Metadiamide compound as well as preparation method and application thereof

Abstract

The invention provides an m-diamide compound as well as a preparation method and application thereof. The m-diamide compound is a compound represented by a formula I, or a stereoisomer, a tautomer, an isotope derivative and a pesticide acceptable salt thereof. The m-diamide compound disclosed by the invention has high insecticidal activity, still has a good insecticidal effect under a low dosage, and is more beneficial to environmental protection; moreover, the insecticidal composition has excellent persistence and quick-acting property on killing pests, and does not easily generate cross resistance with existing m-diamide compounds; the plant safety is realized.

Description

Technical Field

[0001] This application belongs to the field of insecticides, specifically relating to a m-diamide compound, its preparation method, and its application. Background Technology

[0002] In crop production in agriculture, forestry, and horticulture, damage caused by pests remains significant. Due to pest resistance to existing pesticides and their environmental unfriendliness, there is still a need to develop new pesticides, especially highly effective, low-toxicity, and environmentally friendly ones.

[0003] As members of IRAC Group 30, m-diamid compounds act by antagonizing γ-aminobutyric acid (GABA) receptors. Unlike the widely used diamide compounds that face resistance issues, they are gradually becoming a new hot spot in the insecticide market, following neonicotinoids and diamides. However, current m-diamid compounds still suffer from low insecticidal activity.

[0004] In view of this, there is still a need in the field to develop new insecticides with high insecticidal activity to solve the pest control problems faced by agricultural, forestry and horticultural production. Summary of the Invention

[0005] The purpose of this application is to provide a m-diamide compound with high insecticidal activity, which still has a good insecticidal effect at low doses and is more environmentally friendly; moreover, it has excellent residual and rapid effect in killing pests, is not prone to cross-resistance with existing m-diamide compounds, and is plant safe.

[0006] To achieve the above objectives, in a first aspect, this application provides a meta-diamide compound, which is a compound represented by Formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pesticide-acceptable salt thereof:

[0007]

[0008] Wherein, A is an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted saturated, unsaturated or partially unsaturated heterocyclic group, or an optionally substituted aryl vinyl group;

[0009] The substituent on A is selected from one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino.

[0010] R1 is an H, a cycloalkyl-substituted alkyl group, or a cyano-substituted alkyl group;

[0011] W1 is either O or S;

[0012] W2 is either O or S;

[0013] R2 is H or an alkyl group;

[0014] R3 is H, halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamine.

[0015] R4 can be halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino.

[0016] The substituents on the optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamine groups are selected from one or more of halogen, amino, hydroxy, nitro, cyano, and mercapto groups;

[0017] n can be 0, 1, 2, 3, or 4.

[0018] In one set of embodiments, the cycloalkyl group is a C3-10 cycloalkyl group, the aryl group is a C6-14 aryl group, the heterocyclic group is a 3-10 membered heterocyclic group, and the alkyl group is a C1-8 alkyl group; preferably, the cycloalkyl group is a C3-6 cycloalkyl group, the aryl group is a C6-10 aryl group, the heterocyclic group is a 3-6 membered heterocyclic group, and the alkyl group is a C1-6 alkyl group.

[0019] In one set of embodiments, the halogen is fluorine, chlorine, or bromine.

[0020] In one set of embodiments, A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, or an optionally substituted C6-10 arylvinyl group. Preferably, the substituent on A is selected from one or more of halogens, cyano groups, C1-C6 alkyl groups, and halogenated C1-C6 alkyl groups.

[0021] In one set of embodiments, A is selected from one of the following groups:

[0022]

[0023] In one set of embodiments, R1 is H, a C3-C6 cycloalkyl-substituted C1-C6 alkyl, or a cyano-substituted C1-C6 alkyl; preferably, R1 is H, a C3-C4 cycloalkyl-substituted methyl, or a cyano-substituted methyl.

[0024] In one set of embodiments, A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, and R1 is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. Alternatively, A is an optionally substituted C6-C10 arylvinyl group, and R1 is H.

[0025] In one set of embodiments, R4 is a halogen; in another set of embodiments, n = 1, and R4 is located in the adjacent position of the two amide groups.

[0026] Furthermore, the compound represented by formula I is the same as the compound represented by formula IA:

[0027]

[0028] In one set of implementations, W1 is 0.

[0029] In one set of implementations, W2 is 0.

[0030] In one set of implementations, R2 is H.

[0031] In one set of embodiments, the compound represented by formula I is the same as the compound represented by formula IB:

[0032]

[0033] In one set of embodiments, R3 is H or a halogen, preferably H or bromine.

[0034] Furthermore, the compound represented by formula I is the same as the compound represented by formula IC:

[0035]

[0036] In one set of embodiments, the compound represented by formula I is the compound represented by formula IC:

[0037]

[0038] A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, and R1 is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group; or A is an optionally substituted C6-C10 aryl vinyl group and R1 is H.

[0039] Preferably, A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, and R1 is a C3-C4 cycloalkyl-substituted methyl group; or A is an optionally substituted phenyl vinyl group and R1 is H.

[0040] Specifically, the compound represented by Formula I is one of the following compounds, from Formula I-1 to Formula II-28:

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] Secondly, this application provides a method for preparing the aforementioned m-diamide compound, wherein when R1 and R3 are both H, the method includes the following steps:

[0047]

[0048] The preparation method of the aforementioned m-diamide compound, when R1 is H and R3 is not H, includes the following steps:

[0049]

[0050] The preparation method of the aforementioned m-diamide compound, when R1 is H and R3 is not H, includes the following steps:

[0051]

[0052] Preferably, R3 is a halogen, and the compound of formula II reacts with a metal halide to prepare the compound of formula III;

[0053] Or may further include the following steps:

[0054]

[0055] The preparation method of the aforementioned m-diamide compound, when R1 is not H and R3 is H, includes the following steps:

[0056]

[0057] Or may further include the following steps:

[0058]

[0059] X is a leaving group, preferably a halogen.

[0060] The preparation method of the aforementioned m-diamide compound, when neither R1 nor R3 is H, includes the following steps:

[0061] Or may further include the following steps:

[0062]

[0063] X is a leaving group, preferably a halogen.

[0064] The preparation method of the aforementioned m-diamide compound, when neither R1 nor R3 is H, includes the following steps:

[0065] Preferably, R3 is a halogen, and the compound of formula IV reacts with a metal halide to prepare the compound of formula V; or further includes the following steps:

[0066]

[0067] Or it may further include the following steps:

[0068]

[0069] X is a leaving group, preferably a halogen.

[0070] In one set of embodiments, the method for preparing the m-diamide compound further includes a step of preparing a compound of formula a or formula c:

[0071]

[0072] The definitions of the functional groups in the above schemes are as described above. The preparation process of each of the above schemes may include necessary protection and deprotection steps.

[0073] The preparation method of the aforementioned m-diamide compounds is described in detail below.

[0074] 1) Synthesis method of compound g (chlorination reaction)

[0075] Under chlorination conditions, a carboxylic acid compound is used to undergo a substitution reaction with a chlorinating reagent to obtain compound g.

[0076] In the above chlorination reaction, the chlorinating agent can be any chlorinating agent known in the art, such as thionyl chloride, oxaloyl chloride, phosphorus trichloride, phosphorus pentachloride, etc. The amount of chlorinating agent used, relative to the amount of carboxylic acid compound, is preferably 2-10 equivalents, more preferably 2-4 equivalents. The solvent for the chlorination reaction can be thionyl chloride directly, or dichloromethane, tetrahydrofuran, toluene, etc., can be added appropriately. The temperature of the chlorination reaction is preferably 40-100°C, more preferably 40-80°C. The time of the chlorination reaction is preferably 1-12 hours, more preferably within 4 hours.

[0077] 2) Synthetic methods (condensation reactions) of compounds of formula f or i

[0078] The synthetic method for obtaining compound f or i from compound g can be as follows: under alkaline conditions, compound g is subjected to a condensation reaction with an aniline compound of formula h or j to obtain compound f or i.

[0079] The base used in the above condensation reaction can be any acid-binding agent known in the art, such as one or more of sodium hydroxide, potassium carbonate, triethylamine, diethylamine, pyridine, and cesium carbonate, preferably triethylamine. The amount of the acid-binding agent used relative to the amount of compound g is preferably 1.1-1.5 equivalents, more preferably 1.1-1.2 equivalents. The solvent used in the condensation reaction can be toluene, chloroform, N,N-dimethylformamide, or dimethyl sulfoxide, etc. The temperature of the condensation reaction is preferably 80-110°C, more preferably 100-110°C. The time of the condensation reaction is preferably 1-6 hours, more preferably within 3-4 hours.

[0080] 3) Synthetic methods (reduction reactions) for compounds of formula a or c.

[0081] The synthetic method for obtaining compound a or c from compound f or i can be as follows: in the presence of a reducing agent, compound f or i is subjected to a reduction reaction to obtain compound a or c.

[0082] The reducing agent used in the above reduction reaction can be any reducing agent known in the art, such as one or more of stannous chloride, iron powder, and hydrogen, preferably stannous chloride. The amount of the reducing agent used, relative to the amount of compound f or i, is preferably 2-4 equivalents, more preferably 3-4 equivalents. The solvent used in the reduction reaction can be 1,4-dioxane, N,N-dimethylformamide, etc. The temperature of the reduction reaction is preferably 30-60°C, more preferably 50-60°C. The time of the reduction reaction is preferably 3-6 hours, more preferably within 5 hours.

[0083] 4) Synthetic methods for compounds of formula d or e (nucleophilic substitution reaction)

[0084] The synthetic method for obtaining compound d or e from compound a or c can be as follows: in the presence of a metal iodide, compound a or c undergoes a nucleophilic substitution reaction with R1-X to obtain compound d or e.

[0085] The metal iodide used in the above nucleophilic substitution reaction can be any metal iodide known in the art, such as one or more of sodium iodide, potassium iodide, zinc iodide, and cuprous iodide, preferably sodium iodide. The amount of the metal iodide used, relative to the amount of compound a or c, is preferably 1-3 equivalents, more preferably 1-2 or 1-1.5 equivalents. The solvent used in the nucleophilic substitution reaction can be N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, etc. The temperature of the nucleophilic substitution reaction is preferably 60-100°C, more preferably 80-100°C. The time of the nucleophilic substitution reaction is preferably 6-12 hours, more preferably within 10 hours.

[0086] 5) Synthetic methods for compounds of formulas II-V (condensation reactions)

[0087] The synthetic method for preparing formula II-V from compounds a, c, d, and e can be as follows: under alkaline conditions, compounds a, c, d, and e are subjected to a condensation reaction with the corresponding acyl chloride compounds to obtain compounds of formula II-V.

[0088] The base used in the above condensation reaction can be any acid-binding agent known in the art, such as one or more of sodium hydroxide, potassium carbonate, triethylamine, diethylamine, pyridine, and cesium carbonate, preferably triethylamine. The amount of the acid-binding agent used, relative to the amount of compounds a, c, d, and e, is preferably 1.1-1.5 equivalents, more preferably 1.1-1.2 equivalents. The solvent used in the condensation reaction can be toluene, chloroform, N,N-dimethylformamide, or dimethyl sulfoxide, etc. The temperature of the condensation reaction is preferably 80-110°C, more preferably 100-110°C. The time of the condensation reaction is preferably 1-6 hours, more preferably within 3 hours.

[0089] 6) Synthetic methods (substitution reactions) of formulas III and V

[0090] The synthetic method for preparing formulas III and V from compounds II and IV can be as follows: Compounds II and IV undergo an electrophilic substitution reaction in the presence of an oxidizing agent to obtain compounds III and V. Preferably, R3 is a halogen, and a metal halide is used for the reaction.

[0091] The oxidant used in the above substitution reaction can be any oxidant known in the art, such as one or more of sodium hypochlorite solution, hydrogen peroxide solution, and sodium chloride solution, preferably sodium hypochlorite solution. The amount of the oxidant used, relative to the amount of compounds II and IV, is preferably 1.1-1.5 equivalents, more preferably 1.1-1.2 equivalents. The solvent used in the substitution reaction can be dichloromethane, chloroform, N,N-dimethylformamide, or dimethyl sulfoxide, etc. The temperature of the substitution reaction is preferably 30-60°C, more preferably 50-60°C. The time of the substitution reaction is preferably 1-6 hours, more preferably within 3 hours.

[0092] In a third aspect, this application provides an insecticidal composition having at least one of the m-diamide compounds described in the first aspect of this application as an active ingredient; the insecticidal composition further comprises a pesticide-acceptable carrier and / or adjuvant.

[0093] The insecticidal composition of this application can be applied in the form of a formulation, wherein the m-diamid compound is dissolved or dispersed in a carrier as an active component or formulated into a formulation for easier dispersion when used as an insecticide. The insecticidal composition can be formulated into various dosage forms such as liquids, emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, emulsions, water-in-oil emulsions, powders, wettable powders, soluble powders, granules, water-dispersible granules, or capsules.

[0094] The insecticidal composition of this application may contain one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0095] In a fourth aspect, this application also provides the use of the m-diamid compound described in the first aspect or the insecticidal composition described in the third aspect in the control of pests, particularly in the control of plant pests; preferably for use in agriculture, forestry, horticulture, and sanitation. Preferably, an insecticidally effective amount of the m-diamid compound or the insecticidal composition described above is applied to plants, pests, and / or habitats.

[0096] In a fifth aspect, this application also provides a method for controlling pests, comprising applying an insecticidal effective amount of the meta-diamide compound of the first aspect or the insecticidal composition of the third aspect to plants and / or pests and / or habitats.

[0097] The pests described in this application include Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, Blattodea, mites, nematodes, etc., especially Lepidoptera, Coleoptera, and Diptera pests. Preferably, the pests include, but are not limited to, diamondback moth, rice stem borer, cotton bollworm, and corn stink bug.

[0098] The m-diamid compounds described in the first aspect of this application are suitable for controlling various agricultural, forestry, and horticultural pests, sanitary pests, and nematodes that harm plants. The m-diamid compounds described in the first aspect and the insecticidal compositions described in the third aspect of this application can be used in conjunction with one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0099] The beneficial effects of this invention are as follows:

[0100] This application provides a meta-diamide compound that exhibits particularly excellent insecticidal activity against pests such as diamondback moth, rice stem borer, cotton bollworm, and corn stink bug. It has a good effect on controlling Lepidoptera and Coleoptera, and its control effect is even better than some commercially available insecticides.

[0101] The m-diamide compounds described in this application still have good insecticidal effects at low doses, which is more conducive to environmental protection; moreover, they have excellent residual and rapid effects in killing pests and are not prone to cross-resistance with existing m-diamide compounds.

[0102] The m-diamide compounds described in this application maintain excellent insecticidal activity while still exhibiting high safety for corn and wheat. Detailed Implementation

[0103] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0104] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0105] Before describing the invention in detail, it should be understood that the terminology used herein is for describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the appended claims. For a more complete understanding of the invention described herein, the following terms are used, and their definitions are as follows. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0106] definition

[0107] Unless otherwise specified, the following terms used in this invention have the following definitions.

[0108] Features described or illustrated as part of one implementation or set of implementations may be used in another implementation or set of implementations to produce further implementations.

[0109] The “meta-diamide compounds” described in this application include compounds represented by Formula I, or their stereoisomers, tautomers, isotopic compounds, and pesticide-acceptable salts; and the preferred embodiments described in detail.

[0110] In this application, the ring group on This indicates that n R4s can be attached to any possible position on the cyclic group.

[0111] In this application, some of the substituents are... The location indicates the connection point.

[0112] Unless otherwise stated, “optional substitution” means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently substituted by a substituent, which is independently selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto, oxo, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamine; the substituent on the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups may be one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto, oxo, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamine; the substituent on the alkyl group is selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, and mercapto; when the substituent is selected as “oxo”, it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom.

[0113] The term "aryl" refers to an aromatic carbocyclic system containing 6-14 carbon atoms, preferably 6-10 carbon atoms, including monocyclic, bicyclic, and tricyclic systems. Examples of aryl groups include phenyl and naphthyl groups, such as 1-naphthyl, 2-naphthyl, 3-naphthyl, and 4-naphthyl.

[0114] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein the monocyclic, bicyclic, or tricyclic ring does not contain an aromatic ring, including bridged cycloalkyl, spirocyclic, and fused cycloalkyl groups. Preferably, it contains 3-10 carbon atoms (C3-10 cycloalkyl), more preferably 3-8 carbon atoms (C3-8 cycloalkyl), 3-6 carbon atoms (C3-6 cycloalkyl), 4-6 carbon atoms (C4-6 cycloalkyl), or 5-6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0115] The term "heterocyclic group" refers to a saturated, unsaturated, or partially unsaturated monocyclic or polycyclic cyclic system containing a 3-14 member structure, wherein one, two, three, four, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four. Heterocyclic groups can have 3-14, 3-12, 3-10, 3-8, 3-6, 4-6, or 5-6 member structures. Heterocyclic groups can be saturated heterocyclic alkyl groups or unsaturated heteroaryl groups.

[0116] A heteroaryl group represents an aromatic monocyclic or polycyclic system containing a 5-20 member structure, or preferably a 5-10, 5-8, 6-20, 6-10, or 6-8 member structure, more preferably a 5-6 member structure, wherein one, two, three, four, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four. A heteroaryl group can be an aromatic monocyclic ring containing one or two 5-6 member structures selected from N, S, or O, preferably an aromatic monocyclic ring containing one or two N or S members. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazole[1, [2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl, etc.

[0117] Heterocyclic alkyl groups may contain 3-12 ring atoms, wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, including bridged cyclic groups, spirocyclic groups, fused cyclic groups, etc. Preferably, they contain 3-10 ring atoms (3-10-membered heterocyclic alkyl groups), or 3-8 ring atoms (3-8-membered heterocyclic alkyl groups), or 3-6 ring atoms (3-6-membered heterocyclic alkyl groups), or 4-6 ring atoms (4-6-membered heterocyclic alkyl groups), or 5-6 ring atoms (5-6-membered heterocyclic alkyl groups). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). The heterocyclic alkyl group may be a 5-6-membered monocyclic heterocyclic alkyl group containing 1-2 N or O atoms. Examples of heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, and piperazineyl. Zincyl, tetrahydropyranyl, aziridine propane, oxacyclopropane, thiocyclopropane, aziridine butane, oxacyclobutane, thiocyclobutane, oxacyclohexane, morpholinyl, thiomorpholinyl, dioxane, dithiocyclohexyl, oxazolyl, thiazolyl, pyrazolyl, imidazolinidine, tetrahydrofuran-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-1-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-1-yl, piperidin-4-yl, etc., oxacyclohexane-4-yl.

[0118] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably containing 1-20 or 1-18 carbon atoms, more preferably 1-8 carbon atoms (C1-8 alkyl) straight-chain or branched group (the number of carbon atoms is between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7 or 8), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkyl, the number of carbon atoms is between 1 and 6, specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0119] The terms "alkyloxy," "alkylthio," and "alkylamino" refer to -O-alkyl, -S-alkyl, -NH-alkyl, or dialkylamino groups, respectively, with the alkyl group defined as above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, etc.; methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, etc.; methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, etc.

[0120] The term "halogen" refers to F, Cl, Br, and I.

[0121] The m-diamide compounds described in this application are interpreted as including the compound of Formula I and its stereoisomers, tautomers, isotopic compounds, or pesticide-acceptable salts thereof. The stereoisomers, tautomers, isotopic compounds, or pesticide-acceptable salts thereof are obtained by conventional techniques in the art and exert the same or similar effects in vitro and in vivo through substantially the same mechanism of action as the compound.

[0122] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may be present in this compound. Optical isomers refer to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Having an excess of atoms in one configuration (relative to another) results in a higher quantity of that configuration, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and even more preferably an excess greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0123] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0124] The term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine include, but are not limited to: 2 H, 3H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, 80 Br and 125 I. Compounds containing these and / or other isotopes are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art.

[0125] The term "pesticide-acceptable salt" refers to a salt obtained by reacting the m-diamid compound of this application with a chemically acceptable acid, wherein the chemically acceptable acid can be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid); the pesticide-acceptable salt can also be a salt obtained by reacting the m-diamid compound of this application with a chemically acceptable base, wherein the chemically acceptable base can be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.). Further, the pesticide-acceptable salt can be a potassium salt, sodium salt, ammonium salt, calcium salt, pyridine salt, choline salt, hydrochloride salt, phosphate salt, acetate salt, benzenesulfonate salt, or oxalate salt.

[0126] The term "pesticide-acceptable carriers and / or adjuvants" includes, but is not limited to, surfactants, including ionic and nonionic surfactants. The surfactants include emulsifiers, dispersants, or wetting agents. Specifically, the emulsifiers may be polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty amines, and commercially available emulsifiers; the dispersants include sodium lignosulfonate, dispersing agents, calcium lignosulfonate, or methylnaphthalenesulfonate formaldehyde condensate, etc.; the wetting agents include sodium lauryl sulfate, sodium dodecylbenzenesulfonate, or alkylnaphthalenesulfonate, etc. The pesticide-acceptable carriers include solid carriers and / or liquid carriers. Preferably, the solid carriers include natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicate, such as talc; magnesium aluminum silicate, such as kaolinite, montmorillonite, and mica; white carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; and amine salts such as ammonium sulfate and hexamethylenediamine. Preferably, the liquid carrier comprises water and an organic solvent; when water is used as a solvent or diluent, the organic solvent can be used as an adjuvant or antifreeze additive. Preferably, the organic solvent includes aromatic hydrocarbons (e.g., benzene, xylene, or toluene), chlorinated hydrocarbons (e.g., chlorobenzene, vinyl chloride, chloroform, or dichloromethane), aliphatic hydrocarbons (e.g., petroleum fractions, cyclohexane, or light mineral oil), alcohol solvents (e.g., isopropanol, butanol, ethylene glycol, glycerol, or cyclohexanol), ether solvents, ester solvents, ketone solvents (e.g., acetone, cyclohexanone, or N-methylpyrrolidone), or dimethylformamide. During the formulation of the insecticide composition, the active ingredient can be mixed with the liquid carrier and / or solid carrier, and surfactants (e.g., emulsifiers, dispersants, stabilizers, wetting agents) can be added, as well as other adjuvants (e.g., binders, defoamers, oxidants, etc.).

[0127] According to this application, the m-diamide compound can be used in conjunction with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers, and the components can be applied simultaneously, sequentially or separately.

[0128] The effects of specific compounds of this application will be described in detail below through examples.

[0129] Preparation Examples

[0130] Example 1 Preparation of 2-fluoro-3-(N-(cyclopropylmethyl)cyclohexanecarboxylamide)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (I-1)

[0131]

[0132] Step 1: Preparation of 2-fluoro-3-nitrobenzoyl chloride

[0133] 2-Fluoro-3-nitrobenzoic acid (54.1 mmol) was placed in a 150 mL single-necked flask, 60 mL of tetrahydrofuran was added as solvent, thionyl chloride (162.3 mmol) was added, and then 8 drops of DMF were added as activator. The mixture was refluxed in an oil bath at 60 °C for 4 h. After the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the solvent was removed four times with dichloromethane to obtain a yellow oily liquid with a yield of 81.8%.

[0134] Step 2: Preparation of 2-fluoro-3-nitro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0135] 2-Fluoro-3-nitrobenzyl chloride (24.3 mmol) was added to a 150 mL single-necked round-bottom flask and dissolved in 60 mL toluene. DMAP (2.5 mmol) and triethylamine (21.7 mmol) were then added sequentially. The mixture was transferred to an ice bath and stirred. 2-Trifluoromethyl-4-(perfluoropropyl-2-yl)aniline (37.1 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was transferred to an oil bath and refluxed at 110 °C for 4 h. The reaction was monitored by TLC until completion. The mixture was poured into a separatory funnel and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The solution was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was then purified by silica gel column chromatography (petroleum ether:ethyl acetate, 10:1–6:1). A white solid was obtained after column chromatography, with a yield of 53.3%.

[0136] Step 3: Preparation of 2-fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0137] 12.1 mmol of 2-fluoro-3-nitro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 250 mL single-necked flask, and 48.4 mmol of anhydrous stannous chloride and 60 mL of 1,4-dioxane were added sequentially. 25 mL of concentrated hydrochloric acid was added with stirring at room temperature, and the mixture was heated to 60 °C for 6 h. After the reaction was complete as monitored by TLC, the solvent was evaporated to dryness, and then 30 mL of water was added. The system was neutralized with saturated sodium carbonate solution until pH = 7. The system was extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to give a yellow solid in 75.7% yield.

[0138] Step 4: Preparation of 2-fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0139] 5.1 mmol of 2-fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 150 mL single-necked flask, and 6.12 mmol of sodium iodide and 20 mL of DMF were added sequentially. The mixture was stirred, and 7.6 mmol of bromomethylcyclopropane was added dropwise at room temperature. After the addition was complete, the mixture was placed in an oil bath at 100 °C, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted three times with 20 mL of ethyl acetate and 80 mL of water. The organic phases were combined, dried over anhydrous magnesium sulfate, dissolved under reduced pressure, and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:5) to give a white solid in 78.6% yield.

[0140] Step 5: Preparation of 2-fluoro-3-(N-(cyclopropylmethyl)cyclohexanecarboxylamide)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0141] 4 mmol of 2-fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (5.9 mmol), and cyclohexanoyl chloride (5.5 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 52.1%.

[0142] 1H NMR(600MHz,DMSO-d6)δ10.38(s,1H,NH),8.13(m,1H,Ar-H),8.09(m,1H,Ar-H),7.94(m,1H,Ar-H),7.8 4-7.78(m,1H,Ar-H),7.70(m,1H,Ar-H),7.48(m,1H,Ar-H),3.60(dd,J=13.9,7.0Hz,1H,CH),3.37(dd, J=14.0,7.2Hz,1H,CH),2.09-2.02(m,1H,CH),1.61(d,J=23.2,13.6Hz,5H,CH),1.52(d,J=12.9Hz,1H, CH),1.47-1.21(m,3H,CH),1.16-1.06(m,1H,CH),1.03-0.83(m,3H,CH),0.38(d,J=9.1,6.4Hz,2H,CH).

[0143] Example 2 Preparation of 2-fluoro-3-(cyclohexanecarboxylamino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (I-2)

[0144]

[0145] Steps 1-3 are the same as in Example 1.

[0146] Step 4: Preparation of 2-fluoro-3-(cyclohexanecarboxylamino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0147] 3.2 mmol of 2-fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and cyclohexanoyl chloride (4.8 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solid was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to give a yellow solid in 65.7% yield.

[0148] mp122.7-123.7℃.

[0149] 1H NMR(600MHz,DMSO-d6)δ10.40(s,1H,NH),9.78(s,1H,NH),8.12(m,1H,Ar-H),8.07(m ,1H,Ar-H),8.03(m,1H,Ar-H),7.94(m,1H,Ar-H),7.45(m,1H,Ar-H),7.30(m,1H,Ar- H),2.55(m,1H,CH),1.83(d,J=12.9Hz,2H,CH),1.79-1.73(m,2H,CH),1.66(d,J=12. 7Hz,1H,CH),1.42(q,J=12.5,3.3Hz,2H,CH),1.28(m,2H,CH),1.23-1.14(m,1H,CH).

[0150] Example 3: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclohexaneformamido)benzamide (I-3)

[0151]

[0152] Steps 1-5 are the same as in Example 1.

[0153] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclohexaneformamido)benzamide

[0154] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclohexaneformamide)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 63.1%.

[0155] MP156.8-157.5℃ 1H NMR(600MHz,DMSO-d6)δ10.76(s,1H,NH),8.45(m,1H,Ar-H),7.98(m,1H,Ar-H),7 .76(m,1H,Ar-H),7.71(m,1H,Ar-H),7.48(m,1H,Ar-H),3.50(d,J=110.5Hz,2H,CH ),2.03(s,1H,CH),1.67-1.57(m,5H,CH),1.52(d,J=12.9Hz,1H,CH),144-1.31(m, 3H,CH),1.13-1.07(m,1H,CH),0.90(dd,J=18.4,10.9Hz,3H,CH),0.37(s,2H,CH).

[0156] Example 4: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-cinnamonamide benzamide (I-4)

[0157]

[0158] Steps 1-3 are the same as in Example 1.

[0159] Step 4: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-cinnamicamide benzamide

[0160] 3.2 mmol of 2-fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.0 mmol), and cinnamoyl chloride (4.8 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 70.1%.

[0161] Step 5: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-cinnamonamide benzamide

[0162] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-cinnamonamide benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 64.2%.

[0163] mp168.3-169.6℃. 1 H NMR(600MHz,DMSO-d6)δ10.79(s,1H,NH),10.18(s,1H,NH),8.46-8.41(m,1H,Ar-H),8.36(m,1H,Ar-H),8 .00-7.97(m,1H,Ar-H),7.65(m,4H,Ar-H),7.48(d,2H,Ar-H),7.45-7.43(m,2H,Ar-H),7.16(m,1H,Ar-H).

[0164] Example 5: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide (I-5)

[0165]

[0166] Steps 1-4 are the same as in Example 1.

[0167] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide

[0168] 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 2,2-difluorobenzo[1,3]dioxane-5-carboxyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 70.1%.

[0169] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclohexenecarbamate)benzamide

[0170] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide (1.7 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and sodium bromide (1.9 mmol) were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.1%.

[0171] MP156.8-157.5℃ 1 H NMR(600MHz,DMSO-d6)δ10.54(s,1H,NH),8.42(m,1H,Ar-H),7.95(m,1H,Ar-H),7.75(m,1H,Ar-H),7.62(m,1H,Ar-H),7.40(m,2H,A r-H),7.26(m,1H,Ar-H),7.09(m,1H,Ar-H),3.73(d,J=91.7Hz,2H,CH),1.02(s,1H,CH),0.41(s,2H,CH),0.11(d,J=58.5Hz,2H,CH).

[0172] Example 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2-naphthylcarboxamide (I-6)

[0173]

[0174] Steps 1-4 are the same as in Example 1.

[0175] Step 5: N-(cyclopropylmethyl)-N-(2-fluoro-3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)phenyl)-2-naphthylcarboxamide

[0176] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was added dropwise to a 100 mL single-necked round-bottom flask, followed by 30 mL toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and naphthyl chloride (4.2 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and then three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to give a white solid in 65.6% yield.

[0177] mp110.8-110.9℃.

[0178] 1 H NMR(600MHz,DMSO-d6)δ10.23(s,1H,NH),8.09(s,1H,Ar-H),7.98(m,1H,Ar- H),7.92(m,1H,Ar-H).7.88-7.84(m,2H,Ar-H),7.77(m,1H,Ar-H),7.67(m,1H ,Ar-H),7.59-7.49(m,4H,Ar-H),7.40(m,1H,Ar-H),7.30-7.24(m,1H,Ar-H) ,3.66(s,2H,CH),1.08(s,1H,CH),0.44(d,J=7.2Hz,2H,CH),0.14(s,2H,CH).

[0179] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2-naphthylcarboxamide

[0180] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-2-naphthylcarboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 75.7%.

[0181] mp170.1-170.3℃.

[0182] 1 H NMR(600MHz,DMSO-d6)δ10.57(s,1H,NH),8.40(m,1H,Ar-H),7.94(m,2H,Ar-H),7.85(m,2H,Ar-H),7.76(m,1H,Ar-H),7.70(m,1H,Ar-H),7 .52(m,3H,Ar-H),7.38(m,1H,Ar-H),7.28(m,1H,Ar-H),3.77(d,J=47.6Hz,2H,CH),1.11-1.06(m,1H,CH),0.44(s,2H,CH),0.14(s,2H,CH).

[0183] Example 7: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclopropylmethyl)benzoamido)benzamide (I-7)

[0184]

[0185] Steps 1-4 are the same as in Example 1.

[0186] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclopropylmethyl)benzoamido)benzamide

[0187] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and 3-chlorobenzoyl chloride (4.0 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by concentration under reduced pressure. The mixture was then evaporated to dryness and subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 65.2%.

[0188] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclopropylmethyl)benzamido)benzamide

[0189] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclopropylmethyl)benzamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.4%.

[0190] mp170.1-170.3℃.

[0191] 1 H NMR(600MHz,DMSO-d6)δ10.61(s,1H,NH),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.73(m,1H,Ar-H),7.60(m,1H,Ar-H) ,7.36(m,3H,Ar-H),7.22(m,2H,Ar-H),3.71(s,2H,CH),1.03(s,1H,CH),0.42(s,2H,CH),0.11(d,J=35.4Hz,2H,CH).

[0192] Example 8: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclobutanecarboxamido)benzamide (I-8)

[0193]

[0194] Steps 1-4 are the same as in Example 1.

[0195] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclobutanecarboxamido)benzamide

[0196] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and cyclobutyroyl chloride (4.2 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 63.1%.

[0197] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclobutanecarboxamido)benzamide

[0198] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclobutanecarboxamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 63.1%.

[0199] mp170.1-170.3℃. 1H NMR(600MHz,DMSO-d6)δ10.76(s,1H,NH),8.45(m,1H,Ar-H),7.98(m,1H,Ar-H),7.74(m,1H,Ar-H),7.64(m,1H,Ar-H),7.46(m,1H ,Ar-H),3.00-2.91(m,1H,CH),2.17(s,3H,CH),1.73-1.66(m,4H,CH),0.88(s,1H,CH),0.37(d,J=8.1Hz,2H,CH),0.05(s,2H,CH).

[0200] Example 9: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide (I-9)

[0201]

[0202] Steps 1-4 are the same as in Example 1.

[0203] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide

[0204] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and 4,4-difluorocyclohexanediol chloride (4.2 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 64.2%.

[0205] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide

[0206] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask. 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). The solvent was removed by distillation under reduced pressure, and the final product was purified by column chromatography to obtain a white solid in 60.1% yield.

[0207] mp178.3-179.1℃.

[0208] 1 H NMR(600MHz,DMSO-d6)δ10.75(s,1H,NH),8.47-8.42(m,1H,Ar-H),7.98(m,1H,Ar-H),7.80-7.71(m,2H,Ar-H),7.49(m,1 H, Ar-H), 3.57 (d, J = 73.8Hz, 2H, CH), 2.23 (s, 1H, CH), 1.99 (s, 2H, CH), 1.77-1.57 (m, 6H, CH), 0.39 (d, J = 22.4Hz, 2H, CH).

[0209] Example 10: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopropanecarboxamido)benzamide (I-10)

[0210]

[0211] Steps 1-4 are the same as in Example 1.

[0212] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopropanecarboxamido)benzamide

[0213] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and cyclopropionyl chloride (4.2 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 73.1%.

[0214] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopropanecarboxamido)benzamide

[0215] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopropanecarboxamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 64.7%.

[0216] mp178.3-179.1℃.

[0217] 1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H,NH),8.34(m,1H,Ar-H),7.90(m,1H,Ar-H),7.77-7.62(m,2H,Ar-H),7.43(m,1H,Ar-H),3. 66(s,2H,CH),1.29(s,1H,CH),0.90(s,1H,CH),0.80(t,J=9.5,4.7Hz,2H,CH)0.65(d,J=8.5Hz,2H),0.38(q,J=8.5Hz,2H,CH).

[0218] Example 11 Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)pyrazine-2-carboxamide (I-11)

[0219]

[0220] Steps 1-4 are the same as in Example 1.

[0221] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)pyrazine-2-carboxamide

[0222] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and pyrazine carboxyl chloride (4.2 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 70.1%.

[0223] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)pyrazine-2-carboxamide)

[0224] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)pyrazine-2-carboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 62.9%.

[0225] mp178.3-179.1℃.

[0226] 1H NMR(600MHz,DMSO-d6)δ10.61(s,1H,NH),8.90-8.84(m,1H,Ar-H),8.59(m,1H,Ar-H),8.43(m,1H,Ar-H),8.35(m,1H,Ar-H),7.96(m,1H,Ar- H),7.60(m,2H,Ar-H),7.32-7.26(m,1H,Ar-H),3.87(s,1H,CH),3.70(s,1H,CH),1.06(s,1H,CH),0.45(d,J=8.1Hz,2H,CH),0.17(s,2H,CH).

[0227] Example 12: Preparation of N-(2-bromo-4-(perfluoropropyl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-methylbenzamido)benzamide (I-12)

[0228]

[0229] Steps 1-4 are the same as in Example 1.

[0230] Step 5: Preparation of N-(4-(perfluoropropyl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-methylbenzamido)benzamide

[0231] 2.8 mmol of 3-((cyclopropylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene (as solvent), 1 mmol of DMAP, 4.9 mmol of triethylamine, and 4.5 mmol of 3-methylbenzoyl chloride were added sequentially. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 74.1%.

[0232] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-methylbenzamido)benzamide

[0233] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-3-methylbenzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a yellow solid with a yield of 56.7%.

[0234] mp178.3-179.1℃.

[0235] 1 H NMR(600MHz,DMSO-d6)δ10.60(s,1H,NH),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.59(m,2H,Ar-H),7.30(m,1H,Ar-H),7.16(m,1H,Ar-H ),7.10(m,2H,Ar-H),7.03(m,1H,Ar-H),3.69(d,J=78.9Hz,2H,CH),2.21(s,3H,CH),1.03(s,1H,CH),0.41(s,2H,CH),0.11(s,2H,CH).

[0236] Example 13 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-3-methylbenzoamido)benzamide (I-13)

[0237]

[0238] Steps 1-3 are the same as in Example 1.

[0239] Step 4: Preparation of 2-fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide

[0240] 5.1 mmol of 2-fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 150 mL single-necked flask, and 6.12 mmol of sodium iodide and 20 mL of DMF were added sequentially. The mixture was stirred, and 8.1 mmol of bromomethylcyclobutane was added dropwise at room temperature. After the addition was complete, the mixture was placed in an oil bath at 100 °C, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted three times with 20 mL of ethyl acetate and 80 mL of water. The organic phases were combined, dried over anhydrous magnesium sulfate, dissolved under reduced pressure, and purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5) to give a white solid in 78.6% yield.

[0241] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-3-methylbenzamido)benzamide

[0242] 2.8 mmol of 3-((cyclobutylmethyl)amino)-2-fluoro-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide was placed in a 100 mL three-necked flask. 30 mL of toluene (as solvent), DMAP (1 mmol), triethylamine (4.9 mmol), and 3-methylbenzoyl chloride (4.5 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 71.2%.

[0243] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-3-methylbenzamido)benzamide

[0244] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-3-methylbenzamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 65.4%.

[0245] mp178.3-179.1℃.

[0246] 1 H NMR(600MHz,DMSO-d6)δ10.60(s,1H,NH),8.43(m,2H,Ar-H),7.96(m,2H,Ar-H),7.56(m,2H,Ar-H),7.28(m,1H,Ar-H),7.10(m,3H,Ar- H),6.98(m,1H,Ar-H),3.96(s,1H,CH),3.80(s,1H,CH),2.19(s,3H,CH),1.94(s,3H,CH),1.81(d,J=15.9Hz,3H,CH),1.68(s,1H,CH).

[0247] Example 14 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)cyclohexanecarboxamido)benzamide (I-14)

[0248]

[0249] Steps 1-4 are the same as in Example 13.

[0250] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro3-(N-(cyclobutylmethyl)cyclohexanecarboxamido)benzamide

[0251] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and cyclohexanoyl chloride (4.8 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. After evaporation, the solution was subjected to column chromatography with petroleum ether:ethyl acetate (6:1) to obtain a clear liquid with a yield of 69.4%.

[0252] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro3-(N-(cyclobutylmethyl)cyclohexanecarboxamido)benzamide

[0253] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro3-(N-(cyclobutylmethyl)cyclohexanecarboxamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.3%.

[0254] mp178.3-179.1℃.

[0255] 1 H NMR(600MHz,DMSO-d6)δ10.79(s,1H,NH),8.45(m,1H,Ar-H),7.98(m,1H,Ar-H),7.74(m,1H,Ar- H),7.67-7.61(m,1H,Ar-H),7.47(m,1H,Ar-H),3.76(d,J=35.8Hz,1H,CH),3.57(dd,J=13.6,7.4 Hz,1H,CH),2.38(dd,J=15.3,8.3Hz,1H,CH),1.93-1.87(m,2H,CH),1.80-1.75(m,2H,CH),1.60 (t,J=25.5,11.0Hz,7H,CH),1.44-1.28(m,3H,CH),1.18-1.05(m,1H,CH),0.96-0.86(m,2H,CH).

[0256] Example 15 Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carboxamide (I-15)

[0257]

[0258] Steps 1-4 are the same as in Example 1.

[0259] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carboxamide

[0260] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and tetrahydro-2H-pyran-4-carbonyl chloride (1 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. The dried product was then subjected to column chromatography with petroleum ether:ethyl acetate (6:1) to obtain a clear liquid with a yield of 79.5%.

[0261] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carboxamide)

[0262] N-(3-((4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.7 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain 0.8 g of white solid, with a yield of 53.2%.

[0263] mp178.3-179.1℃.

[0264] 1H NMR(600MHz,DMSO-d6)δ10.77(s,1H,NH),8.45(m,1H,Ar-H),7.98(m,1H,Ar-H),7.74(m ,2H,Ar-H),7.49(m,1H,Ar-H),3.82-3.75(m,2H,CH),3.63(s,1H,CH),3.43(d,J=28.0Hz ,1H,CH),2.32(s,1H,CH),1.75-1.57(m,3H,CH),1.53-1.48(m,1H,CH),1.41(d,J=17.6 Hz,1H,CH),0.85(s,2H,CH),0.38(d,J=8.1Hz,2H,CH),0.85(s,2H,CH),0.12(s,2H,CH).

[0265] Example 16 Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-3-methyl-4-chloro-N-(cyclopropylmethyl)benzamide (I-16)

[0266]

[0267] Steps 1-4 are the same as in Example 1.

[0268] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-3-methyl-4-chloro-N-(cyclopropylmethyl)benzamide

[0269] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 3-methyl-4-chlorobenzoyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 72.1%.

[0270] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-3-methyl-4-chloro-N-(cyclopropylmethyl)benzamide)

[0271] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-3-methyl-4-chloro-N-(cyclopropylmethyl)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 71.2%.

[0272] mp178.3-179.1℃.

[0273] 1 H NMR(600MHz,DMSO-d6)δ10.61(s,1H,NH),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.64(m,2H,Ar-H).7.34(m,2H,Ar-H),7.24(m,1 H,Ar-H),7.06(m,1H,Ar-H).3.70(s,2H,CH),2.24(s,3H,CH),1.05-1.01(m,1H,CH),0.41(d,J=8.3Hz,2H,CH),0.12(s,2H,CH).

[0274] Example 17 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-(trifluoromethyl)benzoamido)benzamide (I-17)

[0275]

[0276] Steps 1-4 are the same as in Example 1.

[0277] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-(trifluoromethyl)benzoamido)benzamide

[0278] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 3-fluorobenzoyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 68.3%.

[0279] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-(trifluoromethyl)benzoamido)benzamide

[0280] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3-(trifluoromethyl)benzamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 74.3%.

[0281] mp178.3-179.1℃.

[0282] 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H,NH),8.41(s,1H,Ar-H),7.94(m,1H,Ar-H),7.77(m,1H,Ar-H),7.67(m,1H,Ar-H),7.61(m,2H,Ar-H) ,7.56(m,1H,Ar-H),7.47(m,1H,Ar-H),7.35(m,1H,Ar-H),3.75(d,J=24.6Hz,2H,CH),1.05(s,1H,CH),0.43(s,2H,CH),0.17(s,2H,CH).

[0283] Example 18: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(4-bromo-N-(cyclobutylmethyl)benzoamido)benzamide (I-18)

[0284]

[0285] Steps 1-4 are the same as in Example 13.

[0286] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(4-bromo-N-(cyclobutylmethyl)benzoamide)benzamide

[0287] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 4-bromobenzoyl chloride (2.7 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 70.1%.

[0288] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(4-bromo-N-(cyclobutylmethyl)benzoamido)benzamide

[0289] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(4-bromo-N-(cyclobutylmethyl)benzoamide)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask. 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a yellow solid with a yield of 40.5%.

[0290] mp178.3-179.1℃.

[0291] 1H NMR(600MHz,DMSO-d6)δ10.62(s,1H,NH),8.39(m,1H,Ar-H),7.93(m,1H,Ar-H),7.63(m,1H,Ar-H),7.57(m,1H,Ar-H),7.47-7.41(m, 2H,Ar-H),7.32(m,1H,Ar-H),7.20(m,2H,Ar-H),3.89(s,2H,CH),1.92(s,3H,CH),1.79(s,2H,CH),1.71(s,1H,CH),1.64(s,1H,CH).

[0292] Example 19 Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2-naphthylcarboxamide (I-19)

[0293]

[0294] Steps 1-4 are the same as in Example 13.

[0295] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2-naphthylcarboxamide

[0296] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 2-naphthoyl chloride (3.7 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 68.2%.

[0297] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2-naphthylcarboxamide

[0298] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2-naphthylcarboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 45.7%.

[0299] mp178.3-179.1℃.

[0300] 1 H NMR(600MHz,DMSO-d6)δ10.56(s,1H,NH),8.39(m,1H,Ar-H),7.93(m,1H,Ar-H),7.86(m,3H,Ar-H),7.74(m,1H,Ar-H),7.65 (m,1H,Ar-H),7.51(m,3H,Ar-H),7.30(m,2H,Ar-H),3.96(d,J=54.2Hz,2H,CH),1.97(s,2H,CH),1.76(d,J=61.3Hz,4H,CH).

[0301] Example 20: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)cyclobutylcarbamate)benzamide (I-20)

[0302]

[0303] Steps 1-4 are the same as in Example 13.

[0304] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)cyclobutylcarbamate)benzamide

[0305] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and cyclobutylcarboxylate chloride (5.1 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 72.2%.

[0306] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)cyclobutylcarbamate)benzamide

[0307] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)cyclobutylcarbamate)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.3%.

[0308] mp178.3-179.1℃.

[0309] 1H NMR(600MHz,DMSO-d6)δ10.77(s,1H,NH),8.45(m,1H,Ar-H),7.98(m,1H,Ar-H),7.71(m ,1H,Ar-H),7.56(m,1H,Ar-H),7.44(m,1H,Ar-H),3.90-3.79(m,1H,CH),3.51(q,J=12. 0Hz,1H,CH),2.91(d,J=31.0Hz,1H,CH),2.38(d,J=12.4Hz,1H,CH),2.14(q,J=9.9Hz,2 H,CH),1.90(s,2H,CH),1.77(q,J=8.8Hz,2H,CH),1.65(m,J=58.1,17.4,9.7Hz,6H,CH).

[0310] Example 21: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide (I-21)

[0311]

[0312] Steps 1-4 are the same as in Example 13.

[0313] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide

[0314] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 2,2-difluorobenzo[1,3]dioxene-5-carboxyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 67.4%.

[0315] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide

[0316] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclobutylmethyl)-2,2-difluorobenzo[1,3]dioxane-5-carboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 56.7%.

[0317] mp178.3-179.1℃.

[0318] 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H,NH),8.42(m,1H,Ar-H),7.94(m,1H,Ar-H),7.72(m,1H,Ar-H),7.60(m,1H,A r-H),7.38(m,2H,Ar-H),7.23(m,1H,Ar-H),7.04(m,1H,Ar-H),3.91(d,J=77.7Hz,2H,CH),2.07–1.46(m,7H,CH).

[0319] Example 22: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-isoxazole-4-carboxamide (I-22)

[0320]

[0321] Steps 1-4 are the same as in Example 1.

[0322] Step 5: Preparation of N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-isoxazole-4-carboxamide

[0323] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and isoxazolyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 68.5%.

[0324] Step 6: Preparation of N-(3-((2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-isoxazole-4-carboxamide

[0325] N-(3-((4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(cyclopropylmethyl)-isoxazole-4-carboxamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 54.2%.

[0326] mp178.3-179.1℃.

[0327] 1 H NMR(600MHz,DMSO-d6)δ10.77(s,1H),8.93(m,1H),8.40(m,1H),7.94(m,1H),7.69(m,2H), 7.36(m,1H),6.73(m,1H),3.85(s,1H),3.66(s,1H),1.04(s,1H),0.46(s,2H),0.17(s,2H).

[0328] Example 23: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-bromo-N-(cyclopropylmethyl)benzoamido)benzamide (I-23)

[0329]

[0330] Steps 1-4 are the same as in Example 1.

[0331] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-bromo-N-(cyclopropylmethyl)benzoamido)benzamide

[0332] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 3-bromobenzoyl chloride (2.7 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 68.2%.

[0333] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-bromo-N-(cyclopropylmethyl)benzoamido)benzamide

[0334] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-bromo-N-(cyclopropylmethyl)benzamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.1%.

[0335] mp178.3-179.1℃.

[0336] 1H NMR(600MHz,DMSO-d6)δ10.61(s,1H,NH),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.73(m,1H,Ar-H),7.60(m.1H,Ar-H),7.54-7.47(m,2H, Ar-H),7.35(m,1H,Ar-H),7.24(m,1H,Ar-H),7.18(m,1H,Ar-H),3.71(s,2H,CH),1.03(s,1H,CH),0.42(s,2H,CH),0.18-0.04(m,2H,CH).

[0337] Example 24 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopentanecarbamate)benzamide (I-24)

[0338]

[0339] Steps 1-4 are the same as in Example 1.

[0340] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopentanecarbamate)benzamide

[0341] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and cyclopentanoyl chloride (5.3 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, and after evaporation, column chromatography (petroleum ether: ethyl acetate = 6:1) was performed to obtain a clear liquid with a yield of 69.4%.

[0342] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopentanecarbamate)benzamide

[0343] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)cyclopentanecarbamate)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask. 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). The solvent was removed by distillation under reduced pressure, and the final product was purified by column chromatography to obtain a white solid with a yield of 54.4%.

[0344] mp178.3-179.1℃.

[0345] 1 H NMR(600MHz,DMSO-d6)δ10.79(s,1H,NH),8.46-8.42(m,1H,Ar-H),7.98(m,1H,Ar-H),7.72(m,3H,Ar-H),7.47(m,1H,A r-H),3.64(d,J=36.0Hz,2H,CH),1.68-1.54(m,7H,CH),1.41-1.37(m,2H,CH),0.89(s,1H,CH),0.40-0.36(m,2H,CH).

[0346] Example 25: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-cyano-N-(cyclopropylmethyl)benzoamido)benzamide (I-25)

[0347]

[0348] Steps 1-4 are the same as in Example 1.

[0349] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-cyano-N-(cyclopropylmethyl)benzoamido)benzamide

[0350] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 3-cyanobenzoyl chloride (3.6 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 71.2%.

[0351] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-cyano-N-(cyclopropylmethyl)benzoamido)benzamide

[0352] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-cyano-N-(cyclopropylmethyl)benzamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.7 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 61.3%.

[0353] mp178.3-179.1℃.

[0354] 1 H NMR(600MHz,DMSO-d6)δ10.58(s,1H,NH),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.81-7.75(m,3H,Ar-H).7.59(m,2H ,Ar-H),7.37(m,1H,Ar-H),3.74(d,J=56.2Hz,2H,CH),1.03(s,1H,CH),0.43(s,2H,CH),0.13(d,J=51.6Hz,2H,CH).

[0355] Example 26 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3,3-difluorocyclobutane-1-carbamate)benzamide (I-26)

[0356]

[0357] Steps 1-4 are the same as in Example 1.

[0358] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3,3-difluorocyclobutane-1-carboxamido)benzamide

[0359] 2-Fluoro-3-((cyclopropylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask. 30 mL of toluene was added as solvent, followed by DMAP (1 mmol), triethylamine (4.9 mmol), and 4,4-difluorocyclobutyryl chloride (1 mmol). After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature and washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH). The mixture was then washed three times with saturated brine and three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by concentration under reduced pressure. The mixture was then evaporated to dryness and subjected to column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain a clear liquid with a yield of 70.1%.

[0360] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3,3-difluorocyclobutane-1-carboxamido)benzamide

[0361] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclopropylmethyl)-3,3-difluorocyclobutane-1-carboxamido)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask. 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 68.3%.

[0362] mp178.3-179.1℃.

[0363] 1 H NMR(600MHz,DMSO-d6)δ10.80(s,1H,NH),8.48-8.42(m,1H,Ar-H),7.98(m,1H,Ar-H).7.79-7.67(m,2H,Ar-H),7.49(m,1H,Ar-H ),3.49(s,2H,CH),2.93-2.67(m,4H,CH),2.44(s,1H,CH),0.89(s,1H,CH),0.39(d,J=7.9Hz,2H,CH),0.06(d,J=5.9Hz,2H,CH).

[0364] Example 27 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-4,4-difluorocyclohexane-1-carbamoyl)benzamide (I-27)

[0365]

[0366] Steps 1-4 are the same as in Example 1.

[0367] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide

[0368] 2-Fluoro-3-((cyclobutylmethyl)amino)-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 4,4-difluorocyclohexanoyl chloride (4.2 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 65.7%.

[0369] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide

[0370] 1 mmol of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(N-(cyclobutylmethyl)-4,4-difluorocyclohexane-1-carboxamido)benzamide was placed in a 150 mL single-necked round-bottom flask. 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of 4% sodium hypochlorite aqueous solution was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). The solvent was removed by distillation under reduced pressure, and the final product was purified by column chromatography to obtain a white solid with a yield of 56.2%.

[0371] mp178.3-179.1℃.

[0372] 1 H NMR(600MHz,DMSO-d6)δ10.76(s,1H,NH),8.47-8.42(m,1H,Ar-H),8.00-7.95(m,1H ,Ar-H),7.74(m,1H,Ar-H),7.71-7.64(m,1H,Ar-H),7.48(m,1H,Ar-H),3.77(dd,J= 15.1,7.3Hz,1H,CH),2.43-2.33(m,1H,CH),2.20(d,J=16.1Hz,1H,CH),1.98(s,2H, CH),1.92-1.85(m,2H,CH),1.76(d,J=27.3,11.4Hz,3H,CH),1.70-1.54(m,7H,CH).

[0373] Example 28 Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclobutylmethyl)benzoamido)benzamide (I-28)

[0374]

[0375] Steps 1-4 are the same as in Example 13.

[0376] Step 5: Preparation of N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclobutylmethyl)benzoamido)benzamide

[0377] 2-Fluoro-3-amino-N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)benzamide (2.8 mmol) was placed in a 100 mL three-necked flask, and 30 mL of toluene as solvent, DMAP (1 mmol), triethylamine (4.9 mmol), and 3-chlorobenzoyl chloride (4.0 mmol) were added dropwise. After the addition was complete, the mixture was transferred to an oil bath and reacted for 2 h. After TLC monitoring, the mixture was cooled to room temperature, washed three times with 10% dilute hydrochloric acid (which showed a weakly acidic pH), washed three times with saturated brine, and washed three times with distilled water. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, evaporated to dryness, and then subjected to column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a clear liquid with a yield of 68.2%.

[0378] Step 6: Preparation of N-(2-bromo-4-(perfluoropropyl-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclobutylmethyl)benzoamido)benzamide

[0379] N-(4-(perfluoropropyl-2-yl)-2-(trifluoromethyl)phenyl)-2-fluoro-3-(3-chloro-N-(cyclobutylmethyl)benzoamide)benzamide (1 mmol) was placed in a 150 mL single-necked round-bottom flask, and 15 mL of dichloromethane and 1.9 mmol of sodium bromide were added sequentially. The temperature was raised to 65 °C, and 10 mL of sodium hypochlorite aqueous solution (4%) was added dropwise. After the addition was complete, the reaction was continued for 2 h. After the reaction was complete, the mixture was separated while hot, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dissolved under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate, 3:1–2:1). After removing the solvent by distillation under reduced pressure, the solid was purified by column chromatography to obtain a white solid with a yield of 60.3%.

[0380] mp178.3-179.1℃.

[0381] 1 H NMR(600MHz,DMSO-d6)δ10.76(s,1H,NH),8.62(m,1H,Ar-H),8.43(m,1H,Ar-H),7.96(m,1H,Ar-H),7.69(m,1H,Ar-H),7 .58(m,1H,Ar-H),7.38-7.28(m,3H,Ar-H),7.23(m,1H,Ar-H),7.15(m,1H,Ar-H),3.90(s,2H,CH),2.00-1.63(m,7H,CH).

[0382] Example 29: Inhibitory activity test of m-phenylenediamine compounds containing a diamide structure against diamondback moth.

[0383] The bioactivity of the compound against the diamondback moth was determined using the leaf-dipping method. 0.1000 g each of the compound from the examples and the commercial insecticide chlorantraniliprole were accurately weighed using an electronic balance, dissolved in acetone, and diluted to a final volume of 10 mL in a volumetric flask to prepare 10000 mg / L stock solutions. Based on preliminary experiments, four series of concentrations were set for each agent according to the content of the active ingredient: 100, 10, 1, and 0.1 mg / L. According to the above dosage settings, the 35 compounds and the positive control group (commercial chlorantraniliprole) were diluted to the designed concentrations with an aqueous solution containing 0.1% Tween 80, with each concentration consisting of 100 mL of solution. A 0.1% Tween 80 aqueous solution without the agent was used as a blank control. Each tested agent was diluted to the four set concentrations for later use. Immerse cabbage leaves in the test solution for 15 seconds, then remove and air dry before placing them in disposable plastic boxes. Inoculate each box with 15 healthy, uniform third-instar larvae of the diamondback moth. Each treatment is repeated four times. The treated insects are then reared in an artificial climate chamber with a temperature of (27±0.5)℃, relative humidity of (70±10)%, and a photoperiod L:D = 14h:10h. After 48 hours, record the number of live and dead diamondback moths. Insects that do not move when gently touched with a brush are considered dead. The activity test results are shown in Table 1-1.

[0384] Table 1-1 Insecticidal activity of compounds I-3 to I-28 against diamondback moth

[0385]

[0386] As shown in Table 1-1, most of the compounds in the examples showed superior insecticidal activity against diamondback moth. Some compounds even showed better insecticidal activity than the commercial insecticide chlorantraniliprole. For example, compounds I-9 and I-25 showed excellent insecticidal activity, with compound I-9 exhibiting the best insecticidal activity.

[0387] The data above show that the novel diamide insecticide prepared in this application has high insecticidal activity, and some compounds are more effective than the commercial insecticide chlorantraniliprole.

[0388] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0389] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, this invention will not describe the various possible combinations separately. As long as they do not violate the spirit of this invention, they should also be regarded as the content disclosed by this invention.

Claims

1. A m-diamide compound, characterized in that, The compound represented by Formula I, or its stereoisomers, tautomers, isotopic derivatives, and pesticide-acceptable salts: Wherein, A is an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted saturated, unsaturated or partially unsaturated heterocyclic group, or an optionally substituted aryl vinyl group; The substituent on A is selected from one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. R1 is an H, a cycloalkyl-substituted alkyl group, or a cyano-substituted alkyl group; W1 is either O or S; W2 is either O or S; R2 is H or an alkyl group; R3 is H, halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamine. R4 can be halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. The substituents on the optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamine groups are selected from one or more of halogen, amino, hydroxy, nitro, cyano, and mercapto groups; n can be 0, 1, 2, 3, or 4.

2. The m-diamide compound according to claim 1, characterized in that, A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, or an optionally substituted C6-10 aryl vinyl group; preferably, the substituent on A is selected from one or more of halogen, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl groups.

3. The m-diamide compound according to claim 1, characterized in that, A is selected from one of the following groups:

4. The m-diamide compound according to any one of claims 1-3, characterized in that, R1 is a C1-C6 alkyl group substituted with H, a C3-C6 cycloalkyl group, or a C1-C6 alkyl group substituted with cyano; preferably, R1 is a methyl group substituted with H, a C3-C4 cycloalkyl group, or a methyl group substituted with cyano.

5. The m-diamide compound according to any one of claims 1-4, characterized in that, n=1, R4 is located in the ortho position of the two amide groups; preferably, the compound represented by formula I is the compound represented by formula IA: More preferably, the compound represented by formula I is the compound represented by formula IB:

6. The m-diamide compound according to claim 5, characterized in that, The compound represented by formula I is the same as the compound represented by formula IC: Preferably, A is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted 3-6 membered heterocyclic alkyl group, and R1 is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group; or A is an optionally substituted C6-C10 aryl vinyl group, and R1 is H.

7. The m-diamide compound according to claim 1, characterized in that, The compound represented by Formula I is one of the following compounds, from Formula I-1 to I-28:

8. An insecticidal composition, characterized in that, The active ingredient is at least one of the m-diamide compounds according to any one of claims 1-7; preferably, the insecticidal composition further comprises a pesticide-acceptable carrier and / or adjuvant.

9. Use of the m-diamid compound of any one of claims 1-7 or the insecticidal composition of claim 8 for the control of pests; preferably, applying an insecticidally effective amount of the m-diamid compound or the insecticidal composition as described above to plants, and / or pests, and / or habitats.

10. A method for controlling plant pests, characterized in that, This includes applying an insecticidal effective amount of any of the m-diamide compounds of claims 1-7 or the insecticidal composition of claim 8 to plants, and / or pests, and / or habitats.

11. The use according to claim 9 or the method according to claim 10, characterized in that, The pests are Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, Blattodea, mites, and nematodes; preferably diamondback moth, rice stem borer, cotton bollworm, and corn stink bug.

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