Phenylpyrazole compounds and use thereof

Abstract

Disclosed in the present invention are phenylpyrazole compounds and the use thereof. The structure of the compounds is shown as general formula I, the definition of each substituent in the formula being shown in the description. Further disclosed in the description is the use thereof as an insecticidal and acaricide and an animal parasite control agent.

Description

A phenylpyrazole compound and its application Technical Field

[0001] This invention relates to a phenylpyrazole compound, specifically a novel phenylpyrazole compound and its applications. Background Technology

[0002] Patents CN105873906A and CN106103414A involve certain phenylpyrazole compounds with insecticidal activity. However, their biological activity is still unsatisfactory, thus requiring continuous research and development of new and improved insecticidal compounds. Simultaneously, with the increasing demand for agricultural and livestock products and the growing emphasis on environmental protection, there is a persistent need for new, highly effective, broad-spectrum, and environmentally friendly insecticides.

[0003] No compounds of general formula I as described in this invention and their insecticidal activities have been reported in the prior art. Furthermore, compared with the prior art, the compounds of this invention exhibit higher insecticidal activity. Summary of the Invention

[0004] The purpose of this invention is to provide a phenylpyrazole compound with superior insecticidal and acaricidal activity and its applications. This phenylpyrazole compound can be used to prepare drugs for controlling pests and mites in agriculture and other fields, as well as in the field of veterinary medicine for controlling animal parasites.

[0005] To achieve the objective of this invention, the following technical solution is provided:

[0006] A phenylpyrazole compound has the structure shown in general formula I:

[0007] In general formula I:

[0008] W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl;

[0009] W2 is selected from fluorine or trifluoromethyl;

[0010] Y1 is selected from hydrogen or fluorine;

[0011] Y2 is selected from halogens, C1-C6 haloalkyl groups, or C1-C6 haloalkoxy groups;

[0012] R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0013] R2 is selected from hydrogen or cyano;

[0014] It may be a stereoisomer of a compound of general formula I;

[0015] It may be a salt of a compound of general formula I;

[0016] It may be a salt of a stereoisomer of a compound of general formula I.

[0017] In one possible implementation, in general formula I:

[0018] W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl;

[0019] W2 is selected from fluorine or trifluoromethyl;

[0020] Y1 is selected from hydrogen or fluorine;

[0021] Y2 is selected from chlorine, bromine, iodine, C1-C3 haloalkyl or C1-C3 haloalkoxy;

[0022] R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl;

[0023] R2 is selected from hydrogen or cyano;

[0024] It may be a stereoisomer of a compound of general formula I;

[0025] It may be a salt of a compound of general formula I;

[0026] It may be a salt of a stereoisomer of a compound of general formula I.

[0027] In one possible implementation, in general formula I:

[0028] W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl;

[0029] W2 is selected from fluorine or trifluoromethyl;

[0030] Y1 is selected from hydrogen or fluorine;

[0031] Y2 is selected from chlorine, bromine, iodine, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0032] R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0033] R2 is selected from hydrogen or cyano;

[0034] It may be a stereoisomer of a compound of general formula I;

[0035] It may be a salt of a compound of general formula I;

[0036] It may be a salt of a stereoisomer of a compound of general formula I.

[0037] In one possible implementation, in general formula I: when W1 and W2 are selected from trifluoromethyl compounds, the phenylpyrazole compounds are selected from the compounds in Table 1, which have the structure of general formula I and Y1, Y2, R1, and R2 are as shown in Table 1:

[0038] Table 1

[0039] In one possible implementation, in general formula I: when W1 and W2 are selected from trifluoromethyl compounds, the phenylpyrazole compounds are selected from the compounds in Table 2, which have the structure of general formula I and Y1, Y2, R1, and R2 are as shown in Table 2:

[0040] Table 2

[0041] In one possible implementation, the salt of the compound of formula I includes: a salt formed by the compound of formula I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, trifluoroacetic acid, oxalic acid, malonic acid, methanesulfonic acid, 4-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, maleic acid, salicylic acid, tartaric acid, or citric acid.

[0042] In one possible implementation, the salt of the stereoisomer of the compound of formula I includes: a salt formed by the stereoisomer of the compound of formula I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, trifluoroacetic acid, oxalic acid, malonic acid, methanesulfonic acid, 4-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, maleic acid, salicylic acid, tartaric acid, or citric acid.

[0043] The present invention also includes an intermediate for preparing the above-mentioned phenylpyrazole compounds (i.e., compounds of general formula I), said intermediate compounds being as shown in general formula IV:

[0044] In general formula IV:

[0045] The definitions of W1, W2, Y1, and Y2 are as described above.

[0046] The present invention also includes an intermediate compound for preparing the above-described general formula IV compound, said intermediate compound being as shown in general formula V:

[0047] In general formula V:

[0048] The definitions of W1, W2, Y1, and Y2 are as described above.

[0049] The present invention also includes an intermediate compound for preparing the above-described general formula V compound, said intermediate compound being as shown in general formula VII:

[0050] In general formula VII:

[0051] The definitions of W1, W2, Y1, and Y2 are as described above; Y4 is selected from C1-C6 alkyl groups, preferably C1-C4 alkyl groups, and more preferably methyl or ethyl.

[0052] The present invention also includes an intermediate compound for preparing the above-described compound of general formula VII, said intermediate compound being as shown in general formula IX:

[0053] In general formula IX:

[0054] The definitions of W1, W2, Y1, and Y2 are as described above; Y3 is selected from Cl, Br, or I.

[0055] The present invention also includes an intermediate compound for preparing the above-described compound of general formula IX, said intermediate compound being as shown in general formula X:

[0056] In general formula X:

[0057] The definitions of W1, W2, Y1, and Y2 are as described above.

[0058] The present invention also includes an intermediate compound for preparing the above-described compound of general formula X, said intermediate compound being as shown in general formula XI:

[0059] In general formula XI:

[0060] The definitions of W1, W2, Y1, and Y2 are as described above.

[0061] The present invention also provides a method for preparing the above-mentioned phenylpyrazole compounds (compounds of general formula I, including compounds of general formula I-1 and compounds of general formula I-2), as shown in Scheme 1 and Scheme 2 below.

[0062] Scheme 1 (unless otherwise specified, all groups in the formula are defined as above; LG in the formula represents Cl, Br, or I):

[0063] Compounds of general formula IV are prepared by reacting compounds of general formula V with acyl chloride reagents using conventional methods.

[0064] In one possible implementation, the acyl chloride reagent includes one or more of the following: thionyl chloride, oxalyl chloride, carbonyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, or triphosgene.

[0065] Route 1: Compound I-1 can be prepared by reacting compound IV and compound III in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours; compound I-2 can be prepared by reacting compound I-1 and compound II (alkylating agent) in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0066] Route 2: Compound of general formula VI can be prepared by reacting compound of general formula III and compound of general formula II in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours; compound of general formula I-2 can be prepared by reacting compound of general formula VI and compound of general formula IV in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0067] In one possible implementation, the solvents used in the reactions involved in routes 1 and 2 above include: aromatic hydrocarbons such as benzene, toluene, and xylene; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; esters such as methyl acetate and ethyl acetate; ethers such as tetrahydrofuran, dioxane, diethyl ether, and 1,2-dimethoxyethane; and polar solvents such as water, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, and ethanol, one or more of these.

[0068] In one possible implementation, the bases involved in the reactions of routes 1 and 2 above include: organic bases such as trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine, N,N-diisopropylmethylamine, and N,N-diisopropylethylamine; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal acetates such as potassium acetate and sodium acetate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate; and one or more metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0069] Compounds of general formula V can be prepared by the following route (unless otherwise specified, each group is defined as above; X, Y3 are Cl, Br or I; Y4 is a C1-C6 alkyl group, preferably a C1-C4 alkyl group, more preferably methyl or ethyl):

[0070] Step 1: Preparation of compound of general formula XIII

[0071] Compound of general formula XV can be prepared by reacting compound of general formula XIV in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0072] Step 2: Preparation of compound of general formula XII

[0073] Compounds of general formula XIIII can be prepared by reacting them with NCS, NBS or NIS in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0074] Step 3: Preparation of compounds of general formula XI

[0075] Compounds of general formula XII can be converted into compounds of general formula XI through diazotization and reduction reactions.

[0076] Step 4: Preparation of compound of general formula X

[0077] Compound of general formula XI can be prepared by reacting it with 1,1,3,3-tetramethoxypropane in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0078] Step 5: Preparation of compound of general formula IX

[0079] Compound of general formula X can be prepared by reacting it with NCS, NBS or NIS in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0080] Step 6: Preparation of compounds of general formula VII

[0081] Compound of general formula IX can be prepared by reacting compound of general formula VIII with compound of general formula VIII in a suitable solvent, with a suitable catalyst and base, at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0082] Step 7: Preparation of compound of general formula V

[0083] Compounds of general formula VII can be prepared into compounds of general formula V by conventional alkaline hydrolysis.

[0084] In one possible implementation, the solvents involved in the above steps include: aromatic hydrocarbons such as benzene, toluene, and xylene; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; esters such as methyl acetate and ethyl acetate; ethers such as tetrahydrofuran, dioxane, diethyl ether, and 1,2-dimethoxyethane; and polar solvents such as water, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, and ethanol.

[0085] In one possible implementation, the base involved in the reaction of the above steps includes: organic bases such as trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine, N,N-diisopropylmethylamine, and N,N-diisopropylethylamine; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal acetates such as potassium acetate and sodium acetate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate; and one or more metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0086] In one possible implementation, the catalysts involved in the above steps include: Pd / C, Pd(dppf)Cl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(PPh3)2Br2, Pd(OAc)2, PdCl2, NiCl2(dppp), CuI, CuBr, etc.; and the catalyst ligands include: PPh3, dppf, dppb, Xantphos, etc.

[0087] Scheme 2 (unless otherwise specified, all groups in the formula are defined as above; LG in the formula represents Cl, Br, or I):

[0088] Compounds of general formula XVIII were prepared by reacting compounds of general formula XIX with acyl chloride reagents using conventional methods.

[0089] In one possible implementation, the acyl chloride reagent includes one or more of the following: thionyl chloride, oxalyl chloride, carbonyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, or triphosgene.

[0090] Route 1:

[0091] Step 1: Preparation of compounds of general formula XVII

[0092] Compound of general formula XVII can be prepared by reacting compound of general formula XVIII with compound of general formula III in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0093] Step 2: Preparation of compounds of general formula XVI

[0094] Compounds of general formula XVII can be prepared by reacting them with tetrahydroxydiboron in a suitable solvent, with a suitable catalyst and a base, at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0095] Step 3: Preparation of compound of general formula I-1

[0096] Compound of general formula I-1 can be prepared by reacting compounds of general formula XVI and general formula IX in a suitable solvent, with a suitable catalyst and base, at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0097] Step 4: Preparation of compound of general formula I-2

[0098] Compound I-2 can be prepared by reacting compound I-1 with compound II (alkylating agent) in a suitable solvent at a temperature ranging from -10°C to the solvent boiling point for 0.5-48 hours.

[0099] Route 2:

[0100] Step 1: Preparation of compounds with general formula XXI

[0101] Compound of general formula XVI can be prepared by reacting compound of general formula XVIII with compound of general formula VI in a suitable solvent at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0102] Step 2: Preparation of compound with general formula XX

[0103] Compound of general formula XXI can be prepared by reacting it with tetrahydroxydiboron in a suitable solvent, with a suitable catalyst and a base, at a temperature ranging from -10°C to the boiling point of the solvent for 0.5-48 hours.

[0104] Step 3: Preparation of compound of general formula I-2

[0105] Compound of general formula I-2 can be prepared by reacting compound of general formula XX and compound of general formula IX in a suitable solvent, with a suitable catalyst and base, at a temperature from -10℃ to the boiling point of the solvent for 0.5-48 hours.

[0106] In one possible implementation, the solvents used in the reactions involved in routes 1 and 2 above include: aromatic hydrocarbons such as benzene, toluene, and xylene; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; esters such as methyl acetate and ethyl acetate; ethers such as tetrahydrofuran, dioxane, diethyl ether, and 1,2-dimethoxyethane; and polar solvents such as water, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, and ethanol, one or more of these.

[0107] In one possible implementation, the bases involved in the reactions of routes 1 and 2 above include: organic bases such as trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine, N,N-diisopropylmethylamine, and N,N-diisopropylethylamine; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal acetates such as potassium acetate and sodium acetate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate; and one or more metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0108] In one possible implementation, the catalysts involved in the reactions of routes 1 and 2 above include: Pd / C, Pd(dppf)Cl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(PPh3)2Br2, Pd(OAc)2, PdCl2, NiCl2(dppp), CuI, CuBr, etc.; and the catalyst ligands include: PPh3, dppf, dppb, Xantphos, etc.

[0109] Compounds of general formula II, general formula III, general formula VIII, general formula XIV, general formula XV and general formula XIX are usually commercially available, or can be prepared by conventional methods.

[0110] The embodiments of the present invention also provide the use of the above-mentioned phenylpyrazole compounds in the preparation of insecticides and / or acaricides.

[0111] In one possible implementation, the insecticide is used to control one or more of the following insects:

[0112] Beetles (Coleopteran insects), such as the bean weevil (Callosobruchus Chinensis), the corn weevil (Sitophilus zeamais), the red flour beetle (Tribolium Castaneum), the potato ladybug (Epilachna vigintioctomaculata), the slender-throated click beetle (Agriotes oguraefuscicollis), the multicolored scarab beetle (Anomala rufocuprea), the potato leaf beetle (Leptinotarsa ​​decemlineata), the leaf beetle (Diabrotica spp.), the pine longhorn beetle (Monochamus alternatus endai), the rice root weevil (Lissorhoptrus oryzophilus), and the brown powder beetle (Lyctus bruneus);

[0113] Lepidopteran pests, such as the gypsy moth (Lymantria dispar), the brown tent caterpillar (Malacosoma neustria), the Japanese subspecies of the cabbage white butterfly (Pieris rapae crucivora), the beet armyworm (Spodoptera litura), the cabbage cutworm (Mamestra brassicae), the rice stem borer (Chilo suppressalis), the European corn borer (Ostrinia nubilalis), the fruit borer (Cadra cautella), the chyanokokakumonhamaki (Adoxophyes honmai), the apple leafroller (Cydiapomonella), the yellow cutworm (Agrotis segetum), the large wax moth (Galleria mellonella), the diamondback moth (Plutellaxylostella), the tobacco bud cutworm (Heliothis virescens), and the citrus leafminer (Phyllocnistis citrella);

[0114] Hemipterous pests, such as the black-tailed leafhopper (Nephotettix cincticeps), brown planthopper (Nilaparvata lugens), Comstock mealybug (Pseudococcus comstocki), arrowhead scale (Unaspisyanonensis), peach aphid (Myzuspersicas), apple aphid (Aphispomi), cotton aphid (Aphisgossypii), broad bean aphid (Aphisfabae), turnip aphid (Lipaphis erysimi), pear lace bug (Stephanitis nashi), green ailanthus (Nezara spp.), greenhouse whitefly (Trialeurodes vaporariorum), and Pshylla spp.;

[0115] Thysanoptera pests, such as palm thrips and western flower thrips (Franklinella occidentalis);

[0116] Orthoptera pests, such as the African mole cricket (Gryllotalpa Africana) and the African migratory locust (Locusta migratoria);

[0117] Blattarian pests, such as the German cockroach (Blattella germanica), the American cockroach (Periplaneta americana), the yellow-breasted subterranean termite (Reticulitermes speratus), and the domestic termite (Coptotermes formosanus);

[0118] Dipterous pests, such as housefly (Musca domestica), Aedes aegypti, Deliaplatura, Culexpipienspallens, Anopheles sinensis, Culex tritaeniorhynchus, and Liriomyza trifolii;

[0119] In one possible implementation, the acaricide is used to control one or more of the following mites: Tetrahychus cinnabarinus, Tetrahychus urticae, Panonychus citri, Aculops pelekassi, Tarsonemus spp., etc.

[0120] In one possible implementation, the insecticide and / or acaricide is used to control one or more of armyworms, diamondback moths, and spider mites.

[0121] This invention also provides an insecticide or acaricide formulation, which contains the above-mentioned phenylpyrazole compound as an active ingredient, and also contains one or more excipients.

[0122] In one possible implementation, the insecticide or acaricide formulation is selected from the following dosage forms: solutions, emulsions, wettable powders, granular wettable powders, suspensions, powders, foams, pastes, tablets, granules, aerosols, natural reagents impregnated with active compounds, synthetic reagents impregnated with active compounds, microcapsules, seed coating agents, formulations equipped with combustion devices (such as chimneys and fogging cans, canisters and coils, etc.), and ULVs (cold fog agents, hot fog agents), etc. These insecticide or acaricide formulations or animal parasite control agents can be prepared by known methods, for example, by mixing the active ingredient with fillers (such as liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers), and optionally with surfactants (i.e., emulsifiers and / or dispersants and / or foaming agents).

[0123] In one possible implementation, the excipients include one or more of the following: fillers (e.g., liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers), surfactants (e.g., emulsifiers and / or dispersants and / or foaming agents), binders, and colorants.

[0124] Liquid diluents or carriers may include, for example, aromatic hydrocarbons (xylene, toluene, alkylnaphthalene, etc.), chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons (e.g., chlorobenzene, vinyl chloride, dichloromethane, etc.), aliphatic hydrocarbons (e.g., cyclohexane or paraffin (e.g., mineral oil fractions)), alcohols (e.g., butanol, ethylene glycol, and their ethers or esters, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, etc.), highly polar solvents (e.g., dimethylformamide, dimethyl sulfoxide), water, etc. When water is used as a filler, for example, an organic solvent may be used as a co-solvent;

[0125] Liquefied gas diluents or carriers may include those that exist in gaseous form at atmospheric pressure and temperature, such as propane, nitrogen, carbon dioxide, and aerosol propellants such as halogenated hydrocarbons;

[0126] Solid diluents may include pulverized natural minerals (such as kaolin, clay, talc, chalk, quartz, palygorskite, montmorillonite, or diatomaceous earth) and pulverized synthetic minerals (such as finely dispersed silica, alumina, and silicates).

[0127] Emulsifiers and / or foaming agents may include nonionic and anionic emulsifiers [e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers (such as alkyl aryl polyethylene glycol ethers), alkyl sulfonates, alkyl sulfates and aryl sulfonates] and albumin hydrolysates, etc.

[0128] Dispersants may include lignin sulfite waste liquid and methylcellulose;

[0129] Adhesives may include carboxymethyl cellulose, natural or synthetic polymers (such as gum arabic, polyvinyl alcohol, and polyvinyl acetate).

[0130] Colorants may include inorganic pigments (such as iron oxide, titanium oxide, and Prussian blue), organic dyes such as alizarin dyes, azo dyes, or metal phthalocyanine dyes; and trace elements such as iron salts, manganese salts, boron salts, copper salts, cobalt salts, molybdenum salts, or zinc salts.

[0131] Furthermore, the phenylpyrazole compounds of the present invention can exist as a mixture with a synergist, which itself need not be active. More precisely, it is a compound that enhances the activity of the active compound.

[0132] In one possible implementation, the amount of the aforementioned phenylpyrazole compound contained in the insecticide or acaricide formulation is from 0.1 to 99% by weight, optionally from 0.5 to 90% by weight.

[0133] This invention also provides an insecticide or acaricide composition comprising a mixture of the aforementioned phenylpyrazole compounds and other active compounds (e.g., insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators, herbicides, etc.). This mixture may be provided as an active pharmaceutical ingredient, a commercially available effective formulation, or an application form derived from such formulation.

[0134] This invention also provides a method for controlling agricultural or forestry pests and / or mites, comprising the following steps: applying an effective dose of material to the pests or mites to be controlled or their growth medium, wherein the material is selected from one or more of the following groups: the above-mentioned phenylpyrazole compounds, the above-mentioned insecticide formulations or acaricide formulations, the above-mentioned insecticide compositions or acaricide compositions.

[0135] The embodiments of the present invention also provide the use of the above-mentioned phenylpyrazole compounds in the preparation of animal parasite control agents. In the veterinary field, that is, in veterinary science, the phenylpyrazole compounds of the present invention can be effectively used to combat a variety of harmful animal parasites, especially internal and external parasites.

[0136] In one possible implementation, animal parasites include one or more of the following:

[0137] The order Anoplurida includes genera such as Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., and Solenopotes spp.; in particular, representative examples include the spiny-jawed louse (Linognathus setosus) and the cow tube louse (Solenopotes capillatus).

[0138] The order Mallopha includes the following suborders: cattle gnater (Linognathus vituli), sheep gnater (Linognathus ovillus), Linognathus oviformis, foot gnater (Linognathus pedalis), goat gnater (Linognathus stenopsis), donkey blood louse (Haematopinus asini macrocephalus), cattle blood louse (Haematopinus eurysternus), pig blood louse (Haematopinus suis), head lice (Pediculus humanus capitis), body lice (Pediculus humanus corporis), grape phylloxera (Phylloera vastatrix), pubic lice (Phthirus pubis gida), and the suborders Amblycerina and Ischnocerin, such as the genera Trimenopon spp., Menopon spp., and Trinoton spp. The genera *Bovicola* (spp.), *Bovicola* (spp.), *Werneckiella* (spp.), *Lepikentron* (spp.), *Damalina* (spp.), *Trichodectes* (spp.), and *Felicola* (spp.) are included. Representative examples include, in particular, *Bovicola bovis*, *Bovicola ovis*, *Bovicola limbata*, *Damalina bovis*, *Trichodectes canis*, *Felicola subrostratus*, *Bovicola caprae*, *Lepikentron ovis*, and *Werneckiella equi*.

[0139] Diptera and its suborders Nematocerina and Brachycerina, including genera such as Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmia spp., Hybomitra spp., Atylotus spp., and Tabanus. spp.), *Haematopota* spp., *Philipomyia* spp., *Braula* spp., *Musca* spp., *Hydrotaea* spp., *Stomoxys* spp., *Haematobia* spp., *Morellia* spp., *Fannia* spp., *Glossina* spp., *Calliphora* spp., *Lucilia* spp., *Chrysomyia* spp., *Wohlfahrtia* spp., *Sarcophaga* spp., *Oestrus* spp., *Hypoderma* spp., *Gasterophilus* The genera *Hippobosca*, *Lipoptena*, *Melophagus*, *Rhinoestrus*, and *Tipula* are included. Notably, representative examples include *Aedes aegypti*, *Aedes albopictus*, *Aedes taeniorhynchus*, *Anopheles gambiae*, *Anopheles maculipennis*, *Calliphora erythrocephala*, *Chrysozonapluvialis*, and *Culex pipiens pallens*.The following mosquitoes are listed: *Culex quinquefasciatus*, *Culexpipiens*, *Culex tarsalis*, *Fannia canicularis*, *Sarcophaga carnaria*, *Stomoxys calcitrans*, *Tipulapaludosa*, *Lucilia cuprina*, *Lucilia sericata*, *Simulium reptans*, *Phlebotomus papataasi*, *Phlebotomus longipalpis*, *Odagmia ornata*, *Wilhelmia equina*, *Boophthora erythrocephala*, *Tabanus bromius*, *Tabanus spodopterus*, and *Tabanus spodopterus*. atratus), pig fly (Tabanus sudeticus), horsefly (Hybomitra ciurea), blind horsefly (Chrysops caecutiens), yellow-margined horsefly (Chrysops relictus), high-horned horsefly (Haematopota pluvialis), Haematopota italica, autumn housefly (Musca autumnalis), housefly (Musca domestica), western hornfly (Haematobia irritans irritans), western hornfly (Haematobia irritans exigua), stabbing blood fly (Haematobia stimulans), Hydrotaea irritans, white-spotted toothed fly (Hydrotaea albipuncta), Chrysomya chloropyga, maggot-infested golden fly (Chrysomya bezziana), sheep mad fly (Oestrus ovis), cow dhole fly (Hypoderma bovis), striped dhole fly (Hypoderma lineatum), Przhevalskiana silenus, human skin fly (Dermatobia hominis), sheep tick fly (Melophagus ovinus), Lipoptena capreoli, deer and sheep tick fly (Lipoptena cervi), Hippobosca variegata, horse tick fly (Hippoboscaequina), intestinal maggot (Gasterophilus intestinalis), red-tailed maggot (Gasterophilus haemorroidalis), naked maggot (Gasterophilus interrnis), nasal maggot (Gasterophilus nasalis), black-horned maggot (Gasterophilus nigricornis), black-bellied maggot (Gasterophilus pecorum), and bee fly (Braula coeca);

[0140] Siphonapterida, including genera such as *Pulex* spp., *Ctenocephalides* spp., *Tunga* spp., *Xenopsylla* spp., and *Ceratophyllus* spp.; particularly representative examples include *Ctenocephalides canis*, *Ctenocephalides felis*, *Pulex irritans*, *Tungapenetrans*, and *Xenopsylla cheopis*.

[0141] Heteropterida, for example, genera such as Cimex spp., Triatoma spp., Rhodnius spp., and Panstrongylus spp.;

[0142] Blattodea, including species such as the Oriental cockroach (Blatta orientalis), the American cockroach, the German cockroach, and the genus Supella (e.g., Suppella longipalpa);

[0143] Acari (or Acarina), Metastigmata, and Mesostigmata, including genera such as *Argas* spp., *Ornithodorus* spp., *Otobius* spp., *Ixodes* spp., *Amblyomma* spp., *Rhipicephalus (Boophilus)* spp., *Dermacentor* spp., *Haemophysalis* spp., *Hyalomma* spp., *Dermanyssus* spp., *Rhipicephalus* spp. (the original genus of heteroparasitic mites), *Ornithonyssus* spp., and *Pneumonyssus*. spp.), Pneumonyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp., Acarapis spp.; particularly, representative examples include Argaspersicus, Argas reflexus, Ornithodorus moubata, and Otobius The following ticks are listed: megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens, Rhipicephalus evertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, and Ixodes canisuga.The following ticks are listed: *Ixodes rubicundus*, *Ixodes scapularis*, *Ixodes holocyclus*, *Haemaphysalis concinna*, *Haemaphysalis punctata*, *Haemaphysalis cinnabarina*, *Haemaphysalis otophila*, *Haemaphysalis leachi*, *Haemaphysalis longicorni*, *Dermacentor marginatus*, *Dermacentor reticulatus*, *Dermacentor pictus*, *Dermacentor albipictus*, *Dermacentor andersoni*, *Dermacentor variabilis*, *Hyalomma mauritanicum*, *Rhipicephalus sanguineus*, and *Rhipicephalus sac-like*. The following ticks are listed: *Rhipicephalus appendiculatus*, *Rhipicephalus capensis*, *Rhipicephalus turanicus*, *Rhipicephalus zambeziensis*, *Amblyomma americanum*, *Amblyomma variegatum*, *Amblyomma maculatum*, *Amblyomma hebraeum*, *Amblyomma cajennense*, *Dermanyssus gallinae*, *Ornithonyssus bursa*, *Ornithonyssus sylviarum*, and *Varroajacobsconi*.

[0144] The order Actinedida (prostigmata) and Acaridida (Astigmata) includes species such as *Acarapis* spp., *Cheyletiella* spp., *Ornithocheyletia* spp., *Myobia* spp., *Psorergates* spp., *Demodex* spp., *Trombicula* spp., *Listrophorus* spp., *Acarus* spp., *Tyrophagus* spp., *Caloglyphus* spp., *Hypodectes* spp., *Pterolichus* spp., and *Psoroptes*. The genera *Chorioptes* spp., *Otodectes* spp., *Sarcoptes* spp., *Notoedres* spp., *Knemidocoptes* spp., *Cytodites* spp., and *Laminosioptes* spp.In particular, *Cheyletiellayasguri*, *Cheyletiella blakei*, *Demodex canis*, *Demodex bovis*, *Demodex ovis*, *Demodex caprae*, *Demodex equi*, *Demodex caballi*, *Demodex suis*, *Neotrombicula autumnalis*, *Neotrombicula desaleli*, *Neoschonegastia xerothermobia*, *Trombicula akamushi*, *Otodectes cynotis*, *Notoedres cati*, *Sarcoptis canis*, *Sarcoptes bovis*, *Sarcoptes ovis*, and *Sarcoptes*. The following are listed as mites: rupicaprae, Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psoergates ovis, Pneumonyssoidic mange, Pneumonyssoides caninum, and Acarapis woodi.

[0145] Nematodes, such as southern root-knot nematode (Meloidogyne incognita), pine wood nematode (Bursaphelenchus xylophilus), rice dry tip nematode (Aphelenchoides besseyi), soybean heteroderma nematode (Heterodera glycines), and short-bodied nematodes (Pratylenchus spp.).

[0146] Arthropods, worms, and malaria parasites that infest animals. Controlling arthropods, worms, and / or malaria parasites can reduce mortality in domestic animals and improve animal productivity (meat, milk, wool, fur, eggs, and honey) and health.

[0147] In one possible implementation, the animal parasite control agent is used to control one or more of cat fleas and American ticks.

[0148] In one possible implementation, the animals include one or more of the following: agricultural animals, such as cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, chickens, turkeys, ducks, geese, farmed fish, bees, etc.; pets known as companion animals, such as dogs, cats, caged birds, ornamental fish; and animals used for experiments, such as hamsters, guinea pigs, rats, and mice.

[0149] The present invention also provides an animal parasite control agent, which contains the above-mentioned phenylpyrazole compounds as active ingredients, and also contains one or more excipients.

[0150] In one possible implementation, the animal parasite control agent is selected from the following dosage forms: tablets, capsules, oral liquids, edible medicines, granules, ointments and pills, suppositories, injections (intramuscular, subcutaneous, intravenous, intraperitoneal, etc.), smears, aerosols, and pressureless sprays (e.g., pump sprays and nebulizer sprays).

[0151] In one possible implementation, the amount of the above-mentioned active ingredient contained in the animal parasite control agent is 1 to 80% by weight.

[0152] This invention also provides an animal parasite control composition comprising the above-mentioned phenylpyrazole compounds and other animal parasite control active compounds (e.g., acaricides, insecticides, parasiteicides, antimalarial agents, etc.). This mixture may be provided as an active pharmaceutical ingredient, as a commercially available effective formulation, or as an application form prepared from such formulations.

[0153] This invention also provides a method for controlling animal parasites, comprising the following steps: applying an effective dose of material to the animal parasite to be controlled or its growth medium, wherein the material is selected from one or more of the following: the above-mentioned phenylpyrazole compounds; the above-mentioned animal parasite control agents; and the above-mentioned animal parasite control compositions. For example, administration can be made via enteral methods such as tablets, capsules, decoctions, edible medicines, granules, ointments, pills, or suppositories; non-enteric administration based on skin application, such as injection (intramuscular, subcutaneous, intravenous, intraperitoneal, etc.), implantation, nasal administration, including bathing or soaking, spraying, pouring, dripping, washing, and powdering; and application via the use of model articles containing the active compound, such as collars, ear tags, labels, leg braces, nets, markers, etc. The active compound of this invention has low toxicity and can be safely used in warm-blooded animals. Beneficial effects

[0154] The phenylpyrazole compounds of this invention exhibit unexpectedly excellent insecticidal and acaricidal effects, and also demonstrate suitable control efficacy against toxic pests, without causing phytotoxicity to cultivated crops. Furthermore, the compounds of this invention can be used to control a variety of pests, such as harmful piercing-sucking insects, chewing insects, other plant parasitic pests, stored grain pests, and sanitary pests, and can also be used for disinfection and eradication. Detailed Implementation

[0155] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0156] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, elements, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0157] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0158] Unless otherwise noted, all raw materials used are commercially available.

[0159] In this invention, the terms used have the following meanings:

[0160] In the definitions of general formula compounds given above, the terms used in the compilation generally represent the following substituents:

[0161] Halogens: refer to fluorine, chlorine, bromine or iodine.

[0162] Alkyl: Straight-chain or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl or different butyl, pentyl or hexyl isomers.

[0163] Halogenated alkyl groups: straight-chain or branched alkyl groups in which hydrogen atoms may be partially or completely replaced by halogens, such as monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl, dibromomethyl, tribromomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, heptafluoroisopropyl, perfluoroethyl, etc.

[0164] Cycloalkyl: substituted or unsubstituted cyclic alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; substituents such as methyl, halogen, cyano, etc.

[0165] Halogenated alkoxy groups: The hydrogen atoms on the alkoxy group can be partially or completely replaced by halogens, such as monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0166] Animal parasite control agents: These are active compounds that can effectively reduce the incidence of various parasites in animals infected with parasites. Control means that the active compounds can effectively kill parasites or inhibit their growth or reproduction.

[0167] Insecticides: Substances that kill pests.

[0168] Acaricides: Agents used to control phytophagous mites.

[0169] Synthesis Examples

[0170] Following the synthetic route described above, compounds of general formula I of this invention can be prepared by using different starting materials, as further described in detail below:

[0171] Example 1: Synthesis of intermediate 2-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline

[0172] 2-Difluoromethoxyaniline (20.00 g, 0.12 mol) and sodium bisulfate (3.52 g, 0.03 mol) were dissolved in 100 mL of acetonitrile. 90% sodium dithionite (29.2 g, 0.15 mol) was added in batches with stirring at room temperature. Finally, approximately 40 mL of 2-bromoheptafluoropropane was added. After the addition was complete, the bottle was sealed, and the reaction was carried out under a 2-bromoheptafluoropropane atmosphere with stirring at 65 °C. Liquid phase monitoring showed that the reactants had essentially reacted completely. After the reaction was complete, the reaction solution was diluted with 450 mL of saturated saline solution with stirring. Then, 30 g of solid sodium carbonate was added, followed by extraction with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 41.1 g of a brown liquid. 1 H NMR(600MHz,Chloroform-d)δ7.18(t,2H),6.77(d,1H),6.42(t,1H),4.10(s,2H).

[0173] Example 2: Synthesis of intermediate 2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline

[0174] Weigh 2.50 g (7.66 mmol) of 2-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline and 20 mL of anhydrous acetonitrile into a 100 mL single-necked flask. After stirring for 10 min, N-chlorosuccinimide (NCS) (1.02 g, 7.63 mmol) was slowly added every 5 min. After the addition was complete, the mixture was heated to 50 °C and refluxed for 2 h. The reaction was stopped after the reaction starter spots completely disappeared as monitored by TLC. The reaction was concentrated under reduced pressure to remove residual acetonitrile. Then, the mixture was extracted with ethyl acetate (30 mL) and water (30 mL). After washing the organic phase with water, the mixture was dried and concentrated with anhydrous magnesium sulfate to obtain 2.23 g of 2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline. 1 H NMR(600MHz,Chloroform-d)δ7.39(s,1H),7.19(s,1H),6.51(t,1H),4.57(s,2H).

[0175] Example 3: Synthesis of intermediate 2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline

[0176] 2.21 g (6.75 mmol) of 2-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline and 20 mL of anhydrous acetonitrile were added to separate 100 mL single-necked flasks. After stirring for 10 min, N-bromosuccinimide (1.20 g (6.75 mmol)) was added in portions. After reacting at room temperature for 2 h, the reaction was monitored by TLC until it was complete. The residual solvent was removed by vacuum distillation. The mixture was extracted with 50 mL of ethyl acetate and 50 mL of water. The organic layer was separated, and the aqueous layer was back-extracted twice with 50 mL of ethyl acetate. The organic phases were then combined and washed once with 200 mL of water and once with saturated sodium chloride solution. The mixture was then dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 2.35 g of the intermediate 2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline. 1 H NMR (600MHz, DMSO-d6) δ7.49(s,1H),7.24(s,1H),7.18(t,1H),6.21(s,2H).

[0177] Example 4: Synthesis of intermediate 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-1H-pyrazole

[0178] At room temperature, sodium nitrite (0.44 g, 5.28 mmol) in 4 mL of concentrated sulfuric acid solution was added dropwise to 12 mL of acetic acid solution containing 1.91 g (5.28 mmol). After 30 min, the mixture was heated to 40 °C and reacted for another 30 min. After complete conversion, the mixture was cooled to below 15 °C, and stannous chloride (2.5 g, 13.18 mmol) in 2 mL of concentrated hydrochloric acid solution was added dropwise. The mixture was stirred for 2 h. This confirmed the conversion to a hydrazine intermediate. Tetramethoxypropane (0.95 g, 5.81 mmol) was added, and the reaction was essentially complete by TLC. The reaction was then stopped. Post-treatment: 300 mL of water was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, washed twice with water, washed with 10% hydrochloric acid, extracted once with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to obtain 1.42 g of a brown oily substance. 1 H NMR (600MHz, DMSO-d6) δ8.09(d,1H),7.92(s,1H),7.83(d,1H),7.64(s,1H),7.35(t,1H),6.57(t,1H).

[0179] Example 5: Synthesis of intermediate 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-1H-pyrazole

[0180] The synthesis was carried out using 2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)aniline as the reactant, referring to the synthesis method in Example 4. 1 HNMR(600MHz,Chloroform-d)δ7.78(d,1H),7.74(d,1H),7.60-7.52(m,1H),7.50(d,1H),6.46(t,1H),6.45-6.16(m,1H).

[0181] Example 6: Synthesis of intermediate 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole

[0182] 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-1H-pyrazole (0.32 g, 0.79 mmol), N-iodosuccinimide (0.26 g, 1.16 mmol), 98% concentrated sulfuric acid (0.01 g, 0.10 mmol) and 5 mL of acetonitrile were added to a 100 mL single-necked flask and refluxed at 80 °C for 2 h. The reaction was monitored by TLC until it was complete. The solvent was removed by vacuum distillation, 40 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, extracted once with 40 mL of 10% sodium hydroxide solution, washed once with 40 mL of saturated sodium thiosulfate solution, washed once with water (20 mL), and extracted once with saturated sodium chloride solution (20 mL). The mixture was dried over anhydrous magnesium sulfate, filtered under vacuum, and concentrated to obtain 0.38 g of 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole. 1 H NMR (600MHz, Chloroform-d) δ7.81(s,1H),7.69(d,1H),7.67(s,1H),7.55(d,1H),6.46(t,1H).

[0183] Example 7: Synthesis of intermediate 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole

[0184] The synthesis was carried out using 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-1H-pyrazole as the reactant, referring to the synthesis method in Example 6. 1 H NMR (600MHz, Chloroform-d) δ7.87(s,1H),7.81(s,1H),7.66(s,1H),7.59(s,1H),6.45(t,1H).

[0185] Example 8: Synthesis of intermediate 5-bromo-2-chloro-N-cyclopropylnicotinamide

[0186] Weigh 1.0 g (4.26 mmol) of 5-bromo-2-chloronicotinic acid, 1.51 g (12.70 mmol) of thionyl chloride, and 10 mL of toluene into a 50 mL single-necked flask. Reflux at 110 °C for 2.5 h. After TLC monitoring showed no acidity, the reaction was stopped. Residual toluene and thionyl chloride were removed by vacuum distillation. The concentrate was dissolved in 5 mL of dichloromethane and then added dropwise to a solution of 0.48 g (8.43 mmol) of cyclopropylamine in 10 mL of dichloromethane at 0–5 °C. After 2 hours of reaction, the reaction was monitored by TLC and found to be complete. The reaction solution was distilled under reduced pressure to remove residual dichloromethane. 30 mL of ethyl acetate and 40 mL of water were added for extraction. The aqueous layer was separated and back-extracted once with 30 mL of ethyl acetate. The organic phases were combined and then washed once each with 30 mL of saturated sodium carbonate solution, 40 mL of water, and 30 mL of saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.94 g of a pale yellow solid, namely 5-bromo-2-chloro-N-cyclopropylnicotinamide. 1 H NMR (600MHz, Chloroform-d) δ8.51(d,1H),8.24(d,1H),6.56(s,1H),2.93(dq,1H),0.99-0.86(m,2H),0.74-0.62(m,2H).

[0187] Example 9: Synthesis of intermediate 5-bromo-2-chloro-N-(1-cyanocyclopropyl)nicotinamide

[0188] The product was prepared using 5-bromo-2-chloronicotinic acid and 1-aminocyclopropane-1-nitrile as reactants, following the synthesis method described in Example 8. 1 H NMR (600MHz, Chloroform-d) δ8.54(t,1H),8.25(t,1H),7.22(s,1H),1.69(d,2H),1.42(d,2H).

[0189] Example 10: Synthesis of intermediate 5-bromo-2-chloro-N-cyclopropyl-N-methylnicotinamide

[0190] Under ice bath conditions, 5-bromo-2-chloro-N-cyclopropylnicotinamide (3 g, 10.94 mmol) was dissolved in DMF (20 mL). 60% NaH (1.31 g, 54.70 mmol) was added to the system, and the mixture was stirred for 20 min. Iodomethane (1.86 g, 13.10 mmol) was then added, and the mixture was kept in an ice bath for another 20 min before being moved to room temperature for 2 h. The reaction was monitored by TLC until complete. The solution was extracted with 30 mL of water and ethyl acetate (15 mL × 2), washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and purified by column chromatography to give 2.85 g of a white solid. 1H NMR (600MHz, Chloroform-d) δ 8.48 (s, 1H), 7.76 (s, 1H), 3.12 (s, 3H), 2.77 (ddd, 1H), 0.66 ~ 0.42 (m, 4H).

[0191] Example 11: Synthesis of intermediate 5-bromo-2-chloro-N-(1-cyanocyclopropyl)-N-methylnicotinamide

[0192] The nicotinamide was prepared using 5-bromo-2-chloro-N-(1-cyanocyclopropyl)nicotinamide as a reactant, following the synthesis method of Example 10.

[0193] Example 12: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide (compound 1)

[0194] Compound 5-bromo-2-chloro-N-cyclopropylnicotinamide (0.84 g, 3.07 mmol), cataCXium A-Pd-G2 (0.1 g, 0.15 mmol), tetrahydroxydiborane (0.55 g, 6.13 mmol), DIPEA (1.19 g, 9.21 mmol), and 15 mL of methanol were added to a 25 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 50 °C for 2 h. After the reaction was complete as monitored by TLC, the solvent was removed under reduced pressure. Then, compound 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole (1.65 g, 3.07 mmol), 5 mL of potassium carbonate aqueous solution (1.1 g, 7.68 mmol), and tetra(triphenylphosphine)palladium (0.28 g, 0.24 mmol) were added to the reaction flask. The mixture was purged with nitrogen three more times and reacted at 65 °C for 5 h. After the reaction was complete as monitored by TLC, the filtrate was distilled under reduced pressure, extracted with ethyl acetate (20 mL × 4), the organic phases were combined, washed once with water, extracted once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 1.12 g of pale yellow solid 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide. 1H NMR(600MHz,Chloroform-d)δ8.63(d,1H),8.26(d,1H),8.13(s,1H),7.96(s,1H),7.73(d,1H),7.57(s,1 H),6.72(d,1H),6.51(t,1H),3.05-2.90(m,1H),0.93(td,2H),0.70(td,2H).ESI-MS(m / z):607.03[M+H] + .

[0195] Example 13: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-methylnicotinamide (compound 2)

[0196] White solid. Compound 2 was prepared by using 5-bromo-2-chloro-N-cyclopropyl-N-methylnicotinamide and 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthesis method of Example 12. 1 H NMR(600MHz,Chloroform-d)δ8.56(s,1H),8.04(s,1H),7.87(s,1H),7.71(s,1H),7.67(s,1H),7.52(s,1H ),6.45(t,1H),3.10(s,3H),2.78(p,1H),0.86-0.75(m,2H),0.60-0.52(m,2H).ESI-MS(m / z):621.04[M+H] + .

[0197] Example 14: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide (compound 14)

[0198] White solid. Compound 14 was prepared by using 5-bromo-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1H NMR(600MHz,Chloroform-d)δ8.68(d,1H),8.34(d,1H),8.14(s,1H),7.99(s,1H),7.73(d,1H),7.58 (s,1H),7.27(s,1H),6.51(t,1H),1.76-1.68(m,2H),1.49-1.39(m,2H).ESI-MS(m / z):632.02[M+H] + .

[0199] Example 15: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)-N-methylnicotinamide (compound 15)

[0200] White solid. Compound 15 was prepared by using 5-bromo-2-chloro-N-(1-cyanocyclopropyl)-N-methylnicotinamide and 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropyl-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1 H NMR(600MHz,Chloroform-d)δ8.71(d,0.5 / 1H),8.66(d,0.5 / 1H),8.18(s,0.5 / 1H),8.13(s,0.5 / 1H),8.07(t,0.5 / 1H),8.01(s,0.5 / 1H),7.97(s,0.5 / 1H), 7.90(d,0.5 / 1H),7.73(d,1H),7.57(d,1H),6.51(td,1H),3.26(s,1.5 / 3H),3 .03(s,1.5 / 3H),1.55-1.40(m,2H),0.87(dt,2H).ESI-MS(m / z):646.04[M+H] + .

[0201] Example 16: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropylnicotinamide (compound 27)

[0202] White solid. Compound 27 was prepared by using 5-bromo-2-chloro-N-cyclopropylnicotinamide and 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1H NMR(600MHz,Chloroform-d)δ8.60(s,1H),8.22(s,1H),8.11(s,1H),7.96(s,1H),7.88(s,1H),7.61(s ,1H),6.83(s,1H),6.51(t,1H),2.94(dq,1H),0.91(td,2H),0.69(td,2H).ESI-MS(m / z):650.98[M+H] + .

[0203] Example 17: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropyl-N-methylnicotinamide (compound 28)

[0204] White solid. Compound 28 was prepared by using 5-bromo-2-chloro-N-cyclopropyl-N-methylnicotinamide and 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1 H NMR(600MHz,Chloroform-d)δ8.63(s,1H),8.12(s,1H),7.98(s,1H),7.89(s,1H),7.80(s,1H),7. 62(s,1H),6.53(t,1H),3.15(s,2H),2.85(td,1H),0.74-0.42(m,2H).ESI-MS(m / z):664.99[M+H] + .

[0205] Example 18: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)nicotinamide (compound 40)

[0206] White solid. Compound 40 was prepared by using 5-bromo-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and 1-(2-bromo-6-(difluoromethoxy)-4-(perfluoroprop-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1H NMR(600MHz,Chloroform-d)δ8.68(d,1H),8.34(d,1H),8.14(s,1H),7.98(s,1H),7.92-7.85(m, 1H),7.61(s,1H),7.30(s,1H),6.49(t,1H),1.71(t,2H),1.44(t,2H).ESI-MS(m / z):675.97[M+H] + .

[0207] Example 19: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)-N-methylnicotinamide (compound 41)

[0208] White solid. Compound 41 was prepared by using 5-bromo-2-chloro-N-(1-cyanocyclopropyl)-N-methylnicotinamide and 1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropyl-2-yl)phenyl)-4-iodo-1H-pyrazole as reactants, following the synthetic method of Example 12. 1 H NMR(600MHz,Chloroform-d)δ8.71(d,0.5 / 1H),8.67(d,0.5 / 1H),8.17(s,0 .5 / 1H),8.13(s,0.5 / 1H),8.07(s,0.5 / 1H),7.99(s,0.5 / 1H),7.96(s,0.5 / 1 H),7.89(dd,1.5 / 2H),7.61(d,1H),6.49(td,1H),3.26(s,1.5 / 3H),3.03(s ,1.5 / 3H),1.60-1.38(m,2H),0.96-0.71(m,2H).ESI-MS(m / z):689.99[M+H] + .

[0209] Example 20: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-ethylnicotinamide (compound 3)

[0210] Compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-ethylnicotinamide (0.61 g, 1.01 mmol), 1-iodoethane (0.71 g, 5.0 mmol), sodium hydride (60%, 0.12 g, 3.0 mmol), and 5 mL of tetrahydrofuran were added to a 25 mL single-necked flask and reacted at 60 °C for 5 h. After the reaction was complete as monitored by TLC, the mixture was distilled under reduced pressure, 20 mL of ethyl acetate was added and stirred, filtered, concentrated under reduced pressure, and purified by column chromatography to give 0.58 g of white solid 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-ethylnicotinamide. 1 H NMR(600MHz, Acetonitrile-d3)δ8.69(d,1H),8.25-8.20(m,2H),7.96(s,1H),7.84(s,1H),7.59(s,1H),6. 82(t,1H),3.72-3.41(m,2H),2.81-2.68(m,1H),1.26(t,3H),0.70-0.47(m,4H).ESI-MS(m / z):635.06[M+H] + .

[0211] Example 21: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-propylnicotinamide (compound 4)

[0212] White solid. Compound 4 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide and 1-iodopropane as reactants, following the synthesis method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.69(d,1H),8.22-8.18(m,2H),7.95(d,1H),7.84(s,1H),7.59(s,1H),6.82(t,1 H),3.64-3.34(m,2H),2.80-2.70(m,1H),1.74(h,2H),1.00(t,3H),0.67-0.46(m,4H).ESI-MS(m / z):649.07[M+H] + .

[0213] Example 22: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropyl-N-isopropylnicotinamide (compound 5)

[0214] A pale yellow solid. Compound 5 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide and 2-iodopropane as reactants, following the synthesis method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.67(d,1H),8.24-8.19(m,2H),8.00-7.94(m,2H),7.61(s,1H),6.81( t,1H),4.49-4.42(m,1H),2.67(p,1H),1.40-1.37(m,6H),0.60-0.47(m,4H).ESI-MS(m / z):663.09[M+H] + .

[0215] Example 23: Synthesis of compound N-butyl-2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide (compound 6)

[0216] A pale yellow solid. Compound 6 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-cyclopropylnicotinamide and 1-iodobutane as reactants, following the synthesis method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.68(d,1H),8.23-8.13(m,2H),7.98-7.91(m,2H),7.61(s,1H),6.81(t,1H),3.65-3 .39(m,1H),2.74(tt,1H),1.74-1.66(m,2H),1.44(h,2H),0.99(t,3H),0.69-0.45(m,5H).ESI-MS(m / z):649.07[M+H] + .

[0217] Example 24: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)-N-ethylnicotinamide (compound 16)

[0218] White solid. Compound 16 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide and iodoethane as reactants, following the synthetic method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.74(d,1H),8.25-8.22(m,2H),8.05(s,1H),7.84(s,1H),7.58(s,1H), 6.82(t,1H),3.29(q,1H),1.78-1.60(m,2H),1.54-1.42(m,2H),1.27(t,3H).ESI-MS(m / z):660.05[M+H] + .

[0219] Example 25: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)-N-propylnicotinamide (compound 17)

[0220] White solid. Compound 17 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide and 1-iodopropane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.74(s,1H),8.26-8.15(m,2H),8.05(s,1H),7.84(s,1H),7.58(s,1H),6.82(t,1H),3.21 (t,2H),1.80-1.73(m,2H),1.70-1.62(m,2H),1.61-1.48(m,2H),1.46-1.32(m,2H),0.84(t,3H).ESI-MS(m / z):674.07[M+H] + .

[0221] Example 26: Synthesis of compound 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)-N-isopropylnicotinamide (compound 18)

[0222] White solid. Compound 18 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide and 2-iodopropane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.74(s,1H),8.32-7.96(m,3H),7.84(s,1H),7.58(s,1H),6.82(t,1H) ,4.38-4.35(m,0.5H / 1H),4.02-3.77(m,0.5H / 1H),1.55(m,4H),1.34(m,6H).ESI-MS(m / z):674.07[M+H] + .

[0223] Example 27: Synthesis of compound N-butyl-2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide (compound 19)

[0224] White solid. Compound 19 was prepared by using 2-chloro-5-(1-(2-chloro-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-(1-cyanocyclopropyl)nicotinamide and 1-iodobutane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.74(s,1H),8.26-8.22(m,2H),8.05(s,1H),7.84(s,1H),7.58(s,1H),6.82(t,1H),3.50 -2.84(m,2H),1.72(q,2H),1.69-1.50(m,2H),1.50-1.38(m,2H),1.34-1.17(m,2H),0.81(t,3H).ESI-MS(m / z):687.09[M+H] + .

[0225] Example 28: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropyl-N-ethylnicotinamide (compound 29)

[0226] A grayish-white solid. Compound 29 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropylnicotinamide and iodoethane as reactants, following the synthetic method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.69(d,1H),8.23-8.20(m,2H),7.99-7.94(m,2H),7.63-7.61(m,1H),6.8 1(t,1H),3.76-3.43(m,2H),2.81-2.73(m,1H),1.26(t,3H),0.67-0.49(m,4H).ESI-MS(m / z):679.01[M+H] + .

[0227] Example 29: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropyl-N-propylnicotinamide (compound 30)

[0228] A grayish-white solid. Compound 30 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropylnicotinamide and 1-iodopropane as reactants, following the synthetic method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.69(s,1H),8.24-8.19(m,2H),7.99-7.92(m,2H),7.62(s,1H),6.81(s,1H), 3.58(t,2H),2.78-2.70(m,1H),1.74-1.70(m,2H),1.00(t,3H),0.69-0.49(m,4H).ESI-MS(m / z):693.02[M+H] + .

[0229] Example 30: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropyl-N-isopropylnicotinamide (compound 31)

[0230] Pale yellow solid. Compound 31 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropylnicotinamide and 2-iodopropane as reactants, following the synthesis method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.67(s,1H),8.17(s,2H),7.99-7.94(m,2H),7.62(s,1H),6.80( t,1H),2.67(p,1H),1.41(m,6H),0.89-0.85(m,1H),0.67-0.49(m,4H).ESI-MS(m / z):693.02[M+H] + .

[0231] Example 31: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-butyl-2-chloro-N-cyclopropylnicotinamide (compound 32)

[0232] Pale yellow solid. Compound 32 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-cyclopropylnicotinamide and 1-iodobutane as reactants, following the synthetic method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.69(d,1H),8.22(d,2H),7.97(s,1H),7.95(d,1H),7.62-7.60(m,1H),6.81(t,1H ),3.52(d,3H),2.75(td,1H),1.70(p,2H),1.44(h,2H),0.99(t,3H),0.66-0.50(m,4H).ESI-MS(m / z):707.04[M+H] + .

[0233] Example 32: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)-N-ethylnicotinamide (compound 42)

[0234] White solid. Compound 42 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and iodoethane as reactants, following the synthetic method of Example 20. 1 H NMR(600MHz, Acetonitrile-d3)δ8.74(d,1H),8.22(d,3H),8.05(d,1H),7.97(s,1H),7.62(s,1H),6. 80(t,2H),3.29(s,3H),1.77-1.65(m,3H),1.53-1.43(m,2H),1.27(t,3H).ESI-MS(m / z):704.00[M+H] + .

[0235] Example 33: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)-N-propylnicotinamide (compound 43)

[0236] White solid. Compound 43 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and 1-iodopropane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.75(s,1H),8.27-8.12(m,2H),8.04(d,1H),7.97(s,1H),7.62(s,1H),6. 81(t,1H),3.38-3.01(m,2H),1.80-1.66(m,4H),1.52-1.42(m,2H),0.84(t,3H).ESI-MS(m / z):718.02[M+H] + .

[0237] Example 34: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)-N-isopropylnicotinamide (compound 44)

[0238] White solid. Compound 44 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and 2-iodopropane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.74(d,1H),8.22-8.18(m,2H),8.04(s,1H),7.97(s,1H),7.61(s, 1H),6.80(t,1H),4.41-3.80(m,1H),1.60-1.52(m,2H),1.47-1.19(m,8H).ESI-MS(m / z):718.02[M+H] + .

[0239] Example 35: Synthesis of compound 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-N-butyl-2-chloro-N-(1-cyanocyclopropyl)nicotinamide (compound 45)

[0240] White solid. Compound 45 was prepared by using 5-(1-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropane-2-yl)phenyl)-1H-pyrazol-4-yl)-2-chloro-N-(1-cyanocyclopropyl)nicotinamide and 1-iodobutane as reactants, following the synthetic method of Example 20. 1 HNMR(600MHz, Acetonitrile-d3)δ8.75(d,1H),8.22-8.18(m,2H),8.05(s,1H),7.97(s,1H),7.62(s,1H),6.80(t, 1H),3.34-2.86(m,2H),1.71(p,2H),1.56-1.39(m,4H),1.31-1.19(m,2H),0.81(t,3H).ESI-MS(m / z):732.03[M+H] + .

[0241] Other compounds in general formula I of the present invention can be prepared by referring to the above embodiments.

[0242] Bioactivity assay

[0243] Example 36: Bioactivity determination of armyworm and diamondback moth

[0244] Insecticidal activity assays were conducted on several insects using the compounds of this invention. The assay methods are as follows:

[0245] The test compound was dissolved in a 1:1 mixture of acetone and methanol and then diluted with water containing 0.1% (wt) Tween 80 to the required concentration.

[0246] The activity was determined using the Airbrush spray method with armyworms and diamondback moths as targets.

[0247] (1) Assay for the activity of killing armyworms

[0248] Measurement method: Corn leaves were cut into 2cm long segments, and the airbrush spray pressure was 10psi (approximately 0.7kg / cm). 2 Spray 0.5 mL of the test compound onto both sides of each leaf segment. After air-drying, inoculate each treatment with 10 third-instar larvae, with each treatment replicated three times. After treatment, incubate in an observation room at 25°C and 60–70% relative humidity. Observe the number of surviving insects three days after treatment and calculate the mortality rate.

[0249] The partial test results for armyworms are as follows:

[0250] At a dose of 0.1 mg / L, three days after administration, compounds 1, 2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 27, 28, 29, 30, 31, 32, 40, 41, 42, 43, 44, and 45 all showed a mortality rate of over 90% against armyworms.

[0251] (2) Activity assay for killing diamondback moth

[0252] Measurement method: Cabbage leaves were perforated to form leaf discs with a diameter of 2 cm using a perforator. The airbrush spray pressure was 10 psi (approximately 0.7 kg / cm²). 2 Spray 0.5 mL of the test compound onto both sides of each leaf disc. After air-drying, inoculate each treatment with 10 third-instar larvae, with each treatment replicated three times. After treatment, incubate in an observation room at 25°C and 60–70% relative humidity. Observe the number of surviving insects three days after treatment and calculate the mortality rate.

[0253] The following are some of the test results for the diamondback moth:

[0254] At a dose of 0.1 mg / L, three days after administration, compounds 1, 2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 27, 28, 29, 30, 31, 32, 40, 41, 42, 43, 44, and 45 all showed a mortality rate of over 90% against the diamondback moth.

[0255] Parallel comparative tests were conducted on the insecticidal activity against diamondback moth (3 days after application) of selected compounds from this invention and control compounds, using the same methods as described above; the results are shown in Table 3:

[0256] Table 3. Parallel comparison test of the insecticidal activity of some compounds of the present invention and control compounds against diamondback moth. Note: CK1 to CK8 in the table are all reference compounds provided in this application. These reference compounds can be obtained by referring to the methods of the embodiments of this invention. The raw materials can be prepared according to the methods of the embodiments of this invention, or can be purchased or prepared by conventional methods.

[0257] As shown in Table 3, by comparing the compound of the present invention with the control compound, it can be seen that by replacing OCF3 with OCHF2 in the control compound, the compound of the present invention has unexpectedly high insecticidal activity, thus obtaining a compound with better insecticidal effect.

[0258] Example 37: Bioactivity determination of Tetranychus cinnabarinus

[0259] The greenhouse acaricide activity of the compound of this invention was determined. The determination method is as follows:

[0260] Based on the solubility of the compound to be tested, dissolve it in acetone or dimethyl sulfoxide, and prepare 50 mL of the required concentration of the test solution with 0.1% Tween 80 solution. The content of acetone or dimethyl sulfoxide in the solution shall not exceed 10%.

[0261] Take two true-leaf bean seedlings, inoculate them with 30-40 adult spider mites, investigate the initial population, and then spray the entire plant with a handheld sprayer. Repeat each treatment three times. After treatment, place the plants in a standard observation room and investigate the number of surviving mites after 72 hours to calculate the mortality rate.

[0262] The partial test results for adult Tetranychus cinnabarinus are as follows:

[0263] At a dose of 1.25 mg / L, compounds 1, 2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 27, 28, 29, 30, 31, 32, 40, 41, 42, 43, 44, and 45 all had a mortality rate of over 90% against adult Tetranychus cinnabarinus.

[0264] Example 38: Insecticidal test on cat fleas

[0265] 4 mg of the test compound was dissolved in 40 mL of acetone to obtain an acetone solution with a concentration of 100 mg / L. 400 μL of the solution was then coated onto the bottom and sides of a petri dish with an inner diameter of 5.3 cm. After the acetone evaporated, a thin film of the compound of this invention was formed on the inner wall of the petri dish. The inner wall of the petri dish used was 40 cm. 2 The treatment dosage was 1 μg / cm³. 2Ten adult cat fleas (mixed male and female) were placed in the mixture, which was then covered and stored in a constant temperature chamber at 25°C. The number of dead fleas was checked after 72 hours, and the mortality rate was calculated. The experiment was repeated three times. Test results: Compounds 1, 2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 27, 28, 29, 30, 31, 32, 40, 41, 42, 43, 44, and 45 showed a mortality rate of over 70%.

[0266] Example 39: Insecticidal test against American ticks

[0267] 4 mg of the test compound was dissolved in 40 mL of acetone to obtain an acetone solution with a concentration of 100 mg / L. 400 μL of the solution was then coated onto the bottom and sides of two 5.3 cm inner diameter culture dishes. After the acetone evaporated, a thin film of the compound of this invention was formed on the inner wall of the culture dishes. The inner wall of the culture dishes used was 40 cm. 2 The treatment dosage was 1 μg / cm³. 2 Ten first-generation nymphs (mixed sexes) of American dog ticks were placed in each petri dish, and two petri dishes were combined. The joints were sealed with tape to prevent escape, and the dishes were stored in a constant temperature chamber at 25°C. The number of dead ticks was checked after 24 hours, and the mortality rate was calculated. The experiment was repeated three times. Test results: Compounds 1, 2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 27, 28, 29, 30, 31, 32, 40, 41, 42, 43, 44, and 45 showed mortality rates of over 70%.

Claims

1. A phenylpyrazole compound, characterized in that, The structure of the phenylpyrazole compounds is shown in general formula I: In general formula I: W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl; W2 is selected from fluorine or trifluoromethyl; Y1 is selected from hydrogen or fluorine; Y2 is selected from halogens, C1-C6 haloalkyl groups, or C1-C6 haloalkoxy groups; R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R2 is selected from hydrogen or cyano; It may be a stereoisomer of a compound of general formula I; Or it may be a salt of a compound of general formula I; It may be a salt of a stereoisomer of a compound of general formula I.

2. The phenylpyrazole compound according to claim 1, characterized in that, In general formula I: W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl; W2 is selected from fluorine or trifluoromethyl; Y1 is selected from hydrogen or fluorine; Y2 is selected from chlorine, bromine, iodine, C1-C3 haloalkyl or C1-C3 haloalkoxy; R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C6 cycloalkyl; R2 is selected from hydrogen or cyano; It may be a stereoisomer of a compound of general formula I; Or it may be a salt of a compound of general formula I; It may be a salt of a stereoisomer of a compound of general formula I.

3. The phenylpyrazole compound according to claim 2, characterized in that, In general formula I: W1 is selected from fluorine, trifluoromethyl, or pentafluoroethyl; W2 is selected from fluorine or trifluoromethyl; Y1 is selected from hydrogen or fluorine; Y2 is selected from chlorine, bromine, iodine, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R2 is selected from hydrogen or cyano; It may be a stereoisomer of a compound of general formula I; Or it may be a salt of a compound of general formula I; It may be a salt of a stereoisomer of a compound of general formula I.

4. The phenylpyrazole compound according to claim 1, characterized in that, In general formula I: when W1 and W2 are selected from trifluoromethyl, the phenylpyrazole compounds are selected from the compounds in Table 1, which have the structure of general formula I and Y1, Y2, R1 and R2 as shown in Table 1: Table 1 5. The phenylpyrazole compound according to claim 1, characterized in that, In general formula I: when W1 and W2 are selected from trifluoromethyl, the phenylpyrazole compounds are selected from the compounds in Table 2, which have the structure of general formula I and Y1, Y2, R1 and R2 are as shown in Table 2: Table 2 6. The phenylpyrazole compound according to any one of claims 1-5, characterized in that, Salts of compounds of general formula I include salts formed by compounds of general formula I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, trifluoroacetic acid, oxalic acid, malonic acid, methanesulfonic acid, 4-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, maleic acid, salicylic acid, tartaric acid, or citric acid. And / or, salts of stereoisomers of Formula I include: salts formed by stereoisomers of Formula I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, trifluoroacetic acid, oxalic acid, malonic acid, methanesulfonic acid, 4-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, maleic acid, salicylic acid, tartaric acid, or citric acid.

7. A compound, said compound being an intermediate for preparing a phenylpyrazole compound as described in any one of claims 1-5, characterized in that, The compound has the structure shown in general formula IV: In general formula IV: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5.

8. A compound, said compound being an intermediate in the preparation of the compound of claim 7, characterized in that, The compound has the structure shown in general formula V: In general formula V: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5.

9. A compound, said compound being an intermediate in the preparation of the compound of claim 8, characterized in that, The compound has the structure shown in general formula VII: In general formula VII: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5; Y4 is selected from C1-C6 alkyl groups.

10. A compound, said compound being an intermediate in the preparation of the compound of claim 9, characterized in that, The compound has the structure shown in general formula IX: In general formula IX: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5; Y3 is selected from Cl, Br, or I.

11. A compound, said compound being an intermediate for the preparation of the compound of claim 10, characterized in that, The compound has the structure shown in the general formula X: In general formula X: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5.

12. A compound, said compound being an intermediate for the preparation of the compound of claim 11, characterized in that, The compound has the structure shown in general formula XI: In general formula XI: The definitions of W1, W2, Y1, and Y2 are as defined in any one of claims 1-5.

13. Use of a phenylpyrazole compound according to any one of claims 1-6 in the preparation of insecticides and / or acaricides.

14. The use according to claim 13, characterized in that: The insecticide and / or acaricide are used to control one or more of armyworms, diamondback moths, and spider mites.

15. An insecticide or acaricide formulation, characterized in that: The insecticide or acaricide formulation contains a phenylpyrazole compound as described in any one of claims 1-6 as an active ingredient, and also contains one or more excipients; optionally, the amount of the phenylpyrazole compound as described in any one of claims 1-6 in the insecticide or acaricide formulation is 0.1 to 99% by weight, and more optionally 0.5 to 90% by weight.

16. An insecticide composition or acaricide composition, characterized in that: The mixture includes the phenylpyrazole compounds as described in any one of claims 1-6 and other active compounds, wherein the other active compounds are selected from one or more of insecticides, poison baits, disinfectants, acaricides, nematicides, fungicides, growth regulators, and herbicides.

17. A method for controlling agricultural or forestry pests and / or mites, characterized in that: Apply an effective dose of the material to the pests or mites that need to be controlled, or to their growth medium, wherein the material is selected from one or more of the following: The phenylpyrazole compound according to any one of claims 1-6; The insecticide or acaricide formulation according to claim 15; The insecticide composition or acaricide composition according to claim 16.

18. Use of a phenylpyrazole compound according to any one of claims 1-6 in the preparation of an animal parasite control agent.

19. The use according to claim 18, characterized in that: The animal parasite control agent is used to control one or more of cat fleas and American ticks.

20. An animal parasite control agent, characterized in that: The animal parasite control agent contains a phenylpyrazole compound as described in any one of claims 1-6 as an active ingredient, and also contains one or more excipients; optionally, the amount of the phenylpyrazole compound as described in any one of claims 1-6 in the animal parasite control agent is 1 to 80% by weight.

21. A composition for the prevention and control of animal parasites, characterized in that: The mixture comprises the phenylpyrazole compounds as described in any one of claims 1-6 and other animal parasite control active compounds, wherein the other animal parasite control active compounds are selected from one or more of acaricides, insecticides, parasiteicides, and antimalarial agents.

22. A method for controlling animal parasites, characterized in that: Includes the following steps: An effective dose of the material is applied to the animal parasite or its growth medium that needs to be controlled, wherein the material is selected from one or more of the following: The phenylpyrazole compound according to any one of claims 1-6; The animal parasite control agent according to claim 20; The animal parasite control composition according to claim 21.

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