An isoxazoline compound and use thereof

Abstract

The application discloses an isoxazoline compound as shown in formula (I) and application thereof, wherein R1, R2 and R3 can be selected from halogen atoms, a cyano group, a nitro group, C1-C3 halogenated alkyl and the like; Q can be independently selected from A1-A6; L1 and L2 can be selected from a carboxyl group, C1-C6 alkoxycarbonyl, a C1-C8 alkyl group substituted by a hydroxyl group and the like; Z1 and Z2 can be selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C5 cycloalkyl group or C(O)M, wherein M is a C1-C6 alkyl group, a C2-C6 alkenyl group and the like; the isoxazoline compound provided by the application has no cross resistance with existing insecticides, has the advantages of fast drug efficacy, low dosage and the like, and has excellent prevention and treatment effects on rice resistant Chilo suppressalis, Plutella xylostella, aphids and the like. The application further provides the isoxazoline compound as a salt acceptable to a pesticide, a composition and application.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticides, in particular to an isoxazoline compound and application thereof. BACKGROUND

[0002] In the process of agricultural and forestry production, pests have caused great loss to economic property, and insecticides are widely used in agricultural production and planting. In recent years, with the large and long-term use of insecticides, pests have developed resistance to a large number of existing insecticides, and the dosage must be increased to achieve the original effect, which has caused certain problems to agricultural production, environment and ecology. For example, in the process of rice planting, chlorantraniliprole is a highly effective insecticide for preventing and treating Chilo suppressalis, but after years of continuous use, serious resistance problems have occurred in most parts of the world, which has greatly threatened global rice production. In addition, some insecticides are highly toxic, or some destroy the ecological system through their long-term residual effects. Therefore, it is urgent to continuously develop new insecticides with high activity, low toxicity and environmental friendliness. SUMMARY

[0003] The main purpose of the present application is to provide an isoxazoline compound and application thereof, aiming to solve the serious resistance problems of current insecticides.

[0004] To achieve the above-mentioned purpose, the present application provides an isoxazoline compound, which is a compound shown in the following structural formula (I) or a tautomer, a metabolic isomer, a pharmaceutically acceptable salt or a prodrug thereof:

[0005]

[0006] Q is selected from any one of structures A1 to A6;

[0007]

[0008]

[0009] wherein Q is A1, L1is selected from -C(O)OR4, -C(O)SR4, or -C(O)NHR5, wherein R4is hydrogen, a monovalent metal ion, an ammonium ion, a substituted or unsubstituted C1-C6alkyl, a substituted or unsubstituted C2-C6alkenyl, a substituted or unsubstituted C2-C6alkynyl, a substituted or unsubstituted C3-C5cycloalkyl, a substituted or unsubstituted C3-C5cycloalkyl C1-C3alkyl, a substituted or unsubstituted hydroxyl C1-C4alkyl, a substituted or unsubstituted C1-C2alkoxy C1-C4alkyl, R5is a substituted or unsubstituted C1-C2alkoxy C1-C4alkyl, C1-C3alkoxycarbonyl C1-C3alkyl, wherein the substituents are one or more halogen atoms, a nitro group, a nitroso group, a cyano group, an amino group, a hydroxyl group, wherein R1, R2, R3may be independently selected from a halogen atom, a cyano group, a nitro group, a C1-C3alkyl, a C1-C3haloalkyl, a C1-C3alkoxy, a C1-C3haloalkoxy, a C1-C3alkylthio, or a C1-C3haloalkylthio;

[0010] Further, L1is selected from one or more hydroxyl substituted C1-C8alkyl, one or more hydroxyl substituted C2-C8alkenyl, one or more hydroxyl substituted C2-C8alkynyl, wherein R1, R2, R3may be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3alkyl, a C1-C3haloalkyl, a C1-C3alkoxy, a C1-C3haloalkoxy, a C1-C3alkylthio, or a C1-C3haloalkylthio;

[0011] Z1represents a hydrogen atom, an oxygen atom, a halogen atom, a hydroxyl group, a nitro group, a nitroso group, a cyano group, an amino group, a substituted or unsubstituted C1-C6alkyl, a substituted or unsubstituted C2-C6alkenyl, a substituted or unsubstituted C2-C6alkynyl, a substituted or unsubstituted C3-C5cycloalkyl, a substituted or unsubstituted C1-C3alkyl C3-C5cycloalkyl, a substituted or unsubstituted C1-C6alkoxy C1-C6alkyl, a substituted or unsubstituted C1-C6alkylthio C1-C6alkyl, or -C(O)M, wherein M represents a substituted or unsubstituted C1-C6alkyl, a substituted or unsubstituted C2-C6alkenyl, a substituted or unsubstituted C2-C6alkynyl, a substituted or unsubstituted C3-C5cycloalkyl, a substituted or unsubstituted C1-C3alkyl C3-C5cycloalkyl, a substituted or unsubstituted C1-C6alkoxy C1-C6alkyl, a substituted or unsubstituted C1-C6alkylthio C1-C6alkyl, wherein the substituents can be one or more halogen atoms, a hydroxyl group, a nitro group, a nitroso group, a cyano group, an amino group;

[0012] Q is any one of the structures A2 to A6, R1, R2, R3 can be independently selected from hydrogen atom, halogen atom, cyano group, nitro group, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, C1-C3 alkylthio group or C1-C3 haloalkylthio group; L2 is selected from -C(O)OR6, -C(O)SR6 or -C(O)NHR7, wherein R6 is hydrogen, monovalent metal ion, ammonium ion, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted cyclopropyl C1-C3 alkyl group, and R7 is hydrogen, substituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted C1-C6 alkoxy group, wherein the substituents can be one or more halogen atom, nitro group, nitroso group, cyano group, amino group, C1-C3 alkoxy group;

[0013] In addition, L2 can be selected from one or more hydroxyl-substituted C1-C8 alkyl group, one or more hydroxyl-substituted C2-C8 alkenyl group, one or more hydroxyl-substituted C2-C8 alkynyl group;

[0014] Z2 represents hydrogen atom, oxygen atom, halogen atom, hydroxyl group, nitro group, nitroso group, cyano group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted C1-C3 alkyl C3-C5 cycloalkyl group, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkylthio C1-C6 alkyl group, or -C(O)M, wherein M represents substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C3-C5 cycloalkyl group, substituted or unsubstituted C1-C3 alkyl C3-C5 cycloalkyl group, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkylthio C1-C6 alkyl group, wherein the substituents can be one or more halogen atom, nitro group, nitroso group, cyano group, amino group;

[0015] W represents O or S;

[0016] X represents O or CH2.

[0017] In one embodiment, the isoxazoline compound comprises a structure according to Formula A1, wherein L1is selected from -C(O)OR4, -C(O)SR4, or -C(O)NHR5, wherein R4is hydrogen, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C4cycloalkyl, substituted or unsubstituted C3-C4cycloalkyl C1-C2alkyl, substituted or unsubstituted hydroxy C1-C3alkyl, substituted or unsubstituted C1-C2alkoxy C1-C3alkyl; R5is substituted or unsubstituted C1-C2alkoxy C1-C2alkyl, C1-C3alkoxycarbonyl C1-C2alkyl, wherein the substituents are one or more halogen atoms, nitro, nitroso, cyano, amino, hydroxy, wherein R1, R2, R3may be independently selected from halogen atoms, cyano, nitro, C1-C3alkyl, C1-C3haloalkyl; and further L1may be selected from C1-C5alkyl substituted with one or more hydroxy groups, wherein R1, R2, R3may be independently selected from halogen atoms, cyano, nitro, C1-C3alkyl, C1-C3haloalkyl; Z1represents a hydrogen atom, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted C1-C3alkylcyclopropyl, substituted or unsubstituted C1-C3alkoxy C1-C3alkyl, substituted or unsubstituted C1-C3alkylthio C1-C3alkyl, or C(O)M, wherein M represents substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted C1-C3alkylcyclopropyl, substituted or unsubstituted C1-C3alkoxy C1-C3alkyl, substituted or unsubstituted C1-C3alkylthio C1-C3alkyl, wherein the substituents can be one or more halogen atoms, hydroxy, nitro, nitroso, cyano, amino;

[0018] W represents O or S; and / or,

[0019] The isoxazoline compound comprises a structure shown in formula A1, wherein L1 in the isoxazoline compound is selected from -C(O)OR4, -C(O)SR4 or -C(O)NHR5, wherein R4 is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted hydroxy C1-C3 alkyl, substituted or unsubstituted C1-C2 alkoxy C1-C3 alkyl; R5 is substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl, C1-C2 alkoxycarbonyl C1-C2 alkyl, wherein the substituent is one or more halogen atoms, nitro, nitroso, cyano, amino, hydroxyl, wherein R1, R2, and R3 can be independently selected from halogen atoms, cyano, nitro, C1-C3 alkyl, C1-C2 alkoxy, ... -C3 haloalkyl; L1 may further be selected from one or more hydroxy-substituted C1-C3 alkyl groups, wherein R1, R2, and R3 may independently be selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; Z1 represents a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, or C(O)M, wherein M represents a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C3 alkenyl group, a substituted or unsubstituted C2-C3 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, wherein the substituents may be one or more halogen atoms, nitro groups, nitroso groups, or cyano groups;

[0020] W represents O or S; and / or,

[0021] The isoxazoline compound comprises a structure shown in formula A1, wherein L1 in the isoxazoline compound is selected from -C(O)OR4, -C(O)SR4 or -C(O)NHR5, wherein R4 is hydrogen, sodium ion, potassium ion, ammonium ion, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethyl, hydroxyethyl, methoxyethyl, ethoxyethyl; R5 is methoxyethyl, ethoxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, wherein the substituent is one or more halogen atoms, nitro, nitro, cyano, amino, hydroxyl, wherein R1, R2, and R3 can be independently selected from halogen atoms, cyano, nitro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; L1 can also be selected from -C H2OH, -CH2CH2OH, wherein R1, R2, and R3 can be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, and a trifluoromethoxy group; Z1 represents a hydrogen atom, a methyl group, an ethyl group, a substituted or unsubstituted C2-C3 alkenyl group, a substituted or unsubstituted C2-C3 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, or C(O)M, wherein M represents a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C3 alkenyl group, a substituted or unsubstituted C2-C3 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, and the substituent can be one or more halogen atoms, nitro groups, nitroso groups, and cyano groups.

[0022] In one embodiment, the isoxazoline compound comprises a structure represented by any one of Formulas A2 to A6, wherein:

[0023] R1, R2, and R3 in the isoxazoline compound can be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group;

[0024] L2 is selected from -C(O)OR6, -C(O)SR6 or -C(O)NHR7, wherein R6 is hydrogen, sodium ion, potassium ion, ammonium ion, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted cyclopropyl C1-C3 alkyl; wherein R7 is hydrogen, substituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C3 alkoxy, wherein the substituent is one or more halogen atoms, nitro, nitroso, cyano, amino, C1-C3 alkoxy; L2 can also be selected from one or more hydroxy-substituted C1-C5 alkyl;

[0025] Z2 represents a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C3 alkylcyclopropyl group, a substituted or unsubstituted C1-C3 alkoxyC1-C3 alkyl group, a substituted or unsubstituted C1-C3 alkylthioC1-C3 alkyl group, or C(O)M, wherein M represents a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C3 alkylcyclopropyl group, a substituted or unsubstituted C1-C3 alkoxyC1-C3 alkyl group, a substituted or unsubstituted C1-C3 alkylthioC1-C3 alkyl group, and the substituent group may be one or more halogen atoms, hydroxyl groups, nitro groups, nitroso groups, cyano groups, or amino groups;

[0026] W means O or S;

[0027] X represents O or CH2; and / or,

[0028] R1, R2, and R3 in the isoxazoline compound can be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group;

[0029] L2 is selected from -C(O)OR6, -C(O)SR6 or -C(O)NHR7, wherein R6 is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopropylmethyl; wherein R7 is hydrogen, substituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted cyclopropyl, C1-C3 alkoxy, wherein the substituent is one or more halogen atoms, nitro, nitroso, cyano, methoxy, ethoxy; L2 can also be selected from one or more hydroxy-substituted C1-C5 alkyl;

[0030] Z2 represents a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, or C(O)M, wherein M represents a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2-C4 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C3 alkylcyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, wherein the substituent may be one or more halogen atoms, hydroxyl group, nitro group, nitroso group, cyano group, or amino group;

[0031] W means O or S;

[0032] X represents O or CH2; and / or,

[0033] The isoxazoline compound comprises a structure represented by any one of formulas A2 to A6, wherein R1, R2, and R3 in the isoxazoline compound can be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, and a trifluoromethoxy group;

[0034] L2 is selected from -C(O)OR6, -C(O)SR6 or -C(O)NHR7, wherein R6 is hydrogen, substituted or unsubstituted methyl, ethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl; wherein R7 is hydrogen, halomethyl, haloethyl, halopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, wherein the substituent is one or more halogen atoms, nitro, nitroso, cyano, amino, methoxy, ethoxy; L2 can also be selected from one or more hydroxy-substituted C1-C3 alkyl groups;

[0035] Z2 represents a hydrogen atom, a methyl group, an ethyl group, a substituted or unsubstituted C2-C3 alkenyl group, a substituted or unsubstituted C2-C3 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, or C(O)M, wherein M represents a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C2-C3 alkenyl group, a substituted or unsubstituted C2-C3 alkynyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted C1-C2 alkoxy C1-C2 alkyl group, wherein the substituent group may be one or more halogen atoms, nitro group, nitroso group, or cyano group;

[0036] W means O;

[0037] X represents CH2.

[0038] In one embodiment, the isoxazoline compound as described above further comprises a structure as shown in Formula I' or a tautomer or a pharmaceutically acceptable salt thereof, wherein the carbon at position 5 is a chiral carbon having an R configuration and an S configuration, and the stereochemical purity of the S configuration is 50% to 100%.

[0039]

[0040] The present invention also provides a use of the above-mentioned isoxazoline compound in the preparation of insecticides.

[0041] The present invention also provides an insecticide for killing insects, comprising an active component, wherein the active component comprises the isoxazoline compound described above and / or its tautomers, enantiomers, diastereomers or pesticide-acceptable salts.

[0042] In one embodiment, the mass of the active ingredient accounts for 0.1% to 99% of the mass of the pesticide.

[0043] In one embodiment, the pests include rice-resistant stem borer, diamondback moth, aphids or thrips.

[0044] In one embodiment, the pesticide further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or any combination thereof.

[0045] The present invention also provides an insecticide composition, which comprises an active ingredient and other active compounds; the active ingredient comprises the isoxazoline compound as described in any one of the above items or the tautomers, enantiomers, diastereomers or pesticide-acceptable salts thereof; the other active compounds comprise one or more of insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators and herbicides; and the mass percentage of the active ingredient in the insecticide composition is 1%-99%.

[0046] The present application improves the lipophilicity and transport properties of the isoxazoline compound by selecting suitable groups for each of Q, R1, R2, and R3, and by coordinating suitable groups among L1, L2, Z1, and Z2, thereby increasing the compound's binding ability to the target receptor. When applied in the field of insecticides, the isoxazoline compound provided in the present application is more easily absorbed by pests, thereby having better insecticidal activity. The isoxazoline compound provided in the present application has no cross-resistance with existing insecticides. Compared with existing insecticides on the market, the compound has the advantages of rapid efficacy, low dosage, low toxicity, and environmental friendliness against plant pests, and has excellent insecticidal effects on rice-resistant rice borer, diamondback moth, aphids, thrips, etc. DETAILED DESCRIPTION

[0047] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. In addition, the meaning of "and / or" appearing throughout the text includes three parallel solutions. Taking "A and / or B" as an example, it includes solution A, solution B, or solutions in which both A and B are satisfied. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0048] Currently, the Chilo suppressalis has also developed serious resistance problems in most parts of the world, posing a great threat to global rice production. In addition, some compounds damage the ecosystem through their long-term residual properties.

[0049] In view of this, the present invention provides an isoxazoline compound and its application, wherein the isoxazoline compound is a compound represented by the following structural formula (I) or its tautomers, metabolic isomers, pharmaceutically acceptable salts or prodrugs:

[0050]

[0051] Q is selected from any one of formulas A1 to A6;

[0052]

[0053] wherein Q is A1, L1 is selected from -C(O)OR4, -C(O)SR4 or -C(O)NHR5, wherein R4 is hydrogen, a monovalent metal ion, an ammonium ion, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a C1-C3 alkyl group, a substituted or unsubstituted hydroxyl group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1- C2 alkoxy C1-C4 alkyl, R5 is substituted or unsubstituted C1-C2 alkoxy C1-C4 alkyl, C1-C3 alkoxycarbonyl C1-C3 alkyl, wherein the substituent is one or more halogen atoms, nitro, nitroso, cyano, amino, hydroxyl, wherein R1, R2, R3 can be independently selected from halogen atoms, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio or C1-C3 haloalkylthio;

[0054] In addition, L1 is selected from one or more hydroxy-substituted C1-C8 alkyl groups, one or more hydroxy-substituted C2-C8 alkenyl groups, or one or more hydroxy-substituted C2-C8 alkynyl groups, wherein R1, R2, and R3 are independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkoxy group, a C1-C3 alkylthio group, or a C1-C3 haloalkylthio group;

[0055] Z1 represents a hydrogen atom, an oxygen atom, a halogen atom, a hydroxyl group, a nitro group, a nitroso group, a cyano group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C1-C5 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylthio group, or -C(O)M , wherein M represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkyl group C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group C1-C6 alkyl group, or a substituted or unsubstituted C1-C6 alkylthio group C1-C6 alkyl group, wherein the substituent group may be one or more halogen atoms, hydroxyl group, nitro group, nitroso group, cyano group, or amino group;

[0056] Q is the structure represented by any one of A2 to A6, R1, R2, and R3 can be independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkoxy group, a C1-C3 alkylthio group, or a C1-C3 haloalkylthio group; L2 is selected from -C(O)OR6, -C(O)SR6, or -C(O)NHR7, wherein R6 is hydrogen, a monovalent metal ion, an ammonium ion, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted cyclopropyl C1-C3 alkyl, R7 is hydrogen, substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, wherein the substituents may be one or more halogen atoms, nitro, nitroso, cyano, amino, or C1-C3 alkoxy;

[0057] In addition, L2 can be selected from one or more hydroxy-substituted C1-C8 alkyl groups, one or more hydroxy-substituted C2-C8 alkenyl groups, and one or more hydroxy-substituted C2-C8 alkynyl groups;

[0058] Z2 represents a hydrogen atom, an oxygen atom, a halogen atom, a hydroxyl group, a nitro group, a nitroso group, a cyano group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkyl group C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkylthio group C1-C6 alkyl group, or -C(O) M, wherein M represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkyl group, a substituted or unsubstituted C1-C5 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylthio group, or a substituted or unsubstituted C1-C6 alkyl group, wherein the substituent group may be one or more halogen atoms, a nitro group, a nitroso group, a cyano group, or an amino group;

[0059] W means O or S;

[0060] X represents O or CH2.

[0061] The application can improve the lipophilicity of the isoxazoline compound, increase the binding ability of the compound to the receptor, and be more easily absorbed by pests when applied in the field of insecticides, thereby having better insecticidal activity. The isoxazoline compound provided by the application has no cross-resistance with existing insecticides, and has the advantages of fast drug efficacy, low dosage, low toxicity, and environmental friendliness compared to existing insecticides on the market, and has excellent insecticidal effect on plant pests such as rice-resistant diamondback moth, diamondback moth, aphid, and thrips.

[0062] Further, since compounds containing many fluorine atoms are generally highly toxic and not easily degradable in the environment, L1 and L2 are preferably selected from ester groups, hydroxyl-substituted alkyl groups, and the like, which do not contain fluorine, thereby reducing the number of fluorine atoms in the compound, making the compound less toxic and more environmentally friendly.

[0063] Further, when Q is A1, R1, R2, and R3 are selected from halogen atoms, cyano groups, nitro groups, and C1-C3 haloalkyl groups, and R2 is a fluorine atom, L1 is an ester group or a hydroxyl-substituted alkyl group, which increases the interaction sites between the drug and the receptor and increases the insecticidal effect.

[0064] In some embodiments of the application, the isoxazoline compound not only includes the structure of formula (I), but also includes the structure of formula I' or its tautomer, pharmaceutically acceptable salt, the carbon at position 5 has R configuration and S configuration, and the chiral 5S configuration is more optimal,

[0065]

[0066] and the stereochemical purity of the S configuration is 50% to 100%, preferably 60-100% (S), more preferably 70-100% (S), further preferably 90-100% (S), and more further preferably 95-100% (S).

[0067] The application also provides an insecticide for killing pests, which comprises an active ingredient, and the active ingredient comprises the isoxazoline compound described above and / or the tautomer, enantiomer, diastereomer, or pesticidally acceptable salt thereof.

[0068] In an embodiment, the mass of the active ingredient accounts for 0.1% to 99% of the mass of the insecticide.

[0069] In embodiments of the present application, the mass percentage of the active ingredient in the insecticide composition is 1%-99%. In some specific embodiments of the present application, the mass percentage of the active ingredient in the insecticide composition can be, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99%. In some embodiments of the present application, the mass percentage of the active ingredient in the insecticide composition is 20%-70%.

[0070] In the embodiment of the present application, the pests that the pesticides are used to control include Lepidoptera, Coleoptera or mites, but are not actually limited thereto, such as green bean weevils, corn weevils, red flour beetles, potato beetles, slender-breasted beetles, multi-colored scarab beetles, potato leaf beetles, leaf beetles, pine saw beetles, rice root weevils, brown powder borers; Lepidoptera pests, such as gypsy moths, yellow-brown tent caterpillars, Pieris rapae Japanese subspecies, Spodoptera litura, cabbage armyworms, striped stem borers, corn borers, dried fruit borers, apple moths, yellow cutworms, greater wax moths, diamondback moths, tobacco budworms , citrus leafminer; Hemiptera pests, for example, black-tailed leafhopper, brown planthopper, mealybug, arrow-pointed shield scale, peach aphid, apple aphid, cotton aphid, radish aphid, pear crown lace bug, green toon, greenhouse whitefly; Thysanoptera pests, for example, palm thrips, western flower thrips; Orthoptera pests, for example, African mole cricket, African locust; Blattodea pests, for example, German cockroach, American cockroach, yellow-breasted termite, formosan termite; Diptera pests, for example, one or more of housefly, Aedes aegypti, gray ground fly, Culex pipiens pallens, Anopheles sinensis, Culex tritaeniorhynchus, and clover leafminer. In some embodiments of the present application, the pesticide may also refer to acaricide, and the pests used for prevention and control include but are not limited to spiders (Arachnids), such as mites (Acarina), for example, soft ticks, hard ticks and scabies, such as the long star tick, tropical flower tick, Persian sharp-edged tick, cattle tick, microscopic cattle tick, ricinus tick, gallinaceous mite, sheep scabies, human scabies; Acarus genus, such as apple rust mite; Tenuiphila genus, such as polyphagous tarsonemus; Tenuiphila genus, such as purple short-palped mite; Tetranychus genus, such as cinnabar leaf mite, etc.

[0071] In one embodiment, the dosage form of the pesticide includes tablets, capsules, granules or aqueous solutions.

[0072] The insecticide formulations include, but are not limited to, the above-mentioned dosage forms, and can also be solutions, emulsions, wettable powders, granular wettable powders, suspensions, powders, foams, pastes, tablets, granules, aerosols, natural agents impregnated with active compounds, synthetic agents impregnated with active compounds, microcapsules, seed coating agents, formulations equipped with combustion devices (which can be smoke and fog cartridges, tanks and coils, etc.), cold fogging agents, hot fogging agents, and the like. These insecticide formulations or animal parasite control agents can be prepared by known methods, for example, by mixing the active ingredient with a filler (such as a liquid diluent or carrier, a liquefied gas diluent or carrier, a solid diluent or carrier), and optionally with a surface active agent (i.e. an emulsifying agent and / or a dispersing agent and / or a foaming agent), and the like.

[0073] In an embodiment, the insecticide further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, or any combination thereof, and the insecticide can be replaced according to the use scenario to achieve the best killing effect.

[0074] The present application also provides an insecticide composition comprising an active ingredient and other active compounds; the active ingredient comprises the isoxazoline compound provided in the foregoing of the present application and / or the tautomer, enantiomer, diastereomer, or a pesticidally acceptable salt thereof of the isoxazoline compound provided in the foregoing of the present application; and the other active compounds comprise one or more of an insecticide, a bait, a disinfectant, a miticide, a nematicide, a fungicide, a growth regulator, and a herbicide.

[0075] In an embodiment of the present application, the mass percentage of the active ingredient in the insecticide composition is 1% to 99%. In some specific embodiments of the present application, the mass percentage of the active ingredient in the insecticide composition can be, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%. In some embodiments of the present application, the mass percentage of the active ingredient in the insecticide composition is 20% to 70%.

[0076] The embodiments of the present application are further illustrated in the following examples. Specifically, the isoxazoline compounds described in the present application are shown in formula (I), Q is A1, A2, A3, and some of the isoxazoline compounds are shown in Table 1, but the isoxazoline compounds described in the present application are not limited to all the compounds in Table 1:

[0077]

[0078] wherein Q represents the following structure:

[0079]

[0080] W is an oxygen atom.

[0081] Table 1: Isotiazolin compounds having chemical formula as shown in formula (I)

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] In the table: c-pr represents cyclopropyl

[0102] In particular, the partial compounds of the isoxazoline compounds described in the present application are shown in formula (I), Q is A4, A5, A6, and some of the partial compounds of the isoxazoline compounds are shown in Table 2, but the isoxazoline compounds described in the present application are not limited to all the compounds in Table 2.

[0103]

[0104] Where Q represents the following structure:

[0105]

[0106]

[0107] W is an oxygen atom.

[0108] Table 2: Isoxazoline compounds having the chemical structure shown in formula (I)

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] In the table: c-pr represents cyclopropyl

[0129] The technical solutions of the present application are further described in detail below in combination with specific examples. It should be understood that the following examples are only used to explain the present application and should not be used to limit the present application.

[0130] Example 1

[0131] The synthesis reaction equation of compound No. 1 in Table 1 is shown as follows:

[0132]

[0133] Preparation method: 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid (6.00 g, 11.60 mmol) and dichlorosulfoxide (10 ml) were added to a reaction bottle, and the reaction was stirred under reflux conditions for 3-4 h, and concentrated under reduced pressure to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5- dihydroisoxazol-3-yl)-2-methylbenzoyl chloride. The obtained acyl chloride was dissolved with ethyl acetate, and then added to a saturated sodium carbonate solution of 1- aminocyclopropylcarbonyl methyl ester hydrochloride (2.64 g, 17.40 mmol), and the reaction was carried out at room temperature, and the reaction progress was monitored by spotting. After the reaction was completed, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then rotary evaporated to obtain the product as a yellow solid (5.30 g, yield 85.67%).

[0134] The nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data of the compound is as follows (δ [ppm]): δ 8.98 (s, 1H), 7.81 (d, J = 6.2 Hz, 2H), 7.60 (d, J = 9.4 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 4.35 (q, J = 18.4 Hz, 2H), 3.65 (s, 3H), 2.40 (s, 3H), 1.45 (q, J = 4.6 Hz, 2H), 1.17 (dd, J = 7.7, 4.6 Hz, 2H).

[0135] ESI-MS (m / z): [M-H-] Calc: 531.0507, Found: 531.0508.

[0136] Example 2

[0137] The synthesis reaction equation of compound No. 14 in Table 1 is shown as follows:

[0138] 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2- methylbenzamido)cyclopropane-1-carboxylic acid

[0139]

[0140] Preparation method: 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5- trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide)cyclopropane-1- carboxylate (3.00 g, 5.63 mmol) was added to 5% potassium hydroxide: methanol = 1:1 volume ratio mixture, hydrolyzed at 40-45 °C for 3-4 h. After the reaction was completed, dilute hydrochloric acid was added to acidify, and a solid was precipitated. After suction filtration and washing with distilled water for several times, the product was obtained as a yellow solid (2.45 g, yield 83.80%).

[0141] The compound's nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data are as follows (δ [ppm]): δ 12.45 (s, 1H), 8.87 (s, 1H), 7.81 (d, J = 6.2 Hz, 2H), 7.59 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 4.41-4.28 (m, 2H), 2.39 (s, 3H), 1.40 (dd, J = 7.6, 4.4 Hz, 2H), 1.10 (q, J = 4.5 Hz, 2H).

[0142] ESI-MS (m / z): [M-H-] Calcd for C26H21F6N4O2: 517.0350, Found: 517.0351.

[0143] Example 3

[0144] The synthesis reaction equation of compound No. 27 in Table 1 is shown below:

[0145] Synthesis of 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzamide)cyclopropane-1-carboxylate

[0146]

[0147] Preparation: Add 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.00 g, 2.29 mmol) and thionyl chloride (5 ml) to a reaction flask. Stir the reaction under reflux for 3-4 hours and concentrate under reduced pressure to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl chloride. Dissolve the resulting acid chloride in ethyl acetate and add 1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride (0.36 g, 2.75 mmol) in saturated sodium carbonate solution. React at room temperature with a microplate reader to monitor the reaction progress. After completion of the reaction, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain the product as a yellow solid (1.11 g, 88.79% yield).

[0148] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 8.97 (s, 1H), 7.81 (d, J = 6.1 Hz, 2H), 7.68-7.53 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 4.44-4.26 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.43 (q, J = 4.6 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.15 (q, J = 4.6 Hz, 2H).

[0149] ESI-MS (m / z): [MH-] Calculated value: 545.0658, found: 545.0662.

[0150] Example 4

[0151] The synthetic reaction equation of compound No. 40 in Table 1 is as follows:

[0152] Synthesis of Cyclopropyl 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclopropane-1-carboxylate

[0153]

[0154] Preparation method: Add 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclopropane-1-carboxylic acid (1.00 g, 1.93 mmol) and dichlorothionyl (5 ml) to a reaction flask, stir and react under reflux for 3-4 hours, and concentrate under reduced pressure to obtain its acid chloride. Dissolve the acid chloride in dichloromethane and add it to cyclopropanol (0.17 g, 2.90 mmol), then add solid potassium carbonate and react at 40°C for 3-4 hours. After the reaction is completed, filter out the potassium carbonate, wash with dilute hydrochloric acid (2 mol / L) and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and spin dry to obtain a yellow solid (0.91 g, yield 84.30%).

[0155] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 8.95 (s, 1H), 7.81 (d, J = 6.2 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 4.40-4.28 (m, 2H), 4.12 (tt, J = 6.3, 3.0 Hz, 1H), 2.38 (s, 3H), 1.42 (q, J = 4.6 Hz, 2H), 1.15 (q, J = 4.6 Hz, 2H), 0.71 (q, J = 6.3 Hz, 2H), 0.63-0.57 (m, 2H).

[0156] ESI-MS (m / z): [MH-] Calculated: 557.0663, found: 557.0661.

[0157] Example 5

[0158] The synthetic reaction equation of compound No. 92 in Table 1 is as follows:

[0159] Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-2-methylbenzamide

[0160]

[0161] Preparation: 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.00 g, 2.29 mmol) was added to a reaction flask and dissolved in dichloromethane (5 mL). EDCI (0.65 g, 3.44 mmol) was added and activated in an ice bath for 30 min. 1-Hydroxybenzotriazole (0.37 g, 3.44 mmol) and triethylamine (0.93 g, 9.17 mmol) were added, followed by 1-aminocyclopropylmethanol (0.30 g, 3.44 mmol). The reaction was detected by spot plate detection until complete. After the reaction was completed, dichloromethane was added and the mixture was washed with dilute hydrochloric acid (2 mol / L). Solid potassium carbonate was added and stirred at room temperature for several hours. The potassium carbonate was filtered off, and the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried to obtain a yellow solid (0.81 g, 69.83% yield).

[0162] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 8.56 (s, 1H), 7.81 (d, J = 6.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.8 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.41-4.26 (m, 2H), 3.55 (d, J = 5.7 Hz, 2H), 2.32 (d, J = 18.2 Hz, 3H), 0.79-0.72 (m, 2H), 0.72-0.65 (m, 2H).

[0163] ESI-MS (m / z): [MH-] Calculated: 503.0552, Found: 503.0558.

[0164] Example 6

[0165] The synthetic reaction equation of compound No. 93 in Table 1 is as follows:

[0166] Synthesis of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-2-methylbenzamide

[0167]

[0168] Preparation method: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.00 g, 2.39 mmol) was added to a reaction bottle, dissolved with dichloromethane (5 mL), EDCI (0.69 g, 3.59 mmol) was activated for 30 min in an ice bath, then 1-hydroxybenzotriazole (0.48 g, 3.59 mmol) and triethylamine (0.96 g, 9.56 mmol) were added, and then 1- aminocyclopropanemethanol (0.31 g, 3.59 mmol) was added, and the reaction was detected by spotting on a plate until the reaction was completed. The reaction was detected by spotting on a plate until the reaction was completed. After the reaction was completed, it was spin-dried, dichloromethane was added, washed with dilute hydrochloric acid (2 mol / L), then solid potassium carbonate was added, stirred at room temperature for several hours, the potassium carbonate was filtered off, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, spin-dried to obtain a yellow solid (0.85 g, yield 72.96%).

[0169] The compound has a nuclear magnetic resonance hydrogen spectrum (400 MHz, Chloroform-d) δ 7.53 (d, J = 1.8 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 1.9 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.43 (s, 1H), 4.09 (d, J = 17.2 Hz, 1H), 3.73 (d, J = 2.1 Hz, 3H), 2.47 (s, 3H), 1.05 - 0.99 (m, 2H), 1.00 - 0.94 (m, 2H).

[0170] ESI-MS (m / z): [M-H-] Calc: 485.0647, Found: 485.0652.

[0171] Example 7

[0172] The synthesis reaction equation of compound No. 189 in Table 1 is as follows:

[0173]

[0174] Preparation method: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.00 g, 2.39 mmol) was added to a reaction bottle, dissolved with dichloromethane (5 mL), EDCI (0.69 g, 3.59 mmol) was activated for 30 min in an ice bath, then 1-hydroxybenzotriazole (0.48 g, 3.59 mmol) and triethylamine (0.96 g, 9.56 mmol) were added, and then 1- aminocyclopropanemethanol (0.31 g, 3.59 mmol) was added, and the reaction was detected by spotting on a plate until the reaction was completed. The reaction was detected by spotting on a plate until the reaction was completed. After the reaction was completed, it was spin-dried, dichloromethane was added, washed with dilute hydrochloric acid (2 mol / L), then solid potassium carbonate was added, stirred at room temperature for several hours, the potassium carbonate was filtered off, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, spin-dried to obtain a yellow solid (0.85 g, yield 72.96%).

[0175] The nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.63 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 4.35 (q, J = 18.3 Hz, 2H), 3.69 (s, 3H), 2.72-2.62 (m, 1H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 1.85-1.70 (m, 3H), 1.24 (d, J = 11.1 Hz, 1H), 0.91 (t, J = 7.2 Hz, 3H).

[0176] ESI-MS (m / z): [M-H-] Calcd: 587.0769, Found: 587.0775.

[0177] Example 8

[0178] The synthesis reaction equation of compound No. 202 in Table 1 is as follows:

[0179]

[0180] Preparation method: 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5- dihydroisoxazol-3-yl)-2-methylbenzamido)cyclopropane-1-carboxylate (1.00 g, 1.88 mmol) was dissolved in toluene, heated to 80-100°C, then acryloyl chloride (0.51 g, 5.64 mmol) was added, and reacted at 100°C for 4-5 h. After the reaction was completed, methylene chloride was added, and then washed with dilute hydrochloric acid (2 mol / L), saturated sodium carbonate solution, and saturated sodium chloride solution, respectively. After drying with anhydrous sodium sulfate, the white solid (0.51 g, yield 46.19%) was obtained by silica gel column chromatography.

[0181] The nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.63 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.52 (dd, J = 16.8, 10.4 Hz, 1H), 6.15 (dd, J = 16.8, 1.4 Hz, 1H), 5.76 (dd, J = 10.4, 1.4 Hz, 1H), 4.35 (q, J = 18.3 Hz, 2H), 3.69 (s, 3H), 2.34 (s, 3H), 1.87-1.74 (m, 2H), 1.58-1.35 (m, 2H).

[0182] ESI-MS (m / z): [MH-] Calculated value: 585.0612, found: 585.0614.

[0183] Example 9

[0184] The synthetic reaction equation of compound No. 215 in Table 1 is as follows:

[0185]

[0186] Preparation method: 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclopropane-1-carboxylic acid methyl ester (1.00 g, 1.88 mmol) was dissolved in toluene, the temperature was raised to 80°C-100°C, methoxyacetyl chloride (0.61 g, 5.64 mmol) was added, and the reaction was carried out at 100°C for 4-5 hours. After the reaction was completed, dichloromethane was added after drying, and the mixture was washed with dilute hydrochloric acid (2 mol / L), saturated sodium carbonate solution, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography to obtain a white solid (0.75 g, yield 65.90%).

[0187] The H NMR spectrum (400 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 4.36 (dd, J = 37.5, 18.4 Hz, 3H), 4.15 (t, J = 18.1 Hz, 1H), 3.69 (s, 3H), 3.21 (s, 3H), 2.36 (s, 3H), 1.67 (d, J = 39.6 Hz, 3H), 1.17 (s, 1H).

[0188] ESI-MS (m / z): [MH-] Calculated: 603.0718, Found: 603.0714.

[0189] Example 10

[0190] The synthetic reaction equation of compound No. 228 in Table 1 is as follows:

[0191]

[0192] Preparation method: 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclopropane-1-carboxylic acid methyl ester (1.00 g, 1.88 mmol) was dissolved in toluene, the temperature was raised to 80°C-100°C, cyclopropylcarbonyl chloride (0.59 g, 5.64 mmol) was added, and the reaction was carried out at 100°C for 4-5 hours. After the reaction was completed, dichloromethane was added after drying, and the mixture was washed with dilute hydrochloric acid (2 mol / L), saturated sodium carbonate solution, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography to obtain a white solid (0.57 g, yield 50.42%).

[0193] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.63-7.52 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 4.34 (q, J = 18.3 Hz, 2H), 3.71 (s, 3H), 2.32 (s, 3H), 2.03-1.93 (m, 1H), 1.90-1.79 (m, 2H), 1.63 (s, 1H), 1.42 (s, 1H), 0.91-0.72 (m, 4H).

[0194] ESI-MS (m / z): [MH-] Calculated: 599.0769, Found: 599.0766.

[0195] Example 11

[0196] The synthetic reaction equation of compound No. 258 in Table 1 is as follows:

[0197]

[0198] Preparation: 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (6.00 g, 12.30 mmol) and thionyl chloride (10 ml) were added to a reaction flask. The reaction was stirred at reflux for 3-4 hours and concentrated under reduced pressure to obtain 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-1-naphthoyl chloride. The obtained acid chloride was dissolved in ethyl acetate and added to a saturated sodium carbonate solution of methyl 1-aminocyclopropanecarboxylate hydrochloride (2.80 g, 18.45 mmol). The reaction was allowed to react at room temperature with a microplate reader to monitor the reaction progress. After the reaction, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain the product as a yellow solid (6.46 g, 89.79% yield).

[0199] The hydrogen nuclear magnetic resonance spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ [ppm]): δ 9.30 (s, 1H), 8.84-8.77 (m, 1H), 8.37-8.31 (m, 1H), 8.09 (d, J = 23.6 Hz, 2H), 7.98-7.88 (m, 2H), 7.77-7.68 (m, 2H), 7.63 (d, J = 7.5 Hz, 1H), 4.66-4.57 (m, 2H), 3.73 (s, 3H), 1.52 (dd, J = 7.7, 4.6 Hz, 2H), 1.27 (dd, J = 7.8, 4.6 Hz, 2H).

[0200] ESI-MS (m / z): [MH-] Calculated: 583.0864, ​​Found: 583.0866.

[0201] Example 12

[0202] The synthetic reaction equation of compound No. 473 in Table 1 is as follows:

[0203] Synthesis of methyl 1-(3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamido)cyclopropane-1-carboxylate

[0204]

[0205] Preparation: Add 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride (1.00 g, 2.18 mmol) and thionyl chloride (5 ml) to a reaction flask. Stir and react at reflux for 3-4 hours. Concentrate under reduced pressure to obtain 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride. Dissolve the resulting acid chloride in ethyl acetate and add methyl 1-aminocyclopropanecarboxylate hydrochloride (0.39 g, 2.62 mmol) in a saturated sodium carbonate solution. React at room temperature with a microplate reader to monitor the reaction progress. After the reaction, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then spin-dried to obtain the product as a yellow solid (1.03 g, yield 82.52%).

[0206] The hydrogen nuclear magnetic resonance spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ[ppm]): 1H NMR (500 MHz, DMSO-d6) 8.84 (s, 1H), 7.82 (s, 2H), 7.34 (s, 1H), 4.43-4.27 (m, 2H), 3.62 (s, 3H), 2.40 (s, 3H), 1.44 (q, J = 4.6 Hz, 2H), 1.18 (q, J = 4.7 Hz, 2H).

[0207] ESI-MS (m / z): [MH-] Calculated value: 552.9770, found: 552.9782.

[0208] Example 13

[0209] The synthetic reaction equation of compound No. 489 in Table 1 is as follows:

[0210] Synthesis of Ethyl 1-(3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamido)cyclopropane-1-carboxylate

[0211]

[0212] Preparation: 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride (1.00 g, 2.18 mmol) and thionyl chloride (5 ml) were added to a reaction flask. The reaction was stirred at reflux for 3-4 hours and concentrated under reduced pressure to obtain 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride. The obtained acid chloride was dissolved in ethyl acetate and added to a saturated sodium carbonate solution of ethyl 1-aminocyclopropanecarboxylate (0.38 g, 2.62 mmol). The reaction was allowed to react at room temperature with a microplate reader to monitor the reaction progress. After the reaction, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain the product as a yellow solid (1.08 g, 81.30% yield).

[0213] The hydrogen nuclear magnetic resonance spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ[ppm]): 1H NMR (500 MHz, DMSO-d6) 8.85 (s, 1H), 7.82 (s, 2H), 7.34 (s, 1H), 4.42-4.29 (m, 2H), 4.07 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.43 (q, J = 4.6 Hz, 2H), 1.22-1.08 (m, 5H).

[0214] ESI-MS (m / z): [MH-] Calculated: 566.9927, found: 566.9934.

[0215] Example 14

[0216] The synthetic reaction equation of compound No. 516 in Table 1 is as follows:

[0217] Synthesis of N-(1-(hydroxymethyl)cyclopropyl)-3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamide

[0218]

[0219] Preparation method: Add 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoic acid (1.00 g, 2.18 mmol) to the reaction bottle, dissolve it with dichloromethane (5 mL), add EDCI (0.63 g, 3.28 mmol) and activate it in an ice bath for 30 minutes, then add 1-hydroxybenzotriazole (0.43 g, 3.28 mmol) and triethylamine (0.88 g, 8.73 mmol), and then add 1-aminocyclopropylmethanol (0.29 g, 3.28 mmol), and detect by spot plate until the reaction is completed. After the reaction, the mixture was dried by rotary evaporation and added with dichloromethane. After washing with dilute hydrochloric acid (2 mol / L), solid potassium carbonate was added and stirred at room temperature for several hours. After filtering out the potassium carbonate, the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and rotary evaporation to obtain a yellow solid (0.89 g, yield 77.39%).

[0220] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 8.37 (s, 1H), 7.81 (s, 2H), 7.30 (s, 1H), 5.76 (s, 0H), 4.41-4.28 (m, 2H), 3.51 (s, 2H), 2.37 (s, 3H), 0.81-0.72 (m, 2H), 0.73-0.65 (m, 2H).

[0221] ESI-MS (m / z): [MH-] Calculated value: 524.9821, found: 524.9828.

[0222] Example 15

[0223] The synthetic reaction equation of compound No. 676 in Table 1 is as follows:

[0224]

[0225] Preparation: Add 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (6.00 g, 11.60 mmol) and thionyl chloride (10 ml) to a reaction flask. Stir the reaction under reflux for 3-4 hours and concentrate under reduced pressure to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl chloride. Dissolve the resulting acid chloride in ethyl acetate and add methyl 1-aminocyclobutanecarboxylate (2.25 g, 17.40 mmol) in saturated sodium carbonate solution. React at room temperature with a microplate reader to monitor the reaction progress. After completion of the reaction, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain the product as a yellow solid (6.12 g, 96.39% yield).

[0226] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 9.15 (s, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.62 (d, J = 4.6 Hz, 2H), 7.47-7.43 (m, 1H), 4.35 (q, J = 18.4 Hz, 2H), 3.67 (s, 3H), 2.58 (ddd, J = 12.6, 9.0, 6.0 Hz, 2H), 2.38 (s, 3H), 2.33-2.24 (m, 2H), 2.03-1.88 (m, 2H).

[0227] ESI-MS (m / z): [MH-] Calculated: 545.0663, Found: 545.0658.

[0228] Example 16

[0229] The synthetic reaction equation of compound No. 692 in Table 2 is as follows:

[0230] Synthesis of 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclobutane-1-carboxylic acid

[0231]

[0232] Preparation: Methyl 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclobutane-1-carboxylate (3.00 g, 5.48 mmol) was added to a mixture of 5% potassium hydroxide and methanol in a 1:1 volume ratio and hydrolyzed at 40-45°C for 3-4 hours. After the reaction was completed, dilute hydrochloric acid was added to acidify the mixture. A solid precipitated, which was filtered, rinsed several times with distilled water, and dried to obtain the product as a yellow solid (2.30 g, 78.70% yield).

[0233] The H NMR spectrum (400 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 12.36 (s, 1H), 9.00 (s, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.61 (d, J = 6.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 4.43-4.28 (m, 2H), 2.60-2.52 (m, 2H), 2.39 (s, 3H), 2.30-2.20 (m, 2H), 2.01-1.90 (m, 2H).

[0234] ESI-MS (m / z): [MH-] Calculated: 531.0507, Found: 531.0507.

[0235] Example 17

[0236] The synthetic reaction equation of compound No. 708 in Table 2 is as follows:

[0237] Synthesis of Cyclopropyl 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclobutane-1-carboxylate

[0238]

[0239] Preparation method: Add 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclobutane-1-carboxylic acid (1.00 g, 1.88 mmol) and dichlorothionyl (5 ml) to a reaction flask, stir and react under reflux for 3-4 hours, and concentrate under reduced pressure to obtain its acid chloride. Dissolve the acid chloride in dichloromethane and add it to cyclopropanol (0.16 g, 2.82 mmol), then add solid potassium carbonate and react at 40°C for 3-4 hours. After the reaction, filter out the potassium carbonate, wash with dilute hydrochloric acid (2 mol / L) and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and spin dry to obtain a yellow solid (0.85 g, yield 78.86%).

[0240] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 9.14 (s, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.61 (d, J = 6.3 Hz, 2H), 7.43-7.39 (m, 1H), 4.41-4.28 (m, 2H), 4.11 (tt, J = 6.3, 3.0 Hz, 1H), 2.55 (ddd, J = 12.7, 9.0, 5.8 Hz, 2H), 2.37 (s, 3H), 2.26 (dt, J = 12.4, 9.4 Hz, 2H), 2.01-1.86 (m, 2H), 0.71 (q, J = 6.2 Hz, 2H), 0.63-0.56 (m, 2H).

[0241] ESI-MS (m / z): [MH-] Calculated: 571.0820, Found: 571.0823.

[0242] Example 18

[0243] The synthetic reaction equation of compound No. 740 in Table 1 is as follows:

[0244]

[0245] Preparation: 1-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)cyclobutane-1-carboxylic acid (1.00 g, 1.88 mmol) was dissolved in acetonitrile, and CDI (0.34 g, 2.07 mmol) was added. The mixture was activated at room temperature for 30 min, followed by the addition of 2,2,2-trifluoroethylamine (0.28 g, 2.82 mmol) and DBU (0.30 g, 1.97 mmol). The reaction was performed by spot plate detection until the reaction was complete. After the reaction was completed, dichloromethane was added to the mixture, and the mixture was washed with dilute hydrochloric acid (2 mol / L). Solid potassium carbonate was added and stirred at room temperature for several hours. The potassium carbonate was filtered off, and the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried to obtain a yellow solid (0.86 g, 74.46% yield).

[0246] The H NMR spectrum (500 MHz, DMSO-d6) of the compound was as follows (δ [ppm]): δ 8.91 (s, 1H), 8.13 (t, J = 6.3 Hz, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.4 Hz, 2H), 4.43-4.29 (m, 2H), 3.95-3.85 (m, 2H), 2.56 (dt, J = 12.2, 9.0 Hz, 2H), 2.38 (s, 3H), 2.24 (dd, J = 19.6, 9.4 Hz, 2H), 2.00-1.81 (m, 2H).

[0247] ESI-MS (m / z): [MH-] Calculated value: 612.0697, found: 612.0700.

[0248] Example 19

[0249] The synthetic reaction equation of compound No. 1133 in Table 2 is as follows:

[0250] Synthesis of methyl 1-(3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamido)cyclobutane-1-carboxylate

[0251]

[0252] Preparation: 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride (1.00 g, 2.18 mmol) and thionyl chloride (5 ml) were added to a reaction flask. The reaction was stirred at reflux for 3-4 hours and concentrated under reduced pressure to obtain 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoyl chloride. The obtained acid chloride was dissolved in ethyl acetate and added to a saturated sodium carbonate solution of methyl 1-aminocyclobutanecarboxylate (0.38 g, 2.62 mmol). The reaction was allowed to react at room temperature with a microplate reader to monitor the reaction progress. After the reaction, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain the product as a yellow solid (0.98 g, 79.67% yield).

[0253] The H NMR spectrum (500 MHz, DMSO-d6) of the compound is as follows (δ [ppm]): δ 1H NMR (500 MHz, DMSO-d6) 8.96 (s, 1H), 7.82 (s, 2H), 7.35 (s, 1H), 4.43-4.29 (m, 2H), 3.64 (s, 3H), 2.63-2.52 (m, 2H), 2.40 (s, 3H), 2.35-2.23 (m, 2H), 2.03-1.86 (m, 2H).

[0254] ESI-MS (m / z): [MH-] Calculated value: 566.9927, found: 566.9929.

[0255] Example 20

[0256] The synthetic reaction equation of compound No. 1149 in Table 2 is as follows:

[0257] Synthesis of N-(1-(hydroxymethyl)cyclobutyl)-3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxamide

[0258]

[0259] Preparation: 3-Methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-benzoic acid (1.00 g, 2.18 mmol) was dissolved in dichloromethane (5 mL) and EDCI (0.63 g, 3.28 mmol) was added. The mixture was activated in an ice bath for 30 min, followed by the addition of 1-hydroxybenzotriazole (0.43 g, 3.28 mmol) and triethylamine (0.88 g, 8.73 mmol). 1-Aminocyclobutanemethanol (0.33 g, 3.28 mmol) was then added and the reaction was continued by spot plate detection until complete. After the reaction was completed, dichloromethane was added and the mixture was washed with dilute hydrochloric acid (2 mol / L). Solid potassium carbonate was added and stirred at room temperature for several hours. The potassium carbonate was filtered off, and the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried to obtain a yellow solid (0.89 g, 75.23% yield).

[0260] The nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ [ppm]): δ 7.95 (s, 1H), 7.81 (s, 2H), 7.30 (s, 1H), 4.85 (t, J = 5.8 Hz, 1H), 4.34 (q, J = 18.2 Hz, 2H), 3.61 (d, J = 5.7 Hz, 2H), 2.38 (s, 3H), 2.23 (q, J = 10.0 Hz, 2H), 2.10 (td, J = 9.1, 4.9 Hz, 2H), 1.83 (s, 1H), 1.73 (dt, J = 10.7, 8.5 Hz, 1H).

[0261] ESI-MS (m / z): [M-H-] Calcd: 538.9978, Found: 538.9991.

[0262] Example 21

[0263] The synthesis reaction equation of compound No. 1336 in Table 2 is as follows:

[0264]

[0265] Preparation method: 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid (6.00 g, 11.60 mmol) and dichlorosulfoxide (10 ml) were added into a reaction bottle, and the reaction was stirred under reflux condition for 3-4 h, and concentrated under reduced pressure to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl chloride. The obtained acyl chloride was dissolved with ethyl acetate, and then added into a saturated sodium carbonate solution of 3-aminooxetan-3-carboxylic acid methyl ester (2.28 g, 17.40 mmol), and the reaction was carried out at room temperature, and the reaction progress was monitored by spotting. After the reaction was completed, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the product as a yellow solid (5.46 g, yield 88.51%).

[0266] The nuclear magnetic resonance hydrogen spectrum (500 MHz, DMSO-d6) data of the compound are as follows (δ [ppm]): δ 9.62 (s, 1H), 7.81 (t, J = 6.6 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 4.93 (d, J = 6.7 Hz, 2H), 4.68 (d, J = 6.7 Hz, 2H), 4.36 (q, J = 18.4 Hz, 2H), 3.76 (s, 3H), 2.40 (s, 3H).

[0267] ESI-MS (m / z): [MH-] Calculated: 547.0456, Found: 547.0458.

[0268] In the embodiment of the present invention, the isoxazoline compounds shown by other compound numbers in Table 1-2 can be prepared by making corresponding adjustments in the preparation methods described in the above examples. When the isoxazoline compound is a stereoisomer of the compound of formula I, it can be obtained by conventional methods, such as: starting from optically active reaction raw materials to obtain a reaction product with corresponding optical activity, and performing chiral resolution of the racemic or meso reaction product. This embodiment will not be discussed in detail, and equivalent changes made in the claims are still within the scope of the invention.

[0269] Effect embodiment

[0270] Some of the compounds listed in this application were tested for their activity against various pests.

[0271] (1) Chilo suppressalis activity assay:

[0272] Compound solution preparation: 10 mg of the original drug was weighed on a balance and prepared into a 1% stock solution with DMF. The stock solution was then diluted with distilled water containing 0.1% Tween-80 to four test concentrations of 10 mg / L, 3.0 mg / L, 1.5 mg / L, and 0.85 mg / L.

[0273] Using the immersion method, thin slices of water chestnuts were soaked in the medicine for 30 seconds, and then placed in a plastic box lined with filter paper to dry naturally in the shade. Ten 2-3 year old rice stem borers were placed in each box and observed in a room at 26℃ with 16 hours of light and 8 hours of darkness. The number of dead insects was observed after 3 days to measure the mortality rate.

[0274] The control compound CK01 is chlorantraniliprole as shown in formula (II), the control compound CK02 is as shown in formula (III), and the control compound CK03 is as shown in formula

[0275]

[0276] Among them, the technical drugs are derived from the compounds in Table 1, specifically: 1, 1(5S), 8, 14, 27, 34, 40, 47, 53, 66, 92, 189, 196, 202, 209, 215, 222, 228, 231, 243, 250, 258, 274, 473, 489, 516, 676, 692, 708, 740, 1133, 1149, and 1336. The mortality rate of the compounds to Chilo suppressalis was greater than 80% after 4 days at a concentration of 10 mg / L. Then, some highly active compounds 1, 1(5S), 27, 40, 92, 189, 196, 202, 209, 215, 222, 228, and 243 were tested for activity at low concentrations, and the results are shown in Table 3.

[0277] Table 3: The results of activity determination of some compounds in Table 1-2 on Chilo suppressalis

[0278]

[0279]

[0280]

[0281] Note: The compound number corresponds to Table 1-2, and (5S) after the compound number indicates that the 5 position of general formula (I) is S configuration.

[0282] From Table 3, it can be seen that the compounds 1 (5S), 27, 40, 92, 189, 196, 202, 209, 215, 222, 228, 243 of the application have a mortality rate of more than 80% on Chilo suppressalis at a low concentration of 0.85 mg / L, and a mortality rate of 100% on Chilo suppressalis at a low concentration of 1.5 mg / L.

[0283] The control compound CK01, i.e. chlorantraniliprole, has a mortality rate of only 20% on Chilo suppressalis even at a high concentration of 3.0 mg / L, and CK02 and CK03 have a mortality rate of less than 50% on Chilo suppressalis at 0.85 mg / L, and it is still difficult to reach 80% on resistant Chilo suppressalis even at a concentration of 1.5 mg / L.

[0284] (B) Activity determination on Plutella xylostella:

[0285] Compound solution preparation: 10 mg of technical material was weighed on a balance, and 1% mother liquor was prepared with DMF, and then diluted with distilled water containing 0.1% Tween-80 to 3 mg / L, 1 mg / L, 0.45 mg / L, 0.225 mg / L for standby.

[0286] The leaf blades of Chinese cabbage were immersed in the solution for 10 s, then placed in a plastic box lined with filter paper and naturally air-dried, 10 3rd instar Plutella xylostella were put in each box, and observed in an indoor environment with 16 h light and 8 h darkness at 26℃, and the number of dead insects was observed after 3 days to measure the mortality rate.

[0287] Among them, compounds 1, 1(5S), 8, 14, 27, 34, 40, 47, 53, 66, 92, 189, 196, 202, 209, 215, 222, 228, 231, 243, 250, 258, 274, 473, 489, 516, 676, 692, 708, 740, 1133, 1149, and 1336 all showed a mortality rate of greater than 80% against Plutella xylostella at a concentration of 3 mg / L after 3 days. The activity of 1, 1(5S), 27, 40, 92, 189, 196, 202, 209, 215, 222, 228, and 243 was further tested at lower concentrations (1 mg / L, 0.45 mg / L, and 0.225 mg / L), and the results are shown in Table 4.

[0288] Table 4: Activity test results of some compounds in Table 1-2 against Plutella xylostella

[0289]

[0290]

[0291] Note: The compound numbers correspond to those in Table 1. The number (5S) after the compound number indicates that the 5-position of the general formula (I) is S-configured.

[0292] As shown in Table 4, the compounds 1, 1(5S), 27, 40, 92, 189, 196, 202, 209, 215, 222, 228, and 243 of the present invention had a mortality rate of more than 80% against the diamondback moth at a concentration of 0.225 mg / L, and at a concentration of 0.45 mg / L, the compounds of the present invention had a mortality rate of 100% against the diamondback moth.

[0293] The control compound CK01, also known as chlorantraniliprole, had a mortality rate of only 20% against resistant diamondback moths even at a high concentration of 1 mg / L, while the mortality rates of CK02 and CK03 against diamondback moths were both below 50% at a concentration of 0.225 mg / L, and even at a concentration of 0.45 mg / L, the mortality rate against resistant diamondback moths was still difficult to reach 80%.

[0294] It should be noted that the isoxazoline compounds provided by the present invention have high biological activity against both the striped stem borer and the diamondback moth, and the isoxazoline compounds have no cross-resistance with chlorantraniliprole. In small organic molecule pesticide compounds, due to the different types of substituents, group volumes, and electronegativity, the metabolic performance, conduction performance, and binding performance of the entire molecule in the organism will be very different, and thus the differences in biological activity exhibited will also be very large, and the metabolic performance, conduction performance, and ability of the molecule to bind to the receptor are unpredictable; generally, compounds containing many fluorine atoms are highly toxic and not easily degraded in the environment. The preferred compounds of the present invention are derived from fluorine-free groups such as ester groups and hydroxyl-substituted alkyl groups through L1 and L2, reducing the number of fluorine atoms in such compounds so that the compounds are more environmentally friendly. Compared with existing insecticides on the market, the isoxazoline compounds provided by the present invention have the advantages of fast efficacy, low dosage, and environmental friendliness to plant pests.

[0295] The above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art will readily appreciate that the present invention is susceptible to various modifications and variations. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of the present invention.

Claims

1. An isoxazoline compound, characterized in that The isoxazoline compound has a structure shown in the following structural formula (I): Q is the structure shown in formula A1; Wherein, W represents O or S; L1 is taken from -C(O)OR4, where R4 is at least one of methyl, ethyl, and cyclopropyl; Z1 is C(O)M, where M represents C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, and C1-C3 alkyl; where R1 and R3 can be independently selected from halogen atoms and trifluoromethyl, and R2 is a halogen atom.

2. The isoxazoline compound according to claim 1, wherein The isoxazoline compound comprises a structure shown in formula A1, wherein L1 is selected from -C(O)OR4, wherein R4 is at least one of methyl, ethyl, and cyclopropyl, Z1 is C(O)M, wherein M represents a C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, or C1-C3 alkyl; wherein R1 and R3 are chlorine atoms, and R2 is a fluorine atom; and W represents O.

3. The isoxazoline compound according to claim 1, wherein The isoxazoline compounds also include the structure shown in Formula I' or its tautomers and pharmaceutically acceptable salts, wherein the carbon at position 5 is a chiral carbon and has an R configuration and an S configuration, and the stereochemical purity of the S configuration is 50% to 100%.

4. Use of the isoxazoline compound according to claim 3 in the preparation of insecticides.

5. An insecticide for killing insects, characterized in that: The insecticide comprises an active component, and the active component comprises the isoxazoline compound according to any one of claims 1 to 3 and / or the tautomer, enantiomer, diastereomer or pesticide-acceptable salt thereof of the isoxazoline compound.

6. The insecticide according to claim 5, wherein The mass of the active component accounts for 0.1% to 99% of the mass of the insecticide.

7. The insecticide according to claim 5, wherein The pests include rice-resistant stem borer, diamondback moth, aphids or thrips.

8. The insecticide according to any one of claims 5 to 7, characterized in that The pesticide further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or any combination thereof.

9. An insecticide composition, characterized in that The insecticide composition includes active ingredients and other active compounds; the active ingredients include the isoxazoline compound according to any one of claims 1 or 2 or the tautomers, enantiomers, diastereomers or pesticide-acceptable salts of the isoxazoline compound according to claim 3; the other active compounds include one or more of insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators and herbicides; the mass percentage of the active ingredients in the insecticide composition is 1%-99%.

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