Difluorocyclopropyl-substituted diacylisoxazoline compound and use thereof

Abstract

The present invention provides a compound represented by formula I, or a stereoisomer, nitrogen-oxygen compound, isotopically labeled compound, or agrochemically acceptable salt thereof. X1, X2, X3, X4, X5, R, G, W1, W2, R1, R11, R12, R13, R14, R15, R16, R17, and R18 are as defined in the description. The compound of the present invention has excellent insecticidal effects and broad application prospects.

Description

A difluorocyclopropyl-substituted diacylisoxazoline compound and its applications Technical Field

[0001] This invention belongs to the field of insecticides, specifically relating to a difluorocyclopropyl-substituted diamide isoxazoline compound and its applications. Background Technology

[0002] Diamide isoxazoline insecticides have garnered significant attention globally, representing one of the fastest-growing and most promising insecticide classes in recent years. Their unique mechanism of action and superior performance, particularly in the control of lepidopteran pests, have established a dominant market position, making them one of the four major insecticide categories. Compared to traditional insecticides, diamide isoxazoline insecticides possess unique mechanisms of action and activity characteristics. These products act on ryanodine receptors within insects, causing pests to excessively release calcium ions from their cells. The sustained increase in calcium ion concentration triggers muscle contractions within the pest, leading to weakening and paralysis of receptors, ultimately resulting in the pest's death. Diamide isoxazoline insecticides have three key characteristics: low toxicity, broad insecticidal spectrum, and ovicidal activity.

[0003] During the research process, the inventors of this application discovered a series of novel difluorocyclopropyl-substituted diamide isoxazoline insecticide compounds with higher activity, lower dosage, and more environmentally friendly properties, thus completing this invention. Summary of the Invention

[0004] This invention provides a new class of difluorocyclopropyl-substituted diamide isoxazoline insecticide compounds that are more active, require lower dosages, are less toxic to bees and other insects, and are more environmentally friendly.

[0005] The technical solution provided by this invention is:

[0006] A compound of Formula I, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts.

[0007] Wherein, X1, X2, X3, X4, and X5 are independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, optionally substituted C2-C6 ynyl, -OR3, -OSO2R3, -SR3, and -S(O). pR3, -N(R4)R5, -N=CHOR6, -N=C(R7)OR6, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R8)R7, -C(S)SR7, -C(S)NHR8, -C(S)N(R8)R7, -CH=NOR9, -C(R7)=NOR9, -S(O)2OR7, -S(O)2NHR8, -S(O)2N(R1)R7;

[0008] When two X's are adjacent, they can form -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -OCH2O-, -CH2CH2S-, -CH2SCH2-, -CH2CH2N(R) 10 )-、-CH2N(R 10 )CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2OCH2O-, -OCH2CH2O-, -OCH2CH2S-, -CH2CH=CH-, -OCH=CH-, -SCH=CH-, -N(R 10 )CH=CH-, -OCH=N-, -SCH=N-, -N(R 10 CH=N-、-N(R) 10 N=CH-, -CH=CHCH=CH-, -OCH2CH=CH-, -N=CHCH=CH-, -N=CHCH=N- or -N=CHN=CH- are linked to a benzene ring to form a fused ring;

[0009] R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl.

[0010] R1 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl.

[0011] G is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted arylene, optionally substituted heteroaryl or optionally substituted heterocyclic;

[0012] W1 and W2 are each independently selected from O or S;

[0013] R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C3-C8 halocycloalkenyl, optionally substituted C3-C6 alkynyl or optionally substituted phenyl.

[0014] R4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C4 alkoxy (C1-C4)alkyl, C1-C4 alkylthio (C1-C4)alkyl, optionally substituted phenylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C1-C6 alkoxycarbonyl (C1-C4)alkyl, C1-C6 alkylaminocarbonyl (C1-C4)alkyl, di(C1-C6)aminocarbonyl (C1-C4)alkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 One of the following: haloalkynyl, -OH, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, optionally substituted phenylthio, -SN(R5)R6, -S(O)2R7, -S(O)2N(R1)R7, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R1)R7, -C(S)OR7, -C(S)SR7, -C(S)NHR8, -C(S)N(R1)R7, -C(O)C(O)R7, -C(O)C(O)OR8, -P(O)(OR4)2 or -P(S)(OR4)2;

[0015] R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C1-C4 alkoxy (C1-C4) alkyl, C1-C4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalynyl, -CHO, C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl or C1-C6 alkoxy carbonyl, or R4 and R5 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the nitrogen atom it is bonded to. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl or C1-C6 haloalkyl.

[0016] R6 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl or optionally substituted phenyl;

[0017] R7 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 haloalkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, C1-C6 haloalkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, or optionally substituted phenyl (C1-C4)alkyl.

[0018] R8 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C3-C6 alkenyl or C3-C6 alkynyl, or R8 and R9 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the bonded atom. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl, C1-C6 alkoxy, formyl, C1-C6 alkyl carbonyl or C1-C6 alkoxy-carbonyl.

[0019] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 ynyl, C3-C6 haloynyl or optionally substituted phenyl.

[0020] R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl groups;

[0021] R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, and halo-C3-C8 cycloalkylalkyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom;

[0022] R 12 and R 13 Each is independently selected from one of H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0023] R 14It is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl.

[0024] R 15 and R 16 Each of the following is independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0025] R 17 It is one of H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0026] The condition is to exclude the following compounds:

[0027] Preferably, the present invention provides a compound represented by Formula II:

[0028] Wherein, X1, X2, X3, X4, and X5 are independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, optionally substituted C2-C6 ynyl, -OR3, -OSO2R3, -SR3, and -S(O). p R3, -N(R4)R5, -N=CHOR6, -N=C(R7)OR6, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R8)R7, -C(S)SR7, -C(S)NHR8, -C(S)N(R8)R7, -CH=NOR9, -C(R7)=NOR9, -S(O)2OR7, -S(O)2NHR8, -S(O)2N(R1)R7;

[0029] When two X's are adjacent, they can form -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -OCH2O-, -CH2CH2S-, -CH2SCH2-, -CH2CH2N(R) 10 )-、-CH2N(R 10)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2OCH2O-, -OCH2CH2O-, -OCH2CH2S-, -CH2CH=CH-, -OCH=CH-, -SCH=CH-, -N(R 10 )CH=CH-, -OCH=N-, -SCH=N-, -N(R 10 CH=N-、-N(R) 10 N=CH-, -CH=CHCH=CH-, -OCH2CH=CH-, -N=CHCH=CH-, -N=CHCH=N- or -N=CHN=CH- are linked to a benzene ring to form a fused ring;

[0030] R is one of the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl.

[0031] R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl-C1-C6 alkyl;

[0032] G can be an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted heterocyclic group, preferably.

[0033] in, Indicates the connection end;

[0034] R2 is selected from H, halogen, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, and C3-C8 halocycloalkyl;

[0035] R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C3-C8 halocycloalkenyl, optionally substituted C3-C6 alkynyl or optionally substituted phenyl.

[0036] R4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C4 alkoxy (C1-C4)alkyl, C1-C4 alkylthio (C1-C4)alkyl, optionally substituted phenylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C1-C6 alkoxycarbonyl (C1-C4)alkyl, C1-C6 alkylaminocarbonyl (C1-C4)alkyl, di(C1-C6)aminocarbonyl (C1-C4)alkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 One of the following: haloalkynyl, -OH, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, optionally substituted phenylthio, -SN(R5)R6, -S(O)2R7, -S(O)2N(R1)R7, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R1)R7, -C(S)OR7, -C(S)SR7, -C(S)NHR8, -C(S)N(R1)R7, -C(O)C(O)R7, -C(O)C(O)OR8, -P(O)(OR4)2 or -P(S)(OR4)2;

[0037] R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C1-C4 alkoxy (C1-C4) alkyl, C1-C4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalynyl, -CHO, C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl or C1-C6 alkoxy carbonyl, or R4 and R5 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the nitrogen atom it is bonded to. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl or C1-C6 haloalkyl.

[0038] R6 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl or optionally substituted phenyl;

[0039] R7 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 haloalkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, C1-C6 haloalkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, or optionally substituted phenyl (C1-C4)alkyl.

[0040] R8 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C3-C6 alkenyl or C3-C6 alkynyl, or R8 and R9 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the bonded atom. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl, C1-C6 alkoxy, formyl, C1-C6 alkyl carbonyl or C1-C6 alkoxy-carbonyl.

[0041] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 ynyl, C3-C6 haloynyl or optionally substituted phenyl.

[0042] R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl groups;

[0043] R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, and halo-C3-C8 cycloalkylalkyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom;

[0044] n is a natural number between 0 and 4;

[0045] m is a natural number between 0 and 2.

[0046] The condition is to exclude the following compounds:

[0047] The present invention also provides an insecticidal composition comprising, as an active ingredient, a compound of formula I described herein, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts.

[0048] The present invention has the following beneficial effects:

[0049] Studies of the compounds in this invention have shown that compounds with a 2,2-difluorocyclopropyl group directly linked to an amide group are more effective and exhibit higher safety for beneficial insects. Detailed Implementation

[0050] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0051] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0052] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0053] If the compound of Formula I described in this invention can form geometric isomers, such as E / Z isomers, internal / external isomers, etc., then both the pure isomer and mixtures thereof can be used in the composition of this invention.

[0054] If the compound of Formula I described in this invention has one or more chiral centers and is therefore present as an enantiomer or diastereomer, then the pure enantiomer, the racemic version, or the diastereomer may be used in the compositions of this invention.

[0055] Unless otherwise stated, all technical and technical terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this disclosure are incorporated herein by reference in their entirety.

[0056] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0057] The term "optional" or "optionally substituted" means that the event or situation described below may, but is not guaranteed to, occur. That is, the description includes both the possibility that the event or situation occurs and the possibility that it does not. For example, "optionally substituted by 1, 2, 3, or 4..." includes the case where the group is substituted by 1, 2, 3, or 4 of the said substituents, and the case where the group is not substituted by the said substituents. Further, when the group is substituted by more than one of the said substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same.

[0058] As described in this disclosure, the compounds of this disclosure may optionally be substituted by one or more substituents, such as compounds of the formula above, or specific examples, subclasses, and a class of compounds included in this disclosure. Generally, the term "substitution" means that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent may be substituted at each substituted position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. Wherein, "one or more substituents" means one or more substituents, the number of which is determined by the number of substituted positions of the substituted group. The substituents may include, but are not limited to, hydrogen, oxo (=O), halogen, cyano, nitro, hydroxyl, mercapto, carboxyl, amino, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, etc., wherein the substituents have the meaning described in this disclosure and may be further substituted by the substituents described in this disclosure, either monosubstituted or polysubstituted in the same or different ways.

[0059] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this disclosure are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0060] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-20", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. As another example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. Furthermore, when certain numerical ranges are not defined as "integers", they should be understood to include the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "1-99%" should be understood as not only recording each integer of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, ... 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, but also recording at least the sum of each of these integers with 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.

[0061] Unless otherwise specified, the percentage content in this invention refers to the percentage content by mass.

[0062] In the context of “one or more”, “multiple” or “multiple types” as described in this article, “multiple” or “multiple types” means two or more types, such as an integer number greater than or equal to 2, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0063] The terms “at least one” or “at least one” as used in this document mean “one or more” or “one or more types of”.

[0064] In the description of “one, two or more” and “one, two or more” in this article, “more” or “more kinds” means a number greater than 2, such as integers greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10, etc.

[0065] As used in this disclosure, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. When the number of carbon atoms is not used when describing "alkyl," it means that the alkyl group has any number of carbon atoms. When the number of carbon atoms is used when describing "alkyl," it means that the alkyl group has the stated number of carbon atoms. For example, an alkyl group can be C1-C1. 20 Alkyl group refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this disclosure. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms, such as "C1-C2". 12 "alkyl"; in some embodiments, the alkyl group is an alkyl group containing 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms, i.e. "C1-C6 alkyl"; in still other embodiments, the alkyl group is an alkyl group containing 1-4 (1, 2, 3 or 4) carbon atoms, i.e. "C1-C4 alkyl"; in still other embodiments, the alkyl group contains 1-3 carbon atoms, i.e. "C1-C3 alkyl".

[0066] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), and tert-butyl (t-B). u、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1 -Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0067] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0068] The term "halogenated alkyl" refers to a straight-chain or branched alkoxyalkyl group, for example, substituted with one or more halogen atoms that may be the same or different from each other. For example, "halogenated C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, substituted with one or more halogen atoms that may be the same or different from each other. Examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 1,3-difluoro-2-propyl, 1,3-dichloro-2-propyl, and 1-chloro-3-fluoro -2-propyl, 1,1,1-trifluoro-2-propyl, 2,3,3,3-tetrafluoropropyl, 1,1,1,3,3,3-hexafluoro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-chloro-2-propyl, 1,1,1,3,3,3-hexafluoro-2-bromo-2-propyl, 1,1,2,3,3,3-hexafluoro-2-chloropropyl, 1,1,2,3,3,3-hexafluoro-2-bromopropyl, 1,1,2,3,3,3-hexafluoro-1-bromo-2-propyl, 2,2,3,3,3-pentafluoropropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, nonafluorobutyl, nonafluoroisobutyl, nonafluorosec-butyl, or nonafluorotert-butyl, etc., but not limited to these.

[0069] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0070] The term "(C3-C8)cycloalkyl" refers to cycloalkyl groups with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0071] The term "C3-C8 cycloalkyl-C1-C6 alkyl" refers to cycloalkyl groups with 3 to 8 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, etc., which are linked to chain alkyl groups with 1 to 6 carbon atoms.

[0072] The term "halogenated C3-C8 cycloalkyl" refers to cycloalkyl groups with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which are substituted with halogens, for example, 1-chlorocyclopropyl, 1,1-dichlorocyclopropyl, 1,2-dichlorocyclopropyl, 1-fluorocyclopropyl, 1,1-difluorocyclopropyl, 1,2-difluorocyclopropyl, etc.; but it is not limited to these.

[0073] The term "halogenated C3-C8 cycloalkyl-C1-C6 alkyl" refers to a C3-C8 cycloalkyl-C1-C6 alkyl group in which the cycloalkyl group is replaced by a halogen. An example of cycloalkyl group being replaced by a halogen is "halogenated C3-C8 cycloalkyl".

[0074] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group also includes, as described above, an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0075] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc., but is not limited thereto. The heteroaryl also includes heteroaryl fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring.

[0076] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0077] The term "arylene" includes examples such as 1,3-phenylene, 1,4-phenylene, naphthylene, etc., but is not limited to these.

[0078] The term "hybrid aryl" includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzofurandiyl, benzothiophenediyl, benzozazolediyl, benzothiazolediyl, quinolinediyl, isoquinolinediyl, or quinoxalinediyl.

[0079] In the chemical structure of the compound described in this invention, the bond... No configuration was specified, i.e., key It can be or Or simultaneously include and Two configurations.

[0080] The “acceptable salts” disclosed herein include salts of acid addition and salts of base addition, with suitable bases being hydroxides, carbonates, bicarbonates of alkali metals and alkaline earth metals, particularly sodium, potassium, magnesium, and calcium salts, as well as ammonium, primary, secondary, and tertiary amines having (C1-C4)-alkyl groups, mono-, di-, and tri-alkyl alcohols of (C1-C4)-alkanols, choline, and choline chloride. The salt can be a salt added to an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or a salt added to an organic acid, such as formic acid, carbonic acid, and alkyl acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, and propionic acid, as well as glycolic acid, thiocyanate, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, and saturated, monounsaturated, or diunsaturated C6-C4 alkyl groups. 20 Fatty acids, alkyl sulfate monoesters, alkyl sulfonic acids (sulfonic acids with straight-chain or branched alkyl groups having 1-20 carbon atoms), aryl sulfonic acids or aryl disulfonic acids (aromatic groups with one or two sulfonic acid groups, such as phenyl and naphthyl), alkyl phosphonic acids (phosphonic acids with straight-chain or branched alkyl groups having 1-20 carbon atoms), aryl phosphonic acids or aryl diphosphonic acids (aromatic groups with one or two phosphonic acid groups, such as phenyl and naphthyl), wherein the alkyl and aryl groups may have other substituents, such as p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.

[0081] The leaving group of this invention is usually a halogen (such as fluorine, chlorine, bromine or iodine), p-toluenesulfonyl, methanesulfonyl or other easily leaving groups, but is not limited to these.

[0082] Those skilled in the art understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires the lone pair of electrons to be oxidized into oxides. They also know which nitrogen-containing heterocycles can form N-oxides. Tertiary amines can also form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and diethylene oxides such as dimethyldiethylene oxide. These methods for preparing N-oxides have been extensively described and reviewed in the literature.

[0083] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0084] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0085] This document provides for Formula I compounds comprising one or more isotopically enriched atoms. Formula I compounds may contain atomic isotopes in non-natural proportions on one or more atoms constituting the Formula I compound. In some embodiments, the compound is isotopically labeled, such as isotopically labeled Formula I compounds or their pesticide-pharmaceutical-acceptable salts, stereoisomers, or nitrogen oxides, wherein a portion of one or more atoms is replaced by isotopes of the same element. Exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15O, 17O, 35S, 18F, and 36Cl. Certain isotopically labeled compounds (e.g., 2H, 3H, 11C, 13C, 14C) can be used for compound studies. In some embodiments, the incorporation of heavier isotopes such as deuterium (2H) may provide certain advantages in insecticidal effect due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement).

[0086] This invention first provides a compound of Formula I, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts.

[0087] Wherein, X1, X2, X3, X4, and X5 are independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, optionally substituted C2-C6 ynyl, -OR3, -OSO2R3, -SR3, and -S(O). p R3, -N(R4)R5, -N=CHOR6, -N=C(R7)OR6, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R8)R7, -C(S)SR7, -C(S)NHR8, -C(S)N(R8)R7, -CH=NOR9, -C(R7)=NOR9, -S(O)2OR7, -S(O)2NHR8, -S(O)2N(R1)R7;

[0088] When two X's are adjacent, they can form -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -OCH2O-, -CH2CH2S-, -CH2SCH2-, -CH2CH2N(R) 10 )-、-CH2N(R 10 )CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2OCH2O-, -OCH2CH2O-, -OCH2CH2S-, -CH2CH=CH-, -OCH=CH-, -SCH=CH-, -N(R 10 )CH=CH-, -OCH=N-, -SCH=N-, -N(R 10 CH=N-、-N(R) 10 N=CH-, -CH=CHCH=CH-, -OCH2CH=CH-, -N=CHCH=CH-, -N=CHCH=N- or -N=CHN=CH- are linked to a benzene ring to form a fused ring;

[0089] R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl.

[0090] R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl-C1-C6 alkyl;

[0091] G is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted arylene, optionally substituted heteroaryl or optionally substituted heterocyclic;

[0092] W1 and W2 are each independently selected from O or S;

[0093] R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C3-C8 halocycloalkenyl, optionally substituted C3-C6 alkynyl or optionally substituted phenyl.

[0094] R4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C4 alkoxy (C1-C4)alkyl, C1-C4 alkylthio (C1-C4)alkyl, optionally substituted phenylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C1-C6 alkoxycarbonyl (C1-C4)alkyl, C1-C6 alkylaminocarbonyl (C1-C4)alkyl, di(C1-C6)aminocarbonyl (C1-C4)alkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 One of the following: haloalkynyl, -OH, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, optionally substituted phenylthio, -SN(R5)R6, -S(O)2R7, -S(O)2N(R1)R7, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R1)R7, -C(S)OR7, -C(S)SR7, -C(S)NHR8, -C(S)N(R1)R7, -C(O)C(O)R7, -C(O)C(O)OR8, -P(O)(OR4)2 or -P(S)(OR4)2;

[0095] R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C1-C4 alkoxy (C1-C4) alkyl, C1-C4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalynyl, -CHO, C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl or C1-C6 alkoxy carbonyl, or R4 and R5 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the nitrogen atom it is bonded to. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl or C1-C6 haloalkyl.

[0096] R6 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl or optionally substituted phenyl;

[0097] R7 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 haloalkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, C1-C6 haloalkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, or optionally substituted phenyl (C1-C4)alkyl.

[0098] R8 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C3-C6 alkenyl or C3-C6 alkynyl, or R8 and R9 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the bonded atom. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl, C1-C6 alkoxy, formyl, C1-C6 alkyl carbonyl or C1-C6 alkoxy-carbonyl.

[0099] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 ynyl, C3-C6 haloynyl or optionally substituted phenyl.

[0100] R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl groups;

[0101] R 11 and R18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, and halo-C3-C8 cycloalkylalkyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom;

[0102] R 12 and R 13 Each is independently selected from one of H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0103] R 14 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylacyl or C1-C6 alkylsulfonyl;

[0104] R 15 and R 16 Each of the following is independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0105] R 17 It is one of H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0106] The condition is to exclude the following compounds:

[0107] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0108] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0109] In some technical solutions, R1 is selected from one of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl-C1-C6 alkyl;

[0110] In some technical solutions, R1 is selected from H, C1-C6 alkyl or C1-C6 haloalkyl, with H or methyl being particularly preferred;

[0111] In some technical solutions, G is selected from the following groups: Preferred Specially selected,

[0112] in, Indicates the connection end;

[0113] R2 is selected from H, halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy or C3-C8 halocycloalkyl, preferably H, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkyl, particularly preferably H, hydroxyl, F, Cl, Br, methyl, methoxy or trifluoromethyl;

[0114] n is a natural number between 0 and 4;

[0115] m is a natural number between 0 and 2.

[0116] In some technical solutions, R 11 It is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl; preferably H, C1-C6 alkyl or C3-C8 cycloalkyl, and particularly preferably H, methyl, ethyl, cyclopropyl or cyclobutyl;

[0117] In some technical solutions, R 12 and R 13 Each is independently selected from H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; preferably from H, halogen, or C1-C6 alkyl; particularly preferably from H;

[0118] In some technical solutions, R 14 Selected from H, C1-C6 alkyl, or C1-C6 haloalkyl; preferably H or C1-C6 alkyl.

[0119] In some technical solutions, R 15 and R 16 Each is independently selected from H, halogen or C1-C6 alkyl, with H or halogen being particularly preferred;

[0120] In some technical solutions, R 17It is one of H, halogen or C1-C6 alkyl; preferably one of H, halogen or methyl.

[0121] Preferably, the present invention provides a compound represented by Formula II:

[0122] Wherein, X1, X2, X3, X4, and X5 are independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, optionally substituted C2-C6 ynyl, -OR3, -OSO2R3, -SR3, and -S(O). p R3, -N(R4)R5, -N=CHOR6, -N=C(R7)OR6, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R8)R7, -C(S)SR7, -C(S)NHR8, -C(S)N(R8)R7, -CH=NOR9, -C(R7)=NOR9, -S(O)2OR7, -S(O)2NHR8, -S(O)2N(R1)R7;

[0123] When two X's are adjacent, they can form -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -OCH2O-, -CH2CH2S-, -CH2SCH2-, -CH2CH2N(R) 10 )-、-CH2N(R 10 )CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2OCH2O-, -OCH2CH2O-, -OCH2CH2S-, -CH2CH=CH-, -OCH=CH-, -SCH=CH-, -N(R 10 )CH=CH-, -OCH=N-, -SCH=N-, -N(R 10 CH=N-、-N(R) 10 N=CH-, -CH=CHCH=CH-, -OCH2CH=CH-, -N=CHCH=CH-, -N=CHCH=N- or -N=CHN=CH- are linked to a benzene ring to form a fused ring;

[0124] R is one of the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl.

[0125] R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl-C1-C6 alkyl;

[0126] G can be an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group, an optionally substituted arylene group, an optionally substituted heteroarylene group, or an optionally substituted heterocyclic group, preferably.

[0127] in, Indicates the connection end;

[0128] R2 is selected from H, halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy or C3-C8 halocycloalkyl;

[0129] R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C3-C8 halocycloalkenyl, optionally substituted C3-C6 alkynyl or optionally substituted phenyl.

[0130] R4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C4 alkoxy (C1-C4)alkyl, C1-C4 alkylthio (C1-C4)alkyl, optionally substituted phenylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C1-C6 alkoxycarbonyl (C1-C4)alkyl, C1-C6 alkylaminocarbonyl (C1-C4)alkyl, di(C1-C6)aminocarbonyl (C1-C4)alkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 One of the following: haloalkynyl, -OH, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, optionally substituted phenylthio, -SN(R5)R6, -S(O)2R7, -S(O)2N(R1)R7, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R1)R7, -C(S)OR7, -C(S)SR7, -C(S)NHR8, -C(S)N(R1)R7, -C(O)C(O)R7, -C(O)C(O)OR8, -P(O)(OR4)2 or -P(S)(OR4)2;

[0131] R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C1-C4 alkoxy (C1-C4) alkyl, C1-C4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalynyl, -CHO, C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl or C1-C6 alkoxy carbonyl, or R4 and R5 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the nitrogen atom it is bonded to. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl or C1-C6 haloalkyl.

[0132] R6 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl or optionally substituted phenyl;

[0133] R7 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 haloalkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, C1-C6 haloalkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, or optionally substituted phenyl (C1-C4)alkyl.

[0134] R8 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C3-C6 alkenyl or C3-C6 alkynyl, or R8 and R9 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the bonded atom. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl, C1-C6 alkoxy, formyl, C1-C6 alkyl carbonyl or C1-C6 alkoxy-carbonyl.

[0135] R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 ynyl, C3-C6 haloynyl or optionally substituted phenyl.

[0136] R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl groups;

[0137] R11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, and halo-C3-C8 cycloalkylalkyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom;

[0138] n is a natural number between 0 and 4;

[0139] m is a natural number between 0 and 2.

[0140] In a preferred embodiment, X1, X2, X3, X4 and X5 are each independently selected from H, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

[0141] In a preferred embodiment, R is selected from halogenated C1-C6 alkyl or halogenated C3-C8 cycloalkyl.

[0142] In a preferred embodiment, R1 is selected from H, C1-C6 alkyl, or halogenated C1-C6 alkyl; R2 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halogenated C3-C8 cycloalkyl, or halogenated C3-C8 cycloalkyl-C1-C6 alkyl.

[0143] In the preferred technical solution, n is 0, 1, or 2; m is 0, 1, or 2.

[0144] The condition is to exclude the following compounds:

[0145] Preferably, the present invention provides a compound of formula III.

[0146] Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definitions are as described in General Formula I above.

[0147] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0148] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0149] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl;

[0150] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0151] Table 1 below represents the preferred compounds of Formula III, wherein the structures of A-1, A-2 and A-3 are as follows:

[0152] Preferred compounds from Formula III in Table 1

[0153] This name also provides compounds of formula IV.

[0154] Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definitions are as described in General Formula I above.

[0155] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0156] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0157] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl;

[0158] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0159] Table 2 below represents preferred compounds of formula IV, wherein the structures of A-1, A-2 and A-3 are as follows:

[0160] Preferred compounds in Formula 2 are listed in Table 2.

[0161] Preferably, the present invention provides a compound of formula V.

[0162] Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definition is as described in the general formula I above.

[0163] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0164] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0165] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl.

[0166] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0167] The preferred compounds of formula V are represented in Table 3 below, wherein the structures of A-1, A-2 and A-3 are as follows:

[0168] Table 3 shows the preferred compounds in Formula V.

[0169] Preferably, Formula I is a compound of Formula VI.

[0170] Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definitions are as described in General Formula I above.

[0171] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0172] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0173] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl.

[0174] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0175] Table 4 below represents preferred compounds of formula 4, wherein the structures of A-1, A-2 and A-3 are as follows:

[0176] Preferred compounds in Formula VI of Table 4

[0177] Preferably, Formula I is a compound of Formula VII.

[0178] Among them, X1, X2, X3, X4, X5, R, R1, R2, R 11 R 18 and R 17 The definitions are as described in General Formula I above.

[0179] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0180] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0181] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl;

[0182] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0183] In some technical solutions, R 17 It is one of H, halogen or C1-C6 alkyl; preferably one of H, halogen or methyl.

[0184] Table 5 below represents preferred compounds of formula VII, wherein the structures of A-1, A-2 and A-3 are as follows:

[0185] Preferred compounds in Formula VII of Table 5

[0186] Preferably, the present invention provides a compound of formula VIII.

[0187] Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definition is as described in the general formula I above.

[0188] In some technical solutions, X1, X2, X3, X4 and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, preferably X1, X2, X3, X4 and X5 are each independently selected from H, halogen, halogenated C1-C6 alkyl, halogenated C3-C8 cycloalkyl, particularly preferably H, F, Cl, bromine, trifluoromethyl.

[0189] In some technical solutions, R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl; preferably halogenated C1-C6 alkyl or halogenated C3-C6 cycloalkyl; particularly preferably trifluoromethyl or halogenated cyclopropyl.

[0190] In some technical solutions, R1 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, halo-C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl-C1-C6 alkyl; preferably, R1 is selected from H, C1-C6 alkyl, or C1-C6 haloalkyl, and particularly preferably H or methyl;

[0191] In some technical solutions, R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or halo-C3-C8 cycloalkyl; preferably one of H, C1-C6 alkyl, or C3-C8 cycloalkyl, particularly preferably one of H, methyl, ethyl, cyclopropyl, or cyclobutyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom.

[0192] Table 6 below represents the preferred compounds of formula VIII, wherein the structures of A-1, A-2 and A-3 are as follows:

[0193] Preferred compounds in Formula VIII compounds (Table 6)

[0194] The preferred compounds of this invention are selected from the following compounds:

[0195] The present invention also provides an insecticidal composition comprising, as an active ingredient, a compound represented by Formula I of the present invention, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts.

[0196] Preferably, the above-mentioned insecticidal composition further contains another active ingredient B, which is a neonicotinoid insecticide such as thiamethoxam, imidacloprid, thiamethoxam, acetamiprid, acetamiprid, dinotefuran, epoxim, or selected from one or more of the following: flupyrflufenoxuron, flonicamid, flupyramide, pymetrozine, thiamethoxam, trifluralin, didicoromezotiazine, afidopyropen, pyrifluquinazon, benzpyrimoxan, cyprodinil, difenoconazole, tebuconazole, prothioconazole, cyproconazole, azoxystrobin, pyraclostrobin, pyraclostrobin, pyridaben, metalaxyl, metalaxyl, fludioxonil, prochlorazine, and cyazofamid. Preferably, the mass ratio of compound I to B is 1:100 to 100:1, more preferably 1:10 to 10:1.

[0197] The preparation method of the compound of formula I of the present invention can be carried out by the following scheme:

[0198] Among them, X1, X2, X3, X4, X5, R, G, W1, W2, R1, R 11 R 12 R 13 R 14 R 15 R 16 R 17 and R 18 The definitions are as defined above in this invention.

[0199] The general synthetic steps are to react compound B with intermediate C in the presence of a base and a catalyst to obtain compound I. The base can be an organic base or an inorganic base, and the catalyst is preferably 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate.

[0200] Preferably, the preparation method of the compound of formula II of the present invention can be carried out by the following scheme:

[0201] Among them, X1, X2, X3, X4, X5, R, G, R1, R 11 and R 18 Substituents are defined as defined above in this invention.

[0202] The general synthetic procedure is to react compound B' with intermediate C' in the presence of a base and a catalyst to obtain compound II. The base can be an organic base or an inorganic base, and the catalyst is preferably 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate.

[0203] The present invention also provides an insecticidal composition comprising, as an active ingredient, a compound of Formula I of the present invention, its stereoisomer, its nitrogen oxide compound, or a pesticide-acceptable salt thereof.

[0204] The present invention also provides a method for controlling pests by applying an effective dose of a compound of Formula I, its stereoisomers, its nitrogen oxides, or a pesticide-acceptable salts, or the insecticide composition described herein, to the pest that needs to be controlled or its growth medium.

[0205] The present invention also provides an insecticidal composition comprising, as an active ingredient, a compound of Formula I of the present invention, its stereoisomer, its nitrogen oxide compound, or a pesticide-acceptable salt thereof.

[0206] The present invention also provides a method for controlling pests by applying an effective dose of a compound of Formula I, its stereoisomers, its nitrogen oxides, or a pesticide-acceptable salts, or the insecticide composition described herein, to the pest that needs to be controlled or its growth medium.

[0207] The compounds of this invention, represented by Formula I as active ingredients, exhibit significant insecticidal effects against the aforementioned pests that damage various lowland crops, highland crops, fruit trees, vegetables, other crops, and horticultural products. Therefore, the insecticidal effect of this invention can be achieved by treating the water in paddy fields, the stems and leaves of plants, or the soil of lowland crops, highland crops, fruit trees, vegetables, other crops, and flowers and ornamental plants during the season in which such pests are expected to appear, or before or at the time of their appearance.

[0208] The compounds represented by Formula I of this invention are generally used in suitable formulations appropriate for their intended use, prepared by conventional methods in the art for the preparation of agricultural and horticultural chemicals. They can be used in suitable formulations such as suspensions, emulsions, liquid formulations, water-dispersible powders, granules, powders, tablets, etc., prepared by mixing the aforementioned compounds in appropriate proportions with at least one of suitable inactive carriers and adjuvants, followed by dissolution, separation, suspension, mixing, impregnation, adsorption, or attachment of the components.

[0209] The inactive carriers that can be used in the formulations of this invention can be solid or liquid, and examples particularly include: soybean flour, grain flour, wood flour, bark flour, sawdust, tobacco stem flour, walnut shell flour, bran, cellulose powder, residues after plant extraction, synthetic polymers such as powdered synthetic resins, clays (e.g., kaolin, bentonite, acid clay, etc.), talcs (e.g., talc, pyrophyllite, etc.), silica (e.g., diatomaceous earth, silica sand, mica, white carbon black (also known as hydrous silica powder, hydrous silica powder of synthetic highly dispersible silica, some products containing calcium silicate as the main component)), activated carbon, sulfur powder, pumice, sintered diatomaceous earth, brick pulverizers, fly ash, sand, inorganic mineral powders (e.g., calcium carbonate, calcium phosphate), chemical fertilizers (e.g., ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, ammonium chloride), and compost, which can be used alone or in the form of a mixture of two or more.

[0210] Examples of materials that can be used as inactive carriers in liquid form include materials that function as solvents, and materials that do not function as solvents but can disperse active ingredient compounds with the assistance of other adjuvants.

[0211] Examples of inactive carriers include: water, alcohols (e.g., methanol, ethanol, isopropanol, butanol, ethylene glycol, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone, etc.), ethers (e.g., diethyl ether, dioxane, cellosol, diisopropyl ether, tetrahydrofuran, etc.), aliphatic hydrocarbons (e.g., kerosene, mineral oil, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, solvent oil, alkylnaphthalene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, etc.), esters (e.g., ethyl acetate, butyl acetate, ethyl propionate, diisobutyl phthalate, dibutyl phthalate, dioctyl phthalate, etc.), amides (e.g., dimethylformamide, diethylformamide, dimethylacetamide, etc.), and nitriles (e.g., acetonitrile, etc.), which can be used alone or in mixtures of two or more.

[0212] Other adjuvants may be added to the formulation used in this invention; however, it is also possible to use no other adjuvants.

[0213] Other exemplary examples of adjuvants are as follows:

[0214] Surfactants may be used for the purpose of emulsifying, dispersing, solubilizing and / or wetting active ingredient compounds.

[0215] Examples of surfactants include polyoxyethylene alkyl ethers, polyoxyethylene alkyl aryl ethers, polyoxyethylene higher fatty acid esters, polyoxyethylene resin esters, polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol monooleate, alkyl aryl sulfonates, naphthalene sulfonates, lignin sulfonates, and higher alcohol sulfonates.

[0216] Excipients that may be used for the purpose of dispersing, stabilizing, adhering and / or binding of active ingredient compounds include casein, gelatin, starch, methylcellulose, carboxymethylcellulose, gum arabic, polyvinyl alcohol, turpentine, rice bran oil, bentonite, xanthan gum and lignin sulfonates.

[0217] Examples of additives that can be used to improve the flowability of solid products include waxes, stearates, and alkyl phosphates. Additives such as naphthalene sulfonate condensates or condensed phosphates can be used as suspending agents in suspensions. Defoamers such as silicone oils can also be used as additives.

[0218] Furthermore, the compounds represented by Formula I of this invention are stable to light, heat, oxidation, etc., but stabilizers can be added as needed to obtain more stable compositions. Examples of stabilizers include antioxidants, ultraviolet absorbers, phenolic derivatives such as BHT (2,6-di-tert-butyl-4-methylphenol), BHA (butylated hydroxyanisole), bisphenol derivatives, and aryl amines such as phenyl-α-naphthylamine, phenyl-β-naphthylamine, condensates of aminophene ether and acetone, and benzophenone compounds.

[0219] Furthermore, regarding the effective amount of the compound represented by Formula I of the present invention, it is typically 0.5 to 20% by weight in powders, 5 to 50% by weight in emulsions, 10 to 90% by weight in water-dispersible powders, 0.1 to 20% by weight in granules, and 10 to 90% by weight in flow agents. On the other hand, regarding the amount of carrier in each formulation, it is typically 30 to 99% by weight in powders, 10 to 95% by weight in emulsions, 10 to 90% by weight in water-dispersible powders, 50 to 99% by weight in granules, and 5 to 90% by weight in flow agents. Regarding the amount of such adjuvants, it is typically 0.1 to 30% by weight in powders, 1 to 40% by weight in emulsions, 0.1 to 25% by weight in water-dispersible powders, 0.1 to 30% by weight in granules, and 0.1 to 40% by weight in flow agents.

[0220] To control various pests, a certain amount of the compound represented by Formula I of this invention, which is the effective active ingredient, is applied directly, appropriately diluted with water, or in suspension to crops where the corresponding pests are expected to appear or to areas where such pests are not desired. The dosage depends on various factors, such as the purpose, the pests to be controlled, the plant's growth status, the pest's tendency to appear, climate, environmental conditions, formulation, method of application, location of application, and time of application. The compound represented by Formula I, as the active ingredient, is used at a concentration of 0.005 to 5000 ppm, preferably 0.01 to 1000 ppm, and more preferably 0.01 to 10 ppm. The dosage of the compound represented by Formula I that can be used per hectare is typically in the range of 0.01 to 300 g of the active ingredient. The compounds of this invention exhibit activity against a broad spectrum of invertebrate pests. These pests include invertebrates inhabiting various environments such as plant leaves, roots, soil, harvested crops or other food, buildings, or animal fur. These pests include, for example, invertebrate pests that feed on leaves (including leaf blades, stems, flowers, and fruits), seeds, wood, textile fibers, or animal blood or tissues, thereby causing damage or harm to, for example, growing or stored crops, forest crops, greenhouse crops, ornamental plants, nursery crops, stored food or fiber products, or houses or other structures or their contents, or are harmful to animal health or public health. Those skilled in the art will appreciate that not all compounds are equally effective against all pests throughout their entire life cycle.

[0221] Therefore, these compounds and compositions of the present invention can be used agriculturally to protect field crops from phytophagous invertebrate pests, and also non-agriculturally to protect other horticultural crops and plants from phytophagous invertebrate pests. This use includes protecting crops and other plants (i.e., agricultural and non-agricultural) that contain genetic material introduced through genetic engineering (i.e., transgenics) or mutagenesis to provide advantageous traits. Examples of such traits include herbicide tolerance, tolerance to phytophagous pests (e.g., insects, mites, aphids, spiders, nematodes, snails, plant pathogenic fungi, bacteria, and viruses), improved plant growth, enhanced tolerance to adverse growing conditions (such as high or low temperatures, low or high soil moisture, and high salinity), increased flowering or fruiting, increased yield, accelerated ripening, higher quality and / or nutritional value of harvested products, or improved storage or processing properties of harvested products. Transgenic plants can be modified to express a variety of traits.

[0222] Examples of agricultural or non-agricultural invertebrate pests include the eggs, larvae, and adults of lepidopteran pests, such as armyworms, root-cutting moths, inchworms, and cotton bollworms, corn borers, southern gray-winged armyworms, grassland armyworms, beet armyworms, sea gray-winged armyworms, yellow-striped armyworms, cutworms, bean borers, green fruit borers, cabbage borers, soybean borers, silver-striped cabbage borers, and tobacco borers larvae; and stem borers, sheath moths, web-forming caterpillars, leaf spot moths, cabbage caterpillars, and leaf-carving moths (e.g., corn borers, navel orange borers, corn root borers, grassland borers (Pyralidae: Pyralidae) such as twig borers, sugarcane two-spotted borers, tomato stem borers, rice leaf rollers, grape leaf rollers, melon borers, cabbage core borers, rice stem borers, and sugarcane borers. Rice white stem borer, fruit borer, apple leafroller, citrus borer, red-banded leafroller, rose-striped leafroller, apple light brown leafroller, European grape berry moth, apple terminal bud leafroller, omnivorous leafroller, grape brown leafroller, apple brown leafroller; and many other economically important lepidopteran insects (e.g., diamondback moth, cotton bollworm, gypsy moth, peach fruit borer, peach bark moth, potato tuber moth, spotted leafminer, apple golden leafminer, rice leaf roller, narrow-winged leafroller); eggs, pupae, and adults of cockroaches, including cockroaches of the families Blattodea and Blattodea (e.g., Oriental cockroach, Asian cockroach, German cockroach, brown-banded cockroach, American cockroach, brown cockroach, Madeira cockroach, black-breasted cockroach, Australian cockroach, lobster cockroach); Coleoptera pests include their eggs, larvae, and adults that feed on leaves, fruits, roots, seeds, and vesicle tissue, including weevils of the families Longhorn weevil, Bean weevil, and Cistanche (e.g., cottonseed weevil, rice water weevil, grain weevil, rice weevil, Kentucky bluegrass weevil, Kentucky bluegrass weevil, hunter weevil, Denver long-beaked weevil); flea beetles, melon beetles, rootworms, leaf beetles, potato beetles, and leaf miners of the family Chrysomelidae (e.g., potato beetle, western corn rootworm); scarab beetles and other beetles of the family Scarabaeidae (e.g., Japanese scarab beetle, Oriental scarab beetle, Northern round-headed rhinoceros beetle, Southern round-headed rhinoceros beetle or dung beetles and white grubs, turf black scarab beetle, green-flowered scarab beetle, purple velvet gill beetle); carpet beetles of the family Boreridae; nematodes of the family Click beetles; and bark beetles of the family Bark Boreridae. And the face beetle of the family Tenebrionidae. In addition, agricultural and non-agricultural pests include: eggs, adults, and larvae of Dermoptera pests, including the moth-like insects of the families Gyropodidae and Agropoda; eggs, larvae, adults, and pupae of Hemiptera and Homoptera pests, such as mirid bugs of the family Miridae, leafhoppers of the family Cicadidae, planthoppers of the families Cicadidae and Planthopperidae, treehoppers of the family Cicadaidae, and Psyllididae. Psyllids, whiteflies (Family of the Whitefly family), aphids (Family of the Aphid family), phylloxera (Family of the phylloxera family), mealybugs (Family of the Mealycidae family), scale insects (Family of the Scale family, Scale insects of the Scale family, and Scale insects of the Scale family), lace bugs (Family of the Lacridae family), stink bugs (Family of the Stink bug family), long bugs (such as hairy long bugs and southern wheat bugs, as well as other long bugs of the Long bug family), foam bugs (Family of the Flea family), cucurbit bugs (Family of the Cucurbita family), and red bugs and cotton bollworms (Family of the Red Bug family).This also includes eggs, larvae, pupae, and adults of mites (Acari), such as spider mites and chiggers (e.g., apple red spider mite, two-spotted spider mite); eggs, adults, and larvae of orthoptera pests, including grasshoppers, locusts, and crickets (e.g., migratory grasshoppers (e.g., blood locust, special species locust), American grasshopper (e.g., South American desert locust), desert locust, migratory locust, shrub locust, house cricket, mole cricket (e.g., yellow-brown mole cricket and southern mole cricket); and Diptera pests. Eggs, adults, and larvae of these insects include leaf miners (such as leaf miners, such as vegetable leaf miners, mosquitoes, fruit flies, eye flies (such as Swedish straw flies), maggots, houseflies, etc.). Other arthropod pests involved include spiders such as the brown hermit spider and the black widow spider, and centipedes such as centipedes. The compounds of this invention are also active against nematodes, tapeworms, trematodes, and acanthocephalans, including those with... Members of the orders Strongyloides, Ascarids, Acromura, Micrococcus, Spiralura, and Spurula, which are of economic importance, include, but are not limited to, economically important agricultural pests (i.e., root-knot nematodes, root-rot nematodes, and tire nematodes, etc.) and pests that harm animal and human health (i.e., all economically important trematodes, tapeworms, and roundworms, such as *Strongyloides vulgaris* in horses, *Toxocara canis* in dogs, *Haemaphysalis contortus* in sheep, *Filaria canis* in dogs, *Naja lobata* in horses, and *Fasciola hepatica* in ruminants, etc.). The compounds of this invention exhibit particularly high activity against lepidopteran pests (e.g., rice stem borer, rice leaf roller, corn root webbing caterpillar, bluegrass borer, cotton bollworm, tobacco cutworm larvae, diamondback moth, beet armyworm, cotton bollworm, tea silkworm, armyworm, and vegetable leafminer).

[0223] The compounds of this invention also exhibit significant activity against members of the order Hemiptera, including: strawberry aphid, apple woolly aphid, wheat aphid, potato aphid, peach aphid, lettuce aphid, corn leaf aphid, and brown orange aphid, etc.

[0224] The compounds of this invention are also active against members of the order Hemiptera, including: rice green bug, pumpkin fringe bug, sorghum long bug, bed bug and cotton mirid bug, etc.

[0225] Other insect orders that can be controlled by the compounds of this invention include Thysanura, such as western flower thrips, citrus thrips, soybean thrips, and onion thrips, etc.

[0226] The compound represented by Formula I of this invention, as an active ingredient, can be used alone in the control of various pests or sanitary pests or nematodes that damage rice, fruit trees, vegetables, other crops, and flowers in agriculture, horticulture, and grain products. Furthermore, to obtain excellent control effects against various pests occurring simultaneously, the compound represented by Formula I can be used in combination with at least one other insecticide and / or fungicide.

[0227] The compounds of this invention have a wide range of applications, and the plants or ranges to which they are applied mainly include the following categories: fruits and vegetables, such as cucumber, loofah, watermelon, cantaloupe, pumpkin, gourd, spinach, celery, cabbage, Chinese cabbage, gourd, chili pepper, eggplant, tomato, onion, ginger, garlic, leek, lettuce, green beans, cowpeas, broad beans, radish, carrot, potato, and yam; cereals, such as wheat, barley, corn, rice, and sorghum; fruit trees, such as apple, pear, banana, citrus, grape, lychee, and mango; flowers, such as peony, rose, and flamingo; oil crops, such as peanut, soybean, rapeseed, sunflower, and sesame; sugar crops, such as sugar beet and sugarcane; other crops, such as strawberry, potato, sweet potato, tobacco, and tea; horticulture, forestry, household hygiene, and public health areas, etc. The above-listed plants or ranges do not limit the scope of use of the compounds of this invention.

[0228] The technical solutions disclosed in this invention will be further described in detail below with reference to specific embodiments and biological effect test examples. It should be understood that the following embodiments and biological effect test examples are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0229] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods. Unless otherwise specified, percentage content in these examples refers to mass percentage. The instruments and conditions involved in the chiral preparation method of this invention are as follows: Instrument model: WATERS SFC 200, chromatographic column: IC, 10μm, 30*250mm, mobile phase A: CO2, mobile phase B: IPA, detection wavelength: 214nm, flow rate: 25mL / min, column temperature: room temperature, isocratic elution program: mobile phase A: mobile phase B = 60:40 (V / V). The preparation method of this invention involves a chiral analytical method: instrument: WATERS THAR SFC, chromatographic column: IC, 5μm, 4.6mm*250mm, mobile phase A: CO2, mobile phase B: IPA, detection wavelength: 254nm, flow rate: 1.0mL / min, column temperature: 35℃, isocratic elution program: mobile phase A: mobile phase B = 60:40 (V / V).

[0230] Example 1: 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0231] Step 1: Synthesis of methyl 4-acetylnaphthylcarboxylate

[0232] Under argon protection, 4-acetylnaphtholic acid (5 g, 23.34 mmol) and potassium carbonate (4.83 g, 35.01 mmol) were added sequentially to N,N-dimethylformamide (30 mL), followed by iodomethane (4.97 g, 35.01 mmol), and the mixture was stirred for 3 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain methyl 4-acetylnaphtholic acid (5 g).

[0233] Step 2: Synthesis of tert-butyl (2,2-difluorocyclopropyl)carbamate

[0234] Under argon protection, 2,2-difluorocyclopropanecarboxylic acid (5 g, 40.98 mmol) and triethylamine (8.28 g, 81.96 mmol) were added sequentially to tert-butanol (30 mL), followed by the slow addition of diphenyl azidophosphate (13.53 g, 49.18 mmol), and stirring was continued for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl (2,2-difluorocyclopropyl)carbamate (7.5 g).

[0235] Step 3: Synthesis of (2,2-difluorocyclopropyl)amino hydrochloride

[0236] 7.5 g of (2,2-difluorocyclopropyl)carbamate tert-butyl ester was dissolved in hydrochloric acid / dioxane (4 M, 30 ml) and stirred for 4 hours. The solution was concentrated under reduced pressure to obtain crude (2,2-difluorocyclopropyl)amino hydrochloride, which was used directly in the next step.

[0237] Step 4: (2-(2,2-difluorocyclopropyl)amino)-2-oxoethyl)tert-butyl carbamate

[0238] Under argon protection, N-(tert-butyloxycarbonyl)glycine (9.5 g, 54.28 mmol) was dissolved in dichloromethane (100 ml), and triethylamine (16.45 g, 162.85 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (22.69 g, 59.71 mmol) was slowly added. After stirring for 30 minutes, (2,2-difluorocyclopropyl)amino hydrochloride (7 g) was added, and stirring was continued for 1 hour. Saturated sodium chloride aqueous solution (200 ml) was added, and the mixture was extracted with dichloromethane, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (2-(2,2-difluorocyclopropyl)amino)-2-oxyethyl)carbamate tert-butyl ester (9 g).

[0239] Step 5: Synthesis of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride

[0240] Dissolve tert-butyl (2-(2,2-difluorocyclopropyl)amino)-2-oxoethyl)carbamate (9 g) in hydrochloric acid / dioxane (4 M, 40 ml) and stir for 4 hours. Concentrate under reduced pressure to obtain crude 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (9 g), for later use.

[0241] Step 6: Synthesis of 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one

[0242] Under argon protection, 3,5-dichloro-4-fluorobromobenzene (10 g, 41.0 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and isopropyl magnesium chloride-lithium chloride complex (1.3 M, 35.5 mL) was slowly added dropwise. After stirring for 2 h, the mixture was cooled to -5 °C, and trifluoroacetic anhydride (10.34 g, 49.2 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 3 h. The solution was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was distilled to give intermediate 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one (8.4 g), which was reserved for later use.

[0243] Step 7: Synthesis of methyl (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-1-naphthoic acid ester

[0244] Under argon protection, intermediate 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethane-1-one (6.68 g, 26.28 mmol) and methyl 4-acetylnaphthylcarbamate (5 g, 21.9 mmol) were dissolved in acetonitrile (100 ml), followed by the addition of triethylamine (6.63 g, 65.7 mmol). The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, acetic anhydride (2.9 g, 28.47 mmol) and 4-dimethylaminopyridine (267 mg, 2.19 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-1-naphthoic acid methyl ester (10 g), which was then set aside for later use.

[0245] Step 8: Synthesis of methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoate

[0246] Under argon protection, crude (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-1-naphthoate (10 g) was dissolved in tetrahydrofuran (100 ml), cooled to -5 °C, and hydroxylamine hydrochloride (2.93 g, 42.46 mmol) was added. Then, sodium hydroxide aqueous solution (4 M, 7.5 ml) was slowly added dropwise, and stirring continued for 1 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoate (8 g).

[0247] Step 9: Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid

[0248] Methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (8 g) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml). Sodium hydroxide aqueous solution (4 M, 20 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, and then extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (7.6 g), which was then set aside.

[0249] Step 10: Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0250] Under argon protection, 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (1.2 g, 2.54 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (0.78 g, 7.62 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (1.06 g, 2.79 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (710 mg, 3.81 mmol) was added, and stirring was continued for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide (840 mg).

[0251] 1H NMR (400MHz, CDCl3) δ8.82(d,J=7.9Hz,1H),8.27(d,J=8.0Hz,1H),7.71–7.54(m,5H),7.46(d,J=7.4Hz,1H),7.29(s,1H),7.26(d, J=5.0Hz,1H),4.32–4.20(m,3H),3.90(d,J=17.3Hz,1H),3.45–3.30(m,1H),1.86–1.74(m,1H),1.41(ddd,J=14.5,9.6,5.7Hz,1H).

[0252] Example 2: 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylthiophene-2-carboxamide

[0253] Step 1: Synthesis of (Z)-1-(5-bromo-4-methylthiophen-2-yl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one

[0254] Under argon protection, 3,5-dichloro-4-fluorotrifluoroacetylbenzene (10 g, 38.31 mmol) and 2-acetyl-5-bromo-4-methylthiophene (9.23 g, 42.14 mmol) were dissolved in acetonitrile (200 mL), followed by the addition of triethylamine (11.607 g, 114.93 mmol). The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, acetic anhydride (5.08 g, 49.80 mmol) and 4-dimethylaminopyridine (467 mg, 3.83 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude (Z)-1-(5-bromo-4-methylthiophen-2-yl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one (17 g), which was then set aside.

[0255] Step 2: Synthesis of 3-(5-bromo-4-methylthiophen-2-yl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

[0256] Under argon protection, crude (Z)-1-(5-bromo-4-methylthiophen-2-yl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one (17 g) was dissolved in tetrahydrofuran (200 ml), cooled to -5 °C, and hydroxylamine hydrochloride (5.07 g, 73.59 mmol) was added. Then, sodium hydroxide aqueous solution (4 M, 13.2 ml) was slowly added dropwise, and stirring continued for 1 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-(5-bromo-4-methylthiophen-2-yl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (15.2 g).

[0257] Step 3: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylthiophene-2-carboxylic acid

[0258] Under argon protection, 3-(5-bromo-4-methylthiophen-2-yl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (15.2 g, 31.86 mmol), sodium formate (4.32 g, 63.72 mmol), and acetic anhydride (3.25 g, 31.86 mmol) were sequentially added to N,N-dimethylformamide (200 ml), followed by palladium acetate (0.710 g, 3.2 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (3.71 g, 6.4 mmol). The mixture was heated to 90 °C and stirred for 5 h. After cooling to room temperature, the mixture was acidified with hydrochloric acid (1 M) until pH = 3, and then extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 13.4 g of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylthiophene-2-carboxylic acid, which was then set aside.

[0259] Step 4: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylthiophene-2-carboxamide

[0260] Under argon protection, 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylthiophene-2-carboxylic acid (200 mg, 0.45 mmol) was dissolved in dichloromethane (5 ml), and triethylamine (0.137 g, 1.35 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (188 mg, 0.49 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (70 mg, 0.49 mmol) was added, and stirring was continued for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give compound 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylthiophene-2-carboxamide (125 mg).

[0261] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=6.0Hz,2H),7.10(s,1H),6.71(s,1H),6.52(s,1H),4.17–4.14(m,2H),4.08(d,J=17.0Hz,1H),3 .69(d,J=17.0Hz,1H),3.38(s,1H),2.55(d,J=8.0Hz,3H),1.86(ddd,J=9.6,6.7,3.5Hz,1H),1.43(ddd,J=14.4,9.3,5.1Hz,1H).

[0262] Example 3: 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)isoquinoline-8-carboxamide

[0263] Step 1: Synthesis of intermediate methyl 5-acetylisoquinoline-8-carboxylic acid ester

[0264] Under argon protection, methyl 5-bromoisoquinoline-8-carboxylate (5 g, 18.79 mmol) was added to toluene (30 mL), followed by the sequential addition of tributyl(1-ethoxyethylene)tin (8.8 g, 24.43 mmol) and bis(triphenylphosphine)palladium dichloride (1.31 g, 1.88 mmol). The mixture was heated to 100 °C and stirred for 8 h. The mixture was cooled to room temperature, and 1 M HCl (30 mL) was added, followed by stirring at room temperature for another 2 h. The reaction mixture was neutralized with aqueous sodium carbonate solution (pH 7) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the intermediate methyl 5-acetylisoquinoline-8-carboxylate (4.1 g).

[0265] Step 2: Synthesis of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)isoquinoline-8-carboxylic acid methyl ester

[0266] Under argon protection, intermediates methyl 5-acetylisoquinoline-8-carboxylate (2 g, 8.73 mmol) and 3,5-dichloro-4-fluorotrifluoroacetylbenzene (2.73 g, 10.48 mmol) were dissolved in acetonitrile (30 mL), followed by the addition of triethylamine (2.64 g, 26.19 mmol). The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, acetic anhydride (1.07 g, 10.48 mmol) and 4-dimethylaminopyridine (106 mg, 0.87 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)isoquinoline-8-carboxylic acid methyl ester (3.8 g), which was then set aside for later use.

[0267] Step 3: Synthesis of methyl 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)isoquinoline-8-carboxylic acid

[0268] Under argon protection, crude (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)isoquinoline-8-carboxylic acid methyl ester (3.8 g) was dissolved in tetrahydrofuran (40 ml), cooled to -5 °C, and hydroxylamine hydrochloride (1.11 g, 16.1 mmol) was added. Then, sodium hydroxide aqueous solution (4 M, 2.7 ml) was slowly added dropwise, and stirring continued for 1 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)isoquinoline-8-carboxylic acid methyl ester (3.3 g).

[0269] Step 4: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)isoquinoline-8-carboxylic acid

[0270] Methyl 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)isoquinoline-8-carboxylic acid (3.3 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml). Sodium hydroxide aqueous solution (4 M, 10 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, and then extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)isoquinoline-8-carboxylic acid (3.1 g), which was then used for further processing.

[0271] Step 5: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)isoquinoline-8-carboxamide

[0272] Under argon protection, intermediate 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)isoquinoline-8-carboxylic acid (200 mg, 0.42 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (127 mg, 1.26 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (175 mg, 0.46 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (94 mg, 0.50 mmol) was added, and stirring was continued for 1 hour. Add 20 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 130 mg of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)isoquinoline-8-carboxamide.

[0273] 1 H NMR (400MHz, CDCl3) δ9.79(s,1H),8.91(d,J=6.1Hz,1H),8.67(d,J=6.2Hz,1 H),7.87(d,J=7.5Hz,1H),7.80(d,J=7.5Hz,1H),7.67(d,J=6.0Hz,2H),7.56 (d,J=3.9Hz,1H),7.12(s,1H),4.32(dd,J=13.1,11.2Hz,3H),3.99(d,J=6.2 Hz,1H),3.40(s,1H),1.91–1.79(m,1H),1.50(ddd,J=12.4,8.8,4.3Hz,1H).

[0274] Example 4: 4-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0275] Step 1: Synthesis of methyl (Z)-4-((hydroxyethylamino)methyl)-1-naphthoic acid ester

[0276] Under argon protection, methyl 4-formylnaphthalene-1-carboxylic acid (5 g, 23.34 mmol) was added to a mixed solvent of tetrahydrofuran (25 mL) and water (25 mL), followed by the addition of sodium acetate (5.74 g, 70.02 mmol) and stirring for 3 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl (Z)-4-((hydroxyethylamino)methyl)-1-naphthoic acid (5.1 g).

[0277] Step 2: Synthesis of methyl (Z)-4-(chloro(hydroxyethylamino)methyl)-1-naphthoic acid ester

[0278] Under argon protection, methyl (Z)-4-((hydroxyethylamino)methyl)-1-naphthoic acid (5.1 g, 22.27 mmol) was added to N,N-dimethylformamide (50 mL), followed by slow addition of N-chlorosuccinimide 2 (3.27 g, 24.49 mmol), and stirring was continued for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude methyl (Z)-4-(chloro(hydroxyethylamino)methyl)-1-naphthoic acid (6.8 g), which was then used for further processing.

[0279] Step 3: Synthesis of 3,4-dichloro-5-(trifluoromethyl)aniline

[0280] 2,3-Dichloro-5-nitrotrifluorotoluene (5 g, 19.23 mmol) was dissolved in concentrated hydrochloric acid (20 ml), cooled to 0 °C, and then stannous chloride dihydrate (13.01 g, 57.69 mmol) was slowly added. The mixture was then heated to room temperature and stirred for 6 hours. Water (50 ml) was added, and the mixture was extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the intermediate 3,4-dichloro-5-(trifluoromethyl)aniline (4 g).

[0281] Step 4: Synthesis of 5-bromo-1,2-dichloro-3-(trifluoromethyl)benzene

[0282] The intermediate 3,4-dichloro-5-(trifluoromethyl)aniline (4 g, 17.39 mmol) was added to hydrobromic acid (40 mL), cooled to 0 °C, and an aqueous solution of sodium nitrite (1.24 g, 18.61 mmol) (3.2 mL) was slowly added dropwise, with stirring continued for 30 minutes. At room temperature, the reaction solution was slowly added dropwise to a solution of cuprous bromide (1.24 g, 8.69 mmol) in hydrobromic acid (40 mL), with stirring continued for 2 hours. A saturated aqueous solution of sodium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-bromo-1,2-dichloro-3-(trifluoromethyl)benzene (2 g).

[0283] Step 5: Synthesis of 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

[0284] Under argon protection, 5-bromo-1,2-dichloro-3-(trifluoromethyl)benzene (1 g, 3.4 mmol) was added to a mixed solvent of dioxane (10 ml) and water (2 ml), followed by the sequential addition of potassium carbonate (1.87 g, 13.6 mmol) and tetraphenylphosphine palladium (0.39 g, 0.34 mmol). The mixture was heated to 100 °C and stirred for 4 h. A saturated sodium chloride aqueous solution (20 ml) was added, and the mixture was extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (900 mg).

[0285] Step 6: Synthesis of methyl 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoate

[0286] Under argon protection, crude products of 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (900 mg, 2.91 mmol) and (Z)-4-(chloro(hydroxyethylamino)methyl)-1-naphthoate (1.15 g) were dissolved in ethyl acetate (50 ml), and sodium bicarbonate (1.22 g, 14.55 mmol) was slowly added, with stirring continued for 12 hours. The solution was quenched with aqueous sodium carbonate solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoate (1.1 g).

[0287] Step 7: Synthesis of 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid

[0288] 1.1 g of methyl 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid was dissolved in a mixed solvent of tetrahydrofuran (3 ml) and methanol (3 ml). Sodium hydroxide aqueous solution (4 M, 3 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to obtain 940 mg of 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid, which was then used for further processing.

[0289] Step 9: Synthesis of 4-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0290] Under argon protection, 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (200 mg, 0.38 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (116 mg, 1.15 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (158.8 mg, 0.42 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (106 mg, 0.57 mmol) was added, and stirring was continued for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 4-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide (115 mg).

[0291] Example 5: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)amino)-1-oxopropane-2-yl)isoquinoline-8-carboxamide

[0292] Under argon protection, intermediate 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)isoquinoline-8-carboxylic acid (200 mg, 0.42 mmol) (prepared according to the method of Example 3) was dissolved in dichloromethane (10 ml), triethylamine (127 mg, 1.26 mmol) was added, the mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (175 mg, 0.46 mmol) was slowly added. After stirring for 30 minutes, (2R)-2-amino-N-(2,2-difluorocyclopropyl)propionamide hydrochloride (94 mg, 0.50 mmol) (prepared according to the method of Example 1) was added, and stirring was continued for 1 hour. Add 20 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 100 mg of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)amino)-1-oxopropane-2-yl)isoquinoline-8-carboxamide.

[0293] 1 H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 8.75 (d, J = 5.9Hz, 1H), 8.61 (s, 1H), 7.64 (dd ,J=9.6,5.6Hz,4H),7.36(d,J=6.9Hz,1H),7.29(s,0.5H),7.21(s,0.5H),4.91 –4.80(m,1H),4.27(ddd,J=17.1,5.0,3.3Hz,1H),3.91(dd,J=18.0,7.3Hz,1H) ,3.36(s,1H),1.86–1.74(m,1H),1.55(t,J=7.1Hz,3H),1.43(d,J=7.6Hz,1H).

[0294] Example 6: Synthesis of 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0295] Step 1: Synthesis of methyl 4-[chloro(hydroxyimino)methyl]-2-methylbenzoate

[0296] Under argon protection, methyl (E)-4-[(hydroxyimino)methyl]-2-methylbenzoate (5 g, 25.9 mmol) was added to N,N-dimethylformamide (50 mL), followed by the slow addition of N-chlorosuccinimide 2 (3.8 g, 28.49 mmol), and stirring was continued for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude intermediate 4 (7.5 g), which was then set aside.

[0297] Step 2: Synthesis of 3,5-dichloro-(2,2-difluorocyclopropyl)formylbenzene

[0298] Under argon protection, 3,5-dichloro-1-bromobenzene (5 g, 22.13 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0 °C, and isopropyl magnesium chloride-lithium chloride complex (1.3 M, 34.1 mL) was slowly added dropwise. After stirring for 2 h, the mixture was cooled to -5 °C, and the intermediate 2,2-difluoro-N-methoxy-N-methylcyclopropane-1-carboxamide (4.38 g, 26.56 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 3 h. The mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3,5-dichloro-(2,2-difluorocyclopropyl)formylbenzene (4.6 g).

[0299] Step 3: Synthesis of 1-(3,5-dichlorophenyl)-1-(2,2-difluorocyclopropyl)2-(trimethylsilyl)ethanol-1-ol

[0300] Under argon protection, 3,5-dichloro-(2,2-difluorocyclopropyl)formylbenzene (4.6 g, 18.32 mmol) and cerium trichloride (0.226 g, 0.916 mmol) were dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and a solution of (trimethylsilyl)methylmagnesium chloride diethyl ether (1.0 M, 36.6 mL) was slowly added dropwise, with stirring continued for 3 hours. The solution was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain crude 1-(3,5-dichlorophenyl)-1-(2,2-difluorocyclopropyl)2-(trimethylsilyl)ethanol-1-ol (5 g), which was used directly in the next step.

[0301] Step 4: Synthesis of 1,3-dichloro-5-(1-(2,2-difluorocyclopropyl)vinyl)benzene

[0302] Under argon protection, 5 g of 1-(3,5-dichlorophenyl)-1-(2,2-difluorocyclopropyl)2-(trimethylsilyl)ethanol-1-ol was dissolved in 50 ml of dichloromethane. The mixture was cooled to 0 °C, and 0.16 g (0.74 mmol) of trimethylsilyl trifluoromethanesulfonate was slowly added dropwise while stirring for 1 hour. The mixture was quenched with an aqueous sodium carbonate solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4 g of 1,3-dichloro-5-(1-(2,2-difluorocyclopropyl)vinyl)benzene.

[0303] Step 5: Synthesis of methyl 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate

[0304] Under argon protection, 1,3-dichloro-5-(1-(2,2-difluorocyclopropyl)vinyl)benzene (4 g) and methyl 4-[chloro(hydroxyimino)methyl]-2-methylbenzoate (4 g) were dissolved in ethyl acetate (50 ml), and sodium bicarbonate (6.74 g, 80.3 mmol) was slowly added, with stirring continued for 12 hours. The mixture was quenched with aqueous sodium carbonate solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate (4 g).

[0305] Step 6: Synthesis of 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

[0306] 4 g of methyl 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml). Sodium hydroxide aqueous solution (4 M, 10 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to obtain 3.6 g of 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid, which was then set aside.

[0307] Step 13: Synthesis of compound 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0308] Under argon protection, intermediate 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.2 g, 0.47 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (0.15 g, 1.4 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (0.196 g, 0.52 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (132 mg, 0.71 mmol) was added, and stirring was continued for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 4-(5-(3,5-dichlorophenyl)-5-(2,2-difluorocyclopropyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide (145 mg).

[0309] 1 H NMR (400MHz, CDCl3) δ7.52–7.39(m,5H),7.35(t,J=1.7Hz,1H),7.03(s,1H),6.83(s,1H),4.17(d,J=4.9Hz,2H),3.60(d,J=17.1Hz,1H),3.4 7(d,J=17.1Hz,1H),3.38(s,1H),2.46(s,3H),2.28–2.17(m,1H),1.88–1.70(m,2H),1.70–1.56(m,1H),1.40(ddd,J=14.2,9.7,5.3Hz,1H).

[0310] Example 7: N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

[0311] Step 1: Synthesis of 3,4,5-trichloro-trifluoroacetylbenzene

[0312] Under argon protection, 3,4,5-trichlorobromobenzene (10 g, 38.4 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and isopropyl magnesium chloride-lithium chloride complex (1.3 M, 35.5 mL) was slowly added dropwise. After stirring for 2 h, the mixture was cooled to -5 °C, and trifluoroacetic anhydride (9.68 g, 46.1 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 3 h. The solution was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was distilled to obtain 3,4,5-trichloro-trifluoroacetylbenzene (8.00 g) for later use.

[0313] Step 2: Synthesis of methyl 3-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazo-3-yl]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate

[0314] Under argon protection, methyl 3-[(Z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enyl]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (synthesized according to CN109328017A) (9 g, 18.1 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to -5 °C, and hydroxylamine hydrochloride (2.51 g, 36.1 mmol) was added. Then, sodium hydroxide aqueous solution (4 M, 6 ml) was slowly added dropwise, and stirring continued for 1 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 3-[5-(345-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (7 g).

[0315] Step 3: Synthesis of 3-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazo-3-yl]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylic acid

[0316] Methyl 3-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (7 g, 13.6 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), and sodium hydroxide aqueous solution (4 M, 10 ml) was slowly added dropwise. The mixture was heated to 40 °C and stirred for 1 h.

[0317] The mixture was acidified with hydrochloric acid (1M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 6.5 g of 3-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl-]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylic acid, for later use.

[0318] Step 12: Synthesis of compound N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

[0319] Under argon protection, 3-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl-]-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylic acid (200 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml), and triethylamine (120 mg, 1.2 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (170 mg, 0.45 mmol) was slowly added. After stirring for 30 minutes, 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (84 mg, 0.45 mmol) was added, and stirring was continued for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give compound N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (125 mg).

[0320] Example 8: Synthesis of 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0321] Step 1: Synthesis of methyl 4-acetyl-2-methylbenzoate

[0322] Under argon protection, 2-methyl-4-acetylbenzoic acid (50 g, 280.9 mmol) was dissolved in N,N-dimethylformamide (500 mL), followed by the addition of potassium carbonate (58.2 g, 421.3 mmol) and methyl iodoforme (59.7 g, 421.3 mmol), and stirring was continued for 3 hours. The mixture was filtered, and water (500 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 4-acetyl-2-methylbenzoate (52 g).

[0323] Step 2: Synthesis of methyl (E)-4-(3-(3,5-bis(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-2-methylbenzoate

[0324] Under argon protection, methyl 4-acetyl-2-methylbenzoate (2 g, 10.4 mmol) and 1-(3,5-bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethyl ketone (4.19 g, 13.5 mmol) were dissolved in acetonitrile (20 mL), followed by the addition of triethylamine (3.14 g, 31.12 mmol). The mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, acetic anhydride (1.38 g, 13.52 mmol) and 4-dimethylaminopyridine (127 mg, 1.04 mmol) were added, and the mixture was heated to 70 °C and stirred for 2 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl (E)-4-(3-(3,5-bis(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-2-methylbenzoate (3.3 g).

[0325] Step 3: Synthesis of methyl 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluorocarboxyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate

[0326] Under argon protection, methyl (E)-4-(3-(3,5-bis(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-2-methylbenzoate (3.3 g, 6.8 mmol) was dissolved in tetrahydrofuran (40 ml), cooled to -5 °C, and hydroxylamine hydrochloride (0.95 g, 13.7 mmol) was added. Then, sodium hydroxide aqueous solution (2 M, 10 ml) was slowly added dropwise, and stirring was continued for 10 min. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate (2.8 g).

[0327] Step 4: Synthesis of 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluorocarboxyl)-4,5-dihydroisoxazo-3-yl)-2-methylbenzoic acid

[0328] Methyl 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate (2.8 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml). Sodium hydroxide aqueous solution (4 M, 10 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (2.7 g).

[0329] Step 5: Synthesis of ethyl glycine (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluorocarboxyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)

[0330] Under argon protection, 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (300 mg, 0.62 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of triethylamine (249 mg, 2.5 mmol) and glycine ethyl ester hydrochloride (173 mg, 1.24 mmol). The mixture was cooled to 0 °C, and then n-butylphosphine anhydride (50% ethyl acetate solution, 670 mg, 1.38 mmol) was slowly added. The mixture was stirred for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain ethyl glycine (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine (260 mg).

[0331] Step 6: Synthesis of (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluorocarboxyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine

[0332] Ethyl glycine (260 mg) of (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (2 ml). Sodium hydroxide aqueous solution (4 M, 2 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to give (250 mg) glycine (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine.

[0333] Step 7: Synthesis of 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0334] Under argon protection, (4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoroformyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)glycine (250 mg, 0.42 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of triethylamine (170 mg, 1.68 mmol) and intermediate 3 (109.2 mg, 0.84 mmol). The mixture was cooled to 0 °C, and then n-butylphosphine anhydride (50% ethyl acetate solution, 605 mg, 0.84 mmol) was slowly added. The mixture was stirred for 1 hour. Add 10 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide (160 mg).

[0335] 1 H NMR(400MHz, CDCl3)δ8.08(s,2H),7.97(s,1H),7.56–7.50(m,2H),7.46(d,J=7.9Hz,1H),6.99(s,1H),6.86(t,J=4.9Hz,1H), 4.22(s,1H),4.18–4.14(m,2H),3.75(d,J=17.3Hz,1H),3.41–3.31(m,1H),2.46(s,3H),1.85–1.76(m,1H),1.43–1.32(m,1H).

[0336] Example 9: 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0337] Step 1: Synthesis of 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

[0338] Under argon protection, 10 g (22.98 mmol) of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was dissolved in a mixed solvent of anhydrous ethanol (20 ml) and acetonitrile (4 ml). The mixture was heated to 44 °C, and S(-)-α-phenylethylamine was slowly added. The mixture was stirred for 3 h, cooled to room temperature, and stirred for 1 h. The mixture was filtered, and the filter cake was adjusted to pH 3 with hydrochloric acid aqueous solution (1 M), followed by extraction with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain the intermediate 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (3 g).

[0339] Step 2: 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0340] The reaction procedure was followed in Example 9 to synthesize 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide.

[0341] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=6.0Hz,2H),7.52–7.41(m,3H),7.22(s,1H),7.00(s,1H),4.15(dd,J=7.7,4.0Hz,2H),4.1 1–4.05(m,1H),3.70(d,J=17.2Hz,1H),3.33(d,J=4.2Hz,1H),2.42(s,3H),1.83–1.72(m,1H),1.36(td,J=9.0,4.4Hz,1H).

[0342] Example 10: Synthesis of 4-((R)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0343] Example 11: Synthesis of 4-((S)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0344] Step 1: 4-((R)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

[0345] Synthesis of 4-((S)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

[0346] 4-(5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-2-methylbenzoic acid (1 g) was synthesized according to the method in Example 8. It was then resolved by supercritical fluid chromatography (SFC) to obtain intermediate 4-((R)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-2-methylbenzoic acid (0.41 g) and intermediate 4-((S)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-2-methylbenzoic acid (0.42 g).

[0347] The subsequent steps are synthesized according to the method in Example 9:

[0348] 4-((R)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0349] 1 H NMR (400MHz, CDCl3) δ7.93–7.88(m,1H),7.75(d,J=3.8Hz,1H),7.56–7.45(m,3H),6.64(dd,J=10.7,5.5Hz,2H),4.13( dd,J=10.9,6.3Hz,3H),3.71(d,J=17.2Hz,1H),3.45–3.31(m,1H),2.48(s,3H),1.90–1.76(m,1H),1.45–1.32(m,1H).

[0350] 4-((S)-5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-2-methylbenzamide

[0351] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=4.2Hz,1H),7.75(d,J=4.0Hz,1H),7.50(dd,J=21.0,9.0Hz,3H),6.56(s,1H),6.45(s,1H),4.14(dd,J =11.2,6.1Hz,3H),3.70(d,J=17.2Hz,1H),3.38(t,J=10.5Hz,1H),2.49(s,3H),1.90–1.79(m,1H),1.40(ddd,J=13.9,9.6,4.5Hz,1H).

[0352] Example 12: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylpyridineamide

[0353] The first step is the synthesis of methyl 5-bromo-3-methylpyridinium acid ester.

[0354] Under argon protection, 20 g (90.59 mmol) of 5-bromo-3-methylpyridine-2-carboxylic acid was dissolved in 200 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (19.17 g, 138.88 mmol) and methyl iodoforme (19.71 g, 138.88 mmol) and stirring for 3 hours. The mixture was filtered, and water (200 mL) was added. The extract was then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 5-bromo-3-methylpyridine acid (20.5 g).

[0355] Step 2: Synthesis of methyl 5-(1-ethoxyvinyl)-3-methylpyridinecarboxylate

[0356] Under argon protection, methyl 5-bromo-3-methylpyridinate (20.5 g, 89.13 mmol) was dissolved in anhydrous toluene (200 mL), followed by the sequential addition of tributyl(1-ethoxyvinyl)stanane (48.28 g, 133.69 mmol) and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (3.26 g, 4.46 mmol). The mixture was stirred at 100 °C for 5 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 5-(1-ethoxyvinyl)-3-methylpyridinate (15.6 g).

[0357] Step 3: Synthesis of methyl 5-acetyl-3-methylpyridinium acid ester

[0358] 15.6 g of methyl 5-(1-ethoxyvinyl)-3-methylpyridinium carboxylate was dissolved in acetone (20 ml), and hydrochloric acid aqueous solution (2 M, 8 ml) was slowly added dropwise while stirring for 2 h. The pH of the mixture was adjusted to 8 with saturated sodium carbonate aqueous solution, and then extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 13 g of methyl 5-acetyl-3-methylpyridinium carboxylate.

[0359] Step 4: Synthesis of methyl (E)-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3-methylpyridinecarboxylate

[0360] Under argon protection, methyl 5-acetyl-3-methylpyridinium acid (2 g, 10.36 mmol) and 3,5-dichloro-4-fluorotrifluoroacetylbenzene (3.5 g, 13.47 mmol) were dissolved in acetonitrile (20 mL), followed by the addition of triethylamine (3.14 g, 31.09 mmol). The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, acetic anhydride (1.37 g, 13.47 mmol) and 4-dimethylaminopyridine (127 mg, 1.04 mmol) were added, and the mixture was heated to 80 °C and stirred for 2 h. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (E)-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3-methylpyridinecarboxylate (3.4 g).

[0361] Step 5: Synthesis of methyl 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium ester

[0362] Under argon protection, methyl (E)-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3-methylpyridinecarboxylate (3.4 g, 7.8 mmol) was dissolved in tetrahydrofuran (50 ml), cooled to -5 °C, and hydroxylamine hydrochloride (1.08 g, 15.59 mmol) was added. Then, sodium hydroxide aqueous solution (2 M, 10 ml) was slowly added dropwise, and stirring was continued for 10 min. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried (using sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylate (3.1 g).

[0363] Step 6: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinic acid

[0364] Methyl 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinic acid (3.1 g) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and methanol (8 ml). Sodium hydroxide aqueous solution (4 M, 8 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to obtain 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinic acid (2.8 g), which was then set aside.

[0365] Step 7: Synthesis of ethyl glycine (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinyl)glycine

[0366] Under argon protection, 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridine acid (300 mg, 0.69 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of triethylamine (208 mg, 2.06 mmol) and glycine ethyl ester hydrochloride (192 mg, 1.38 mmol). The mixture was cooled to 0 °C, and then n-butylphosphine anhydride (50% ethyl acetate solution, 993 mg, 1.38 mmol) was slowly added. The mixture was stirred for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain ethyl glycine (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinyl)glycine (250 mg).

[0367] Step 8: Synthesis of (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-3-yl)-3-methylpyridinyl)glycine

[0368] Ethyl glycine (250 mg) of (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinyl)glycine was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (2 ml). Sodium hydroxide aqueous solution (4 M, 2 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to obtain (230 mg) glycine (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinyl)glycine for later use.

[0369] Step 9: Preparation of compound 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylpyridine amide

[0370] Under argon protection, (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinyl)glycine (230 mg, 0.47 mmol) was dissolved in dichloromethane (10 ml), and triethylamine (141 mg, 1.40 mmol) and (2,2-difluorocyclopropyl)amino hydrochloride (prepared according to the method of Example 1) (122.2 mg, 0.94 mmol) were added. The mixture was cooled to 0 °C, and n-butylphosphine anhydride (50% ethyl acetate solution, 676.8 mg, 0.94 mmol) was slowly added. The mixture was stirred for 1 hour. Add 10 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylpyridineamide (170 mg).

[0371] 1 H NMR (400MHz, CDCl3) δ8.71(d,J=11.4Hz,1H),8.67(s,1H),7.96(s,1H),7.62(t,J=8.0Hz,2H),6.62(s,1H),4.15 (dd,J=9.7,6.3Hz,3H),3.77(d,J=17.3Hz,1H),3.38(s,1H),2.81(s,3H),1.91–1.79(m,1H),1.49–1.37(m,1H).

[0372] Example Thirteen: Synthesis of 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(((R)-2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0373] Step 1: Synthesis of (R)-2,2-difluorocyclopentane-1-amine

[0374] Under argon protection, (1S)-2,2-difluorocyclopropane-1-carboxylic acid (5 g, 40.98 mmol) and triethylamine (8.28 g, 81.96 mmol) were added sequentially to tert-butanol (30 mL), followed by the slow addition of diphenyl azidophosphate (13.53 g, 49.18 mmol), and stirring was continued for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (R)-2,2-difluorocyclopentane-1-amine (7.5 g).

[0375] Step 2: Synthesis of (R)-2,2-difluorocyclopentane-1-amine hydrochloride

[0376] (R)-2,2-difluorocyclopentane-1-amine (7.5 g) was dissolved in hydrochloric acid / dioxane (4 M, 30 ml) and stirred for 4 hours. The solution was concentrated under reduced pressure to obtain crude (R)-2,2-difluorocyclopentane-1-amine hydrochloride (4.3 g), which was used directly in the next step.

[0377] Step 3: Synthesis of (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid

[0378] 4 g of methyl 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml). Sodium hydroxide aqueous solution (4 M, 20 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. SFC was then used to prepare (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (1.2 g) for later use.

[0379] Step 4: Synthesis of (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine ethyl ester

[0380] Under argon protection, (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (300 mg, 0.63 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of triethylamine (250 mg, 2.5 mmol) and glycine ethyl ester hydrochloride (175 mg, 1.26 mmol). The mixture was cooled to 0 °C, and n-butylphosphine anhydride (50% ethyl acetate solution, 680 mg, 1.28 mmol) was slowly added. The mixture was stirred for 1 hour. Add 30 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine ethyl ester (270 mg).

[0381] Step 5: Synthesis of (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine

[0382] Ethyl glycine (270 mg) of (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (2 ml). Sodium hydroxide aqueous solution (4 M, 2 ml) was slowly added dropwise, and the mixture was heated to 40 °C and stirred for 1 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 2, then extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried (using sodium sulfate), filtered, and concentrated under reduced pressure to give (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine (230 mg), which was used directly in the next step.

[0383] Step 6: Synthesis of 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(((R)-2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide

[0384] Under argon protection, (S)-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthyl)glycine 12 (230 mg, 0.43 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of triethylamine (175 mg, 1.72 mmol) and (R)-2,2-difluorocyclopentane-1-amine hydrochloride (110 mg, 0.86 mmol). The mixture was cooled to 0 °C, and n-butylphosphine anhydride (50% ethyl acetate solution, 465 mg, 0.65 mmol) was slowly added. The mixture was stirred for 1 hour. Add 10 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(((R)-2,2-difluorocyclopropyl)amino)-2-oxoethyl)-1-naphthamide (160 mg).

[0385] 1 H NMR (400MHz, CDCl3) δ8.81(d,J=8.4Hz,1H),8.27(d,J=8.2Hz,1H),7.69–7.54(m,5H),7.46(d,J=7.3Hz,1H),7.02(s,1H ),6.86(s,1H),4.32–4.19(m,3H),3.88(d,J=17.3Hz,1H),3.38(s,1H),1.88–1.72(m,1H),1.40(dd,J=12.0,6.8Hz,1H).

[0386] Example 14: Synthesis of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-((2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)carboxyl)-3-methylpyridine 1-oxide

[0387] Under argon protection, 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)-3-methylpyridineamide (200 mg, 0.35 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 °C, and then m-chloroperoxybenzoic acid (120 mg, 0.7 mmol) was added. The mixture was then stirred at room temperature for 16 h. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-((2-((2,2-difluorocyclopropyl)amino)-2-oxoethyl)carboxyl)-3-methylpyridine 1-oxide (130 mg).

[0388] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.53 (dd, J = 13.4, 7.1Hz, 3H), 4. 31–3.96(m,3H),3.75(t,J=24.4Hz,1H),3.33(s,1H),2.41(s,3H),1.73(s,1H),1.45(s,1H).

[0389] Example 15: 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-(((2,2-difluorocyclopropyl)methyl)amino)-1-oxopropane-2-yl)-2-methylbenzamide

[0390] Step 1: Synthesis of intermediate 2,2-difluoro-N-(4-methoxybenzyl)cyclopropane-1-carboxamide

[0391] Under argon protection, 2,2-difluorocyclopropanecarboxylic acid (5 g, 40.98 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (0.12 g, 1.2 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (17.13 g, 45.08 mmol) was slowly added. After stirring for 30 minutes, 4-methoxybenzylamine (6.18 g, 45.08 mmol) was added, and stirring was continued for 1 hour. Saturated sodium chloride aqueous solution (100 ml) was added, and the mixture was extracted with dichloromethane, dried (sodium sulfate), filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the intermediate 2,2-difluoro-N-(4-methoxybenzyl)cyclopropane-1-carboxamide (10 g).

[0392] Step 2: Synthesis of intermediate 1-(2,2-difluorocyclopropyl)-N-(4-methoxybenzyl)methylamine

[0393] Under argon protection, the intermediate 2,2-difluoro-N-(4-methoxybenzyl)cyclopropane-1-carboxamide (10 g, 41.45 mmol) was dissolved in tetrahydrofuran (200 ml), cooled to 0 °C, and lithium aluminum hydride (2.3 g, 62.17 mmol) was added in portions. After stirring for 30 minutes, the temperature was raised to 60 °C and stirred for 4 hours. The mixture was then cooled in an ice-water bath, and water (6.9 ml) was carefully added dropwise, followed by a 15% sodium hydroxide aqueous solution (2.5 ml). The mixture was stirred at room temperature for about 30 minutes, filtered, and concentrated under reduced pressure to obtain crude intermediate 1-(2,2-difluorocyclopropyl)-N-(4-methoxybenzyl)methylamine (9 g), which was used directly in the next step.

[0394] Step 3: Synthesis of intermediate 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)methyl)(4-methoxybenzyl)amino)-1-oxopropyl-2-yl)-2-methylbenzamide

[0395] Under argon protection, the intermediate (4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)-D-alanine was...

[0396] (500 mg, 0.98 mmol, synthesized using a method similar to that in Example 13) was dissolved in dichloromethane (10 ml), and triethylamine (297 mg, 2.94 mmol) was added. The mixture was cooled to 0 °C, and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-onium 3-oxide hexafluorophosphate (560 mg, 1.47 mmol) was slowly added. After stirring for 30 minutes, crude intermediate 18 (334 mg, 1.47 mmol) was added, and stirring was continued for 1 hour. Add 100 ml of saturated sodium chloride aqueous solution, extract with dichloromethane, dry (sodium sulfate), filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain intermediate 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)methyl)(4-methoxybenzyl)amino)-1-oxopropyl-2-yl)-2-methylbenzamide (450 mg).

[0397] Step 4: Synthesis of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)methyl)amino)-1-oxopropyl-2-yl)-2-methylbenzamide

[0398] Under argon protection, the intermediate 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)methyl)(4-methoxybenzyl)amino)-1-oxopropyl-2-yl)-2-methylbenzamide (300 mg) was dissolved in trifluoroacetic acid (5 ml), heated to 60 °C, and stirred for 2 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((2R)-1-((2,2-difluorocyclopropyl)methyl)amino)-1-oxopropyl-2-yl)-2-methylbenzamide (220 mg).

[0399] 1H NMR(400MHz, CDCl3) δ7.59(d,J=6.0Hz,2H),7.54–7.46(m,2H),7.43(d,J=7.8Hz,1H),6.51(d,J=6.5Hz,2H),4.66(dd,J=6.9,4.2Hz,1H),4.12– 4.05(m,1H),3.69(d,J=17.2Hz,2H),3.24–3.12(m,1H),2.46(s,3H),1. 93–1.78(m,1H),1.54–1.41(m,4H),1.14(ddd,J=11.2,7.7,4.3Hz,1H).

[0400] Table 7 shows the compounds of the present invention and control compounds prepared according to the above embodiments and methods.

[0401] II. Indoor drug efficacy test

[0402] (i) Indoor efficacy test of the compound against green caterpillars

[0403] 1. Test materials

[0404] 1.1 Test Target

[0405] Cabbage worm (Pierisrapae).

[0406] 1.2 Instruments and Equipment

[0407] Electronic balance (sensitivity 0.1mg), capillary tube, filter paper, paintbrush, 9cm diameter petri dish, beaker, pipette or pipette, tweezers, etc.

[0408] 1.3 Sample Preparation

[0409] The cabbage caterpillars were reared indoors continuously as third-instar larvae. A layer of moist, sterile filter paper was placed at the bottom of a transparent plastic box (sprayed with water daily to maintain humidity, but without standing water). Cabbage leaves were laid flat inside the box, with 10 third-instar larvae per box. Fresh, pesticide-free cabbage leaves were used as feed, soaked in a 0.5% sodium hypochlorite solution for 5 minutes after harvesting daily, rinsed with clean water, and dried before use. The temperature was maintained at 25℃±1℃, precisely controlled using an artificial climate chamber, and recorded three times daily. Humidity was maintained at 70%±5%, regulated by a humidifier and ventilation system to prevent fluctuations exceeding ±10%. Light intensity was 14L:10D (simulating natural diurnal rhythms) at 5000 lux (LED light source), avoiding direct sunlight to prevent dehydration of the larvae.

[0410] 2. Experimental Design

[0411] 2.1 Preparation of test reagents

[0412] The test compound was dissolved in dimethyl sulfoxide to prepare the parent drug, and then diluted with an aqueous solution containing 0.2% Tween 80 to concentrations of 40 ppm, 20 ppm, 10 ppm, and 1 ppm. Treatment with dimethyl sulfoxide solvent (CK) served as a blank control, and a water control was also included.

[0413] 2.2 Chemical treatment

[0414] Third-instar larvae were selected using a brush and placed in a petri dish. The capillary tube was cleaned with solvent, and each larva in the petri dish was treated with a 1.0 μL drop of the drug solution onto its pronotum. The treated larvae were then transferred to normal rearing conditions. Each treatment was repeated four times, with 20 larvae per replicate. Mortality was assessed 24 hours after treatment, and the total number of larvae and the number of dead larvae were recorded. The average value was taken.

[0415] 3. Evaluation Criteria and Results

[0416] Based on the survey data, calculate the mortality rate for each treatment. Calculate using formula (1), and round the result to two decimal places:

[0417] In the formula:

[0418] P—mortality rate, expressed as a percentage (%);

[0419] K—represents the number of dead insects, in heads;

[0420] N—represents the total number of insects treated, in units of heads.

[0421] In the table: A indicates a control efficacy of 95-100%; B indicates a control efficacy of 85-95%; C indicates a control efficacy of 70-85%; D indicates a control efficacy of 50-70%; E indicates a control efficacy of 30-50%; F indicates a control efficacy of 10-30%; and G indicates a control efficacy of 0-10%.

[0422] Table 8. Indoor Test Results of Green Caterpillars

[0423] (ii) Indoor efficacy test of the compound against thrips

[0424] 1. Test materials

[0425] 1.1 Test Target

[0426] Palm thrips (Thripspalmi Karny).

[0427] 1.2 Instruments and Equipment

[0428] Electronic balance (sensitivity 0.1mg), insect cage, volumetric flask, 9cm diameter petri dish, beaker, pipette, tweezers, filter paper, marker, stopwatch, etc.

[0429] 1.3 Sample Preparation

[0430] The palm thrips, the target species in the experiment, were continuously reared as adults indoors. 50mL centrifuge tubes were used as rearing containers, with four fresh, young chili leaves placed inside for the thrips to feed on and lay eggs. The tubes were sealed with cotton balls to prevent escape, and the chili leaves were replaced with fresh leaves every three days. The laboratory temperature was maintained at 25℃±1℃, precisely controlled using an artificial climate chamber, and recorded three times daily. Humidity was maintained at 70%±5%, regulated using a humidifier and ventilation system to prevent fluctuations exceeding ±10%. Light intensity was 14L:10D (simulating natural diurnal rhythms) and 5000 lux (LED light source), avoiding direct sunlight to prevent dehydration of the insects.

[0431] 2. Experimental Design

[0432] 2.1 Drug Preparation

[0433] The test compound was dissolved in dimethyl sulfoxide to prepare the parent drug, and then diluted with an aqueous solution containing 0.2% Tween 80 to concentrations of 40 ppm, 20 ppm, 10 ppm, and 1 ppm. Treatment with dimethyl sulfoxide solvent (CK) served as a blank control, and a water control was also included.

[0434] 2.2 Chemical treatment

[0435] After immersing thrips in the drug solution for 5–10 seconds, excess solution was absorbed with filter paper, and the test insects were transferred to normal rearing conditions. Each treatment was repeated four times, with 20 thrips immersed in each replicate. The mortality rate of the test insects was investigated 24 hours after treatment, and the total number of thrips and the number of dead thrips were recorded. The average value of the results was taken.

[0436] 3. Evaluation Criteria and Results

[0437] Based on the survey data, calculate the mortality rate for each treatment. Calculate using formula (1), and round the result to two decimal places:

[0438] In the formula:

[0439] P—mortality rate, expressed as a percentage (%);

[0440] K—represents the number of dead insects, in heads;

[0441] N—represents the total number of insects treated, in units of heads.

[0442] In the table: A indicates a control efficacy of 95-100%; B indicates a control efficacy of 85-95%; C indicates a control efficacy of 70-85%; D indicates a control efficacy of 50-70%; E indicates a control efficacy of 30-50%; F indicates a control efficacy of 10-30%; and G indicates a control efficacy of 0-10%.

[0443] Table 9. Indoor Test Results of Thrips

[0444] (iii) Indoor activity test of compounds against Tetranychus bisporus

[0445] 1. Test materials

[0446] 1.1 Test Target

[0447] Two-spotted spider mite (Tetranychus urticae Koch).

[0448] 1.2 Instruments and Equipment

[0449] Standard laboratory equipment, Potter spray tower, constant temperature insect rearing room, etc.

[0450] 1.3 Sample Preparation

[0451] Two-spotted spider mites were continuously reared indoors as 3-5 day old female adults. Filter paper was placed at the bottom of 9cm diameter glass petri dishes, and a suitable amount of water was added to maintain humidity. Healthy strawberry leaves were used as food, with the undersides of the leaves facing upwards. The leaves were replaced regularly to maintain freshness, and the edges were surrounded with absorbent cotton to prevent escape. The laboratory temperature was maintained at 25℃±1℃, precisely controlled using an artificial climate chamber, and recorded three times daily. Humidity was maintained at 80%±5%, regulated using a humidifier and ventilation system to avoid fluctuations exceeding ±10%. The light intensity was 14L:10D (simulating natural diurnal rhythm) and 5000 lux (LED light source), avoiding direct sunlight to prevent dehydration of the mites.

[0452] 2. Experimental Design

[0453] 2.1 Drug Preparation

[0454] The test compound was dissolved in dimethyl sulfoxide to prepare the parent drug, and then diluted with an aqueous solution containing 0.2% Tween 80 to concentrations of 40 ppm, 20 ppm, 10 ppm, and 1 ppm. Treatment with dimethyl sulfoxide solvent (CK) served as a blank control, and a water control was also included.

[0455] 2.2 Chemical treatment

[0456] Stabilize the spray pressure of the Potter spray tower at 1.47 × 10⁻⁶. 5 First, clean the spray nozzle twice with acetone, then twice with distilled water. Using a brush, select 20 insects of similar physiological condition and place them in a petri dish. Then, place the petri dish on the bottom of the Potter spray tower for quantitative spraying (1 ml). After the solution settles for 1 minute, remove the insects and place them in a temperature of 25±1℃, relative humidity of 80%±5%, and a photoperiod of L:D = 14:10h for rearing and observation. Each treatment was repeated four times. After treatment, investigate the mortality of the insects 24 hours later, recording the total number of insects and the number of dead insects. The average value of the results is taken.

[0457] 3. Evaluation Criteria and Results

[0458] Based on the survey data, calculate the mortality rate for each treatment. Calculate using formula (1), and round the result to two decimal places:

[0459] In the formula:

[0460] P—mortality rate, expressed as a percentage (%);

[0461] K—represents the number of dead insects, in heads;

[0462] N—represents the total number of insects treated, in units of heads.

[0463] In the table: A indicates a control efficacy of 95-100%; B indicates a control efficacy of 85-95%; C indicates a control efficacy of 70-85%; D indicates a control efficacy of 50-70%; E indicates a control efficacy of 30-50%; F indicates a control efficacy of 10-30%; and G indicates a control efficacy of 0-10%.

[0464] Table 10 Results of the experiment to control Tetranychus spp. 2

[0465] III. Field efficacy test

[0466] I) Field Effect Test of Caterpillar

[0467] 1.1 Test targets and crops

[0468] Target: Caterpillar

[0469] Crop: Shanghai green

[0470] 1.2 Test Methods

[0471] 1.2.1 Field trial for controlling caterpillars

[0472] The experiment was conducted in Zhengjiaying Village, Xinjie Town, Jinning District, Kunming City, Yunnan Province, using Shanghai bok choy as the test crop. The test compounds were prepared to a concentration of 66.7 ppm, with a water-based blank control. The experimental treatment area was 4 m², with each treatment replicated four times in a randomized block design.

[0473] Use a Huayou brand electric backpack sprayer for routine spraying. Survey the initial insect population before application, and conduct surveys again at 1, 2, 8, and 13 days after application, checking and recording the number of active caterpillars on the marked leaves. Calculate the caterpillar reduction rate and the control effect.

[0474] Method for calculating the efficacy after pesticide application:

[0475] 2. Results Analysis

[0476] Table 11 Results of the experiment to control the caterpillar Note: The efficacy (%) in the table is the average of each replicate.

[0477] II) Field Effect Test of Thrips

[0478] 1.1 Test targets and crops

[0479] Target: Thrips

[0480] Crop: Rose (Variety: Elsa)

[0481] 1.2 Test Methods

[0482] 1.2.1 Field Trial for Thrips Control

[0483] The experiment was conducted in Kunyang Subdistrict, Jinning District, Kunming City, Yunnan Province, using roses as the test crop. The test compounds were prepared to a concentration of 66.7 ppm, with a water-based blank control. The experimental treatment area was 4 m², with each treatment replicated four times in a randomized block design.

[0484] Use a Huayou brand electric backpack sprayer for routine spraying. Survey the initial thrips population before application, and conduct surveys again at 1, 2, 8, and 13 days after application, checking and recording the number of active thrips on marked leaves. Calculate the thrips reduction rate and the control effect.

[0485] Method for calculating the efficacy after pesticide application:

[0486] 2. Results and Analysis

[0487] Table 12 Results of Thrips Control Trial Note: The efficacy (%) in the table is the average of each replicate.

[0488] III) Field efficacy trial of the two-spotted spider mite

[0489] 1.1 Test targets and crops

[0490] Target: Two-spotted Tetranychus

[0491] Crop: Rose (Variety: Peach Snow Mountain)

[0492] 1.2 Test Methods

[0493] 1.2.1 Field trial for the control of two-spotted spider mites

[0494] The experiment was conducted in Huichang Village, Kunyang Subdistrict, Jinning District, Kunming City. The test crop was a rose, specifically the variety "Mitao Xueshan". The test compound was prepared to a concentration of 66.7 ppm, with a water blank control included. The experimental treatment area was 4 m². 2 Each treatment was repeated 4 times in a randomized block arrangement.

[0495] A Huayou brand electric backpack sprayer was used for conventional spraying. The initial insect population was assessed before application, and again at 1, 2, 5, 8, and 13 days after application. The number of active two-spotted spider mites on marked leaves was checked and recorded. The mite population reduction rate was calculated, and the control effect was determined.

[0496] Method for calculating the efficacy after pesticide application:

[0497] 2. Results and Analysis

[0498] Table 13 Results of the experiment to control two-spotted spider mite Note: The efficacy (%) in the table is the average of each replicate.

[0499] IV) Field Effect Test of Red Spider Mites

[0500] 1.1 Test targets and crops

[0501] Target: Red spider

[0502] Crop: Citrus

[0503] 1.2 Test Methods

[0504] 1.2.1 Field trial for controlling spider mites

[0505] The experiment was conducted in Lipu City, Guilin, Guangxi Zhuang Autonomous Region, using citrus as the test crop. The test compounds were prepared at a concentration of 66.7 ppm, with a water blank control included. The experimental treatment area was 4 m², with each treatment replicated four times in a randomized block design.

[0506] A Huayou brand electric backpack sprayer was used for conventional spraying. The initial mite population was assessed before application, and again at 1, 2, 5, 8, and 13 days after application. The number of active red spider mites on marked leaves was checked and recorded. The mite population reduction rate was calculated to determine the control effect.

[0507] Method for calculating the efficacy after pesticide application:

[0508] 2. Results and Analysis

[0509] Table 14 Results of the experiment on controlling spider mites Note: The efficacy (%) in the table is the average of each replicate.

[0510] IV. Toxicological Testing

[0511] 1. Materials and Methods

[0512] 1.1 Test Materials

[0513] 1.1.1 Test organisms

[0514] Italian honeybees (Apis mellifera L.) were selected as the experimental organisms and introduced from Yangjiapailou Bee Farm in Hangzhou, Zhejiang Province, where they were routinely raised. Healthy adult worker bees of uniform size were selected for the experiment, and those exposed to acute oral toxicity were starved for 2 hours prior to exposure.

[0515] 1.1.2 Test reagents and main reagents

[0516] Test reagents: The compound formulation of this invention, with 80% dimethoate crude oil as the reference. Main reagents: Dimethyl sulfoxide (analytical grade, Yonghua Chemical Technology (Jiangsu) Co., Ltd.); Tween-80 (analytical grade, Tianjin Damao Chemical Reagent Factory); deionized water (Hangzhou Wahaha). Preparation of the compound formulation of this invention: The test compound, 10% Tween-80 (m:V), and dimethyl sulfoxide (added to 100%) were processed into a high-concentration stock solution in the laboratory, and then diluted with 50% sucrose solution. The compound formulation of this invention was used for toxicity testing on bees.

[0517] 1.2 Acute oral toxicity test of the compound on bees: test method

[0518] The compound formulations of this invention were diluted to prepare the predetermined concentrations. A control group (dimethyl sulfoxide) and a blank control group were also set up, with three replicates in each group. According to the requirements of "Chemical Pesticide Environmental Safety Evaluation Test Guidelines Part 10: Acute Toxicity Tests for Bees (GB / T 31270.10—2014)," oral feeding exposure was used. 200 μL of the above-mentioned concentration test solution was added to the feeder, and the consumption was measured after 3-4 hours. The solution was then replaced with a 50% sucrose aqueous solution (m:m) without the test substance. Both the treatment and control groups had three replicates, with 10 bees (adult worker bees) per replicate. The experiment was conducted for 48 hours under dark conditions at a temperature of 23-27℃ and a relative humidity of 50.0%-70.0%. The number of dead bees was investigated at 48 hours.

[0519] 1.3 Data Processing

[0520] The toxicity test data were statistically analyzed using Excel, and the median lethal concentration (LD50) was calculated using Probit and linear regression models in SPSS 19.0 software. 50 .

[0521] 1.4 Results

[0522] Table 15 Results of acute oral toxicity tests on honeybees

[0523] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A compound of Formula I, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts. in, X1, X2, X3, X4, and X5 are each independently selected from H, halogen, nitro, cyano, azide, -SCN, -SF5, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl, optionally substituted C2-C6 ynyl, -OR3, -OSO2R3, -SR3, and -S(O). p R3, -N(R4)R5, -N=CHOR6, -N=C(R7)OR6, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R8)R7, -C(S)SR7, -C(S)NHR8, -C(S)N(R8)R7, -CH=NOR9, -C(R7)=NOR9, -S(O)2OR7, -S(O)2NHR8, -S(O)2N(R1)R7; When two X's are adjacent, they can form -CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -OCH2O-, -CH2CH2S-, -CH2SCH2-, -CH2CH2N(R) 10 )-、-CH2N(R 10 )CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2OCH2O-, -OCH2CH2O-, -OCH2CH2S-, -CH2CH=CH-, -OCH=CH-, -SCH=CH-, -N(R 10 )CH=CH-, -OCH=N-, -SCH=N-, -N(R 10 CH=N-、-N(R) 10 N=CH-, -CH=CHCH=CH-, -OCH2CH=CH-, -N=CHCH=CH-, -N=CHCH=N- or -N=CHN=CH- are linked to a benzene ring to form a fused ring; R is one of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl. R1 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl. G is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted arylene, optionally substituted heteroaryl or optionally substituted heterocyclic; W1 and W2 are each independently selected from O or S; R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C3-C8 halocycloalkenyl, optionally substituted C3-C6 alkynyl or optionally substituted phenyl. R4 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C4 alkoxy (C1-C4)alkyl, C1-C4 alkylthio (C1-C4)alkyl, optionally substituted phenylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C1-C6 alkoxycarbonyl (C1-C4)alkyl, C1-C6 alkylaminocarbonyl (C1-C4)alkyl, di(C1-C6)aminocarbonyl (C1-C4)alkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 One of the following: haloalkynyl, -OH, C1-C6 alkylcarbonyloxy, C1-C6 alkylthio, C1-C6 haloalkylthio, optionally substituted phenylthio, -SN(R5)R6, -S(O)2R7, -S(O)2N(R1)R7, -CHO, -C(O)R7, -C(O)OR7, -C(O)SR7, -C(O)NHR8, -C(O)N(R1)R7, -C(S)OR7, -C(S)SR7, -C(S)NHR8, -C(S)N(R1)R7, -C(O)C(O)R7, -C(O)C(O)OR8, -P(O)(OR4)2 or -P(S)(OR4)2; R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C1-C4 alkoxy (C1-C4) alkyl, C1-C4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C3-C6 haloalynyl, -CHO, C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl or C1-C6 alkoxy carbonyl, or R4 and R5 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the nitrogen atom it is bonded to. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl or C1-C6 haloalkyl. R6 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl or optionally substituted phenyl; R7 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 haloalkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, C1-C6 haloalkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, or optionally substituted phenyl (C1-C4)alkyl. R8 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl (C1-C4)alkyl, C1-C6 alkoxy (C1-C4)alkyl, C1-C6 alkylthio (C1-C4)alkyl, cyano (C1-C6)alkyl, C3-C6 alkenyl or C3-C6 alkynyl, or R8 and R9 together form a C2-C6 alkylene chain, which can form a 3- to 7-membered ring with the bonded atom. In this case, the alkylene chain can contain one oxygen atom, sulfur atom or nitrogen atom, and can be substituted by any halogen atom, C1-C6 alkyl, C1-C6 alkoxy, formyl, C1-C6 alkyl carbonyl or C1-C6 alkoxy-carbonyl. R9 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted phenyl (C1-C4)alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 ynyl, C3-C6 haloynyl or optionally substituted phenyl. R 10 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted phenyl groups; R 11 and R 18 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, and halo-C3-C8 cycloalkylalkyl; or R 11 and R 18 It forms substituted cyclopropanes with the attached carbon atom; R 12 and R 13 Each is independently selected from one of H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 14 It is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C6 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl. R 15 and R 16 Each of the following is independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 17 It is one of H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; The condition is that it does not contain the following compounds:

2. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to claim 1, characterized in that, Selected from compounds shown in Formula II: Among them, X1, X2, X3, X4, X5, R, R1, R 11 and R 18 The definition is as defined in claim 1.

3. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to claim 1 or 2, characterized in that: G is selected from the following groups: Here, "---" indicates the connection end; R2 is selected from H, halogen, cyano, hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy or C3-C8 halocycloalkyl; n is a natural number between 0 and 4; m is a natural number between 0 and 2.

4. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-3, characterized in that: X1, X2, X3, X4 and X5 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, nitro, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl; preferably H, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

5. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-3, characterized in that: R is selected from one of halogenated C1-C6 alkyl or halogenated C3-C8 cycloalkyl.

6. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-3, characterized in that: R1 is selected from H, C1-C6 alkyl, or halogenated C1-C6 alkyl.

7. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-3, characterized in that, R2 is selected from H, halogen, C1-C6 alkyl, or halogenated C1-C6 alkyl.

8. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-3, characterized in that: n is 0, 1, or 2.

9. The compound, its stereoisomer, nitrogen oxide, isotope, and pesticide-acceptable salt according to any one of claims 1-8, characterized in that... Selected from the following compounds:

10. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-9, characterized in that... Selected from the following compounds:

11. The compound, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts according to any one of claims 1-10, characterized in that... Selected from the following compounds:

12. An insecticidal composition, characterized in that, The active ingredient contains the compound of any one of claims 1-11, its stereoisomers, nitrogen oxides, isotopes, and pesticide-acceptable salts.

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