Aromatic heterocycle substituted amide compound as well as preparation method and application thereof

Abstract

The invention provides an aromatic heterocycle substituted amide compound as well as a preparation method and application thereof. The amide compound has a structure as shown in a formula I which is described in the specification. The aromatic heterocyclic ring substituted amide compound provided by the invention can have high insecticidal activity at a low dosage; and due to good effect under low dosage, the medicine dosage is reduced, environmental protection is facilitated, and the application prospect is wide.

Description

Technical Field

[0001] The present invention belongs to the field of insecticides, and particularly relates to an amide compound substituted with an aromatic heterocycle, a preparation method thereof, and an application thereof. Background Art

[0002] In crop production such as agriculture and horticulture, the damage caused by pests and the like is still very significant. Due to the resistance of pests to existing insecticides and the environmental unfriendliness of existing pesticides, there has always been a need to develop new insecticides with better activity, lower dosage, and more environmentally friendly.

[0003] The insecticidal activity of amide compounds has been reported. For example, CN102119143A discloses compounds KC1 and KC2 (i.e., compounds 17-1150 and 7-1621 in CN102119143A) and their insecticidal activity. These disclosed compounds have insecticidal activity, however, the insecticidal effect is not good or the quick-acting property is not good at low doses.

[0004]

[0005] In this field, it is still necessary to actively develop new insecticides that can have quick-acting property and high activity at low doses to meet the needs of agriculture and forestry. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide an amide compound substituted with an aromatic heterocycle, a preparation method thereof, and an application thereof, and in particular to provide an amide compound containing a furan ring, a thiophene ring, a 6-chloropyridine ring, a 5-chlorothiazole ring, a 5-chlorothiophene ring or a pyridazine ring, a preparation method thereof, and an application thereof. The amide compound has a good insecticidal effect at low doses, and has a low dosage, which is more conducive to environmental protection.

[0007] To achieve this purpose, the present invention adopts the following technical solutions:

[0008] On the one hand, the present invention provides an amide compound substituted with an aromatic heterocycle, and the amide compound has a structure shown in the following formula I:

[0009]

[0010] In formula I,

[0011] Q is selected from one of the following Q1, Q2, Q3, Q4 or Q5:

[0012]

[0013] Z1, Z2, Z3, Z4, and Z5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, or C1-C6 haloalkylsulfonyl;

[0014] Y is selected from one of the following Y1, Y2, Y3, Y4, Y5, or Y6:

[0015]

[0016] X is selected from chlorine, bromine, or iodine;

[0017] A is selected from N, C-F, or C-H;

[0018] R1 is selected from hydrogen or fluorine;

[0019] R2 is selected from difluoromethoxy, trifluoromethyl, or a halogen atom;

[0020] W1 and W2 are each independently an oxygen atom or a sulfur atom.

[0021] In the present invention, as a preferred technical solution, Z1, Z2, Z3, Z4, and Z5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl, or trifluoromethylsulfonyl; Y is selected from one of Y1, Y2, Y3, Y4, Y5, or Y6; X is selected from chlorine, bromine, or iodine; A is selected from N, C-F, or C-H; R1 is selected from hydrogen or a fluorine atom; R2 is selected from difluoromethoxy or a bromine atom; W1 and W2 are selected from oxygen.

[0022] As a further preferred technical solution of the present invention, the aromatic heterocyclic ring-substituted amide compound is any one of the compounds shown in Table 1 having the general formula I as follows.

[0023]

[0024] Table 1

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] It should be noted that "H" represents a hydrogen atom, "O" represents an oxygen atom, "N" represents a sulfur atom, "S" represents a sulfur atom, "F" represents a fluorine atom, "Cl" represents a chlorine atom, "Br" represents a bromine atom, "I" represents an iodine atom, "CF3" represents a trifluoromethyl group, and "OCF2H" represents a difluoromethoxy group.

[0043] In the present invention, as a particularly preferred technical solution, the amide compound substituted with an aromatic heterocycle is any one selected from the following compounds:

[0044]

[0045] The numbers of the compounds correspond to the numbers of the compounds in Table 1.

[0046] As used herein, the term "alkyl" refers to an alkyl group in linear or branched form, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and other groups. Haloalkyl refers to a group in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms. Alkoxy refers to a group in which an oxygen atom is connected to the end of an alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and the like. Haloalkoxy refers to a group in which one or more hydrogen atoms on the alkoxy group are replaced by halogen atoms. Halogen is F, Cl, Br or I.

[0047] As used herein, the term "C1-C6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl and the like. The term "C1-C6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy and the like. "C1-C6 haloalkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms with halogen atom substitution, including, without limitation, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl and the like. "C1-C6 haloalkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms with halogen atom substitution, including, without limitation, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like. As used herein, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. As used herein, the term "C3-C8 halocycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms with halogen substitution on the ring, including, without limitation, 1-chlorocyclopropyl, 1-fluorocyclopropyl, perfluorocyclopropyl and the like

[0048] In the present invention, C1-C6, C3-C8, etc. before the specific group represent the number of carbon atoms contained in the group. For example, C1-C6 represents a group in which the number of carbon atoms can be 1, 2, 3, 4, 5 or 6, and C3-C8 represents a group in which the number of carbon atoms can be 3, 4, 5, 6, 7 or 8, and so on.

[0049] The compound of general formula I of the present invention can be prepared by the following method. Unless otherwise specified, the definitions of each group in the reaction formula are the same as above.

[0050] Preparation method 1:

[0051] The structure of the compound of general formula I of the present invention is as follows and can be prepared by the following method:

[0052]

[0053] Among them, R1 is selected from hydrogen and fluorine; LG is selected from fluorine, chlorine, bromine, C1-C 12 alkoxy, C1-C 12 alkyloxycarbonyloxy or C1-C 12 alkylcarbonyloxy; Hal is selected from fluorine, chlorine, bromine or iodine.

[0054] 1-(i): The compound of general formula III reacts with the compound of general formula IV to obtain the compound of general formula V.

[0055] In the present invention, the molar ratio of the compound of general formula III to the compound of general formula IV in step 1-(i) is 0.5-2:1, and the reaction is carried out in the presence of substances such as reducing agents. The temperature of the reaction is greater than or equal to -20°C and less than or equal to the boiling point of the reaction solvent. The reaction time is 0.5-48 hours.

[0056] 1-(ii): The compound of general formula V reacts with the compound of general formula VI to obtain the compound of general formula VII.

[0057] In the present invention, the molar ratio of the compound of general formula V to the compound of general formula VI in step 1-(ii) is 0.5-2:1, and the reaction is carried out in the presence of basic substances such as organic bases and / or inorganic bases. The temperature of the reaction is greater than or equal to -10°C and less than or equal to the boiling point of the reaction solvent. The reaction time is 0.5-48 hours.

[0058] 1-(iii): The compound of general formula VII is hydrolyzed to obtain the compound of general formula VIII.

[0059] In step 1-(iii), the compound of general formula VII is hydrolyzed in the presence of a basic substance to prepare the compound of general formula VIII.

[0060] 1-(iv): The compound of general formula VIII undergoes a substitution reaction to obtain the compound of general formula II.

[0061] In this step, by a known method, the compound of general formula VIII is reacted with a compound containing an LG group such as thionyl chloride, oxalyl chloride or triphosgene, etc., and then the compound represented by general formula II is prepared.

[0062] 1-(v): The compound of general formula II reacts with the compound of general formula IX to obtain the compound of general formula I

[0063] In the present invention, the molar ratio of the compound of general formula II to the compound of general formula IX is 0.5-2:1, and the reaction is carried out in the presence of a basic substance, and the basic substance is an organic base and / or an inorganic base.

[0064] The solvent for the reaction described in Step 1-(v) is any one or a combination of at least two of halogenated hydrocarbons, aromatic hydrocarbons, linear or cyclic ethers, esters, ketones, nitriles or aprotic polar inert solvents. The reaction temperature is greater than or equal to -70 °C and less than or equal to the boiling point of the reaction solvent. The reaction time is 0.5 - 48 hours.

[0065] Preparation method 2:

[0066] The general formula I compound of the present invention can be prepared by another method as follows:

[0067]

[0068] 2-(i): The general formula XI compound is obtained by subjecting the general formula X compound to a substitution reaction

[0069] That is, in this step, by a known method, the general formula X compound is reacted with thionyl chloride, oxalyl chloride, triphosgene, etc., and then a compound represented by the general formula XI containing an LG group is prepared.

[0070] 2-(ii): The general formula XII compound is obtained by reacting the general formula XI compound with the general formula IX compound.

[0071] The compound represented by the general formula XI is reacted with the compound represented by the general formula IX under the same conditions as described in 1-(v) to prepare the compound represented by the general formula XII.

[0072] 2-(iii): The general formula XIII compound is obtained by subjecting the general formula XII compound to a reduction reaction

[0073] The aromatic carboxylic acid amide derivative having a nitro group represented by the general formula XII can be converted into an aromatic carboxylic acid amide derivative having an amino group represented by the general formula XIII through a reduction reaction. Examples of the reduction reaction include a method using a hydrogenation reaction and a method using a metal compound (such as stannous chloride) or a metal (zinc powder, iron powder, etc.).

[0074] The method using a hydrogenation reaction can be carried out in a suitable solvent in the presence of a catalyst under normal pressure or pressure in a hydrogen atmosphere. Examples of the catalyst in the hydrogenation reaction include palladium catalysts such as palladium-carbon, cobalt catalysts, ruthenium catalysts, platinum catalysts, etc. Examples of the solvent include alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene and toluene; linear or cyclic ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate.

[0075] The method using a metal compound or a metal is carried out in any one or a mixed solvent of at least two of methanol, ethanol or ethyl acetate.

[0076] 2-(iv): Reacting the compound of general formula XIII with the compound of general formula IV to obtain the compound of general formula XIV.

[0077] React the compound represented by general formula XIII with the compound represented by general formula IV under the same conditions as described in step 1-(i), and further prepare the compound represented by general formula XII.

[0078] 2-(v): Reacting the compound of general formula XIV with the compound of general formula VI to obtain the compound of general formula I.

[0079] React the compound represented by general formula XIV with the compound represented by general formula VI under the same conditions as described in step 1-(ii), and further prepare the compound represented by general formula XII.

[0080] On the other hand, the present invention also provides an intermediate for preparing the amide compound as described above, which has the structure shown in formula XIV:

[0081]

[0082] Wherein X, Y, A, W2, R1 and R2 have the same defined ranges as in the compound of general formula I, and will not be elaborated herein.

[0083] In the present invention, the preparation method of the intermediate compound of formula XIV has been involved when describing the preparation method of formula I above, and will not be elaborated herein.

[0084] In the present invention, representative compounds of the intermediate compound of formula XIV of the compounds of the present invention are shown in Table 2, but the intermediate compounds of the present invention are not limited to the compounds shown in Table 2.

[0085] Table 2

[0086]

[0087] On the other hand, the present invention provides the tautomer, enantiomer, diastereomer or salt of the amide compound as described above.

[0088] In the present invention, the tautomer, enantiomer, diastereomer or salt of the amide compound can also exert the same effect as the amide compound, and has good insecticidal effect and quick efficacy at low doses.

[0089] On the other hand, the present invention provides the application of the amide compound as described above in preventing and controlling pests and nematodes in the fields of agriculture, forestry and horticulture.

[0090] The amide compounds of the present invention are suitable for controlling various agricultural and forestry, horticultural pests, sanitary pests and nematodes that harm rice, corn, wheat, potatoes, fruit trees, vegetables, other crops and flowers, etc.

[0091] In the present invention, the pests include Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, spider mite pests and nematodes, mosquitoes, flies, ants, etc.

[0092] Preferably, the pests include but are not limited to: Helicoverpa armigera, Plutella xylostella, Spodoptera exigua, Spodoptera litura, Pieris rapae, Chilo suppressalis, Tryporyza incertulas, Sesamia inferens, Spodoptera frugiperda, Cnaphalocrocis medinalis, Thrips oryzae, Frankliniella occidentalis, Thrips palmi, Thrips tabaci, Thrips zingiberis, Thrips mangiferae, Myzus persicae, Aphis gossypii, Aphis medicaginis, Aphis citricola, Sitobion avenae, flea beetles, stink bugs, Laodelphax striatellus, Nilaparvata lugens, Sogatella furcifera, termites, mosquitoes and flies, Tetranychus cinnabarinus, Panonychus citri.

[0093] The compounds of the present invention have a wide range of applications. The plants or ranges to which they are applied mainly include the following categories: fruits and vegetables, such as cucumbers, loofahs, watermelons, melons, pumpkins, hanging melons, spinach, celery, cabbages, Chinese cabbages, gourds, peppers, eggplants, tomatoes, onions, gingers, garlics, leeks, asparagus lettuce, kidney beans, cowpeas, broad beans, radishes, carrots, potatoes, yams; cereals, such as wheat, barley, corn, rice, sorghum; fruit trees, such as apples, pears, bananas, citrus fruits, grapes, lychees, mangoes; flowers, such as peonies, roses, anthuriums; oil crops, such as peanuts, soybeans, rapeseed, sunflowers, sesame seeds; sugar crops, such as beets, sugar canes; other crops, such as strawberries, potatoes, sweet potatoes, tobacco and tea; horticulture, forestry, household hygiene, public health areas, etc.; the above-listed plants or ranges do not limit the scope of use of the amide compounds of the present invention.

[0094] On the other hand, the present invention provides an insecticide composition, which includes an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient is the amide compound as described above.

[0095] The composition of the present invention can be applied in the form of a preparation. The compound of general formula I is dissolved or dispersed in a carrier or formulated into a preparation so as to be more easily dispersed when used as an insecticide.

[0096] In the present invention, the insecticide composition can be made into dosage forms such as wettable powders, suspensions, emulsifiable concentrates or emulsions.

[0097] The insecticide composition of the present invention can be used in the fields of agriculture, forestry, hygiene, etc.

[0098] Preferably, in the pesticide composition, the weight percentage of the active ingredient is 1-99%, such as 1%, 10%, 20%, 35%, 55%, 75%, 95% or 99%.

[0099] Preferably, the agrochemically acceptable carrier includes a surfactant.

[0100] In the present invention, the surfactant is an ionic surfactant or a non-ionic surfactant.

[0101] The surfactant includes an emulsifier, a dispersant or a wetting agent. The emulsifier can be polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene fatty amine, and commercially available emulsifiers (agricultural emulsifier 2201B, agricultural emulsifier 0203B, agricultural emulsifier 100#, agricultural emulsifier 500#, agricultural emulsifier 600#, agricultural emulsifier 600-2#, agricultural emulsifier 1601, agricultural emulsifier 2201, agricultural emulsifier NP-10, agricultural emulsifier NP-15, agricultural emulsifier 507#, agricultural emulsifier OX-635, agricultural emulsifier OX-622, agricultural emulsifier OX-653, agricultural emulsifier OX-667, ning emulsifier 36#, etc.). The dispersant includes sodium lignin sulfonate, Nekal, calcium lignin sulfonate, methylnaphthalene sulfonic acid formaldehyde condensate, etc. The wetting agent includes sodium lauryl sulfate, sodium dodecyl benzene sulfonate, alkyl naphthalene sulfonate, etc.

[0102] Preferably, the agrochemically acceptable carrier includes a solid carrier and / or a liquid carrier.

[0103] Preferably, the solid carrier includes natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicate such as talc; magnesium aluminum silicate such as kaolinite, kaolin, montmorillonite and mica; white carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; amine salts such as ammonium sulfate, hexamethylenediamine. The liquid carrier includes water and organic solvents. When water is used as a solvent or diluent, the organic solvent can also be used as an adjuvant or an antifreeze additive. Suitable organic solvents include aromatic hydrocarbons such as xylene, toluene, etc.; chlorinated hydrocarbons, such as chlorobenzene, vinyl chloride, chloroform, dichloromethane, etc.; aliphatic hydrocarbons, such as petroleum fractions, cyclohexane, light mineral oil; alcohols, such as isopropyl alcohol, butanol, ethylene glycol, glycerol and cyclohexanol, etc.; and their ethers and esters; and ketones, such as acetone, cyclohexanone, and dimethylformamide and N-methylpyrrolidone.

[0104] During the preparation of the pesticide composition, the active ingredient can be mixed with the liquid carrier and / or the solid carrier, and at the same time, a surfactant (such as an emulsifier, a dispersant, a stabilizer, a wetting agent) can be added, and other auxiliaries (such as a binder, an antifoaming agent, an oxidant, etc.) can also be added.

[0105] On the other hand, the present invention provides a method for controlling pests, which method comprises applying an effective dose of the amide compound or insecticide composition as described above to the pests to be controlled or the medium on which they grow.

[0106] Preferably, the effective dose is 7.5 - 1000 g per hectare, such as 7.5 g, 50 g, 100 g, 180 g, 250 g, 350 g, 450 g, 600 g, 800 g or 1000 g; more preferably, the effective dose is 15 - 600 g per hectare.

[0107] The composition of the present invention can be applied to pests or their growth medium in the form of a formulation. When the general formula compound I is used as an active ingredient and dissolved or dispersed in a carrier or formulated into a formulation for easier dispersion as an insecticide. For example: these chemical formulations can be formulated into various liquid agents, emulsifiable concentrates, suspension concentrates, aqueous suspension concentrates, microemulsions, emulsions, aqueous emulsion concentrates, powders, wettable powders, soluble powders, granules, water-dispersible granules or capsules.

[0108] For certain applications, such as in agriculture, one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers, etc. can be added to the insecticidal composition of the present invention, thereby additional advantages and effects can be produced.

[0109] Compared with the prior art, the present invention has the following beneficial effects:

[0110] The amide compound of the present invention has a remarkable effect on controlling pests, nematodes in the fields of agriculture and forestry and pests in the sanitation field, and can take effect faster at a low concentration of 0.1 - 1 ppm: it can exhibit good insecticidal activity one day after application, and can reach >90% insecticidal activity within 3 days, thereby reducing the harm caused by excessive drug concentration to plants, the environment and humans, and also resulting in less drug residue during application, which is more conducive to environmental protection and ecological civilization. Detailed Embodiments

[0111] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations of the present invention. Unless otherwise specified, when performing nuclear magnetic resonance hydrogen spectrum test characterization on the compounds in the embodiments and the present invention, the corresponding samples are all dissolved in deuterated dimethyl sulfoxide (DMSO-d6), and the hydrogen spectrum data are obtained by using a 400 MHz nuclear magnetic resonance spectrometer, and the chemical shift unit is ppm (i.e., δ: ppm); the eluent for column chromatography purification is prepared according to the volume ratio of the indicated n-hexane (abbreviation: HEX): ethyl acetate (abbreviation: EA).

[0112] Synthesis Examples

[0113] Synthesis Example 1

[0114] Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-6-(N-(furan-2-ylmethyl)benzamido)picolylamide (Preparation of Compound 1):

[0115] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-6-((furan-2-ylmethyl)amino)picolylamide

[0116]

[0117] Dissolve 6-amino-N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)picolylamide (5.26 g, 10.0 mmol) in 1,2-dichloroethane (100 mL). Successively add furan-2-carbaldehyde (1.01 g, 10.5 mmol) and acetic acid (3.60 g, 60 mmol). Stir at room temperature for 1 h, then add sodium triacetoxyborohydride (6.36 g, 30.0 mmol). Monitor the reaction by TLC until completion. Adjust the reaction mixture to pH 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (100 mL). Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and purify the residue by column chromatography (HEX:EA = 20:1) to obtain a white solid (5.02 g, yield 82.8%).

[0118] 1 H NMR: 10.20 (s, 1H), 7.95 - 7.35 (m, 5H), 7.33 (t, J = 72.8 Hz, 1H), 7.26 (d, J = 6.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.47 - 6.27 (m, 2H), 4.67 (d, J = 5.6 Hz, 2H).

[0119] (2) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-6-(N-(furan-2-ylmethyl)benzamido)picolylamide

[0120]

[0121] To a solution of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-6-((furan-2-ylmethyl)amino)pyridine-3-carboxamide (0.16 g, 0.26 mmol) in acetonitrile (5 mL), potassium iodide (18 mg, 0.11 mmol) and benzoyl chloride (45 mg, 0.32 mmol) were added successively. The reaction was carried out at 82 °C for 6 h. After the reaction mixture was cooled to room temperature, it was diluted with 30 mL of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give a yellow liquid (0.14 g, yield 74.9%).

[0122] of Compound 1 1 H NMR: 10.27 (s, 1H), 8.00 - 7.37 (m, 9H), 7.36 (t, J = 72.8 Hz, 1H), 7.32 - 6.29 (m, 3H), 5.45 (s, 2H).

[0123] Synthesis Example 2

[0124] Preparation of N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluoro-3-(N-(furan-2-ylmethyl)benzamide) (Compound 8):

[0125] (1) Synthesis of N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluoro-3-((furan-2-ylmethyl)amino)benzamide

[0126]

[0127] 3-Amino-N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluorobenzamide (1.00 g, 1.8 mmol) was dissolved in 1,2-dichloroethane (25 mL). Furan-2-carbaldehyde (0.16 g, 1.7 mmol) and acetic acid (0.66 g, 10.8 mmol) were added successively. The mixture was stirred at room temperature for 1 h, and then sodium triacetoxyborohydride (1.2 g, 5.4 mmol) was added. The reaction was monitored by TLC until completion. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (HEX:EA = 7:1) to give a white solid (0.37 g, yield 68.1%).

[0128] 11H NMR: 10.40 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 12.0 Hz, 2H), 7.62–7.53 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.33–7.11 (m, 3H), 6.40 - 6.37 (m, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.39 (s, 2H).

[0129] (2) Synthesis of N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluoro-3-(N-(furan-2-ylmethyl)benzamide

[0130]

[0131] To a solution of N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluoro-3-((furan-2-ylmethyl)amino)benzamide (0.20 g, 0.31 mmol) in toluene (5 mL) were added successively potassium carbonate (0.87 g, 0.62 mmol) and benzoyl chloride (53 mg, 0.38 mmol), and the mixture was refluxed for 6 h. The reaction solution was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 6:1) to give a yellow liquid (0.08 g, yield 34.3%).

[0132] Of compound 8 1 1H NMR: 10.66 (s, 1H), 8.50 (s, 2H), 8.10–8.02 (m, 3H), 7.88 (s, 1H), 7.79 (s,1H), 7.59 (s, 1H), 7.36–7.30 (m, 3H), 6.38 - 6.30 (m, 2H), 5.07 (s, 2H).

[0133] Synthesis Example 3

[0134] Preparation of N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluoro-3-(N-(furan-2-ylmethyl)benzamide (Compound 81):

[0135] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-6-((thiophen-2-ylmethyl)amino)pyridinecarboxamide

[0136]

[0137] Dissolve 6-amino-N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)nicotinamide (5.26 g, 10.0 mmol) in 1,2-dichloroethane (100 mL). Sequentially add thiophene-2-carbaldehyde (1.18 g, 10.5 mmol) and acetic acid (3.60 g, 60 mmol). Stir at room temperature for 1 h, then add sodium triacetoxyborohydride (6.36 g, 30.0 mmol). Monitor the reaction by TLC until completion. Adjust the reaction mixture to pH 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (100 mL). Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and purify the residue by column chromatography (HEX:EA = 15:1) to obtain a yellow solid (4.95 g, yield 79.6%).

[0138] 1 H NMR: 10.20 (s, 1H), 7.93 - 7.30 (m, 5H), 7.32 (t, J = 72.8 Hz, 1H), 7.29 - 6.92 (m, 3H), 6.79 (d, J = 8.0 Hz), 4.85 (d, J = 5.6 Hz)

[0139] (2) Synthesis of N-(2,6-dibromo-4-(2,2,2-trifluoropropyl)phenyl)-4-fluoro-3-((furan-2-ylmethyl)amino)benzamide

[0140]

[0141] To a solution of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-((thiophen-2-ylmethyl)amino)nicotinamide (0.17 g, 0.29 mmol) in acetonitrile (5 mL), sequentially add potassium iodide (19 mg, 0.11 mmol) and benzoyl chloride (49 mg, 0.35 mmol). React at 82 °C for 5 h. Cool the reaction mixture to room temperature, dilute with 30 mL of ethyl acetate, wash successively with saturated aqueous sodium bicarbonate (30 mL) and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (PE:EA = 5:1) to obtain a white solid (0.15 g, yield 71.2%).

[0142] For compound 81 1 HNMR: 10.34 (s, 1H), 7.98 - 7.92 (m, 5H), 7.53 - 7.48 (m, 3H), 7.40 - 7.36 (m, 2H), 7.38 (t, J = 72.8 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.90 - 6.86 (m, 1H), 5.65 (s, 2H).

[0143] Synthesis Example 4

[0144] Preparation of N-(2,6-dibromo-4-(2,2,2-trifluoro-1-(trifluoromethyl)ethyl)phenyl)-4-fluoro-3-(N-(furan-2-ylmethyl)benzamide (Compound 164):

[0145] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoro-1-(trifluoromethyl)ethyl)phenyl)-6-(((2-chlorothiazol-5-yl)methyl)amino)picolylamide

[0146]

[0147] Dissolve 6-amino-N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoro-1-(trifluoromethyl)ethyl)picolylamide (2.63 g, 5.0 mmol) in 1,2-dichloroethane (50 mL). Sequentially add 2-chlorothiazole-5-carbaldehyde (0.78 g, 5.3 mmol) and acetic acid (1.80 g, 30 mmol). Stir at room temperature for 1 h, and add sodium triacetoxyborohydride (3.18 g, 15.0 mmol) in portions. Monitor the reaction by TLC until completion. Adjust the reaction solution to pH 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (60 mL). Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate, then concentrate under reduced pressure. Purify the residue by column chromatography (HEX:EA = 12:1) to obtain a yellow liquid (1.28 g, yield 38.9%).

[0148] 1 H NMR: 10.20 (s, 1H), 7.95 - 7.14 (m, 6H), 7.31 (t, J = 72.8 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.84 (d, J = 6.0 Hz, 2H).

[0149] (2) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoro-1-(trifluoromethyl)ethyl)phenyl)-6-(N-((2-chlorothiazol-5-yl)methyl)-4-fluorobenzamido)picolylamide

[0150]

[0151] To a solution of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-6-(((2-chlorothiazol-5-yl)methyl)amino)pyridinecarboxamide (0.17 g, 0.26 mmol) in acetonitrile (5 mL), potassium iodide (17 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (49 mg, 0.31 mmol) were added successively. The reaction was carried out at 82 °C for 6 hours. The reaction solution was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to obtain a white solid (0.14 g, yield 71.0%).

[0152] of Compound 164 1 HNMR: 10.35 (s, 1H), 7.97 (s, 1H), 7.88 - 7.82 (m, 2H), 7.59 (s, 1H), 7.56 (s, 1H), 7.51 - 7.44 (m, 2H), 7.38 (t, J = 72.8 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 6.4, 2.4 Hz, 1H), 5.62 (s, 2H).

[0153] Synthesis Example 5

[0154] Preparation of the synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-3-(N-((5-chlorothiophen-2-yl)methyl)-4-fluorobenzamido)-2-fluorobenzamide (212):

[0155] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-3-(((5-chlorothiophen-2-yl)methyl)amino)-2-fluorobenzamide

[0156]

[0157] Dissolve 3-amino-N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-2-fluorobenzamide (5.43 g, 10.0 mmol) in 1,2-dichloroethane (100 mL), and successively add 5-chlorothiophene-2-carbaldehyde (1.54 g, 10.5 mmol) and acetic acid (3.60 g, 60 mmol). Stir at room temperature for 1 h, and add sodium triacetoxyborohydride (6.36 g, 30.0 mmol) in portions. Monitor the reaction by TLC until completion. Adjust the reaction solution to pH 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (100 mL), wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (HEX:EA = 10:1) to obtain a white solid (4.89 g, yield 72.6%).

[0158] 1 H NMR: 10.31 (s, 1H), 7.90 (s, 1H), 7.61 - 7.47 (m, 1H), 7.35 (t, J = 72.8 Hz, 1H), 7.11 - 7.02 (m, 1H, Ar-H), 7.00 - 6.94 (m, 2H), 6.94 - 6.88 (m, 1H), 6.87~6.80 (m, 1H), 6.68 - 6.53 (m, 1H), 4.51 (d, J = 5.2 Hz, 2H).

[0159] (2) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-3-(N-((5-chlorothiophen-2-yl)methyl)-4-fluorobenzamido)-2-fluorobenzamide

[0160]

[0161] In a solution of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-3-(((5-chlorothiophen-2-yl)methyl)amino)-2-fluorobenzamide (0.20 g, 0.30 mmol) in acetonitrile (5 mL), successively add potassium iodide (20 mg, 0.12 mmol) and 4-fluorobenzoyl chloride (57 mg, 0.36 mmol), and react at 82 °C for 8 h. Cool the reaction solution to room temperature, dilute with 30 mL of ethyl acetate, wash successively with saturated aqueous sodium bicarbonate (30 mL) and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (PE:EA = 4:1) to obtain a white solid (0.16 g, yield 67.7%).

[0162] Of compound 212 1HNMR: 10.32 (s, 1H), 8.03–7.98 (m, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.57–7.51 (m, 2H), 7.44–7.38 (m, 3H), 7.32 (t, J = 72.8 Hz, 1H), 7.13–7.06 (m, 2H), 6.92 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 5.25~4.95 (m, 2H).

[0163] Synthesis Example 6

[0164] Preparation of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-3-(N-((6-chloropyridin-3-yl)methyl)benzamido)-2-fluorobenzamide (245):

[0165] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-3-(((6-chloropyridin-3-yl)methyl)amino)-2-fluorobenzamide

[0166]

[0167] Dissolve 3-amino-N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-2-fluorobenzamide (0.82 g, 0.15 mmol) in acetic acid (2.7 g, 45 mmol), add 6-chloronicotinaldehyde (0.26 g, 1.8 mmol), stir at room temperature for 1 h, and then add sodium triacetoxyborohydride (0.39 g, 1.8 mmol). Monitor the reaction by TLC until it is completed. Adjust the reaction solution to pH 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (100 mL). Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate, then concentrate under reduced pressure. Purify the residue by column chromatography (HEX:EA = 18:1) to obtain a yellow solid (0.46 g, yield 46.0%).

[0168] 1 H NMR: 10.31 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.06-7.99 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.33 (t, J = 72.8 Hz, 1H), 7.30-7.24 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 4.58 (s, 2H).

[0169] (2)Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-3-((N-((6-chloropyridin-3-yl)methyl)benzamido)-2-fluorobenzamide

[0170]

[0171] To a solution of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropan-2-yl)phenyl)-3-(((5-chlorothiophen-2-yl)methyl)amino)-2-fluorobenzamide (0.24 g, 0.36 mmol) in acetonitrile (8 mL), potassium iodide (24 mg, 0.14 mmol) and benzoyl chloride (60 mg, 0.43 mmol) were added successively, and the mixture was reacted at 82 °C for 8 h. The reaction solution was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to obtain a yellow solid (0.19 g, yield 69.1%).

[0172] Of compound 245 1 HNMR: 10.33 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.84 (dd, J = 8.4, 2.4 Hz, 1H), 7.55 - 7.45 (m, 4H), 7.41 - 7.33 (m, 3H), 7.32 (t, J = 72.8 Hz, 1H), 7.30 - 7.19 (m, 3H), 5.25 – 4.88 (m, 2H).

[0173] Synthesis Example 7

[0174] Preparation of 3-(N-((6-chloropyridin-3-yl)methyl)-4-cyanobenzamido)-N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluorobenzamide (253):

[0175] (1)Synthesis of 3-((6-chloropyridin-3-yl)methyl)amino)-N-(2,6-dibromo-4-(2,2,2-trifluoropropan-2-yl)phenyl)-4-fluorobenzamide

[0176]

[0177] 3-Amino-N-(2,6-dibromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl)-4-fluorobenzamide (3.00 g, 5.40 mmol) was dissolved in 1,2-dichloroethane (75 mL). 6-Chloronicotinaldehyde (0.48 g, 2.56 mmol) and acetic acid (1.98 g, 32.4 mmol) were added successively. The mixture was stirred at room temperature for 1 h, and then sodium triacetoxyborohydride (1.73 g, 8.1 mmol) was added. The reaction was monitored by TLC until completion. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (80 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (HEX:EA = 8:1) to give a yellow liquid (1.92 g, yield 52.3%).

[0178] 1 1H NMR: 10.37 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.03 (s, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 10.8 Hz, 2H), 7.20 (d, J = 9.2 Hz, 1H), 6.62 (s, 1H), 4.45 (s, 2H).

[0179] (2) Synthesis of 3-(N-((6-chloropyridin-3-yl)methyl)-4-cyanobenzamide)-N-(2,6-dibromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl)-4-fluorobenzamide

[0180]

[0181] To a solution of 3-((6-chloropyridin-3-yl)methyl)amino)-N-(2,6-dibromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl)-4-fluorobenzamide (0.2 g, 0.29 mmol) in toluene (5 mL), anhydrous K2CO3 (82 mg, 0.59 mmol) and 4-cyanobenzoyl chloride (64 mg, 0.38 mmol) were added successively. The mixture was refluxed for 8 h. The reaction solution was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate (30 mL) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give a brown liquid (0.16 g, yield 67.3%).

[0182] of compound 253 1HNMR: 10.59 (s, 1H), 8.36 (s, 1H), 8.07 (s, 3H), 8.01 (s, 1H), 7.86 (s, 2H), 7.77 (s, 2H), 7.57 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 5.13 (s, 2H).

[0183] Synthesis Example 8

[0184] Preparation of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-3-(N-((6-chloropyridin-3-yl)methyl)benzamido)-2-fluorobenzamide (280):

[0185] (1) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-6-(pyrimidin-5-ylmethyl)aminopyridinecarboxamide

[0186]

[0187] Dissolve 6-amino-N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)pyridinecarboxamide (0.90 g, 1.7 mmol) in acetic acid (20 mL), successively add pyrimidine-5-carbaldehyde (0.19 g, 1.7 mmol), stir at room temperature for 1 h, and add sodium triacetoxyborohydride (1.09 g, 5.1 mmol) in portions. Monitor the reaction by TLC until completion. Adjust the reaction solution to pH 8 with saturated aqueous sodium bicarbonate, extract with ethyl acetate (70 mL). Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (HEX:EA = 2:1) to obtain a yellow solid (0.36 g, yield 30.8%).

[0188] 1 H NMR: 10.13 (s, 1H), 9.05 (s, 1H), 8.88 (s, 2H), 7.92 (s, 1H), 7.61 (dd, J = 8.4, 7.2 Hz, 2H), 7.54 (s, 1H), 7.30 (t, J = 72.8 Hz, 1H), 7.28 (d, J = 6.7 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 6.1 Hz, 2H).

[0189] (2) Synthesis of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan-2-yl)phenyl)-6-(4-cyano-N-pyrimidin-5-ylmethyl)benzamidopyridinecarboxamide

[0190]

[0191] To a solution of N-(2-bromo-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-((pyrimidin-5-ylmethyl)amino)pyridinecarboxamide (0.14 g, 0.23 mmol) in acetonitrile (4 mL) were added 4-cyanobenzoyl chloride (45 mg, 0.27 mmol) and potassium iodide (18 mg, 0.11 mmol), and the mixture was refluxed for 2 h. The reaction solution was cooled to room temperature, diluted with 20 mL of ethyl acetate and 20 mL of water, and the organic phase was washed successively with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1) to give a yellow solid (0.05 g, yield 29.3%).

[0192] of Compound 280 1 HNMR: 10.48 (s, 1H), 9.61 (s, 1H), 9.46 (s, 1H), 8.27 (d, J = 8.4 Hz, 2H), 8.20–8.09 (m, 4H), 7.94 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.34 (t, J = 72.8 Hz, 1H), 5.00 (s, 2H).

[0193] Synthesis Example 9

[0194] Preparation of N-(2-chloro-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-(4-cyano-N-((pyrimidin-5-ylmethyl)benzamido)pyridinecarboxamide (281):

[0195] (1) Synthesis of N-(2-chloro-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-((pyrimidin-5-ylmethyl)amino)pyridinecarboxamide

[0196]

[0197] 6-Amino-N-(2-chloro-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)picolinamide (1.0 g, 2.1 mmol) was dissolved in acetic acid (10 mL). Pyrimidine-5-carbaldehyde (0.24 g, 2.3 mmol) was added successively, and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.32 g, 6.3 mmol) was added portionwise. The reaction was monitored by TLC until completion. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (70 mL), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (HEX:EA = 7:3) to give a yellow solid (0.75 g, yield 55.2%).

[0198] 1 1H NMR: 10.14 (s, 1H), 9.05 (s, 1H), 8.88 (s, 2H), 7.84 - 7.81 (m, 1H), 7.61 (dd, J = 8.4, 7.2 Hz, 2H), 7.53 - 7.48 (m, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 72.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.72 (s, 2H).

[0199] (2) Synthesis of N-(2-chloro-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-(4-cyano-N-pyrimidin-5-ylmethyl)benzamido)picolinamide

[0200]

[0201] To a solution of N-(2-chloro-6-(difluoromethoxy)-4-(2,2,2-trifluoropropyl)phenyl)-6-(pyrimidin-5-ylmethyl)amino)picolinamide (0.13 g, 0.23 mmol) in acetonitrile (5 mL) were added 4-cyanobenzoyl chloride (45 mg, 0.27 mmol) and potassium iodide (18 mg, 0.11 mmol) successively. The mixture was refluxed for 2 h. After cooling to room temperature, the reaction solution was diluted with 20 mL of ethyl acetate and 20 mL of water. The organic phase was washed successively with saturated aqueous sodium bicarbonate (30 mL) and saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (PE:EA = 1:1) to give a yellow solid (0.05 g, yield 31.1%).

[0202] Of compound 281 11H NMR: 10.19 (s, 1H), 9.06 (s, 1H), 8.89 (s, 2H), 7.91 (t, J = 7.8 Hz, 1H), 7.85 (s, 2H), 7.80 (d, J = 1.6 Hz, 1H), 7.79 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.55–7.52 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 72.8 Hz, 1H), 5.48 (s, 2H).

[0203] Some of the compounds in Table 1 were prepared by referring to the similar methods in Synthesis Examples 1-9. The NMR data of some of the compounds are given in Table 3 below.

[0204] Table 3

[0205]

[0206]

[0207]

[0208]

[0209] Other compounds of General Formula I of the present invention can be synthesized by referring to the above methods.

[0210] Formulation Example 1

[0211] In this example, the preparation of the preparation using Compound 1 of the present invention as a representative compound is as follows:

[0212] 30 parts by weight of Compound 1 of the present invention, 15 parts by weight of polyoxyethylene styryl phenyl ether, 10 parts by weight of phosphorous acid, and 45 parts by weight of xylene were uniformly mixed to obtain an emulsifiable concentrate with a concentration of 30% of Compound 1 of the present invention.

[0213] Formulation Example 2

[0214] In this example, the preparation of the preparation using Compound 16 of the present invention as a representative compound is as follows:

[0215] 20 parts by weight of Compound 16 of the present invention, 2 parts by weight of sodium dodecyl sulfate, 2 parts by weight of dialkyl sulfosuccinate, 1 part by weight of sodium salt of β-naphthalenesulfonic acid formaldehyde condensate, and 75 parts by weight of diatomaceous earth were uniformly stirred and mixed to obtain a wettable powder of 20% of Compound 16 of the present invention.

[0216] Formulation Example 3

[0217] In this example, the compound 65 of the present invention was used as a representative compound to prepare a preparation, as follows:

[0218] 30 parts by weight of the compound 65 of the present invention, 10 parts by weight of ethylene glycol, 6 parts by weight of nonylphenol polyoxyethylene ether, 10 parts by weight of sodium lignosulfonate, 10 parts by weight of carboxymethyl cellulose, 1 part by weight of silicone oil aqueous solution, and water was made up to 100 parts by weight to obtain a 30% suspending agent of the compound 65 of the present invention.

[0219] Biological Activity Test Example

[0220] The compound of the present invention obtained above was tested on various pests. Unless otherwise specified in the examples and the present invention: The sample preparation method was to weigh 10 mg of the original drug of the sample to be tested, dissolve it in 1 mL of DMF, prepare a 10000 ppm stock solution, and dilute the stock solution to the required concentration with 0.05% Tween-80 water for activity testing. The mortality rate was the mortality rate caused by the pest death at the test concentration of the compound, and the calculation formula was mortality rate (%) = number of dead insects / total number of insects * 100.

[0221] Test Example 1 Insecticidal activity of the compound against Tetranychus cinnabarinus

[0222] Cut single broad bean leaves with stems and insert them into a penicillin bottle filled with 20 mL of clear water. About 20 adult mites of Tetranychus cinnabarinus were inoculated on each leaf. After 24 h, check the number of adult mites at the beginning, and select single leaves with more than 15 mites for the test. Immerse the single leaf with adult mites in the liquid medicine for 10 s, take it out and dry it, and place it in an observation room for cultivation at a temperature of 20 - 26 °C, a light of 14 hL:10 hD, and a humidity of 40 - 60%. Investigate the number of dead and live mites 3 days after treatment and calculate the mortality rate.

[0223] When the concentration of the compounds 16, 48, 49, 70, 145, 151, 152, 154, 225, 232, 230, 233, 236, 267 of the present invention was 100 ppm, the mortality rate of Tetranychus cinnabarinus was > 90% 3 days after treatment.

[0224] According to the above method, compounds 151, 230 and 233 were selected and compared with KC1 for the insecticidal activity against Tetranychus cinnabarinus to compare the insecticidal activity. The test results are shown in Table 4.

[0225] Table 4 Comparison of the activities of the compounds of the present application, KC1 and KC2 against Tetranychus cinnabarinus

[0226]

[0227] It can be seen from Table 4 that compared with the existing compounds, the compounds of the present invention not only have greatly improved insecticidal activity, but also have the advantage that they can still exert good insecticidal effects after a large reduction in dosage.

[0228] Test Example 2 Insecticidal Activity of Compounds against Aphis medicaginis

[0229] In this example, the insecticidal activity test against Aphis medicaginis was carried out, and the specific method is as follows:

[0230] Preparation of 3-day-old nymphs: Cut the single leaf of broad bean with stem and insert it into a penicillin bottle (capacity 20 mL) filled with clear water. Transfer 5 adult aphids of Aphis medicaginis to each single leaf and cover it with a plastic cup with holes pricked. Remove the adult aphids after 24 h. Conduct a base number survey before the test, and select the single leaf with more than 15 nymphs for the test.

[0231] Insect dipping method: Immerse the single leaf of broad bean (with nymphs) in the medicinal liquid for 10 s, take it out and dry it, and repeat 3 times. Place it on the culture rack in the observation room and cover it with a plastic cup with holes pricked. Investigate the number of dead and live insects after 3 days.

[0232] The following compounds showed good insecticidal effects at a concentration of 100 ppm and 3 days after treatment, with the pest mortality rate > 90%: 65, 76, 260.

[0233] According to the above method, compounds 65, 76, and 260 were selected and compared with KC1 and KC2 for the insecticidal activity against Aphis medicaginis to compare the insecticidal activity. The test results are shown in Table 5.

[0234] Table 5 Comparison of the Insecticidal Activity of the Compounds of the Present Application with KC1 and KC2 against Aphis medicaginis

[0235] Pharmaceutical Concentration Mortality Rate / % (3 days after treatment) 65 100 ppm 96.88 76 100 ppm 94.04 260 100 ppm 100.00 KC1 400 ppm 0.00 KC2 400 ppm 0.00

[0236] It can be seen from Table 5 that compared with the existing compounds, the compounds of the present invention not only greatly improve the insecticidal activity, but also have the advantage of still being able to exert good insecticidal effects after a large reduction in dosage.

[0237] Test Example 3 Insecticidal Activity of Compounds against Plutella xylostella

[0238] The leaf disc feeding method was used for the activity test. Immerse the cabbage leaf discs in the medicinal liquid for 10 s, dry them and place them in a petri dish, with 4 discs in each dish, and put filter paper in the petri dish to keep moisture. Transfer 10 test insects of Plutella xylostella to each dish, and repeat 3 times. Place it in a light incubator at a temperature of 25 °C, with a light cycle of 14 hL:10 hD for cultivation. Investigate the number of dead insects of Plutella xylostella 3 days after treatment and calculate the mortality rate.

[0239] The test results are as follows:

[0240] Compounds 16, 171, 217, 225, 233, 245, 248, 261, 281 had a mortality rate ≥ 90% against Plutella xylostella at a concentration of 1 ppm and 3 days after treatment.

[0241] Compounds 41, 70, 145, and 230 had a mortality rate of ≥80% against Plutella xylostella at a concentration of 1 ppm, 3 days after treatment.

[0242] According to the above method, some compounds of the present invention were selected for parallel determination and comparison of the insecticidal activity against Plutella xylostella with KC1 and KC2. The test results are shown in Table 6.

[0243] Table 6 Comparison of the insecticidal activity of the compounds of the present invention with KC1 and KC2 against Plutella xylostella

[0244]

[0245] As can be seen from Table 6, compared with the existing compounds, Compound 230 of the present invention not only greatly improves the insecticidal activity, but also has the advantage of still being able to exert a good insecticidal effect after a large reduction in dosage.

[0246] Test Example 4 Insecticidal activity of the compounds against Mythimna separata

[0247] The activity test was carried out by the method of soaking corn seedlings for feeding. Cut the above-ground part of the fresh corn seedlings grown indoors, about 10 cm long, for standby. Immerse the corn seedlings in the liquid medicine for 10 s, dry them in the shade, and then cut them into leaf segments of 3 - 5 cm and place them in a petri dish, with 3 leaf segments in each dish. Add 10 third-instar larvae of Mythimna separata to each dish, and repeat 3 times. Place them in a light incubator at a temperature of 25 °C, with a light cycle of 14 h L:10 h D for cultivation. Investigate the number of dead insects 1, 2, and 3 days after treatment, and calculate the mortality rate.

[0248] Compounds 9, 93, 141, 212, 217, 230, 233, 234, 245, 248, 260, 261, 262, 267, and 281 had a mortality rate of ≥90% against Mythimna separata at a concentration of 1 ppm, 3 days after treatment.

[0249] Compounds 152, 164, 171, and 236 had a mortality rate of ≥80% against Mythimna separata at a concentration of 1 ppm, 3 days after treatment.

[0250] Compounds 233, 248, and 261 had a mortality rate of ≥90% against Mythimna separata at a concentration of 0.1 ppm, 3 days after treatment.

[0251] According to the above method, some compounds of the present invention were selected for parallel determination of the insecticidal activity against Mythimna separata with KC1 and KC2. The test results are shown in Table 7.

[0252] Table 7 Comparison of the insecticidal activity of the compounds of the present invention with KC1 and KC2 against Mythimna separata

[0253]

[0254] As can be seen from Table 7, compared with the existing compounds, the compounds of the present invention not only greatly improve the insecticidal activity, but also have the advantage that a good insecticidal effect can still be achieved after a substantial reduction in dosage.

[0255] The present invention uses the above embodiments to illustrate the amide compounds of the present invention, their preparation methods and applications. However, the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent substitution of each raw material of the products of the present invention, the addition of auxiliary components, and the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. An amide compound substituted with an aromatic heterocycle, characterized in that, The amide compound has the structure shown in the following formula I: In formula I, Q is selected from one of the following Q1, Q2, Q3, Q4 or Q5: Z1, Z2, Z3, Z4, Z5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; Y is selected from one of the following Y1, Y2, Y3, Y4, Y5 or Y6: X is selected from chlorine, bromine or iodine; A is selected from N, C-F or C-H; R1 is selected from hydrogen or fluorine; R2 is selected from difluoromethoxy, trifluoromethyl or a halogen atom; W1 and W2 are each independently an oxygen atom or a sulfur atom.

2. The aromatic heterocycle-substituted amide compound according to claim 1, wherein In formula I, Z1, Z2, Z3, Z4, Z5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl; Y is selected from one of Y1, Y2, Y3, Y4, Y5 or Y6; X is selected from chlorine, bromine or iodine; A is selected from N, C-F or C-H; R1 is selected from hydrogen or a fluorine atom; R2 is selected from difluoromethoxy or a bromine atom; W1 and W2 are selected from oxygen.

3. The aromatic heterocyclic ring-substituted amide compound according to claim 1, wherein In formula I, Z1, Z2, Z3, Z4, Z5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or trifluoromethylsulfonyl; Y is selected from one of Y1, Y2, Y3, Y4, Y5 or Y6; X is selected from chlorine, bromine or iodine; A is selected from N, C-F or C-H; R1 is selected from hydrogen or fluorine; R2 is selected from difluoromethoxy or a bromine atom; W1 and W2 are selected from oxygen.

4. The aromatic heterocyclic ring-substituted amide compound according to any one of claims 1-3, characterized in that, The amide compound is any one selected from the following compounds:

5. The tautomer, enantiomer, diastereomer or salt thereof of the aromatic heterocyclic ring-substituted amide compound according to any one of claims 1-4.

6. An intermediate compound for preparing the amide compound substituted with an aromatic heterocycle as described in any one of claims 1-5, characterized in that, It has the structure shown in the following formula II: In formula II, X is selected from chlorine, bromine or iodine; A is selected from N, C-F or C-H; R1 is selected from hydrogen or a fluorine atom; R2 is selected from difluoromethoxy, trifluoromethyl or a halogen atom; W2 is selected from an oxygen atom or a sulfur atom. Y is selected from one of the following Y1, Y2, Y3, Y4, Y5 or Y6:

7. Use of the aromatic heterocyclic ring-substituted amide compound according to any one of claims 1-4 or the tautomer, enantiomer, diastereomer or salt thereof of the aromatic heterocyclic ring-substituted amide compound according to claim 5 in controlling plant pests.

8. An insecticide composition, characterized in that, The pesticidal composition comprises an active ingredient and a pesticidally acceptable carrier, and the active ingredient is an amide compound as described in any one of claims 1-4 or a tautomer, enantiomer, diastereomer or salt of the amide compound as described in claim 5.

9. The pesticidal composition according to claim 8, characterized in that, The weight percentage content of the active ingredient in the pesticidal composition is 1-99%.

10. A method for controlling pests, characterized in that, The method is as follows: applying an effective dose of an amide compound substituted with an aromatic heterocycle as described in any one of claims 1-4 or a tautomer, enantiomer, diastereomer or salt of the amide compound substituted with an aromatic heterocycle as described in claim 5 or a pesticidal composition as described in claim 8 or 9 to a pest to be controlled or a medium on which the pest grows; Preferably, the effective dose is 7.5-1000 g per hectare; more preferably, the effective dose is 15-600 g per hectare.

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