet milling and sieving, and the mixture passing through 44 μm is collected to obtain WP with a mass fraction of 15 wt%.

[0153] The quality of the above WP samples was tested according to the standard method of GB / T 14825-1993. The results showed that the time for the samples to reach wetness was less than 2 minutes, the suspension rate was greater than 70% after stirring and standing for 1 hour, and the pH value was 6.8~7.2.

[0154] Application Example 2 Preparation of suspending agent (SC): Based on the effective content of the formulation to be processed, weigh 1% by weight of heterocyclic amide oxime ether derivatives (particle size of 300 mesh, selected from compounds A3, A5, A9, A14, A25, A31, A33, A38, and A44), 0.2% by weight of wetting agent (Pingpingjia), 0.3% by weight of dispersing and suspending agent (Lafenative powder), 0.2% by weight of thickener (xanthan gum), 0.3% by weight of stabilizer (bentonite), 3% by weight of antifreeze (polyethylene glycol 400), and 0.1% by weight of defoamer (lauric acid). Add water to 100% to obtain a mixture of 1% SC, i.e., 1 wt% SC.

[0155] The mixture was prepared into a slurry, then ground 3-4 times in a sand mill. Finally, the pH value, fluidity and wettability were adjusted to obtain SC with an effective ingredient content of 1wt%.

[0156] Application Example 3 Preparation of suspension concentrate (SC): Based on the effective content of the formulation to be processed, weigh 10% by weight of heterocyclic amide oxime ether derivatives (particle size of 300 mesh, selected from compounds A4, A10, A11, A13, A19, A20, A34, A40 and A45), 1.0% by weight of water-soluble wetting agent (Pingpingjia), 1.0% by weight of dispersing and suspending agent (Nongru 11#), 0.2% by weight of thickener (dextrin), 0.5% by weight of stabilizer (magnesium aluminum silicate), 3% by weight of antifreeze (polyethylene glycol 400), and 0.1% by weight of defoamer (organosilicon). Add water to 100% to obtain a mixture of 10 wt% effective ingredient suspension concentrate, i.e., 10 wt% SC.

[0157] The mixture was prepared into a slurry, then ground 3-4 times in a sand mill. Finally, the pH value, fluidity and wettability were adjusted to obtain SC with an effective ingredient content of 10wt%.

[0158] Application Example 4 Preparation of suspending agent (SC): Based on the effective content of the formulation to be processed, weigh 20% by weight of heterocyclic amide oxime ether derivatives (particle size of 300 mesh, selected from compounds A15, A16, A17, A18, A26, A32, A35, A41, A42 and A46), 1.5% by weight of water-soluble wetting agent (Pingpingjia), 2.0% by weight of dispersing and suspending agent (Lafenative powder), 0.2% by weight of thickener (xanthan gum), 0.5% by weight of stabilizer (bentonite), 3% by weight of antifreeze (polyethylene glycol 400), and 0.2% by weight of defoamer (lauric acid). Add water to 100% to obtain a mixture of 20 wt% SC, which is the effective content of the suspending agent.

[0159] The mixture is prepared into a slurry, then ground 3-4 times in a sand mill. Finally, the pH value, fluidity and wettability are adjusted to obtain SC with an effective ingredient content of 20wt%.

[0160] The quality of SC samples in Application Examples 2-4 was tested according to the standard method of NY / T 4014-2021. The results showed that the relative error of the effective ingredient content was ±0.1~0.5%, no stratification or sedimentation occurred after 30 days of indoor storage, and the samples could maintain a stable suspension state when diluted with water. The effective suspension rate was greater than 90% after standing for 1 hour.

[0161] Application Example 5 Preparation of water-dispersible granules (WG): Based on the effective content of the formulation to be processed, weigh out the following components by weight: 0.1% of a heterocyclic amide-containing oxime ether derivative (300 mesh particle size, compounds A3, A21, A22, A23, A24, A36), 1% of calcium dodecylbenzenesulfonate, 2% of PO-EO-block polyether, 3% of urea, 20.9% of disintegrant (ammonium sulfate and sucrose in a 3:1 mass ratio), and 73% of carrier (kaolin). This yields a mixture for preparing water-dispersible granules with an effective content of 0.1%, i.e., 0.1 wt% WG. The mixture is then subjected to air jet milling. The particles with a diameter less than 10 μm are collected and sequentially extruded and dried to obtain 0.1 wt% WG of the effective ingredient content.

[0162] Application Example 6 Preparation of water-dispersible granules (WG): Based on the effective content of the formulation to be processed, weigh out the following by weight: 3% of heterocyclic amide oxime ether derivatives (particle size of 200 mesh, compounds A27, A28, A29, A30, A33, A37, A47), 5% of naphthalene sulfonate dispersant GY-D10, 2% of sodium butylbenzene sulfonate, 3% of urea, 15% of disintegrant (potassium sulfate and sodium chloride in a mass ratio of 4:1), and 72% of carrier (bentonite). This mixture is used to prepare water-dispersible granules with an effective content of 3%, i.e., 3wt% WG.

[0163] The mixtures were separately subjected to air jet milling, and the mixtures with a particle size of less than 10 μm were collected and then extruded, granulated and dried to obtain 3wt% WG with different contents of active ingredients.

[0164] The quality of WG samples in Application Examples 5-6 was tested according to the standard method of HG / T 4463-2012. The results showed that the time for both types of WG samples to reach wet disintegration was less than 2 minutes, the suspension rate after stirring and standing for 1 hour was greater than 70%, and the pH value was 6.8~7.2.

[0165] Drug efficacy test examples (1) Experiments were conducted to control potato late blight and pepper blight, as follows: A. Test samples: The 15% wettable powder (WP) of Application Example 1 and the 10% suspension (SC) of Application Example 3 were used as test samples. The control test sample was Bissillo 10% suspension (tetrazopyridine) manufactured by Nippon Soda. A water control was set up.

[0166] B. Greenhouse pot experiment conditions: Potato seedlings and pepper seedlings at the 4-5 leaf stage, one seedling per pot; cultivated in a glass greenhouse at a temperature of 15-25℃.

[0167] C. Test methods: I. Preparation of test solution: Weigh the above test samples respectively, and dilute them with water to prepare three treatment concentrations of drug solution with the effective components of the compound being 100 mg ai / L, 30 mg ai / L and 10 mg ai / L respectively.

[0168] II. Test Procedure: Three pots of potato seedlings and pepper seedlings were sprayed with three different treatment concentrations of the pesticide solution for each sample using a throat sprayer until the solution flowed between the leaves. After 24 hours, the prepared potato late blight pathogen (… Phytophthora infestans ) and Phytophthora capsici ( P. capsici10 μL of sporangium suspension was dripped onto each leaf, for a total of 30 leaflets (10 leaves per pot of seedlings). When the inoculum was almost dry, the pots were placed in a greenhouse and covered with plastic sheeting for 24 hours of humidified culture in the dark. The plastic sheeting was then removed, and culture continued (for protective effect determination). Alternatively, after inoculation and humidified culture in the dark for 24 hours, the plant was sprayed with the fungicide, dried, and then placed in a greenhouse at 15-25℃ for curative effect determination. Seven days after inoculation, the number and length of lesions were investigated, and the control efficacy was calculated using the following formula: Efficacy % = [1 - (length of treated lesions ÷ length of blank control lesions)] × 100%.

[0169] D. Test results: listed in Tables 1 and 2.

[0170] Table 1. Protective effect (%) against potato late blight and pepper blight

[0171] Table 2. Therapeutic effects (%) on control of potato late blight and pepper blight

[0172] As shown in Tables 1 and 2, the heterocyclic amide-containing oxime ether derivatives provided by this invention have good preventive and curative effects against potato late blight and pepper blight. The preventive effect against potato late blight is higher than that against pepper blight, and the protective effect is higher than the curative effect. Although the preventive effects of Z / E mixed samples A39 and A40 are lower than those of the corresponding Z-type compounds A6 and A13, they still show ideal effects in controlling potato late blight and pepper blight. Compared with the control samples, most of the tested samples are significantly better than Bisoxime (tetrazopyridine), especially in terms of curative effect at low doses, indicating that the heterocyclic amide-containing oxime ether derivatives of this invention have better systemic curative activity than tetrazopyridine. Comparative compounds A43 and A45 only show certain preventive and curative effects at high doses, which is qualitatively different from the control effects of the compounds of this invention.

[0173] (2) Conduct experiments on the control of grape downy mildew and cucumber downy mildew, as follows: A. Test samples: The 1% and 20% suspensions of Application Example 2 and Application Example 4 were used as test samples; the control test samples were Bissero 10% suspension (tetrazopyridine) produced by Nippon Soda, and 50wt% dimethomorph suspension (SC) sold by Qingdao Xiaofeng Biotechnology Co., Ltd., with water as a control.

[0174] B. Greenhouse pot experiment conditions: 5-leaf stage cucumber seedlings (variety: Xintai Mici) and grape seedlings (variety: Muscat) with vines about 1.2 meters long, one seedling per pot; cultivated in a glass greenhouse at a temperature of 20~30℃.

[0175] C. Test methods: I. Preparation of test solution: Weigh out the above-mentioned test sample suspensions and dilute them with water to 100 mg ai / L, 30 mg ai / L and 10 mg ai / L respectively to prepare three treatment concentrations of drug solution.

[0176] II. Test Procedure: Four pots of cucumber seedlings and three pots of grape seedlings were sprayed with three different concentrations of each compound using a throat sprayer until the solution flowed between the leaves. After 24 hours, 10 μL of the prepared sporangium suspensions of cucumber downy mildew and grape downy mildew were inoculated onto 15 leaves (one inoculation point on each side of the vein of each leaf, for a total of 30 inoculation points). After drying, the pots were placed in a greenhouse, covered with plastic sheeting, and incubated in the dark for 24 hours. The plastic sheeting was then removed, and the plants were incubated for another 7 days. The diameter of the lesions was assessed and classified into five levels: 0 (no disease), 1 (1 mm), 2 (2 mm), 3 (3 mm), and 4 (5 mm). The control efficacy was calculated using the following formula: Efficacy % = [1 - (diameter of treated lesions ÷ diameter of blank control lesions)] × 100%.

[0177] D. Test results: listed in Table 3.

[0178] Table 3. Experimental effects (%) on the control of grape downy mildew and cucumber downy mildew

[0179] As shown in Table 3, the heterocyclic amide-containing oxime ether derivatives provided by this invention have excellent preventive effects against grape downy mildew and cucumber downy mildew. Although there are certain differences in activity among different compounds, all are significantly better than the control compounds A44 and A46. The Z-isomers A3 and A26 are also significantly more effective at controlling downy mildew at medium and low doses than the corresponding Z / E mixtures A38 and A41. The effects of all tested samples are significantly better than the most widely used control agent, dimethomorph, in current production, and the dosage is only 1 / 5 to 1 / 20 or lower. At the same time, the compounds of this invention are also significantly more effective at controlling downy mildew than the latest highly effective omphacid agent, Bismuth subtilis.

[0180] (3) Soil treatment experiments were conducted to control damping-off disease in tomatoes and peppers, as detailed below: A. Test Samples: Water-dispersible granules from Application Examples 5 and 6 were used as test samples. The control test sample was 98wt% oxadixyl soluble powder produced by Beijing Beinong Luheng Technology Development Co., Ltd., purchased online.

[0181] B. Greenhouse Pot Experiment Method: Natural soil was collected from a vegetable garden in the suburbs of Nanjing. After crushing and mixing, 5 mL of *Pythium spp.* sporangia suspension was sprayed onto each kilogram of soil and mixed thoroughly. A portion of the soil was then mixed with 0.1 g of the test agent containing the active ingredient of the compound, and further mixed with the soil until the final soil concentration was 30 mg ai and 10 mg ai. The control agent, oxadixyl, was set at a final soil concentration of 50 mg ai / kg. The moisture content was determined by the condition of being able to form a clump by hand but crumble when released. The treated soil was placed in 50×30cm plastic pots, and tomato and pepper seeds were sown separately. The pots were then cultured in a glass greenhouse under sunlight and at 15-25℃. The disease incidence rate was checked after 15 days. The control efficacy was calculated using the following formula: Control efficacy % = [1 - (the percentage of diseased plants treated ÷ the percentage of diseased plants in the blank control)] × 100%.

[0182] C. Test results: listed in Table 4.

[0183] Table 4. Experimental effects (%) on the control of damping-off disease in tomatoes and peppers

[0184] Table 4 shows that soil treatment with the heterocyclic amide-containing oxime ether derivative provided by this invention has a significant control effect on seedling diseases of tomatoes and peppers, and is better than the commonly used soil treatment agent hymexazol, requiring only 1 / 5 of the dosage of the control agent. The isolates from diseased seedlings treated with hymexazol were identified as *Phytophthora* (…). Phytophthora spp.) accounted for 57.60%, Pythium ( Pythium spp. accounted for 40.32%, and Rhizoctonia solani ( Rhizoctonia (spp.) accounted for 2.08%.

[0185] (4) The control activity against grape downy mildew was determined using the leaf disc flotation method and compared with that of tetrazolium and fluthiazopyr. Specific test methods and results are as follows: A. Test Samples: Representative compounds A1, A3, A6, A13, A26, A38, A39, A40, A41, A42, A43, and A47, representing heterocyclic amide oxime ether derivatives, were selected as test samples. Fluoxetine and tetrazolium were used as control samples. The test samples and control samples were dissolved in DMSO and then diluted with tap water to concentrations of 3.2, 0.8, 0.2, and 0.05 μg / mL, respectively. A drug-free control was also included.

[0186] B. Test pathogen: Downy mildew-infected leaves were collected from untreated vineyards, brought back indoors, washed, and cultured in a moist environment for sporangia. The sporangia were then washed with 4°C water and prepared into 10... 5 / mL sporangium suspension, spray inoculated.

[0187] C. Test grape leaves: Muscat grapes, a susceptible variety grown in a greenhouse. The 3rd to 5th leaves from the vines were collected to prepare leaf discs with a diameter of 20 mm.

[0188] D. Operating Procedures: 1. Pour the prepared drug solutions of different concentrations into transparent plastic boxes with sides of 200mm.

[0189] 2. Float the prepared disease-free grape leaf discs face down on the liquid, with 15 leaf discs per treatment concentration.

[0190] 3. Use a back-head sprayer to evenly spray the sporangium suspension onto all floating leaf discs.

[0191] 4. After covering, place in an incubator at 18-20°C and incubate in the dark for 12 hours, then incubate in the light and dark for 12 hours for 7 days.

[0192] E. Experimental Results: Based on the presence of mold (sporangia) on the leaf disc, the results were categorized into 5 levels. Completely disease-free was marked "-", 1-3 mold spots were marked "+", 4-10 mold spots were marked "++", mold spots covering 10%-75% of the leaf disc area were marked "++++", and mold spots covering more than 75% of the leaf disc area were marked "++++". The results are shown in Table 5.

[0193] Table 5. Experimental effects on the control of grape downy mildew

[0194] As shown in Table 5, compounds A1, A3, A6, A13, A26, A38, A39, A40, A41, and A42 of this invention showed higher efficacy against *Pericarpium sclerotiorum* than the control agent tetrazolium, but slightly lower efficacy than fluthiazolinone. Among them, the Z-isomer of this invention showed higher activity against *Pericarpium sclerotiorum* than the Z / E mixture; the comparative compounds A43 and A47 showed very low activity against *Pericarpium sclerotiorum*. (5) Cross-resistance determination The specific test methods and results are as follows: A. Test Samples: Representative compounds A1, A3, A26, and A35 containing heterocyclic amide oxime ether derivatives were selected as test samples. The control test samples were fluthiazopyrone, dimethomorph, metalaxyl, and pyraclostrobin.

[0195] B. Test methods: I. Preparation of drug solution and preparation of drug-containing culture medium plates: The above test samples were dissolved in methanol to prepare a 10 mg / mL drug stock solution. The drug stock solution was added to lima bean agar medium melted at about 45°C to an effective final concentration of 5 μg / mL. The solution was poured into a 90 mm diameter petri dish and cooled to prepare a drug-containing plate. A control plate without drug was also prepared.

[0196] II. Test Procedure: From the edges of colonies of susceptible *Phytophthora capsici* parent strains and resistant strains of fluoxetine, dimethomorph, metalaxyl, and azoxystrobin, cultured on lima bean agar plates, 5 mm diameter mycelial blocks were prepared and transferred to the center of each drug-containing plate, mycelial side up. The plates were then incubated at 25°C for 5 days, and colony growth was observed. Strains that grew normally on the drug-containing plates were resistant (marked R); those that did not grow at all were susceptible (marked S).

[0197] The inhibition rate is calculated as follows: Inhibition rate % = [1 - (colony growth diameter of the treated bacteria ÷ colony growth diameter of the blank control)] × 100%.

[0198] C. Test Results: The test results are listed in Table 6.

[0199] Table 6 Results of cross-resistance test

[0200] As shown in Table 6, the representative compounds of the heterocyclic amide-containing oxime ether derivatives provided by this invention exhibit similar inhibitory activity against the mycelial growth of two sensitive parental strains of *Phytophthora capsici* as their growth inhibition rates against other resistant strains, with no cross-resistance. This indicates that the target of the heterocyclic amide-containing oxime ether derivatives of this invention differs from that of other fungicides.

[0201] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. An oxime ether derivative containing a heterocyclic amide, characterized in that: It has the structure shown in Equation I: ； M is selected from one of the substituted oxygen-containing five-membered heterocycles and the substituted sulfur-containing five-membered heterocycles; The hydrogen atoms on the oxygen-containing five-membered heterocycle are replaced by substituent groups, the sulfur-containing five-membered heterocycle is replaced by an oxygen-containing five-membered heterocycle, and the number of substituent groups is 1 to 3, of which at least one substituent group is a halogen. The substituent groups include 1 to 3 of the following: H, F, Cl, Br, I, and C1 to C4 alkyl groups.

2. The heterocyclic amide-containing oxime ether derivative according to claim 1, characterized in that: The oxygen-containing five-membered heterocycle is selected from one of furan-2-yl, furan-3-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, and 1,3,4-oxadiazol-2-yl; The sulfur-containing five-membered heterocycle is selected from one of thiophene-2-yl, thiophene-3-yl, thiazolyl-4-yl, thiazolyl-5-yl, isothiazol-4-yl, isothiazol-5-yl, and 1,3,4-thiadiazol-2-yl.

3. The heterocyclic amide-containing oxime ether derivative according to any one of claims 1-2, characterized in that: The heterocyclic amide-containing oxime ether derivatives are selected from one of the following compounds: ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide, ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide, ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide, ( Z )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide, ( Z )-3-Fluoro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-4-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-4,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-3-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, (Z)-4-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, (Z)-2,5-dichloro-N-(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, (Z)-2,5-dibromo-N-(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-3-carboxamide, ( Z )-4-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)oxazol-5-carboxamide, ( Z )-3-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isoxazole-5-carboxamide, ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2,5-dichloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2-chloro-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2-bromo-5-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z )-2-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide, ( Z )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide, ( Z )-2-chloro-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide, ( Z )-2-bromo-4-methyl- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazol-5-carboxamide, ( Z )-3,4-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide, ( Z )-5-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, ( Z )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, ( Z / E )-5-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)furan-2-carboxamide, ( Z / E )-3-chloro- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z / E )-4,5-dibromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, ( Z / E )-2-bromo- N -(6-(((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)thiazolyl-4-carboxamide, ( Z / E )-3,4-dichloro- N -(6-(((((1-methyl-1) H -Tetrazole-5-yl)(phenyl)methylene)amino)oxy)methyl)pyridin-2-yl)isothiazolyl-5-carboxamide.

4. The method for preparing the heterocyclic amide-containing oxime ether derivative according to any one of claims 1-3, characterized in that: Includes the following steps: Compound II, Compound III, catalyst, and organic solvent were mixed and subjected to an amidation reaction to obtain an oxime ether derivative containing a heterocyclic amide; The structural formula of compound II is shown in Formula II, and the structural formula of compound III is shown in Formula III: ； ； Wherein, R is a C1~C4 alkyl group; M is selected from one of the following: substituted oxygen-containing five-membered heterocycles or substituted sulfur-containing five-membered heterocycles. The catalyst is selected from one of the following: alkaline catalyst, metal catalyst, and aluminum catalyst; the organic solvent is selected from one of the following: benzene, toluene, and xylene.

5. The method for preparing the heterocyclic amide-containing oxime ether derivative according to any one of claims 1-3, characterized in that: Includes the following steps: Compound II, compound IV, catalyst, and organic solvent were mixed and subjected to an amidation reaction to obtain an oxime ether derivative containing a heterocyclic amide; The structural formula of compound IV is shown in Formula IV: ； Wherein, M is selected from one of the substituted oxygen-containing five-membered heterocycles or the substituted sulfur-containing five-membered heterocycles; The catalyst is selected from Lewis acid catalysts, organic catalysts, condensation catalysts, triphenylphosphine catalytic systems, and DMAP catalytic systems, and the organic solvent is selected from DMF, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

6. The method for preparing the heterocyclic amide-containing oxime ether derivative according to any one of claims 1-3, characterized in that: The process includes the following steps: mixing compound II, compound V, an acid-binding agent, and an organic solvent to carry out an amidation reaction, yielding an oxime ether derivative containing a heterocyclic amide; compound V is shown in formula V: ； Wherein, M is selected from one of the substituted oxygen-containing five-membered heterocycles or the substituted sulfur-containing five-membered heterocycles; The acid-binding agent is an organic or inorganic base, and the organic solvent is selected from one of DMF, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, benzene, toluene, and xylene.

7. An agricultural fungicide, characterized in that: Includes one of the heterocyclic amide-containing oxime ether derivatives according to any one of claims 1-3, agriculturally acceptable salts thereof, hydrates thereof, and solvates thereof, wherein the heterocyclic amide-containing oxime ether derivatives include (Z) isomers, (E) isomers, or mixtures of (Z) and (E) isomers.

8. The application of the agricultural fungicide as described in claim 7 in the prevention and control of plant oomycete diseases and plant fungal diseases.

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