An arylcarboxamide acyl isoxazoline compound and isomers thereof or a pharmaceutically acceptable salt thereof, and uses thereof

Abstract

The application provides an arylcarboxamide acyl isoxazoline compound and an isomer or a pharmaceutically acceptable salt thereof, and an application thereof, and the structure of the arylcarboxamide acyl isoxazoline compound is shown in formula (I): (I); wherein R1, R2, R3, R4 and R5 are independently selected from a hydrogen atom, a halogen atom and the like; L1 is a C1-C6 linear or branched alkylene; R6 is selected from a cyano group, a C1-C5 alkyl group substituted with a first substituent or unsubstituted and the like; R7 is selected from a hydrogen atom, a C1-C8 alkyl group substituted with a second substituent or unsubstituted and the like; R8 is selected from any one of a C1-C4 alkyl group, a C1-C4 haloalkyl group and the like; Z1 is a sulfur atom, an oxygen atom or -NH-; and Z2 is a sulfur atom or an oxygen atom. The arylcarboxamide acyl isoxazoline compound has no cross-resistance with existing insecticides, has a high and efficient prevention and control effect on pests, is low in toxicity to aquatic organisms, is environment-friendly, and is suitable for large-scale application.

Description

Technical Field

[0001] This invention relates to the field of organic compound technology, specifically to an arylformamide acyl isoxazoline compound and its isomers or pharmaceutically acceptable salts thereof, and their applications. Background Technology

[0002] In the production and cultivation of agricultural crops and forestry plants, pests can cause serious economic losses, thus necessitating the use of insecticides for pest control. In recent years, however, the long-term and large-scale use of insecticides has led to the development of resistance in many pests to a large number of existing pesticides. Higher dosages are now required to achieve the desired control effect, posing numerous challenges to agricultural production and the ecological environment. For example, chlorantraniliprole is a commonly used and highly effective insecticide for controlling rice stem borers, corn borers, cotton bollworms, and diamondback moths. However, after years of continuous use, serious resistance problems have emerged in most parts of the world, particularly in rice cultivation, where resistant rice stem borers have had a significant impact on rice production. Furthermore, some pesticides have high toxicity to non-target organisms such as aquatic organisms like fish, or have long residual periods, causing serious damage to ecosystems. Therefore, there is an urgent need for a new type of insecticide that is highly effective, low in toxicity, and environmentally friendly. Summary of the Invention

[0003] In view of this, this application provides an arylformamide acyl isoxazoline compound, its isomers, or pharmaceutically acceptable salts thereof, and their applications. On the one hand, this arylformamide acyl isoxazoline compound exhibits no cross-resistance with existing insecticides and demonstrates highly effective pest control, particularly against the rice stem borer. On the other hand, this compound exhibits low toxicity to aquatic organisms, is environmentally friendly, and is suitable for large-scale application.

[0004] The first aspect of this application provides an arylformamide acyl isoxazoline compound and its isomers or pharmaceutically acceptable salts thereof, the structure of which is shown in formula (I): (Ⅰ); In equation (Ⅰ), Q is the structure shown in equation (Q-1) or the structure shown in equation (Q-2): (Q-1); (Q-2); R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen atom, halogen atom, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, and C1-C8 haloalkoxy. L1 is a C1-C6 straight-chain or branched alkylene group; R6 is selected from cyano, C1-C5 alkyl with or without first substituted group, C1-C5 alkoxy with or without first substituted group, C1-C5 alkoxycarbonyl with or without first substituted group, C3-C5 cycloalkyl ester with or without first substituted group, C1-C4 alkylene C1-C4 alkoxy with or without first substituted group, and -C(=O)NHR 6a Any one of them, where R 6a It is selected from any one of C1-C5 alkyl groups substituted or unsubstituted with the first substituent group, and C3-C6 cycloalkyl groups substituted or unsubstituted with the first substituent group; the first substituent group is a halogen atom, a cyano group, or a C1-C5 alkoxy group; R7 is selected from hydrogen atom, C1-C8 alkyl with or without second substitution group, C2-C8 alkenyl with or without second substitution group, C2-C8 alkynyl with or without second substitution group, C3-C6 cycloalkyl with or without second substitution group, C1-C4 alkylene C3-C6 cycloalkyl with or without second substitution group, C1-C4 alkylene C1-C4 alkoxy with or without second substitution group, C1-C4 alkylene C1-C4 alkylthio with or without second substitution group, and -C(=O)R. 7a Any one of them, where R 7a It is selected from any one of the following: C1-C8 alkyl with or without a second substituent group; C2-C8 alkenyl with or without a second substituent group; C2-C8 alkynyl with or without a second substituent group; C1-C8 alkoxy with or without a second substituent group; C3-C6 cycloalkyl with or without a second substituent group; C1-C4 alkylene C3-C6 cycloalkyl with or without a second substituent group; and C1-C4 alkylene C1-C4 alkoxy with or without a second substituent group; wherein the second substituent group is a halogen atom, a cyano group, or a hydroxyl group; R8 is selected from any one of C1-C4 alkyl, C1-C4 haloalkyl, cyano, and halogen atoms; Z1 is a sulfur atom, an oxygen atom, or -NH-; Z2 is a sulfur atom or an oxygen atom.

[0005] In some embodiments of this application, R6 is selected from cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, C3-C5 cycloalkyl ester, C1-C3 alkylene C1-C3 alkoxy, and -C(=O)NHR. 6a Any one of them, where R 6aSelected from any one of C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, and halocyclopropyl; R7 is selected from hydrogen atom, C1-C5 alkyl with or without second substitution group, C2-C5 alkenyl with or without second substitution group, C2-C5 alkynyl with or without second substitution group, cyclopropyl with or without second substitution group, C1-C3 alkylenecyclopropyl with or without second substitution group, C1-C3 alkyleneC1-C3 alkoxy with or without second substitution group, C1-C3 alkyleneC1-C3 alkylthio with or without second substitution group, and -C(=O)R 7a Any one of them, where R 7a It is selected from any one of the following: C1-C3 alkyl with or without second substitution group; C2-C5 alkenyl with or without second substitution group; C2-C5 alkynyl with or without second substitution group; C1-C3 alkoxy with or without second substitution group; cyclopropyl with or without second substitution group; C1-C3 alkylenecyclopropyl with or without second substitution group; and C1-C3 alkyleneC1-C3 alkoxy with or without second substitution group; wherein the second substitution group is a halogen atom or a cyano group; Z1 is an oxygen atom or -NH-; and Z2 is an oxygen atom.

[0006] In some embodiments of this application, Q has a structure as shown in formula (Q-1); R6 is selected from cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl and -C(=O)NHR 6a Any one of them, where R 6a R7 is selected from any one of C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, and halocyclopropyl; R7 is selected from C1-C3 alkyl with or without a second substituted group, C2-C4 alkenyl with or without a second substituted group, C2-C4 alkynyl with or without a second substituted group, cyclopropyl with or without a second substituted group, C1-C3 alkylenecyclopropyl with or without a second substituted group, C1-C3 alkyleneC1-C3 alkoxy with or without a second substituted group, C1-C3 alkyleneC1-C3 alkylthio with or without a second substituted group, and -C(=O)R 7a Any one of them, where R 7aIt is selected from any one of the following: C1-C3 alkyl with or without second substitution group; C2-C4 alkenyl with or without second substitution group; C2-C4 alkynyl with or without second substitution group; cyclopropyl with or without second substitution group; C1-C2 alkylene cyclopropyl with or without second substitution group; and C1-C2 alkylene C1-C2 alkoxy with or without second substitution group; wherein the second substitution group is a halogen atom or a cyano group; Z1 is an oxygen atom or -NH-; and Z2 is an oxygen atom.

[0007] In some embodiments of this application, R1, R2, and R3 are each independently selected from any one of hydrogen atoms, halogen atoms, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 alkoxy groups, and C1-C2 haloalkoxy groups; R4 and R5 are hydrogen atoms; R8 is methyl or trifluoromethyl; and L1 is a C1-C2 alkylene group.

[0008] In some embodiments of this application, Q has the structure shown in formula (Q-1); R1, R2, and R3 are each independently selected from any one of hydrogen atom, halogen atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R4 and R5 are hydrogen atoms; R6 is selected from cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkoxycarbonyl, C1-C3 haloalkoxycarbonyl, and -C(=O)NHR 6a Any one of them, where R 6a R7 is selected from any one of C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, and halocyclopropyl; R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propynyl, ethynyl, propynyl, butynyl, cyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, methylene-2-fluorocyclopropyl, methylene-2,2-difluorocyclopropyl, methylene methoxy, methylene ethoxy, and -C(=O)R. 7a Any one of them, where R 7a It is selected from any one of methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propynyl, ethynyl, propynyl, butynyl, methylene methoxy, and methylene ethoxy; R8 is methyl or trifluoromethyl; L1 is selected from any one of -CH2-, -CH2-CH2-, and -C(CH3)H-; Z1 is an oxygen atom; Z2 is an oxygen atom.

[0009] In some embodiments of this application, R1, R2, and R3 are each independently selected from any one of hydrogen atom, chlorine atom, fluorine atom, and trifluoromethyl; R4 and R5 are hydrogen atoms; R6 is selected from any one of cyano, trifluoromethyl, methoxy, -C(=O)OCH3, C(=O)OCH2CF3, and -C(=O)NHCH2CF3; R7 is selected from any one of hydrogen atom, methyl, ethyl, n-propyl, propenyl, methylene methoxy, methylene cyclopropyl, methylene ethoxy, -C(=O)CH2CH3, -C(=O)CH=CH2, -C(=O)CH2OCH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, and -C(=O)-cyclopropyl; R8 is methyl; L1 is -CH2-; Z1 is an oxygen atom or -NH-; Z2 is an oxygen atom.

[0010] In some embodiments of this application, the isomers include stereoisomers, the structures of which are shown in formula (I'): (Ⅰ'); In formula (Ⅰ'), * represents a chiral carbon atom; Based on the content of the stereoisomers with R and S configurations of the chiral carbon atom, wherein the stereochemical purity of the stereoisomers with S configuration is 50%-100%.

[0011] The second aspect of this application provides the use of the arylformamide acyl isoxazoline compound and its isomers or pharmaceutically acceptable salts provided in the first aspect in the preparation of insecticides in the agricultural, forestry or health fields.

[0012] A third aspect of this application provides an insecticide comprising an active ingredient and excipients; the active ingredient comprises the arylformamide acyl isoxazoline compound and its isomers or pharmaceutically acceptable salts provided in the first aspect; the excipients comprise one or more of a pharmaceutically acceptable carrier, excipient, and adjuvant; wherein the active ingredient comprises 1%-99% by mass in the insecticide.

[0013] A fourth aspect of this application provides an insecticide composition comprising an active ingredient and other active compounds; the active ingredient comprises arylformamide acyl isoxazoline compounds and their isomers or pharmaceutically acceptable salts thereof provided in the first aspect; the other active compounds comprise one or more of insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators, and herbicides; wherein the active ingredient in the insecticide composition comprises 1%-99% by mass. Detailed Implementation

[0014] The technical solutions in the embodiments of this application are described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0015] This application provides an arylformamide acyl isoxazoline compound and its isomers or pharmaceutically acceptable salts thereof, the structure of which is shown in formula (I): (Ⅰ); In equation (Ⅰ), Q is the structure shown in equation (Q-1) or the structure shown in equation (Q-2): (Q-1); (Q-2); R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen atom, halogen atom, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, and C1-C8 haloalkoxy. L1 is a C1-C6 straight-chain or branched alkylene group; R6 is selected from cyano, C1-C5 alkyl with or without first substituted group, C1-C5 alkoxy with or without first substituted group, C1-C5 alkoxycarbonyl with or without first substituted group, C3-C5 cycloalkyl ester with or without first substituted group, C1-C4 alkylene C1-C4 alkoxy with or without first substituted group, and -C(=O)NHR 6a Any one of them, where R 6a It is selected from any one of C1-C5 alkyl groups substituted or unsubstituted with the first substituent group, and C3-C6 cycloalkyl groups substituted or unsubstituted with the first substituent group; the first substituent group is a halogen atom, a cyano group, or a C1-C5 alkoxy group; R7 is selected from hydrogen atom, C1-C8 alkyl with or without second substitution group, C2-C8 alkenyl with or without second substitution group, C2-C8 alkynyl with or without second substitution group, C3-C6 cycloalkyl with or without second substitution group, C1-C4 alkylene C3-C6 cycloalkyl with or without second substitution group, C1-C4 alkylene C1-C4 alkoxy with or without second substitution group, C1-C4 alkylene C1-C4 alkylthio with or without second substitution group, and -C(=O)R. 7a Any one of them, where R 7aIt is selected from any one of the following: C1-C8 alkyl with or without a second substituent group; C2-C8 alkenyl with or without a second substituent group; C2-C8 alkynyl with or without a second substituent group; C1-C8 alkoxy with or without a second substituent group; C3-C6 cycloalkyl with or without a second substituent group; C1-C4 alkylene C3-C6 cycloalkyl with or without a second substituent group; and C1-C4 alkylene C1-C4 alkoxy with or without a second substituent group; wherein the second substituent group is a halogen atom, a cyano group, or a hydroxyl group; R8 is selected from any one of C1-C4 alkyl, C1-C4 haloalkyl, cyano, and halogen atoms; Z1 is a sulfur atom, an oxygen atom, or -NH-; Z2 is a sulfur atom or an oxygen atom.

[0016] The arylformamide acyl isoxazoline compounds provided in this application introduce three- or four-membered alicyclic rings containing substituents into the main structure containing a formamide acyl group. On the one hand, these alicyclic structures increase the lipophilicity of the compounds, making them easily absorbed by the insect epidermis and thus exhibiting excellent insecticidal effects. On the other hand, the three- or four-membered alicyclic rings effectively increase the volume of the compound molecule, thereby fully utilizing the binding space with the receptor and increasing the activity of the compound. In addition, the larger molecular weight helps to reduce the synthesis and production costs of the compounds, making them suitable for large-scale production. Furthermore, the arylformamide acyl isoxazoline compounds with this structure exhibit low toxicity to non-target organisms such as aquatic organisms like fish and water fleas, making them environmentally friendly and suitable for large-scale application.

[0017] In the embodiments of this application, Q is a structure as shown in formula (Q-1) or a structure as shown in formula (Q-2): (Q-1); (Q-2).

[0018] In some embodiments of this application, Q may be, for example, the structure shown in formula (Q-1). In other embodiments of this application, Q may be, for example, the structure shown in formula (Q-2). By introducing a three- or four-membered alicyclic ring with specific substituents into the formamide acyl group-containing main structure of arylformamide acyl isoxazoline compounds, these substituted alicyclic structures with specific substituents can effectively increase the lipophilicity of the compound, making it easier for it to be absorbed by the phospholipid layer of the insect cell membrane, thereby exhibiting excellent insecticidal effects. Furthermore, these alicyclic structures effectively increase the volume and molecular weight of the compound. On the one hand, this increases the binding space with the receptor, thereby further increasing the activity of the compound and enhancing its insecticidal effect; on the other hand, the selection of a larger molecular weight terminal Q group can effectively reduce the amount of main raw materials used in the synthesis of the compound, thereby reducing the synthesis and production costs of the compound and making it suitable for large-scale production. In some embodiments, Q is the structure shown in formula (Q-1), and the three-membered alicyclic structure can further enhance the binding affinity between the compound and the receptor, thereby further enhancing its insecticidal effect.

[0019] In this embodiment, R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen atom, halogen atom, cyano group, nitro group, C1-C8 alkyl group, C1-C8 haloalkyl group, C1-C8 alkoxy group, and C1-C8 haloalkoxy group. In this embodiment, the halogen atom may be, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0020] In this application, the C1-C8 alkyl group can be either a straight-chain alkyl group or a branched-chain alkyl group. In this application, the number of carbon atoms in the C1-C8 alkyl group can be, for example, 1, 2, 3, 4, 5, 6, 7, or 8. In some specific embodiments, the C1-C8 alkyl group can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl.

[0021] In this application, the C1-C8 haloalkyl group can be either a straight-chain haloalkyl group or a branched-chain haloalkyl group. In this application, the number of carbon atoms in the C1-C8 haloalkyl group can be, for example, 1, 2, 3, 4, 5, 6, 7, or 8. In this application, the C1-C8 haloalkyl group can be a C1-C8 fluoroalkyl group, a C1-C8 chloroalkyl group, a C1-C8 bromoalkyl group, or a C1-C8 iodoalkyl group. In this application, the C1-C8 haloalkyl group can be an alkyl group substituted with one halogen atom or an alkyl group substituted with multiple halogen atoms; when substituted with multiple halogen atoms, the halogen atoms can be the same or different. In some embodiments of this application, the C1-C8 haloalkyl group can be a C1-C8 fluoroalkyl group. Specifically, for example, it can be monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0022] In the embodiments of this application, the C1-C8 alkoxy group can be either a straight-chain alkoxy group or a branched-chain alkoxy group. In the embodiments of this application, the number of carbon atoms in the C1-C8 alkoxy group can be, for example, 1, 2, 3, 4, 5, 6, 7, or 8. In some specific embodiments of this application, the C1-C8 alkoxy group can be, for example, a methoxy group, an ethoxy group, or a propoxy group.

[0023] In this application, the C1-C8 haloalkoxy group can be either a straight-chain haloalkoxy group or a branched-chain haloalkoxy group. In this application, the number of carbon atoms in the C1-C8 haloalkoxy group can be, for example, 1, 2, 3, 4, 5, 6, 7, or 8. In this application, the C1-C8 haloalkoxy group can be a C1-C8 fluoroalkoxy group, a C1-C8 chloroalkoxy group, a C1-C8 bromoalkoxy group, or a C1-C8 iodoalkoxy group. The C1-C8 haloalkoxy group can be an alkoxy group substituted with one halogen atom or an alkoxy group substituted with multiple halogen atoms; when substituted with multiple halogen atoms, the halogen atoms can be the same or different. In some embodiments of this application, the C1-C8 haloalkoxy group can be a C1-C8 fluoroalkoxy group. Specifically, for example, it can be a monofluoromethoxy, difluoromethoxy, or trifluoromethoxy group.

[0024] In some embodiments of this application, R1, R2, and R3 are each independently selected from any one of hydrogen atoms, halogen atoms, cyano groups, nitro groups, C1-C8 alkyl groups, C1-C8 haloalkyl groups, C1-C8 alkoxy groups, and C1-C8 haloalkoxy groups; R4 and R5 are hydrogen atoms. In some specific embodiments of this application, R1, R2, and R3 are each independently selected from any one of hydrogen atoms, halogen atoms, C1-C2 alkyl groups, C1-C2 haloalkyl groups, C1-C2 alkoxy groups, and C1-C2 haloalkoxy groups; R4 and R5 are hydrogen atoms. In some specific embodiments, R1, R2, and R3 may, for example, be independently selected from any one of hydrogen atoms, chlorine atoms, fluorine atoms, and trifluoromethyl groups; R4 and R5 may, for example, be hydrogen atoms. By further optimizing R1, R2, R3, R4, and R5 as described above, the insecticidal effect of the insecticide can be further improved.

[0025] In this application, L1 is a C1-C6 straight-chain or branched alkylene group. In this application, alkylene refers to a divalent saturated hydrocarbon group formed by removing two hydrogen atoms from an alkane. In this application, L1 can be a straight-chain alkylene group or a branched alkylene group. In this application, the number of carbon atoms in the C1-C6 straight-chain or branched alkylene group can be, for example, 1, 2, 3, 4, 5, or 6. In some specific embodiments, it can be, for example, methylene (-CH2-), ethylene (-CH2-CH2- or -CH(CH3)-), propylene (-CH2-CH2-CH2- or -CH(CH3)CH2-), etc.

[0026] In this embodiment, R6 is selected from cyano, C1-C5 alkyl with or without first substituted group, C1-C5 alkoxy with or without first substituted group, C1-C5 alkoxycarbonyl with or without first substituted group, C3-C5 cycloalkyl ester with or without first substituted group, C1-C4 alkylene C1-C4 alkoxy with or without first substituted group, and -C(=O)NHR. 6a Any one of them, where R 6a The compound is selected from any one of C1-C5 alkyl groups with or without a first substituent group, and any one of C3-C6 cycloalkyl groups with or without a first substituent group; the first substituent group is a halogen atom, a cyano group, or a C1-C5 alkoxy group. In some embodiments of this application, R6 is selected from any one of cyano, trifluoromethyl, methoxy, -C(=O)OCH3, C(=O)OCH2CF3, and -C(=O)NHCH2CF3. By selecting the above-mentioned groups for R6, the efficacy of the compound can be further improved while its toxicity is reduced. In some specific embodiments of this application, R6 is a cyano group, in which case the compound has low toxicity to fish while exhibiting excellent insecticidal effects; in other specific embodiments of this application, R6 is a haloalkyl group, such as trifluoromethyl, in which case the compound has good insecticidal effects while having extremely low toxicity to fish, making it environmentally friendly.

[0027] In this application, the C1-C5 alkyl groups can be either straight-chain alkyl groups or branched-chain alkyl groups. In this application, the number of carbon atoms in the C1-C5 alkyl groups can be, for example, 1, 2, 3, 4, or 5. In some specific embodiments, the C1-C5 alkyl groups can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or pentyl.

[0028] In the embodiments of this application, the C1-C5 alkoxy group can be either a straight-chain alkoxy group or a branched-chain alkoxy group. In the embodiments of this application, the number of carbon atoms in the C1-C5 alkoxy group can be, for example, 1, 2, 3, 4, or 5. In some specific embodiments of this application, the C1-C8 alkoxy group can be, for example, a methoxy group, an ethoxy group, or a propoxy group.

[0029] In this application, the C1-C5 alkoxycarbonyl group is a group combining an alkoxy group and a carbonyl group, specifically -C(=O)OR (R is an alkyl group). In this application, the number of carbon atoms in the C1-C5 alkoxycarbonyl group can be, for example, 1, 2, 3, 4, or 5. In some specific embodiments, the C1-C5 alkoxycarbonyl group can be, for example, methoxycarbonyl (-C(=O)OCH) or ethoxycarbonyl (C(=O)OCH2CF3). In this application, the C3-C5 cycloalkyl ester group is a group combining a C3-C5 cycloalkyl group and an ester group, specifically -C(=O)O-cycloalkyl. In some specific embodiments, it can be, for example, -C(=O)O-cyclopropane.

[0030] In some embodiments of this application, R 6a It can be a C1-C5 alkyl group that has been substituted or unsubstituted with the first substituent group. In other embodiments of this application, R 6a It can be a C3-C6 cycloalkyl group that has been substituted or unsubstituted with the first substituent group.

[0031] In this embodiment, the first substituent is a halogen atom, a cyano group, or a C1-C5 alkoxy group. In this embodiment, the halogen atom may be, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In some specific embodiments, the first substituent may be, for example, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methoxy group, an ethoxy group, or a propoxy group.

[0032] In this embodiment, R7 is selected from hydrogen atoms, C1-C8 alkyl groups (substituted or unsubstituted with a second substituent), C2-C8 alkenyl groups (substituted or unsubstituted with a second substituent), C2-C8 alkynyl groups (substituted or unsubstituted with a second substituent), C3-C6 cycloalkyl groups (substituted or unsubstituted with a second substituent), C1-C4 alkylene C3-C6 cycloalkyl groups (substituted or unsubstituted with a second substituent), C1-C4 alkylene C1-C4 alkoxy groups (substituted or unsubstituted with a second substituent), C1-C4 alkylene C1-C4 alkylthio groups (substituted or unsubstituted with a second substituent), and -C(=O)R. 7a Any one of them, where R 7aThe second substituent is selected from any one of the following: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C3-C6 cycloalkyl, C1-C4 alkylene C3-C6 cycloalkyl, and C1-C4 alkylene C1-C4 alkoxy; the second substituent is a halogen atom, a cyano group, or a hydroxyl group. In some embodiments of this application, R7 is selected from any one of hydrogen atom, trifluoromethyl, n-propyl, propenyl, methylene methoxy (-CH2-OCH3), methylene cyclopropyl, methylene ethoxy (-CH2-OCH2CH3), -C(=O)CH2CH3, -C(=O)CH=CH2, -C(=O)CH2OCH3, and -C(=O)-cyclopropyl. By selecting the aforementioned groups from R7, the efficacy of the compound can be further enhanced while its toxicity can be reduced.

[0033] In this application, the C1-C8 alkyl group can be either a straight-chain alkyl group or a branched-chain alkyl group. In this application, the number of carbon atoms in the C1-C8 alkyl group can be, for example, 1, 2, 3, 4, 5, 6, 7, or 8. In some specific embodiments, the C1-C8 alkyl group can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl.

[0034] In this embodiment, the C2-C8 alkenyl group can be either a straight-chain alkenyl group or a branched alkenyl group. In this embodiment, the number of carbon atoms in the C2-C8 alkenyl group can be, for example, 2, 3, 4, 5, 6, 7, or 8. In some specific embodiments, the C2-C8 alkenyl group can be, for example, vinyl, propenyl, or allyl.

[0035] In this application, the C2-C8 alkynyl group can be either a straight-chain alkynyl group or a branched-chain alkynyl group. In this application, the number of carbon atoms in the C2-C8 alkynyl group can be, for example, 2, 3, 4, 5, 6, 7, or 8. In some specific embodiments, the C2-C8 alkynyl group can be, for example, acetylene, propynyl, or butynyl.

[0036] In this application, the number of carbon atoms in the C3-C6 cycloalkyl group can be, for example, 3, 4, 5, or 6. In some specific embodiments, the C3-C6 cycloalkyl group can be, for example, cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments of this application, the C3-C6 cycloalkyl group can be, for example, cyclopropane or cyclobutane.

[0037] In the embodiments of this application, C1-C4 alkylene and C3-C6 cycloalkyl refer to groups obtained by combining alkylene groups having 1-4 carbon atoms and cycloalkyl groups having 3-6 carbon atoms. In some embodiments of this application, C1-C4 alkylene and C3-C6 cycloalkyl groups may be, for example, methylenecyclopropyl.

[0038] In the embodiments of this application, C1-C4 alkylene C1-C4 alkoxy refers to a group obtained by combining an alkylene group with 1-4 carbon atoms and an alkoxy group with 1-4 carbon atoms, specifically -alkylene-O-alkyl. In some specific embodiments, C1-C4 alkylene C1-C4 alkoxy can be, for example, methylene methoxy (-CH2-O-CH3) or methylene ethoxy (-CH2-O-CH2CH3).

[0039] In the embodiments of this application, C1-C4 alkylene C1-C4 alkylthio group refers to a group obtained by combining an alkylene group with 1-4 carbon atoms and an alkylthio group with 1-4 carbon atoms, specifically -alkylene-S-alkyl. In some specific embodiments, C1-C4 alkylene C1-C4 alkylthio group can be, for example, -CH2-S-CH3 or -CH2-S-CH2CH3.

[0040] In this application, the second-generation substituent is a halogen atom, a cyano group, or a hydroxyl group. In this application, the halogen atom may be, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In some specific embodiments, the first substituent may be, for example, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, or a hydroxyl group.

[0041] In this application, R8 is selected from C1-C4 alkyl, C1-C4 haloalkyl, cyano, or halogen atoms. In some specific embodiments, R8 may be, for example, methyl, ethyl, trifluoromethyl, cyano, chlorine, or fluorine atoms.

[0042] In this application, Z1 is a sulfur atom, an oxygen atom, or -NH-; Z2 is a sulfur atom or an oxygen atom. In some specific embodiments, both Z1 and Z2 are oxygen atoms. In other embodiments, Z1 is -NH- and Z2 is an oxygen atom.

[0043] This application achieves its effect by specifically selecting the various groups in the structure shown in formula (I), enabling them to work synergistically. This results in a compound that is easily absorbed by the insect's exoskeleton, exhibiting excellent insecticidal efficacy while maintaining low toxicity to aquatic organisms such as fish, and is environmentally friendly. Furthermore, this compound shows no cross-resistance with existing insecticides, and most insects do not develop resistance to it, making it suitable for large-scale application.

[0044] This application also provides an isomer of an arylformamide acyl isoxazoline compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. In the embodiments of this application, the isomers include, but are not limited to, stereoisomers and tautomers. Specifically, the stereoisomers include, but are not limited to, optical isomers, and can be classified into R-configurations and S-configurations.

[0045] In some embodiments of this application, the stereoisomers of the arylformamide acyl isoxazoline compound are shown in formula (Ⅰ'): (Ⅰ'); In formula (Ⅰ'), * represents a chiral carbon atom. Specifically, this chiral carbon atom is the carbon atom at the fifth position of the isoxazoline heterocycle.

[0046] In some embodiments of this application, based on the content of the stereoisomers with R and S configurations of the chiral carbon atom, the stereochemical purity of the stereoisomers with S configurations is 50%-100%. Compared to the R configuration, the S configuration has higher activity. By controlling the stereochemical purity of the aforementioned stereoisomers with S configurations within the above range, the drug and receptor can bind more tightly, thereby further improving its insecticidal effect. In this application, stereochemical purity refers to the percentage of the amount of the stereoisomer relative to the total amount of stereoisomers having a chiral center, which can be specifically measured by high-performance liquid chromatography.

[0047] This application also provides the use of the arylformamide acyl isoxazoline compounds and their isomers or pharmaceutically acceptable salts provided above in the preparation of insecticides in the agricultural, forestry or health fields.

[0048] This application also provides an insecticide comprising an active ingredient and excipients; wherein the active ingredient comprises the arylformamide acyl isoxazoline compounds and their isomers or pharmaceutically acceptable salts thereof provided above, and the excipients comprise one or more of a pharmaceutically acceptable carrier, excipient, and adjuvant.

[0049] In some embodiments of this application, the mass percentage of the active ingredient in the insecticide is 1%-99%. In some specific embodiments of this application, the mass percentage of the active ingredient in the insecticide may be, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99%.

[0050] In this application, the insecticide can be used to control pests including but not limited to rice stem borer, diamondback moth, aphids, spider mite, thrips, mosquitoes, flies, ants, and animal parasites.

[0051] In this application, the insecticides exist in forms including, but not limited to, solutions, emulsions, wettable powders, granular wettable powders, suspensions, powders, foams, ointments, tablets, granules, aerosols, natural reagents impregnated with active compounds, synthetic reagents impregnated with active compounds, microcapsules, seed coating agents, formulations equipped with combustion devices (the combustion devices may be chimneys and fog cans, canisters and coils, etc.), as well as cold fog agents, hot fog agents, etc. These insecticides can be prepared by known methods, for example, by mixing the active component with fillers (such as liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers), and optionally with surfactants (i.e., emulsifiers and / or dispersants and / or foaming agents).

[0052] This application also provides an insecticide composition comprising an active ingredient and other active compounds. The active ingredient comprises the arylformamide acyl isoxazoline compounds and their isomers or pharmaceutically acceptable salts thereof provided above. The other active compounds include one or more of insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators, and herbicides.

[0053] In some embodiments of this application, the mass percentage of the active ingredient in the insecticide composition is 1%-99%. In some specific embodiments of this application, the mass percentage of the active ingredient in the insecticide composition may be, for example, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99%.

[0054] The insecticide and insecticide composition provided in this application do not exhibit cross-resistance with existing insecticides. Compared with existing insecticides on the market, this compound has advantages such as rapid efficacy, low dosage, low toxicity, and environmental friendliness against plant pests. It has excellent control efficacy against rice stem borer and good safety against aquatic fish.

[0055] The embodiments of the present invention will be further described below with reference to several examples. Specifically, this application provides some compounds of the phenylisooxazoline amide class as shown in formula (II), and some phenylisooxazoline amide compounds are listed in Table 1. However, the phenylisooxazoline amide class of the present invention is not limited to all compounds in Table 1: (II); In equation (Ⅰ), Q is the structure shown in equation (Q-1) or the structure shown in equation (Q-2): (Q-1); (Q-2); Table 1: Phenylisoxazoline amide compounds with chemical structures as shown in formula (II)

[0056] Example 1 Preparation method of compound number 1 in Table 1: (1) Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide:

[0057] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (2 g, 4.59 mmol) was dissolved in excess thionyl chloride, heated to 80 °C, and reacted for 4 h. The thionyl chloride was then evaporated to dryness and dissolved in acetonitrile, which was then added to a constant-pressure funnel for later use. In a separate three-necked flask, ammonium chloride (0.490 g, 9.17 mmol) was added and dissolved in a 5:1 mixture of deionized water and acetonitrile. In a beaker, potassium hydroxide (0.5 g, 9.17 mmol) was added and dissolved in deionized water. This solution was then slowly added dropwise to the ammonium chloride solution in the three-necked flask using a constant-pressure funnel, while the product from the acetonitrile solution was simultaneously added dropwise to the three-necked flask through the constant-pressure funnel. The reaction was stopped after the white fumes in the three-necked flask disappeared. The mixture was extracted with ethyl acetate 2-3 times, washed with dilute hydrochloric acid 2-3 times, and then washed with saturated brine 2-3 times. The mixture was then evaporated to dryness to obtain a pale yellow solid (1.84 g, yield 92.21%).

[0058] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 7.89 – 7.84 (m, 1H), 7.80 (d, J = 6.2 Hz, 2H), 7.63 – 7.58 (m, 2H), 7.52 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 4.34 (q, J = 18.3 Hz, 2H), 2.43 (s, 3H).

[0059] ESI-MS (m / z): [MH-] Theoretical value: 433.01, Measured value: 433.013.

[0060] (2) Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0061] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(trifluoromethyl)cyclopropane-methanol (178 mmL, 1.72 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.36 g, yield 57.67%).

[0062] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.28 (s, 1H), 7.82 (d, J = 6.1 Hz, 2H), 7.67 – 7.60 (m, 2H), 7.50 (d, J = 7.9 Hz, 1H), 4.42 – 4.31 (m, 2H), 4.29 (s, 2H), 2.37 (s, 3H), 1.05 (d, J = 5.1 Hz, 2H), 1.01 (d, J = 5.5 Hz, 2H).

[0063] ESI-MS (m / z): [MH-] Theoretical value: 599.04, Measured value: 599.038.

[0064] Example 2 Preparation method of compound number 14 in Table 1: (1) Synthesis of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide:

[0065] 4-(5-(3,5-dichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (2 g, 4.78 mmol) was dissolved in excess thionyl chloride, heated to 80 °C, and reacted for 4 h. The thionyl chloride was then evaporated to dryness and dissolved in acetonitrile, which was then added to a constant-pressure funnel for later use. In a separate three-necked flask, ammonium chloride (0.511 g, 9.56 mmol) was added and dissolved in a 5:1 mixture of deionized water and acetonitrile. In a beaker, potassium hydroxide (0.536 g, 9.56 mmol) was added and dissolved in deionized water. This solution was slowly added dropwise to the ammonium chloride solution in the three-necked flask using a constant-pressure funnel, while the product dissolved in acetonitrile was simultaneously added dropwise to the three-necked flask through the constant-pressure funnel. After the white fumes in the three-necked flask disappear, the reaction is stopped. The mixture is extracted with ethyl acetate 2-3 times, washed with dilute hydrochloric acid 2-3 times, and then washed with saturated brine 2-3 times. The mixture is then evaporated to dryness to obtain a pale yellow solid (1.96 g, yield 98.23%).

[0066] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.86 (s, 1H), 7.79 (dt, J = 3.9, 1.8 Hz, 1H), 7.65 (d, J = 1.9 Hz, 2H), 7.64 – 7.59 (m, 2H), 7.52 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 4.43 – 4.28 (m, 2H), 2.43 (s, 3H).

[0067] ESI-MS (m / z): [MH-] Theoretical value: 415.02, Measured value: 415.023.

[0068] (2) Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0069] 4-(5-(3,5-dichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.20 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(trifluoromethyl)cyclopropane-methanol (186 mmL, 1.72 mmol) was added, and the reaction was carried out at room temperature, monitored by TLC until completion. After the reaction, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.37 g, yield 51.34%).

[0070] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 11.29 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 – 7.61 (m, 4H), 7.50 (d, J = 8.0 Hz, 1H), 4.45 – 4.26 (m, 4H), 2.39 (s, 3H), 1.05 (d, J = 4.8 Hz, 2H), 1.01 (d, J = 5.1 Hz, 2H).

[0071] ESI-MS (m / z): [MH-] Theoretical value: 581.05, Measured value: 581.047.

[0072] Example 3 Preparation method of compound number 15 in Table 1: (1) Synthesis of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide:

[0073] 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (2 g, 4.43 mmol) was dissolved in excess thionyl chloride, heated to 80 °C, and reacted for 4 h. The thionyl chloride was then evaporated to dryness and dissolved in acetonitrile, which was then added to a constant-pressure funnel for later use. In a separate three-necked flask, ammonium chloride (0.496 g, 8.85 mmol) was added and dissolved in a 5:1 mixture of deionized water and acetonitrile. In a beaker, potassium hydroxide (0.473 g, 8.85 mmol) was added and dissolved in deionized water. This solution was slowly added dropwise to the ammonium chloride solution in the three-necked flask using a constant-pressure funnel, while the product dissolved in acetonitrile was simultaneously added dropwise to the three-necked flask through the constant-pressure funnel. The reaction was stopped after the white fumes in the three-necked flask disappeared. The mixture was extracted with ethyl acetate 2-3 times, washed with dilute hydrochloric acid 2-3 times, and then washed with saturated brine 2-3 times. The mixture was then evaporated to dryness to obtain a pale yellow solid (2.01 g, yield 81.74%).

[0074] The 1H NMR (500 MHz, DMSO) data of the compound are as follows (δ [ppm]): δ 8.08 –8.04 (m, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 11.0 Hz, 2H), 7.67 –7.61 (m, 2H), 7.55 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 4.43 (q, J = 18.4 Hz, 2H), 2.46 (s, 3H).

[0075] ESI-MS (m / z): [MH-] Theoretical value: 449.05, Measured value: 449.049.

[0076] (2) Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0077] 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.11 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(trifluoromethyl)cyclopropane-methanol (172 mmol, 1.66 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.372 g, 54.37% yield).

[0078] 1H NMR spectrum of the compound 1 The following are the H NMR (500 MHz, DMSO) data (δ [ppm]): δ 11.29 (s, 1H), 8.01 (d, J = 1.6 Hz, 2H), 7.90 (s, 1H), 7.70 – 7.63 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 4.43 (q, J = 18.3 Hz, 2H), 4.30 (s, 2H), 1.07 – 1.03 (m, 2H), 1.01 (d, J = 4.1 Hz, 2H).

[0079] ESI-MS (m / z): [MH-] Theoretical value: 615.07, Measured value: 615.072.

[0080] Example 4 Preparation method of compound number 38 in Table 1: Synthesis of (1-trifluoromethylcyclopropyl)methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoylcarbamate:

[0081] Add (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) to a reaction flask, dissolve in 10 mL of tetrahydrofuran, add sodium hydride (0.06 g, 1.44 mmol) under ice bath conditions, stir for about 1 h, then add methyl bromide (88 mmL, 1.04 mmol), and monitor the reaction until completion by TLC. After the reaction is complete, remove the tetrahydrofuran, dissolve in ethyl acetate, wash 2-3 times with dilute hydrochloric acid and saturated brine respectively, dry with anhydrous magnesium sulfate, filter, and obtain a yellow-green viscous product (0.116 g, 72.6% yield) by column chromatography.

[0082] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 7.82 (d, J = 6.1 Hz, 2H), 7.67 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.36 (d, J = 8.2 Hz, 2H), 4.16 (s, 2H), 3.40 (s, 3H), 2.34 (s, 3H), 0.89 (q, J = 5.1 Hz, 2H), 0.74 (s, 2H).

[0083] ESI-MS (m / z): [MH-] Theoretical value: 643.0643, Measured value: 643.064.

[0084] Example 5 Preparation method of compound number 90 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methylallyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0085] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.36 mmol) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, bromopropene (0.09 g, 0.72 mmol) was slowly added, and after stirring until homogeneous, potassium carbonate (0.12 g, 0.75 mmol) was slowly added. The reaction was then carried out at room temperature for 1 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a green, viscous product (0.19 g, 91.6% yield).

[0086] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.79 (d, J = 6.2 Hz, 2H), 7.62 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.93 (ddd, J = 22.6, 10.6, 5.5 Hz, 1H), 5.24 – 5.16 (m, 2H), 4.41 (d, J = 5.4 Hz, 2H), 4.37 – 4.25 (m, 2H), 4.10 (d, J = 12.8 Hz, 2H), 2.26 (s, 3H), 0.88 (t, J = 5.8 Hz, 2H). 0.75 (d, J = 21.2 Hz, 2H).

[0087] ESI-MS (m / z): [MH-] Theoretical value: 639.06938, Measured value: 639.068.

[0088] Example 6 Preparation methods of compound number 129 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(propionyl)carbamate:

[0089] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Propionyl chloride (0.04 g, 0.43 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.051 g, 0.5 mmol) was then slowly added. The reaction was allowed to proceed at room temperature for 6 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.17 g, 78.5% yield).

[0090] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.84 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 6.1 Hz, 2H), 7.77 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 4.44 – 4.33 (m, 2H), 4.30 (d, J = 9.2 Hz, 2H), 2.95 (q, J = 7.2 Hz, 2H), 2.56 (s,3H), 1.07 (t, J = 7.3 Hz, 3H), 0.94 (t, J = 5.9 Hz, 2H), 0.84 (d, J = 13.3 Hz, 2H).

[0091] ESI-MS (m / z): [MH-] Theoretical value: 655.0643, Measured value: 655.064.

[0092] Example 7 Preparation methods of compound number 147 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methacryloyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0093] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Acryloyl chloride (0.04 g, 0.43 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.051 g, 0.5 mmol) was then slowly added. The reaction was allowed to proceed at room temperature for 8 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was purified by column chromatography to obtain a white solid product (0.15 g, 73.8% yield).

[0094] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.85 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 6.1 Hz, 2H), 7.77 (d, J = 1.8 Hz, 1H), 7.69 (dd, J =8.1, 1.8 Hz, 1H), 4.45 (s, 1H), 4.41 (s, 1H), 4.38 (s, 1H), 4.31 (s, 2H), 2.96 (q, J = 7.3 Hz, 2H), 2.56 (s, 3H), 0.95 (t, J = 3.5 Hz, 2H), 0.86 (d, J = 2.9Hz, 2H).

[0095] ESI-MS (m / z): [MH-] Theoretical value: 653.04865, Measured value: 653.04811.

[0096] Example 8 Preparation methods of compound number 185 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(2-methoxyacetyl)carbamate:

[0097] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Methoxyacetyl chloride (0.043 g, 0.4 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.05 g, 0.05 mmol) was then slowly added, and the reaction was carried out at room temperature for 8 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, and the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The product was dried over anhydrous magnesium sulfate, filtered, and the solution was obtained by column chromatography as a yellow-green viscous product (0.196 g, 87.6% yield).

[0098] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.89 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 6.1 Hz, 2H), 7.70 (d, J = 8.3 Hz, 1H), 4.55 (d, J =21.9 Hz, 2H), 4.45 – 4.33 (m, 2H), 4.29 (d, J = 8.3 Hz, 2H), 3.32 (d, J = 14.1Hz, 3H), 2.61 – 2.52 (m, 3H), 0.94 (t, J = 6.0 Hz, 2H), 0.85 (s, 2H).

[0099] ESI-MS (m / z): [MH-] Theoretical value: 671.05921, Measured value: 671.05865.

[0100] Example 9 Preparation methods of compound number 217 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(cyclopropylcarbonyl)(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0101] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Cyclopropylformyl chloride (0.045 g, 0.43 mmol) was slowly added under nitrogen protection. After stirring until homogeneous, triethylamine (0.051 g, 0.5 mmol) was slowly added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until completion. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.197 g, 88.3% yield).

[0102] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.74 – 7.70 (m, 1H), 4.47 – 4.37 (m,2H), 4.36 (s, 2H), 2.54 (s, 3H), 1.77 (tt, J = 7.8, 4.6 Hz, 1H), 1.08 – 1.06(m, 2H), 1.04 – 1.02 (m, 2H), 0.98 (t, J = 3.5 Hz, 2H), 0.90 (d, J = 5.1 Hz, 2H).

[0103] ESI-MS (m / z): [MH-] Theoretical value: 667.06430, Measured value: 667.06451.

[0104] Example 10 Preparation method of compound number 233 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0105] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was added to a reaction flask and dissolved in 20 mL of oxalyl chloride. The reaction apparatus was placed in an oil bath under nitrogen protection and heated to reflux at 70 °C. The mixture was stirred for 5 h. After the reaction was completed, the oxalyl chloride was removed by rotary evaporation to obtain a yellow oily liquid. 20 mL of anhydrous tetrahydrofuran was added to the intermediate product. 1-(hydroxymethyl)cyclopropane-1-carboxynitrile (0.123 g, 1.26 mmol) was added at room temperature. The mixture was stirred for 3 h. After the reaction was completed by TCL spotting, the tetrahydrofuran was removed by rotary evaporation. The product was dissolved in ethyl acetate, washed twice with saturated brine, dried with anhydrous magnesium sulfate, filtered, and the white product (0.56 g, 87.5% yield) was obtained by column chromatography.

[0106] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.35 (s, 1H), 7.77 (d, J = 6.1 Hz, 2H), 7.64 – 7.56 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H),4.39 – 4.21 (m, 2H), 4.13 (s, 2H), 2.35 (s, 3H), 1.30 (q, J = 4.9 Hz, 2H), 1.15(q, J = 5.0 Hz, 2H).

[0107] ESI-MS (m / z): [MH-] Theoretical value: 556.04595, Measured value: 556.04498.

[0108] Example 11 Preparation methods of compound number 246 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0109] 4-(5-(3,5-dichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.20 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(hydroxymethyl)cyclopropane-1-carboxynitrile (152 mmol, 1.72 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.37 g, yield 55.03%).

[0110] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 11.40 (s, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.70 – 7.62 (m, 4H), 7.54 (d, J = 8.0 Hz, 1H), 4.45 – 4.29 (m, 2H), 4.18 (s, 2H), 2.41 (s, 3H), 1.34 (q, J = 4.8 Hz, 2H), 1.22 – 1.15 (m, 2H).

[0111] ESI-MS (m / z): [MH-] Theoretical value: 538.05, Measured value: 538.055.

[0112] Example 12 Preparation methods of compound number 247 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0113] 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.11 mmol) was dissolved in excess oxalyl chloride, heated to 70 °C, and reacted for 4 h. The remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(hydroxymethyl)cyclopropaneformonitrile (140 ml, 1.66 mmol) was added, and the reaction was carried out at room temperature, monitored by TLC until completion. After the reaction, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.36 g, 56.55% yield).

[0114] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 11.37 (s, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.67 – 7.60 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 4.50 – 4.35 (m, 2H), 4.15 (s, 2H), 2.38 (s, 3H), 1.33 (q, J = 4.7 Hz, 2H), 1.18 – 1.15 (m, 2H).

[0115] ESI-MS (m / z): [MH-] Theoretical value: 572.08, Measured value: 572.081.

[0116] Example 13 Preparation methods of compound number 266 in Table 1: Synthesis of methyl 2-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)valerate (1-cyanocyclopropyl) ester:

[0117] (0.2 g, 0.36 mmol) methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, bromopropane (0.09 g, 0.72 mmol) was slowly added, and the mixture was stirred until homogeneous. Potassium carbonate (0.12 g, 0.75 mmol) was then slowly added, and the reaction was carried out at 60 °C for 6 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, and the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The product was dried over anhydrous magnesium sulfate, filtered, and the green viscous product (0.18 g, 87.2% yield) was obtained by column chromatography.

[0118] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.82 (d, J = 6.1 Hz, 2H), 7.65 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 7.9, 1.7 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 4.40 – 4.28 (m, 2H), 4.01 (d, J = 2.0 Hz, 2H), 3.88 – 3.79 (m,2H), 2.32 (s, 3H), 1.71 (hept, J = 7.5 Hz, 2H), 1.12 (q, J = 4.4 Hz, 2H), 0.97(t, J = 7.5 Hz, 3H), 0.92 – 0.87 (m, 2H).

[0119] ESI-MS (m / z): [MH-] Theoretical value: 598.0929, Measured value: 598.093.

[0120] Example 14 Preparation methods of compound number 270 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(methoxymethyl)carbamate:

[0121] (0.2 g, 0.36 mmol) methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, bromomethyl methyl ether (0.1 g, 0.72 mmol) was slowly added, and after stirring until homogeneous, potassium carbonate (0.12 g, 0.75 mmol) was slowly added. The temperature was then raised to 50 °C and the reaction was carried out for 18 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, and the product was dissolved in ethyl acetate. The solution was washed twice with dilute hydrochloric acid and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a green viscous product (0.14 g, 65.4% yield).

[0122] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.82 (d, J = 6.1 Hz, 2H), 7.68 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.45 – 7.36 (m, 1H), 5.21 (s, 2H), 4.42 – 4.28 (m, 2H), 4.03 (s, 2H), 3.43 (s, 3H), 2.38 (s, 3H), 1.10 (q, J = 4.6 Hz, 2H), 0.87 (q, J = 5.0 Hz, 2H).

[0123] ESI-MS (m / z): [MH-] Theoretical value: 600.0721, Measured value: 600.072.

[0124] Example 15 Preparation method of compound number 322 in Table 1: Synthesis of methyl 2-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)-4-pentenoic acid (1-cyanocyclopropyl) ester:

[0125] (0.2 g, 0.36 mmol) methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, bromopropene (0.09 g, 0.72 mmol) was slowly added, and after stirring until homogeneous, potassium carbonate (0.12 g, 0.75 mmol) was slowly added. The reaction was then carried out at room temperature for 1 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, and the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The product was dried over anhydrous magnesium sulfate, filtered, and the green viscous product (0.19 g, 88.6% yield) was obtained by column chromatography.

[0126] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.83 (d, J = 6.1 Hz, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.00 (ddt, J = 17.3, 10.7, 5.5 Hz, 1H), 5.36 – 5.22 (m, 2H), 4.47 (dd, J = 4.5, 2.9 Hz, 2H), 4.42 – 4.27 (m, 2H), 4.03 (d, J = 2.1 Hz, 2H),2.34 (s, 3H), 1.17 – 1.08 (m, 2H), 0.91 (t, J = 3.7 Hz, 2H).

[0127] ESI-MS (m / z): [MH-] Theoretical value: 596.07725, Measured value: 596.0773.

[0128] Example 16 Preparation method of compound 361 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(propionyl)carbamate:

[0129] (0.2 g, 0.36 mmol) methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) was added to a reaction flask and dissolved in 10 mL of dichloromethane. Propionyl chloride (0.04 g, 0.43 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.051 g, 0.5 mmol) was then slowly added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until complete. The dichloromethane was removed by rotary evaporation, and the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The product was dried over anhydrous magnesium sulfate, filtered, and subjected to column chromatography to obtain a yellow-green viscous product (0.15 g, 64.5% yield).

[0130] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.88 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 6.1 Hz, 2H), 7.79 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 4.39 (dd, J = 38.7, 18.4 Hz, 2H), 4.23 (s, 2H), 2.98 (q, J = 7.2 Hz, 2H), 2.59(s, 3H), 1.25 – 1.20 (m, 2H), 1.10 (t, J = 7.3 Hz, 3H), 1.03 (dd, J = 7.3, 4.9Hz, 2H).

[0131] ESI-MS (m / z): [M+Na+] Theoretical value: 636.0686, measured value: 636.069.

[0132] Example 17 Preparation methods of compound number 379 in Table 1: Synthesis of methyl 1-cyanocyclopropyl carbamate: (4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)-2-methylbenzoyl)carbamate)

[0133] (4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) methyl ester (0.2 g, 0.36 mmol) was added to a reaction flask and dissolved in 10 mL of anhydrous dichloromethane. Then, acryloyl chloride (0.065 g, 0.72 mmol) was slowly added, and after stirring until homogeneous, triethylamine (0.1 g, 1 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 18 h. The reaction was monitored by TLC until complete. The solution was diluted with dichloromethane, washed twice with dilute hydrochloric acid, and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.18 g, 78.5% yield).

[0134] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.83 (d, J = 6.1 Hz, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.00 (ddt, J = 17.3, 10.7, 5.5 Hz, 1H), 5.36 – 5.22 (m, 2H), 4.47 (dd, J = 4.5, 2.9 Hz, 2H), 4.42 – 4.27 (m, 2H), 4.03 (d, J = 2.1 Hz, 2H),2.34 (s, 3H), 1.17 – 1.08 (m, 2H), 0.91 (t, J = 3.7 Hz, 2H).

[0135] ESI-MS(m / z): [M+Na + Theoretical value: 634.053, measured value: 634.048.

[0136] Example 18 Preparation method of compound number 417 in Table 1: Synthesis of (1-cyanocyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(2-methoxyacetyl)carbamate:

[0137] (0.2 g, 0.36 mmol) methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (1-cyanocyclopropyl) was added to a reaction flask and dissolved in 10 mL of dichloromethane. Methoxyacetyl chloride (0.043 g, 0.4 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.05 g, 0.05 mmol) was then slowly added. After reacting for 30 min, methoxyacetyl chloride (0.022 g, 0.2 mmol) was added again, and the reaction was continued at room temperature for 8 h. The reaction was monitored by TLC until complete. The dichloromethane was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and subjected to column chromatography to obtain a yellow-green viscous product (0.11 g, 56.1% yield).

[0138] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.90 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 6.1 Hz, 2H), 7.78 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 4.58 (s, 2H), 4.39 (dd, J = 38.1, 18.4 Hz, 2H), 4.20 (s, 2H), 4.15 (d, J = 6.4Hz, 3H), 2.57 (s, 3H), 1.22 (dd, J = 7.1, 5.1 Hz, 2H), 1.01 (q, J = 5.0 Hz, 2H).

[0139] ESI-MS(m / z): [M+Na + Theoretical value: 652.0635, measured value: 652.063.

[0140] Example 19 Preparation methods of compound number 465 in Table 1: Synthesis of methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid ester:

[0141] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was added to a reaction flask and dissolved in 20 mL of oxalyl chloride. The reaction apparatus was placed in an oil bath under nitrogen protection and heated to reflux at 70 °C. The mixture was stirred for 5 h. After the reaction was completed, the oxalyl chloride was removed by rotary evaporation to obtain a yellow oily liquid. 20 mL of anhydrous tetrahydrofuran was added to the intermediate product. Methyl 1-(hydroxymethyl)cyclopropane-1-carboxylic acid (0.163 g, 1.26 mmol) was added at room temperature. The mixture was stirred for 3 h. After the reaction was completed by TCL spot monitoring, the tetrahydrofuran was removed by rotary evaporation. The product was dissolved in ethyl acetate, washed twice with saturated brine, dried with anhydrous magnesium sulfate, filtered, and the white product (0.592 g, 87.2% yield) was obtained by column chromatography.

[0142] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.17 (s, 1H), 7.81 (d, J = 6.0 Hz, 2H), 7.58 (dd, J = 7.9, 1.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.35 (q, J = 18.3 Hz, 2H), 4.22 (d, J = 14.0 Hz, 2H), 3.61 (s, 3H), 2.34 (s,3H), 1.16 (q, J = 4.1 Hz, 2H), 1.03 (q, J = 4.0 Hz, 2H).

[0143] ESI-MS (m / z): [MH-] Theoretical value: 589.05618, Measured value: 589.05615.

[0144] Example 20 Preparation methods of compound number 478 in Table 1: Synthesis of methyl 1-((((4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid ester:

[0145] 4-(5-(3,5-dichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.20 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. Methyl 1-(hydroxymethyl)cyclopropanecarboxylate (0.24 g, 1.72 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.364 g, yield 51.36%).

[0146] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.19 (s, 1H), 7.75 (t, J = 1.9 Hz, 1H), 7.69 – 7.60 (m, 4H), 7.49 (d, J = 8.0 Hz, 1H), 4.44 – 4.29 (m, 2H), 4.24 (s, 2H), 3.63 (s, 3H), 1.19 (q, J = 4.0 Hz, 2H), 1.05 (q, J = 4.1 Hz, 2H).

[0147] ESI-MS (m / z): [MH-] Theoretical value: 571.07, Measured value: 571.065.

[0148] Example 21 Preparation methods of compound number 479 in Table 1: Synthesis of methyl-1-((((4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid ester:

[0149] 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.11 mmol) was dissolved in excess oxalyl chloride, heated to 70 °C, and reacted for 4 h. The remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. Methyl 1-(hydroxymethyl)cyclopropanecarboxylate (180 mm, 1.66 mmol) was added, and the reaction was carried out at room temperature, monitored by TLC until completion. After the reaction, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.36 g, yield 53.48%).

[0150] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.17 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.64 – 7.57 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 4.41 (q, J = 18.4 Hz, 2H), 4.21 (s, 2H), 3.61 (s, 3H), 2.35 (s, 3H), 1.17 – 1.14 (m, 2H), 1.03 (q, J = 4.0 Hz, 2H).

[0151] ESI-MS (m / z): [MH-] Theoretical value: 605.09, Measured value: 605.092.

[0152] Example 22 Preparation methods of compound number 498 in Table 1: Synthesis of methyl 1-(((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(propyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid:

[0153] Methyl 4-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, bromopropane (0.083 g, 0.68 mmol) was slowly added, and the mixture was stirred until homogeneous. Potassium carbonate (0.1 g, 0.7 mmol) was then slowly added. The reaction was then carried out at 70 °C for 4 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a green, viscous product (0.19 g, 88.5% yield).

[0154] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.82 (d, J = 5.9 Hz, 2H), 7.59 – 7.53 (m, 2H), 7.25 (d, J = 7.9 Hz, 1H), 4.30 (d, J = 6.1Hz, 2H), 4.06 (q, J = 11.6 Hz, 2H), 3.77 (dd, J = 8.5, 6.2 Hz, 2H), 3.53 (s, 3H), 2.26 (s, 3H), 1.64 (h, J = 7.1 Hz, 2H), 0.92 (t, J = 7.5 Hz, 3H), 0.89 (d, J = 3.8Hz, 2H), 0.72 (s, 2H).

[0155] ESI-MS(m / z): [MH - Theoretical value: 631.10313, measured value: 631.103.

[0156] Example 23 Preparation method of compound number 538 in Table 1: Synthesis of methyl 1-((((cyclopropylmethyl)(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid:

[0157] Methyl 4-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of tetrahydrofuran. Then, (bromomethyl)cyclopropane (0.092 g, 0.68 mmol) was slowly added, and after stirring until homogeneous, potassium carbonate (0.1 g, 0.7 mmol) was slowly added. The temperature was then raised to 70 °C and the reaction was carried out for 8 h. The reaction was monitored by TLC until complete. The tetrahydrofuran was removed by vortexing, and the product was dissolved in ethyl acetate. The solution was washed twice with dilute hydrochloric acid and twice with saturated brine. The solution was dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a green viscous product (0.16 g, 76.8% yield).

[0158] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.84 (d, J = 6.1 Hz, 2H), 7.62 – 7.54 (m, 2H), 7.28 (d, J = 7.9 Hz, 1H), 4.38 – 4.27 (m,2H), 4.13 – 4.02 (m, 2H), 3.73 (d, J = 7.2 Hz, 2H), 3.55 (s, 3H), 2.30 (s, 3H), 1.23 (dtt, J = 13.7, 8.8, 4.8 Hz, 1H), 0.91 (s, 2H), 0.81 – 0.71 (m, 2H), 0.52(dt, J = 8.2, 3.0 Hz, 2H), 0.42 – 0.32 (m, 2H).

[0159] ESI-MS(m / z): [MH - Theoretical value: 643.10313, measured value: 643.103.

[0160] Example 24 Preparation method of compound number 593 in Table 1: Synthesis of methyl 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(propionyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid:

[0161] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Propionyl chloride (0.04 g, 0.43 mmol) was slowly added under nitrogen protection. After stirring until homogeneous, triethylamine (0.051 g, 0.5 mmol) was slowly added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.18 g, 78.5% yield).

[0162] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.81 (d, J = 6.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 4.43 – 4.31 (m, 2H), 4.24 (d, J = 13.2 Hz, 2H), 3.46 (s, 3H), 2.93 (q, J = 7.3Hz, 2H), 2.51 (d, J = 6.4 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H), 1.02 (p, J = 5.6 Hz, 2H), 0.88 (t, J = 3.5 Hz, 2H).

[0163] ESI-MS (m / z): [MH-] Theoretical value: 645.08239, Measured value: 645.082.

[0164] Example 25 Preparation method of compound number 611 in Table 1: Synthesis of methyl 1-(((acryloyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid ester:

[0165] Methyl 4-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Acryloyl chloride (0.04 g, 0.43 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.051 g, 0.5 mmol) was then slowly added, and the reaction was carried out at room temperature for 8 h. The reaction was monitored by TLC until completion. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a white solid (0.13 g, 64.2% yield).

[0166] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.82 (d, J = 6.1 Hz, 2H), 7.78 – 7.72 (m, 2H), 7.68 (dd, J = 8.0, 1.8 Hz, 1H), 6.88 (dd, J =17.0, 10.4 Hz, 1H), 6.43 (dd, J = 17.0, 1.2 Hz, 1H), 6.07 (dd, J = 10.4, 1.2 Hz,1H), 4.43 – 4.31 (m, 2H), 4.29 (s, 2H), 3.51 (s, 3H), 2.49 (s, 3H), 1.05 (q, J = 4.1 Hz, 2H), 0.90 (t, J = 3.5 Hz, 2H).

[0167] ESI-MS (m / z): [MH-] Theoretical value: 643.06674, Measured value: 643.06616.

[0168] Example 26 Preparation methods of compound number 649 in Table 1: Synthesis of methyl 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(2-methoxyacetyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid:

[0169] Methyl 4-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Methoxyacetyl chloride (0.043 g, 0.4 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.05 g, 0.05 mmol) was then slowly added, and the reaction was carried out at room temperature for 8 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, and the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, and twice with saturated brine. The product was dried over anhydrous magnesium sulfate, filtered, and subjected to column chromatography to obtain a yellow-green viscous product (0.14 g, 62.1% yield).

[0170] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.83 –7.79 (m, 3H), 7.76 (s, 1H), 7.70 (dd, J = 7.9, 1.8 Hz, 1H), 4.56 (s, 2H), 4.43– 4.35 (m, 3H), 4.26 (s, 2H), 3.63 (d, J = 2.7 Hz, 3H), 3.47 (s, 3H), 3.35 (s,3H), 1.04 (q, J = 3.9 Hz, 2H), 0.88 (p, J = 4.9 Hz, 2H).

[0171] ESI-MS (m / z): [MH-] Theoretical value: 661.07731, Measured value: 661.077.

[0172] Example 27 Preparation method of compound number 681 in Table 1: Synthesis of methyl 1-((((cyclopropylcarbonyl)(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid ester:

[0173] Methyl 4-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyloxy)methyl)cyclopropane-1-carboxylic acid (0.2 g, 0.34 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Cyclopropylformyl chloride (0.045 g, 0.43 mmol) was slowly added under nitrogen protection. After stirring until homogeneous, triethylamine (0.051 g, 0.5 mmol) was slowly added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.2 g, 89.3% yield).

[0174] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 7.82 (d, J = 6.1 Hz, 2H), 7.74 – 7.66 (m, 3H), 4.39 (t, J = 16.4 Hz, 2H), 4.30 (s, 2H), 3.51 (s, 3H), 2.48 (s, 3H), 1.10 – 1.05 (m, 4H), 1.02 (dt, J = 6.2, 3.0 Hz, 2H), 0.91 (t, J = 3.5 Hz, 2H).

[0175] ESI-MS (m / z): [MH-] Theoretical value: 657.08239, Measured value: 657.0816.

[0176] Example 28 Preparation method of compound number 697 in Table 1: Synthesis of 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid-2,2,2-trifluoroethyl ester:

[0177] Add 0.5 g (1.15 mmol) of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide to a reaction flask, dissolve it in 20 mL of oxalyl chloride, place the reaction apparatus in an oil bath under nitrogen protection, heat to reflux at 70 °C, and stir for 5 h. After the reaction is complete, remove the oxalyl chloride by rotary evaporation to obtain a yellow oily liquid. Add 20 mL of anhydrous tetrahydrofuran to the intermediate product, and then add 0.16 g (1.37 mmol) of ethyl 1-(hydroxymethyl)cyclopropanecarboxylic acid at room temperature. Stir the reaction for 3 h. After the reaction was completed by TCL spot monitoring, tetrahydrofuran was removed by vortexing, ethyl acetate was added to dissolve it, and then it was washed twice with saturated brine. After drying with anhydrous magnesium sulfate, it was filtered and the product was obtained by column chromatography as a white product (0.571 g, yield 82.2%) of 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid.

[0178] Weigh 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid (0.5 g, 0.86 mmol), N-methylimidazolium (NMI, 0.2 g, 0.0026 mol), trifluoroethanol (0.13 g, 0.0013 mol), and acetonitrile (20 mL) into a 50 mL round-bottom flask. Stir at room temperature for 5 min. Monitor by TLC. Benzoic acid is completely converted into the active intermediate. Weigh N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 0.3 g, 0.00113 mol) and add it to the above reaction solution. Stir the reaction for 50 min. Monitor by TLC. The active intermediate is completely converted into the product. After the reaction was completed, a large amount of ethyl acetate was added to dilute the reaction solution. Then, the solution was washed twice with water and twice with saturated saline solution. The solution was dried with anhydrous magnesium sulfate and the solution was evaporated to dryness to obtain a white solid (0.45 g, yield 78.2%), which was then stored at low temperature.

[0179] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 8.05 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.80 (d, J = 1.7 Hz, 1H), 7.73 (dd, J=8.2, 1.7 Hz, 1H), 4.62 (s, 2H), 4.48 – 4.32 (m, 2H), 3.37 (s, 2H), 2.61 (s,3H), 1.35 (q, J = 4.0 Hz, 2H), 1.27 (q, J = 4.1 Hz, 2H).

[0180] ESI-MS (m / z): [MH-] Theoretical value: 657.04356, Measured value: 657.04291.

[0181] Example 29 Preparation methods of compound number 929 in Table 1: Synthesis of (1-((2,2,2-trifluoroethyl)carbamoyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0182] Add 0.5 g (1.15 mmol) of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide to a reaction flask, dissolve it in 20 mL of oxalyl chloride, place the reaction apparatus in an oil bath under nitrogen protection, heat to reflux at 70 °C, and stir for 5 h. After the reaction is complete, remove the oxalyl chloride by rotary evaporation to obtain a yellow oily liquid. Add 20 mL of anhydrous tetrahydrofuran to the intermediate product, and then add 0.16 g (1.37 mmol) of ethyl 1-(hydroxymethyl)cyclopropanecarboxylic acid at room temperature and stir for 3 h. After the reaction was completed by TCL spot monitoring, tetrahydrofuran was removed by vortexing, ethyl acetate was added to dissolve it, and then it was washed twice with saturated brine. After drying with anhydrous magnesium sulfate, it was filtered and the product was obtained by column chromatography as a white product (0.571 g, yield 82.2%) of 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid.

[0183] Weigh 1-((((4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamoyl)oxy)methyl)cyclopropane-1-carboxylic acid (0.5 g, 0.86 mmol), N-methylimidazolium (NMI, 0.2 g, 0.0026 mol), trifluoroethylamine (0.13 g, 0.0013 mol), and acetonitrile (20 mL) into a 50 mL round-bottom flask. Stir at room temperature for 5 min. Monitor by TLC. Benzoic acid is completely converted into the active intermediate. Weigh N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 0.3 g, 0.00113 mol) and add it to the above reaction solution. Stir the reaction for 50 min. Monitor by TLC. The active intermediate is completely converted into the product. After the reaction was completed, a large amount of ethyl acetate was added to dilute the reaction solution. Then, the solution was washed twice with water and twice with saturated saline solution. The solution was dried with anhydrous magnesium sulfate and the solution was evaporated to dryness to obtain a white solid (0.45 g, yield 78.2%), which was then stored at low temperature.

[0184] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.20 (s, 1H), 8.20 (s, 1H), 7.82 (s, 2H), 7.62 (s, 2H), 7.48 (s, 1H), 4.36 (dd, J =31.8, 17.8 Hz, 2H), 4.24 (s, 2H), 3.87 (s, 2H), 2.56 (d, J = 41.4 Hz, 3H), 1.12 (s, 2H), 0.92 (s, 2H).

[0185] ESI-MS (m / z): [MH-] Theoretical value: 656.05955, Measured value: 656.0597.

[0186] Example 30 Preparation methods of compound number 1188 in Table 1: Synthesis of (1-methoxycyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0187] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was added to a reaction flask and dissolved in 20 mL of oxalyl chloride. The reaction apparatus was placed in an oil bath under nitrogen protection and heated to reflux at 70 °C. The mixture was stirred for 5 h. After the reaction was completed, the oxalyl chloride was removed by rotary evaporation to obtain a yellow oily liquid. 20 mL of anhydrous tetrahydrofuran was added to the intermediate product. At room temperature, (1-methoxycyclopropyl)methanol (0.135 g, 1.32 mmol) was added and the mixture was stirred for 3 h. After the reaction was completed by TCL spot monitoring, the tetrahydrofuran was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with saturated brine, dried with anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography (0.34 g, yield 50.4%).

[0188] 1H NMR spectrum of the compound 1 H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.27 (s, 1H), 7.76 (d, J = 6.1 Hz, 2H), 7.62 – 7.57 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 4.33 (q, J = 18.3 Hz, 2H), 4.21 (s, 2H), 3.20 (s, 3H), 2.35 (s, 3H), 0.74 (q, J =5.1 Hz, 2H), 0.61 (q, J = 5.0 Hz, 2H).

[0189] ESI-MS (m / z): [MH-] Theoretical value: 561.06126, Measured value: 561.060.

[0190] Example 31 Preparation method of compound number 1215 in Table 1: Synthesis of (1-trifluoromethylcyclobutyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate:

[0191] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was added to a reaction flask and dissolved in 20 mL of oxalyl chloride. The reaction apparatus was placed in an oil bath under nitrogen protection and heated to reflux at 70 °C. The mixture was stirred for 5 h. After the reaction was completed, the oxalyl chloride was removed by rotary evaporation to obtain a yellow oily liquid. 20 mL of anhydrous tetrahydrofuran was added to the intermediate product. At room temperature, (1-trifluoromethylcyclobutyl)methanol (0.2 g, 1.32 mmol) was added and the mixture was stirred for 3 h. After the reaction was completed by TCL spot monitoring, the tetrahydrofuran was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with saturated brine, dried with anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography (0.54 g, yield 73.2%).

[0192] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 11.33 (s, ¹H), 7.82 (d, J = 6.1 Hz, 2H), 7.66 – 7.62 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 4.43 – 4.31 (m, 4H), 2.37 (s, 3H), 2.25 – 2.19 (m, 2H), 2.09 – 2.00 (m, 4H).

[0193] ESI-MS(m / z): [MH - Theoretical value: 613.05373, measured value: 613.0535.

[0194] Example 32 Preparation method of compound 1242 in Table 1: Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(((1-(trifluoromethyl)cyclopropyl)methyl)carbamoyl)benzamide:

[0195] 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. (1-(trifluoromethyl)cyclopropyl)methylamine hydrochloride (0.303 g, 1.72 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give a white solid (0.103 g, yield 14.93%).

[0196] 1H NMR spectrum of the compound 1 ¹H NMR (500 MHz, DMSO) data are as follows (δ [ppm]): δ 10.92 (s, 1H), 8.74 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 6.1 Hz, 2H), 7.66 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 18.4 Hz, 2H), 3.57 (d, J = 6.1 Hz, 2H), 2.41 (s, 3H), 1.02–0.94 (m, 4H).

[0197] ESI-MS (m / z): [MH-] Theoretical value: 598.05, Measured value: 598.054.

[0198] Example 33 Preparation methods of compound number 1269 in Table 1: Synthesis of N-(((1-cyanocyclopropyl)methyl)carbamoyl)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide:

[0199] 4-(5-(3,5-dichloro-4-fluorophenyl)5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (0.5 g, 1.15 mmol) was dissolved in excess oxalyl chloride and heated to 70 °C. After reacting for 4 h, the remaining oxalyl chloride was evaporated to dryness and dissolved in anhydrous tetrahydrofuran. 1-(aminomethyl)cyclopropyl nitrile hydrochloride (0.302 g, 1.72 mmol) was added, and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion. After the reaction was complete, the tetrahydrofuran was evaporated to dryness, dissolved in ethyl acetate, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was purified by column chromatography to give a white solid (0.13 g, 19.75% yield).

[0200] 1H NMR spectrum of the compound 1 The following are the 1H NMR (500 MHz, DMSO) data (δ [ppm]): δ 10.95 (s, 1H), 8.80 (t, J = 6.2 Hz, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.67 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.1, 1.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 4.37 (q, J = 18.3 Hz, 2H), 3.43 (d, J = 6.2 Hz, 2H), 2.43 (s, 3H), 1.26 – 1.23 (m, 3H), 1.16 – 1.13 (m, 2H).

[0201] ESI-MS (m / z): [MH-] Theoretical value: 555.06, Measured value: 555.061.

[0202] Example 34 Preparation methods of compound number 1379 in Table 1: Synthesis of (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)(isopropoxycarbonyl)carbamate:

[0203] (1-(trifluoromethyl)cyclopropyl)methyl(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)carbamate (0.2 g, 0.33 mmol) was added to a reaction flask and dissolved in 10 mL of toluene. Isopropyl chloroformate (0.06 g, 0.4 mmol) was slowly added under nitrogen protection, and the mixture was stirred until homogeneous. Triethylamine (0.05 g, 0.5 mmol) was then slowly added. The reaction was allowed to proceed at room temperature for 12 h. The reaction was monitored by TLC until complete. The toluene was removed by rotary evaporation, the product was dissolved in ethyl acetate, washed twice with dilute hydrochloric acid, washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the product was obtained by column chromatography as a yellow-green viscous product (0.14 g, 72.6% yield).

[0204] 1H NMR spectrum of the compound 1 The following are the H NMR (600 MHz, DMSO) data (δ [ppm]): δ 7.81 (d, J = 6.2 Hz, 2H), 7.77 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.1, 1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 4.93 (hept, J = 6.5 Hz, 1H), 4.43 – 4.32 (m, 4H), 2.48 (s, 3H), 1.14 (d, J = 6.4 Hz, 6H), 1.00 (t, J = 3.5 Hz, 2H), 0.94 (d, J = 6.1 Hz, 2H).

[0205] ESI-MS (m / z): [MH-] Theoretical value: 685.07486, Measured value: 685.07477.

[0206] In this embodiment of the invention, the stereochemical purity of the S-configuration stereoisomer is 50% or higher. Other phenylisoxazoline amide compounds listed in Table 1 can be prepared by adjusting the preparation method described in the above embodiments. When the phenylisoxazoline amide compound is a stereoisomer of the compound represented by general formula (I), it can be obtained by conventional methods, such as obtaining a reaction product with corresponding chirality from a chiral reactant, or performing chiral resolution on the reaction product. This will not be discussed further in this embodiment. Equivalent variations made in the claims are still within the scope of the invention.

[0207] Effect Example Some of the compounds listed in this application were tested for activity against a variety of pests.

[0208] (1) Assay for the activity of rice stem borer: Preparation of compound solution: Weigh 10 mg of the original drug using a balance, prepare a 1% stock solution with DMF (N,N-dimethylformamide), and then dilute it with distilled water containing 0.1% Tween-80 to prepare three test concentrations of 5 mg / L, 3.0 mg / L, and 1.0 mg / L for later use.

[0209] The immersion method was used. After soaking the water chestnut slices in the medicine for 25 seconds, they were placed in a plastic box lined with filter paper and air-dried naturally. Ten second-instar rice stem borers were placed in each box and observed in a room at 26°C for 16 hours of light and 8 hours of darkness. The number of dead insects was observed within 96 hours, and the mortality rate was calculated.

[0210] The structures of the control compounds CK01, CK02, and CK03 are shown below: (CK01); (CK02); (CK03).

[0211] Compounds 1, 14, 15, 17, 38, 90, 129, 147, 147 (5S), 185, 217, 233, 246, 247, 266, 270, 322, 361, 379, 417, 465, 478, 479, 498, 538, 593, 611, 649, 681, 697, 929, 1188, 1215, 1242, 1269, 1379, and 1397 in Table 1 showed a lethality of over 80% against rice stem borer after 4 days at a concentration of 5 mg / L. Then, low-concentration activity tests were performed on compounds 1, 38, 129, 147, 147 (5S), 185, 233, 322, 361, 379, 417, 465, 498, 538, 593, 611, 649, 681, 697, 1188, 1215, 1242, and 1269 in Table 1, and the results are shown in Table 2.

[0212] Table 2: Results of activity assays on rice stem borer for some compounds in Table 1.

[0213] Note: Compound numbers correspond to those in Table 1. (2) Activity assay of diamondback moth: Preparation of compound solution: Weigh 10 mg of the original drug using a balance, prepare a 1% stock solution with DMF, and then dilute it with distilled water containing 0.1% Tween-80 to prepare four test concentrations of 3 mg / L, 1 mg / L, 0.5 mg / L and 0.1 mg / L for later use.

[0214] The immersion method was used. After soaking the leaves of Chinese cabbage in the pesticide for 10 seconds, they were placed in a plastic box lined with filter paper and allowed to air dry naturally. Ten second-instar diamondback moths were inoculated into each box. The insects were observed in an indoor environment at 26℃ for 16 hours of light and 8 hours of darkness. The number of dead insects was observed within 72 hours, and the mortality rate was calculated.

[0215] Compounds 1, 14, 15, 17, 38, 90, 129, 147, 147(5S), 185, 217, 233, 246, 247, 266, 270, 322, 361, 379, 417, 465, 478, 479, 498, 538, 593, 611, 649, 681, 697, 929, 1188, 1215, 1242, 1269, 1379, and 1397 all showed a mortality rate of over 80% against diamondback moth after 3 days at a concentration of 3 mg / L. Then, low-concentration activity tests were conducted on 1, 38, 129, 147, 147 (5S), 185, 233, 322, 361, 379, 417, 465, 498, 538, 593, 611, 649, 681, 697, 1188, 1215, 1242, and 1269, and the results are shown in Table 3.

[0216] Table 3: Results of activity assays on diamondback moth for some compounds in Table 1.

[0217] Note: Compound numbers correspond to those in Table 1. (3) Toxicity test of mosquitofish: Weigh 10 mg of the original drug using a balance, prepare a 1% stock solution with ethanol, and then dilute it with lake water to prepare test concentrations of 2.0 mg / L and 5 mg / L for later use. Take 200 mL of the prepared specific concentration drug solution and transfer it into a 500 mL beaker. Transfer 5 mosquitofish with a length of about 1 cm into each beaker and raise them for 96 h. Observe the number of fish deaths and calculate the mortality rate as shown in Table 4 below.

[0218] Table 4. Mortality rates of various compounds on mosquitofish

[0219] As can be seen from the data in Tables 2 and 3, compared with the control compounds CK01, CK02, and CK03, the phenylformamide acyl isoxazoline compounds provided in this application exhibit high insecticidal activity against both rice stem borer and diamondback moth, and these phenylformamide acyl isoxazoline compounds show no cross-resistance with chlorantraniliprole (CK01) in Comparative Example 1. In small organic molecule pesticide compounds, due to differences in the type of substituents, group volume, saturation, and electronegativity, the binding capacity, metabolic performance, and transport properties of the entire molecule in vivo can vary greatly, resulting in significant differences in biological activity. Furthermore, the metabolic performance, transport properties, and binding capacity of a molecule to its receptor are unpredictable and require considerable creative effort to determine.

[0220] As can be seen from the data in Table 4, although CK02 and CK03 also have good insecticidal effects, their high toxicity to non-target organisms such as fish limits their practical application in production and daily life. In contrast, compounds 1, 147, 185, and 233 of this application, while possessing high insecticidal activity, exhibit low toxicity to fish, making them suitable for large-scale production applications.

[0221] The preferred embodiments have been described in detail above, but the present invention is not limited to the specific implementation methods described above. Those skilled in the art can make various specific modifications under the guidance of this application without departing from the scope of protection of this application, and these modifications all fall within the scope of protection of the present invention.

Claims

1. An arylformamide acyl isoxazoline compound and its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, The structure of the arylformamide acyl isoxazoline compound is shown in formula (Ⅰ): (Ⅰ)； In equation (Ⅰ), Q is the structure shown in equation (Q-1) or the structure shown in equation (Q-2): (Q-1); (Q-2); Among them, R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen atoms, halogen atoms, and C1-C8 haloalkyl groups; L1 is -CH2-; R6 is selected from any one of cyano, trifluoromethyl, methoxycarbonyl, -C(=O)CH2CF3 and -C(=O)NHCH2CF3; R7 is selected from hydrogen atom, C1-C3 alkyl, C2-C4 alkenyl, C1-C3 alkylenecyclopropyl, C1-C3 alkyleneC1-C3 alkoxy, and -C(=O)R. 7a Any one of them, where R 7a Selected from any one of C1-C3 alkyl, C2-C5 alkenyl, cyclopropyl, and C1-C3 alkylene-C1-C3 alkoxy groups; R8 is a C1-C4 alkyl group; Z1 is an oxygen atom or -NH-; Z2 is an oxygen atom.

2. The arylformamide acyl isoxazoline compound and its stereoisomers or pharmaceutically acceptable salts as described in claim 1, characterized in that, R1, R2, and R3 are each independently selected from any one of hydrogen atom, chlorine atom, fluorine atom, and trifluoromethyl; R4 and R5 are hydrogen atoms; R7 is selected from any one of hydrogen atom, methyl, n-propyl, propenyl, methylene methoxy, methylene cyclopropyl, C(=O)CH2CH3, -C(=O)CH=CH2, -C(=O)CH2OCH3, -C(=O)CH(CH3)2 and -C(=O)-cyclopropyl; R8 is a methyl group; L1 is -CH2-; Z1 is an oxygen atom or -NH-; Z2 is an oxygen atom.

3. The arylformamide acyl isoxazoline compound and its stereoisomers or pharmaceutically acceptable salts as described in claim 1, characterized in that, The structure of the stereoisomer is shown in formula (I'): (Ⅰ’)； In formula (Ⅰ'), It is a chiral carbon atom; Based on the content of the stereoisomers with R and S configurations of the chiral carbon atom, wherein the stereochemical purity of the stereoisomers with S configuration is 50%-100%.

4. The use of an arylformamide acyl isoxazoline compound as described in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, in the preparation of an insecticide in the agricultural, forestry, or health fields.

5. An insecticide, characterized in that, The insecticide contains an active ingredient and excipients; the active ingredient contains an arylformamide acyl isoxazoline compound as described in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof; the excipients contain one or more pharmaceutically acceptable carriers and excipients; the active ingredient in the insecticide has a mass percentage content of 1%-99%.

6. An insecticide composition, characterized in that, The insecticide composition contains an active ingredient and other active compounds; the active ingredient contains an arylformamide acyl isoxazoline compound as described in any one of claims 1-3, its stereoisomers, or pharmaceutically acceptable salts thereof, and the other active compounds are one or more of insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth regulators, and herbicides; the active ingredient in the insecticide composition has a mass percentage of 1%-99%.

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