Aromatic heterocyclic amide derivative and its application

Abstract

The present invention relates to an aromatic heterocyclic amide derivative and a preparation method and application thereof. The structure of the derivative is shown in general formula I, and the definition of each substituent is as described in the specification and claims. The derivative of the present invention is based on the structure of a succinate dehydrogenase inhibitor fungicide, retains the heterocyclic amide part, extends the amine connecting bridge part, and has significant activity in inhibiting plant pathogens. A‑CONH‑Ph‑K‑Y‑M(Ⅰ)

Description

Technical Field

[0001] The invention relates to an aromatic heterocyclic amide derivative and application thereof. Background Art

[0002] Succinate dehydrogenase inhibitor (SDHI) fungicides are a type of agricultural fungicide with a novel mechanism of action that was developed following the methoxyacrylate fungicides. The main mechanism of action is to inhibit the activity of succinate dehydrogenase in pathogens, thereby interfering with their respiration. They are specific, have strong efficacy, lasting effect, and significant yield-increasing effects.

[0003] However, succinate dehydrogenase inhibitor fungicides have a medium-to-high risk of resistance and are harmful to aquatic organisms, and diverse creative research is needed to mitigate or resolve the above-mentioned resistance and aquatic toxicity problems. Summary of the invention

[0004] The object of the present invention is to provide a novel aromatic heterocyclic amide derivative having significant activity of inhibiting plant pathogens.

[0005] The first aspect of the present invention provides a compound represented by formula (I), its optical isomers, cis-trans isomers, or its pesticide-acceptable salts:

[0006] A-CONH-Ph-KYM (Ⅰ)

[0007] In the formula, A is a substituted or unsubstituted 5-6 membered heteroaryl group;

[0008] K is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heterocyclyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0009] Y is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heterocyclic group, a substituted or unsubstituted 5-6 membered heteroaryl group, or a substituted or unsubstituted nitrogen, oxygen or / and sulfur containing aliphatic chain,

[0010] M is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heterocyclyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group;

[0011] Wherein, each of the above substitutions independently refers to substitution by one or more groups selected from the following group: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy;

[0012] Each of the above heteroaryl groups and heterocyclic groups independently contains 1, 2, 3 or 4 heteroatoms selected from the following group: O, N, S.

[0013] In another preferred embodiment, A is a substituted 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is selected from the following group: pyrazolyl, pyridyl, thienyl, pyridazinyl, thiazolyl, furanyl, pyrazinyl or 1,4-thioxazolyl; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1~C4 alkyl, C1~C4 alkoxy, C1~C4 halogenated alkyl, C1~C4 halogenated alkoxy.

[0014] In another preferred embodiment, A is substituted pyrazolyl, pyridyl, thienyl. In another preferred embodiment, the substitution refers to substitution by 1 or 2 groups selected from the following group: halogen, C1-C3 alkyl, C1-C3 halogenated alkyl, preferably fluoroalkyl. In another preferred embodiment, the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl.

[0015] In another preferred embodiment, K is substituted or unsubstituted phenyl, pyrazolyl, pyridyl, thiazolyl, furyl, pyrazinyl or thienyl; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy.

[0016] In another preferred embodiment, K is substituted or unsubstituted phenyl, pyrazolyl, pyridyl, thiazolyl, furanyl, pyrazinyl or thienyl. More preferably, K is substituted or unsubstituted phenyl, pyridyl, furanyl, thienyl. In another preferred embodiment, the substitution refers to mono- or poly-substitution by halogen. In another preferred embodiment, the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br.

[0017] In another preferred embodiment, Y is substituted or unsubstituted phenyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, furyl, pyrazinyl, thienyl, oxadiazolyl, thiadiazolyl, and the substitution refers to substitution by 1, 2 or 3 groups selected from the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy; or

[0018] Y is a group selected from the following group: Wherein R, R', and R" are each independently: H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy.

[0019] In another preferred embodiment, Y is substituted or unsubstituted phenyl, pyrazolyl, thiazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, or selected from the following groups: The substitution refers to substitution by 1 or 2 groups selected from the following group: halogen, hydroxyl, nitro, cyano, methyl, methoxy, halomethyl, halomethoxy; R and R' are each independently: H, halogen, methyl, methoxy, halomethyl, halomethoxy.

[0020] In another preferred embodiment, Y is substituted or unsubstituted phenyl, pyrazolyl, thiazolyl, furanyl, thienyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, R and R' are each independently: H, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy.

[0021] In another preferred embodiment, M is substituted or unsubstituted phenyl, pyrazolyl, pyridyl, thiazolyl, furyl, pyrazinyl or thienyl; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy.

[0022] In another preferred embodiment, M is substituted or unsubstituted phenyl, pyrazolyl, pyridyl, thiazolyl, furanyl, pyrazinyl or thienyl. More preferably, M is substituted or unsubstituted phenyl, pyridyl, furanyl, thienyl. In another preferred embodiment, the substitution refers to mono- or poly-substitution by halogen. In another preferred embodiment, the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br.

[0023] In another preferred embodiment, the compound is any one of compounds I-1 to I-220.

[0024] The second aspect of the present invention provides an agricultural composition comprising:

[0025] (a) the compound of the first aspect, its optical isomers, cis-trans isomers, or pesticide-acceptable salts, or combinations thereof; and

[0026] (b) pesticide-acceptable carriers and / or excipients.

[0027] In another preferred embodiment, the agricultural composition comprises 0.001 wt % to 99.99 wt % of the compound described in the first aspect, its optical isomers, cis-trans isomers, or pesticide-acceptable salts, or combinations thereof, based on the total weight of the composition as 100%.

[0028] The third aspect of the present invention provides the use of the compound described in the first aspect, its optical isomers, cis-trans isomers, or pesticide-acceptable salts or the agricultural composition described in the second aspect for preventing and controlling agricultural plant diseases, or for preparing a fungicide for preventing and controlling agricultural plant diseases.

[0029] In another preferred embodiment, the plant disease is a plant disease caused by plant pathogenic bacteria of the phylum Ascomycota, Basidiomycota, Deuteromycota or Oomycota.

[0030] In another preferred embodiment, the Ascomycota include Sclerotinia such as Sclerotinia sclerotiorum, Sphaerotheca such as Powdery mildew of cucumber, Gibberella such as Gibberella sclerotiorum, and the like.

[0031] In another preferred embodiment, the Basidiomycota includes Puccinia such as wheat stripe rust, leaf rust, stem rust and the like.

[0032] In another preferred embodiment, the Ascomycota include Rhizoctonia such as rice sheath blight, Botrytis such as cucumber gray mold, Macrophoma such as apple ring rot, and the like.

[0033] In another preferred embodiment, the Oomycetes include Phytophthora such as Psora infestans, Ronophthora such as Psora parasitica and the like.

[0034] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0035] The inventors of the present application have conducted extensive and in-depth research, and have synthesized a novel aromatic heterocyclic amide derivative by extending the amine bridge in accordance with the chemical structure of succinate dehydrogenase inhibitor fungicides, which has significant activity in inhibiting plant pathogens and is applied to the research on fungicide creation. On this basis, the present invention was completed.

[0036] the term

[0037] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0038] In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C4" refers to having 1, 2, 3 or 4 carbon atoms, and so on. "5-6 membered" refers to having 5 or 6 ring atoms, and so on.

[0039] The term "alkyl" refers to a straight or branched chain alkyl group, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or the like.

[0040] The term "alkenyl" is intended to mean a straight or branched hydrocarbon group containing at least one double bond, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl or the like.

[0041] The term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond, such as ethynyl, propynyl or the like.

[0042] The term "alkoxy" refers to a straight or branched chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.

[0043] The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "halogenated" refers to a group substituted by the same or different one or more halogen atoms mentioned above, for example trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl or the like.

[0044] The term "heterocyclyl" refers to a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g. 1, 2, 3 or 4) ring heteroatom (e.g. N, O or S), for example tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, morpholinyl.

[0045] The term "heteroaryl" refers to an aromatic cyclic group containing at least one (e.g., 1, 2, 3 or 4) ring heteroatom (e.g., N, O or S), for example, pyrazolyl, furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl, pyranyl, oxadiazolyl, thiadiazolyl, and the like.

[0046] In the present invention, the substitution is mono- or poly-substitution, and the poly-substitution is di-, tri-, tetra- or penta-substitution. The di-substitution means having two substituents, and so on.

[0047] The term "active substance of the present invention" or "active compound of the present invention" refers to a compound having a structure represented by the general formula (I) or an optical isomer, cis-trans isomer, or a pesticidally acceptable salt thereof.

[0048] The term "pesticide acceptable salt" means that the anion of the salt is known and acceptable when forming a pharmaceutically acceptable salt of a fungicide. Preferably, the salt is water-soluble. Suitable acid addition salts formed by the compound of formula (I) include salts formed by inorganic acids, such as hydrochlorides, phosphates, sulfates, nitrates; and salts formed by organic acids, such as acetates, benzoates, etc.

[0049] Examples of diseases to be controlled include, but are not limited to: downy mildew (cucumber downy mildew, rape downy mildew, soybean downy mildew, beet downy mildew, sugarcane downy mildew, tobacco downy mildew, pea downy mildew, loofah downy mildew, wax gourd downy mildew, melon downy mildew, cabbage downy mildew, spinach downy mildew, radish downy mildew, grape downy mildew, onion downy mildew), white rust (rape white rust, cabbage white rust), damping-off disease (rape damping-off disease, tobacco damping-off disease, tomato damping-off disease, pepper damping-off disease, eggplant damping-off disease, cucumber damping-off disease, cotton seedling damping-off disease), cotton rot (pepper cotton rot, loofah cotton rot, wax gourd cotton rot), blight (broad bean blight, cucumber blight, wax gourd blight, watermelon blight, melon blight, pepper blight, leek blight, garlic blight, cotton blight), late blight (potato late blight, tomato late blight), etc.;Root rot (pepper root rot, eggplant root rot, kidney bean root rot, cucumber root rot, bitter melon root rot, cotton root rot, broad bean root rot), damping-off (cotton seedling damping-off, sesame damping-off, pepper damping-off, cucumber damping-off, cabbage damping-off), Verticillium wilt (cotton verticillium wilt, sunflower verticillium wilt, tomato verticillium wilt, pepper verticillium wilt, eggplant verticillium wilt), black spot (zucchini black spot, wax gourd black spot, melon black spot), gray mold (cotton boll black gray mold, hemp gray mold, tomato gray mold, pepper gray mold, kidney bean gray mold, vegetable gray mold, vegetable gray mold, kiwi gray mold, grass duck gray mold), brown spot (cotton brown spot, yellow Brown spot of hemp, brown spot of beet, brown spot of peanut, brown spot of pepper, brown spot of wax gourd, brown spot of soybean, brown spot of sunflower, brown spot of pea, brown spot of broad bean), black spot (false black spot of flax, black spot of rape, black spot of sesame, black spot of sunflower, black spot of castor, black spot of tomato, black spot of pepper, black spot of eggplant, black spot of kidney bean, black spot of cucumber, black spot of celery, black spot of carrot, black spot of apple, black spot of peanut), spot blight (spot blight of tomato, spot blight of pepper, spot blight of celery), early blight (early blight of tomato, early blight of pepper, early blight of eggplant, early blight of potato, early blight of celery), ring rot (soybean ring rot disease, sesame ring rot, bean ring rot), leaf blight (sesame leaf blight, sunflower leaf blight, watermelon leaf blight, melon leaf blight), stem base rot (tomato calyx base rot, bean stem base rot), and others (corn round spot, hemp waist break, rice blast, chestnut black sheath, sugarcane eye spot, cotton boll rot, peanut crown rot, soybean stem rot, soybean black spot, melon large spot, peanut web spot, tea red leaf spot, pepper white star, wax gourd leaf spot, sprout black rot, tired vegetable heart rot, hemp leaf mold, hemp spot, jute stem spot, soybean purple spot, sesame leaf spot, castor gray spot, tea brown leaf spot, eggplant brown round star, vegetable Bean red spot, bitter gourd white spot, watermelon spot, jute rot, sunflower root rot, kidney bean carbon rot, eggplant stick leaf spot, cucumber target spot, tomato leaf mold, eggplant leaf mold, broad bean red spot, etc.; Basidiomycete diseases, such as rust (wheat stripe rust, wheat stem rust, wheat leaf rust, flower rust, sunflower rust, sugarcane rust, leek rust, onion rust, chestnut rust, soybean rust), smut (corn silk smut, corn smut, sorghum silk smut, sorghum scattered black spike, sorghum hard smut, sorghum column smut, chestnut grain black spike, sugarcane black spike, kidney bean rust) and others (such as wheat sheath blight, rice sheath blight, etc.);Ascomycete diseases, such as powdery mildew (wheat powdery mildew, Shantou vegetable powdery mildew, sesame powdery mildew, sunflower powdery mildew, beet powdery mildew, eggplant powdery mildew, pea powdery mildew, loofah powdery mildew, pumpkin powdery mildew, zucchini powdery mildew, wax gourd powdery mildew, melon powdery mildew, grape powdery mildew, broad bean powdery mildew), sclerotinia (flax sclerotinia, rape sclerotinia, soybean sclerotinia, peanut sclerotinia, tobacco sclerotinia, pepper sclerotinia, eggplant sclerotinia, bean sclerotinia, pea sclerotinia, cucumber sclerotinia, bitter melon sclerotinia, wax gourd sclerotinia, watermelon sclerotinia, celery sclerotinia), black spot (apple black spot, pear black spot), club root disease (cabbage club root disease, cabbage club root disease, cauliflower club root disease, kohlrabi club root disease, mustard club root disease, radish club root disease, turnip club root disease, rape club root disease). ;

[0050] Fungicide composition containing "active substance of the present invention"

[0051] The "active substances of the present invention" can be prepared into fungicide compositions by conventional methods. These active compounds can be made into conventional preparations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with active substances, microcapsules in polymers, coating compounds for seeds, and preparations for use with combustion devices, such as fumigation cartridges, fumigation pots and fumigation trays, and ULV cold mist and hot mist preparations.

[0052] These preparations can be produced in a known manner, for example by mixing the active compound with an extender, i.e. a liquid, liquefied gas or solid diluent or carrier and optionally a surfactant, i.e. an emulsifier and / or dispersant and / or foam former. For example, when water is used as the extender, an organic solvent can also be used as an auxiliary agent.

[0053] When a liquid solvent is used as a diluent or carrier, it is basically suitable, such as: aromatic hydrocarbons, for example xylene, toluene or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, for example chlorobenzene, vinyl chloride or methylene chloride; aliphatic hydrocarbons, for example cyclohexane or paraffin, for example mineral oil fractions; alcohols, for example ethanol or ethylene glycol and their ethers and lipids; ketones, for example acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly used polar solvents, for example dimethylformamide, dimethyl sulfoxide and water.

[0054] A diluent or carrier for liquefied gas refers to a liquid that will become a gas at normal temperature and pressure, such as an aerosol propellant, such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide.

[0055] Solid carriers can be ground natural minerals, such as kaolin, clay, talc, quartz, atavistic clay, montmorillonite, or diatomaceous earth; and ground synthetic minerals, such as highly dispersed silicic acid, alumina and silicates. Solid carriers for particles are ground and classified natural zircons, such as calcite, marble, pumice, sepiolite, dolomite, inorganic and organic coarse powder synthetic particles, and organic materials such as sawdust, coconut shells, corn cobs and tobacco stem particles, etc.

[0056] Nonionic and anionic emulsifiers can be used as emulsifiers and / or foam formers. For example, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and albumin hydrolysates. Dispersants include lignin sulfite waste liquor and methylcellulose.

[0057] Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, may be used in the formulation.

[0058] Colorants such as inorganic dyes, such as iron oxide, cobalt oxide and Prussian blue; organic dyes, such as azo dyes or metal phthalocyanine dyes; trace nutrients, such as salts of iron, manganese, boron, copper, cobalt, aluminum and zinc, etc. can be used.

[0059] The "active compound of the present invention" may be present in a mixture with other active compounds in their commercial preparations or in the use formulations prepared from these preparations. These other active compounds are insecticides, bactericides, fungicides, herbicides, growth control agents, etc. Insecticides include, for example, phosphates, carbamates, chlorinated hydrocarbons, and substances produced by microorganisms, such as avermectin, etc., and fungicides include strobilurins, amides, triazoles, etc.

[0060] In addition, the "active compounds of the present invention" may also be present in their commercial preparations or dosage forms prepared from these preparations as a mixture with synergists. These synergists are compounds that enhance the action of the active compounds. Since the active compounds themselves are active, it is not necessary to add synergists.

[0061] These preparations usually contain 0.001 to 99.99% by weight, preferably 0.01 to 99.9% by weight, more preferably 0.05 to 90% by weight of the "active compound of the invention", based on the total weight of the fungicide composition. The concentration of the active compound in the commercial preparations or use forms can vary within a wide range. The concentration of the active compound in the use form can be from 0.0000001 to 100% (g / v), preferably between 0.0001 and 1% (g / v).

[0062] Tests have shown that the compound represented by formula (I), its optical isomers, cis-trans isomers, or its pesticide-acceptable salts have good control effects on cucumber gray mold, rapeseed sclerotinia, and rice sheath blight.

[0063] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually performed under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and weight parts.

[0064] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0065] Example 1

[0066] The preparation process of (E)-3-(difluoromethyl)-1-methyl-N-(3'-(phenoxymethyl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide is as follows:

[0067]

[0068] Reaction reagents and conditions: (a) dichloromethane, N,N-dimethylformamide, room temperature, 0.5 hours; (b) dichloromethane, pyridine, 0℃→room temperature, 1 hour; (c) 1,4-dioxane, potassium carbonate, water, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 100℃, reflux, argon protection; (d) potassium carbonate, potassium iodide, acetonitrile, 4 hours, 60℃;

[0069] Specifically, the following steps are included:

[0070] Intermediate 1 [3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carbonyl chloride]

[0071]

[0072] 3-Difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid (0.707 g, 4.01 mmol) was added to a 50 mL eggplant-shaped bottle, 20 mL of dichloromethane was added, oxalyl chloride (1.29 g, 9.96 mmol) was added, and 1 drop of N,N-dimethylformamide was added. The reaction solution was stirred and refluxed at room temperature, and it was obvious that the reaction solution gradually changed from turbid to clear. TLC was used to track the reaction, and the reaction was terminated after 1 hour. The solvent was spin-dried to obtain intermediate 1, which was redissolved in 10 mL of dichloromethane for standby use.

[0073] Intermediate 2 [N-2-bromo-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide]

[0074]

[0075] In a 100mL eggplant-shaped bottle, 2-bromoaniline (1.860g, 10.49mmol) was added, 20mL of dichloromethane was added to dissolve, pyridine (1.277g, 16.06mmol) was added dropwise at 0°C while stirring the intermediate 1 obtained by the one-step reaction (dropping time was 5min), after reacting for 15min, the reaction was transferred to room temperature to continue the reaction, and the reaction was tracked by TLC. After 1 hour, the reaction was terminated. The reaction solution was washed and purified with water, saturated sodium chloride aqueous solution, 0.5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, and dichloromethane was collected, and the solvent was spin-dried to obtain intermediate 2 (off-white solid, 3.042g, 87.84%). 1 H NMR (400MHz, DMSO) δ9.78(s,1H),8.51(s,1H),7.71(dd,J=8.0,1.2Hz,1H),7.54(dd,J=7.9,1.4Hz, 1H), 7.42 (td, J=7.9, 1.3Hz, 1H), 7.31 (t, J=54.0Hz, 3H), 7.21 (td, J=7.8, 1.5Hz, 1H), 3.97 (s, 3H).

[0076] Intermediate 3 [N-(3'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide]

[0077]

[0078] In a 50 mL eggplant-shaped flask, the intermediate 2 (0.798 g, 2.42 mmol) obtained in the previous step was added, followed by (3-(bromomethyl)phenyl)boric acid (0.604 g, 2.81 mmol), 10 mL of 1,4-dioxane, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.111 g, 0.15 mmol), and 10 mL of potassium carbonate aqueous solution (2 M). The mixture was protected by argon and deoxygenated in vacuo for 30 min. The mixture was stirred and refluxed at 100°C for reaction. The reaction was monitored by TLC. The reaction was terminated after 1.5 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was dried by spin drying. An appropriate amount of ethyl acetate was added, and 3 g of silica gel was added. The mixture was mixed well and then dried by spin drying. The mixture was loaded by dry method and subjected to silica gel column chromatography. Gradient elution was performed with petroleum ether→petroleum ether:ethyl acetate=1:1 (V:V)→petroleum ether:ethyl acetate=1:2 (V:V). The solvent was dried by spin drying to obtain intermediate 3 (light yellow solid, 0.894 g, 87.99%). 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.70(s,1H),8.26(s,1H),7.91(s,1H),7.50(d,J=10.0Hz ,2H),7.48(s,1H),7.42(s,1H),7.32(s,1H),7.21(d,J=29.0Hz,2H),4.98(s,2H),3.81(s,3H).

[0079] Compound I-217 [(E)-3-(difluoromethyl)-1-methyl-N-(3'-(phenoxymethyl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide]

[0080]

[0081] The intermediate 3 (0.882 g, 2.1 mmol) was placed in a 100 mL eggplant-shaped bottle, 15 mL of acetonitrile was added to dissolve, calcium carbonate (0.308 g, 3.08 mmol), potassium iodide (0.863 g, 4.21 mmol) was added, and then excess phenol (0.395 g, 4.2 mmol) was slowly added to the reaction solution at 0 ° C, argon protection, vacuumed for 30 min, transferred to 60 ° C, stirred and refluxed for reaction, TLC tracking reaction, and the reaction was terminated after 4 hours. The reaction solution was spin-dried, an appropriate amount of dichloromethane was added, 3 g of silica gel was added, mixed evenly and then spin-dried, dry-loaded, silica gel column chromatography, petroleum ether → petroleum ether: ethyl acetate = 2: 1 (V: V) → petroleum ether: ethyl acetate = 2: 1 (V: V) gradient elution, spin-dried solvent to obtain compound I-217 (yellow solid, 0.354 g, 38.93%). 1H NMR(400MHz,DMSO-d6)δ8.83(s,4H),8.72(s,4H),8.23(s,4H),7.91(s,4H),7.57–7.51(m,11H),7.4 8(s,5H),7.33(s,9H),7.21(d,J=18.5Hz,6H),7.10(s,8H),6.91(s,2H),5.14(s,8H),3.81(s,12H).

[0082] HRMS (ESI) m / z [M+H] + C 25 H 21 F2N3O2, calculated value: 433.1602, found value: 434.1601.

[0083] Example 2

[0084]

[0085] The preparation of [2-chloro-N-(3'-(phenoxymethyl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0086] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0087] The final test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.61(s,1H),8.48(s,1H),8.22(s,1H),7.90(d,J=10.0Hz,2H),7.55(t,J= 12.5Hz,3H),7.48(s,1H),7.31(s,3H),7.22(s,1H),7.10(s,2H),6.92(s,1H),5.14(s,2H); HRMS(ESI)m / z[M+H] + C 25 H 19 ClN2O2, calculated value: 414.1135, found value: 415.1137.

[0088] Example 3

[0089]

[0090] The preparation of (E)-3-(difluoromethyl)-1-methyl-N-(4'-(5-phenyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0091] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is (3-formylphenyl)boric acid.

[0092] The phenol raw material described in step (d) is benzohydrazide.

[0093] The final test results are as follows: 1 H NMR(400MHz,DMSO-d6)δ8.94(s,4H),8.70(s,4H),8.22(s,4H),7.98(d,J=10.0Hz,16H),7.6 1(s,11H),7.51(s,3H),7.32(s,5H),7.27–7.09(m,14H),3.82(s,12H); HRMS(ESI)m / z[M+H] + C 26 H 19 F2N5O2, calculated value: 471.1507, found value: 472.1509.

[0094] Example 4

[0095]

[0096] The preparation of [2-chloro-N-(4'-(5-phenyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0097] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0098] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is (3-formylphenyl)boric acid.

[0099] The phenol raw material described in step (d) is benzohydrazide.

[0100] The final test results are as follows: 1H NMR(400MHz,DMSO-d6)δ9.62(s,4H),8.57(d,J=70.0Hz,8H),8.22(s,4H),7.97(d,J=10.0Hz,17H), 7.86(s,2H),7.62(s,11H),7.51(s,3H),7.31(s,4H),7.21(d,J=15.0Hz,12H); HRMS(ESI)m / z[M+H] + C 26 H 17 ClN4O2, calculated value: 452.1040, found value: 453.1039.

[0101] Example 5

[0102]

[0103] The preparation of (E)-3-(difluoromethyl)-1-methyl-N-(4'-(3-phenyl-1,2,4-thiadiazol-5-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0104] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is (4-cyanophenyl)boric acid.

[0105] The phenol raw material described in step (d) is thiobenzamide.

[0106] The final test results are as follows: 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.70(s,1H),8.24(d,J=20.0Hz,3H),7.93(s,2H),7 .52(d,J=10.0Hz,4H),7.33(s,1H),7.29–7.15(m,4H),3.81(s,3H).;HRMS(ESI)m / z[M+H] + C 26 H 19 F2N5OS, calculated value: 487.1278, measured value: 488.1280.

[0107] Example 6

[0108]

[0109] The preparation of [2-chloro-N-(4'-(3-phenyl-1,2,4-thiadiazol-5-yl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0110] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0111] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is (4-cyanophenyl)boric acid.

[0112] The phenol raw material described in step (d) is thiobenzamide.

[0113] The final test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.37(s,27H),8.54(d,J=70.0Hz,55H),8.31(s,1H),8.26(d,J=20.0Hz,78H),7.95( s,52H),7.88(s,14H),7.50(d,J=10.0Hz,99H),7.33(s,25H),7.21(d,J=15.0Hz,80H); HRMS(ESI)m / z[M+H] + C 26 H 17 ClN4OS, calculated value: 468.0812, found value: 469.0811.

[0114] Example 7

[0115]

[0116] The preparation of (E)-3-(difluoromethyl)-1-methyl-N-(4'-(3-phenyl-1,2,4-oxadiazol-5-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0117] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is 4-aminomethylphenylboric acid.

[0118] The phenol raw material described in step (d) is benzaldehyde.

[0119] The final test results are as follows: 1H NMR(400MHz,DMSO-d6)δ9.01(s,4H),8.73(s,4H),8.22(s,4H),7.95(s,8H),7.85(s,7H),7.55–7. 47(m,15H),7.32(s,5H),7.24(d,J=15.0Hz,12H),7.11(s,2H),3.81(s,12H); HRMS(ESI)m / z[M+H] + C 26 H 19 F2N5O2, calculated value: 471.1507, found value: 472.1508.

[0120] Example 8

[0121]

[0122] The preparation of [2-chloro-N-(4'-(3-phenyl-1,2,4-oxadiazol-5-yl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0123] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0124] The (3-(bromomethyl)phenyl)boric acid raw material in step (c) is 4-aminomethylphenylboric acid.

[0125] The phenol raw material described in step (d) is benzaldehyde.

[0126] The final test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 2H), 8.54 (d, J = 70.0Hz, 4H), 8.24 (s, 2H), 7.94 (s, 4H), 7.86 ( d,J=5.0Hz,5H),7.55–7.47(m,8H),7.32(s,2H),7.21(d,J=15.0Hz,6H); HRMS(ESI)m / z[M+H] + C 26 H 17 ClN4O2, calculated value: 452.1040, found value: 453.1039.

[0127] Example 9

[0128]

[0129] (E)-3-(Difluoromethyl)-1-methyl-N-(3'-((phenoxyimino)methyl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

[0130] ] was prepared by a synthetic method similar to that of Example 18, except that:

[0131] The aminophenylboronic acid raw material in step (c) is (3-formylphenyl)boric acid.

[0132] The phenol raw material described in step (d) is o-phenylhydroxylamine (phenol can be reacted with potassium tert-butoxide in a methanol solution for 0.5 h, and then DMF is used as a solvent and 2,4,6-trimethylbenzenesulfonylhydroxylamine is reacted under ice bath conditions for 1 h to obtain o-phenylhydroxylamine)

[0133] In the last step of the reaction, intermediate 3 (0.817 g, 2.3 mmol) was added to a 100 mL eggplant-shaped bottle, a certain amount of water, 15 ml of acetic acid and 15 ml of DMSO were added to the bottle, and then o-phenylhydroxylamine (0.501 g, 4.6 mmol) was slowly added to the reaction solution at 0°C, stirred at room temperature and refluxed, and the reaction was tracked by TLC. The reaction was terminated after 24 hours. The reaction solution was spin-dried, an appropriate amount of ethyl acetate was added, 3 g of silica gel was added, mixed evenly and then spin-dried, dry-loaded, silica gel column chromatography, petroleum ether→petroleum ether: ethyl acetate = 2: 1 (V: V)→petroleum ether: ethyl acetate = 2: 1 (V: V) gradient elution, spin-dried solvent to obtain compound I-219 (white solid, 0.294 g, 28.66%).

[0134] The final test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 5H), 8.72 (s, 5H), 8.30 (s, 5H), 8.24 (s, 5H), 7.85 (d, J = 5.0Hz, 10H), 7.54 (t, J=12.5Hz,15H),7.32(s,6H),7.30–7.17(m,18H),6.81(d,J=15.0Hz,15H),3.80(s,15H); HRMS(ESI)m / z[M+H] + C 25 H 20 F2N4O2, calculated value: 446.1554, found value: 447.1553.

[0135] Example 10

[0136]

[0137] The preparation of (E)-2-chloro-N-(3'-((phenoxyimino)methyl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 18, except that:

[0138] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is prepared by using 2-chloronicotinic acid

[0139] The final test results are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.61(s,1H),8.50(s,1H),8.29(s,1H),8.22(s,1H),7.92–7.80(m,3H),7.5 5(s,1H),7.51(d,J=4.5Hz,2H),7.31(s,1H),7.22(d,J=15.0Hz,3H),6.81(d,J=15.0Hz,3H); HRMS(ESI)m / z[M+H] + C 25 H 18 ClN3O2, calculated value: 427.1088, found value: 428.1090.

[0140] Embodiment 11

[0141] The preparation process of (E)-3-(difluoromethyl)-1-methyl-N-(4'-(5-phenylthiophene-2-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide is as follows:

[0142]

[0143] Reaction reagents and conditions: (a) dichloromethane, N,N-dimethylformamide, room temperature, 0.5 hours; (b) dichloromethane, pyridine, 0℃→room temperature, 1 hour; (c) 1,4-dioxane, potassium carbonate, water, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 100℃, reflux, argon protection; (d) 1,4-dioxane, potassium carbonate, water, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 100℃, reflux, argon protection; (e) 1,4-dioxane, potassium carbonate, water, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 100℃, reflux, argon protection;

[0144] Specifically, the following steps are included:

[0145] Intermediate 1 [3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carbonyl chloride]

[0146]

[0147] 3-Difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid (0.707 g, 4.01 mmol) was added to a 50 mL eggplant-shaped bottle, 20 mL of dichloromethane was added, oxalyl chloride (1.29 g, 9.96 mmol) was added, and 1 drop of N,N-dimethylformamide was added. The reaction solution was stirred and refluxed at room temperature, and it was obvious that the reaction solution gradually changed from turbid to clear. TLC was used to track the reaction, and the reaction was terminated after 1 hour. The solvent was spin-dried to obtain intermediate 1, which was redissolved in 10 mL of dichloromethane for standby use.

[0148] Intermediate 2 [N-2-bromo-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide]

[0149]

[0150] In a 100mL eggplant-shaped bottle, 2-bromoaniline (1.860g, 10.49mmol) was added, 20mL of dichloromethane was added to dissolve, pyridine (1.277g, 16.06mmol) was added dropwise at 0°C while stirring the intermediate 1 obtained by the one-step reaction (dropping time was 5min), after reacting for 15min, the reaction was transferred to room temperature to continue the reaction, and the reaction was tracked by TLC. After 1 hour, the reaction was terminated. The reaction solution was washed and purified with water, saturated sodium chloride aqueous solution, 0.5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, and dichloromethane was collected, and the solvent was spin-dried to obtain intermediate 2 (off-white solid, 3.042g, 87.84%). 1 H NMR (400MHz, DMSO) δ9.78(s,1H),8.51(s,1H),7.71(dd,J=8.0,1.2Hz,1H),7.54(dd,J=7.9,1.4Hz, 1H), 7.42 (td, J=7.9, 1.3Hz, 1H), 7.31 (t, J=54.0Hz, 3H), 7.21 (td, J=7.8, 1.5Hz, 1H), 3.97 (s, 3H).

[0151] Intermediate 3 [N-(4'-bromo-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide]

[0152]

[0153] In a 50 mL eggplant-shaped flask, the intermediate 2 (0.798 g, 2.42 mmol) obtained in the previous step was added, (4-bromophenyl)boric acid (0.607 g, 3.02 mmol), 10 mL of 1,4-dioxane, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.111 g, 0.15 mmol), 10 mL of potassium carbonate aqueous solution (2 M), argon protection, vacuum deoxygenation for 30 min, stirring and reflux reaction at 100 °C, TLC tracking reaction, the reaction was completed after 1.5 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was dried by spin drying. An appropriate amount of ethyl acetate was added, and 3 g of silica gel was added. The mixture was mixed well and then dried by spin drying. The mixture was loaded by dry method and subjected to silica gel column chromatography. Gradient elution was performed with petroleum ether→petroleum ether:ethyl acetate=1:1 (V:V)→petroleum ether:ethyl acetate=1:2 (V:V). The solvent was dried by spin drying to obtain intermediate 3 (brown solid, 0.765 g, 77.82%). 1 H NMR (400MHz, DMSO-d6) δ8.81(s,2H),8.72(s,2H),8.22(s,2H),7.56–7.48(m,9H),7.31(s,2H),7.15(d,J=49.7Hz,3H),3.83(s,6H).

[0154] Intermediate 4[(5-phenylthiophene-2-yl)boronic acid]

[0155]

[0156] In a 50 mL eggplant-shaped flask, (5-bromothiophene-2-yl)boric acid (0.621 g, 3.00 mmol) was added, followed by bromobenzene (0.565 g, 3.60 mmol), 10 mL of 1,4-dioxane, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.111 g, 0.15 mmol), and 10 mL of potassium carbonate aqueous solution (2 M). The mixture was protected by argon and deoxygenated in vacuo for 30 min. The mixture was stirred and refluxed at 100°C for reaction. The reaction was monitored by TLC. The reaction was terminated after 1.5 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was dried by spin drying. An appropriate amount of ethyl acetate was added, and 3 g of silica gel was added. The mixture was mixed well and then dried by spin drying. The mixture was loaded by dry method and subjected to silica gel column chromatography. Gradient elution was performed with petroleum ether → petroleum ether: ethyl acetate = 1:1 (V:V) → petroleum ether: ethyl acetate = 1:2 (V:V). The solvent was dried by spin drying to obtain intermediate 4 (white solid, 0.496 g, 81.05%). 1 H NMR (400MHz, DMSO-d6) δ7.80(s,5H),7.45(s,8H),7.32(s,3H),1.73(s,6H).

[0157] Compound I-55 [(E)-3-(difluoromethyl)-1-methyl-N-(4'-(5-phenylthiophen-2-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide]

[0158]

[0159] In a 100 mL eggplant-shaped flask, intermediate 3 (0.765 g, 1.9 mmol) was added, followed by intermediate 4 (0.496 g, 2.43 mmol), 10 mL of 1,4-dioxane, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.111 g, 0.15 mmol), and 10 mL of potassium carbonate aqueous solution (2 M). The mixture was protected by argon and deoxygenated in vacuo for 30 min. The mixture was stirred and refluxed at 100 °C for reaction. The reaction was monitored by TLC. The reaction was terminated after 1.5 hours. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was dried by spin drying. An appropriate amount of ethyl acetate was added, and 3 g of silica gel was added. The mixture was mixed well and then dried by spin drying. The sample was loaded by dry method and eluted by silica gel column chromatography with gradient elution of petroleum ether → petroleum ether: ethyl acetate = 1:1 (V:V) → petroleum ether: ethyl acetate = 1:2 (V:V). The solvent was dried by spin drying to obtain compound I-55 (white solid, 0.526 g, 56.99%). 1 H NMR(400MHz,DMSO-d6)δ8.81(s,19H),8.72(s,19H),8.21(s,20H),7.86(d,J=69.9Hz,73H),7.79– 7.79(m,2H),7.47(d,J=20.1Hz,73H),7.32(d,J=10.0Hz,58H),7.26–7.16(m,66H),3.81(s,57H).

[0160] HRMS (ESI) m / z [M+H] + C 28 H 21 F2N3OS, calculated value: 485.1373, measured value: 486.1371.

[0161] Example 12

[0162]

[0163] The preparation of [2-chloro-N-(4'-(4-phenylthiophene-2-yl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 28, except that:

[0164] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0165] The final test results are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.45(s,19H),8.55(d,J=70.0Hz,39H),8.31(s,1H),8.22(s,20H),7.96(s,37H),7.86(s,10H),7 .55(s,22H),7.51(d,J=15.0Hz,54H),7.38(s,58H),7.31(d,J=5.0Hz,31H),7.21(d,J=15.0Hz,57H); HRMS(ESI)m / z[M+H] + C 28 H 19 ClN2OS, calculated value: 466.0907, found value: 467.0908.

[0166] Embodiment 13

[0167]

[0168] The preparation of [(E)-3-(difluoromethyl)-1-methyl-N-(4'-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide] was carried out by a synthetic method similar to that of Example 28, except that:

[0169] The reaction of (5-bromothiophene-2-yl)boronic acid and bromobenzene in step (d) is changed to the reaction of 4-(N,N-dimethylcarbamoyl)phenylboronic acid and benzenethioic acid, hydrazide.

[0170] The final test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.79(s,2H),8.72(s,2H),8.25(s,2H),8.02(d,J=4.2Hz,1H),7.97(d,J=35 .0Hz,7H),7.53(d,J=5.0Hz,8H),7.33(s,2H),7.27–7.11(m,7H),3.81(s,6H); HRMS(ESI)m / z[M+H] + C 26 H 19 F2N5OS, calculated value: 487.1278, measured value: 488.1276.

[0171] Embodiment 14

[0172]

[0173] The preparation of [2-chloro-N-(4'-(5-phenyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-2-yl)nicotinamide] was carried out by a synthetic method similar to that of Example 28, except that:

[0174] The 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid raw material described in step (a) is 2-chloronicotinic acid.

[0175] The reaction of (5-bromothiophene-2-yl)boronic acid and bromobenzene in step (d) is changed to the reaction of 4-(N,N-dimethylcarbamoyl)phenylboronic acid and benzenethioic acid, hydrazide.

[0176] The final test results are as follows: 1 H NMR(400MHz, DMSO-d6)δ9.73(s,10H),8.61(s,10H),8.47(s,10H),8.22(s,10H),8.17–8.05(m,2H),7.97(d,J= 35.0Hz,39H),7.87(s,5H),7.55(d,J=5.0Hz,37H),7.31(s,9H),7.20(d,J=15.0Hz,29H).;HRMS(ESI)m / z[M+H] + C 26 H 17 ClN4OS, calculated value: 468.0812, found value: 469.0813.

[0177] Example 15 Biological Activity Experiment

[0178] Activation culture of plant pathogenic fungi

[0179] The slant culture of cucumber gray mold was picked up with an inoculation needle and inoculated into a potato dextrose agar solid medium plate for activation, and then activated and cultured in a (21±1)°C constant temperature incubator for 4 days.

[0180] The slant culture of Sclerotinia sclerotiorum was picked up with an inoculation needle and inoculated into a potato dextrose agar (PDA) plate for activation, and then activated and cultured in a (25±1)°C incubator for 2 days.

[0181] The slant culture of rice sheath blight pathogen was picked up with an inoculation needle and inoculated into a potato dextrose agar solid medium (PDA) plate for activation, and then activated and cultured in a (25±1)°C constant temperature incubator for 2 days.

[0182] Determination of antibacterial activity by mycelial growth rate method

[0183] Place a sterile Erlenmeyer flask containing 49 mL of PDA culture medium in a microwave oven to melt the PDA, then place it in a constant temperature oven to maintain the culture medium temperature at 55-60°C. Quickly pour 1 mL of the pre-prepared drug-containing solution into a sterile workbench, mix thoroughly, and pour into 3 sterile culture dishes with a diameter of 9 cm to make drug-containing plates, which are then cooled and solidified.

[0184] The 1 mL of pre-prepared drug-containing solution includes 0.5 mL of drug-containing dimethyl sulfoxide (DMSO) solution and 0.5 mL of 0.1% Tween 80 aqueous solution, wherein the blank control uses 0.5 mL of DMSO + 0.5 mL of 0.1% Tween 80 aqueous solution.

[0185] The activated plant pathogenic fungi for test were selected, and plant pathogenic fungi with similar growth potential (growth diameter difference within 1 cm) were selected, and holes were punched along the outer edge of the colony growth with the help of a hole puncher to obtain the plant pathogenic fungi cake for test (with a diameter of 5 mm); the cake was transferred to the center of the previously prepared PDA plate with an inoculation needle, so that the mycelium surface of the cake was attached to the surface of the PDA culture medium, and the plates inoculated with different plant pathogenic fungi were placed at 25±1℃ or 21±1℃ for 48-96h.

[0186] The colony growth diameter was determined by the cross method, and the inhibition rate was calculated using the following formula:

[0187]

[0188] The list of compounds of formula (I) and their antibacterial activities (mycelial growth inhibition rate against rapeseed sclerotinia at a concentration of 1 ppm, cucumber gray mold at a concentration of 10 ppm, and rice sheath blight at a concentration of 1 ppm) are shown in Tables 1 to 4 below:

[0189] In the table: SS represents Sclerotinia sclerotiorum;

[0190] BC stands for Botrytis cinerea;

[0191] RS stands for Rhizoctonia solani.

[0192] Table 1

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] The inhibition rate of fluopyram (1 μg / mL) against Sclerotinia sclerotiorum of rapeseed is 70-90%, the inhibition rate of fluopyram (10 μg / mL) against Botrytis cinerea of ​​cucumber is 50-60%, and the inhibition rate of fluopyram (1 μg / mL) against Sheath blight of rice is 70-90%.

[0217] From the data in the table, it can be seen that the compounds of the present invention have an inhibitory effect on rice sheath blight, rapeseed sclerotinia and melon gray mold. Among them, for cucumber gray mold, most compounds have a biological activity that is basically equivalent to that of fluopyram, and the biological activity of some compounds is even better than that of fluopyram. For example, the inhibition rate of compounds I-109 to I-125 in Table 1 against cucumber gray mold is greater than 70%.

[0218] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by formula (I), or a pesticide-acceptable salt thereof: A-CONH-Ph-KYM(Ⅰ) In the formula, A is a substituted or unsubstituted 5-6 membered heteroaryl group; K is a substituted or unsubstituted phenyl group; Y is a substituted or unsubstituted 5-6 membered heteroaryl or a substituted or unsubstituted nitrogen, oxygen and / or sulfur containing aliphatic chain, M is a substituted or unsubstituted phenyl group; in, Each of the above substitutions independently refers to substitution by one or more groups selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy; Each of the above heteroaryl groups independently contains 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N, and S.

2. The compound according to claim 1, characterized in that A is a substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is selected from the following group: pyrazolyl, pyridyl, thienyl, pyridazinyl, thiazolyl, furanyl or pyrazinyl; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1~C4 alkyl, C1~C4 alkoxy, C1~C4 halogenated alkyl, C1~C4 halogenated alkoxy.

3. The compound according to claim 1, characterized in that A is a substituted pyrazolyl, pyridyl or thienyl group; the substitution refers to substitution by 1 or 2 groups selected from the following group: halogen, C1-C3 alkyl, C1-C3 halogenated alkyl.

4. The compound according to claim 1, characterized in that A is a substituted pyrazolyl, pyridyl or thienyl group; the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, difluoromethyl, trifluoromethyl, dichloromethyl or trichloromethyl.

5. The compound according to claim 1, characterized in that K is a substituted or unsubstituted phenyl group; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy.

6. The compound according to claim 5, characterized in that K is a substituted or unsubstituted phenyl group; the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br.

7. The compound according to claim 1, characterized in that Y is substituted or unsubstituted pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, furyl, pyrazinyl, thienyl, oxadiazolyl, thiadiazolyl, wherein the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy; or Y is a group selected from the following group:

8. The compound according to claim 1, characterized in that Y is a substituted or unsubstituted thienyl, oxadiazolyl, or thiadiazolyl group, wherein the substitution refers to substitution by 1 or 2 groups selected from the following group: halogen, hydroxyl, methyl, methoxy, halomethyl, or halomethoxy.

9. The compound according to claim 1, characterized in that Y is substituted or unsubstituted thienyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, wherein the substitution refers to substitution by 1 or 2 groups selected from the following group: halogen, hydroxyl, methyl, methoxy, halomethyl, halomethoxy.

10. The compound according to claim 1, characterized in that M is a substituted or unsubstituted phenyl group; the substitution refers to substitution by 1, 2 or 3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy.

11. The compound according to claim 10, characterized in that M is a substituted or unsubstituted phenyl group; the substitution refers to substitution by 1 or 2 groups selected from the following group: F, Cl, Br.

12. The compound according to claim 1, characterized in that The compound is any one of compounds I-1 to I-220:

13. An agricultural composition comprising: (a) the compound according to any one of claims 1 to 12 or its pesticidally acceptable salt, or a combination thereof; and (b) pesticide-acceptable carriers and / or excipients.

14. Use of the compound according to any one of claims 1 to 12, or the agrochemically acceptable salt thereof, or the agricultural composition according to claim 13, characterized in that: Used for preventing and controlling agricultural plant diseases, or for preparing fungicides for preventing and controlling agricultural plant diseases.

15. The use according to claim 14, characterized in that The plant diseases are plant diseases caused by plant pathogenic bacteria of the phylum Ascomycota, Basidiomycota, Deuteromycota or Oomycota.

16. The use according to claim 15, characterized in that The plant pathogenic bacteria of the phylum Ascomycota are selected from the group consisting of plant pathogenic bacteria of the genera Sclerotinia, Sphaerotheca, and Gibberella; The plant pathogenic bacteria of the phylum Basidiomycetes are plant pathogenic bacteria of the genus Puccinia; The plant pathogenic bacteria of the phylum Deuteromycetes are selected from the plant pathogenic bacteria of the genera Rhizoctonia, Botrytis and Macrophoma; The plant pathogenic bacteria of the phylum Oomycetes are selected from the plant pathogenic bacteria of the genera Phytophthora and Ronophthora.

17. The use according to claim 15, characterized in that The plant pathogenic bacteria of the phylum Ascomycota are selected from: rapeseed sclerotinia, cucumber powdery mildew, and wheat fusarium; The plant pathogenic bacteria of the phylum Basidiomycetes are selected from: wheat stripe rust, leaf rust, and stem rust; The plant pathogenic bacteria of the phylum Deuteromycota are selected from: rice sheath blight, cucumber gray mold, and apple ring rot; The plant pathogenic bacteria of the phylum Oomycetes are selected from: potato infestation pathogen and soybean downy mildew pathogen.

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