Oxime ether derivatives containing piperidine and piperazine, and preparation method and application thereof, and agricultural fungicide

Abstract

This invention discloses oxime ether derivatives containing piperidine and piperazine, their preparation methods and applications, and agricultural fungicides, belonging to the field of agricultural chemistry. The structural formula of the oxime ether derivatives containing piperidine and piperazine is: [structural formula would be inserted here]. This invention utilizes the aforementioned oxime ether derivatives containing piperidine and piperazine, their preparation methods and applications, and agricultural fungicides. The oxime ether derivatives containing piperidine and piperazine have unique structures, are convenient to synthesize, and exhibit extremely high selective antibacterial activity against plant pathogenic oomycetes. They do not exhibit cross-resistance with existing fungicides and can be used in combination with various fungicides to control drug-resistant diseases. In particular, they can solve the problem of having no effective treatment for multidrug-resistant diseases and provide excellent chemical protection and systemic therapeutic effects against drug-resistant crop diseases.

Description

Technical Field

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

[0002] Downy mildew and blight caused by oomycetes are major agricultural epidemics that can infect various crops, including fruits, vegetables, grains, oilseeds, and garden crops. They cause devastating diseases such as late blight in potatoes, blight in peppers, downy mildew in cucumbers, and downy mildew in grapes. These diseases spread rapidly and cause significant losses, making chemical control the core prevention and control method. The mainstream oomytic fungicides on the market include various categories such as acylalanine fungicides (e.g., metalaxyl), carboxylic amide fungicides (e.g., flumorph), cyanoacetamide oximes (e.g., cymoxanil), methoxyacrylate fungicides (e.g., azoxystrobin), tetrazolium oximes (e.g., tetrazolium pyraclostrobin), and sulfadiazine fungicides (e.g., cyazofamid), accounting for more than 20% of the fungicide market.

[0003] However, long-term, large-scale application of these selective oomycetes easily leads to high levels of resistance and multi-resistance, leaving researchers helpless in the face of sudden and severe outbreaks of oomycete diseases. The invention of novel, safe, and highly effective oomycetes with novel structures, unique modes of action, stable physicochemical properties, and superior systemic conductivity is a significant social need for ensuring sustainable, efficient, and green control of oomycete diseases. Oxime ethers, piperidines, and piperazines are all classic molecular skeletons with excellent fungicidal activity, and several commercially available fungicides have been developed using these single skeletons. However, using oxime ethers or piperidine / piperazine ring active groups alone not only results in severe structural homogenization but also specific binding sites to target proteins, lacking high activity against oomycetes and easily leading to resistance.

[0004] In summary, the development of novel antibacterial compounds that are easy to synthesize, tightly bind to molecular targets, are highly selective for oomycetes, can overcome existing pesticide resistance, and have a low risk of developing resistance themselves are of great application value for enriching pesticide structural resources and improving the ability to control oomycete diseases. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the prior art by providing oxime ether derivatives containing piperidine and piperazine, their preparation methods and applications, and agricultural fungicides. By optimizing the combination of piperidine, piperazine, and morpholine with oxime ether structures, the resulting oxime ether derivatives containing piperidine and piperazine exhibit extremely high selective antibacterial activity against plant pathogenic oomycetes. They do not exhibit cross-resistance with existing fungicides and can be used in combination with various fungicides to control drug-resistant diseases, especially solving the problem of having no effective treatment for multidrug-resistant diseases.

[0006] To achieve the above objectives, the present invention provides oxime ether derivatives containing piperidine and piperazine, wherein the structural formula of the oxime ether derivatives containing piperidine and piperazine is as follows: Formula I; M includes CY-R 1 NR 2 O, S, each corresponding to the following structural types of formula I: Formula I-1, Formula I-2, Formula I-3, Formula I-4; R includes H, halogens, and C. 1-6 Alkyl, C 1-6 One or both of alkoxyformyl and substituted phenylcarbamoyl; the substitution refers to substitution by 1 to 3 of the following groups: H, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano; Y includes H and halogens; R 1 Including H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkenyl, C containing 1-3 halogens 1-6 Alkyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-6 Alkoxyformyl, C 1-6 Alkoxyformylmethyl, C 1-6 Alkoxyformylamino, C 1-6 Diol ketal, substituted phenyl, substituted five-membered heterocyclic, substituted six-membered heterocyclic, substituted benzo[a]hexacyclic, substituted benzoyl, substituted five-membered heterocyclic formyl, substituted six-membered heterocyclic formyl, substituted phenoxy, (substituted phenyl)(substituted pyridyl)methyloxy; the substitution refers to being substituted by 1 to 3 of the following groups: H, halogen, C 1-6 Alkyl, C 1-6 Alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano; R 2 Including H, C 1-6 Alkyl, C 3-6 cycloalkyl groups, C-type carbons containing 1-3 halogens 1-6 Alkyl, C 1-6 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-6 Alkoxyformyl, substituted benzoyl, substituted benzyloxyformyl, substituted five-membered heterocyclic formyl, substituted six-membered heterocyclic formyl, substituted benzo[a]heterocyclic formyl, C 1-6 Alkylsulfonyl, NC 1-6 Alkylaminosulfonyl, N,N-diC 1-6Alkylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, substituted five-membered heterocyclic, substituted six-membered heterocyclic, substituted benzo[a]hexacyclic, di(substituted phenyl)methyl; the substitution refers to substitution by 1 to 3 of the following groups: H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C 1-6 Alkoxyformyl group.

[0007] Preferably, when M includes CY-R 1 At that time, R includes H, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxyformyl or substituted phenylcarbamoyl, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, methyl; Y includes H, R 1 Including H, halogens, C 1-4 Alkoxy, methylene, trifluoromethyl, cyano, C 1-4 Alkoxyformylmethyl, C 1-4 Alkoxyformylamino, C 1-4 Diol ketal, substituted phenyl, substituted benzo[a]heterocyclic, substituted benzoyl, substituted phenoxy, (substituted phenyl)(substituted pyridyl)methyloxy, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, trifluoromethyl, trifluoromethoxy; When M includes CY-R 1 At that time, R includes H, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxyformyl or substituted phenylcarbamoyl, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, methyl; Y includes halogens; R 1 Including H and halogens; When M includes NR 2 When O and S are present, R includes H, halogens, and C. 1-4 One or two of the alkyl groups; R 2 Including C 1-4 Alkyl, C 1-4 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-4 Alkoxyformyl, substituted benzyloxyformyl, substituted benzoyl, substituted furanyl, C 1-4 Alkylsulfonyl, N,N-diC 1-4 Alkylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, di(substituted phenyl)methyl, substituted pyridyl, substituted pyrimidinyl, substituted benzothiazolyl, substituted benzoisothiazolyl, substituted benzothiophene, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, trifluoromethyl, nitro, cyano, C1-4 Alkoxyformyl group.

[0008] Furthermore, When M includes CY-R 1 In this case, R includes H, methyl, ethoxyformyl, and 2,6-dimethylphenylcarbamoyl; Y includes H, R 1 Including H, Br, methoxy, methylene, trifluoromethyl, cyano, methoxyformylmethyl, tert-butoxyformylamino, ethylene glycol ketal, substituted phenyl, benzisoxazolyl, substituted benzimidazolyl, substituted benzoyl, substituted phenoxy, (substituted phenyl)(pyridyl)methyloxy, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, trifluoromethyl, trifluoromethoxy; When M includes CY-R 1 In this case, R includes H, methyl, ethoxyformyl, and 2,6-dimethylphenylcarbamoyl; Y includes F; R 1 Including F; When M includes NR 2 When R includes H; R 2 Including methyl, acetyl, cyclopropylformyl, phenylformyl, furanyl, tert-butoxyformyl, benzyloxyformyl, methanesulfonyl, N,N-dimethylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, di(substituted phenyl)methyl, substituted pyridyl, pyrimidinyl, benzothiazolyl, benzoisothiazolyl, benzothiophene, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, methyl, methoxy, trifluoromethyl, nitro, cyano, ethoxyformyl; When M includes O, R includes H and 2,6-dimethyl; When M includes S, R includes H.

[0009] Furthermore, oxime ether derivatives containing piperidine and piperazine include ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(piperidin-1-yl)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(2-methylpiperidin-1-yl)ethyl-1-one, ( Z )-1-(4-cyanopiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-bromopiperidin-1-yl)-2-((((1-methyl-1) H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(trifluoromethyl)piperidin-1-yl)ethyl-1-one, ( Z )-1-(4-methoxypiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-(1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidin-4-yl)methyl acetate, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methylenepiperidin-1-yl)ethyl-1-one, ( Z )-1-(4,4-difluoropiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(ethylene glycol ketal)piperidin-1-yl)ethyl-1-one, ( Z )-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidine-2-carboxylic acid ethyl ester, ( Z )-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidin-4-ylcarbamate tert-butyl ester, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one, ( Z )-1-(4-(3-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-fluorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z)-1-(4-(4-chlorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(2-trifluoromethyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-ethyl-1-one, ( Z )-1-(4-(4-fluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2,4-difluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-N-(2,6-dimethylphenyl)-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidine-3-carboxamide, ( Z )-1-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethyl-1-one, ( Z )-1-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methylpiperazin-1-yl)ethyl-1-one, ( Z )-1-(4-acetylpiperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(cyclopropaneformyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(furan-2-formyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzoyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-carboxylic acid tert-butyl ester, ( Z )-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-carboxylic acid benzyl ester, (Z)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methanesulfonyl)piperazin-1-yl)ethyl-1-one, ( Z )-N,N-dimethyl-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-sulfonamide, ( Z )-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-((4-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one, ( Z )-1-(4-((4-chloro-3-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperazin-1-yl)ethyl-1-one, ( Z )-1-(4-(4-fluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-methylphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-cyanophenyl)piperazin-1-yl)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(2-nitrophenyl)piperazin-1-yl)ethyl-1-one, (Z)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-nitrophenyl)piperazin-1-yl)ethyl-1-one, ( Z )-4-(4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-yl)ethyl benzoate, (Z )-1-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl-1-one, ( Z )-1-(4-(3-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H-Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-nitropyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-nitropyridin-2-yl)piperazin-1-yl)acet-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(5-bromo-3-nitropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzo[d]thiazo-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinyl ethyl-1-one, ( Z )-1-(2,6-dimethylmorpholino)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-thiomorpholinoethyl-1-one, ( Z / E )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one, ( Z / E )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z / E )-2-((((1-methyl-1 H -tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinoethyl-1-one.

[0010] The present invention also provides a method for preparing the above-mentioned oxime ether derivatives containing piperidine and piperazine, comprising the following steps: Compound II, Compound III, a base, and an organic solvent were mixed and subjected to a substitution reaction to obtain oxime ether derivatives containing piperidine and piperazine. The structural formula of compound II is shown in Formula II, and the structural formula of compound III is shown in Formula III: Formula II; Formula III; X includes Cl, Br, and I; M and R are defined as in Equation I.

[0011] Preferably, the base is selected from organic or inorganic bases, including sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic solvent includes DMF, acetonitrile, tetrahydrofuran, dioxapentane, acetone, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, and ethyl acetate.

[0012] Furthermore, the bases include cesium carbonate and potassium carbonate, and the organic solvents include acetonitrile and tetrahydrofuran.

[0013] Preferably, the molar volume ratio of compound II, compound III, base, and organic solvent is 1 mmol: (0.8-1.6) mmol: (1-4) mmol: (5-100) mL, the temperature of the substitution reaction is 5-120℃, and the time is 0.5-96 h.

[0014] Furthermore, the molar volume ratio of compound II, compound III, base, and organic solvent is 1 mmol: (1-1.2) mmol: (1-3) mmol: (20-35) mL, the temperature of the substitution reaction is 20-80℃, and the time is 4-24 h.

[0015] In this invention, the preparation of compound II was carried out 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 preparation of compound III was carried out according to the methods described in [ChemMedChem (2025), 20(2), e202400567] and [European Journal of Medicinal Chemistry (2013), 62, 677-687].

[0016] The present invention also provides the application of oxime ether derivatives containing piperidine and piperazine, wherein the above-mentioned oxime ether derivatives containing piperidine and piperazine are used to prevent and control plant diseases or to prepare agricultural fungicides.

[0017] Preferably, the plant diseases are caused by oomycetes of the order Peronomycetes.

[0018] Furthermore, plant diseases are those caused by the genera *Phytophthora*, ...

[0019] This invention also provides an agricultural fungicide, comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the aforementioned oxime ether derivatives containing piperidine and piperazine, and its ( Z ) type isomers, ( E ) type isomers, ( Z ) type isomers and ( E The adjuvant is a mixture of isomers of type 1, at least one of its agriculturally acceptable salts, hydrates or solvates; the adjuvant is an agriculturally acceptable adjuvant, including one or more of carriers, solvents, cosolvents, surfactants, dispersants, emulsifiers, wetting agents, suspending agents, thickeners, stabilizers, defoamers, antifreeze agents and synergists.

[0020] Preferably, the content of the active ingredient in the agricultural fungicide is 0.1-99.9 wt%; the formulation of the agricultural fungicide includes mother powder, mother liquor, emulsifiable concentrate, suspension concentrate, aqueous solution, water emulsion, microemulsion, powder, wettable powder, soluble powder, granules, water-dispersible granules, oil, smoke agent or bait.

[0021] In this invention, excipients can be used to process the oxime ether derivatives containing piperidine and piperazine in this invention into any of the above-mentioned formulations using existing pesticide production technology, such as wettable powder (WP), suspension concentrate (SC), or water-dispersible granules (WG), according to actual needs.

[0022] Therefore, the present invention utilizes the above-mentioned oxime ether derivatives containing piperidine and piperazine, their preparation methods and applications, and agricultural fungicides, which have the following beneficial effects: (1) The oxime ether derivatives containing piperidine and piperazine of the present invention combine piperidine, piperazine and morpholine with oxime ether in an optimized manner. The structure is unique and novel, and has extremely high selective antibacterial activity against plant pathogenic oomycetes. It can be used to control plant oomycete diseases.

[0023] (2) The piperidine and piperazine-containing oxime ether derivatives of the present invention are safe for plants and have good environmental compatibility. When used for the prevention and control of diseases in agricultural and garden crops, they are selective and meet the development direction of new targeted fungicides that are safe, efficient, low toxicity, low residue and environmentally compatible, and meet the requirements of ensuring environmental and ecological safety. At the same time, they do 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, they can solve the problem of no drug available for the treatment of multi-drug resistant diseases and have a good chemical protection, systemic therapeutic and eradication effect on drug-resistant crop diseases.

[0024] (3) The oxime ether derivatives containing piperidine and piperazine of the present invention have stable physicochemical properties and can be processed into different pesticide formulations and applied using different methods to control various crop oomycete diseases. In addition, they have high antibacterial activity, long-lasting effect, low dosage per unit area, low cost, long suitable application time, high input-output ratio, and good economic benefits, which meet the requirements of modern agricultural development.

[0025] (4) The synthetic route of the oxime ether derivatives containing piperidine and piperazine provided by the present invention is short, the synthetic method is convenient and the synthetic cost is low.

[0026] The technical solution of the present invention will be further described in detail below through embodiments. Detailed Implementation

[0027] The technical solution of the present invention will be further described below through embodiments.

[0028] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0029] In this invention, unless otherwise specified, the test materials and instruments are all conventional test materials in the field and can be purchased through commercial channels.

[0030] In this invention, the preparation of the sporangium or zoospore suspension of the pathogenic oomycete inoculum involves culturing *Phytophthora indicum*, *Phytophthora capsici*, or *Pythium spp.* on CMA medium at 20°C for 3 days. After 3 days, mycelia are picked from the edge of the colony and inoculated into Petri liquid culture medium and shaken for 2-3 days. The mixture is then filtered through gauze and centrifuged at 1000 rpm for 5 minutes to collect sporangia and zoospores separately. These are then resuspended in sterile water, and the sporangium concentration is adjusted to 1 × 10⁻⁶. 5 Adjust the zoospore concentration to 1×10⁶ / mL. 6 The concentration of sporangia and zoospores was increased to 1 / mL, respectively. These were used for spray inoculation, soil irrigation, soil mixing inoculation, or seed dressing inoculation of potted seedlings treated with piperidine and piperazine oxime ether derivatives and blank control. The bioactivity of the piperidine and piperazine oxime ether derivatives in controlling plant diseases was investigated and analyzed when the crop seedlings (blank control) that were not treated with piperidine and piperazine oxime ether derivatives were fully infected.

[0031] Example 1 ( Z )-2-((((1-methyl-1 H The preparation method of 1-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(piperidin-1-yl)ethyl-1-one includes the following steps: 1 mmol of compound II and 2.2 mmol of cesium carbonate (base) were added to 30 mL of acetonitrile (organic solvent), and stirred for 0.5 h. Then, 1.05 mmol of compound III (2-chloro-1-(piperidin-1-yl)ethyl-1-one) was added, and the mixture was heated to 50 °C with stirring. The reaction progress was monitored by thin-layer chromatography, and the reaction was completed after 6 h. The mixture was filtered, and the solvent was removed by vacuum distillation of the filtrate. 20 mL of ethyl acetate was added to dissolve the filtrate, and the solution was washed with 20 mL of saturated brine. The extract was then extracted, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate and petroleum ether, volume ratio 1:4) to obtain the target product: ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(piperidin-1-yl)ethyl-1-one, white solid, yield 67.9%, melting point 127.7-128.9℃.

[0032] The molecular structure of the target product was confirmed by proton nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Its structural formula is as follows: The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ:7.54-7.51 (m, 2H, PhH), 7.45-7.41 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.90(s, 2H, OCH2), 4.26 (s, 3H, NCH3), 3.55 (t, J = 5.6 Hz, 2H, NCH2), 3.29 (t, J =5.5 Hz, 2H, NCH2), 1.70-1.64 (m, 2H, CH2), 1.60-1.55 (m, 4H, 2CH2); HR-MS(ESI) m / z [M+H] + calcd for C 16 H 21 N6O2: 329.1721, found: 329.1722.

[0033] Example 2 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(2-methylpiperidin-1-yl)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(2-methylpiperidin-1-yl)ethyl-1-one, the substitution reaction time is 8 h, and the target product is a white solid with a yield of 71.5% and a melting point of 126.1-127.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ: 7.53-7.51 (m,2H, PhH), 7.46-7.41 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.98-4.40 (m, 2H,OCH2+ NCH), 4.26 (s, 3H, NCH3), 3.90-2.71 (m, 2H, NCH2), 1.72-1.37 (m, 4H,CH2), 1.22 (d, J = 28.4 Hz, 3H, CH3); HR-MS (ESI) m / z [M+H]+ calcd for C 17 H 23 N6O2:343.1877, found: 343.1879.

[0034] Example 3 ( Z )-1-(4-cyanopiperidin-1-yl)-2-((((1-methyl-1) H The preparation method of 1-tetrazole-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 1-(2-chloroacetyl)piperidin-4-carboxynitrile, the substitution reaction time is 5 h, and the target product is a white solid with a yield of 73.6% and a melting point of 129.4-130.4 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.50-7.47 (m, 2H,PhH), 7.45-7.41 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 4.90 (s, 2H, OCH2),4.21 (s, 3H, NCH3), 3.76 (br, 1H, 0.5NCH2), 3.56 (br, 2H, NCH2), 3.36 (br, 1H,0.5NCH2), 2.93 (br, 1H, CH), 1.91 (br, 2H, CH2), 1.85 (br, 2H, CH2); HR-MS(ESI) m / z [M+H] + calcd for C 17 H 20 N7O2: 354.1673, found: 354.1670.

[0035] Example 4 ( Z )-1-(4-bromopiperidin-1-yl)-2-((((1-methyl-1) HThe preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-bromo-1-(4-bromopiperidin-1-yl)ethyl-1-one, the base used is 2.1 mmol of potassium carbonate, the organic solvent is 20 mL of tetrahydrofuran, the substitution reaction time is 4 h, and the target product is a yellow solid with a yield of 62.9% and a melting point of 134.5-135.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.49 (m, 1H, PhH), 7.48-7.42 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.91 (s, 2H, OCH2), 4.46-4.41 (m, 1H, 0.5NCH2), 4.23 (s, 3H, NCH3), 3.77-3.73 (m, 1H, 0.5NCH2), 3.64-3.57 (m, 2H, CH+0.5NCH2), 3.33-3.29 (m, 1H, 0.5NCH2), 2.06-2.15 (m, 2H,CH2), 2.02-1.92 (m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 16 H 20 BrN6O2:407.0826, found: 407.0826.

[0036] Example 5 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-(trifluoromethyl)piperidin-1-yl)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(trifluoromethyl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 8 h, and the target product is a white solid with a yield of 54.2% and a melting point of 172.1-173.1 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50(m, 2H, ArH), 7.44-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, ArH), 4.91 (q, J = 14.3Hz, 2H, OCH2), 4.67 (d, J = 12.8 Hz, 1H, 0.5NCH2), 4.23 (s, 3H, NCH3), 3.76 (d, J = 13.2 Hz, 1H, 0.5NCH2), 3.66 (t, J = 12.8 Hz, 1H, 0.5NCH2), 2.63 (t, J = 12.8 Hz,1H, 0.5NCH2), 3.32-3.27 (m, 1H, CH), 1.96 (d, J = 11.8 Hz, 2H, CH2), 1.52 (q, J =12.6 Hz, 2H, CH2); 19 F NMR (376 MHz, CDCl3) δ -73.84; HR-MS (ESI) m / z [M+H] + calcdfor C 17 H 20 F3N6O2: 397.1594, found: 397.1594.

[0037] Example 6 ( Z )-1-(4-methoxypiperidin-1-yl)-2-((((1-methyl-1) H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-methoxypiperidin-1-yl)ethyl-1-one, the substitution reaction time is 5 h, and the target product is a white solid with a yield of 83.7% and a melting point of 136.7-137.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.49 (m, 2H, PhH), 7.44-7.41 (m, 1H, PhH), 7.38-7.34 (m, 2H, PhH), 4.92 (s, 2H, OCH2), 4.25 (s, 3H, NCH3), 3.85-3.79 (m, 1H, 0.5NCH2), 3.56-3.50 (m, 1H, 0.5NCH2), 3.48-3.43 (m, 1H, CH), 3.41-3.35 (m, 1H, 0.5NCH2), 3.34 (s, 3H, OCH3), 3.21-3.15 (m, 1H, 0.5NCH2), 1.87-1.80 (m, 2H, CH2), 1.62-1.54 (m, 2H, CH2); HR-MS(ESI) m / z [M+H] + calcd for C 17 H 23 N6O3: 359.1826, found: 359.1828.

[0038] Example 7 ( Z )-2-(1-(2-((((1-methyl-1 H The preparation method of methyl 2-(1-(2-chloroacetyl)piperidin-4-yl)acetate was the same as in Example 1, except that compound III was methyl 2-(1-(2-chloroacetyl)piperidin-4-yl)acetate, the substitution reaction time was 6 h, and the target product was a yellow oil with a yield of 72.4%. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.46 (d, J = 2.5Hz, 2H, PhH), 7.42-7.22 (m, 3H, PhH), 4.85 (d, J = 3.1 Hz, 2H, OCH2), 4.48 (s,1H, 0.5NCH2), 4.20 (dd, J = 7.3, 3.6 Hz, 3H, NCH3), 3.63 (dd, J= 9.0, 4.2 Hz, 3H,OCH3), 3.57 (s, 1H, 0.5NCH2), 3.00 (d, J = 8.1 Hz, 1H, 0.5NCH2), 2.59 (d, J = 4.3Hz, 1H, 0.5NCH2), 2.22 (s, 2H, COCH2), 1.99 (s, 1H, CH), 1.74 (s, 2H, CH2),1.14 (s, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 19 H 25 N6O4: 401.1932, found: 401.1935.

[0039] Example 8 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-methylenepiperidin-1-yl)ethyl-1-one was the same as that in Example 1, except that compound III was 2-chloro-1-(4-methylenepiperidin-1-yl)ethyl-1-one, the substitution reaction time was 5 h, and the target product was a white solid with a yield of 90.2% and a melting point of 138.0-138.9 °C. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.4Hz, 2H, PhH), 7.46-7.42 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.93 (s, 2H,OCH2), 4.82 (s, 2H, C=CH2), 4.25 (s, 3H, NCH3), 3.61 (t, J = 5.6 Hz, 2H, NCH2), 3.35 (t, J = 5.6 Hz, 2H, NCH2), 2.25 (t, J = 5.6 Hz, 4H, 2CH2); HR-MS (ESI) m / z [M+H] + calcd for C 17 H21 N6O2: 341.1721, found: 341.1723.

[0040] Example 9 ( Z )-1-(4,4-difluoropiperidin-1-yl)-2-((((1-methyl-1) H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4,4-difluoropiperidin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 89.5% and a melting point of 151.6-152.8 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.49(m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 4.92 (s, 2H,OCH2), 4.21 (s, 3H, NCH3), 3.73 (t, J = 5.4 Hz, 1H, NCH2), 3.48 (t, J = 5.2 Hz,1H, NCH2), 2.06-1.95 (m, 4H, 2CH2); 19 F NMR (376 MHz, CDCl3) δ -98.09; HR-MS (ESI) m / z [M+H] + calcd for C 16 H 19 F2N6O2: 365.1532, found: 365.1536.

[0041] Example 10 ( Z )-2-((((1-methyl-1 HThe preparation method of 2-chloro-1-(4-(ethylene glycol ketal)piperidin-1-yl)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(ethylene glycol ketal)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 77.6% and a melting point of 213.2-214.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50 (m, 2H, PhH), 7.46-7.42 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.92 (s, 2H, OCH2), 4.25 (s, 3H, NCH3), 3.99 (s, 4H, CH2CH2), 3.71 (t, J = 5.6 Hz, 2H, NCH2), 3.43(t, J = 5.6 Hz, 2H, NCH2), 1.87-1.80 (t, J = 5.8 Hz, 4H, 2CH2); HR-MS (ESI) m / z [M+H] + calcd for C 18 H 23 N6O4: 387.1775, found: 387.1778.

[0042] Example 11 ( Z )-1-(2-((((1-methyl-1 H The preparation method of ethyl 1-(2-chloroacetyl)piperidine-2-carboxylate was the same as in Example 1, except that compound III was ethyl 1-(2-chloroacetyl)piperidine-2-carboxylate, the substitution reaction time was 5 h, and the target product was a yellow oil with a yield of 57.4%. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.58-7.48 (m, 2H,PhH), 7.43 (dd, J= 10.3, 4.3 Hz, 1H, PhH), 7.37 (t, J = 7.4 Hz, 2H, PhH), 5.27(d, J = 5.1 Hz, 1H, NCH), 4.96 (dd, J = 35.6, 15.1 Hz, 2H, OCH2), 4.24 (d, J = 2.9Hz, 3H, NCH3), 4.22-4.19 (m, 2H, COOCH2), 3.52 (d, J = 12.8 Hz, 1H, 0.5NCH2),3.29 (td, J = 13.1, 2.9 Hz, 1H, 0.5NCH2), 2.29 (d, J = 13.6 Hz, 1H, 0.5CH2), 1.77(d, J = 2.9 Hz, 1H, 0.5CH2), 1.70 (dd, J = 16.4, 9.0 Hz, 2H, CH2), 1.51-1.34 (m,2H, CH2), 1.28 (t, J = 7.2 Hz, 3H, CH3); HR-MS (ESI) m / z [M+H] + calcd for C 19 H 25 N6O4:401.1932, found: 401.1929.

[0043] Example 12 ( Z )-1-(2-((((1-methyl-1 H The preparation method of tert-butyl tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidin-4-ylcarbamate is the same as that in Example 1, except that: compound III is 1-(2-chloroacetyl)piperidin-4-ylcarbamate, the substitution reaction time is 6 h, and the target product is a white solid with a yield of 60.9% and a melting point of 119.1-120.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50 (m, 2H, PhH), 7.46-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 4.89 (s, 2H, OCH2), 4.47-4.43 (m, 2H, NH+0.5NCH2), 4.23 (s, 3H, NCH3), 3.69 (br, 1H, CH), 3.61 (d, J = 13.8 Hz, 1H, 0.5NCH2), 3.11 (t, J = 12.0 Hz, 1H, 0.5NCH2), 2.80 (t, J = 13.5Hz, 1H, 0.5NCH2), 2.01 (t, J = 13.6 Hz, 2H, CH2), 1.45 (s, 9H, 3CH3), 1.31-1.26(m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 30 N7O4: 444.2354, found: 444.2356.

[0044] Example 13 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-phenylpiperidin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a yellow solid with a yield of 69.0% and a melting point of 111.9-113.0 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6Hz, 2H, PhH), 7.45-7.42 (m, 1H, PhH), 7.39-7.30 (m, 4H, PhH), 7.23 (d, J = 7.1Hz, 1H, PhH), 7.18 (d, J= 7.9 Hz, 2H, PhH), 4.94 (s, 2H, OCH2), 4.71 (d, J =13.1 Hz, 1H, 0.5NCH2), 4.26 (s, 3H, NCH3), 3.74 (t, J = 13.3 Hz, 1H, 0.5NCH2),3.16 (t, J = 12.8 Hz, 1H, 0.5NCH2), 2.79-2.68 (m, 2H, 0.5NCH2+CH), 1.99-1.91 (m,2H, CH2), 1.69-1.60 (m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 25 N6O2:405.2034, found: 405.2036.

[0045] Example 14 ( Z )-1-(4-(3-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-bromo-1-(4-(3-bromophenyl)piperidin-1-yl)ethyl-1-one, the base used is 2.15 mmol of potassium carbonate, the organic solvent is 25 mL of tetrahydrofuran, the substitution reaction time is 6 h, and the target product is a white solid with a yield of 52.8% and a melting point of 127.3-128.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.54-7.52 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.34 (m, 4H, PhH), 7.19 (t, J = 7.7 Hz, 1H, PhH), 7.15 (d, J = 7.8 Hz, 1H, PhH), 4.94 (s, 2H, OCH2), 4.72 (d, J= 13.4 Hz,1H, 0.5NCH2), 4.26 (s, 3H, NCH3), 3.75 (t, J = 13.6 Hz, 1H, 0.5NCH2), 3.15 (t, J =12.0 Hz, 1H, 0.5NCH2), 2.78-2.67 (m, 2H, 0.5NCH2+CH), 1.92 (d, J = 13.4 Hz, 2H,CH2), 1.67-1.57 (m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 24 BrN6O2:483.1138, found: 483.1139.

[0046] Example 15 ( Z )-1-(4-(4-fluorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(4-fluorophenyl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a yellow solid with a yield of 73.1% and a melting point of 131.5-132.9 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.53 (d, J =7.4 Hz, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.14 (dd, J =8.5, 5.4 Hz, 2H, PhH), 7.00 (t, J = 8.6 Hz, 2H, PhH), 4.94 (s, 2H, OCH2), 4.71(d, J = 13.2 Hz, 1H, 0.5NCH2), 4.26 (s, 3H, NCH3), 3.75 (t, J= 13.2 Hz, 1H,0.5NCH2), 3.16 (t, J = 12.1 Hz, 1H, 0.5NCH2), 2.79-2.68 (m, 2H, 0.5NCH2+CH),1.91 (d, J = 13.3 Hz, 2H, CH2), 1.66-1.56 (m, 2H, CH2); 19 F NMR (376 MHz, CDCl3) δ -116.40; HR-MS (ESI) m / z [M+H] + calcd for C 22 H 24 FN6O2: 423.1939, found: 423.1936.

[0047] Example 16 ( Z )-1-(4-(4-chlorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(4-chlorophenyl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 8 h, and the target product is a white solid with a yield of 66.3% and a melting point of 126.3-127.5 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.54-7.52 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.29 (d, J = 8.4 Hz, 2H, PhH), 7.12 (t, J = 8.4 Hz, 2H, PhH), 4.94 (s, 2H, OCH2), 4.72 (d, J = 13.4 Hz,1H, 0.5NCH2), 4.26 (s, 3H, NCH3), 3.75 (t, J = 14.0 Hz, 1H, 0.5NCH2), 3.16 (t, J=12.3 Hz, 1H, 0.5NCH2), 2.79-2.67 (m, 2H, 0.5NCH2+CH), 1.91 (d, J = 12.9 Hz, 2H,CH2), 1.67-1.55 (m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 24 ClN6O2:439.1644, found: 439.1640.

[0048] Example 17 ( Z )-1-(4-(4-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-bromo-1-(4-(4-bromophenyl)piperidin-1-yl)ethyl-1-one, the base used is 3 mmol of potassium carbonate, the organic solvent is 35 mL of tetrahydrofuran, the substitution reaction temperature is 20 °C, the substitution reaction time is 17 h, and the target product is a white solid with a yield of 53.6% and a melting point of 138.3-139.2 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.54-7.52 (m, 2H,PhH), 7.48-7.42 (m, 3H, PhH), 7.40-7.37 (m, 2H, PhH), 7.06 (d, J = 8.4 Hz, 2H,PhH), 4.94 (s, 2H, OCH2), 4.72 (d, J = 13.3 Hz, 1H, 0.5NCH2), 4.26 (s, 3H,NCH3), 3.74 (t, J = 13.8 Hz, 1H, 0.5NCH2), 3.16 (t, J = 12.0 Hz, 1H, 0.5NCH2),2.77-2.67 (m, 2H, 0.5NCH2+CH), 1.91 (d, J= 13.3 Hz, 2H, CH2), 1.67-1.55 (m, 2H,CH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 24 BrN6O2: 485.1121, found: 485.1119.

[0049] Example 18 ( Z )-1-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(6-fluorobenzo[d]isoxazo-3-yl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 16 h, and the target product is a white solid with a yield of 74.4% and a melting point of 193.0-194.0 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.65-7.63(m, 1H, ArH), 7.53-7.38 (m, 5H, PhH), 7.26 (d, J = 8.1 Hz, 1H, ArH), 7.06 (t, J =8.4 Hz, 1H, ArH), 4.96 (s, 2H, OCH2), 4.57 (d, J = 12.4 Hz, 1H, 0.5NCH2), 4.25(s, 3H, NCH3), 3.82 (d, J = 13.0 Hz, 1H, 0.5NCH2), 3.40-3.35 (m, 1H, CH), 3.29(t, J = 12.5 Hz, 1H, 0.5NCH2), 3.01 (t, J = 12.5 Hz, 1H, 0.5NCH2), 2.18-2.13 (m,2H, CH2), 2.04-1.93 (m, 2H, CH2); 19 F NMR (376 MHz, CDCl3) δ -109.01; HR-MS (ESI) m / z [M+H] + calcd for C 23 H 23 FN7O3: 464.1841, found: 464.1840.

[0050] Example 19 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-(2-trifluoromethyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl-1-one was the same as that in Example 1, except that: compound III was 2-chloro-1-(4-(2-trifluoromethyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl-1-one, the substitution reaction time was 18 h, and the target product was a yellow oil with a yield of 58.5%. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.88 (d, J =7.9 Hz, 1H, ArH), 7.52-7.46 (m, 4H, ArH), 7.42-7.32 (m, 3H, PhH), 7.28-7.24(m, 1H, ArH), 5.00 (q, J = 14.3 Hz, 2H, OCH2), 4.88 (d, J = 12.6 Hz, 1H, 0.5NCH2),4.68 (t, J = 11.2 Hz, 1H, NCH), 4.23 (s, 3H, NCH3), 3.95 (d, J = 12.8 Hz, 1H,0.5NCH2), 3.26 (t, J = 12.7 Hz, 1H, 0.5NCH2), 2.80 (t, J = 12.8 Hz, 1H, 0.5NCH2),2.50 (d, J = 10.8 Hz, 2H, CH2), 2.08 (d, J = 10.6 Hz, 2H, CH2); 19F NMR (376 MHz, CDCl3) δ -61.46; HR-MS (ESI) m / z [M+H] + calcd for C 24 H 24 F3N8O2: 513.1969, found: 513.1964.

[0051] Example 20 ( Z )-1-(4-(4-fluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 9 h, and the target product is a white solid with a yield of 66.6% and a melting point of 186.3-187.1 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.00 (dd, J =8.8, 5.4 Hz, 2H, PhH), 7.55-7.53 (m, 2H, PhH), 7.48-7.45 (m, 1H, PhH), 7.42-7.38 (m, 2H, PhH), 7.19 (t, J = 8.6 Hz, 2H, PhH), 4.94 (s, 2H, OCH2), 4.52 (d, J = 13.4 Hz, 1H, 0.5NCH2), 3.76 (d, J = 13.4 Hz, 1H, 0.5NCH2), 4.26 (s, 3H, NCH3), 3.52 (tt, J = 10.6, 3.9 Hz, 1H, COCH), 3.23 (t, J = 12.5 Hz, 1H, 0.5NCH2), 2.96(t, J = 10.8 Hz, 1H, 0.5NCH2), 1.99 (t, J= 13.8 Hz, 2H, CH2), 1.89-1.69 (m, 2H, CH2); 19 F NMR (376 MHz, CDCl3) δ -104.53; HR-MS (ESI) m / z [M+H] + calcd for C 23 H 24 FN6O3:451.1888, found: 451.1886.

[0052] Example 21 ( Z )-1-(4-(2,4-difluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(2,4-difluorobenzoyl)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 64.0% and a melting point of 168.1-169.2 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.86 (q, J =7.8 Hz, 1H, PhH), 7.52-7.50 (m, 2H, PhH), 7.43-7.41 (m, 1H, PhH), 7.38-7.36(m, 2H, PhH), 7.00, (t, J = 8.1 Hz, 1H, ArH), 6.90 (t, J = 9.3 Hz, 1H, ArH), 4.92(s, 2H, OCH2), 4.48 (d, J = 12.6 Hz, 1H, 0.5NCH2),4.25 (s, 3H, NCH3), 3.72 (d, J =13.1 Hz, 1H, 0.5NCH2), 3.38 (br, 1H, COCH), 3.19 (t, J = 12.6 Hz, 1H, 0.5NCH2),2.90 (t, J= 12.4 Hz, 1H, 0.5NCH2), 1.98 (d, J = 12.8 Hz, 2H, CH2), 1.73-1.62 (m,2H, CH2); 19 F NMR (376 MHz, CDCl3) δ -101.49, -101.53, -106.46, -106.49; HR-MS(ESI) m / z [M+H] + calcd for C 23 H 23 F2N6O3: 469.1794, found: 469.1795.

[0053] Example 22 ( Z )-N-(2,6-dimethylphenyl)-1-(2-((((1-methyl-1 H The preparation method of 1-(2-iodoacetyl)-N-(2,6-dimethylphenyl)piperidine-3-carboxamide was the same as that in Example 1, except that: compound III was 1-(2-iodoacetyl)-N-(2,6-dimethylphenyl)piperidine-3-carboxamide, the base used was 3 mmol of potassium carbonate, the organic solvent was 30 mL of tetrahydrofuran, the substitution reaction temperature was 80 °C, and the substitution reaction time was 8 h. The target product was a white solid with a yield of 65.6% and a melting point of 171.1-172.0 °C. The structural formula was: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.45-7.39 (m, 4H,PhH), 7.32-7.28 (m, 2H, PhH), 7.10-7.03 (m, 3H, 2PhH+NH), 5.34 (d, J = 5.1 Hz,1H, 0.5NCH2), 4.99 (s, 2H, OCH2), 4.19 (s, 3H, NCH3), 3.65 (d, J = 13.2 Hz, 1H,0.5NCH2), 3.34 (td, J = 13.0, 2.0 Hz, 1H, COCH), 2.37 (d, J= 13.9 Hz, 1H,0.5NCH2), 2.18 (s, 6H, 2CH3), 1.89-1.75 (m, 3H, 0.5NCH2+CH2), 1.70-1.62 (m,1H, 0.5CH2), 1.54-1.47 (m, 1H, 0.5CH2); HR-MS(ESI) m / z [M+H] + calcd forC 25 H 30 N7O3: 476.2405, found: 476.2404.

[0054] Example 23 ( Z )-1-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-(2,4-difluorophenoxy)piperidin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a yellow solid with a yield of 82.6% and a melting point of 125.7-126.8 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50(m, 2H, PhH), 7.44-7.42 (m, 1H, PhH), 7.38-7.36 (m, 2H, PhH), 7.01-6.97 (m,1H, ArH), 6.89-6.77 (m, 2H, ArH), 4.93 (s, 2H, OCH2), 4.44 (br, 1H, OCH), 4.24 (s, 3H, NCH3), 3.75-3.69 (m, 3H, 1.5NCH2), 3.33 (br, 1H, 0.5NCH2), 1.88(br, 4H, 2CH2); 19 F NMR (376 MHz, CDCl3) δ -117.73, -117.74, -127.45, -127.46;HR-MS (ESI) m / z [M+H] + calcd for C 22 H23 F2N6O3: 457.1794, found: 457.1793.

[0055] Example 24 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethyl-1-one was the same as that in Example 1, except that: compound III was 2-chloro-1-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethyl-1-one, the substitution reaction time was 12 h, and the target product was a white solid with a yield of 70.4% and a melting point of 131.2-132.0 °C. The structural formula is as follows: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50(m, 2H, PhH), 7.45-7.43 (m, 1H, PhH), 7.38-7.35 (m, 2H, PhH), 7.14 (d, J = 8.6Hz, 2H, PhH), 6.92-6.89 (m, 2H, PhH), 4.92 (s, 2H, OCH2), 4.58-4.53 (m, 1H,OCH), 4.24 (s, 3H, NCH3), 3.75-3.66 (m, 2H, NCH2), 3.62-3.55 (m, 1H, 0.5NCH2), 3.36-3.30 (m, 1H, 0.5NCH2), 1.96-1.89 (m, 2H, CH2), 1.87-1.81 (m, 2H, CH2); 19 FNMR (376 MHz, CDCl3) δ -58.32; HR-MS (ESI) m / z [M+H] + calcd for C 23 H 24 F3N6O4:505.1806, found: 505.1804.

[0056] Example 25 ( Z)-1-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)ethyl-1-one, the added base is potassium carbonate, the organic solvent is tetrahydrofuran, the substitution reaction time is 24 h, and the target product is a white solid with a yield of 73.3% and a melting point of 169.1-170.2 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 8.51 (s, 1H,PyH), 7.70 (t, J = 7.2 Hz, 1H, PyH), 7.50 (d, J = 6.2 Hz, 3H, ArH), 7.43-7.36 (m,5H, ArH), 7.29 (d, J = 7.9 Hz, 2H, ArH), 7.18 (br, 1H, ArH), 5.61 (s, 1H, OCH), 4.89 (s, 2H, OCH2), 4.23 (s, 3H, NCH3), 3.81 (br, 1H, 0.5NCH2), 3.73 (m, 1H,OCH), 3.55 (br, 1H, 0.5NCH2), 3.48 (br, 1H, 0.5NCH2), 3.19 (br, 1H, 0.5NCH2),1.88-1.74 (m, 4H, 2CH2); HR-MS (ESI) m / z [M+H] + calcd for C 28 H 29 ClN7O3: 546.2015, found: 546.2010.

[0057] Example 26 ( Z )-2-((((1-methyl-1 HThe preparation method of 2-chloro-1-(4-methylpiperazin-1-yl)ethyl-1-one was the same as in Example 1, except that: the amount of compound II added was 2 mmol, the amount of cesium carbonate added was 4.5 mmol, the amount of acetonitrile added was 50 mL, the amount of compound III was 2.05 mmol, the substitution reaction time was 10 h, the amount of ethyl acetate was 40 mL, the amount of saturated brine was 40 mL, and the volume ratio of ethyl acetate to petroleum ether as eluent was 1:3. The target product was a yellow solid with a yield of 75.9% and a melting point of 156.3-157.3 °C. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.53-7.51 (m, 2H, PhH), 7.46-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 4.90 (s, 2H, OCH2), 4.20 (s, 3H, NCH3), 3.64 (t, J = 4.5 Hz, 2H, NCH2), 3.38 (t, J = 5.0 Hz, 2H,NCH2), 2.38-2.42 (m, 4H, 2NCH2), 2.32 (s, 3H, NCH3); HR-MS (ESI) m / z [M+H] + calcdfor C 16 H 22 N7O2: 344.1830, found: 344.1832.

[0058] Example 27 ( Z )-1-(4-acetylpiperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-acetylpiperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 75.4% and a melting point of 135.5-136.9 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.3Hz, 1H, PhH), 7.44 (d, J = 6.8 Hz, 1H, PhH), 7.40-7.36 (m, 3H, PhH), 4.92 (d, J =8.6 Hz, 2H, OCH2), 4.21 (d, J = 9.0 Hz, 3H, NCH3), 3.65-3.60 (m, 4H, 2NCH2), 3.50 (t, J = 4.9 Hz, 2H, NCH2), 3.43-3.39 (m, 2H, NCH2), 2.13 (s, 3H, COCH3); HR-MS (ESI) m / z [M+H] + calcd for C 17 H 22 N7O3: 372.1779, found: 372.1776.

[0059] Example 28 ( Z )-1-(4-(cyclopropaneformyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(cyclopropaneformyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 68.7% and a melting point of 146.1-147.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50 (m, 2H, 2PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 4.93 (s, 2H, OCH2CO), 4.22 (s, 3H, NCH3), 3.70 (br, 6H, 3NCH2), 3.41 (br, 2H, NCH2), 1.73 (br, 1HCOCH), 1.04-1.00 (br, 2H, CH2), 0.84-0.80 (br, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 19 H 24 N7O3: 398.1935, found: 398.1936.

[0060] Example 29 ( Z )-1-(4-(furan-2-formyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(furan-2-formyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 15 h, and the target product is a white solid with a yield of 81.2% and a melting point of 129.3-130.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50 (m, 3H,2PhH+Furan-H), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 7.09 (d, J = 3.5Hz, 1H, Furan-H), 6.51 (dd, J HR-MS (ESI) m / z [M+H]+ calcd for C 20 H 22 N7O4: 424.1728, found: 424.1724.

[0061] Example 30 ( Z )-1-(4-(benzoyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(benzoyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a colorless oil with a yield of 69.2%. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.49 (m, 2H,PhH), 7.47-7.36 (m, 8H, PhH), 4.92 (s, 2H, OCH2), 4.20 (s, 3H, NCH3), 3.78(br, 2H, NCH2), 3.62 (br, 3H, 1.5NCH2), 3.47 (br, 3H, 1.5NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 24 N7O3: 434.1935, found: 434.1932.

[0062] Example 31 ( Z )-4-(2-((((1-methyl-1 H The preparation method of tert-butyl piperazine-1-carboxylate (-tetrazole-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-carboxylate is the same as that in Example 26, except that: compound III is tert-butyl piperazine-1-carboxylate, the base used is 4.4 mmol potassium carbonate, the organic solvent is 60 mL tetrahydrofuran, the substitution reaction time is 16 h, and the target product is a white solid with a yield of 69.9% and a melting point of 112.5-113.7 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows:1 H-NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4Hz, 2H, PhH), 7.44 (t, J = 7.5 Hz, 1H, PhH), 7.376 (t, J = 7.7 Hz, 2H, PhH), 4.91(s, 2H, OCH2), 4.22 (s, 3H, NCH3), 3.59 (br, 2H, NCH2), 3.46 (br, 4H, 2NCH2), 3.36 (br, 2H, NCH2), 1.47 (s, 9H, C(CH3)3); HR-MS (ESI) m / z [M+H] + calcd forC 20 H 28 N7O4: 430.2197, found: 430.2195.

[0063] Example 32 ( Z )-4-(2-((((1-methyl-1 H The preparation method of 4-(2-chloroacetyl)piperazine-1-carboxylic acid benzyl ester was the same as in Example 26, except that compound III was 4-(2-chloroacetyl)piperazine-1-carboxylic acid benzyl ester, the substitution reaction time was 12 h, and the target product was a yellow solid with a yield of 77.6% and a melting point of 122.3-123.8 °C. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.49-7.47 (m, 2H, PhH), 7.43-7.39 (m, 1H, PhH), 7.35-7.30 (m, 7H, PhH), 5.13 (s, 2H, OCH2Ph), 4.90 (s, 2H, OCH2CO), 4.20 (s, 3H, NCH3), 3.57 (br, 2H, NCH2), 3.51 (br, 4H,2NCH2), 3.35 (t, J = 4.8 Hz, 2H, NCH2); HR-MS (ESI) m / z [M+H] +calcd for C 23 H 26 N7O4:464.2041, found: 464.2043.

[0064] Example 33 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methanesulfonylpiperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-methanesulfonyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 71.9% and a melting point of 178.9-180.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.45 (m, 3H,PhH), 7.41-7.37 (m, 2H, PhH), 4.92 (s, 2H, OCH2), 4.17 (s, 3H, NCH3), 3.73 (s,2H, NCH2), 3.50 (s, 2H, NCH2), 3.23 (d, J = 18.2 Hz, 4H, 2NCH2), 2.81 (s, 3H,CH3); HR-MS (ESI) m / z [M+H] + calcd for C 16 H 22 N7O4S: 408.1449, found: 408.1448.

[0065] Example 34 ( Z )-N,N-dimethyl-4-(2-((((1-methyl-1 H The preparation method of 4-(2-chloroacetyl)-N,N-dimethylpiperazine-1-sulfonamide was the same as that in Example 26, except that compound III was 4-(2-chloroacetyl)-N,N-dimethylpiperazine-1-sulfonamide, the substitution reaction time was 10 h, and the target product was a white solid with a yield of 59.8% and a melting point of 149.7-150.9 °C. The structural formula is as follows: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.49 (m, 2H,PhH), 7.47-7.44 (m 1H, PhH), 7.40-7.36 (m, 2H, PhH), 4.91 (s, 2H, OCH2), 4.20(s, 3H, NCH3), 3.68 (br, 2H, NCH2), 3.45 (br, 2H, NCH2), 3.26 (br, 4H, 2NCH2), 2.84 (s, 6H, N(CH3)2); HR-MS (ESI) m / z [M+H] + calcd for C 17 H 25 N8O4S: 437.1714, found: 437.1712.

[0066] Example 35 ( Z )-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 79.4% and a melting point of 169.6-170.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.6Hz, 2H, PhH), 7.50 (d, J = 8.6 Hz, 2H, PhH), 7.46-7.31 (m, 5H, PhH), 4.84 (s,2H, OCH2), 4.14 (s, 3H, NCH3), 3.68 (s, 2H, NCH2), 3.47 (s, 2H, NCH2), 3.00(d, J = 16.0 Hz, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] +calcd for C 21 H 23 ClN7O4S:504.1215, found: 504.1212.

[0067] Example 36 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-((4-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-((4-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 15 h, and the target product is a white solid with a yield of 76.3% and a melting point of 170.2-171.1 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.89 (d, J =8.2 Hz, 2H, PhH), 7.81 (d, J = 8.4 Hz, 2H, PhH), 7.46-7.30 (m, 5H, PhH), 4.84(s, 2H, OCH2), 4.13 (s, 3H, NCH3), 3.69 (s, 2H, NCH2), 3.49 (s, 2H, NCH2), 3.04 (d, J = 18.2 Hz, 4H, 2NCH2); 19 F NMR (376 MHz, CDCl3) δ -63.09; HR-MS (ESI) m / z [M+H] + calcd for C 22 H 23 F3N7O4S: 538.1479, found: 538.1475.

[0068] Example 37 ( Z )-1-(4-((4-chloro-3-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 HThe preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-((4-chloro-3-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 15 h, and the target product is a white solid with a yield of 68.4% and a melting point of 203.4-204.3 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.04 (d, J =1.9 Hz, 1H, PhH), 7.87 (dd, J = 8.4, 2.0 Hz, 1H, PhH), 7.79 (d, J = 8.4 Hz, 1H,PhH), 7.48-7.35 (m, 5H, PhH), 4.84 (s, 2H, OCH2), 4.11 (s, 3H, NCH3), 3.73 (s,2H, NCH2), 3.50 (s, 2H, NCH2), 3.06 (d, J = 3.4 Hz, 4H, 2NCH2); 19 F NMR (376 MHz, CDCl3) δ -62.99; HR-MS (ESI) m / z [M+H] + calcd for C 22 H 22 ClF3N7O4S: 572.1089, found: 572.1085.

[0069] Example 38 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-phenylpiperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 87.6% and a melting point of 171.6-172.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.4Hz, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.30 (t, J = 8.1Hz, 2H, PhH), 6.95-6.91 (m, 3H, PhH), 4.95 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.78 (t, J = 4.7 Hz, 2H, NCH2), 3.54 (t, J = 5.0 Hz, 2H, NCH2), 3.19 (br, 4H,2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 24 N7O2: 406.1986, found: 406.1983.

[0070] Example 39 ( Z )-1-(4-(4-fluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a pink solid with a yield of 82.9% and a melting point of 166.3-167.2 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.53-7.50(m, 2H, PhH), 7.45-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 7.01-6.96 (m,2H, PhH), 6.91-6.87 (m, 2H, PhH), 4.94 (s, 2H, OCH2), 4.23 (s, 3H, NCH3), 3.77(t, J= 4.7 Hz, 2H, NCH2), 3.53 (t, J = 4.6 Hz, 2H, NCH2), 3.09 (br, 4H, 2NCH2); 19 FNMR (376 MHz, CDCl3) δ -123.01; HR-MS (ESI) m / z [M+H] + calcd for C 21 H 23 FN7O2:424.1892, found: 424.1894.

[0071] Example 40 ( Z )-1-(4-(2-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(2-chlorophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 82.1% and a melting point of 131.7-132.7 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.53-7.51 (m, 2H,PhH), 7.44-7.40 (m, 1H, PhH), 7.37-7.34 (m, 3H, PhH), 7.22 (td, J = 7.7, 1.4Hz, 1H, PhH), 7.02-6.98 (m, 2H, PhH), 4.94 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.77 (br, 2H, NCH2), 3.53 (t, J = 4.3 Hz, 2H, NCH2), 3.00 (t, J = 4.8 Hz, 4H,2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 23 ClN7O2: 440.1596, found: 440.1598.

[0072] Example 41 ( Z )-1-(4-(4-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-chlorophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 91.8% and a melting point of 188.6-189.7 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.50 (m, 2H,PhH), 7.45-7.42 (m, 1H, PhH), 7.38-7.35 (m, 2H, PhH), 7.21 (d, J = 8.9 Hz, 2H, PhH), 6.83 (d, J = 9.0 Hz, 2H, PhH), 4.93 (s, 2H, OCH2), 4.22 (s, 3H, NCH3), 3.75 (br, 2H, NCH2), 3.52 (br, 2H, NCH2), 3.13 (t, J = 4.8 Hz, 4H, 2NCH2); HR-MS(ESI) m / z [M+H] + calcd for C 21 H 23 ClN7O2: 440.1596, found: 440.1593.

[0073] Example 42 ( Z )-1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 75.7% and a melting point of 165.4-166.5 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.53-7.50(m, 2H, PhH), 7.45-7.41 (m, 1H, PhH), 7.40-7.34 (m, 2H, PhH), 6.93-6.80 (m,3H, PhH), 4.94 (d, J = 5.8 Hz, 2H, OCH2), 4.23 (d, J = 3.9 Hz, 3H, NCH3), 3.77(br, 2H, NCH2), 3.53 (br, 2H, NCH2), 3.00 (br, 4H, 2NCH2); 19 F NMR (376 MHz, CDCl3) δ -117.49, -117.51, -118.80, -118.82; HR-MS (ESI) m / z [M+H] + calcd forC 21 H 22 F2N7O2: 442.1798, found: 442.1802.

[0074] Example 43 ( Z )-1-(4-(4-methylphenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-methylphenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a yellow solid with a yield of 76.0% and a melting point of 156.1-157.1 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.53-7.51 (m, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 7.10 (d, J = 8.2 Hz, 2H, PhH), 6.85 (d,J = 8.4 Hz, 2H, PhH), 4.95 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.78 (t, J = 5.0 Hz, 2H, NCH2), 3.53 (t, J = 4.9 Hz, 2H, NCH2), 3.13 (br, 4H,2NCH2), 2.29 (s, 3H, CH3); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 26 N7O2: 420.2143, found: 420.2153.

[0075] Example 44 ( Z )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 90.2% and a melting point of 172.3-173.4 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4Hz, 2H, PhH), 7.41 (d, J = 7.3 Hz, 1H, PhH), 7.37-7.33 (m, 2H, PhH), 7.18 (t, J =8.6 Hz, 1H, PhH), 6.53-6.42 (m, 3H, PhH), 4.92 (s, 2H, OCH2), 4.22 (s, 3H,NCH3), 3.78 (s, 3H, OCH3), 3.74 (br, 2H, NCH2), 3.50 (br, 2H, NCH2), 3.16 (br,4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C22 H 26 N7O3: 436.2092, found: 436.2090.

[0076] Example 45 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-cyanophenyl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-cyanophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 20 h, and the target product is a white solid with a yield of 77.8% and a melting point of 169.5-170.7 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.55-7.50 (m, 4H,PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 6.87 (d, J = 9.0 Hz, 2H,PhH), 4.96 (s, 2H, OCH2), 4.20 (s, 3H, NCH3), 3.79 (br, 2H, NCH2), 3.56 (br,2H, NCH2), 3.36 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 23 N8O2:431.1939, found: 431.1938.

[0077] Example 46 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(2-nitrophenyl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(2-nitrophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 18 h, and the target product is a yellow solid with a yield of 69.6% and a melting point of 161.1-162.1 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.9,1.1 Hz, 1H, PhH), 7.54-7.51 (m, 3H, PhH), 7.47-7.44 (m, 1H, PhH), 7.40-7.37(m, 2H, PhH), 7.18-7.14 (m, 2H, PhH), 4.94 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.79 (t, J = 4.7 Hz, 2H, NCH2), 3.54 (t, J = 4.7 Hz, 2H, NCH2), 3.08-3.06 (m, 4H,2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 23 N8O4: 451.1837, found: 451.1837.

[0078] Example 47 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-nitrophenyl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-nitrophenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 20 h, and the target product is a yellow solid with a yield of 77.7% and a melting point of 166.6-167.5 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.16 (d, J = 9.4Hz, 2H, PhH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m,2H, PhH), 6.84 (d, J= 9.4 Hz, 2H, PhH), 4.95 (s, 2H, OCH2), 4.19 (s, 3H, NCH3), 3.81 (br, 2H, NCH2), 3.59 (br, 2H, NCH2), 3.46 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 23 N8O4: 451.1837, found: 451.1841.

[0079] Example 48 ( Z )-4-(4-(2-((((1-methyl-1 H The preparation method of ethyl 4-(4-(2-bromoacetyl)piperazin-1-yl)benzoate was the same as in Example 26, except that: compound III was ethyl 4-(4-(2-bromoacetyl)piperazin-1-yl)benzoate, the base used was 4.1 mmol potassium carbonate, the organic solvent was 45 mL tetrahydrofuran, the substitution reaction time was 10 h, and the target product was a white solid with a yield of 85.5% and a melting point of 160.7-161.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.9Hz, 2H, PhH), 7.52-7.50 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.39-7.36 (m,2H, PhH), 6.87 (d, J = 8.9 Hz, 2H, PhH), 4.95 (s, 2H, OCH2), 4.33 (q, J = 7.1 Hz, 2H, COOCH2), 4.23 (s, 3H, NCH3), 3.79 (t, J = 4.8 Hz, 2H, NCH2), 3.55 (t, J = 4.8Hz, 2H, NCH2), 3.35 (t, J = 4.9 Hz, 4H, 2NCH2), 1.38 (t, J= 7.1 Hz, 3H, CCH3); HR-MS (ESI) m / z [M+H] + calcd for C 24 H 28 N7O4: 478.2197, found: 478.2193.

[0080] Example 49 ( Z )-1-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 24 h, and the target product is a white solid with a yield of 56.8% and a melting point of 116.2-117.1 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.49 (d, J =7.6 Hz, 2H, PhH), 7.42-7.40 (m, 1H, PhH), 7.35-7.29 (m, 6H, PhH), 6.96 (t, J =8.5 Hz, 4H, PhH), 4.85 (s, 2H, OCH2), 4.26 (s, 1H, NCH), 4.20 (s, 3H, NCH3), 3.60 (br, 2H, NCH2), 3.36 (br, 2H, NCH2), 2.36 (br, 4H, 2NCH2); 19 F NMR (376MHz, CDCl3) δ -115.07; HR-MS (ESI) m / z [M+H] + calcd for C 28 H 28 F2N7O2: 532.2267, found: 532.2265.

[0081] Example 50 ( Z)-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 24 h, and the target product is a yellow solid with a yield of 60.7% and a melting point of 85.8-86.8 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5Hz, 2H, PhH), 7.41-7.3 (m, 7H, PhH), 7.29-7.17 (m, 5H, PhH), 4.83 (s, 2H,OCH2), 4.23 (s, 1H, NCH), 4.20 (s, 3H, NCH3), 3.59 (br, 2H, NCH2), 3.33 (br,2H, NCH2), 2.35 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 28 H 29 ClN7O2:530.2066, found: 530.2061.

[0082] Example 51 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 69.3% and a melting point of 188.0-188.9 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.20 (dd, J= 4.8,1.2 Hz, 1H, PyH), 7.55-7.51 (m, 3H, PyH+2PhH), 7.46-7.43 (m, 1H, PhH), 7.39-7.36 (m, 2H, PhH), 6.71-6.66 (m, 2H, PyH), 4.95 (s, 2H, OCH2), 4.24 (s, 3H,NCH3), 3.77-3.74 (m, 2H, NCH2), 3.64-3.61 (m, 2H, NCH2), 3.58-3.55 (m, 2H,NCH2), 3.52-3.49 (m, 2H, NCH2); HR-MS(ESI) m / z [M+H] + calcd for C 20 H 23 N8O2:407.1939, found: 407.1941.

[0083] Example 52 ( Z )-1-(4-(3-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-chloropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 58.7% and a melting point of 113.7-115.2 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 4.7,1.4 Hz, 1H, PyH), 7.63 (dd, J = 7.8, 1.4 Hz, 1H, PyH), 7.53 (d, J = 7.3 Hz, 2H,PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 6.91 (dd, J= 7.8, 4.8Hz, 1H, PyH), 4.96 (s, 2H, OCH2), 4.26 (s, 3H, NCH3), 3.79 (t, J = 4.8 Hz, 2H,NCH2), 3.55 (t, J = 4.8 Hz, 2H, NCH2), 3.38 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 20 H 22 ClN8O2: 441.1549, found: 441.1554.

[0084] Example 53 ( Z )-1-(4-(4-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(4-chloropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 15 h, and the target product is a white solid with a yield of 69.5% and a melting point of 163.9-165.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.08 (d, J = 5.3Hz, 1H, PyH), 7.53-7.49 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m,2H, PhH), 6.68 (d, J = 5.2 Hz, 1H, PyH), 6.64 (s, 1H, PyH), 4.95 (s, 2H, OCH2), 4.23 (s, 3H, NCH3), 3.76-3.72 (m, 2H, NCH2), 3.65-3.63 (m, 2H, NCH2), 3.59-3.56 (m, 2H, NCH2), 3.51-3.48 (m, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd forC20 H 22 ClN8O2: 441.1549, found: 441.1559.

[0085] Example 54 ( Z )-1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 70.0% and a melting point of 155.9-157.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.4Hz, 1H, PyH), 7.53-7.50 (m, 2H, PhH), 7.49-7.43 (m, 2H, PyH+PhH), 7.40-7.36(m, 2H, PhH), 6.60 (d, J = 9.0 Hz, 1H, PyH), 4.95 (s, 2H, OCH2), 4.23 (s, 3H,NCH3), 3.76-3.73 (m, 2H, NCH2), 3.60-3.58 (m, 2H, NCH2), 3.55-3.53 (m, 2H,NCH2), 3.51-3.48 (m, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 20 H 22 ClN8O2:441.1549, found: 441.1553.

[0086] Example 55 ( Z )-1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 HThe preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-bromo-1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)ethyl-1-one, the base used is 4.2 mmol potassium carbonate, the organic solvent is 55 mL tetrahydrofuran, the substitution reaction temperature is 70 °C, the substitution reaction time is 10 h, and the target product is a white solid with a yield of 62.1% and a melting point of 162.6-163.9 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.00 (d, J = 5.2Hz, 1H, PyH), 7.53-7.49 (m, 2H, PhH), 7.47-7.43 (m, 1H, PhH), 7.40-7.36 (m,2H, PhH), 6.84-6.82 (m, 2H, PyH), 4.95 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.75(t, J = 4.9 Hz, 2H, NCH2), 3.64 (t, J = 4.9 Hz, 2H, NCH2), 3.57 (t, J = 5.1 Hz, 2H,NCH2), 3.50 (t, J = 5.1 Hz, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 20 H 22 BrN8O2:485.1044, found: 485.1051.

[0087] Example 56 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 18 h, and the target product is a yellow oil with a yield of 55.5%, and the structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.47 (d, J =3.4 Hz, 1H, PyH), 7.91 (dd, J = 7.8, 1.3 Hz, 1H, PyH), 7.54-7.52 (m, 2H, PhH), 7.46-7.43 (m, 1H, PhH), 7.40-7.36 (m, 2H, PhH), 7.09 (dd, J = 7.6, 4.9 Hz, 1H,PyH), 4.95 (s, 2H, OCH2), 4.26 (s, 3H, NCH3), 3.77 (t, J = 4.7 Hz, 2H, NCH2), 3.53 (t, J = 4.7 Hz, 2H, NCH2), 3.30-3.25 (m, 6H, 2NCH2); 19 F NMR (376 MHz, CDCl3) δ -60.29; HR-MS (ESI) m / z [M+H] + calcd for C 21 H 22 F3N8O2: 475.1812, found: 475.1820.

[0088] Example 57 ( Z )-2-((((1-methyl-1 H The preparation method of 2-chloro-1-(4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 65.8% and a melting point of 176.7-177.8 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 8.41 (s, 1H,PyH), 7.66 (d, J = 8.6 Hz, 1H, PyH), 7.51-7.37 (m, 5H, PhH), 6.68 (d, J = 8.7 Hz,1H, PyH), 4.95 (s, 2H, OCH2), 4.23 (s, 3H, NCH3), 3.74 (br, 4H, 2NCH2), 3.69(br, 2H, NCH2), 3.52 (br, 2H, NCH2); 19 F NMR (376 MHz, CDCl3) δ -61.12; HR-MS (ESI) m / z [M+H] + calcd for C 21 H 22 F3N8O2: 475.1812, found: 475.1807.

[0089] Example 58 ( Z )-1-(4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 18 h, and the target product is a white solid with a yield of 66.6% and a melting point of 127.7-128.9 °C. The structural formula is: ; The proton nuclear magnetic resonance (NMR) spectrum, fluorine spectrum, and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 8.41 (s, 1H, PyH), 7.81 (s, 1H, PyH), 7.51 (d, J = 6.7 Hz, 2H, PhH), 7.44 (t, J = 6.7 Hz, 1H, PhH), 7.37 (t, J= 7.2 Hz, 2H, PhH), 4.96 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.78 (br, 2H, NCH2), 3.54 (br, 6H, 3NCH2); 19 F NMR (376 MHz, CDCl3) δ -61.44; HR-MS (ESI) m / z [M+H] + calcd for C 21 H 21 ClF3N8O2: 509.1423, found: 509.1420.

[0090] Example 59 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 71.1% and a melting point of 159.1-160.3 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.43 (d, J = 2.0Hz, 1H, PyH), 7.67 (dd, J = 9.0, 2.3 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44 (m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 6.63 (d, J = 9.0 Hz, 1H, PyH),4.95 (s, 2H, OCH2), 4.20 (s, 3H, NCH3), 3.78-3.71 (m, 6H, 2NCH2), 3.53-3.50(m, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 21 H 22N9O2: 432.1891, found: 432.1893.

[0091] Example 60 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-nitropyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-nitropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 18 h, and the target product is a yellow solid with a yield of 56.3% and a melting point of 140.2-141.5 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 4.6,1.7 Hz, 1H, PyH), 7.67 (dd, J = 8.0, 1.7 Hz, 1H, PyH), 7.53-7.36 (m, 5H, PhH), 6.87 (dd, J = 8.0, 4.5 Hz, 1H, PyH), 4.94 (s, 2H, OCH2), 4.24 (s, 3H, NCH3), 3.79-3.77 (m, 2H, NCH2), 3.56-3.46 (m, 6H, 3NCH2); HR-MS (ESI) m / z [M+H] + calcdfor C 20 H 22 N9O4: 452.1789, found: 452.1793.

[0092] Example 61 ( Z )-2-((((1-methyl-1 HThe preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-nitropyridin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(5-nitropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 20 h, and the target product is a yellow solid with a yield of 66.5% and a melting point of 172.3-173.6 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 9.06 (d, J = 2.6Hz, 1H, PyH), 8.26 (dd, J = 9.4, 2.6 Hz, 1H, PyH), 7.52-7.45 (m, 3H, PhH), 7.41-7.37 (m, 2H, PhH), 6.60 (d, J HR-MS (ESI) m / z [M+H] + calcd for C 20 H 22 N9O4: 452.1789, found: 452.1793.

[0093] Example 62 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazole-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 20 h, and the target product is a yellow solid with a yield of 68.3% and a melting point of 201.5-202.8 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1H-NMR (400 MHz, CDCl3) δ 8.21 (d, J = 9.1Hz, 1H, PyH), 8.15 (d, J = 3.0 Hz, 1H, PyH), 7.51-7.45 (m, 3H, PhH), 7.41-7.37(m, 2H, PhH), 7.25 (dd, J HR-MS (ESI) m / z [M+H] + calcd for C 20 H 22 N9O4: 452.1789, found: 452.1794.

[0094] Example 63 ( Z )-1-(4-(5-bromo-3-nitropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-bromo-1-(4-(5-bromo-3-nitropyridin-2-yl)piperazin-1-yl)ethyl-1-one, the base used is 4.3 mmol potassium carbonate, the organic solvent is 65 mL tetrahydrofuran, the substitution reaction temperature is 20 °C, and the substitution reaction time is 10 h. The target product is a yellow oil with a yield of 52.6% and the structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.2, Hz, 1H, PyH), 8.32 (d, J= 2.1 Hz, 1H, PyH), 7.52-7.50 (m, 2H, PhH), 7.48-7.44(m, 1H, PhH), 7.40-7.37 (m, 2H, PhH), 4.93 (s, 2H, OCH2), 4.22 (s, 3H, NCH3),3.78-3.76 (m, 2H, NCH2), 3.56-3.44 (m, 6H, 3NCH2); HR-MS (ESI) m / z [M+H] + calcdfor C 20 H 21 BrN9O4: 530.0894, found: 530.0900.

[0095] Example 64 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 12 h, and the target product is a white solid with a yield of 74.4% and a melting point of 161.2-162.1 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.21 (d, J = 4.7Hz, 2H, Pyr-H), 7.52-7.50 (m, 2H, PhH), 7.46-7.42 (m, 1H, PhH), 7.39-7.35 (m,2H, PhH), 6.56 (t, J = 4.8 Hz, 1H, Pyr-H), 4.96 (s, 2H, OCH2), 4.25 (s, 3H,NCH3), 3.90-3.85 (m, 4H, 2NCH2), 3.70 (t, J = 4.6 Hz, 2H, NCH2), 3.46 (t, J = 4.6Hz, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C19 H 22 N9O2: 408.1891, found: 408.1893.

[0096] Example 65 ( Z )-1-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)ethyl-1-one, the base used is 4.5 mmol potassium carbonate, the organic solvent is 70 mL tetrahydrofuran, the substitution reaction time is 20 h, and the target product is a white solid with a yield of 87.1% and a melting point of 124.3-125.5 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1Hz, 1H, ArH), 7.81 (d, J = 8.1 Hz, 1H, ArH), 7.52-7.45 (m, 3H, ArH), 7.43-7.32(m, 4H, ArH), 4.96 (s, 2H, OCH2), 4.25 (s, 3H, NCH3), 3.83 (br, 2H, NCH2), 3.59 (br, 2H, NCH2), 3.52 (t, J = 5.0 Hz, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcdfor C 22 H 23 N8O2S: 463.1659, found: 463.1661.

[0097] Example 66 ( Z )-1-(4-(benzo[d]thiazo-2-yl)piperazin-1-yl)-2-((((1-methyl-1 HThe preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)ethyl-1-one, the base used is 4.45 mmol potassium carbonate, the organic solvent is 50 mL tetrahydrofuran, the substitution reaction time is 20 h, and the target product is a white solid with a yield of 76.7% and a melting point of 212.1-213.0 °C. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.7Hz, 1H, ArH), 7.57 (d, J = 7.2 Hz, 1H, ArH), 7.51-7.43 (m, 3H, ArH), 7.39-7.32(m, 3H, ArH), 7.12 (t, J = 7.2 Hz, 1H, ArH), 4.93 (s, 2H, OCH2), 4.22 (s, 3H,NCH3), 3.77 (br, 2H, NCH2), 3.67 (br, 4H, 2NCH2), 3.52 (t, J = 5.0 Hz, 2H,NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 23 N8O2S: 463.1659, found: 463.1656.

[0098] Example 67 ( Z )-1-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl-1-one, the base used is 4.15 mmol potassium carbonate, the solvent is 40 mL tetrahydrofuran, the substitution reaction time is 24 h, and the target product is a colorless oil with a yield of 67.4%. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.1Hz, 1H, ArH), 7.52 (d, J = 7.4 Hz, 2H, ArH), 7.44-7.33 (m, 5H, ArH), 7.27 (t, J =7.7 Hz, 1H, ArH), 6.85 (d, J = 7.6 Hz, 1H, ArH), 4.93 (s, 2H, OCH2), 4.25 (s,3H, NCH3), 3.82 (br, 2H, NCH2), 3.54 (br, 2H, NCH2), 3.09 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 23 H 24 N7O2S: 462.1707, found: 462.1702.

[0099] Example 68 ( Z )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinyl ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-morpholinyl ethyl-1-one, the substitution reaction time is 5 h, and the target product is a colorless oil with a yield of 66.5%. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.36 (m, 5H,PhH), 4.90 (s, 2H, OCH2), 4.22 (s, 3H, NCH3), 3.72-3.67 (m, 4H, 2OCH2), 3.62(t, J = 4.7 Hz, 2H, NCH2), 3.39 (t, J = 4.7 Hz, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C15 H 19 N6O3: 331.1518, found: 331.1511.

[0100] Example 69 ( Z )-1-(2,6-dimethylmorpholino)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(2,6-dimethylmorpholino)ethyl-1-one, the substitution reaction time is 6 h, and the target product is a white solid with a yield of 70.9%. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.49 (m, 2H,PhH), 7.46-7.43 (m, 1H, PhH), 7.39-7.35 (m, 2H, PhH), 4.95-4.83 (m, 2H,OCH2), 4.36 (d, J = 13.2 Hz, 1H, 0.5NCH2), 4.22 (s, 3H, NCH3), 3.60-3.52 (m, 2H,2OCH), 3.42 (d, J = 13.0 Hz, 1H, 0.5NCH2), 2.81 (q, J = 12.9, 10.9 Hz, 2H,0.5NCH2), 2.39 (q, J = 12.9, 11.1 Hz, 2H, 0.5NCH2), 1.21 (t, J = 4.9 Hz, 6H,2CH3); HR-MS (ESI) m / z [M+H] + calcd for C 17 H 23 N6O3: 359.1831, found: 359.1830.

[0101] Example 70 ( Z )-2-((((1-methyl-1 HThe preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)-1-thiomorpholinyl ethyl-1-one is the same as that in Example 26, except that: compound III is 2-bromo-1-thiomorpholinyl ethyl-1-one, the base used is 4.25 mmol potassium carbonate, the solvent is 50 mL tetrahydrofuran, the substitution reaction time is 5 h, and the target product is a pale yellow oil with a yield of 84.2%. The structural formula is: ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: 1 H-NMR (400 MHz, CDCl3) δ : 7.51-7.35 (m, 5H,PhH), 4.90 (s, 2H, OCH2), 4.23 (s, 3H, NCH3), 3.83-3.81(m, 2H, NCH2), 3.70-3.68 (m, 2H, NCH2), 2.62-3.56 (m, 4H, CH2SCH2); HR-MS (ESI) m / z [M+H] + calcd forC 15 H 19 N6O2S: 347.1290, found: 347.1292.

[0102] Example 71 ( Z / E )-2-((((1-methyl-1 H The preparation method of 2-tetrazo-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one is the same as that in Example 1, except that: compound III is 2-chloro-1-(4-phenylpiperidin-1-yl)ethyl-1-one, the substitution reaction time is 15 h, and purification by silica gel column chromatography is not performed. The target product is a yellow viscous liquid with a yield of 96.9%, and its structural formula is: and ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H, PhH), 7.45-7.42 (m, 1H, PhH), 7.39-7.30 (m, 4H, PhH), 7.23 (d, J= 7.1 Hz, 1H, PhH), 7.18(d, J = 7.9 Hz, 2H, PhH), 4.94 (s, 2H, OCH2), 4.71 (d, J = 13.1 Hz, 1H, 0.5NCH2),4.26 (s, 3H, NCH3), 3.74 (t, J = 13.3 Hz, 1H, 0.5NCH2), 3.16 (t, J = 12.8 Hz, 1H,0.5NCH2), 2.79-2.68 (m, 2H, 0.5NCH2+CH), 1.99-1.91 (m, 2H, CH2), 1.69-1.60 (m,2H, CH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 25 N6O2: 405.2034, found: 405.2036.

[0103] E -isomer: 1 H-NMR (400 MHz, CDCl3) δ : 7.65-7.62 (m, 2H, PhH), 7.53-7.49(m, 3H, PhH), 7.40-7.32 (m, 2H, PhH), 7.24-7.19 (m, 3H, PhH), 4.88 (s, 2H,OCH2), 4.71 (d, J = 13.1 Hz, 1H, 0.5NCH2), 4.23 (s, 3H, NCH3), 3.74 (t, J = 13.3Hz, 1H, 0.5NCH2), 3.16 (t, J = 12.8 Hz, 1H, 0.5NCH2), 2.79-2.69 (m, 2H, 0.5NCH2+CH), 1.99-1.92 (m, 2H, CH2), 1.69-1.61 (m, 2H, CH2); HR-MS (ESI) m / z [M+H] + calcdfor C 22 H 25 N6O2: 405.2034, found: 405.2032.

[0104] Example 72 ( Z / E )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethyl-1-one, the substitution reaction time is 16 h, and purification by silica gel column chromatography is not performed. The target product is a light yellow viscous liquid with a yield of 97.3% and the structural formula is: and ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2H, PhH), 7.41(d, J = 7.3 Hz, 1H, PhH), 7.37-7.33 (m, 2H, PhH), 7.18 (t, J = 8.6 Hz, 1H, PhH), 6.53-6.45 (m, 3H, PhH), 4.92 (s, 2H, OCH2), 4.22 (s, 3H, NCH3), 3.78 (s, 3H,OCH3), 3.74 (br, 2H, NCH2), 3.50 (br, 2H, NCH2), 3.16 (br, 4H, 2NCH2); HR-MS(ESI) m / z [M+H] + calcd for C 22 H 26 N7O3: 436.2092, found: 436.2090.

[0105] E -Isomeric: 1 H-NMR (400 MHz, CDCl3) δ : 7.68-7.68 (m, 2H, PhH), 7.46-7.42(m, 3H, PhH), 7.18 (t, J= 8.6 Hz, 1H, PhH), 6.47-6.42 (m, 3H, PhH), 4.98 (s,2H, OCH2), 4.20 (s, 3H, NCH3), 3.78 (s, 3H, OCH3), 3.74 (br, 2H, NCH2), 3.50(br, 2H, NCH2), 3.06 (br, 4H, 2NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 22 H 26 N7O3:436.2092, found: 436.2092.

[0106] Example 73 ( Z / E )-2-((((1-methyl-1 H The preparation method of 2-tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinyl ethyl-1-one is the same as that in Example 26, except that: compound III is 2-chloro-1-morpholinyl ethyl-1-one, the substitution reaction time is 10 h, and purification by silica gel column chromatography is not performed. The target product obtained is a light yellow oil with a yield of 95.7% and the structural formula is: and ; The proton nuclear magnetic resonance spectrum and high-resolution mass spectrometry are as follows: Z -Isomeric: 1 H-NMR (400 MHz, CDCl3) δ : 7.52-7.36 (m, 5H, PhH), 4.90 (s,2H, OCH2), 4.22 (s, 3H, NCH3), 3.72-3.67 (m, 4H, 2OCH2), 3.62(t, J = 4.7 Hz, 2H,NCH2), 3.39 (t, J = 4.7 Hz, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 15 H 19 N6O3:331.1518, found: 331.1511.

[0107] E -Isomeric: 1 H-NMR (400 MHz, CDCl3) δ : 7.67-7.64 (m, 2H, PhH), 7.49-7.46(m, 3H, ArH), 4.94 (s, 2H, OCH2), 4.22 (s, 3H, NCH3), 3.69-3.58 (m, 6H, 2OCH2+NCH2), 3.41-3.38 (m, 2H, NCH2); HR-MS (ESI) m / z [M+H] + calcd for C 15 H 19 N6O3:331.1518, found: 331.1515.

[0108] Experimental Example 1 (1) Prepare a 15% wettable powder by mass fraction of piperidine and piperazine oxime ether derivatives of Examples 16 and 58: Weigh 15% of the target product of Example 16 (particle size of 300 mesh), 79% of light calcium carbonate as carrier, and 6% of sodium lignosulfonate as surfactant to obtain a mixture of 15% wettable powder of active ingredient; subject the mixture to air jet milling and sieving in sequence, collect the mixture passing through 44 μm to obtain the 15% wettable powder of piperidine and piperazine oxime ether derivatives of Example 16; use the same steps as above to obtain the 15% wettable powder of piperidine and piperazine oxime ether derivatives of Example 58.

[0109] (2) Prepare a 10% suspension of the piperidine and piperazine oxime ether derivatives of Examples 16 and 58: Weigh 10% of the target product (300 mesh particle size) of Example 16, 0.5% of the leveling agent as a wetting agent, 0.5% of the dispersing agent as a suspending agent, 0.2% of the xanthan gum as a thickener, 0.3% of the bentonite as a stabilizer, 3% of the polyethylene glycol 400 as an antifreeze agent, and 0.1% of the lauric acid as a defoamer, add water to 100%, and obtain a mixture of suspensions with an effective ingredient content of 10%; adjust the mixture into a slurry, and then grind it 3-4 times in a sand mill. Finally, adjust the pH value, flowability and wettability to obtain a 10% suspension of the piperidine and piperazine oxime ether derivatives of Example 16; use the same steps as above to obtain a 10% suspension of the piperidine and piperazine oxime ether derivatives of Example 58.

[0110] (3) Prepare 5% water-dispersible granules from the piperidine and piperazine oxime ether derivatives of Examples 16 and 58: Weigh 5% of the target product (300 mesh), 1.2% of calcium dodecylbenzenesulfonate, 2.3% of PO-EO-block polyether, 3% of urea, 20% of disintegrant (specifically ammonium sulfate and sucrose in a mass ratio of 3:1), and 68.5% of kaolin as a carrier to obtain a 5% water-dispersible granule mixture; pulverize the mixture by air jet, collect the mixture with a particle size of less than 10 μm, and then extrude and dry it to obtain the 5% water-dispersible granules from the piperidine and piperazine oxime ether derivatives of Example 16; using the same steps as above, obtain the 5% water-dispersible granules from the piperidine and piperazine oxime ether derivatives of Example 58.

[0111] The quality of the 15% wettable powder was tested according to the standard method of GB / T 14825-1993. The results showed that the wetting time of the 15% wettable powder containing piperidine and piperazine oxime ether derivatives in Example 16 and the 15% wettable powder containing piperidine and piperazine oxime ether derivatives in Example 58 was less than 2 minutes, the suspension rate after stirring and standing for 1 hour was greater than 80%, and the pH value was 6.9-7.2.

[0112] The quality of the 10% suspension concentrate was tested according to the standard method of NY / T 4014-2021. The results showed that the relative error of the effective ingredient content of the 10% suspension concentrate containing piperidine and piperazine oxime ether derivatives in Example 16 and the 10% suspension concentrate containing piperidine and piperazine oxime ether derivatives in Example 58 was ±0.1-0.3%. After being placed indoors for 30 days, there was no stratification or precipitation. It could maintain a stable suspension state when diluted with water. The effective suspension rate of both was greater than 92% after standing for 1 hour.

[0113] The quality of the 5% water-dispersible granules was tested according to the standard method of HG / T 4463-2012. The results showed that the wet disintegration time of the 5% water-dispersible granules containing piperidine and piperazine oxime ether derivatives in Example 16 and the 5% water-dispersible granules containing piperidine and piperazine oxime ether derivatives in Example 58 was less than 2 min, the suspension rate after stirring and standing for 1 h was greater than 80%, and the pH value was 6.9-7.2.

[0114] The above experiments show that the oxime ether derivatives containing piperidine and piperazine of the present invention have excellent formulation processing adaptability, and can be used to prepare commonly used pesticide formulations such as wettable powders, suspensions, and water-dispersible granules, and can be formulated with different active ingredient specifications of 5%, 10%, and 15% for use.

[0115] Experiment Example 2 In vitro antibacterial activity assay: Based on literature such as *Pesticide Bioassay* edited by Shen Jinliang (China Agriculture Press, 2013, Beijing), the bioactivity of the piperidine and piperazine-containing oxime ether derivatives provided in this invention against *Phytophthora infestans* (causing late blight in potatoes and tomatoes) and *Phytophthora capsici* (causing blight in various melons and vegetables) was determined. The piperidine and piperazine-containing oxime ether derivatives of this invention were dissolved in dimethyl sulfoxide (DMSO) or methanol to obtain a stock solution with a concentration of 1 mg / mL. The stock solution was then diluted with sterile water to a concentration of 10 μg / mL. The solution was then added to potato dextrose agar (PDA) medium or lima bean medium cooled to 45°C and mixed thoroughly to achieve a concentration of 0.1 mg / mL for the piperidine and piperazine-containing oxime ether derivatives. μg / mL was used for initial screening of antibacterial activity against the tested pathogens. Subsequently, based on the activity of piperidine and piperazine oxime ether derivatives and the sensitivity of the pathogens, five series of drug-containing media with final concentrations of at least 10, 1, 0.1, 0.01, and 0.001 μg / mL were prepared. When extremely highly active compounds were screened, the final concentration was further diluted to 0.0001 and 0.00001 μg / mL. At the same time, a medium containing an equal amount of solvent but without piperidine and piperazine oxime ether derivatives was prepared as a blank control. The tested plant pathogens *Phytophthora indicum* and *Phytophthora capsici* were inoculated. The median inhibitory concentration (EC50) on colony growth was measured when the pathogen colonies on the control medium plate approached the edge of the petri dish (φ90 mm) at an appropriate temperature. 50 ).

[0116] According to the above-described method for determining in vitro antibacterial activity, the inhibition rates of the oxime ether derivatives containing piperidine and piperazine in Examples 1-73 against *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora nigra* at 0.1 μg / mL were determined. Simultaneously, the EC50 of the oxime ether derivatives containing piperidine and piperazine in Examples 13-17, 52, 56, 58, 65, and 67 were also determined. 50 The values ​​and measurement results are listed in Tables 1, 2, 3 and 4, respectively.

[0117] Table 1. In vitro antibacterial activity of oxime ether derivatives containing piperidine and piperazine in Examples 1-25

[0118] Table 2. EC values ​​of oxime ether derivatives containing piperidine and piperazine in Examples 13-17 50 Value (μg / mL)

[0119] As shown in Tables 1 and 2, the oxime ether derivatives containing piperidine and piperazine in Examples 1-25 all exhibited significant antibacterial activity against *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora nigra*. Among them, Examples 13-17 showed the most outstanding activity, achieving 100% inhibition rates against *Pythium spp.* and *Phytophthora capsici*, the same as the control agent tetrazolium pyridazine; the inhibition rate against *Phytophthora nigra* also exceeded 70%, significantly better than the control agent dimethomorph. The EC50 values ​​of Examples 13-17 against *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora nigra* were also shown. 50 The value ranges were 0.0076-0.0112 μg / mL, 0.0025-0.0078 μg / mL, and 0.0028-0.0069 μg / mL, respectively, among which the EC in Example 16... 50 The values ​​were 0.0076 μg / mL, 0.0025 μg / mL and 0.0028 μg / mL, respectively, showing outstanding antibacterial activity, significantly better than the control drug dimethomorph, and close to the control drug tetrazolium.

[0120] Table 3. In vitro antibacterial activity of oxime ether derivatives containing piperidine and piperazine in Examples 26-73

[0121] Table 4. EC50 of some piperidine and piperazine-containing oxime ether derivatives 50 Value (μg / mL)

[0122] As shown in Tables 3 and 4, the piperidine and piperazine-containing oxime ether derivatives of Examples 26-73 all exhibited significant antibacterial activity against *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora nigra*. At a concentration of 0.1 μg / mL, the piperidine and piperazine-containing oxime ether derivatives of Examples 40, 49, 50, 52, 56, 58, 65, and 67 showed inhibition rates of over 90% against *Pythium spp.*, while the piperidine and piperazine-containing oxime ether derivatives of Examples 52, 56, 58, and 67 showed significant inhibitory activity against *Pythium spp.*. The inhibition rate against *Phytophthora capsici* reached over 90%. Examples 52, 56, and 58, containing piperidine and piperazine oxime ether derivatives, showed inhibition rates exceeding 80% against *Phytophthora muscardina*, with Example 58 achieving inhibition rates of 100%, 100%, and 83.3% against the three pathogens, respectively, all significantly superior to the control agent dimethomorph. Examples 52, 56, 58, 65, and 67, containing piperidine and piperazine oxime ether derivatives, showed EC50% inhibition rates against *Pythium spp.*, *Phytophthora capsici*, and *Phytophthora muscardina*. 50The value ranges were 0.0077-0.0146 μg / mL, 0.0059-0.0159 μg / mL, and 0.0065-0.0103 μg / mL, respectively, among which the EC in Example 58... 50 The values ​​were 0.0077 μg / mL, 0.0059 μg / mL and 0.0065 μg / mL, respectively, showing outstanding antibacterial activity, which was significantly better than the control agent dimethomorph.

[0123] Experimental Example 3 In vivo antibacterial assay: The treatment was conducted on both pepper fruits and leaves, with tetrazolium pyridamole as a control. The piperidine and piperazine-containing oxime ether derivatives from Example 16 and tetrazolium pyridamole were dissolved in a certain amount of DMSO and then prepared into solutions with concentrations of 50 μg / mL and 25 μg / mL using a 0.1% Tween-80 aqueous solution. A blank control (CK) containing equal amounts of DMSO and Tween-80 was used. Small wounds were created on the surface of pepper fruits or leaves, and mycelial cakes of *Phytophthora capsici* with a diameter of 0.5 cm were inoculated. The wounds were incubated at 20°C for 24 h in a biochemical incubator. The prepared mycelial solutions were then evenly sprayed onto the surface of the fruits or leaves. The infected area was measured after 6 days to assess the treatment effect. Simultaneously, the prepared mycelial solutions were evenly sprayed, and after 24 h, the same method was used for inoculation. The infected area was measured again after 6 days to calculate the protective effect. Each treatment was repeated three times, and the average value was calculated.

[0124] The potted efficacy test was conducted on pepper plants, with 10% tetrazolium pyridamole suspension as the control and water as the blank control (CK). The 15% wettable powder and 10% tetrazolium pyridamole suspension from Example 16 were prepared into solutions with concentrations of 50 μg / mL and 25 μg / mL, respectively, using water. 1 mL of a zoospore suspension of Phytophthora capsici (spore concentration 1×10⁻⁶) was used as the control. 6 The above-mentioned pesticide solution (approximately 1 / mL) was applied to the soil around the plant roots. After 24 hours, the plant was evenly sprayed with the prepared pesticide solution or water. Two weeks later, the plant was examined for disease occurrence and the treatment effect was calculated. Simultaneously, the same method was used to inoculate the plant after evenly spraying the prepared pesticide solution or water. After 24 hours, the same method was applied. Two weeks later, the disease occurrence was examined and the protective effect was calculated. Each treatment was repeated three times. Disease occurrence was scored based on the length of the stem lesions (1 to 5 points): 1 point indicates a stem lesion less than 5 mm; 2 points indicate 5-10 mm; 3 points indicate 10-20 mm; 4 points indicate a stem lesion greater than 20 mm; 5 points indicate plant wilting.

[0125] Disease Index (DI) = ∑(disease occurrence rate × number of plants) / total number of plants in this treatment; Treatment (or protective) effect (%) = [(DI value of blank control group - DI value of drug treatment group) / DI value of blank control group] × 100%.

[0126] Based on the above-described in vivo antibacterial assay method, the antibacterial effect of the piperidine and piperazine-containing oxime ether derivatives of Example 16 against *Phytophthora capsici* at 50 μg / mL and 25 μg / mL was determined. The results of the assays on pepper fruits, pepper leaves, and pepper plants are listed in Tables 5, 6, and 7, respectively.

[0127] Table 5. Antifungal effect of Example 16 on Phytophthora capsici, the causal agent of pepper disease on pepper fruits.

[0128] Table 6. Antifungal effect of Example 16 on Phytophthora capsici, the causal agent of pepper blight, on pepper leaves.

[0129] Table 7. Antifungal effect of Example 16 on Phytophthora capsici, the causal agent of pepper disease, on pepper plants.

[0130] As can be seen from Table 5, the oxime ether derivative containing piperidine and piperazine in Example 16 showed a remarkable inhibitory effect on Phytophthora capsici, the causal agent of pepper blight, on pepper fruits. At 50 μg / mL and 25 μg / mL, the protective effects reached 88.9% and 77.7%, respectively, which are close to the 92.1% and 81.5% of the control agent tetrazolium ester; the therapeutic effects reached 81.0% and 69.6%, respectively, which are close to the 84.5% and 73.5% of the control agent tetrazolium ester.

[0131] As can be seen from Table 6, the oxime ether derivative containing piperidine and piperazine in Example 16 also showed outstanding antibacterial effect against Phytophthora capsici on pepper leaves. At 50 μg / mL and 25 μg / mL, the protective effects reached 90.9% and 78.9%, respectively, which are close to the 93.3% and 82.1% of the control agent tetrazolium ester; the therapeutic effects reached 81.6% and 70.5%, respectively, which are close to the 84.7% and 74.2% of the control agent tetrazolium ester.

[0132] As can be seen from Table 7, the oxime ether derivatives containing piperidine and piperazine in Example 16 also showed significant antifungal effects against Phytophthora capsici on pepper plants. At 50 μg / mL and 25 μg / mL, the protective effects reached 85.4% and 75.2%, respectively, which are close to the 89.1% and 79.6% of the control agent tetrazolium pyridamole. The therapeutic effects reached 80.0% and 68.8%, respectively, which are close to the 83.7% and 72.6% of the control agent tetrazolium pyridamole.

[0133] Experiment Example 4 According to the in vivo antibacterial assay method in Experiment Example 3 above, the antibacterial effect of the piperidine and piperazine-containing oxime ether derivative of Example 58 against Phytophthora capsici at 50 μg / mL and 25 μg / mL was determined (the only difference is that the antibacterial effect test of Example 58 on Phytophthora capsici on pepper plants used its 10% suspension). The test results on pepper fruits, pepper leaves and pepper plants are listed in Tables 8, 9 and 10, respectively.

[0134] Table 8. Antifungal effect of Example 58 on Phytophthora capsici, the causal agent of pepper disease, on pepper fruits.

[0135] Table 9. Antifungal effect of Example 58 on Phytophthora capsici, the causal agent of pepper blight, on pepper leaves.

[0136] Table 10. Antifungal effect of Example 58 on Phytophthora capsici, the causal agent of pepper disease, on pepper plants.

[0137] As can be seen from Table 8, the oxime ether derivatives containing piperidine and piperazine in Example 58 showed significant antifungal effects against Phytophthora capsici on pepper fruits. At 50 μg / mL and 25 μg / mL, the protective effects reached 86.1% and 74.2%, respectively, which were slightly lower than the 93.2% and 81.3% of the control agent tetrazolium. The therapeutic effects reached 77.2% and 65.5%, respectively, which were slightly lower than the 84.0% and 72.4% of the control agent tetrazolium.

[0138] As can be seen from Table 9, the oxime ether derivative containing piperidine and piperazine in Example 58 also showed significant antibacterial effects against Phytophthora capsici on pepper leaves. At 50 μg / mL and 25 μg / mL, the protective effects reached 87.6% and 75.8%, respectively, which were slightly lower than the 93.8% and 82.2% of the control agent tetrazolium. The therapeutic effects reached 78.4% and 66.1%, respectively, which were slightly lower than the 84.2% and 72.8% of the control agent tetrazolium.

[0139] As can be seen from Table 10, the oxime ether derivatives containing piperidine and piperazine in Example 58 also showed significant inhibitory effects against Phytophthora capsici on pepper plants. At 50 μg / mL and 25 μg / mL, the protective effects reached 82.8% and 72.6%, respectively, which were slightly lower than the 90.5% and 79.9% of the control agent tetrazolium. The therapeutic effects reached 75.5% and 65.2%, respectively, which were close to the 82.6% and 71.8% of the control agent tetrazolium.

[0140] Experimental Example 5 Cross-resistance determination: The piperidine and piperazine oxime ether derivatives and other fungicides with different chemical structures from Examples 16, 50, 58, and 67, including fluthiazopyrone, dimethomorph, metalaxyl, and azoxystrobin, were dissolved in methanol to prepare a 10 mg / mL stock solution. The stock solution was then added to lima bean agar medium melted at approximately 45°C to an effective final concentration of 5 μg / mL. The solution was poured into 90 mm diameter petri dishes and cooled to prepare drug-containing plates. A control plate without drug was also prepared. From the edges of colonies of susceptible *Phytophthora capsici* strains I and II, and resistant strains to 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 (denoted as R); those that did not grow at all were susceptible (denoted as S).

[0141] The inhibition rate is calculated as follows: Inhibition rate = [1 - (diameter of colony growth in the treated group / diameter of colony growth in the blank control group)] × 100%.

[0142] The results are shown in Table 11.

[0143] Table 11 Data on cross-resistance determination

[0144] As shown in Table 11, the oxime ether derivatives containing piperidine and piperazine provided by this invention exhibit similar inhibitory activity against the mycelial growth of two sensitive strains of *Phytophthora capsici* as their inhibition rate against other resistant strains, with no cross-resistance. This indicates that the target of the oxime ether derivatives containing piperidine and piperazine of this invention differs from that of other fungicides.

[0145] Therefore, this invention utilizes the above-mentioned oxime ether derivatives containing piperidine and piperazine, their preparation methods and applications, and agricultural fungicides. The oxime ether derivatives containing piperidine and piperazine have unique structures, convenient synthesis methods, and extremely high selective antibacterial activity against plant pathogenic oomycetes. They do not exhibit cross-resistance with existing fungicides and can be used in combination with various fungicides to control drug-resistant diseases. In particular, they can solve the problem of having no cure for multidrug-resistant diseases and have excellent chemical protection and systemic therapeutic effects against drug-resistant crop diseases.

[0146] 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 piperidine and piperazine, characterized in that: The structural formulas of oxime ether derivatives containing piperidine and piperazine are as follows: Equation I; M includes CY-R 1 NR 2 O, S; R includes H, halogens, and C. 1-6 Alkyl, C 1-6 One or both of alkoxyformyl and substituted phenylcarbamoyl, wherein the substitution refers to substitution by 1 to 3 of the following groups: H, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano; Y includes H and halogens; R 1 Including H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkenyl, C containing 1-3 halogens 1-6 Alkyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-6 Alkoxyformyl, C 1-6 Alkoxyformylmethyl, C 1-6 Alkoxyformylamino, C 1-6 Diol ketal, substituted phenyl, substituted five-membered heterocyclic, substituted six-membered heterocyclic, substituted benzo[a]hexacyclic, substituted benzoyl, substituted five-membered heterocyclic formyl, substituted six-membered heterocyclic formyl, substituted phenoxy, (substituted phenyl)(substituted pyridyl)methyloxy, wherein the substitution refers to substitution by 1 to 3 of the following groups: H, halogen, C 1-6 Alkyl, C 1-6 Alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano; R 2 Including H, C 1-6 Alkyl, C 3-6 cycloalkyl groups, C-type carbons containing 1-3 halogens 1-6 Alkyl, C 1-6 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-6 Alkoxyformyl, substituted benzoyl, substituted benzyloxyformyl, substituted five-membered heterocyclic formyl, substituted six-membered heterocyclic formyl, substituted benzo[a]heterocyclic formyl, C 1-6 Alkylsulfonyl, NC 1-6 Alkylaminosulfonyl, N,N-diC 1-6 Alkylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, substituted five-membered heterocyclic, substituted six-membered heterocyclic, substituted benzo[a]hexacyclic, di(substituted phenyl)methyl, wherein the substitution refers to substitution by 1 to 3 of the following groups: H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, C 1-6 Alkoxyformyl group.

2. The oxime ether derivative containing piperidine and piperazine according to claim 1, characterized in that: When M includes CY-R 1 At that time, R includes H, halogens, and C. 1-4 Alkyl, C 1-4 alkoxyformyl or substituted phenylcarbamoyl, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, methyl; Y includes H; R 1 Including H, halogens, C 1-4 Alkoxy, methylene, trifluoromethyl, cyano, C 1-4 Alkoxyformylmethyl, C 1-4 Alkoxyformylamino, C 1-4 Diol ketal, substituted phenyl, substituted benzo[a]heterocyclic, substituted benzoyl, substituted phenoxy, (substituted phenyl)(substituted pyridyl)methyloxy, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, trifluoromethyl, trifluoromethoxy; When M includes CY-R 1 At that time, R includes H, halogens, and C. 1-4 Alkyl, C 1-4 alkoxyformyl or substituted phenylcarbamoyl, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, methyl; Y includes halogen; R 1 Including H and halogens; When M includes NR 2 When O and S are present, R includes H, halogens, and C. 1-4 One or two of the alkyl groups; R 2 Including C 1-4 Alkyl, C 1-4 Alkyl formyl, C 3-6 Cycloalkylformyl, C 1-4 Alkoxyformyl, substituted benzyloxyformyl, substituted benzoyl, substituted furanyl, C 1-4 Alkylsulfonyl, N,N-diC 1-4 Alkylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, di(substituted phenyl)methyl, substituted pyridyl, substituted pyrimidinyl, substituted benzothiazolyl, substituted benzoisothiazolyl, substituted benzothiophene, wherein the substitution refers to substitution by 1 to 2 of the following groups: H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, trifluoromethyl, nitro, cyano, C 1-4 Alkoxyformyl group.

3. The oxime ether derivative containing piperidine and piperazine according to claim 2, characterized in that: When M includes CY-R 1 In this case, R includes H, methyl, ethoxyformyl, or 2,6-dimethylphenylcarbamoyl; Y includes H; R 1 Including H, Br, methoxy, methylene, trifluoromethyl, cyano, methoxyformylmethyl, tert-butoxyformylamino, ethylene glycol ketal, substituted phenyl, benzisoxazolyl, substituted benzimidazolyl, substituted benzoyl, substituted phenoxy, (substituted phenyl)(pyridyl)methyloxy, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, trifluoromethyl, trifluoromethoxy; When M includes CY-R 1 In this case, R includes H, methyl, ethoxyformyl, and 2,6-dimethylphenylcarbamoyl; Y includes F; R 1 Including F; When M includes NR 2 When R includes H; R 2 Including methyl, acetyl, cyclopropylformyl, phenylformyl, furanyl, tert-butoxyformyl, benzyloxyformyl, methanesulfonyl, N,N-dimethylaminosulfonyl, substituted phenylsulfonyl, substituted phenyl, di(substituted phenyl)methyl, substituted pyridyl, pyrimidinyl, benzothiazolyl, benzoisothiazolyl, benzothiophene, wherein the substitution refers to being substituted by 1 to 2 of the following groups: H, F, Cl, Br, methyl, methoxy, trifluoromethyl, nitro, cyano, ethoxyformyl; When M includes O, R includes H and 2,6-dimethyl; When M includes S, R includes H.

4. The oxime ether derivative containing piperidine and piperazine according to claim 3, characterized in that: Oxime ether derivatives containing piperidine and piperazine include ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(piperidin-1-yl)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(2-methylpiperidin-1-yl)ethyl-1-one, ( Z )-1-(4-cyanopiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-bromopiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(trifluoromethyl)piperidin-1-yl)ethyl-1-one, ( Z )-1-(4-methoxypiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-(1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidin-4-yl)methyl acetate, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methylenepiperidin-1-yl)ethyl-1-one, ( Z )-1-(4,4-difluoropiperidin-1-yl)-2-((((1-methyl-1) H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(ethylene glycol ketal)piperidin-1-yl)ethyl-1-one, ( Z )-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidine-2-carboxylic acid ethyl ester, ( Z )-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidin-4-ylcarbamate tert-butyl ester, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one, ( Z )-1-(4-(3-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-fluorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-chlorophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-bromophenyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(2-trifluoromethyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-ethyl-1-one, ( Z )-1-(4-(4-fluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2,4-difluorobenzoyl)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-N-(2,6-dimethylphenyl)-1-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperidine-3-carboxamide, ( Z )-1-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethyl-1-one, ( Z )-1-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methylpiperazin-1-yl)ethyl-1-one, ( Z )-1-(4-acetylpiperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(cyclopropaneformyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(furan-2-formyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzoyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-carboxylic acid tert-butyl ester, ( Z )-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-carboxylic acid benzyl ester, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-methanesulfonyl)piperazin-1-yl)ethyl-1-one, ( Z )-N,N-dimethyl-4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-sulfonamide, ( Z )-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-((4-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)ethyl-1-one, ( Z )-1-(4-((4-chloro-3-trifluoromethylphenyl)sulfonyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperazin-1-yl)ethyl-1-one, ( Z )-1-(4-(4-fluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-chlorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-methylphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-cyanophenyl)piperazin-1-yl)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(2-nitrophenyl)piperazin-1-yl)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(4-nitrophenyl)piperazin-1-yl)ethyl-1-one, ( Z )-4-(4-(2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)acetyl)piperazine-1-yl)ethyl benzoate, ( Z )-1-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethyl-1-one, ( Z )-1-(4-(3-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(3-nitropyridin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(5-nitropyridin-2-yl)piperazin-1-yl)acet-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(5-bromo-3-nitropyridin-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)aceto-1-one, ( Z )-1-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzo[d]thiazo-2-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-1-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinyl ethyl-1-one, ( Z )-1-(2,6-dimethylmorpholino)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-thiomorpholinoethyl-1-one, ( Z / E )-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-(4-phenylpiperidin-1-yl)ethyl-1-one, ( Z / E )-1-(4-(3-methoxyphenyl)piperazin-1-yl)-2-((((1-methyl-1 H -Tetrazol-5-yl)(phenyl)methylene)amino)oxy)ethyl-1-one, ( Z / E )-2-((((1-methyl-1 H -tetrazol-5-yl)(phenyl)methylene)amino)oxy)-1-morpholinoethyl-1-one.

5. The method for preparing the oxime ether derivative containing piperidine and piperazine according to any one of claims 1-4, characterized in that: Includes the following steps: Compound II, Compound III, a base, and an organic solvent were mixed and subjected to a substitution reaction to obtain oxime ether derivatives containing piperidine and piperazine. The structural formula of compound II is shown in Formula II, and the structural formula of compound III is shown in Formula III: Formula II; Formula III; X includes Cl, Br, and I; M and R are defined as in Equation I.

6. The method for preparing oxime ether derivatives containing piperidine and piperazine according to claim 5, characterized in that: The base is selected from organic or inorganic bases, including sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic solvent includes DMF, acetonitrile, tetrahydrofuran, dioxapentane, acetone, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, and ethyl acetate.

7. The method for preparing oxime ether derivatives containing piperidine and piperazine according to claim 5, characterized in that: The molar volume ratio of compound II, compound III, base, and organic solvent is 1 mmol : (0.8-1.6) mmol : (1-4) mmol : (5-100) mL, the temperature of the substitution reaction is 5-120℃, and the time is 0.5-96 h.

8. The application of oxime ether derivatives containing piperidine and piperazine, characterized in that: The oxime ether derivatives containing piperidine and piperazine as described in any one of claims 1-4 may be used to prevent and control plant diseases or to prepare agricultural fungicides.

9. The application of the oxime ether derivatives containing piperidine and piperazine according to claim 8, characterized in that: Plant diseases are caused by oomycetes, plant pathogens of the order Peronomycetes.

10. An agricultural fungicide, comprising an active ingredient and pharmaceutically acceptable excipients, characterized in that: The active ingredient includes the oxime ether derivatives containing piperidine and piperazine as described in any one of claims 1-4, and their ( Z ) type isomers, ( E ) type isomers, ( Z ) type isomers and ( E A mixture of type I isomers, at least one of their agriculturally acceptable salts, hydrates or solvates.

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