Substituted isoxazoline derivatives

Abstract

This invention relates to isoxazoline compounds of formula (I), wherein each variable has the meaning as defined in the specification, to compositions comprising them, to combinations of active compounds comprising them, and to their use in protecting growing plants and animals from invertebrate pests or infestation, and also to seeds comprising such compounds.

Description

[0001] This invention relates to isoxazoline compounds of formula I, their N-oxides, stereoisomers, and agricultural or veterinary salts:

[0002]

[0003] in

[0004] R 1 It is a C1-C2 haloalkyl group;

[0005] W is a phenyl group or a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members; wherein W is unsubstituted, partially or completely replaced by R. 2 replace;

[0006] R 2 For halogen, OR 21 NR 22 R 23 CN, NO2, Si(CH3)3, SbF5, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl-S(O) m C1-C3 haloalkyl-S(O) m C1-C3 alkoxy-C1-C4 alkyl, C1-C3 haloalkoxy-C1-C4 alkyl, C1-C3 alkyl-S(O) m -C1-C4 alkyl, C1-C3 haloalkyl-S(O) m -C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; these groups are optionally R 211 replace;

[0007] m is 0, 1, or 2;

[0008] R 21 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or C1-C4 alkyl-S(O). m Si(C1-C4 alkyl)3, these groups are unsubstituted, partially or completely replaced by R 211 replace;

[0009] R 211 It can be halogen, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C4 alkenoxy, C3-C4 haloalkenoxy, C3-C4 alkynoxy, C3-C4 haloalynoxy, or C1-C4 alkyl-S(O). m C1-C4 haloalkyl-S(O) mC3-C4 alkenyl-S(O) m C3-C4 haloalkenyl-S(O) m C3-C4 yntylic-S(O) m C3-C4 haloalkynyl-S(O) m And oxygenation;

[0010] C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkenyl, C3-C8 halocycloalkenyl;

[0011] R 22 R 23 The derivatives are H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, which are unsubstituted or partially or completely replaced by R. 221 Replace; or

[0012] C1-C6 alkyl-C(=O)OR 13 C1-C6 alkyl-C(=U)N(R) 12a )R 12b C1-C6 alkyl-C (=NR) 12 )N(R 12a )R 12b S(O) m R 13 S(O) m N(R 12a )R 12b C(=U)R 11 C(=O)OR 13 C(=U)N(R) 12a )R 12b C(=S)SR 13 C(=NR) 12 )R 11 ;

[0013] C3-C8 cycloalkyl, C3-C8 halocycloalkyl;

[0014] R 221 The possible values ​​are CN, NO2, OH, SH, SCN, SF5, Si(C1-C4 alkyl)3, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 alkyl-S(O). m C1-C6 haloalkyl-S(O) m C(=O)N(R) 12a )R 12b ;

[0015] Unsubstituted, partially or completely halogenated and / or partially or completely substituted with C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and oxosubstituted C3-C8 cycloalkyl; or

[0016] Two Rs on the same carbon atom of an alkyl, alkenyl, ynyl, or cycloalkyl group. 221 They can be combined as =O, =CH (C1-C4 alkyl), =C (C1-C4 alkyl)2, =N (C1-C6 alkyl), or =NO (C1-C6 alkyl); or

[0017] R 22 and R 23 Together with the nitrogen atoms they are bonded to, they form 3, 4, 5, or 6 fully unsaturated heterocycles, which may additionally contain an atom selected from N, O, and S(O). m The heteroatom is a ring member and the heterocycle is not substituted or is partially or completely replaced by R. 14 Replace; or

[0018] R 22 and R 23 Together they form a group = C(R) 11 )2、=S(O) m (R 13 )2、=S(O) m R 13 N(R 12a )R 12b ;

[0019] X is NR 3 O, S(O) m Or CH2;

[0020] R 3 OR 21 Or, for example, R 5 Defined groups;

[0021] G is a phenyl group or a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members; wherein G is unsubstituted, partially or completely replaced by R. 4 replace;

[0022] R 4 For example, for R 2 Defined groups;

[0023] U is either O or S;

[0024] R 5The following are unsubstituted or partially or completely replaced by H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, or C1-C6 haloalkylthio, wherein the alkyl group is H, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 alkylthio, or C1-C6 haloalkylthio, and is not substituted or is partially or completely replaced by R. 51 Replace; or

[0025] C1-C6 alkyl-C(=O)OR 13 C1-C6 alkyl-C(=U)N(R) 12a )R 12b C1-C6 alkyl-C (=NR) 12 )N(R 12a )R 12b 、N(R 12a )R 12b S(O) m R 13 S(O) m N(R 12a )R 12b C(=U)R 11 C(=O)OR 13 C(=U)N(R) 12a )R 12b C(=S)SR 13 C(=NR) 12 )R 11 C3-C8 cycloalkyl, C3-C8 halocycloalkyl, phenyl, containing 1, 2, 3 or 4 atoms selected from N, O and S(O). m The heteroatom is a 3, 4, 5, 6, or 7-member saturated or partially unsaturated heterocycle, or contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S(O). m The heteroatoms are 5- or 6-membered heteroaryl groups that are ring members, and these rings are either unsubstituted or partially or completely replaced by R. 52 replace;

[0026] R 51 Halogen, CN, NO2, OH, SH, SCN, SF5, Si(C1-C4 alkyl)3, N(R) 12a )R 12b C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl-S(O) m C1-C6 haloalkyl-S(O) m C(=O)N(R) 12a )R 12b ;

[0027] C3-C8 cycloalkyl that is not substituted, partially or completely halogenated and / or partially or completely substituted with CN, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and oxosubstituted.

[0028] N(R 12a )R 12b S(O) m R 13 S(O) m N(R 12a )R 12b C(=U)R 11 C(=O)OR 13 C(=U)N(R) 12a )R 12b C(=S)SR 13 C(=NR) 12 )R 11 ;

[0029] Phenyl, benzyl, phenoxy, or containing one, two, or three radicals selected from N, O, and S(O). m The heteroatoms are 3, 4, 5, 6, or 7-member saturated, partially or fully unsaturated heterocycles, wherein these rings are unsubstituted or partially or completely replaced by R. 14 Replace; or

[0030] Two Rs on the same carbon atom of an alkyl, alkenyl, ynyl, or cycloalkyl group. 51 They can be combined as =O, =CH(C1-C4 alkyl), =C(C1-C4 alkyl)2, =N(C1-C6 alkyl) or =NO(C1-C6 alkyl);

[0031] R 52 For example, R 51 The groups defined herein are selected from C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups, which are unsubstituted, partially or completely halogenated and / or substituted by one or two CN, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or oxo groups.

[0032] R 6 For example, for R 5 The defined group; or

[0033] R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form 3, 4, 5, 6, 7, or 8-membered saturated, partially, or fully unsaturated heterocycles, which may additionally contain one or two selected from N, O, and S(O). m The heteroatom is a ring member and the heterocycle is not substituted or is partially or completely replaced by R.14 Replace; or

[0034] R 5 and R 6 Together they form a group = C(R) 11 )2、=S(O) m (R 13 )2、=S(O) m N(R 12a )R 12b =NR 12 or = NOR 13 ;or

[0035] R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form mesonic entities;

[0036] At point G, Y has one or two ring atoms of G between the junctions of G and X and Y; Y is a direct bond or CR bond. 7 R 8 ;

[0037] R 7 R 8 Each group is independently selected from H, halogen, CN, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 ynyl groups, which may be partially or completely halogenated and / or may be halogenated.

[0038] One or more R 81 replace;

[0039] R 81 CN, N3, NO2, SCN, SF5, C3-C8 cycloalkyl, C3-C8 halocycloalkyl;

[0040] Si(C1-C4 alkyl)3, OR 13 OSO2R 13 S(O) m R 13 NR 22 R 23 C(=O)NR 22 R 23 ;

[0041] or

[0042] R 7 and R 8 Together with the carbon atoms they are bonded to, they form 3, 4, 5, 6, 7, or 8-membered saturated or partially unsaturated carbon rings or heterocycles, wherein the heterocycle contains 1, 2, 3, or 4 independently selected carbon atoms.

[0043] N, O and S(O) mheteroatoms or heteroatom groups as ring members, these rings are unsubstituted or

[0044] The object is enclosed by one or two R groups 14 replace;

[0045] R 11 The possible values ​​are CN, NO2, OH, SH, SCN, SF5, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 alkyl-S(O). m C1-C6 haloalkyl-S(O) m Si(C1-C4 alkyl)3

[0046] C(=O)N(R 12a )R 12b ,

[0047] C3-C8 cycloalkyl groups that are not substituted or are partially or completely halogenated and / or substituted with one or two C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and oxosubstituted;

[0048] Phenyl, benzyl, phenoxy, containing 1, 2, or 3 heteroatoms (N, O, and S(O)). m The ring members are 3, 4, 5, 6, or 7 saturated, partially or fully unsaturated heterocycles, which are either unsubstituted or partially or completely halogenated and / or R-substituted. 14 Replace; or

[0049] Two Rs on the same carbon atom of an alkyl, alkenyl, ynyl, or cycloalkyl group. 11 They can be combined to form =O, =CH (C1-C4 alkyl), =C (C1-C4 alkyl)C1-C4 alkyl, =N (C1-C6 alkyl), or =NO (C1-C6 alkyl); and

[0050] R bonded to cycloalkyl ring 11 Additionally, they are C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups, which are unsubstituted, partially or completely halogenated, and / or substituted with one or two CN groups, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and oxo groups; and

[0051] Group = C(R) 11 2. N = C(R) 11 2. C(=U)R 11 and C(=NR) 12 )R 11 R in 11Additionally selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, which are unsubstituted, partially or completely halogenated and / or substituted by one or two groups CN, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and oxo.

[0052] R 12 It can be H, C1-C6 alkoxy, C1-C6 haloalkoxy, or S(O). m -C1-C4 alkyl groups, S(O) m -C1-C4 haloalkyl, Si(C1-C4 alkyl)3,

[0053] C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl groups, which are unsubstituted or partially or completely halogenated and / or converted to Cn, C1-C4 alkoxy, C1-C4 haloalkoxy, or S(O) groups. m -C1-C4 alkyl groups, S(O) m -C1-C4 haloalkyl, unsubstituted or C3-C6 cycloalkyl and oxosubstituted with one or two halogens and / or CN;

[0054] Unsubstituted or partially or completely halogenated and / or substituted with CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or S(O) m -C1-C4 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkyl-C1-C4 alkyl—these rings may be substituted by one or two halogens and / or CN—and oxo-substituted C3-C8 cycloalkyl;

[0055] Phenyl, benzyl, pyridyl, phenoxy, unsubstituted or partially or completely halogenated and / or substituted with halogen, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl and (C1-C6 alkoxy)carbonyl; and comprising 1, 2 or 3 substituted groups selected from N, O and S(O). m The heteroatom is a 3, 4, 5, or 6-member saturated, partially, or fully unsaturated heterocycle, wherein the heterocycle is optionally surrounded by one or more R atoms. 14 replace;

[0056] R 12a and R 12b Having R 12 The given meaning; or

[0057] R 12a and R 12bTogether with the nitrogen atoms they are bonded to, they form 3, 4, 5, 6, or 7-member saturated, partially unsaturated, or maximally unsaturated heterocycles, wherein the heterocycle may additionally contain one or two atoms selected from N, O, and S(O). m The heteroatom or heteroatom group is a ring member, the heterocycle is unsubstituted or substituted by one or more substituents, halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, C1-C4 haloalkoxy groups, and oxo groups; or

[0058] R 12a and R 12 With them in group C (=NR) 12 )N(R 12a )R 12b The nitrogen atoms bonded together form 3, 4, 5, 6, or 7 saturated, partially unsaturated, or maximally unsaturated heterocycles, wherein the heterocycle may additionally contain 1 or 2 atoms selected from N, O, and S(O). m The heteroatom or heteroatom group is a ring member, the heterocycle is not substituted or is substituted by one or more substituents, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and oxo;

[0059] R 13 It is H, Si(C1-C4 alkyl)3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, which is unsubstituted or partially or completely halogenated and / or substituted with C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O). m -C1-C4 alkyl and oxo-substituted;

[0060] Unsubstituted or partially or completely halogenated and / or converted to C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O) m -C1-C4 alkyl and oxo-substituted C3-C8 cycloalkyl;

[0061] Phenyl, benzyl, pyridyl and phenoxy compounds that are not substituted or are partially or completely substituted with halogenated and / or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy and (C1-C6 alkoxy)carbonyl;

[0062] R 14 The compounds are halogens, NO2, CN, OH, SH, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, and S(O). m -C1-C4 alkyl groups, S(O) m-C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 haloalkylcarbonyl, C1-C4 alkoxycarbonyl, C1-C4 haloalkoxycarbonyl, C(=O)NR 12a R 12b Si(C1-C4 alkyl)3;

[0063] C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl groups, which are unsubstituted or partially or completely halogenated and / or converted to C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O) groups. m -C1-C4 alkyl and oxo-substituted;

[0064] Unsubstituted or partially or completely halogenated and / or converted to C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O) m -C1-C4 alkyl and oxo-substituted C3-C8 cycloalkyl;

[0065] Phenyl, benzyl, pyridyl, and phenoxy compounds that are not substituted or are partially or completely substituted with halogenated and / or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, and (C1-C6 alkoxy)carbonyl groups; or

[0066] Two R atoms coexisting on the same atom in an unsaturated or partially unsaturated ring 14 It can be =O, =S, =N(C1-C6 alkyl), =NO(C1-C6 alkyl), =CH(C1-C4 alkyl), or =C(C1-C4 alkyl)C1-C4 alkyl; or

[0067] Two Rs on two adjacent carbon atoms 14 Together with the carbon atoms they are bonded to, they form 4, 5, 6, 7, or 8-member saturated, partially unsaturated, or maximally unsaturated rings, wherein the ring may contain one or two atoms selected from N, O, and S(O). m The heteroatom or heteroatom group is a ring member and the ring is optionally substituted by one or more groups C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and / or C1-C4 haloalkoxy;

[0068] m can be 0, 1, or 2 independently.

[0069] The present invention also provides an agricultural composition comprising at least one compound of formula I, its stereoisomer and / or its arable salt and at least one liquid and / or solid carrier, particularly at least one arable inert liquid and / or solid carrier.

[0070] The present invention also provides a veterinary composition comprising at least one compound of formula I, its stereoisomer and / or its veterinary salt and at least one liquid and / or solid carrier, particularly at least one veterinary inert liquid and / or solid carrier.

[0071] The present invention also provides a method for controlling invertebrate pests, the method comprising treating the pest, its food source, its habitat or breeding ground or cultivated plants in which the pest grows or may grow, plant propagation material (e.g., seeds), soil, area, material or environment or material to be protected against pest infestation or infestation, cultivated plants, plant propagation material (e.g., seeds), soil, surface or space with an insecticidal amount of a compound of formula I as defined herein or a salt thereof.

[0072] The present invention also relates to plant propagation materials, particularly seeds, comprising at least one compound of formula I and / or its agriculturally usable salts.

[0073] The present invention further relates to a method for treating or protecting an animal from parasitic infestation or infection, comprising contacting the animal with an effective amount of a compound of formula I or a veterinary salt thereof. Contacting the animal with compound I, its salt, or the veterinary composition of the present invention means administering or injecting it into the animal.

[0074] WO 2010 / 020522 and WO 2010 / 135360 describe structurally related active compounds. These compounds are mentioned as potentially useful for controlling invertebrate pests.

[0075] However, there remains a need for highly effective and versatile agents for controlling invertebrate pests. Therefore, the object of this invention is to provide compounds that exhibit good insecticidal activity against a wide variety of invertebrate pests, especially difficult-to-control pests such as insects, and display a broad activity spectrum.

[0076] These objectives have been found to be achieved by compounds of formula I and their stereoisomers, salts, tautomers and N-oxides, especially their agricultural salts, as described and defined below.

[0077] Compound I (Formula IO), where U is O, can be prepared by reacting an activated carboxylic acid derivative of Formula II or the corresponding carboxylic acid IIa with a compound of Formula III in an amidation reaction. R in Formula II represents a leaving group, preferably a halogen such as Cl or Br, or a C1-C6 alkoxy such as OCH3 or OC2H5. Amine III is preferably its ammonium salt. + HNR 5 R 6 A - Used where A is an anion, preferably a halide such as Cl or Br.

[0078]

[0079] The saponification is carried out under conditions generally known in the art, for example, by dissolving compound II in tetrahydrofuran (THF), methanol, or a mixture of water or solvents, and adding alkali metal hydroxides, such as LiOH, NaOH, and KOH, either as solids or in solution, to the mixture. The reaction can be carried out at room temperature (20-25°C) or at elevated temperatures. Compound IIa is usually obtained by post-treatment in a conventional manner via aqueous extraction [see WO 2013 / 032804].

[0080] The amidation of compound II is typically carried out with an acyl chloride or by first converting the carboxylic acid of formula IIa to the corresponding acyl chloride with oxaloyl chloride [(COCl)2] or thionyl chloride (SOCl2), followed by reaction with the amine of formula III. Suitable reaction conditions are described in the literature, for example in WO 2004 / 22536. The reaction is typically carried out in the presence of organic bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt), pyridine, substituted pyridines such as cetirizine or rutidine. Optionally, a nucleophilic catalyst such as 4-(N,N-dimethylamino)pyridine (DMAP) may be used in this reaction. Suitable solvents are haloalkanes such as dichloromethane, chloroform, and chlorobenzene, or polar aprotic solvents such as THF and N,N-dimethylformamide (DMF), or aromatic hydrocarbons such as benzene, toluene, o-xylene, m-xylene, and p-xylene, or mixtures thereof. This conversion is typically carried out at temperatures ranging from -40°C to 120°C, preferably from 0°C to 40°C. The feedstocks usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of III based on II.

[0081] Alternatively, amidation of carboxylic acid IIa is carried out in the presence of a coupling agent. Suitable coupling agents (activators) are known and are selected, for example, from carbodiimides such as N,N-dicyclohexylcarbodiimide (DCC) and N,N-diisopropylcarbodiimide (DCI), and benzotriazole derivatives such as 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine. 3-Oxide hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HBTU) and 1-[di(dimethylamino)methylene]-5-chlorobenzotriazole 3-Oxide hexafluorophosphate (HCTU) or Derivative activators, such as 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (T3P) and (benzotriazol-1-yloxy)tri(dimethylamino). Hexafluorophosphate (BOP), (benzotriazol-1-yloxytripyrroleyl) Py-BOP (hexafluorophosphate), brominated tripyrroleyl Hexafluorophosphate (Py-BrOP). Activators are often used in excess. This benzotriazole and... The coupling agent is typically used in an alkaline medium. 2,4,6-Tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (T3P) is preferably used as the coupling agent (activator). Suitable reaction conditions are described in the literature, for example in WO 2015 / 128358. The reaction is typically carried out in the presence of a base, such as a tertiary amine base, iPr2Net, or Et3N. Suitable solvents are, for example, halogenated hydrocarbons such as dichloromethane, chloroform, and chlorobenzene. The conversion is typically carried out at temperatures ranging from 0 to 160°C, preferably from 25 to 100°C. The starting materials typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of III based on II. The amine of formula III is commercially available or can be obtained by methods known in the art (e.g., WO 2016 / 168056, WO 2016 / 168058, WO 2016 / 168059, WO 2018 / 071327, WO 2019 / 194982, WO 2011 / 067272, WO 2005 / 085216).

[0082] Where X is NR 3 Compound II (Formula II.1) can be made by isoformation of Formula IIIA Zolpidem and X H The halogen is a halide of formula IV, preferably a bromide or iodide, prepared by reacting it in the Buchwald-Hartwig reaction (e.g., WO2017 / 069980).

[0083]

[0084] The conversion is typically carried out at a temperature of 20–180 °C, preferably 60–100 °C, in an inert solvent in the presence of a base and a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)[Pd2(dba)3], 9,9-dimethyl-4,5-di(diphenylphosphine)xanthos, or [2-(di-tert-butylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos Pd G1) [see WO 2017 / 069980].

[0085] Suitable solvents are ethers, such as diethyl ethers. Alkanes and THF, etc., or alcohols such as butanol and tert-amyl alcohol, etc., or polar aprotic solvents such as DMF, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), etc.

[0086] Preferred use of 1,4-di Alkane. Mixtures of the solvents may also be used.

[0087] Suitable bases are typically inorganic compounds, such as alkali metal and alkaline earth metal carbonates, like Li₂CO₃, K₂CO₃, CaCO₃, and CsCO₃, or organic compounds, such as alkali metal alkoxides, like lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide, etc. CsCO₃ is particularly preferred. Bases are usually used in equimolar amounts; however, they can also be used in excess.

[0088] The reactants typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of III based on IV.

[0089] Compound IV may be commercially available or known from the literature [e.g., see US2011 / 0251247; THL1997, 38, 1559] or may be prepared according to the cited literature.

[0090] Where R 3 Compound IIIA, with H, can be prepared by oxo-Michael addition of hydroxylamine, hydroxyurea, or a salt of any of them (collectively referred to as compound VA) to acrylonitrile of formula V.

[0091]

[0092] The reaction of acrylonitrile of formula V with compound VA is usually carried out in an inert solvent in the presence of a base at a temperature of -30°C to 120°C, preferably 25-80°C.

[0093] Suitable solvents are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, etc.; or halogenated hydrocarbons, such as dichloromethane, chloroform, chlorobenzene, etc.; or aromatic hydrocarbons, such as toluene, o-xylene, m-xylene, p-xylene, etc.; or ethers, such as diethyl ether, methyl tert-butyl ether (MTBE), etc. Alkanes, anetholes, and THF, or nitriles such as acetonitrile and propionitrile; in addition, there are DMSO, DMF, DMA, and water.

[0094] Alcohols, such as methanol, are preferred, but mixtures of the solvents may also be used.

[0095] Suitable bases are typically inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, Ca(OH)2, etc., or alkali metal and alkaline earth metal carbonates, such as Li2CO3, K2CO3, and CaCO3, etc., or alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH, CaH2, etc. In addition, organic bases, such as alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, etc., or alkali metal ammonium bases, such as lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, etc., are also suitable. Alkali metal alkoxides, such as sodium methoxide, are particularly preferred. Bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0096] The feedstocks typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of vitamin A based on vitamin B.

[0097] Furthermore, in certain situations, it may be advantageous to use a phase-transfer catalyst in this reaction, such as quaternary ammonium salts like tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, etc. If desired, a chiral phase-transfer catalyst can be used in this reaction [see Org. Process Res.Dev. 2015, 19, 1731-1746; and references therein], such as cinchona-derived quaternary ammonium salts like (R)-[(1S,2S,4S,5R)-1-(acridin-9-ylmethyl)-5-vinylquinine ring-1-] [-2-yl]-(6-methoxy-4-quinolinyl)methanol bromide (CAS No. 466639-23-6; e.g. US2014 / 0350261) was used to synthesize enantiomeric enriched compound III.

[0098] Compound V can be prepared by reacting the ketone of formula VI with the Horner-Wadsworth-Emmons of compound VII.

[0099]

[0100] This conversion is typically carried out in an inert solvent in the presence of a base at a temperature of 0–120 °C, preferably 25–80 °C [see J. Org. Chem. 1985, 50, 15, 2624, and references therein].

[0101] Suitable solvents are ethers, such as THF, diethyl ether, MTBE, dimethoxyethane (DME), etc. Alkanes, etc., or nitriles, such as acetonitrile, propionitrile, etc., or aromatic hydrocarbons, such as benzene, toluene, o-xylene, m-xylene, p-xylene, etc. THF is preferred, and mixtures of the solvents may also be used.

[0102] Suitable bases are usually inorganic compounds, such as alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH, CaH2, etc.

[0103] In addition, organic bases, such as alkali metal ammonium bases, such as lithium (trimethylsilyl)amino, sodium (trimethylsilyl)amino, potassium (trimethylsilyl)amino, etc., or alkali metal alkoxides, such as lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide, etc., or tertiary amines, such as triethylamine, diisopropylethylamine and N-methylpiperidine, or amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc., are preferred. Bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0104] In addition, in some cases it may be advantageous to use alkali metal or alkaline earth metal additives such as LiCl, LiBr, MgCl2, MgBr2, etc. in this reaction.

[0105] The reactants typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use VI in excess of VII.

[0106] Compounds VI and VII are commercially available or known from the literature [see, for example, WO 2005 / 085216, WO 2011 / 067272] or can be prepared according to the cited literature.

[0107] Alternatively, the compound of formula II.1 can be made by making X H The isocyanate of halogen formula VIII Azoline halogen compounds, preferably bromides or chlorides, and amines of formula IXa (X = NHR) 3 It is prepared by reacting in an acid-promoted ipso substitution reaction:

[0108]

[0109] This conversion is typically carried out in an inert solvent in the presence of an acid at temperatures ranging from 25 to 200°C, preferably from 60 to 150°C.

[0110] Suitable solvents are alcohols, such as 2,4-dimethylpentane-3-ol, n-butanol, sec-butanol, tert-butanol, etc., or aromatic hydrocarbons, such as toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichlorobenzene, etc., as well as DMSO, DMF, DMA, NMP, etc., with alcohols, such as 2,4-dimethylpentane-3-ol, being preferred. Mixtures of the aforementioned solvents may also be used.

[0111] Suitable acids and acidic catalysts are typically inorganic acids, such as HCl, HBr, H₂SO₄, HClO₄, etc., as well as organic acids such as toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, etc. Acids are usually used in catalytic amounts; however, they can also be used in equimolar amounts, in excess, or, where appropriate, as solvents.

[0112] The reactants typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of IXa based on VIII.

[0113] Compound IX is commercially available or known from the literature [see WO 2016 / 168056, WO 2016 / 168058, WO2016 / 168059, WO 2018 / 071327, WO 2019 / 194982, WO 2010 / 135360] or can be prepared according to the cited literature.

[0114] On the other hand, compounds of formula VIII can be prepared by reacting an alkene of formula X with a dihaloformaldehyde oxime of formula XI in a 1,3-dipolar cycloaddition reaction:

[0115]

[0116] This conversion is typically carried out in an inert solvent in the presence of a base at a temperature of 0-100°C, preferably 25-80°C [see WO 2010 / 135360].

[0117] Suitable solvents are esters such as ethyl acetate, or water, and mixtures of said solvents may also be used. Suitable bases are typically inorganic compounds, such as alkali metal and alkaline earth metal carbonates, such as Li₂CO₃, K₂CO₃, and CaCO₃, and alkali metal bicarbonates, such as NaHCO₃. Alkali metal bicarbonates, such as NaHCO₃, are particularly preferred. Bases are usually used in excess; however, they can also be used in molar amounts.

[0118] The reactants typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of XI based on X.

[0119] Compound X can also be obtained by brominizing the ketone of formula VI with methyltriphenyl. Prepared by reacting in the Wittig reaction:

[0120]

[0121] The Wittig reaction is preferably carried out at a temperature of 0-60°C in an inert solvent such as THF in the presence of a base such as potassium tert-butoxide, under conditions known in the art.

[0122] Furthermore, compounds of formula II can also be made by making X H The isocyanate of halogen formula VIII Azoline halogen compounds, preferably bromides or chlorides, are prepared by reacting with compounds of formula IX in a base-promoted ipso substitution reaction:

[0123]

[0124] The conversion is typically carried out in an inert solvent in the presence of a base at a temperature of 25–200 °C, preferably 60–150 °C [see WO 2010 / 135360].

[0125] Suitable solvents include DMF, DMA, NMP, DMSO, etc., with DMF or NMP being preferred. Mixtures of these solvents may also be used.

[0126] Suitable bases are typically inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, like LiOH, NaOH, KOH, Ca(OH)₂, etc., or alkali metal and alkaline earth metal hydrides, like LiH, NaH, KH, CaH₂, etc., or alkali metal and alkaline earth metal carbonates, like Li₂CO₃, K₂CO₃, and CaCO₃. Bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0127] Furthermore, compounds of formula II can be prepared by reacting an alkene of formula X with an oxime of formula XII in which Ar is an aromatic group in a 1,3-dipolar cycloaddition:

[0128]

[0129] This conversion is typically carried out in an inert solvent in the presence of a base and a silver(I) salt, such as silver nitrate, at a temperature of 0–100 °C, preferably 25–60 °C [see WO 2010 / 135360].

[0130] Suitable solvents are nitriles, such as acetonitrile and propionitrile. Suitable bases are usually inorganic compounds, such as alkali metal and alkaline earth metal carbonates, such as Li₂CO₃, K₂CO₃, and CaCO₃, as well as alkali metal bicarbonates, such as NaHCO₃. K₂CO₃ is particularly preferred. Bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0131] The reactants typically react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of X based on XII.

[0132] Compound XII can be prepared as described in the literature [see WO 2010 / 135360] or according to the cited literature.

[0133] Compounds of formula I', where U is S, can be prepared by reacting the corresponding oxo-compound (U is O) with a Lawesson reagent (CAS 19172-47-5), for example, see Jesberger et al., Synthesis, 2003, 1929-1958 and its references. Solvents such as HMPA or THF can be used at elevated temperatures such as 60-100 °C. Preferred reaction conditions are 65 °C in THF.

[0134] The raw materials required for the preparation of compound I are commercially available or known from the literature [e.g., see WO 2005 / 085216, WO2010 / 135360, WO 2011 / 067272, WO 2016 / 168056, WO 2016 / 168058, WO 2016 / 168059, WO2018 / 071327, WO 2019 / 194982] or can be prepared according to the cited literature.

[0135] The reaction mixture is post-processed in a conventional manner, such as by mixing with water, separating the phases, and purifying the crude product by appropriate hydrochromatography. Some intermediates and final products are obtained as colorless or light brown viscous oils, which are purified or have volatile components removed under reduced pressure and at gently elevated temperatures. If the intermediates and final products are obtained as solids, they can also be purified by recrystallization or leaching.

[0136] If individual compounds I cannot be prepared by the above-described method, they can be prepared by deriving other compounds I.

[0137] However, if the synthesis yields a mixture of isomers, separation is not usually required, as the isomers may interconvert in certain circumstances during post-treatment for application or during application (e.g., under the influence of light, acid, or alkali). Such transformations can also occur post-application, for example in the treated plant or in the pest being controlled.

[0138] In a preferred embodiment, compound I exists as a mixture of compounds IA and IB, wherein in the isocyanate... Compound IA, which has an S configuration in the zoline ring, is present in an amount greater than 50% by weight, especially at least 70% by weight, more particularly at least 85% by weight, and specifically at least 90% by weight, based on the total weight of compounds IA and IB.

[0139]

[0140] In a particularly preferred embodiment of the invention, the method includes the step of contacting a plant, its parts, its propagation material, pests, its food sources, habitats or breeding grounds with an insecticidal amount of a compound of formula IA.

[0141] Compounds of formulas IA and IB can be obtained in enantiomeric purity by known separation methods, preferably by chiral chromatography. This is preferably for intermediate compounds of formulas III and IIIa, or compounds of formulas II and IIa.

[0142] In the definitions of the variables above, the organic structural groups mentioned are collective terms, like the term halogen, representing the enumeration of each group member. Prefix C n -C m In each case, it indicates the possible number of carbon atoms in the group.

[0143] The term "partially or completely substituted" means that the group is usually substituted by the same or different groups.

[0144] The term "halogen" in each case refers to fluorine, bromine, chlorine, or iodine, especially fluorine, chlorine, or bromine.

[0145] As used herein and in the alkyl structural portion of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl, the term "alkyl" in each case generally means a straight-chain or branched alkyl group having 1-10 carbon atoms, often 1-6 carbon atoms, preferably 1-4 carbon atoms, and more preferably 1-3 carbon atoms. Examples of alkyl groups are methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.

[0146] As used herein, and in the haloalkyl structural moiety of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy, and haloalkoxyalkyl groups, the term "haloalkyl" in each case generally refers to a straight-chain or branched alkyl group having 1-10 carbon atoms, often 1-6 carbon atoms, and preferably 1-4 carbon atoms, wherein the hydrogen atoms of the group are partially or completely replaced by halogen atoms. Preferred haloalkyl structural moieties are selected from C1-C4 haloalkyl groups, more preferably C1-C3 or C1-C2 haloalkyl groups, especially C1-C2 fluoroalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, etc.

[0147] As used herein, the term "alkoxy" in each case refers to a straight-chain or branched alkyl group bonded by an oxygen atom and typically having 1-10 carbon atoms, often 1-6 carbon atoms, and preferably 1-4 carbon atoms. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, tert-butoxy, etc.

[0148] As used herein, the term "alkoxyalkyl" refers to an alkyl group that typically comprises 1 to 10, often 1 to 4, preferably 1 to 2 carbon atoms, wherein one carbon atom carries an alkoxy group as defined above, typically comprising 1 to 4, preferably 1 to 2 carbon atoms. Examples are CH2OCH3, CH2-OC2H5, 2-methoxyethyl, and 2-ethoxyethyl.

[0149] As used herein, the term "haloalkoxy" in each case refers to a straight-chain or branched alkoxy group having 1-10 carbon atoms, often 1-6 carbon atoms, and preferably 1-4 carbon atoms, wherein the hydrogen atoms of the group are partially or completely replaced by halogen atoms, especially fluorine atoms. Preferred haloalkoxy structural moieties include C1-C4 haloalkoxy groups, especially C1-C2 fluoroalkoxy groups, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, etc.

[0150] As used herein, the term "alkylthio (S-alkyl)" refers to a straight-chain or branched saturated alkyl group having 1-10 carbon atoms, preferably 1-4 carbon atoms (=C1-C4 alkylthio), more preferably 1-3 carbon atoms, linked via sulfur atoms.

[0151] As used herein, the term "haloalkylthio" refers to an alkylthio group as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine, and / or iodine.

[0152] As used herein, the term "alkyl sulfinyl" (alkyl sulfinyl: C1-C6 alkyl-S(O)-) refers to a straight-chain or branched saturated alkyl group having 1-10 carbon atoms, preferably 1-4 carbon atoms (=C1-C4 alkyl sulfinyl), and more preferably 1-3 carbon atoms, bonded by the sulfur atom of the sulfinyl group at any position in the alkyl group (as described above).

[0153] As used herein, the term "halogenated alkyl sulfinyl" refers to an alkyl sulfinyl group as described above, wherein the hydrogen atoms are partially or completely substituted with fluorine, chlorine, bromine, and / or iodine.

[0154] As used herein, the term "alkylsulfonyl" (alkyl-S(O)2-) refers to a straight-chain or branched saturated alkyl group having 1-10 carbon atoms, preferably 1-4 carbon atoms (=C1-C4 alkylsulfonyl), more preferably 1-3 carbon atoms, bonded at any position in the alkyl group via a sulfur atom of the sulfonyl group.

[0155] As used herein, the term "haloalkylsulfonyl" refers to an alkylsulfonyl group as described above, wherein the hydrogen atoms are partially or completely substituted with fluorine, chlorine, bromine, and / or iodine.

[0156] The term "alkyl carbonyl" refers to an alkyl group as defined above, which is bonded to the rest of the molecule via a carbonyl (C=O) carbon atom.

[0157] The term "halogenated alkyl carbonyl" refers to an alkyl carbonyl group as described above, wherein the hydrogen atoms are partially or completely substituted by fluorine, chlorine, bromine and / or iodine.

[0158] The term "alkoxycarbonyl" refers to an alkyl carbonyl group as defined above, which is bonded to the rest of the molecule via an oxygen atom.

[0159] The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl group as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.

[0160] The term "alkenyl" as used herein generally refers to a monounsaturated hydrocarbon group having 2-10, often 2-6, and preferably 2-4 carbon atoms, such as vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methylallyl (2-methylpropen-2-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbuten-2-yl, 2-ethylpropen-2-yl, etc.

[0161] The term “halogenated alkenyl” as used in this article refers to alkenyl groups as defined above, in which hydrogen atoms are partially or completely replaced by halogen atoms.

[0162] The term "alkynyl" as used herein generally refers to a monounsaturated hydrocarbon group having 2-10, often 2-6, and preferably 2-4 carbon atoms, such as ethynyl, propynyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylpropyn-2-yn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbutyn-2-yn-1-yl, 1-ethylpropyn-2-yn-1-yl, etc.

[0163] The term “haloalkynyl” as used in this article refers to an alkynyl group as defined above, in which hydrogen atoms are partially or completely replaced by halogen atoms.

[0164] The term "cycloalkyl" as used herein, and in the cycloalkyl structural part of cycloalkoxy and cycloalkylthio, in each case means a monocyclic alicyclic group generally having 3-10 carbon atoms or 3-6 carbon atoms, such as cyclopropyl (c-C3H5), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0165] The term "halocycloalkyl" as used herein and in the halocycloalkyl structural portion of halocycloalkoxy and halocycloalkylthioyl groups in each case refers to a monocyclic alicyclic group generally having 3-10 carbon atoms or 3-6 carbon atoms, wherein at least one, for example 1, 2, 3, 4 or 5 hydrogen atoms are replaced by a halogen, especially fluorine or chlorine. Examples include 1- and 2-fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclopropyl, 1-, 2- and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-, 2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlorocyclopentyl, etc.

[0166] The term "halocycloalkenyl" as used herein, and in the halocycloalkenyl structural portion of halocycloalkenyloxy and halocycloalkenylthioyl groups, in each case denotes a monocyclic monounsaturated nonaromatic group generally having 3-10, for example 3 or 4 or 5-10 carbon atoms, preferably 3-8 carbon atoms, wherein at least one, for example 1, 2, 3, 4 or 5 hydrogen atoms are replaced by a halogen, especially fluorine or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.

[0167] The term “cycloalkenylalkyl” refers to a cycloalkenyl group as defined above that is bonded to the remainder of the molecule via an alkyl group, such as a C1-C5 alkyl or a C1-C4 alkyl group, especially a methyl group (= cycloalkenylmethyl).

[0168] The term "carbocyclic" or "carbocyclic group" generally includes 3-12 members, preferably 3-8 or 5-8, more preferably 5 or 6 members, of a monocyclic nonaromatic ring containing 3-12, preferably 3-8 or 5-8, more preferably 5 or 6 carbon atoms. The preferred term "carbocyclic" covers cycloalkyl and cycloalkenyl groups as defined above.

[0169] The term "heterocyclic" or "heterocyclic group" typically includes 3-12 members, preferably 3-6 members, and especially 6-membered monocyclic heterocyclic nonaromatic groups. Heterocyclic nonaromatic groups typically contain 1, 2, 3, 4, or 5, preferably 1, 2, or 3, heteroatoms selected from N, O, and S as ring members, wherein the S atom as a ring member can exist as S, SO, or SO2. Examples of 5- or 6-membered heterocyclic groups include saturated or unsaturated non-aromatic heterocycles, such as ethylene oxide, oxetane, thioheterocyclic, thioheterocyclic-S-oxide (S-oxothioheterocyclic), thioheterocyclic-S-dioxide (S-dioxothioheterocyclic), pyrrolyl, pyrrololinyl, pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxopentaneyl, tetrahydrothiophenyl, S-oxotetrahydrothiophenyl, S-dioxotetrahydrothiophenyl, dihydrothiophenyl, S-oxodihydrothiophenyl, S-dioxodihydrothiophenyl. azolealkyl, Azoline, thiazoline, oxothionylpentyl, piperidinyl, piperazine, pyranyl, dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-di- Alkyl, thiaranyl, S-oxothiaranyl, S-dioxothiaranyl, dihydrothiaranyl, S-oxodihydrothiaranyl, S-dioxodihydrothiaranyl, tetrahydrothiaranyl, S-oxotetrahydrothiaranyl, S-dioxotetrahydrothiaranyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl, etc. Examples of heterocycles containing one or two carbonyl groups as ring members include pyrrolidine-2-keto, pyrrolidine-2,5-diketo, imidazolidine-2-keto, etc. Alzolidine-2-one, thiazolidin-2-one, etc.

[0170] The term "heteroaryl" includes monocyclic 5- or 6-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring members. Heteroaryl groups containing N or S can act as positively charged... The salt exists and forms a mesonized entity together with adjacent atoms. Examples of 5- or 6-membered heteroaromatic groups include pyridyl (2-, 3-, or 4-pyridyl), pyrimidinyl (2-, 4-, or 5-pyrimidinyl), pyrazinyl, pyridazinyl (3- or 4-pyridazinyl), thiopheneyl (2- or 3-thiopheneyl), furanyl (2- or 3-furanyl), and pyrroleyl (2- or 3-pyrroleyl). Azolium group, i.e., 2-, 3-, or 5- azole group, iso Azolium group, i.e., 3-, 4-, or 5-isopropylamine Azolium, thiazolyl (i.e., 2-, 3-, or 5-thiazolyl), isothiazolium (i.e., 3-, 4-, or 5-isothiazolyl), pyrazolium (i.e., 1-, 3-, 4-, or 5-pyrazolium), and 1-, 2-, 4-, 5-imidazolyl. Diazoles, such as 2- or 5-[1,3,4] Diazolyl, 4- or 5-(1,2,3-) (diazole) group, 3- or 5-(1,2,4-) (diazole) group, 2- or 5-(1,3,4-thiadiazole) group, thiadiazole group, such as 2- or 5-(1,3,4-thiadiazole) group, 4- or 5-(1,2,3-thiadiazole) group, 3- or 5-(1,2,4-thiadiazole) group, triazole group, such as 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H- or 4H-1,2,4-triazol group, and tetrazol group, i.e., 1H- or 2H-tetrazol group. The term "heteroaryl" also includes bicyclic 8- to 10-membered heteroaryl groups comprising 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, wherein a 5- or 6-membered heteroaryl ring is fused to a phenyl ring or a 5- or 6-membered heteroaryl group. Examples of 5- or 6-membered heteroaromatic rings fused to a phenyl ring or a 5- or 6-membered heteroaromatic group include benzofuranyl, benzothiophenyl, indoleyl, indazoleyl, benzimidazolyl, and benzo[] Thiazolyl, benzo[ diazole group, benzothiadiazole group, benzo[] Azine, quinolinyl, isoquinolinyl, purine, 1,8-diazanaphthyl, pteridinyl, pyrido[3,2-d]pyrimidinyl or pyridoimidazolyl, etc. These fused heteroaryl groups can be bonded to the remainder of the molecule via any ring atom of a 5 or 6-membered heteroaryl ring or via a carbon atom of the fused phenyl structural moiety.

[0171] The terms “heterocyclic alkyl” and “heteroaryl alkyl” refer to heterocyclic or heteroaryl groups as defined above, which are bonded to the remainder of the molecule via a C1-C5 or C1-C4 alkyl group, especially a methyl group (=heterocyclic methyl or heteroaryl methyl, respectively).

[0172] The terms “arylalkyl” and “phenylalkyl” refer to aryl and phenyl groups as defined above, respectively, bonded to the remainder of the molecule via a C1-C5 alkyl or C1-C4 alkyl group, especially a methyl group (=arylmethyl or phenylmethyl, respectively), examples of which include benzyl, 1-phenylethyl, 2-phenylethyl, 2-phenoxyethyl, etc.

[0173] The terms “alkylene,” “cycloalkylene,” “heterocyclic alkylene,” “alkenylene,” “cycloalkenylene,” “heterocyclic alkenylene,” and “alkynylene” refer to alkyl, cycloalkyl, heterocyclic alkyl, alkenyl, cycloalkenyl, heterocyclic alkenyl, and alkynyl groups as defined above, which are bonded to the remainder of the molecule via two atoms of the respective group, preferably via two carbon atoms, and thus represent a linking group between two structural parts of the molecule.

[0174] In a particular embodiment, the variables of Formula I compound have the following meanings, which, individually and in combination, constitute a particular embodiment of Formula I compound.

[0175] Embodiments and preferred compounds of the present invention for use in methods of killing pests and for pesticidal applications are summarized in the following paragraphs.

[0176] For each variable, the particularly preferred embodiments of the intermediates correspond to those of the compound of formula I.

[0177] In one implementation, W is the group WA:

[0178]

[0179] in

[0180] A 1 A 2 A 3 For N or CR 2 The condition is that at least two are CR. 2 ;

[0181] R 2 The preferred elements, independently of each other, are H, halogen, C1-C4 haloalkyl, C1-C4 halocycloalkyl, C1-C3 haloalkoxy, and S(O). m -C1-C3 alkyl groups, S(O) m -C1-C3 haloalkyl.

[0182] W is preferably the WP group:

[0183]

[0184] Where R 2a R 2b and R 2c For group R 2.

[0185] R 2a The preferred materials are F, Cl, Br, CF3, SCF3 and OCF3.

[0186] R 2b and R 2c Preferably, the components are independently selected from H, F, Cl, Br, CF3, SCF3, and OCF3.

[0187] R is the preferred choice 2a R 2b and R 2c Each of the following combinations, where each row of table W represents a combination with R 2a R 2b and R 2c The substitution method of the phenyl ring (“WP”) in the structural part.

[0188] Table W

[0189]

[0190] Among the compounds of formula I, groups W-8, W-9, and W-11 are preferred. W-11 is particularly preferred.

[0191] Another embodiment of W is a 5- or 6-membered heteroaryl group, such as thiophene, pyrazole, imidazole, or pyridine, which are surrounded by 1 or 2 groups R. 2a Or C1-C2 alkoxy-C1-C2 alkyl substitution.

[0192] R 1 CF3 is preferred.

[0193] X is preferably NR 3 In another preferred embodiment, X is NR. 3 Or O.

[0194] In one embodiment of the compound of formula I as defined in claim 1, R 21 The groups are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or Si (C1-C4 alkyl)3, and these groups are unsubstituted, partially or completely replaced by R. 211 replace.

[0195] R 3 Preferably, it is H, C1-C4 alkyl, which is unsubstituted or surrounded by one or two groups CN, C3-C4 cycloalkyl, C1-C2 alkoxy, or contains elements selected from N, O, and S(O). m The heteroatom is substituted as a 4-membered heterocyclic group of the ring member. R is particularly preferred. 3 It can be H or CH3.

[0196] In another implementation, R 3 It can be OH, C1-C4 alkoxy, or C1-C4 alkoxycarbonyl.

[0197] In one implementation, G is the group GQ:

[0198]

[0199] in

[0200] Q 1 Q 2 Q 3 Q 4 For N or CR 4 The condition is that at least three are CR. 4 ;

[0201] R 4 The preferred elements, independently of each other, are H, halogen, CN, C1-C4 alkyl, C1-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 halocycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and S(O). m -C1-C3 alkyl groups, S(O) m -C1-C3 haloalkyl.

[0202] G is preferably a group G1, G2, G3 or G4:

[0203]

[0204] Where # represents the key with X, % represents the key with Y, is a direct key, and R 41 and R 42 H or R group 4 Preferably, H, or halogen, CN, halomethyl, or halomethoxy. In a particularly preferred embodiment, R 41 Halogens such as Cl and R 42 For H.

[0205] Another embodiment of G is a 5-membered heteroaryl group, such as thiophene or imidazole, where the cyclic group R 2a Or C1-C2 alkoxy substitution.

[0206] Y is preferably a direct bond.

[0207] In another embodiment, Y is the spacer base CR 7 R 8 In this group, R 7 and R 8 Preferably, they are all H or halogens, such as F, or R. 7 and R 8 Together, they form a 3- or 4-member saturated carbon ring.

[0208] Preferred R 5 It is a C1-C4 alkyl, a C1-C4 haloalkyl, an optionally substituted C3-C4 cycloalkyl, a phenyl substituted with one or two halogens, NH2, NHC(O)-C1-C4 alkyl, or a 6-membered heteroaryl group containing 1-3 N atoms as ring members.

[0209] In another implementation, R 5 It is composed of CN, C1-C2 alkyl, C1-C2 haloalkyl, or contains 1-4 alkyl groups selected from N, O, and S(O). m The heteroatom is a cyclopropyl group that is partly or completely unsubstituted by a heterocycle as a member of the ring, the heterocycle being optionally substituted by a halogen, CN, C1-C4 alkyl, cyano-C1-C4 alkyl, C1-C4 haloalkyl, C1-C2 alkoxy-C1-C2 alkyl and / or oxo.

[0210] In another implementation, R 5 It is a phenyl group substituted with one or two substituted halogens, CN, C1-C4 alkyl, C1-C4 haloalkyl, NH2, NHC(O)-C1-C4 alkyl, NHC(O)-C1-C4 haloalkyl, NHC(O)-C1-C4 alkoxy, NHC(O)-C1-C2 alkyl-C3-C4 cycloalkyl.

[0211] R 6 Preferably, it is H or C1-C4 alkyl, C3-C4 cycloalkyl-C1-C2 alkyl, C1-C4 alkylcarbonyl, or C1-C4 alkoxycarbonyl. Particularly preferred is R. 6 It is H or C1-C2 alkyl.

[0212] The preferred embodiment is a compound of formula I, wherein:

[0213] R 1 It is a C1-C2 haloalkyl group;

[0214] W is a phenyl group or a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members; wherein W is unsubstituted, partially or completely replaced by R. 2 replace;

[0215] R 2 For halogen, OR 21 C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl-S(O) m C1-C3 haloalkyl-S(O) m C1-C3 alkoxy-C1-C4 alkyl; these groups are optionally R 211 Replacement; m is 0, 1, or 2;

[0216] R 21 The groups are H, C1-C6 alkyl, and these groups are unsubstituted, partially or completely replaced by R. 211 Replace; R 211 It is a halogen;

[0217] X is NR 3 O or S(O) m ;R 3 OR 21 Or, for example, R 5 Defined groups;

[0218] G is a phenyl group or a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members; wherein G is unsubstituted, partially or completely replaced by R. 4 Replace; R 4 For example, for R 2 Defined groups;

[0219] U is O;

[0220] R 5 H, C1-C6 alkyl, C1-C6 haloalkyl, which is unsubstituted or partially or completely replaced by R 51 Replace; or

[0221] N(R 12a )R 12b S(O) m R 13 C(=O)OR 13 C(=U)N(R) 12a )R 12b ,

[0222] C3-C8 cycloalkyl, C3-C8 halocycloalkyl, phenyl, containing 1, 2, 3 or 4 atoms selected from N, O and S(O). m The heteroatom is a 3, 4, 5, 6, or 7-member saturated or partially unsaturated heterocycle, or contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S(O). m The heteroatoms are 5- or 6-membered heteroaryl groups that are ring members, and these rings are either unsubstituted or partially or completely replaced by R. 52 replace;

[0223] R 51 Halogen, CN, N(R) 12a )R 12b C(=O)N(R) 12a )R 12b ;

[0224] Unsubstituted, partially halogenated and / or CN-substituted C3-C8 cycloalkyl groups;

[0225] S(O) m R 13 C(=U)N(R) 12a )R 12b ; Phenyl or containing 1, 2 or 3 atoms selected from N, O, S(O). m The heteroatom is a 3, 4, 5, 6, or 7-member saturated, partially, or fully unsaturated heterocycle; or

[0226] R 52 For example, R 51 The groups defined in the document;

[0227] R 6 For example, for R 5 The defined group; or

[0228] R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form mesonic entities;

[0229] At point G, Y has one or two ring atoms of G between the junctions of G and X and Y; Y is a direct bond or CR bond. 7 R 8 ;R 7 R 8 It is H or halogen.

[0230] The preferred embodiment is a compound of formula I, which corresponds to formula I' shown below, wherein the variables are as defined and preferred above.

[0231]

[0232] Another preferred embodiment is a compound of formula I, which corresponds to formula I.1 shown below, wherein the variables are as defined and preferred above.

[0233]

[0234] Another preferred embodiment is a compound of formula I, corresponding to formula I.2 shown below, wherein the variables are as defined and preferred above. One embodiment relates to a compound of formula I.2, wherein X is O or S(O). m Especially O.

[0235] Another preferred embodiment is a compound of formula I, corresponding to formula I.3 shown below, wherein the variables are as defined and preferred above. One embodiment relates to a compound of formula I.3, where X is NR. 3 Especially NH.

[0236]

[0237] Especially considering their intended use, compounds of formula I compiled in the table below are preferred, corresponding to R in which 42 Formula I.1 represents H. Furthermore, the particular preference for each substituent mentioned in the table as the substituent itself is independent of any combination thereof.

[0238] Table 1: Where R 5 For H, R 6 For each compound, c-C3H5 and other variables correspond to Formula I.1 in row A of Table A.

[0239] Table 2: Where R 5 CH3, R 6 For each compound, c-C3H5 and other variables correspond to Formula I.1 in row A of Table A.

[0240] Table 3: Where R 5 For CH2CH3, R 6 For each compound, c-C3H5 and other variables correspond to Formula I.1 in row A of Table A.

[0241] Table 4: Where R 5 For H, R 6 For (1-CN)-c-C3H4, and for each of the other variables, corresponding to Formula I.1 in row A of Table A.

[0242] Table 5: Where R 5 CH3, R 6 For (1-CN)-c-C3H4, and for each of the other variables, corresponding to Formula I.1 in row A of Table A.

[0243] Table 6: Where R 5 For CH2CH3, R 6 For (1-CN)-c-C3H4, and for each of the other variables, corresponding to Formula I.1 in row A of Table A.

[0244] Table 7: Where R 5 For H, R 6 For CH2CF3, and other variables for each compound, in each case corresponding to Formula I.1 in row A of Table A.

[0245] Table 8: Where R 5 CH3, R 6 For CH2CF3, and other variables for each compound, in each case corresponding to Formula I.1 in row A of Table A.

[0246] Table 9: Where R5 For CH2CH3, R 6 For CH2CF3, and other variables for each compound, in each case corresponding to Formula I.1 in row A of Table A.

[0247] Table 10: R in the table 5 For H, R 6 The value is 2,4-F2-C6H3, and other variables for each compound correspond to line I.1 of Table A in each case.

[0248] Table 11: Where R 5 CH3, R 6 The value is 2,4-F2-C6H3, and other variables for each compound correspond to Formula I.1 in row A of Table A.

[0249] Table 12: Where R 5 For CH2CH3, R 6 The value is 2,4-F2-C6H3, and other variables for each compound correspond to Formula I.1 in row A of Table A.

[0250] Table 13: Where R 5 For H, R 6 (4R)-2-ethyl-3-oxoisocyanate The 4-azolidinyl group and other variables for each compound correspond in each case to the compound of formula I.1 in row A of Table A.

[0251] Table 14: Where R 5 CH3, R 6 (4R)-2-ethyl-3-oxoisocyanate The 4-azolidinyl group and other variables for each compound correspond in each case to the compound of formula I.1 in row A of Table A.

[0252] Table 15: Where R 5 For CH2CH3, R 6 (4R)-2-ethyl-3-oxoisocyanate The 4-azolidinyl group and other variables for each compound correspond to Formula I.1 in a row of Table A. (Table A of Compounds)

[0253]

[0254]

[0255]

[0256] The term "compound of the present invention" refers to a compound of formula I or "compound I", and includes its salts, tautomers, stereoisomers and N-oxides.

[0257] The present invention also relates to an agricultural chemical composition comprising an adjuvant and at least one compound I.

[0258] The agricultural chemical composition contains an effective amount of compound I for killing insects.

[0259] Compound I can be converted into types commonly used in agrochemical compositions, such as solutions, emulsions, suspensions, powders, pastes, granules, molded products, capsules, and mixtures thereof. Examples of composition types include suspensions (e.g., SC, OD, FS), emulsifiable concentrates (e.g., EC), emulsions (e.g., EW, EO, ES, ME), capsules (e.g., CS, ZC), pastes, tablets, wettable powders or granules (e.g., WP, SP, WS, DP, DS), molded products (e.g., BR, TB, DT), granules (e.g., WG, SG, GR, FG, GG, MG), insecticides (e.g., LN), and gel formulations for treating plant propagation materials such as seeds (e.g., GF). These and other composition types are defined in "Catalogue of pesticide formulation types and international coding system," Technical Monograph, Vol. 2, 6th edition, May 2008, CropLife International.

[0260] The compositions are prepared in a known manner, for example as described in Mollet and Grubemann, Formulation technology, Wiley VCH, Weinheim, 2001; or Knowles, New developments in crop protection product formulation, Agrow Reports DS243, T&F Informa, London, 2005.

[0261] Suitable additives include solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetting agents, auxiliary agents, solvents, penetration enhancers, protective colloids, adhesives, thickeners, humectants, repellents, attractants, feeding stimulants, compatibilizers, bactericides, antifreeze agents, defoamers, colorants, tackifiers and binders.

[0262] Suitable solvents and liquid carriers are water and organic solvents. Suitable solid carriers or fillers are mineral soils.

[0263] Suitable surfactants are surface-active compounds, such as anionic, cationic, nonionic, and amphoteric surfactants, block polymers, and polyelectrolytes. These surfactants can be used as emulsifiers, dispersants, solvents, wetting agents, penetration enhancers, protective colloids, or auxiliaries. Surfactants are listed in McCutcheon's, Volume 1: Emulsifiers & Detergents, McCutcheon's Directories, Glen Rock, USA, 2008 (International or North American Ed.). Suitable anionic surfactants are alkali metal, alkaline earth metal, or ammonium salts of sulfonic acids, sulfuric acids, phosphoric acids, and carboxylic acids. Suitable nonionic surfactants are alkoxylates, N-substituted fatty acid amides, amine oxides, esters, glycosyl surfactants, and polymeric surfactants. Suitable cationic surfactants are quaternary surfactants.

[0264] Agricultural chemical compositions typically contain 0.01-95% by weight, preferably 0.1-90% by weight, and most preferably 0.5-75% by weight of an active substance. The active substance is used at a purity of 90-100%, preferably 95-100%.

[0265] Various types of oils, wetting agents, adjuvants, or fertilizers can be added as premixes to active substances or compositions containing them, or, if appropriate, added (in a barrel mix) just before use. These agents can be mixed with the compositions of the present invention at a weight ratio of 1:100 to 100:1.

[0266] Users typically use the compositions of this invention in pre-dosing devices, backpack sprayers, spray cans, spray aircraft, or irrigation systems. The agrochemical composition is usually formulated with water, buffers, and / or other adjuvants to the desired application concentration, thereby obtaining a ready-to-use spray or the agrochemical composition of this invention. 20-2000 liters of ready-to-use spray are typically applied per hectare of agricultural land.

[0267] Compound I is suitable for protecting crops, plants, plant propagation materials such as seeds, or soil or water bodies in which plants grow from animal pests. Therefore, the present invention also relates to a plant protection method comprising contacting the crop, plant, plant propagation material such as seeds, or soil or water body in which the plant is to be protected against animal pests from infestation or contamination with an insecticidal amount of Compound I.

[0268] Compound I is also suitable for the control or prevention of animal pests. Therefore, the present invention also relates to a method for the control or prevention of animal pests, comprising contacting an animal pest, its habitat, breeding ground or food source or crop, plant, plant propagation material such as seeds or soil, or an area, material or environment in which the animal pest grows or may grow, with an insecticidal effective amount of compound I.

[0269] Compound I is effective against any and all developmental stages, such as eggs, larvae, pupae, and adults, through contact with and uptake of both.

[0270] Compound I can be applied directly or in the form of a composition comprising them.

[0271] It can be applied to crops, plants, and plant propagation materials before and after pest infestation.

[0272] The term "contact" in this article includes both direct contact (the direct application of a compound / composition to animal pests or plants) and indirect contact (the application of a compound / composition to its location).

[0273] The term "animal pests" includes arthropods, gastropods, and nematodes. According to the invention, preferred animal pests are arthropods, especially insects and spiders, with insects being particularly important.

[0274] The term "plant" includes cereals such as durum wheat and other wheat, rye, barley, triticale, oats, rice, or corn (silage corn and sweet corn / corn, as well as field corn); beets such as sugar beets or fodder beets; fruits such as pome fruits, drupes, or berries such as apples, pears, plums, peaches, nectarines, almonds, cherries, papayas, strawberries, raspberries, blackberries, or gooseberries; legumes such as beans, lentils, peas, alfalfa, or soybeans; oilseed plants such as rapeseed (oilseed rape), rapeseed, mustard, olives, sunflowers, coconuts, cocoa beans, castor oil plants, oil palms, peanuts, or soybeans; cucurbitaceous plants such as squash, pumpkins, cucumbers, or melons; and fiber plants. Examples of wild animals include: cotton, flax, hemp, or jute; citrus fruits such as oranges, lemons, grapefruits, or tangerines; vegetables such as eggplants, spinach, lettuce (e.g., head lettuce), chicory, cabbage, asparagus, carrots, onions, garlic, leeks, tomatoes, potatoes, gourds, or bell peppers; laurels such as avocados, cinnamon, or camphor; energy and raw material plants such as corn, soybeans, rapeseed, sugarcane, or oil palm; tobacco; nuts such as walnuts; pistachios; coffee; tea; bananas; grapevines; hops; stevia; natural rubber plants or ornamental and forest plants, shrubs, broad-leaved or evergreen trees, eucalyptus; turf; lawns; grasses. Preferred plants include potatoes, sugar beets, tobacco, wheat, rye, barley, oats, rice, corn, cotton, soybeans, rapeseed, legumes, sunflowers, coffee, or sugarcane; fruits; grapevines; ornamental plants; or vegetables such as cucumbers, tomatoes, green beans, or squash.

[0275] The term "seed" includes seeds and plant propagules, including true seeds, seed slices, suckers, bulbs, tubers, fruits, tubers, grains, cuttings, and pruning branches, and preferably refers to true seeds.

[0276] "Pesticide effective dose" refers to the amount of active ingredient required to achieve an observable effect on growth, including necrosis, death, inhibition, prevention, and removal effects, as well as disruptive effects or effects that reduce the presence and activity of target organisms. The pesticide effective dose can vary for the various compounds / compositions used in this invention. The pesticide effective dose of a composition will also vary depending on key conditions such as the desired pesticidal effect and duration, climate, target species, location, and method of application.

[0277] For use in treating crops, for example by foliar application, the application rate of the active ingredient of the present invention can be 0.0001-4000 g / ha, for example 1 g-2 kg / ha or 1-750 g / ha, ideally in the range of 1-100 g / ha.

[0278] Compound I is also suitable for use against non-crop pests. For use against said non-crop pests, Compound I can be used as bait compositions, gels, general insect sprays, aerosols, ultra-low volume applications, and mosquito nets (impregnated or surface-applied).

[0279] The term "non-crop pests" refers to pests that are particularly relevant to non-crop targets, such as ants, termites, wasps, flies, ticks, mosquitoes, bedbugs, crickets, or cockroaches, such as Aedes aegypti, Musca domestica, and Tribolium spp.; termites such as Reticulitermes flavipes and Coptotermes formosanus; cockroaches such as Blatella germanica and Periplaneta americana; and ants such as Solenopsis invicta, Linepithemahumile, and Camponotus pennsylvanicus.

[0280] The bait can be a liquid, solid, or semi-solid formulation (e.g., a gel). For use in bait compositions, the typical content of the active ingredient is 0.001-15% by weight, ideally 0.001-5% by weight of the active compound.

[0281] Compound I and its compositions can be used to protect wood materials such as trees, fences, railway sleepers, frames, works of art, and buildings, as well as building materials, furniture, leather, fibers, vinyl products, wires and cables, from ants, termites and / or beetles that damage wood or textiles, and to prevent ants and termites from damaging crops or humans (e.g. when pests invade houses and public facilities or nest in yards, orchards or parks).

[0282] The conventional application rate for material protection is, for example, 0.001-2000 g or 0.01-1000 g of active compound / m³. 2 For the material being treated, ideally, the concentration of active compound is 0.1-50 g / m³. 2 The material being processed.

[0283] Insecticidal compositions used for impregnating materials typically contain 0.001-95% by weight, preferably 0.1-45% by weight, more preferably 1-25% by weight, at least one repellent and / or insecticide.

[0284] The compounds of this invention are particularly suitable for the effective control of animal pests, such as arthropods and nematodes, including:

[0285] Insects selected from the suborder Auchenorrhyncha, such as the small green leafhopper (Amrasca biguttula), the genus Empoasca spp., the two-spotted black-tailed leafhopper (Nephotettix virescens), the white-backed planthopper (Sogatellafurcifera), the genus Mahanarva spp., the gray planthopper (Laodelphax striatellus), the brown planthopper (Nilaparvata lugens), and the citrus psyllid (Diaphorina citri);

[0286] Lepidoptera, such as the genus *Helicoverpa*, *Heliothisvirescens*, *Lobesia botrana*, *Ostrinia nubilalis*, *Plutella xylostella*, *Pseudoplusia includens*, *Scirpophagaincertulas*, *Spodoptera*, *Trichoplusia ni*, *Tuta absoluta*, *Cnaphalocrocis medialis*, *Cydiapomonella*, *Chilo suppressalis*, *Anticarsia gemmatalis*, *Agrotis ipsilon*, and *Chrysodeixis includens*.

[0287] Stink bugs, such as those in the genus *Lygus* spp.; stink bugs such as those in the genus *Euschistus* spp.; *Halyomorpha halys*; *Nezara viridula*; *Piezodorus guildinii*; *Dichelops furcatus*.

[0288] Thrips, such as the genera *Frankliniella*, *Thrips*, and *Dichromothrips corbettii*;

[0289] Aphids, such as pea aphid (Acyrthosiphon pisum), aphid (Aphis spp.), peach aphid (Myzuspersicae), constrictor aphid (Rhopalosiphum spp.), wheat aphid (Schizaphis graminum), and nest aphid (Megoura viciae);

[0290] Whiteflies, such as the greenhouse whitefly (Trialeurodes vaporariorum) and the genus Bemisia spp.;

[0291] Coleoptera, including species such as *Phyllotreta* spp., *Melanotus* spp., *Meligethes aeneus*, *Leptinotarsadecimlineata*, *Ceutorhynchus* spp., *Diabrotica* spp., *Anthonomus grandis*, *Atomaria linearia*, *Agriotes* spp., and *Epilachna* spp.;

[0292] Flies, such as the genera *Delia*, *Ceratitis capitate*, *Bactrocera*, and *Liriomyza*.

[0293] The superfamily Coccoidea includes species such as the red round scale (Aonidiella aurantia) and Ferrisia virgate.

[0294] Arthropods (mites) of the class Arachnida, such as Penthhaleus major and Eotetranychus spp.;

[0295] Nematodes, such as soybean cyst nematode (Heterodera glycines), root-knot nematode (Meloidogynesp.), short-bodied nematode (Pratylenchus spp.), and Caenorhabditis elegans.

[0296] Compound I is suitable for treating or protecting animals from parasitic infestation or infection. Therefore, the present invention also relates to the use of the compound of the invention in the manufacture of medicaments for treating or protecting animals from parasitic infestation or infection. Furthermore, the present invention relates to a method for treating or protecting animals from parasitic infestation and infection, comprising administering orally, topically, or parenterally to an animal an effective amount of compound I for killing parasites.

[0297] This invention also relates to the non-therapeutic use of the compounds of this invention in the treatment or protection of animals against parasitic infestation and infection. Furthermore, this invention relates to a non-therapeutic method for treating or protecting animals against parasitic infestation and infection, comprising applying a parasite-killing effective amount of compound I to the site.

[0298] The compounds of the present invention are further suitable for the prevention or control of parasites in and on animals. Furthermore, the present invention relates to a method for the prevention or control of parasites in and on animals, comprising contacting the parasites with an effective amount of the compound of the present invention for killing parasites.

[0299] This invention also relates to the non-therapeutic use of compound I in the prevention or control of parasites. Furthermore, this invention relates to a non-therapeutic method for the prevention or control of parasites, comprising applying a parasite-killing effective amount of compound I to the site.

[0300] Compound I is effective through both contact (via soil, glass, walls, mosquito nets, carpets, blankets, or animal parts) and ingestion (e.g., bait). Furthermore, Compound I can be applied to any and all developmental stages.

[0301] Compound I can be applied directly or in the form of a composition comprising them.

[0302] The term “site” refers to a habitat, food source, breeding ground, or area, material, or environment in which parasites grow or may grow outside of animals.

[0303] As used herein, the term "parasite" includes both internal and external parasites. In some embodiments of the invention, internal parasites may be preferred. In other embodiments, external parasites may be preferred. Infections in warm-blooded animals and fish include lice, biting lice, ticks, sheep nasal fly larvae, sheep tick flies, chelicerae, houseflies, flies, maggot fly larvae, chiggers, black flies, mosquitoes, and fleas.

[0304] The compounds of this invention are particularly effective against the following parasites: temperate bed bug (Cimex lectularius), blood-red fan tick (Rhipicephalus sanguineus), and cat flea (Ctenocephalides felis).

[0305] The term "animal" as used herein includes warm-blooded animals (including humans) and fish. Preferred mammals include cattle, sheep, pigs, camels, deer, horses, piglets, poultry, rabbits, goats, dogs, and cats; buffalo, donkeys, fallow deer, and reindeer; as well as fur-bearing animals such as mink, chinchillas, and raccoons; birds such as hens, geese, turkeys, and ducks; and fish such as freshwater and saltwater fish such as salmon, carp, and eels. Domesticated animals, such as dogs or cats, are particularly preferred.

[0306] Compound I can be administered at a total dose of 0.5-100 mg / kg / day, preferably 1-50 mg / kg / day.

[0307] For oral administration to warm-blooded animals, compound I can be formulated into animal feed, animal feed premix, animal feed concentrate, pellets, solutions, pastes, suspensions, extracts, gels, tablets, large pellets, and capsules. For oral administration, the selected dosage form should provide the animal with 0.01-100 mg / kg body weight / day, preferably 0.5-100 mg / kg body weight / day of compound I.

[0308] Alternatively, compound I can be administered parenterally to animals, for example, via intracavitary, intramuscular, intravenous, or subcutaneous injection. Compound I can be dispersed or dissolved in a carrier physiologically acceptable for subcutaneous injection. Alternatively, compound I can be formulated into an implant for subcutaneous administration. Furthermore, compound I can be administered transdermally to animals. For parenteral administration, the selected dosage form should provide animals with 0.01-100 mg / kg body weight / day of compound I.

[0309] Compound I can also be administered topically to animals in the form of infusions, powders, granules, rings, medallions, sprays, shampoos, spot-on and pour-on formulations, as well as ointments, oil-in-water or water-in-oil emulsions. For topical application, infusions and sprays typically contain 0.5–5,000 ppm, preferably 1–3,000 ppm of Compound I. Furthermore, Compound I can be formulated into ear patches for animals, particularly tetrapods such as cattle and sheep.

[0310] The oral solution is administered directly.

[0311] The solution can be applied by dripping, rubbing, sprinkling, or spraying onto the skin.

[0312] Apply or coat the gel to the skin or introduce it into the body cavity.

[0313] Spray formulations are poured or sprayed onto a defined area of ​​skin, where the active compound penetrates the skin and acts via systemic absorption. Spray formulations are prepared by dissolving, suspending, or emulsifying the active compound in a suitable skin-compatible solvent or solvent mixture.

[0314] The emulsion can be administered orally, transdermally, or as an injection.

[0315] The suspension can be administered orally or topically / transdermally.

[0316] Semi-solid formulations can be administered orally or topically / transdermally.

[0317] To produce solid dosage forms, the active compound is mixed with a suitable excipient, and if appropriate, an adjuvant is added, and the desired dosage form is prepared.

[0318] The compositions that can be used in this invention typically contain about 0.001-95% of compound I.

[0319] The ready-to-use formulation contains a compound that acts on parasites, preferably ectoparasites, at a concentration of 10 ppm to 80 wt%, preferably 0.1 to 65 wt%, more preferably 1 to 50 wt%, and most preferably 5 to 40 wt%.

[0320] The preparation diluted before use contains a compound that acts on ectoparasites at a concentration of 0.5-90% by weight, preferably 1-50% by weight.

[0321] In addition, the formulation contains a compound of formula I that combats endoparasites at a concentration of 10 wt ppm to 2 wt%, preferably 0.05 to 0.9 wt%, and very particularly preferably 0.005 to 0.25 wt%.

[0322] The solid formulation that releases the compounds of the present invention can be administered over three weeks at a total amount of 10-300 mg / kg, preferably 20-200 mg / kg, and most preferably 25-160 mg / kg, based on the total body weight of the treated animal.

[0323] A. Preparation Examples

[0324] By appropriately modifying the starting materials and using the procedure given in the synthesis instructions, other compounds I were obtained. The compounds obtained in this manner, along with their physical data, are listed in the table below.

[0325] The products shown below were characterized by their mass ([m / z]) or retention time (RT; [min.]) determined by melting point determination, NMR spectroscopy, or HPLC-MS or HPLC spectroscopy.

[0326] HPLC-MS = Mass spectrometry coupled with high performance liquid chromatography;

[0327] HPLC Method A: Shimadzu LC2010, Column: Waters XBridge C18, 150mm × 4.6mm ID × 5μm; Mobile Phase: A: Water + 0.1% TFA; B: Acetonitrile + 0.1% TFA; Temperature: 40℃; Gradient: 10% B to 100% B in 5 min; 100% B for 2 min; 10% B for 3 min; Flow Rate: 1.4 ml / min; Run Time: 10 min; PDA Detector.

[0328] Example 1: 2-Chloro-N-(2,4-difluorophenyl)-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-iso [Azol-3-yl]amino]benzamide [I-38]

[0329] Step 1 At 0°C, n-BuLi (87.3 mL, 0.22 mol) was added to a solution of i-PrMgCl (99 mL, 0.20 mol) in THF (600 mL), followed by dropwise addition of 1-bromo-3-(trifluoromethyl)benzene (45 g, 0.20 mol) in THF (50 mL). The resulting mixture was stirred at 0°C for 30 min, at which point HPLC analysis showed the reaction was complete. Then, 2,2-trifluoro-N-methoxy-N-methylacetamide (94.5 g, 0.60 mol) was added dropwise at 0°C, and the reaction was heated to ambient temperature (20-25°C; RT) and stirred at this temperature for 3 h. The reaction mixture was poured into an NH4Cl solution (saturated aqueous solution, 600 mL), and the aqueous phase was extracted with EtOAc (3 × 400 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 400 mL), dried over Na2SO4, filtered, and concentrated to give 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]acetone (37 g, yield 77%) as a yellow oil, which can be used directly in the next step without further purification.

[0330] Step 2To a solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl ketone (37.0 g, 0.153 mol) in THF (400 mL), 2-diethoxyphosphonoacetonitrile (26.6 g, 0.153 mol), LiBr (13.3 g, 0.153 mol), and Et3N (31.0 g, 0.306 mol) were added at 20–25 °C. The resulting reaction mixture was then heated to 70 °C and stirred at this temperature for 16 h. The reaction mixture was then cooled to 20–25 °C, filtered, and the filtrate was extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 200 mL), dried on Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 5:1) to give (Z)-4,4,4-trifluoro-3-[3-(trifluoromethyl)phenyl]but-2-enonitrile (30 g, 75%) as a colorless oil.

[0331] 1 H-NMR (400MHz, CDCl3, RT): δ7.82 (br d, J=7.9Hz, 1H), 7.77 (s, 1H), 7.67-7.74 (m, 1H), 7.59-7.66 (m, 1H), 5.91-6.42 (m, 1H).

[0332] Step 3 Hydroxyurea (12.0 g, 0.159 mol) and NaOMe (10.7 g, 0.204 mol) were added in portions to a solution of (Z)-4,4,4-trifluoro-3-[3-(trifluoromethyl)phenyl]but-2-enonitrile (30 g, 0.11 mol) in MeOH (300 mL) at 25 °C. The resulting mixture was then heated to 80 °C and stirred at that temperature for 16 h. The reaction mixture was then poured into H2O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 100 mL), dried on Na2SO4, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 5:1) gave 5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate as a white solid. Azolium-3-amine (16g, 48%).

[0333] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.82 (br d, J=7.9Hz, 1H), 7.77 (s, 1H), 7.67-7.74 (m, 1H), 7.59-7.66 (m, 1H), 5.91-6.42 (m, 1H).

[0334] Step 4 At 20-25℃, 5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate iso ... Azolium-3-amine (5.00 g, 16.8 mmol) in 1,4-dioxane Pd₂(dba)₃ (1.54 g, 1.68 mmol, CAS No. 51364-51-3), Xantphos (1.45 g, 2.51 mmol, CAS No. 161265-03-8), Cs₂CO₃ (8.21 g, 25.2 mmol), and tert-butyl 5-bromo-2-chlorobenzoate (5.38 g, 18.5 mmol) were added to a solution of alkane (50 mL). The reaction mixture was then heated to 80 °C and stirred at that temperature for 16 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 × 40 mL), and the combined organic extracts were washed with NaCl solution (40 mL), dried over Na₂SO₄, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 3:1), 2-chloro-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate was given as a brown solid. tert-butyl benzoate (7.0 g, 88%).

[0335] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.79(br d, J=7.9Hz, 1H), 7.82 (s, 1H), 7.70 (d, J=7.8Hz, 1H), 7.53-7.62 (m, 3H), 7.34 ( d, J=8.5Hz, 1H), 3.93 (d, J=16.1Hz, 1H), 3.58 (d, J=16.1Hz, 1H), 1.61 (s, 9H).

[0336] Step 5 At 20-25℃, 2-chloro-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate is converted to ... I₂ (3.37 g, 13.3 mmol) was added to a solution of tert-butyl benzoate [3-yl]amino]benzoate (7.0 g, 13.3 mmol) in a mixture of MeCN (80 mL) and H₂O (1.0 mL), and the reaction was heated to 80 °C and stirred at that temperature for 16 h. The reaction mixture was poured into H₂O (100 mL), the pH was adjusted to 3 with HCl solution (2.0 N, in H₂O), the aqueous phase was extracted with EtOAc (3 × 80 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 80 mL), dried on Na₂SO₄, filtered and concentrated to give 2-chloro-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-iso [Azol-3-yl]amino]benzoic acid (4.0 g, 64%).

[0337] 1 H-NMR (400MHz, DMSO-d6, RT): δ10.3 (s, 1H), 9.58 (s, 1H), 7.83-7.97 (m, 3H), 7.69-7.80 (m, 2H), 7.47 (s, 2H), 7.63 (s, 1H), 3.79-4.18 (m, 2H).

[0338] Step 6 At 20-25℃, 2-chloro-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate is converted to ... [Azol-3-yl]amino]benzoic acid (1.0 g, 2.2 mmol) was added to a solution of HATU (1.26 g, 3.31 mmol, CAS No. 148893-10-1), Et3N (672 mg, 6.63 mmol), and 2,4-difluoroaniline (200 mg, 2.43 mmol) in DMF (10 mL), and the reaction mixture was stirred at this temperature for 16 h. The mixture was poured into H2O (10 mL), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 2 × 10 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 75:25), the title compound 2-chloro-N-(2,4-difluorophenyl)-5-[[5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4H-isocyanate was given as a yellow solid. [I-38](200 mg, 16%).

[0339] 1H NMR (400MHz, CDCl3, RT): δ10.3 (s, 1H), 9.59 (s, 1H), 7.85-7.98 (m, 3H), 7.70-7.82 (m, 2H), 7.64 (s, 1H), 7.48 (s, 2H), 7.32-7.41 (m, 1H), 7.14 (br t, J=7.8Hz, 1H), 3.78-4.16 (m, 2H).

[0340] Example 2: N-(1-cyanocyclopropyl)-3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-30]azol-3-yl]amino]-2,6-difluorobenzamide

[0341] Step 1 A solution of 1-bromo-3,5-dichlorobenzene (250 g, 0.960 mol) in THF (1.0 L) was added dropwise to a suspension of Mg(O) chips (27.7 g, 1.15 mol) in THF (300 mL) at 20-25 °C. The solution was then heated to 70 °C and stirred at that temperature for 1 h. The reaction mixture was then cooled to 0 °C, and 2,2,2-trifluoro-N-methoxy-N-methylacetamide was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at that temperature for 1 h. The resulting solution was quenched with NH4Cl solution (1.2 L saturated aqueous solution), the aqueous phase was extracted with EtOAc (3 × 500 mL), the combined organic extracts were washed with NaCl solution (2 × 1.2 L saturated aqueous solution), filtered, and concentrated. 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl ketone (300 g, 64%) was purified by distillation at 110 °C and under reduced pressure to a pale yellow oil. 1 H-NMR (400MHz, CDCl3, RT): δ=7.92 (d, J=1.0Hz, 2H), 7.70 (t, J=1.9Hz, 1H).

[0342] Step 2t-BuOK solution (1.0 M, 123 mL, 0.139 mol) was added dropwise to a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl ketone (25 g, 0.11 mol) and Ph3PMeBr (1.3 g, 12 mmol) in THF (400 mL) at 20–25 °C, and the mixture was stirred at this temperature for 2 h. The mixture was then quenched with H2O (1.0 L), the aqueous phase was extracted with EtOAc (3 × 300 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 1.0 L), dried on Na2SO4, filtered, and concentrated. Purification by column chromatography (petroleum ether [PE]) gave 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (70 g, 73%) as a yellow oil.

[0343] 1 H-NMR (400MHz, CDCl3, RT): δ7.41-7.39 (m, 1H), 7.36-7.34 (m, 2H), 6.07-6.03 (m, 1H), 5.84-5.81 (m, 1H).

[0344] Step 3 1,1-Dibromoformaldehyde oxime (22.5 g, 113 mmol) and NaHCO3 (78.1 g, 0.928 mol) were added to a solution of 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (22.0 g, 92.8 mmol) in EtOAc (220 mL) at 20-25 °C. The mixture was then heated to 50 °C and stirred at that temperature for 12 h. The reaction mixture was quenched with H2O (300 mL), extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 300 mL), dried on Na2SO4, filtered, and concentrated. Purification was achieved by preparation (petroleum ether) to give 3-bromo-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. Azole (64g, 63%).

[0345] 1 H-NMR (400MHz, CDCl3, RT): δ=7.48-7.44 (m, 1H), 7.44-7.38 (m, 2H), 3.92 (d, J=17.8Hz, 1H), 3.57 (dd, J=0.6, 17.8Hz, 1H).

[0346] Step 4 At 20-25℃, 3-bromo-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate iso ... A solution of azole (0.50 g, 1.38 mmol) in 2,4-dimethylpentan-3-ol (5.0 mL) was added with methyl 3-amino-2,6-difluorobenzoate (0.257 g, 1.38 mmol) and TsOH (0.183 g, 0.964 mmol). The mixture was then heated to 130 °C and stirred at this temperature for 16 h. At this point, LCMS showed approximately 30% of the desired compound. The reaction mixture was quenched with H₂O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 100 mL), dried on Na₂SO₄, filtered, and concentrated. The residue was purified by preparation (petroleum ether) to give 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a yellow solid. Methyl 2,6-difluorobenzoate (0.24 g, 38%).

[0347] 1 H-NMR (400MHz, CDCl3, RT): δ8.21 (dt, J=5.4, 9.4Hz, 1H), 7.48 (s, 2H), 7.46-7.42 (m, 1H), 6.98 (dt, J=1.8, 9.2Hz, 1H), 6.11 (br s, 1H), 3.94 (s, 1H), 3.59 (d, J=16.0Hz, 1H), 1.56 (s, 3H).

[0348] Step 5 At 20-25℃, 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] Methyl azole-3-yl]amino]-2,6-difluorobenzoate (1.10 g, 2.34 mmol) was added to a solution of methyl benzoate in THF (220 mL) with LiOH·H₂O (0.148 g, 3.52 mmol), and the mixture was heated to 70 °C and stirred at that temperature for 5 days. The reaction mixture was quenched with H₂O (200 mL), the aqueous phase was adjusted to pH 5 with aqueous HCl solution, and then extracted with EtOAc (3 × 60 mL). The combined organic extracts were washed with NaCl solution (200 mL), dried on Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (NH₄HCO₃) to give 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. [Azol-3-yl]amino]-2,6-difluorobenzoic acid (0.65 g, 61%).

[0349] 1H NMR (400MHz, CDCl3, RT): δ7.47 (s, 1H), 7.38 (s, 2H), 4.68 (br s, 2H), 3.48 (d, J=17.2Hz, 1H), 3.19 (br d, J=17.2Hz, 1H), 1.26 (s, 1H). Step 6 At 20-25℃, 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] [Azolium-3-yl]amino]-2,6-difluorobenzoic acid (0.30 g, 0.66 mmol) in MeCN (4.0 mL) was supplemented with 1-aminocyclopropaneformonitrile (93.5 mg, 0.793 mmol) and N,N,N',N'-tetramethylchloroformamidin. Hexafluorophosphate (“TCFH”) (0.278 g, 0.991 mmol) and N-methylimidazole (“NMI”) (0.217 g, 2.64 mmol) were added, and the reaction mixture was stirred at this temperature for 16 h. The reaction mixture was quenched with H2O (10 mL), filtered, and the filtrate was extracted with EtOAc (3 × 3.0 mL). The combined organic extracts were washed with NaCl solution (10 mL), dried on Na2SO4, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 100:0-65:35; gradient) gave the title compound N-(1-cyanocyclopropyl)-3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanopropyl) as a white solid. [I-30](0.116g, 34%).

[0350] 1 H-NMR (400MHz, methanol-d4, RT): δ8.12 (dt, J=5.7, 9.3Hz, 1H), 7.56 (s, 3H), 7.04 (dt, J=1.7, 9.0Hz, 1H), 4.86 (s, 47H), 3.98 (d, J=17.0Hz, 1H), 3.71 (d, J=17.0Hz, 1H), 1.63-1.57 (m, 2H), 1.34-1.31 (m, 2H).

[0351] Example 3: 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-48][azol-3-yl]amino]-N-(2,4-difluorophenyl)-2-fluorobenzamide

[0352] Step 1 At 20-25℃, 3-bromo-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate iso ... Azole (0.50 g, 1.38 mmol, prepared as described in Example 2; steps 1-3) was added to a solution of 2,4-dimethylpentane-3-ol (5.0 mL) with 3-bromo-2-fluoroaniline (0.178 g, 1.38 mmol) and TsOH (0.183 g, 0.964 mmol). The reaction was then heated to 120 °C and stirred at this temperature for 48 h. At this point, LCMS analysis showed approximately 20% of the desired product. The reaction mixture was quenched with H₂O (100 mL), filtered, and the filtrate was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with NaCl solution (100 mL saturated aqueous solution), dried on Na₂SO₄, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 100:0-90:10; gradient), it yielded N-(3-bromo-2-fluorophenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. Zolpidem (78 mg, 12%).

[0353] 1 H-NMR (400MHz, CDCl3, RT): δ8.04 (dt, J=1.3, 8.0Hz, 1H), 7.54-7.48 (m, 2H), 7.47-7.40 (m, 1H), 7.23-7.13 (m, 1H), 7.09-7.00 (m, 1H), 6.19 (br s, 1H), 4.03-3.92 (m, 1H), 3.60 (br d, J=16.1Hz, 1H).

[0354] Step 2 : To N-(3-bromo-2-fluorophenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso A solution of 3-oxalool-3-amine (500 mg, 1.06 mmol) in toluene (5.0 mL) was reacted with potassium vinyltrifluoroborate (212 mg, 1.59 mmol), t-Bu3P-Pd-G2 (54 mg, 0.11 mmol, CAS No. 1375325-71-5), and K2CO3 solution (0.525 mL, 2 M, in H2O). The reaction was then heated to 80 °C and stirred at that temperature for 12 h. The mixture was quenched with H2O (20 mL), filtered, and the filtrate was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried over Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 100:0-95:5; gradient) to give 5-(3,5-dichlorophenyl)-N-(2-fluoro-3-vinylphenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. Zyrazole-3-amine (286 mg, 65%).

[0355] 1 H NMR (400MHz, CDCl3, RT): δ7.94 (br t, J=7.1Hz, 1H), 7.50 (s, 2H), 7.45-7.41 (m, 1H), 7.18-7.08 (m, 2H), 6.85 (dd, J=11.2, 17.7Hz, 1H), 6.18 (br s, 1H), 5.83 (dd, J=0.8, 17.7Hz, 1H), 5.42 (dd, J=0.8, 11.2Hz, 1H), 3.97 (d, J=16.1Hz, 1H), 3.59 (br d, J=16.1Hz, 1H).

[0356] Step 3 At 0°C, 5-(3,5-dichlorophenyl)-N-(2-fluoro-3-vinylphenyl)-5-(trifluoromethyl)-4H-iso... A solution of 3-azolyl-3-amine (3.0 g, 7.2 mmol) in a mixture of THF (20 mL) and H₂O (10 mL) was mixed with N-methylmorpholine-N-oxide (2.01 g, 17.2 mmol), NaIO₄ (1.50 g, 7.02 mmol), and K₂O₅O₄ (21 mg, 0.006 mmol), and the resulting reaction mixture was stirred at 0–2 °C for 16 h. The mixture was then quenched with H₂O (30 mL), filtered, and the filtrate was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 30 mL), dried over Na₂SO₄, filtered, and concentrated to give 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a yellow solid. [3.0 g, crude product]azol-3-yl]amino]-2-fluorobenzaldehyde was used in the next step without further purification.

[0357] 1 H NMR (400MHz, CDCl3, RT): δ=10.3 (s, 1H), 8.37 (br t, J=8.1Hz, 1H), 7.54-7.45 (m, 4H), 7.46-7.40 (m, 1H), 6.36 (br s, 1H), 4.05-3.97 (m, 1H), 3.64 (br d, J=16.3Hz, 1H).

[0358] Step 4 At 20-25℃, 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] [Azol-3-yl]amino]-2-fluorobenzaldehyde (0.50 g, 1.2 mmol) in 1,4-di[ NaClO2 (0.214 g, 2.4 mmol) and NH3SO3 (46 mg, 4.8 mmol) were added to a solution of a mixture of alkane (3.6 mL) and H2O (1.2 mL), and the reaction mixture was stirred at this temperature for 40 min. The mixture was quenched with H2O (10 mL), filtered, and the filtrate was extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried on Na2SO4, filtered, and concentrated. Purification by preparative HPLC (TFA) yielded 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a yellow solid. [Azol-3-yl]amino]-2-fluorobenzoic acid (1.33 g, 52%).

[0359] 1 H NMR (400MHz, DMSO-d6, RT): δ=9.18 (d, J=1.8Hz, 1H), 8.13 (dt, J=1.5, 7.9Hz, 1H), 7.78 (t, J=1.8Hz, 1H) , 7.60 (d, J=1.6Hz, 2H), 7.46-7.36 (m, 1H), 7.23 (t, J=8.0Hz, 1H), 4.08-3.97 (m, 1H), 3.93-3.85 (m, 1H).

[0360] Step 5 At 20-25℃, 3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] [3-[ ... [I-48](53 mg, 13%). [I-3-yl]amino]-N-(2,4-difluorophenyl)-2-fluorobenzamide [I-48](53 mg, 13%).

[0361] 1 H-NMR (400MHz, CDCl3, RT): δ8.45 (dt, J=6.0, 9.1Hz, 1H), 8.36-8.29 (m, 1H), 7.78-7.67 (m, 1H), 7.51 (d, J=1.6Hz, 2H), 7. 48-7.43 (m, 1H), 7.39-7.30 (m, 1H), 6.99-6.88 (m, 2H), 6.30-6.23 (m, 1H), 3.99 (d, J=16.1Hz, 1H), 3.62 (d, J=16.0Hz, 1H).

[0362] Example 4: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)iso [I-114]azolidin-4-ylbenzamide

[0363] Synthesis of [(4R)-3-oxo-2-(2,2,2-trifluoroethyl)iso [Zolpidem-4-yl]ammonium chloride:

[0364] Step 1 At 20-25℃, (4R)-4-aminoisocyanate isomerization occurs. Triethylamine (5.20 g, 51.4 mmol) was added to a solution of 3-oxazolidinone (5.00 g, 49.0 mmol) in THF (75 mL) and water (50 mL). The reaction mixture was cooled to 10 °C and a solution of di-tert-butyl carbonate (11.2 g, 51.4 mmol) in THF (25 mL) was added dropwise. The resulting mixture was stirred at 20–25 °C for 18 h. THF was then removed under reduced pressure. The residue was treated with HCl solution (2.0 N, in H2O) until pH 2–3 was reached and stirred for 45 min. The resulting precipitate was filtered off, washed with H2O (2 × 20 mL) and cyclohexane (2 × 10 mL), and dried under reduced pressure at 40 °C to give N-[(4R)-3-oxoisocyanate] as a white solid. [4-yl] tert-butyl carbamate (5.32 g, 52%).

[0365] HPLC-MS (Method A): Retention time = 0.659 min, m / z = 285 ([M+H]). + ).

[0366] Step 2 At 20-25℃, N-[(4R)-3-oxoisocyanate] [4R-4-yl]tert-butyl carbamate (2.00 g, 9.89 mmol) was added to a solution of triethylamine (3.00 g, 29.7 mmol) in THF (30 mL). The reaction mixture was cooled to 0 °C and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (2.98 g, 12.9 mmol) was added. The resulting mixture was stirred at 20–25 °C for 96 h. The reaction was quenched in H₂O (20 mL), the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic extracts were washed with H₂O (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was dissolved in MTBE (20 mL). The precipitate was filtered off and dried under reduced pressure at 30 °C to give N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isocyanate as a white solid. [Zolpidem-4-yl] tert-butyl carbamate (1.32 g, 47%).

[0367] HPLC-MS (Method A): Retention time = 0.948 min, m / z = 229 ([M+H]). + ).

[0368] Step 3 At 0°C, N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isocyanate iso ... [4-yl] tert-butyl carbamate (1.32 g, 4.64 mmol) was added dropwise to a solution of 1,4-dichloromethane (10 mL) with HCl (4 M, in 1,4-di-di-methyl) In dichloromethane (4.64 mL, 18.6 mmol), the reaction mixture was stirred at 20–25 °C for 19 h and then concentrated under reduced pressure. The residue was redissolved in dichloromethane and concentrated under reduced pressure. The residue was redissolved in dichloromethane (3 mL), the precipitate was filtered off and dried under reduced pressure at 40 °C to give the title [(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isocyanate]. [Zolpidem-4-yl]ammonium chloride (906 mg, 88%).

[0369] 1 H-NMR (400MHz, DMSO-d6, RT): δ4.70 (d, J=8.7Hz, 1H), 4.61 (t, J=8.7Hz, 1H), 4.49 (q, J=9.1Hz, 2H), 4.34 (t, J=9.0Hz, 1H).

[0370] Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]benzoic acid:

[0371] Step 1 At 20-25℃, it reacts with 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate. Azoxyl-3-amine (1.5 g, 4.7 mmol, synthesized similarly as described above) and methyl 5-bromo-2-chlorobenzoate (1.18 g, 4.73 mmol) were synthesized in 1,4-dioxane. Tris(dibenzylacetone)dipalladium(O) (216 mg, 0.23 mmol), 4,5-di(diphenylphosphino)-9,9-dimethylxanthone (328 mg, 0.57 mmol), and Cs₂CO₃ (4.62 g, 14.2 mmol) were added to a solution of cyclohexane (50 mL). The resulting mixture was heated to 80 °C and stirred at that temperature for 5 h. After cooling to 20–25 °C, the reaction mixture was diluted with EtOAc (50 mL) and washed with ammonium chloride solution (saturated aqueous solution, 1 × 45 mL) and NaCl solution (saturated aqueous solution, 1 × 45 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, cyclohexane / EtOAc = 100:0–65:35) gave 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso Methyl benzoate [3-yl]amino]benzoate (1.12 g, 48%). HPLC-MS (Method A): Retention time = 1.392 min, m / z = 485 ([M+H) + ); 1 H-NMR (400MHz, CDCl3, RT): δ7.82 (d, J=2.8Hz, 1H), 7.57-7.45 (m, 3H), 7.36 (d, J=8. 8Hz, 1H), 6.28 (s, 1H), 3.92 (s, 3H), 3.89 (d, J=16.2Hz, 1H), 3.49 (d, J=16.1Hz, 1H).

[0372] Step 2 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. Methyl benzoate (1.12 g, 2.31 mmol) in THF (5.0 mL) and MeOH (5.0 mL) was reacted dropwise with a solution of LiOH (968 mg, 23.1 mmol) in H₂O (5 mL). HPLC-MS analysis after 4 h showed the reaction was complete. The reaction mixture was treated with HCl solution (2.0 N, in H₂O) until pH 1 was reached. The resulting mixture was extracted with EtOAc (3 × 5.0 mL). The organic phase was washed with NaCl solution (saturated aqueous solution, 25 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso...] [Azol-3-yl]amino]benzoic acid (1.10 g, quantitative). This crude product was used in the next step without further purification.

[0373] HPLC-MS (Method A): Retention time = 1.261 min, m / z = 472 ([M+H]). + ); 1 H-NMR (400MHz, DMSO-d6, RT): δ7.92 (d, J=2.6Hz, 1H), 7.84 (d, J=6.3Hz, 2H), 7.54-7.42 (m, 2H), 3.97 (d, J=17.1Hz, 1H), 3.86 (d, J=17.2Hz, 1H).

[0374] Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)iso [I-114]azolidin-4-yl]benzamide:

[0375] Step 1 At 20-25℃, the 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [3-yl]amino]benzoic acid (100 mg, 0.21 mmol) and [(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isocyanate] [Zolpidem-4-yl]ammonium chloride (56 mg, 0.21 mmol) was added to a solution of 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (50%, in EtOAc, 809 mg, 1.27 mmol), iPr2NEt (82 mg, 0.64 mmol), and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in CH2Cl2 (8.0 mL), and the resulting reaction mixture was stirred at this temperature for 3 h. Then CH2Cl2 (5.0 mL) was added, and the reaction mixture was washed with H2O (10 mL). The organic phase was separated, dried on Na2SO4, and evaporated under reduced pressure. Purified by column chromatography (SiO2, cyclohexane / EtOAc = 100:0-30:70), the substance yielded the title 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl-5-(trifluoromethyl)-4H-isocyanate] as a white waxy compound. [Azol-3-yl]amino]-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)iso [I-114] (70 mg, 52%).

[0376] HPLC-MS (Method A): Retention time = 1.303 min, m / z = 637 ([M+H]). + ); 1 H-NMR (500MHz, CDCl3, RT): δ7.62-7.56 (m, 1H), 7.43 (dd, J=6.6, 2.9Hz, 2H), 7.25 (t, J=2.7Hz, 1H), 7.17 (d, J=8.8Hz, 1H), 5.02 (p, J=7.7, 6.5Hz, 1H), 4. 81 (t, J=8.6Hz, 1H), 4.34 (t, J=10.5Hz, 1H), 4.24 (dt, J=16.3, 8.1Hz, 1H), 4 .13 (dt, J=15.8, 8.1Hz, 1H), 3.85 (d, J=16.5Hz, 1H), 3.49 (d, J=16.5Hz, 1H).

[0377] Example 5: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [[(4R)-2-ethyl-3-oxoiso]azol-3-yl]methylamino]-N-[(4R)-2-ethyl-3-oxoiso] [I-119]azolidin-4-ylbenzamide

[0378] Step 1At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. Methyl benzoate (200 mg, 0.41 mmol, prepared as described above) was added to a solution of acetonitrile (5.0 mL) with K₂CO₃ (114 mg, 0.82 mmol), followed by iodomethane (88 mg, 0.62 mmol). The reaction mixture was stirred at 20–25 °C for 5 days. HPLC-MS analysis showed that the reaction was complete at this point. The reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (3 × 5 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, cyclohexane / EtOAc = 100:0–50:50) yielded 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate as an oil. Methyl benzoate [3-yl]methylamino]benzoate (100 mg, 49%).

[0379] HPLC-MS (Method A): Retention time = 1.426 min, m / z = 500 ([M+H]) + ); 1 H-NMR (400MHz, CDCl3, RT): δ7.62 (d, J=2.7Hz, 1H), 7.52-7.46 (m, 3H), 7.24 (dd, J=8.6 , 2.8Hz, 1H), 3.95 (s, 3H), 3.65 (d, J=16.5Hz, 1H), 3.30 (s, 3H), 3.20 (d, J=16.5Hz, 1H).

[0380] Step 2 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. Methyl benzoate [3-yl]methylamino]benzoate (191 mg, 0.38 mmol) was reacted dropwise with a solution of LiOH·H₂O (160 mg, 3.80 mmol) in H₂O (2.0 mL) in THF (2.0 mL) and MeOH (2.0 mL). HPLC-MS analysis after 4 h showed the reaction was complete. The reaction mixture was treated with HCl solution (2.0 N, in H₂O) until pH 1 was reached and concentrated under reduced pressure. The residue was dissolved in H₂O (10 mL), the aqueous phase was extracted with EtOAc (2 × 5 mL), the combined organic extracts were washed with H₂O (5 mL) and NaCl solution (saturated aqueous solution, 5 mL), dried on Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]methylamino]benzoic acid (130 mg, 70%).

[0381] HPLC-MS (Method A): Retention time = 1.267 min, m / z = 485 ([M+H]). + ); 1 H-NMR (500MHz, methanol-d4, RT): δ7.71 (d, J=2.5Hz, 1H), 7.66 (d, J=6.2Hz, 2H), 7.52 (d, J=8.6Hz, 1 H), 7.41 (dd, J=8.6, 2.6Hz, 1H), 3.82 (d, J=17.0Hz, 1H), 3.59 (d, J=17.0Hz, 1H), 3.28 (s, 3H).

[0382] Step 3 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. [3-yl]azolyl]methylamino]benzoic acid (40 mg, 0.08 mmol) and (4R)-4-amino-2-ethylisocyanate A solution of 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (50%, in EtOAc, 414 mg, 0.49 mmol) was added to CH2Cl2 (8.0 mL), followed by iPr2NEt (32 mg, 0.25 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The resulting reaction mixture was stirred at 20–25 °C for 2 h. Then, CH2Cl2 (5 mL) was added and the reaction mixture was washed with H2O (10 mL). The organic phase was dried over Na2SO4 and evaporated under reduced pressure. 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate was purified by column chromatography (SiO2, cyclohexane / EtOAc = 100:0-0:100) to give the product. [[(4R)-2-ethyl-3-oxoiso]azol-3-yl]methylamino]-N-[(4R)-2-ethyl-3-oxoiso] [I-119] (34 mg, 69%).

[0383] HPLC-MS (Method A): Retention time = 1.268 min, m / z = 597 ([M+H]). + ); 1 H-NMR (500MHz, CDCl3, RT): δ7.52 (t, J=2.6Hz, 1H), 7.49 (d, J=5.9Hz, 2H), 7.45 (d, J=8.6Hz, 1H), 7.19 (dd, J=8.6, 2.7Hz, 1H), 4.96 (t, J=8.3Hz, 1H), 4.8 8 (dddd, J=10.3, 8.0, 4.3, 2.0Hz, 1H), 4.07 (dd, J=10.6, 8.6Hz, 1H), 3.74-3. 60 (m, 2H), 3.29 (s, 3H), 3.18 (dd, J=16.5, 3.3Hz, 1H), 1.27 (t, J=7.1Hz, 3H).

[0384] Example 6: Synthesis of 2-chloro-N-(1-cyano-1-methylethyl)-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]benzamide [I-58]

[0385] Step 1 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. A solution of 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazene 2,4,6-trioxide (50%, in EtOAc, 810 mg, 1.27 mmol) was added to CH2Cl2 (8.0 mL), followed by 4-dimethylaminopyridine (78 mg, 0.64 mmol). The reaction mixture was heated to 100 °C in a microwave oven and maintained for 45 min. HPLC-MS analysis at this point indicated that the reaction was complete. The reaction mixture was cooled to 20–25 °C, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, cyclohexane / EtOAc = 100:0-0:100, gradient) to give 2-chloro-N-(1-cyano-1-methylethyl)-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [I-58](53 mg, 46%).

[0386] HPLC-MS (Method A): Retention time = 1.295 min, m / z = 538 ([M+H]). + ); 1 H-NMR (400MHz, methanol-d4, RT): δ7.71 (d, J=6.2Hz, 2H), 7.55 (d, J=2.5Hz, 1H), 7.44 (dd, J=8.8, 2.7Hz, 1 H), 7.36 (d, J=8.8Hz, 1H), 3.95 (d, J=16.8Hz, 1H), 3.70 (d, J=16.8Hz, 1H), 2.15 (s, 3H), 1.75 (s, 3H).

[0387] Example 7: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [I-62][azol-3-yl]amino]-N-(4-fluoro-3-pyridyl)benzamide

[0388] Step 1 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. [Azoxyl-3-yl]amino]benzoic acid (100 mg, 0.21 mmol, prepared as described above) and (4-fluoro-3-pyridyl)ammonium chloride (38 mg, 0.25 mmol) in CH2Cl2 (6.0 mL) were reacted with 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (50%, in EtOAc, 810 mg, 1.27 mmol), followed by iPr2NEt (82 mg, 0.64 mmol) and 4-dimethylaminopyridine (78 mg, 0.64 mmol). The reaction mixture was heated to 40 °C in a microwave oven and maintained for 30 min. HPLC-MS analysis at this point indicated that the reaction was complete. The reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (3 × 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (RP, MeCN / H2O = 0:100-100:0, gradient) to obtain 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [I-62](16 mg, 13%). [I-62](16 mg, 13%).

[0389] HPLC-MS (Method A): Retention time = 1.205 min, m / z = 566.9 ([M+H]) + ); 1 1H-NMR (400MHz, methanol-d4, RT): δ 9.13 (d, J = 9.4Hz, 1H), 8.46–8.38 (m, 1H), 7.74–7.67 (m, 3H), 7.50 (dd, J = 8.8, 2.7Hz, 1H), 7.45–7.32 (m, 2H), 3.97 (d, J = 16.8Hz, 1H), 3.72 (d, J = 16.8Hz, 1H).

[0390] Example 8: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-N-[1-(difluoromethylsulfonyl)azacyclobutane-3-yl]benzamide [I-41]

[0391] Step 1A solution of difluoromethanesulfonyl chloride (1.75 g, 11.6 mmol) in CH2Cl2 (5.0 mL) was added dropwise to a solution of N-(azircyclobutane-3-yl)carbamate (1.00 g, 5.81 mmol) and iPr2NEt (1.88 g, 14.5 mmol) in CH2Cl2 (10 mL) under an argon atmosphere, and the resulting mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 20–25 °C and stirred at this temperature for 1 h, followed by quenching with water (20 mL). The organic phase was separated, dried on Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (NH2- column, cyclohexane / EtOAc = 100:0–50:50, gradient) yielded N-[1-(difluoromethanesulfonyl)azircyclobutane-3-yl]carbamate (386 mg, 23%).

[0392] HPLC-MS (Method A): Retention time = 0.889 min, m / z = 256 ([M+H]). + ); 1 H-NMR (400MHz, CDCl3, RT): δ4.97 (s, 1H), 4.58 (s, 1H), 4.39 (t, J = 8.1Hz, 2H), 4.15-4.07 (m, 2H), 1.45 (s, 9H).

[0393] Step 2 [1-(difluoromethanesulfonyl)azacyclobutane-3-yl]ammonium chloride: Dissolve N-[1-(difluoromethanesulfonyl)azacyclobutane-3-yl]tert-butyl carbamate (386 mg, 1.35 mmol) in HCl solution (4 N, in 1,4-di... The mixture was stirred in 15 mL of alkane at 20–25 °C for 17 h. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in CH₂Cl₂ and concentrated under reduced pressure (3×) to give [1-(difluoromethylsulfonyl)azacyclobutane-3-yl]ammonium chloride (367 mg, quantitative). The crude product was used in the next step without further purification.

[0394] 1 H-NMR (400MHz, methanol-d4, RT): δ 4.46 (t, J = 7.8Hz, 2H), 4.25-4.18 (m, 2H).

[0395] Step 3 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. [Azolium-3-yl]amino]benzoic acid (100 mg, 0.21 mmol, prepared as described in the examples above) and [1-(difluoromethylsulfonyl)azacyclobutane-3-yl]ammonium chloride (59 mg, 0.27 mmol) were added to a solution of bromo(tripyrrolidine-1-yl) in CH2Cl2 (6.0 mL). Hexafluorophosphate (124 mg, 0.27 mmol) and iPr2NEt (110 mg, 0.85 mmol). The resulting reaction mixture was stirred at this temperature for 17 h, and then concentrated under reduced pressure. Purification by column chromatography (RP, MeCN / H2O = 0:100-100:0, gradient) gave 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a beige solid. [I-41](69 mg, 43%).

[0396] HPLC-MS (Method A): Retention time = 1.304 min, m / z = 641 ([M+H]) + ); 1 ¹H-NMR (500 MHz, methanol-d⁴, RT): δ 7.69 (d, J = 6.1 Hz, 2H), 7.59 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 8.8, 2.7 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.45 (t, J = 8.1 Hz, 2H), 4.28–4.22 (m, 2H), 3.95 (d, J = 16.7 Hz, 1H), 3.70 (d, J = 16.8 Hz, 1H). Example 9: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-N-[1-(trifluoromethylsulfonyl)azacyclobutane-3-yl]benzamide [I-77]

[0397] Step 1A solution of trifluoromethanesulfonyl chloride (979 mg, 5.81 mmol) in CH2Cl2 (5.0 mL) was added dropwise to a solution of N-(azacyclobutane-3-yl)carbamate (500 mg, 2.90 mmol) and iPr2NEt (938 mg, 7.26 mmol) in CH2Cl2 (10 mL) under an argon atmosphere at 0 °C, and the resulting mixture was stirred at this temperature for 1 h. The reaction mixture was then heated to 20–25 °C and stirred at this temperature for 1.5 h, followed by quenching with H2O (10 mL). The organic phase was separated, dried on Na2SO4, filtered, and concentrated under reduced pressure to give N-[1-(trifluoromethanesulfonyl)azacyclobutane-3-yl]carbamate (806 mg, 91%) as a white solid.

[0398] 1 H-NMR (400MHz, CDCl3, RT): δ5.09 (s, 1H), 4.60 (s, 1H), 4.42 (t, J = 8.1Hz, 2H), 4.17-4.09 (m, 2H), 1.45 (s, 9H).

[0399] Step 2 : Dissolve N-[1-(trifluoromethanesulfonyl)azacyclobutane-3-yl]carbamate tert-butyl ester (806 mg, 2.65 mmol) in HCl (4 N, in 1,4-di... In alkane, add 20 mL and stir overnight at 20-25 °C. Filter off the resulting precipitate and dilute with 1,4-dicarboxylic acid. Washed with alkane and dried under reduced pressure, the product was given as a white solid [1-(trifluoromethylsulfonyl)azacyclobutane-3-yl]ammonium chloride (483 mg, 76%). 1 H-NMR (400MHz, DMSO-d6, RT): δ8.87 (s, 3H), 4.46-4.31 (m, 4H), 4.27-4.16 (m, 1H).

[0400] Step 3 At 20-25℃, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. A solution of 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane-3-yl]ammonium chloride (51 mg, 0.21 mmol) in CH2Cl2 (6.0 mL) was reacted with 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (405 mg, 0.64 mmol), followed by iPr2NEt (55 mg, 0.42 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol). The resulting reaction mixture was stirred at 20–25 °C for 2 h. Then, CH2Cl2 (5.0 mL) was added, and the reaction mixture was washed with water (10 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purified by column chromatography (SiO2, cyclohexane / EtOAc = 100:0-60:40, gradient) to obtain 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate] in beige wax. [I-77](34 mg, 49%).

[0401] HPLC-MS (Method A): Retention time = 1.365 min, m / z = 658 ([M+H]) + ); 1 H-NMR (400MHz, CDCl3, RT): δ7.52-7.44(m, 2H), 7.37-7.28(m, 2H), 7.15(d, J=8.9Hz, 1H), 4.85-4.74(m, 1H), 4.47(t, J=8.3Hz, 2H), 4.33 (dd, J=10.4, 3.9Hz, 2H), 3.84 (d, J=16.5Hz, 1H), 3.49 (d, J=16.5Hz, 1H), 1.91 (s, 1H), 1.43 (s, 1H).

[0402] Example 10: Synthesis of 2-chloro-N-(1-cyanocyclopropyl)-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]benzamide [I-60]

[0403] Step 1To a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl ketone (30.0 g, 0.123 mol) in THF (400 mL), 2-diethoxyphosphonoacetonitrile (21.7 g, 0.125 mmol), Et3N (34.8 g, 246 mmol), and LiBr (10.8 g, 0.123 mol) were added. The resulting reaction mixture was then heated to 70 °C and stirred at that temperature for 16 h. The reaction mixture was poured into H2O (300 mL), and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with NaCl solution (2 × 150 mL), dried over Na2SO4, filtered, and concentrated. (Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enonitrile (29.0 g, 88%) was obtained as a brown oil by column chromatography (petroleum ether / EtOAc = 10:1).

[0404] 1 H-NMR (400MHz, CDCl3, RT): δ7.49-7.55 (m, 1H), 7.40 (d, J=1.4Hz, 1H), 7.33 (s, 1H), 5.96-6.31 (m, 1H).

[0405] Step 2 NaOMe (8.16 g, 0.155 mol) and hydroxyurea (8.61 g, 0.114 mol) were added to a solution of (Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enonitrile (29.0 g, 0.104 mol) in MeOH (300 mL) at 20-25 °C. The reaction was then heated to 80 °C and stirred at this temperature for 16 h. The mixture was then poured into H2O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 100 mL), dried on Na2SO4, filtered, and concentrated to give 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. Zyrazole-3-amine (22g, 70%).

[0406] 1 H-NMR (400MHz, CDCl3, RT): δ7.45 (s, 2H), 7.40-7.43 (m, 1H), 4.07 (br s, 2H), 3.68-3.74 (m, 1H), 3.34 (d, J=16.4Hz, 1H).

[0407] Step 3 At 20-25℃, it reacts with 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate. Azolium-3-amine (10.0 g, 33.4 mmol) in 1,4-dioxane Pd₂(dba)₃ (3.06 g, 3.34 mmol, CAS No. 51364-51-3), Xantphos (2.90 g, 5.02 mmol, CAS No. 161265-03-8), Cs₂CO₃ (16.4 g, 50.2 mmol), and tert-butyl 5-bromo-2-chlorobenzoate (10.7 g, 36.7 mmol) were added to a solution of alkane (100 mL). The reaction mixture was then heated to 80 °C and stirred at that temperature for 16 h. The mixture was poured into H₂O (80 mL), extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 80 mL), dried on Na₂SO₄, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 3:1), 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was given as a brown solid. tert-butyl benzoate (12.0 g, 71%).

[0408] 1 H-NMR (400MHz, DMSO-d6, RT): δ9.61 (s, 1H), 7.76 (d, J = 2.43Hz, 2H), 7.65 (s, 2H), 7.44-7.48 (m, 2H), 3.74-3.98 (m, 2H), 1.54 (s, 9H). Step 4 At 0°C, 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate iso ... [3-yl]amino]tert-butyl benzoate (1.00 g, 1.96 mmol) was added in portions to a solution of NaH (0.157 g, 3.92 mmol) in DMF (10 mL), and the mixture was stirred at this temperature for 0.5 h. Bromomethylcyclopropane (0.397 g, 2.94 mmol) was added, and the reaction was heated to 20–25 °C and stirred at this temperature for 16 h. The mixture was poured into H₂O (10 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried on Na₂SO₄, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 1:1) and preparative HPLC yielded 2-chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a brown solid. tert-butyl benzoate (700 mg, 59%).

[0409] 1 H-NMR (400MHz, CDCl3, RT): δ7.44-7.56 (m, 2H), 7.39 (s, 3H), 7.16-7.26 (m, 1H), 3.75 (ddd, J=6.62, 4.17, 2.51Hz, 1H ), 3.47-3.55 (m, 2H), 3.08-3.18 (m, 1H), 1.62 (s, 9H), 1.01-1.13 (m, 1H), 0.47 (d, J=7.91Hz, 2H), -0.01-0.21 (m, 2H).

[0410] Step 5 At 20-25℃, 2-chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was used to convert the chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] I2 (316 mg, 1.25 mmol) was added to a solution of tert-butyl benzoate [3-yl]amino]benzoate (700 mg, 1.25 mmol) in MeCN (8.0 mL) and H2O (1.0 mL). The reaction mixture was then heated to 80 °C and stirred at that temperature for 16 h. The mixture was poured into H2O (10 mL), the pH of the aqueous phase was adjusted to 3 with HCl (2.0 N, in H2O), and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried on Na2SO4, filtered, and concentrated to give 2-chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a brown solid. [Azol-3-yl]amino]benzoic acid (0.30 g, 47%).

[0411] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.64-7.68 (m, 1H), 7.39-7.59 (m, 3H), 7.12-7 .21(m, 1H), 6.96-7.03(m, 1H), 3.44-3.64(m, 4H), 0.43-0.59(m, 1H), 0.30(br d, J=8.00Hz, 2H), 0.00(br s, 2H).

[0412] Step 6 At 20-25℃, 2-chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was used to convert the chloro-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] [3-yl]amino]benzoic acid (300 mg, 0.592 mmol) was added to a solution in MeCN (5.0 mL) with NMI (195 mg, 4.70 mmol), TCFH (301 mg, 0.892 mmol), and 1-aminocyclopropaneformonitrile (134 mg, 2.10 mmol), and the resulting reaction mixture was stirred at this temperature for 18 h. The reaction mixture was quenched in H2O (10 mL), and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with NaCl solution (40 mL, saturated aqueous solution), dried over Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 1:1) to give the title 2-chloro-N-(1-cyanocyclopropyl)-5-[cyclopropylmethyl-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyano[] [I-60](220 mg, 65%).

[0413] 1 H-NMR (400MHz, DMSO-d6, RT): δ9.34 (s, 1H), 7.70-7.83 (m, 1H), 7.51-7.61 (m, 3H), 7.41-7.48 (m, 2H), 3.51 (d, J=6.88Hz, 2H), 1.54-1.60 (m, 2H), 1.23-1.32 (m, 2H), 0.91-1.04 (m, 1H), 0.32-0.43 (m, 2H), 0.02-0.13 (m, 2H).

[0414] Example 11: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [I-61][azol-3-yl]amino]-N-(1-oxothioheterocyclic butane-3-yl)benzamide

[0415] Step 1 At -78°C, 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. [Azolium-3-yl]amino]-N-(thiocyclobutane-3-yl)benzamide (161 mg, 0.3 mmol; synthesized similarly as described in the examples above) was added to a solution of 3-chloroperoxybenzoic acid (66 mg, 0.3 mmol) in CH2Cl2 (10 mL). The cooling bath was removed and the resulting mixture was heated to -20 °C over 30 min. The reaction mixture was quenched with Na2S2O3 solution (2.0 mL saturated aqueous solution) and NaHCO3 solution (10 mL saturated aqueous solution), and the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude residue was recrystallized from CH2Cl2 to give 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [I-61](102 mg, 62%).

[0416] HPLC-MS (Method A): Retention time = 1.090 min, m / z = 519 ([M+H]) + ); 1 H-NMR (400MHz, methanol-d4, RT): δ7.70 (d, J=6.2Hz, 2H), 7.60 (d, J=2.5Hz, 1H), 7.42-7.35 (m, 2H), 4.56 (tt, J=10.2, 7 .5Hz, 1H), 4.22 (ddt, J=11.7, 7.4, 2.6Hz, 2H), 3.95 (d, J=16.8Hz, 1H), 3.82-3.66 (m, 2H), 3.35 (d, J=3.1Hz, 1H).

[0417] Example 12: Synthesis of N-(3-amino-2,4-difluorophenyl)-2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]benzamide [I-4]

[0418] Step 1 : To 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azolium-3-yl]amino]benzoic acid (18.0 g, 39.6 mmol, prepared similarly as described in the examples above) and N-(3-amino-2,6-difluorophenyl)-N-tert-butoxycarbonylcarbamate tert-butyl ester (12.0 g, 34.8 mmol, prepared as described in WO2016 / 168059) were added to a solution in MeCN (100 mL) along with TFCH (14.7 g, 52.3 mmol) and NMI (3.79 g, 69.8 mmol), and the resulting reaction mixture was stirred at 50 °C for 16 h. The mixture was poured into H2O (200 mL), and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with H2O (3 × 20 mL) and NaCl solution (saturated aqueous solution, 2 × 20 mL), dried on Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 3:1) to give N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-yl]amino]benzoyl]amino]-2,6-difluorophenyl]carbamate tert-butyl ester (12.5 g, 46%).

[0419] 1 H-NMR (400MHz, DMSO-d6, RT): δ10.4 (1H, s), 9.58 (1H, s), 7.75-7.62 (1H, m), 7.62 (3H, m), 7.44 (2 H, s), 7.25-7.20 (1H, s), 6.73-6.67 (1H, t, J=8.8Hz), 3.93 (2H, q, J=17.2, 27.2Hz), 1.37 (18H, m).

[0420] Step 2 : To N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-amino]azolyl]amino]2,6-difluorophenyl]carbamate tert-butyl ester (24 g, 31 mmol) was added to a solution of EtOAc (50 mL) and EtOAc / HCl (300 mL) was added. The reaction was stirred at 20-25 °C for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was recrystallized from MTBE (10 mL) to give N-(3-amino-2,4-difluorophenyl)-2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-4](13.0 g, 73%).

[0421] 1H-NMR (400MHz, DMSO-d6, RT): δ10.1 (1H, s), 9.51 (1H, s), 7.79-7.65 (2H, m), 7.61 (3H, m), 7.40 (1H, s), 6.92-6.87 (1H, m), 6.87-6.75 (1H, m), 5.30 (2H, s), 3.99-3.33 (2H, m).

[0422] Example 13: Synthesis of 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-N-[3-[(2,2-difluoroacetyl)amino]-2,4-difluorophenyl]benzamide [I-6]

[0423] Step 1 : To N-(3-amino-2,4-difluorophenyl)-2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azolium-3-yl]amino]benzamide (700 mg, 1.20 mmol, prepared as described above) and 2,2-difluoroacetic acid (190 mg, 1.98 mmol) in a solution of MeCN (10 mL) were reacted with NMI (380 mg, 4.63 mmol) and TFCH (556 mg, 1.98 mmol). The resulting reaction was heated to 80 °C and stirred at this temperature for 16 hours. The mixture was poured into H2O (20 mL), and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with H2O (3 × 20 mL) and NaCl solution (saturated aqueous solution, 1 × 20 mL), dried on Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc = 3:1) and preparative HPLC to give 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-6](90 mg, 23%). [3-[(2,2-difluoroacetyl)amino]-2,4-difluorophenyl]benzamide [I-6](90 mg, 23%).

[0424] 1 H-NMR (400MHz, DMSO-d6, RT): δ10.8 (1H, s), 10.45 (1H, s), 9.63 (1H, s), 7.79-7.78 (1H, s), 7.71-7. 69 (1H, s), 7.65 (3H, m), 7.48-7.48 (2H, m), 7.27-7.24 (1H, s), 6.68-6.41 (1H, m), 3.99-3.86 (2H, m).

[0425] Example 14: Synthesis of 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [1-(1-methylpyrazol-4-yl)cyclopropyl]benzamide [I-125]

[0426] Step 1 : To 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Azoxyl-3-amine (8.00 g, 26.8 mmol, synthesized similarly to the examples above) and Et3N (11.0 g, 107 mmol) were added to a solution of Boc2O (17.6 g, 80.5 mmol) and DMAP (654 mg, 5.36 mmol) in THF (80 mL), and the resulting reaction mixture was stirred at 20 °C for 16 h. The mixture was poured into H2O (120 mL), extracted with EtOAc (2 × 30 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purified by column chromatography (petroleum ether / EtOAc = 3:1), it gave N-tert-butoxycarbonyl-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-yl] tert-butyl carbamate (12.7 g, 96%).

[0427] Step 2 At 20-25℃, N-tert-butoxycarbonyl-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-[ ... [3-yl] tert-butyl carbamate (9.08 g, 75%).

[0428] Step 3 : To N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-yl]-tert-butyl carbamate (6.00 g, 15.1 mmol) was added to a solution of K₂CO₃ (6.30 g, 45.3 mmol) and MeI (4.40 g, 30.1 mmol) in MeCN (60 mL). The reaction mixture was then heated to 60 °C and stirred at that temperature for 16 h. The mixture was poured into H₂O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with NaCl solution (saturated aqueous solution, 1 × 30 mL), dried over Na₂SO₄, filtered, and concentrated. Purification was achieved by column chromatography (petroleum ether / EtOAc = 3:1) to give N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a brown solid. tert-butyl azole-3-yl]-N-methylcarbamate (5.58 g, 94%).

[0429] Step 4 At 0°C, N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] [3-yl]-N-methylcarbamate tert-butyl ester (8.55 g, 2.08 mmol) was added to a solution of HCl (4.0 M, 200 mL, in EtOAc) in 30 mL of EtOAc. The reaction mixture was then heated to 20–25 °C and stirred at this temperature for 16 h. The mixture was concentrated and the crude product was purified by column chromatography (petroleum ether / EtOAc = 3:1) to give 5-(3,5-dichlorophenyl)-N-methyl-5-(trifluoromethyl)-4H-isocyanate as a white solid. Azolium-3-amine (5.55g, 85%).

[0430] 1 H-NMR (400MHz, CDCl3, RT): δ7.47 (br s, 2H), 7.40 (s, 1H), 3.75 (br s, 1H), 3.36 (br s, 1H), 2.93 (br s, 3H).

[0431] Step 5 : 5-(3,5-dichlorophenyl)-N-methyl-5-(trifluoromethyl)-4H-isocyanate under an argon atmosphere at 20-25℃ Azoxyl-3-amine (2.00 g, 6.39 mmol) and methyl 5-bromo-2-chlorobenzoate (1.59 g, 6.39 mmol) in 1,4-dioxane Cs₂CO₃ (6.24 g, 19.2 mmol) was added to a solution of cyclohexane (40 mL), followed by 4,6-di(diphenylphosphino)-9,9-dimethylxanthone (443 mg, 0.77 mmol) and tris(dibenzylacetone)dipalladium(O) (292 mg, 0.32 mmol). The reaction mixture was heated to 80 °C and stirred overnight at that temperature. The mixture was cooled to 20–25 °C, diluted with EtOAc (50 mL), and the organic phase was washed with NH₄Cl solution (saturated aqueous solution, 1 × 40 mL), NaCl solution (saturated aqueous solution, 1 × 40 mL), dried over Na₂SO₄, filtered, and concentrated. 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was purified by column chromatography (SiO₂, cyclohexane / EtOAc = 100:0–65:35) to obtain 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate]. Methyl benzoate [3.17 g, quantitative].

[0432] HPLC-MS (Method A): Retention time = 1.413 min, m / z = 481 ([M+H]) + ); 1 H-NMR (400MHz, CDCl3, RT): δ7.61 (d, J=2.7Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.40 (q, J=1.6Hz, 3H ), 7.29-7.19 (m, 1H), 3.95 (s, 3H), 3.63 (d, J=16.5Hz, 1H), 3.29 (s, 3H), 3.20 (d, J=16.6Hz, 1H).

[0433] Step 6 At 20-25℃, 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. Methyl benzoate [3.17 g, 6.58 mmol] azole-3-yl]methylamino]benzoate was reacted dropwise with a solution of LiOH (2.76 g, 65.81 mmol) in H2O (10 mL) in THF (20 mL) and MeOH (20 mL). HPLC-MS analysis after 4 hours showed the reaction was complete. The reaction mixture was treated with HCl solution (2.0 N, in H2O) until pH 1 was reached and concentrated. The residue was dissolved in H2O (5.0 mL) and the aqueous phase was extracted with ethyl acetate (3 × 5 mL). The combined organic extracts were washed with H2O (1 × 5 mL) and NaCl solution (saturated aqueous solution, 1 × 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a yellow solid. [Azol-3-yl]methylamino]benzoic acid (2.52 g, 82%).

[0434] HPLC-MS (Method A): Retention time = 1.266 min, m / z = 467 ([M+H]) + ); 1 H-NMR (400MHz, methanol-d4, RT): δ7.71 (d, J=2.7Hz, 1H), 7.52 (d, J=8.2Hz, 4H), 7.40 (d d, J=8.6, 2.8Hz, 1H), 3.82 (d, J=17.0Hz, 1H), 3.58 (d, J=17.0Hz, 1H), 3.28 (s, 3H).

[0435] Step 7 At 20-25℃, 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. A solution of 1-(1-methyl-1H-pyrazol-4-yl)cyclopropylamine (35 mg, 0.26 mmol) in CH2Cl2 (6.0 mL) was reacted with 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (50%, in EtOAc, 816 mg, 1.28 mmol) and DMAP (78 mg, 0.64 mmol), and the resulting reaction mixture was stirred at this temperature for 3 h. Then, CH2Cl2 (5 mL) was added, the organic phase was washed with H2O (1 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. 2-Chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was purified by column chromatography (SiO2, cyclohexane / EtOAc = 100:0-0:100) to obtain 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate]. [1-(1-methylpyrazol-4-yl)cyclopropyl]benzamide [I-125] (96 mg, 77%).

[0436] HPLC-MS (Method A): Retention time = 1.260 min, m / z = 588 ([M+H]) + )

[0437] 1H-NMR (500MHz, CDCl3, RT): δ7.47-7.41 (m, 2H), 7.39 (s, 4H), 7.15 (dd, J=8.6, 2.8Hz, 1H), 7.06 (s, 1H), 3.83 (s, 3H) ), 3.64 (d, J=16.6Hz, 1H), 3.26 (s, 3H), 3.21 (d, J=16.6Hz, 1H), 2.00 (s, 1H), 1.30-1.24 (m, 2H), 1.21-1.15 (m, 2H).

[0438] Example 15: Synthesis of N-[4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-111] ethyl carbamate [I-111] and N-[4-chloro-3-[(1-cyanocyclopropyl)ethoxycarbonylcarbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azolium-3-yl]ethyl carbamate [I-100]

[0439] Step 1 At 0°C, 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanopropyl] [Zyrazo-3-yl]amino]benzamide (1.00 g, 1.98 mmol, synthesized similarly to the examples above) was added dropwise to a solution of NaH (93.0 mg, 3.88 mmol) in DMF (10 mL), and the reaction mixture was stirred at this temperature for 0.5 h. Ethyl chloroformate (413 mg, 3.88 mmol) was added dropwise at 0 °C, and the reaction was then heated to 20–25 °C and stirred at this temperature for 16 h. The mixture was poured into H₂O (10 mL), the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The sample was separated and purified by column chromatography (petroleum ether / EtOAc = 1:1) and preparative HPLC to obtain N-[4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyano[] as a white solid. [3-yl]carbamate ethyl ester [I-111] (140 mg, 28%) and give N-[4-chloro-3-[(1-cyanocyclopropyl)ethoxycarbonylcarbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-100] ethyl 3-azolyl carbamate (166 mg, 29%).

[0440] N-[4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyano] [I-111] ethyl carbamate [I-111]:

[0441] 1 H-NMR (400MHz, DMSO-d6, RT): δ9.51 (s, 1H), 7.80 (t, J=1.88Hz, 1H), 7.56-7.69 (m, 3H), 7.40-7.55 (m, 2H), 4.50 (d, J=1 8.51Hz, 1H), 4.26 (d, J=18.51Hz, 1H), 4.11-4.18 (m, 2H), 1.50-1.62 (m, 2H), 1.20-1.32 (m, 2H), 1.16 (t, J=7.07Hz, 3H).

[0442] N-[4-chloro-3-[(1-cyanocyclopropyl)ethoxycarbonylcarbamoyl]phenyl]-N-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso...] [I-100] ethyl carbamate [I-100]: 1 H-NMR (400MHz, DMSO-d6, RT): δppm 7.79 (t, J=1.81Hz, 1H), 7.63 (d, J=1.50Hz, 2H), 7.56-7.60 (m, 2H), 7.48-7.52 (m, 1H), 4.47 (d, J=18.51Hz, 1H), 4.23 (d, J=18.51Hz, 1H) , 4.14 (q, J=7.00Hz, 2H), 4.05 (q, J=7.21Hz, 2H), 1.85-1.90 (m, 2H), 1.47-1.58 (m, 2H), 1.14 (t, J=7.07Hz, 3H), 0.93 (t, J=7.13Hz, 3H).

[0443] Example 16: Synthesis of 2-chloro-5-[[5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-iso [I-131]azol-3-yl]amino]-N-(2,4-difluorophenyl)benzamide

[0444] Step 1At -20°C, iPrMgCl·LiCl solution (1.3M, in THF, 150mL, 0.191mol) was added dropwise to a solution of 1,3-dichloro-5-iodobenzene (40.0g, 0.147mol) in MTBE (600mL), and the resulting mixture was stirred at this temperature for 2h. Then, methyl 2-chloro-2,2-difluoroacetate (32.0g, 0.220mol) was added dropwise to the above mixture, the cooling bath was removed, and stirring was continued at 20-25°C for 16h. The resulting mixture was poured into H2O (500mL), the aqueous phase was extracted with MTBE (2×200mL), the combined organic extracts were washed with H2O (1×300mL) and NaCl solution (saturated aqueous solution, 1×300mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 100:1), 2-chloro-1-(3,5-dichlorophenyl)-2,2-difluoroethyl ketone (10 g, 26%) was obtained as a yellow oil.

[0445] 1 H NMR (400MHz, CDCl3, RT): δppm 7.97 (s, 2H), 7.67-7.71 (m, 1H) Step 2 t-BuOK (6.4 g, 58 mmol) was slowly added to a mixture of 2-chloro-1-(3,5-dichlorophenyl)-2,2-difluoroethyl ketone (10 g, 38.6 mmol) and Ph3PMeBr (20 g, 57.9 mmol) in THF (200 mL) at 0 °C and under a N2 atmosphere. The cooling bath was removed, and the reaction mixture was stirred at 20–25 °C for 16 h. The reaction mixture was poured into H2O (500 mL), and the aqueous phase was extracted with MTBE (2 × 200 mL). The combined organic extracts were washed with H2O (1 × 300 mL) and NaCl solution (saturated aqueous solution, 1 × 300 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 100:1), 1,3-dichloro-5-[1-[chloro(difluoro)methyl]vinyl]benzene (18 g, 61%) was obtained as a yellow oil.

[0446] 1 H-NMR (400MHz, CDCl3, RT): δppm 7.41 (t, J=1.8Hz, 1H), 7.36 (d, J=1.8Hz, 2H), 6.00 (s, 1H), 5.66 (t, J=1.6Hz, 1H).

[0447] Step 3NaHCO3 (2.5 g, 29 mmol) and ethyl 2-chloro-2-hydroxyiminoacetate (4.4 g, 29 mmol) were added in a single addition to a solution of 1,3-dichloro-5-[1-[chloro(difluoro)methyl]vinyl]benzene (5.0 g, 19 mmol) in EtOAc (100 mL) at 20–25 °C under a N2 atmosphere. The reaction mixture was then heated to 50 °C and stirred at that temperature for 16 h. The reaction mixture was poured into water (500 mL), and the aqueous phase was extracted with MTBE (2 × 200 mL). The combined organic extracts were washed with water (300 mL) and NaCl solution (saturated aqueous solution, 1 × 300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (SiO2, petroleum ether / EtOAc = 10:1) to give 5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-iso Ethyl 3-azole carboxylate (4.07 g, 56%).

[0448] 1 H-NMR (400MHz, CDCl3, RT): δppm 7.41-7.52 (m, 3H), 4.37 (q, J=7.1Hz, 2H), 4.01 (d, J=18.5Hz, 1H), 3.60 (d, J=18.5Hz, 1H), 1.38 (t, J=7.1Hz, 3H).

[0449] Step 4 At 0°C, 5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate iso ... Ethyl 3-carboxylate (10 g, 22 mol) in THF (150 mL) was added dropwise to LiOH·H2O (4.3 g, 107 mmol) in H2O (40 mL) and stirred for 4 h. The resulting mixture was poured into water H2O (30 mL) and THF was removed under reduced pressure and at 35 °C. The pH of the residue was adjusted to about 2-3 with HCl solution (2.0 N, in H2O, 50 mL) at 0 °C. The aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure to give 5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate as a yellow solid. Azoxyl-3-carboxylic acid (crude) can be used in the next step without further purification. 1H-NMR (400MHz, DMSO-d6, RT): δ 8.01 (s, 1H), 7.74 (s, 3H), 3.93-4.01 (m, 1H), 3.36 (br d, J = 16.9Hz, 1H).

[0450] Step 5 At 20-25℃, 5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate isomerized. A solution of 3-oxazolium-3-carboxylic acid (3.0 g, 8.1 mmol) in THF (60 mL) was added in one step with iPr2NEt (2.25 g, 17.4 mmol), 2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphazenecyclohexane 2,4,6-trioxide (“T3P”) (7.2 g, 11 mmol), and (H3C)3SiN3 (1.3 g, 11 mmol), and the reaction mixture was stirred at this temperature for 30 min. Then t-BuOH (2.5 g, 34.8 mmol) was added, and the mixture was heated to 70 °C and stirred at this temperature for 16 h. The resulting mixture was poured into water (H2O) (500 mL), and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with H2O (1 × 300 mL) and NaCl solution (saturated aqueous solution, 1 × 300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (SiO2, petroleum ether / EtOAc = 5:1) to give N-[5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate as a yellow solid. [3-yl] tert-butyl carbamate (1.9 g, 56%).

[0451] 1 H-NMR (400MHz, CDCl3, RT): δ7.48 (s, 2H), 7.41 (s, 1H), 7.11 (br s, 1H), 4.28 (d, J=18.4Hz, 1H), 3.88 (d, J=18.5Hz, 1H), 1.50 (s, 9H).

[0452] Step 6 At 20-25℃, N-[5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate isomerization is carried out. [3-yl]-tert-butyl carbamate (5.0 g, 12 mmol) was added in a single addition of HCl / EtOAc (100 mL) to a solution in EtOAc (50 mL), and the reaction mixture was stirred at this temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a NaHCO3 solution (saturated aqueous solution, 1 × 50 mL). The aqueous phase was extracted with EtOAc (2 × 100 mL), and the combined organic extracts were washed with H2O (300 mL) and NaCl solution (saturated aqueous solution, 1 × 300 mL), dried on Na2SO4, filtered, and concentrated. The residue was prepared with n-hexane (50 mL), filtered, and the filter cake was concentrated to give 5-[chloro(difluoro)methyl]-5-(3,5-dichlorophenyl)-4H-isocyanate as a pale yellow solid. Zyrazole-3-amine (2.5g, 67%).

[0453] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.74 (s, 1H), 7.58 (s, 2H), 6.00 (s, 2H), 3.61-3.69 (m, 1H), 3.48-3.55 (m, 1H).

[0454] The product can then be further converted into, for example, compound I-131, similar to the embodiments described above.

[0455] Example 17: Synthesis of tert-butyl 5-bromo-2-(trifluoromethoxy)benzoate

[0456] Step 1 A solution of 1-bromo-4-(trifluoromethoxy)benzene (10.0 g, 41.5 mmol) in THF (60.0 mL) was slowly added to (iPr)₂NLi solution (2.0 M, in THF, 24.9 mL) at -60 °C under a N₂ atmosphere, and the resulting mixture was stirred at this temperature for 2 h. Then, solid CO₂ (18.3 g, 415 mmol) was added, and the mixture was heated to 20–25 °C and stirred at this temperature for 16 h. The solvent was evaporated, and the crude product was dissolved in NaOH solution (1.0 N, in H₂O, 15.0 mL). The aqueous phase was washed with CH₂Cl₂ (3 × 20 mL) and the pH was adjusted to approximately 3–4 with HCl solution (4.0 M, in H₂O). The resulting suspension was filtered, and the filter cake was washed with H2O (2 × 5.0 mL) and dried under vacuum to give 5-bromo-2-(trifluoromethoxy)benzoic acid (5.70 g, 48%) as a white solid.

[0457] 1H-NMR (400MHz, DMSO-d6, RT): δ8.04 (d, J=2.80Hz, 1H), 7.92 (dd, J=2.40Hz, 1H), 7.47-7.45 (m, 1H).

[0458] Step 2 H₂SO₄ (1.79 g, 18.2 mmol, 973 μL) was added to a suspension of MgSO₄ (8.78 g, 73.0 mmol) in CH₂Cl₂ (30 mL) at 20–25 °C. After 10 min, 5-bromo-2-(trifluoromethoxy)benzoic acid (5.20 g, 18.2 mmol) and t-BuOH (6.76 g, 91.2 mmol, 8.72 mL) were added. The resulting mixture was stirred at 20–25 °C for 48 h. The mixture was quenched with NaHCO₃ solution (50 mL saturated aqueous solution), extracted with EtOAc (3 × 25 mL), dried over Na₂SO₄, filtered, and concentrated. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 50:1-3:1), tert-butyl 5-bromo-2-(trifluoromethoxy)benzoate (4.20 g, 68%) was obtained as a light yellow oil.

[0459] 1 H-NMR (400MHz, CDCl3, RT): δ 8.00 (d, J=2.40Hz, 1H), 7.64 (dd, J=2.40Hz, 1H), 7.18 (d, J=8.40Hz, 1H), 1.59 (s, 9H).

[0460] The product can then be further converted into compounds such as I-70, I-71, I-72, I-87, and I-103, similar to the examples above.

[0461] Example 18: Synthesis of 2-cyano-3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyano-[] [Azol-3-yl]amino]benzoic acid Step 1 LiOH·H2O (5.24 g, 124 mmol) was added to a solution of methyl 3-bromo-2-iodobenzoate (30.0 g, 124 mmol) in THF (60.0 mL) and H2O (60.0 mL) at 20-25 °C, and the resulting mixture was stirred at this temperature for 12 h. The pH of the mixture was then adjusted to 1-2 with HCl solution (1.0 N, in H2O), and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried on Na2SO4, filtered, and concentrated to give 3-bromo-2-iodobenzoic acid (27.0 g, 91%) as a yellow oil.

[0462] 1 H-NMR (400MHz, CDCl3, RT): δ7.84-7.82 (m, 1H), 7.74-7.72 (m, 1H), 7.33-7.30 (m, 1H).

[0463] Step 2 H₂SO₄ (8.10 g, 82.5 mmol) was added to a suspension of MgSO₄ (39.7 g, 330 mmol) in CH₂Cl₂ (190 mL) at 20–25 °C. After 15 min, 3-bromo-2-iodobenzoic acid (27.0 g, 82.5 mmol) and t-BuOH (30.6 g, 412 mmol) were added, and the resulting mixture was stirred at this temperature for 16 h. The mixture was poured into a NaHCO₃ solution (saturated aqueous solution, 150 mL), and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 100:1–1:1) gave tert-butyl 3-bromo-2-iodobenzoate (29.0 g, 91%) as a white solid.

[0464] 1 H-NMR (400MHz, CDCl3, RT): δ7.70-7.67 (m, 1H), 7.37-7.34 (m, 1H), 7.24 (d, J=8.0Hz, 1H), 1.62 (s, 9H).

[0465] Step 3 CuCN (8.14 g, 90.8 mmol) was added to a solution of tert-butyl 3-bromo-2-iodobenzoate (29.0 g, 75.7 mmol) in N-methyl-2-pyrrolidone (300 mL) at 20–25 °C. The resulting mixture was heated to 60 °C and stirred at this temperature for 5 h. The reaction mixture was then filtered, the filter cake was washed with EtOAc (3 × 70 mL), and the combined filtrates were concentrated under reduced pressure. Purification by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1–3 / 1) gave tert-butyl 3-bromo-2-cyanobenzoate (18.0 g, 83%) as a white solid.

[0466] 1 H-NMR (400MHz, CDCl3, RT): δ 8.01-7.99 (m, 1H), 7.87-7.85 (m, 1H), 7.52-7.48 (m, 1H), 1.65 (s, 9H).

[0467] Step 4: 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate under N2 atmosphere at 20-25℃ Azoxyl-3-amine (10.0 g, 33.4 mmol) and tert-butyl 3-bromo-2-cyanobenzoate (9.91 g, 35.1 mmol) in 1,4-dioxane Xantphos (2.90 g, 5.02 mmol), Cs₂CO₃ (16.3 g, 50.1 mmol), and Pd₂(dba)₃ (3.06 g, 3.34 mmol) were added to a solution of alkane (60.0 mL). The resulting mixture was heated to 80 °C and stirred at that temperature for 18 h. The reaction mixture was filtered, the filter cake was washed with EtOAc (2 × 80 mL), and the combined filtrates were concentrated. Purification was performed by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1-1 / 1) to give 2-cyano-3-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyano] as a white solid. tert-butyl benzoate (6.00 g, 36%).

[0468] 1 H-NMR (400MHz, CDCl3, RT): δ9.14 (s, 1H), 8.19 (d, J = 12.0Hz, 1H), 7.78-7.73 (m, 2H), 7.64-7.62 (m, 3H), 4.23-3.93 (m, 2H), 1.54 (s, 9H).

[0469] The product can then be further converted into, for example, compounds I-82, I-86, I-93, and I-94, similar to the embodiments described above.

[0470] Example 19: Synthesis of 3-chloro-6-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Zol-3-yl]amino]pyridine-2-carboxylic acid Step 1After 15 min, 3,6-dichloropyridine-2-carboxylic acid (10.0 g, 52.1 mmol) and t-BuOH (19.3 g, 260 mmol, 24.9 mL) were added to a suspension of MgSO4 (25.1 g, 208 mmol) and H2SO4 (5.11 g, 52.1 mmol, 2.78 mL) in CH2Cl2 (70 mL) at 20–25 °C, and the resulting reaction mixture was stirred at this temperature for 24 h. The reaction mixture was quenched by adding NaHCO3 solution (50 mL saturated aqueous solution), the aqueous phase was extracted with EtOAc (2 × 50 mL), the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 30:1-3:1), tert-butyl 3,6-dichloropyridine-2-carboxylate (9.60 g, 74%) was given as a yellow solid.

[0471] 1 H-NMR (400MHz, CDCl3, RT): δ7.70 (d, J=8.4Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 6.84 (d, J=8.8Hz, 1H), 1.63 (s, 9H).

[0472] Step 2 : Under a nitrogen atmosphere, 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate iso ... Azoxyl-3-amine (10.0 g, 33.4 mmol) and tert-butyl 3,6-dichloropyridine-2-carboxylate (8.30 g, 33.4 mmol) in 1,4-di- Cs₂CO₃ (16.4 g, 50.2 mmol), Xantphos (2.90 g, 5.02 mmol), and Pd₂(dba)₃ (3.06 g, 3.34 mmol) were added to a solution of alkane (200 mL). The reaction mixture was then heated to 80 °C and stirred at that temperature for 24 h. The mixture was then filtered and concentrated. Purified by column chromatography (SiO₂, petroleum ether / EtOAc = 100:1-1:1) to give 3-chloro-6-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a yellow solid. tert-butyl azole-3-yl]amino]pyridine-2-carboxylate (9.60 g, 74%).

[0473] 1 H-NMR (400MHz, CDCl3, RT): δ7.55 (d, J=2.0Hz, 4H), 7.28 (d, J=2.0Hz, 1H), 3.78-3.71 (m, 2H), 1.69 (s, 9H).

[0474] Step 3 : 3-chloro-6-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [3-yl]amino]pyridine-2-carboxylic acid tert-butyl ester (7.00 g, 13.7 mmol) was dissolved in F3CCO2H (35.0 mL), heated to 40 °C, and stirred at this temperature for 12 h. The mixture was then poured into water (10 mL), and the resulting solid was washed with water (2 × 15 mL) and dried. Purification by reversed-phase HPLC (neutral conditions) yielded 3-chloro-6-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a pink solid. [Azol-3-yl]amino]pyridine-2-carboxylic acid (2.25 g, 45%).

[0475] 1 H-NMR (400MHz, CDCl3, RT): δ7.83-7.75 (m, 2H), 7.64-7.59 (m, 3H), 7.30 (s, 1H), 4.01-3.59-3.76 (m, 2H).

[0476] The product can then be further converted into compounds such as I-80, I-83, and I-96, similar to the examples above.

[0477] Example 20: Synthesis of methyl 5-bromo-2-(difluoromethoxy)benzoate

[0478] Step 1 Sodium dichlorofluoroacetate (79.1 g, 519 mmol) was added to a solution of methyl 5-bromo-2-hydroxybenzoate (100 g, 432 mmol) and Na₂CO₃ (55.0 g, 518 mmol) in DMF (1.0 L) at 20–25 °C. The mixture was then heated to 90 °C and stirred at this temperature for 14 hours. The reaction mixture was then cooled to 20–25 °C, the pH was adjusted to 6–7 with HCl solution (1.0 M, in H₂O), and the aqueous phase was extracted with EtOAc (2 × 500 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 100:1–1:1) gave methyl 5-bromo-2-(difluoromethoxy)benzoate (15.0 g, 6%) as a yellow oil.

[0479] 1 H-NMR (400MHz, CDCl3): δ8.00 (d, J=4.0Hz, 1H), 7.64-7.61 (m, H), 7.15 (d, J=4.0Hz, 1H), 6.55-6.36 (m, 1H), 3.92 (s, 1H).

[0480] The product can then be further converted into, for example, compounds I-65, I-67, I-74, I-95, and I-105, similar to the examples above.

[0481] Example 21: Synthesis of methyl 5-bromo-2-(trifluoromethyl)benzoate

[0482] Step 1 A mixture of methyl 5-bromo-2-iodobenzoate (20.0 g, 58.6 mmol), methyl 2,2-difluoro-2-fluorosulfonyl acetate (16.9 g, 87.9 mmol), and CuBr (1.01 g, 7.04 mmol) in N-methyl-2-pyrrolidone (120 mL) was degassed and purged with N2 (3×) at 20–25 °C. The mixture was then heated to 100 °C and stirred at that temperature for 18 h. The reaction mixture was then cooled to 20–25 °C, filtered, and the filter cake was washed with EtOAc (3×100 mL). The combined filtrates were diluted with H2O (100 mL), the phases were separated, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Methyl 5-bromo-2-(trifluoromethyl)benzoate (15.0 g, 72%) was purified by column chromatography (SiO2, petroleum ether / EtOAc = 50:1-3:1) to obtain a light yellow oil.

[0483] 1 H-NMR (400MHz, CDCl3, RT): δ7.93 (s, 1H), 7.74-7.72 (m, 1H), 7.60 (d, J=8.0Hz, 1H), 3.94 (s, 3H).

[0484] The product can then be further converted into compounds such as I-66, I-79, and I-107, similar to the examples above.

[0485] Example 22: Synthesis of (1-isocyanate) (Azol-4-ylcyclopropyl)ammonium chloride

[0486] Step 1 : At -70℃ and in a N2 atmosphere, it can be directed towards different A solution of 200 mg, 2.13 mmol, and Ti(Oi-Pr)₄ (665 mg, 2.34 mmol) in Et₂O (10 mL) was added dropwise with EtMgBr solution (3.0 M, 1.49 mL, 4.46 mmol in Et₂O). The mixture was stirred at this temperature for 10 min, then warmed to 20–25 °C and stirred at this temperature for an additional 0.5 h. BF₃·Et₂O (604 mg, 4.25 mmol) was then added and the mixture was stirred at 20–25 °C for another 1 h. The reaction mixture was quenched with ice water (10 mL) and filtered to give 1-isocyanate as a yellow solution. Azolium-4-ylcyclopropylamine is used directly in the next step.

[0487] Step 2 : To 1-different Azoxyl-4-ylcyclopropylamine (550 mg, 4.43 mmol, from the theoretical yield of the prior reaction) was added to a solution of THF (10 mL) and H₂O (10 mL) with NaOH (6.0 M, 3.69 mL in H₂O) and Boc₂O (4.83 g, 22.2 mmol), and the resulting mixture was stirred at 20–25 °C for 15 h. The reaction mixture was then extracted with EtOAc (3 × 10 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (SiO₂, petroleum ether / EtOAc = 99:1–66:33; gradient) to give N-(1-isocyclopropylamine) as a pale yellow solid. tert-butyl 4-azolo-cyclopropyl)carbamate (0.6 g, 60%).

[0488] 1 H NMR (400MHz, CDCl3, RT): δ8.28 (br s, 1H), 8.19 (br s, 1H), 5.31-5.07 (m, 1H), 1.44 (s, 9H), 1.24-1.18 (m, 2H), 1.11-1.02 (m, 2H). Step 3 : N-(1-iso tert-butyl 4-(4-ylcyclopropyl)carbamate in HCl / di The solution in alkane (4.0 N, 2.0 mL) was stirred at 20–25 °C for 15 h. Then MTBE (50 mL) was added, and the mixture was stirred for 10 min, followed by filtration. The filter cake was dried under reduced pressure to obtain (1-isocyanate) as a pale yellow solid. Azolium-4-ylcyclopropyl)ammonium chloride (240 mg, 57%).

[0489] 1H-NMR (400MHz, DMSO-d6, RT): δ9.18 (br s, 3H), 9.06 (s, 1H), 8.80 (s, 1H), 1.51-1.30 (m, 2H), 1.22-1.02 (m, 2H).

[0490] The product can then be further converted into, for example, compounds I-163 and I-164, similar to the examples above.

[0491] Example 23: Synthesis of (1- (Azol-4-ylcyclopropyl)ammonium chloride

[0492] Step 1 : At -70℃ and in a N2 atmosphere A solution of EtMgBr (3.0 M, 3.70 mL, 11.1 mmol) was added dropwise to a solution of azole-4-carboxynitrile (500 mg, 5.30 mmol) and Ti(Oi-Pr)4 (1.66 g, 5.83 mmol) in Et2O (25 mL). The mixture was stirred at this temperature for 10 min, then warmed to 20–25 °C and stirred at this temperature for an additional 1 h. The mixture was cooled to 0 °C, BF3·Et2O (1.51 g, 10.6 mmol) was added, and the mixture was stirred at 20–25 °C for 1 h. The reaction mixture was then quenched at 0 °C with ice water (25 mL) and filtered to give a yellow solution of 1- Azolium-4-ylcyclopropylamine is used directly in the next step.

[0493] Step 2 : To 1- Azoxyl-4-ylcyclopropylamine (660 mg, 5.32 mmol) was added to a solution of MeCN (25 mL) and H2O (25 mL) with NaOH (6.0 M, 4.43 mL in H2O) and Boc2O (5.8 g, 26.6 mmol). The mixture was stirred at 20–25 °C for 15 h. The mixture was then extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (SiO2, petroleum ether / EtOAc = 99:1–50:50) to give N-(1-) a yellow solid. tert-butyl 4-azolo-cyclopropyl)carbamate (360 mg, 30%).

[0494] 1H-NMR (400MHz, DMSO-d6, RT): δ 8.20 (s, 1H), 7.65 (br d, J = 12.8Hz, 2H), 1.44-1.33 (m, 9H), 1.17-1.07 (m, 2H), 1.04-0.93 (m, 2H).

[0495] Step 3 : N-(1- tert-butyl 4-(4-ylcyclopropyl)carbamate (360 mg, 1.62 mmol) in HCl / dioxane The solution in alkane (4.0 M, 4.0 mL) was stirred at 20–25 °C for 15 h. Then MTBE (50 mL) was added, and the mixture was stirred for another 10 min, followed by filtration. The filter cake was dried under reduced pressure to obtain (1-) a light red solid. Azolium-4-ylcyclopropyl)ammonium chloride (260 mg, crude).

[0496] 1 H-NMR (400MHz, DMSO-d6, RT): δ11.5 (br s, 1H), 9.23 (br s, 3H), 8.42 (d, J=0.9Hz, 1H), 8.17 (d, J=0.9Hz, 1H), 1.50-1.35 (m, 2H), 1.25-1.04 (m, 2H).

[0497] The product can then be further converted into, for example, compounds I-152 and I-155, similar to the examples above.

[0498] Example 24: Synthesis of 1-[1-(ethoxymethyl)pyrazol-4-yl]cyclopropylamine

[0499] Step 1 NaH (60% by weight, 1.03 g, 25.8 mmol in mineral oil) was added dropwise to a solution of 1H-pyrazole-4-carboxynitrile (2.00 g, 21.5 mmol) in DMF (20 mL) under a N2 atmosphere at 0 °C. The mixture was stirred at this temperature for 30 min, and then chloromethoxyethane (2.40 g, 25.8 mmol) was added dropwise to DMF (20 mL). The mixture was gradually heated to 20–25 °C and stirred at this temperature for 15 h. The reaction mixture was then poured into ice water (100 mL), extracted with MTBE (3 × 20 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 99:1-33:66), 1-(ethoxymethyl)pyrazole-4-carboxynitrile (2.10 g, 65%) was given as a white solid.

[0500] 1 H-NMR (400MHz, CDCl3, RT): δ 8.01 (s, 1H), 7.83 (s, 1H), 5.47 (s, 2H), 3.57 (q, J=7.1Hz, 2H), 1.20 (t, J=7.1Hz, 3H).

[0501] Step 2 EtMgBr solution (3.0 M, 4.60 mL, 13.9 mmol in Et2O) was added dropwise to a solution of 1-(ethoxymethyl)pyrazole-4-carboxynitrile (1.00 g, 6.62 mmol) and Ti(Oi-Pr)4 (2.07 g, 7.28 mmol) in Et2O (30 mL) at -70 °C and N2. The mixture was stirred at this temperature for 10 min, then warmed to 20 °C and stirred at this temperature for 1 h. The mixture was cooled to 0 °C, BF3·Et2O (1.88 g, 13.2 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then quenched with ice water (60 mL), filtered to obtain a crude product, which was purified by preparative HPLC to give 1-[1-(ethoxymethyl)pyrazole-4-yl]cyclopropylamine (320 mg, 27%) as a pale yellow solid.

[0502] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.63 (s, 1H), 7.29 (s, 1H), 5.30 (s, 2H), 3.46-3.41 (m, 2H), 2.24 (br s, 2H), 1.05 (t, J=7.0Hz, 3H), 0.86-0.78 (m, 2H), 0.73-0.66 (m, 2H).

[0503] The product can then be further converted into, for example, compound I-149, similar to the examples above.

[0504] Example 25: Synthesis of [1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropyl]ammonium chloride

[0505] Step 1NaH (60% by weight, 1.03 g, 25.8 mmol in mineral oil, 2.00 g) was added dropwise to a solution of 1H-pyrazole-3-carboxynitrile (2.00 g, 21.5 mmol) in DMF (20 mL) at 0 °C and N2, and the mixture was stirred at this temperature for 30 min. Chloromethoxyethane (2.40 g, 25.8 mmol) was added dropwise to DMF (20 mL), and the mixture was gradually heated to 25 °C and stirred at this temperature for 15 h. The reaction mixture was then poured into ice water (100 mL), the aqueous phase was extracted with MTBE (3 × 20 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 99:1-33:66), 1-(ethoxymethyl)pyrazole-3-carboxynitrile (1.20 g, 37%) was obtained as a colorless oil.

[0506] 1 H-NMR (400MHz, CDCl3, RT): δ7.67 (d, J=2.4Hz, 1H), 6.74 (d, J=2.4Hz, 1H), 5.47 (s, 2H), 3.54 (q, J=7.0Hz, 2H), 1.18 (t, J=7.1Hz, 3H).

[0507] Step 2 EtMgBr solution (3.0 M, 5.50 mL, 16.6 mmol) was added dropwise to a solution of 1-(ethoxymethyl)pyrazol-3-carboxynitrile (1.20 g, 7.92 mmol) and Ti(Oi-Pr)4 (2.48 g, 8.71 mmol) in Et2O (60 mL) at -70 °C and N2. The mixture was stirred at this temperature for 10 min, then warmed to 20 °C and stirred at this temperature for 1 h. The mixture was cooled to 0 °C, BF3·Et2O (2.26 g, 15.8 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then quenched with ice water (60 mL) and filtered to give 1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropylamine (1.4 g, crude) as a yellow solution, which was used directly in the next step.

[0508] Step 3To a solution of 1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropylamine (1.32 g, 7.28 mmol) in MeCN (60 mL) and H₂O (60 mL), an aqueous solution of NaOH (6 M, 6.1 mL) and Boc₂O (7.95 g, 36.4 mmol) were added, and the resulting mixture was stirred at 20 °C for 15 h. The mixture was then extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 99:1-50:50) gave N-[1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropyl]tert-butyl carbamate (630 mg, 31%) as a white solid.

[0509] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.69 (s, 1H), 7.58 (s, 1H), 6.05 (s, 1H), 5.27 (s, 2H), 3.44 (q, J=6.7Hz, 2H), 1.38 (s, 8H), 1.14-0.88 (m, 7H). Step 4 : N-[1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropyl]tert-butyl carbamate (630 mg, 2.24 mmol) was dissolved in HCl / dimethylphenol ether. The solution in alkane (4M, 5.6 mL) was stirred at 25 °C for 15 h. Then MTBE (6 mL) was added, the mixture was stirred for 10 min, and then filtered. The filter cake was dried under reduced pressure to give [1-[1-(ethoxymethyl)pyrazol-3-yl]cyclopropyl]ammonium chloride (400 mg, 81%) as a white solid.

[0510] 1 H-NMR (400MHz, DMSO-d6, RT): δ8.98(br s, 3H), 7.91 (d, J=2.4Hz, 1H), 6.33 (d, J=2.4Hz, 1H), 5.36 (s, 2H), 3.48 (q, J=7.1Hz, 2H), 1.47-1.37 (m, 2H), 1.19-1.12 (m, 2H), 1.07 (t, J=7.0Hz, 3H).

[0511] The product can then be further converted into, for example, compound I-153, similar to the examples above.

[0512] Example 26: Synthesis of [1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropyl]ammonium chloride

[0513] Step 1NaH (60% by weight, 6.15 g, 155 mmol in mineral oil) was added dropwise to a solution of 1H-imidazolium-4-carboxynitrile (12.0 g, 128 mmol) in DMF (150 mL) under a N2 atmosphere at 0 °C. The resulting mixture was stirred at this temperature for 30 min, and then chloromethoxyethane (14.6 g, 155 mmol) was added dropwise to DMF (50 mL). The mixture was gradually heated to 25 °C and stirred for 15 h. The reaction mixture was then poured into ice water (500 mL), and the aqueous phase was extracted with MTBE (3 × 100 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 100 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. Purified by column chromatography (SiO2, petroleum ether / EtOAc = 99:1-50:50), 1-(ethoxymethyl)pyrazole-3-carboxynitrile (2.0 g, 11%) was obtained as a yellow oil.

[0514] Step 2 EtMgBr solution (3.0 M, 2.2 mL, 6.6 mmol in Et2O) was added dropwise to a solution of 1-(ethoxymethyl)pyrazole-3-carboxynitrile (0.50 g, 3.3 mmol) and Ti(Oi-Pr)4 (1.03 g, 3.64 mmol) in Et2O (15 mL) at -70 °C and N2. The mixture was stirred at this temperature for 10 min, then warmed to 20 °C and stirred at this temperature for 1 h. The mixture was cooled to 0 °C, BF3·Et2O (0.94 g, 6.6 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then quenched with ice water (15 mL) and filtered to give 1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropylamine (0.60 g, crude) as a yellow solution, which was used directly in the next step.

[0515] Step 3 To a solution of 1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropylamine (0.60 g, 3.3 mmol) in MeCN (15 mL) and H₂O (15 mL), 2.8 mL of 6.0 M NaOH aqueous solution and 3.61 g of Boc₂O (16.6 mmol) were added, and the mixture was stirred at 20 °C for 15 h. The mixture was then extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 99:1-50:50) gave N-[1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropyl]tert-butyl carbamate (390 mg, 41%) as a pale yellow solid.

[0516] Step 4 : N-[1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropyl]tert-butyl carbamate (390 mg, 1.38 mmol) was dissolved in HCl / dimethyldimethylamine. The solution in alkane (4.0 M, 10 mL) was stirred at 25 °C for 15 h. Then MTBE (6 mL) was added, the mixture was stirred for 10 min, and then filtered. The filter cake was dried under reduced pressure to give [1-[1-(ethoxymethyl)imidazol-4-yl]cyclopropyl]ammonium chloride (230 mg, 90%) as a white solid.

[0517] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.58 (d, J=1.3Hz, 1H), 7.08 (d, J=1.4Hz, 1H), 5.24 (s, 2H), 3.40 (d, J=7.1Hz, 2H), 1.09-1.06 (m, 3H), 0.90-0.85 (m, 2H), 0.78-0.70 (m, 2H).

[0518] The product can then be further converted into, for example, compound I-161, similar to the examples above.

[0519] Example 27: Synthesis of 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [I-162]azol-3-yl]amino]-N-(1-pyridazin-4-ylcyclopropyl)benzamide

[0520] Step 1 : 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso A solution of 1,2,4,5-tetraazine (480 mg, 5.80 mmol) in toluene (20 mL) was stirred at 110 °C for 5 days. The mixture was then filtered, and the filter cake was prepared with EtOAc (50 mL) and filtered again to give 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a pale yellow solid. [I-162](300 mg, 45%).

[0521] 1H-NMR (400MHz, DMSO-d6, RT): δ9.59 (s, 1H), 9.34 (s, 1H), 9.19-8.98 (m, 2H), 7.79 (s, 1H), 7.66 (s, 2H), 7.53 (d, J=2 .3Hz, 1H), 7.52-7.46 (m, 2H), 7.43 (dd, J=2.6, 5.6Hz, 1H), 4.00-3.85 (m, 2H), 1.62-1.50 (m, 2H), 1.45-1.36 (m, 2H).

[0522] Example 28: Synthesis of 5-(2,6-dichloro-4-pyridyl)-5-(trifluoromethyl)-4H-iso 3-azole-amine Step 1 The reaction mixture was prepared at 20–25 °C under a nitrogen atmosphere by adding di(pinacolyl)diboron (6.69 g, 26.4 mmol), KOAc (6.69 g, 26.4 mmol), and Pd(dppf)Cl2 (1.5 g, 2.2 mmol) to a solution of 4-bromo-2,6-dichloropyridine (5.00 g, 22.0 mmol) in DMF (60 mL). The reaction mixture was then heated to 100 °C and stirred at that temperature for 1 h. The reaction mixture was then quenched with H2O (50 mL), the aqueous phase was extracted with EtOAc (3 × 60 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 2 × 20 mL), dried on Na2SO4, filtered and concentrated to give 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)pyridine (7.2 g) as a yellow solid, which was used directly in the next step without further purification.

[0523] Step 2 : 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (5.00 g, 18.2 mmol) was reacted under a nitrogen atmosphere at 20-25 °C. 2-Bromo-3,3,3-trifluoroprop-1-ene (6.38 g, 36.5 mmol), K2CO3 (4.72 g, 36.5 mmol), and Pd(PPh3)2Cl2 (1.28 g, 1.82 mmol) were added to a solution of alkane (50 mL) and H2O (10 mL). The mixture was heated to 80 °C and stirred at this temperature for 12 h in a sealed container. The reaction mixture was then quenched with H2O (50 mL), the aqueous phase was extracted with EtOAc (3 × 60 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried on Na2SO4, filtered, and concentrated. 2,6-Dichloro-4-[1-(trifluoromethyl)vinyl]pyridine (2.20 g, 50%) was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100:0-15:85) as a colorless oil.

[0524] 1 H-NMR (400MHz, CDCl3, RT): δ7.32-7.32 (m, 1H), 7.34 (s, 1H), 6.22 (s, 1H), 6.03 (d, J=0.88Hz, 1H).

[0525] Step 3 Di(4-methoxybenzyl)amine (0.940 g, 46.7 mmol) and iPr2NEt (0.500 g, 38.6 mmol) were added dropwise to a solution of 1,1-dibromoformaldehyde oxime (1.00 g, 38.6 mmol) in 100 mL of THF under a nitrogen atmosphere at -70 °C. The mixture was stirred at this temperature for an additional 10 min, and then a solution of 6-dichloro-4-[1-(trifluoromethyl)vinyl]pyridine (1.47 g, 38.6 mmol) and iPr2NEt (1.00 g, 77.2 mmol) in 10 mL of THF was added dropwise to the above reaction solution at -70 °C. The reaction mixture was warmed to 20–25 °C and then stirred at this temperature for 12 h. The reaction mixture was quenched with H₂O (50 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 100 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 100:0-18:82) gave 5-(2,6-dichloro-4-pyridyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-isocyanate as a yellow solid. Azolium-3-amine (1.50g, 46%).

[0526] 1H-NMR (400MHz, CDCl3, RT): δ7.45 (s, 2H), 7.06 (d, J=8.6Hz, 4H), 6.82-6.89 (m, 4H), 4.27 (s, 4H), 3.81 (s, 6H).

[0527] Step 4 : 5-(2,6-dichloro-4-pyridyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-iso 200 mg of 3-azole-amine (0.370 mmol) was dissolved in 5.0 mL of F3CCO2H, and the resulting mixture was stirred at 20–25 °C for 12 h. The reaction mixture was then quenched with 10 mL of H2O, and the aqueous phase was extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried over Na2SO4, filtered, and concentrated. The solution was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100:0–35:75, gradient) to give 5-(2,6-dichloro-4-pyridyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. Zolpidem (30 mg, 27%).

[0528] 1 H-NMR (400MHz, CDCl3, RT): δ7.47 (s, 2H), 3.74 (d, J=16.5Hz, 1H), 3.29 (d, J=16.9Hz, 1H).

[0529] The product can then be further converted into, for example, compound I-173, similar to the examples above.

[0530] Example 29: Synthesis of 5-(4-bromo-2-thienyl)-5-(trifluoromethyl)-4H-iso 3-azole-amine

[0531] Step 1CsF (1.60 g, 10.3 mmol) and Me3Si-CF3 (9.00 g, 52.3 mmol) were added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (10.0 g, 52.3 mmol) in THF (100 mL) at 0 °C, and the resulting mixture was stirred at this temperature for 2 h. The reaction mixture was then carefully quenched by dropwise addition of HCl solution (2 N, in H2O, 90 mL), followed by stirring at 0 °C for an additional 2 h. The aqueous phase was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried on Na2SO4, filtered, and concentrated to give 1-(4-bromo-2-thienyl)-2,2,2-trifluoroethanol (16.3 g, crude) as a yellow oil.

[0532] Step 2 The reaction mixture was prepared by adding 3-oxo-1λ5,2-benzoiodopyrazine-1,1,1(3H)-trimethyl ester of triacetic acid (“Dies-Martin oxidant”) (25.1 g, 59.2 mmol) in portions to a mixture of 1-(4-bromo-2-thienyl)-2,2,2-trifluoroethanol (10.3 g, 39.5 mmol) in CH2Cl2 (100 mL) at 0 °C. The reaction mixture was then stirred at 20–25 °C for 3 h. The reaction mixture was then quenched with NaHCO3 solution (300 mL saturated aqueous solution), and the aqueous phase was extracted with CH2Cl2 (3 × 200 mL). The combined organic extracts were washed with Na2S2O3 (1 × 200 mL saturated aqueous solution) and NaCl solution (1 × 200 mL saturated aqueous solution), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether = 100%), 1-(4-bromo-2-thienyl)-2,2,2-trifluoroethyl ketone (6.10 g, 60%) was obtained as a yellow oil. 1 H-NMR (400MHz, CDCl3, RT): δ7.86 (s, 1H), 7.80 (s, 1H).

[0533] Step 3At 0 °C, t-BuOK solution (35 mL, 1.0 M, in THF) was added dropwise to a mixture of 1-(4-bromo-2-thienyl)-2,2,2-trifluoroethyl ketone (7.50 g, 29.0 mmol) and MePPh3Br (12.4 g, 34.7 mmol) in THF (80 mL), and the resulting mixture was stirred at this temperature for 3 h. The mixture was then poured into NH4Cl solution (50 mL saturated aqueous solution), and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with NaCl solution (1 × 60 mL saturated aqueous solution), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (petroleum ether = 100%) gave 4-bromo-2-[1-(trifluoromethyl)vinyl]thiophene (4.70 g, 63%) as a red oil.

[0534] 1 H-NMR (400MHz, CDCl3, RT): δ7.22 (d, J=1.1Hz, 1H), 7.13 (s, 1H), 5.90-5.84 (m, 2H).

[0535] Step 4 A solution of 1,1-dibromoformaldehyde oxime (4.73 g, 23.3 mmol) in THF (10 mL) and iPr2NEt (2.50 g, 19.4 mmol) was added dropwise to a solution of di(4-methoxybenzyl)amine (5.00 g, 19.4 mmol) in THF (30 mL) at -70 °C, and the mixture was stirred at this temperature for 30 min. Then, 4-bromo-2-[1-(trifluoromethyl)vinyl]thiophene (5.00 g, 19.4 mmol) was slowly added at -78 °C, and the mixture was warmed to 20-25 °C and stirred at this temperature for 16 h. The reaction mixture was then poured into H2O (20 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (SiO2, EtOAc / petroleum ether = 15:85), 5-(4-bromo-2-thienyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-isocyanate was given as a yellow solid. Zyrazole-3-amine (4.90 g, 46%).

[0536] 1H-NMR (400MHz, CDCl3, RT): δ7.30 (s, 1H), 7.08 (d, J=8.6Hz, 5H), 6.91-6.81 (m, 4H), 4.25 (s, 4H), 3.82 (s, 6H), 3.78 (d, J=16.0Hz, 1H), 3.44 (d, J=16.0Hz, 1H).

[0537] Step 5 : 5-(4-bromo-2-thienyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-iso A mixture of 2.25 g, 4.05 mmol of azole-3-amine in 15 mL of F3CCO2H was stirred at 50 °C for 16 h. The mixture was then quenched with 100 mL of saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were washed with 1 × 30 mL of saturated NaCl solution, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (EtOAc / petroleum ether = 36:74) yielded 5-(4-bromo-2-thienyl)-5-(trifluoromethyl)-4H-isocyanate as a yellow oil. Azolium-3-amine (1.10 g, 86%).

[0538] 1 H-NMR (400MHz, CDCl3, RT): δ7.30 (d, J=1.4Hz, 1H), 7.11 (s, 1H), 3.72 (d, J=16.3Hz, 1H), 3.40-3.33 (m, 1H).

[0539] The product can then be further converted into, for example, compound I-175, similar to the examples above.

[0540] Example 30: Synthesis of N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-5-[4-(trifluoromethyl)-2-thienyl]-4H-iso 3-azole-amine

[0541] Step 1 At 20°C, 5-(4-bromo-2-thienyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-isocyanate was used. Azoxyl-3-amine (6.30 g, 11.3 mmol, synthesized as described above) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (161 mg, 1.13 mmol) were synthesized in 1,4-dioxanediamine. CuI (108 mg, 0.56 mmol) and NaI (3.4 g, 22.7 mmol) were added to the mixture in alkane (60 mL), and the mixture was purged with N2 for 3 min. The vial was sealed, and the mixture was stirred at 120 °C for 16 h. The mixture was then filtered through diatomaceous earth, and the filter cake was washed with EtOAc (200 mL). The filtrate was mixed with H2O (50 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried on Na2SO4, filtered, and concentrated. The solution was purified by column chromatography (EtOAc = 15% in PE) to give 5-(4-iodo-2-thienyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-iso Azolium-3-amine (5.90 g, 87%).

[0542] 1 H-NMR (400MHz, CDCl3, RT): δ7.46 (d, J=1.1Hz, 1H), 7.12 (s, 1H), 7.07 (d, J=8.5Hz, 4H), 6.86 (d, J=8.6Hz, 4H), 4.25 (s, 4H), 3.82 (s, 6H), 3.78 (d, J=16.0Hz, 1H), 3.45 (d, J=16.0Hz, 1H).

[0543] Step 2 At 20-25℃, 5-(4-iodo-2-thienyl)-N,N-di[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-4H-iso A mixture of 3-azole-amine (5.90 g, 9.80 mmol) in NMP (60 mL) was added to CuI (5.60 g, 29.4 mmol) and purged with N2 for 3 min, followed by the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (9.4 g, 49 mmol). The vial was sealed and the reaction mixture was stirred at 130 °C for 1 h. The mixture was then filtered and the filter cake was washed with EtOAc (200 mL). The filtrate was mixed with H2O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 80 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 100 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (EtOAc = 19% in PE) to give N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-5-[4-(trifluoromethyl)-2-thienyl]-4H-iso Zyrazole-3-amine (4.00 g, 75%).

[0544] 1 H-NMR (400MHz, CDCl3, RT): δ7.80-7.76 (m, 1H), 7.14-7.02 (m, 5H), 6.90-6.81 (m, 4H), 4.29-4.24 (m, 4H), 3.84-3.78 (m, 7H), 3.51-3.42 (m, 1H).

[0545] The product can then be further converted into, for example, compound I-177, similar to the examples above.

[0546] Example 31: Synthesis of 1-[2-(ethoxymethyl)-5-(trifluoromethyl)pyrazol-3-yl]-2,2,2-trifluoroethyl ketone Step 1 NaH (11.5 g, 286 mmol) was added to a solution of 3-(trifluoromethyl)-1H-pyrazole (50.0 g, 367 mmol) in THF (500 mL) at 0 °C, and the mixture was stirred at this temperature for an additional 0.5 h. Then, chloromethoxyethane (42 g, 441 mmol) was added, and the reaction was stirred at 0 °C for 2 h. The mixture was quenched with H₂O (200 mL), the aqueous phase was extracted with EtOAc (3 × 200 mL), the combined organic phases were washed with NaCl solution (saturated aqueous solution, 1 × 100 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (MTBE = 3% in petroleum ether) gave 1-(ethoxymethyl)-3-(trifluoromethyl)pyrazole (22.0 g, 31%) as a yellow oil.

[0547] 1 H-NMR (400MHz, CDCl3, RT): δ7.64 (s, 1H), 6.61 (d, J=2.4Hz, 1H), 5.49 (s, 2H), 3.56 (q, J=7.0Hz, 2H), 1.19 (t, J=7.0Hz, 3H).

[0548] Step 2Carefully add 1-(ethoxymethyl)-3-(trifluoromethyl)pyrazole (7.00 g, 36.1 mmol) in THF (20 mL) to an n-BuLi solution (2.5 M, in THF, 21.0 mL, 54.1 mmol) at -78 °C and stir the mixture at this temperature for 0.5 h. Then add 2,2,2-trifluoro-N-methoxy-N-methylacetamide (16.8 g, 108 mmol) at -78 °C and stir the reaction at this temperature for 4 h. The mixture is then quenched with H2O (100 mL), the aqueous phase is extracted with EtOAc (3 × 100 mL), the combined organic extracts are washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried on Na2SO4, filtered and concentrated. Purified by column chromatography (EtOAc in petroleum ether = 31%), it is given as a yellow oil (4.90 g, 47%).

[0549] 1 H-NMR (400MHz, CDCl3, RT): δ7.37 (d, J=1.4Hz, 1H), 5.91 (s, 2H), 3.63-3.57 (m, 2H), 1.18 (t, J=7.0Hz, 3H).

[0550] The product can then be further converted into, for example, compound I-178, similar to the examples above.

[0551] Example 32: Synthesis of 3-chloro-5-(trifluoromethylthioalkyl)benzaldehyde

[0552] Step 1 N-bromosuccinimide (23.0 g, 129 mmol) was added fractionally to a solution of 4-(trifluoromethylthioalkyl)aniline (25.0 g, 129 mmol) in DMF (250 mL) at 20–25 °C, and the resulting reaction mixture was stirred at this temperature for 16 h. The mixture was then poured into H₂O (100 mL), and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with H₂O (100 mL) and NaCl solution (saturated aqueous solution, 2 × 50 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 10:1) gave 2-bromo-4-(trifluoromethylthioalkyl)aniline (24.5 g, 70%) as a brown solid.

[0553] 1 H-NMR (400MHz, CDCl3, RT): δ7.71 (d, J=1.8Hz, 1H), 7.38 (dd, J=8.4, 1.8Hz, 1H), 6.76 (d, J=8.3Hz, 1H), 4.21-4.71 (m, 2H).

[0554] Step 2 N-chlorosuccinimide (29.6 g, 221 mmol) was added fractionally to a solution of 2-bromo-4-(trifluoromethylthioalkyl)aniline (30.0 g, 144 mmol) in DMF (300 mL) at 20–25 °C, and the reaction mixture was stirred at this temperature for 16 h. The reaction mixture was then poured into H₂O (200 mL), and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with H₂O (100 mL) and NaCl solution (saturated aqueous solution, 2 × 80 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 10:1) gave 2-bromo-6-chloro-4-(trifluoromethylthioalkyl)aniline (26.0 g, 88%) as a brown solid.

[0555] 1 H NMR (400MHz, CDCl3, RT): δ7.65 (d, J=1.9Hz, 1H), 7.53 (d, J=1.9Hz, 1H), 4.86 (br s, 2H).

[0556] Step 3 ONOtBu (8.00 g, 78.8 mmol) was added to a solution of 2-bromo-6-chloro-4-(trifluoromethylthioalkyl)aniline (20.0 g, 65.6 mmol) in DMF (250 mL) at 0 °C, and the reaction mixture was stirred at 20–25 °C for 16 h. The reaction mixture was then poured into H₂O (100 mL), and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with H₂O (1 × 80 mL) and NaCl solution (saturated aqueous solution, 2 × 60 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 10:1) gave 1-bromo-3-chloro-5-(trifluoromethylthioalkyl)benzene (14.0 g, 74%) as a brown oil.

[0557] 1 H-NMR (400MHz, CDCl3, RT): δppm 7.71 (s, 1H), 7.63-7.67 (m, 1H), 7.60 (d, J=1.5Hz, 1H).

[0558] Step 4Et3N (10 g, 0.10 mol), Pd(dppf)Cl2 (1.22 g, 1.70 mmol), and HSiEt3 (7.95 g, 68.5 mmol) were added to a solution of 1-bromo-3-chloro-5-(trifluoromethylthioalkyl)benzene (10.0 g, 34.3 mmol) in DMF (120 mL) at 20–25 °C. The reaction mixture was then stirred at 50 °C under CO gas (50 Psi) for 1 h. The reaction mixture was then poured into water (100 mL), and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 3 × 50 mL), dried on Na2SO4, filtered, and concentrated. 3-Chloro-5-(trifluoromethylthioalkyl)benzaldehyde (3.0 g, 36%) was purified by column chromatography (petroleum ether / EtOAc = 10:1) as a colorless oil.

[0559] 1 H-NMR (400MHz, CDCl3, RT): δ10.0 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.90 (s, 1H).

[0560] The product can then be further converted into, for example, compound I-165, similar to the examples above.

[0561] Example 33: N-(3-bromo-2-fluorophenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso 3-Azole-3-amine chiral segregation into corresponding (S)- and (R)-enantiomers

[0562] Step 1 N-(3-bromo-2-fluorophenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate was transported via a chiral SFC (column: DAICL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 23%-23%, 2.8 min). The 3-azole-amine (6.00 g, 20.1 mmol) was isolated and obtained as follows:

[0563] (5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate is a white solid. Zyrazole-3-amine (2.58 g, 43%). 1H NMR (400MHz, CDCl3, RT): δ7.45 (s, 2H), 7.39-7.43 (m, 1H), 4.06 (s, 2H), 3.71 (d, J=16.4Hz, 1H), 3.34 (d, J=16.8Hz, 1H); analytical SFC (CHIRALPAK IC-3 100mm×4.6mm ID3μm, CO2 / MeOH (0.05%DEA), 3.4mL·min -1 1800psi, 35℃, gradient from 5% to 40% over 2 min and hold at 40% for 1 min, then from 40% to 5% for 1 min): t R =1.64 min, er = 99.5:0.5. The product can then be further converted into, for example, compounds I-137, I-140, I-145, I-146, I-147, and I-174, similar to the examples above.

[0564] And (5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate, which is a white solid. Azole-3-amine (2.56 g, 43%). 1 H-NMR (400MHz, CDCl3, RT): δ7.45 (s, 2H), 7.39-7.43 (m, 1H), 4.05 (s, 2H), 3.71 (d, J=16.2Hz, 1H), 3.34 (d, J=16.4Hz, 1H); Analytical SFC (CHIRALPAK IC-3 100mm×4.6mmI.D.3μm, CO2 / MeOH (0.05%DEA), 3.4mL·min -1 1800psi, 35℃, gradient from 5% to 40% over 2 min and hold at 40% for 1 min, then from 40% to 5% for 1 min): t R =1.44min, er>99.5:0.5. The product can then be further converted into, for example, compounds I-136, I-139, I-141, I-143 and I-144, similar to the examples above.

[0565] Example 34: Synthesis of 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]methylamino]benzoic acid

[0566] Step 1 : 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate under N2 atmosphere at 20-25℃ Azole-3-amine (662 mg, 2.21 mmol, synthesized as described in the examples above) in 1,4-dioxane Methyl 2-bromo-5-iodobenzoate (830 mg, 2.43 mmol), Cs₂CO₃ (1.45 g, 4.42 mmol), Pd₂(dba)₃ (200 mg, 0.22 mmol), and Xantphos (256 mg, 0.44 mmol) were added to a solution of alkane (20 mL). The resulting reaction mixture was heated to 80 °C and stirred at that temperature for 16 h. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by column chromatography (SiO₂, petroleum ether / EtOAc = 100:0-92:8) to give 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Methyl benzoate (900 mg, 80%).

[0567] 1 H-NMR (400MHz, CDCl3, RT): δ7.81 (d, J=2.8Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.48 (s, 2H), 7. 45-7.40 (m, 2H), 6.12 (s, 1H), 3.94 (s, 3H), 3.90 (d, J=16.1Hz, 1H), 3.53 (d, J=16.3Hz, 1H).

[0568] Step 2 At 0°C, 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Methyl benzoate (800 mg, 1.57 mmol) was added in portions to a solution of methyl benzoate in DMF (10 mL) with NaH (75 mg, 1.88 mmol), and the resulting mixture was stirred at this temperature for 0.5 h. MeI (268 mg, 1.88 mmol) was added to the reaction mixture, and the reaction was stirred at 20–25 °C for 3 h. The reaction mixture was quenched with H₂O (20 mL), the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated to give crude 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a yellow solid. Methyl benzoate [3-yl]methylamino]benzoate (850 mg, 92%).

[0569] Step 3 At 20-25℃, 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate...] Methyl benzoate [3-yl]methylamino]benzoate (800 mg, 1.53 mmol) was added to a solution of THF (10 mL) and H₂O (3.0 mL) with LiOH·H₂O (96 mg, 2.3 mmol), and the reaction was stirred at this temperature for 48 h. The reaction solution was adjusted to pH 4 with HCl solution (1 N, in H₂O), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated to give 2-bromo-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a yellow solid. [Azol-3-yl]methylamino]benzoic acid (700 mg, 90%).

[0570] 1 H-NMR (400MHz, DMSO-d6, RT): δ14.1-13.0 (m, 1H), 7.76 (t, J=1.9Hz, 1H), 7.72-7.67 (m, 2H), 7.59 (d, J=1.5Hz, 2H), 7.42 (dd, J=2.7, 8.7Hz, 1H), 3.97-3.76 (m, 2H), 3.23 (s, 3H).

[0571] The product can then be further converted into, for example, compound I-148, similar to the examples described above.

[0572] Example 35: Synthesis of 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]thioalkyl]benzamide [II-2]

[0573] Step 1 At 0 °C, NaH (60 wt%, in mineral oil, 1.97 g, 49.3 mmol) was added fractionally to a solution of 3-bromo-4-chlorothiophenol (11.8 g, 49.3 mmol) in THF (240 mL), and the resulting mixture was stirred at this temperature for 1 h. The reaction mixture was then quenched with ice water (200 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 50 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (petroleum ether / EtOAc = 99:1-85:15) gave di[(3-bromo-4-chlorophenyl)thioalkyl]methyl ketone oxime (2.40 g, 20%) as a pale yellow solid.

[0574] 1H-NMR (400MHz, DMSO-d6, RT): δ=12.7 (s, 1H), 7.58 (d, J=8.3Hz, 1H), 7.54 (d, J=8.4Hz, 1H), 7.51 ( d, J=2.1Hz, 1H), 7.44 (dd, J=2.1, 8.3Hz, 1H), 7.27 (d, J=2.1Hz, 1H), 7.13 (dd, J=2.2, 8.4Hz, 1H). Step 2 To a solution of di[(3-bromo-4-chlorophenyl)thioalkyl] ketone oxime (400 mg, 0.82 mmol) and 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (474 ​​mg, 1.97 mmol) in THF (10 mL), AgNO3 (209 mg, 0.82 mmol) and K2CO3 (113 mg, 0.82 mmol) were added, and the resulting mixture was stirred at 50 °C for 15 h. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / EtOAc = 99:1-90:10; gradient) to give 3-(3-bromo-4-chlorophenyl)thioalkyl-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Azole (75 mg, 18%).

[0575] 1 H-NMR (400MHz, CDCl3, RT): δ7.82 (d, J=2.0Hz, 1H), 7.54-7.47 (m, 1H), 7.47-7.4 1 (m, 2H), 7.39 (d, J=1.1Hz, 2H), 3.75 (d, J=17.3Hz, 1H), 3.38 (d, J=17.3Hz, 1H).

[0576] Step 3 : Under 0℃ and N2 atmosphere, 3-(3-bromo-4-chlorophenyl)thioalkyl-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Azole (200 mg, 0.396 mmol) was added dropwise to a solution of iPrMgCl·LiCl (1.3 M, 0.609 mL, 0.791 mmol) in THF (5 mL). The mixture was stirred at this temperature for 0.5 h, then CO2 (dry ice, 2.0 g) was added and the mixture was gradually heated to 20–25 °C. Stirring was continued at 20–25 °C for 1 h, and then the reaction mixture was poured into HCl solution (0.5 N, in H2O, 10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were dried on Na2SO4, filtered, and concentrated. Purification by preparative HPLC (TFA) yielded 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate as a white solid. [Azol-3-yl]thioalkyl]benzoic acid (150 mg, 80%).

[0577] 1 H-NMR (400MHz, DMSO-d6, RT): δ=7.77 (t, J=1.7Hz, 1H), 7.68 (br s, 1H), 7.55 (d, J=1.1Hz, 2H), 7.51-7.40 (m, 2H), 3.92 (br d, J=2.3Hz, 2H). Step 4 At 20-25℃, 2-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate isomerized. [3-yl]thioalkyl]benzoic acid (300 mg, 0.637 mmol) was added to a solution in MeCN (6.0 mL) with NMI (157 mg, 1.91 mmol) and TCFH (215 mg, 0.765 mmol), and the mixture was stirred at this temperature for 0.5 h. Then, 1-aminocyclopropaneformonitrile (90.7 mg, 0.765 mmol) was added, and the reaction mixture was stirred at 20–25 °C for 15 h. The reaction mixture was then poured into H₂O (50 mL), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried over Na₂SO₄, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 99:1-50:50), 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanopropyl) was given as a white solid. [Azolium-3-yl]thioalkyl]benzamide [II-2] (120 mg, 32%).

[0578] 1H-NMR (400MHz, DMSO-d6, RT): δ9.47 (s, 1H), 7.80 (t, J=1.8Hz, 1H), 7.73 (s, 1H), 7 .72-7.68(m, 1H), 7.66-7.62(m, 1H), 7.55(d, J=1.6Hz, 2H), 3.97(s, 2H), 3.31(br s, 2H), 1.57 (br d, J=2.8Hz, 2H), 1.27 (br d, J=2.6Hz, 2H).

[0579] Example 36: Synthesis of 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso [II-3-]azol-3-yl]sulfonyl]benzamide

[0580] Step 1 At 0°C, 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanopropyl] [220 mg, 0.411 mmol, synthesized as described in the examples above]azol-3-yl]thioalkyl]benzamide [II-2] (220 mg, 0.411 mmol, synthesized as described in the examples above) was added in portions to a solution of m-chloroperoxybenzoic acid (85 wt%, 418 mg, 2.06 mmol) in THF (4.0 mL), and the resulting mixture was stirred at 20–25 °C for 15 h. The reaction mixture was then poured into a solution of 20 mL of NaHCO3 (saturated aqueous solution) and Na2SO3 (saturated aqueous solution), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried on Na2SO4, filtered, and concentrated. The synthesized 2-chloro-N-(1-cyanocyclopropyl)-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanopropyl) was purified by column chromatography (petroleum ether / EtOAc = 99:1-50:50) and given as a colorless syrup. [II-3](145 mg, 62%).

[0581] 1 H-NMR (400MHz, methanol-d4, RT): δ8.12-8.10 (m, 1H), 8.10-8.07 (m, 1H), 7.84 (d, J=9.3Hz, 1H), 7.63-7.55 (m, 1H), 7.51 (d, J=1.4Hz, 2H), 4.27 (d, J=18.6Hz, 1H), 4.01 (d, J=18.6Hz, 1H), 1.64-1.56 (m, 2H), 1.44-1.35 (m, 2H).

[0582] Example 37: Synthesis of 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [II-8]azol-3-yl]oxy]-N-(3,5-difluoro-2-pyridyl)benzamide

[0583] Step 1 To a solution of 1,3-dichloro-2-fluoro-5-[1-(trifluoromethyl)vinyl]benzene (16.0 g, 61.8 mmol, synthesized as described in the examples above) and 1,1-dibromoformaldehyde oxime (15.0 g, 74.1 mmol) in EtOAc (160 mL), NaHCO3 (51.9 g, 617 mmol) was added in portions, and the resulting mixture was stirred at 50 °C for 15 h. The reaction mixture was then poured into H2O (100 mL), and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 100 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 99:1-90:10), 3-bromo-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate was given as a yellow solid. Azole (16.5g, 70%).

[0584] 1 H-NMR (400MHz, CDCl3, RT): δ7.49 (d, J=5.9Hz, 2H), 3.93 (d, J=17.8Hz, 1H), 3.56 (dd, J=0.8, 17.8Hz, 1H).

[0585] Step 2 To a solution of 2-chloro-5-hydroxybenzoic acid (1.09 g, 6.30 mmol) in N-methyl-2-pyrrolidone (20 mL), add NaOH (504 mg, 12.6 mmol) and pyridine (15 mL) at 20-25 °C, then stir the mixture at 90 °C for 20 min. Then add 3-bromo-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate. Azole (2.0 g, 5.25 mmol). After TLC analysis (petroleum ether / EtOAc = 5:1) showed that the reaction was complete, the mixture was poured into H2O (100 mL) and adjusted to pH = 4 with 2.0 M HCl aqueous solution. The aqueous phase was extracted with EtOAc (3 × 30 mL), the combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 10 mL), dried on Na2SO4, filtered and concentrated to give 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso...] as a black oil. [Azolium-3-yl]oxy]benzoic acid (2.7 g, crude) was used directly in the next step without further purification.

[0586] Step 3 : 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso A solution of 580 mg [3-yl]oxy]benzoic acid in SOCl2 (6.0 mL, excess) was stirred at 60 °C for 3 h. The mixture was concentrated, dissolved in CH2Cl2 (6.0 mL), and 3,5-difluoropyridine-2-amine (604 mg, 1.23 mmol) in pyridine (12.0 mL) and CH2Cl2 (12 mL) was added dropwise at 0 °C. After the addition, the mixture was stirred at 25 °C for 15 h. The mixture was poured into HCl solution (1.0 M, in H2O, 50 mL), and the aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 30 mL), dried on Na2SO4, filtered, and concentrated. Purified by column chromatography (petroleum ether / EtOAc = 99:1-90:10), 2-chloro-5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate was obtained as a pale yellow oil. [II-8](280 mg, 39%).

[0587] 1 ¹H-NMR (400MHz, methanol-d⁴, RT): δppm 8.24 (br s, 1H), 7.71–7.77 (m, 1H), 7.71 (s, 2H), 7.57 (br d, J = 9.03Hz, 2H), 7.46 (dd, J = 8.91, 2.76Hz, 1H), 4.01–4.19 (m, 1H), 3.84–3.95 (m, 1H).

[0588] Example 38: Synthesis of 3-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-iso Methyl 2-(3-yl)-ethylamino]thiophene-2-carboxylate

[0589] Step 1 LiN(i-Pr)₂ (2.0 M, in THF / heptane / ethylbenzene, 15.4 mL, 30.9 mmol) was added dropwise to a solution of 3-chlorothiophene-2-carboxylic acid (2.00 g, 12.3 mmol) in THF (30 mL) at -60 °C under a N₂ atmosphere, and the mixture was stirred at this temperature for 1 h. Then, a solution of 1,2-dibromo-1,1,2,2-tetrafluoroethane (6.24 g, 24.7 mmol) in THF (2.0 mL) was added dropwise to the above reaction mixture, and stirring was continued for another 1 h. The reaction mixture was then poured into an HCl solution (1.0 N, in H₂O, 20 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated to give crude 5-bromo-3-chlorothiophene-2-carboxylic acid (2.5 g, 86%) as a yellow solid.

[0590] 1 H-NMR (400MHz, DMSO-d6, RT): δ7.47 (s, 1H), 3.07 (s, 1H).

[0591] Step 2 5-Bromo-3-chlorothiophene-2-carboxylic acid (2.2 g, 9.2 mmol) was dissolved in HCl / MeOH (20 mL) and the solution was stirred at 65 °C for 16 h. The reaction mixture was then concentrated under reduced pressure, quenched with NaHCO3 solution (50 mL saturated aqueous solution), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with NaCl solution (1 × 10 mL saturated aqueous solution), dried over Na2SO4, filtered, and concentrated. Methyl 5-bromo-3-chlorothiophene-2-carboxylic acid (700 mg, 30%) was obtained by column chromatography (SiO2, petroleum ether / EtOAc = 100:0-94:6).

[0592] 1 H-NMR (400MHz, CDCl3, RT): δ7.04-7.01 (m, 1H), 3.89 (s, 3H).

[0593] Step 3 : Methyl 5-bromo-3-chlorothiophene-2-carboxylate (700 mg, 2.75 mmol) was reacted with 1,4-dimethyl bromo-3-chlorothiophene-2-carboxylate at 20-25 °C and under a N2 atmosphere. Add 5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate to the solution in alkane (8.0 mL). The mixture was prepared with 3-azolyl-3-amine (746 mg, 2.5 mmol), Cs₂CO₃ (1.63 mg, 5.00 mmol), Pd₂(dba)₃ (229 mg, 0.25 mmol), and Xantphos (289 mg, 0.500 mmol), and then stirred at 80 °C for 16 h. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by column chromatography (SiO₂, petroleum ether / EtOAc = 100:0-84:16) to give 3-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate] as a white solid. Methyl azole-3-yl]amino]thiophene-2-carboxylate (1.3g, 70%).

[0594] 1 H-NMR (400MHz, CDCl3, RT): δ7.81 (s, 1H), 7.46 (s, 2H), 7.42 (s, 1H), 7.27 (s, 1H), 6.63 (s, 1H), 3.96-3.88 (m, 2H), 3.85 (s, 3H), 3.61-3.52 (m, 1H).

[0595] Step 4 At 0°C, 3-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate iso ... Methyl 3-azolyl]amino]thiophene-2-carboxylate (800 mg, 1.69 mmol) was added dropwise to a solution of t-BuOK (285 mg, 2.54 mmol) in THF (8.0 mL), and the mixture was stirred at this temperature for 0.5 h. Then, EtOTf (360 mg, 2.03 mmol) was added dropwise, and the reaction mixture was stirred at 20–25 °C for 16 h. The reaction mixture was then quenched with H₂O (20 mL), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with NaCl solution (saturated aqueous solution, 1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (SiO₂, petroleum ether / EtOAc = 100:0–83:17) yielded a yellow solid, giving the title 3-chloro-5-[[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isocyanate]. Methyl methazine-3-yl]ethylamino]thiophene-2-carboxylate (400 mg, 46%).

[0596] 1H-NMR (400MHz, CDCl3, RT): δ8.17 (br s, 1H), 8.01 (br d, J=8.6Hz, 2H), 7.75-7.44 (m, 2H), 7.32 (br d, J=8.4Hz, 2H), 7.23 (br d, J=8.3Hz, 2H), 6.94-6.61 (m, 1H), 5.86 (d, J=17.6Hz, 1H), 5.40 (d, J=10.9Hz, 1H), 2.97 (s, 1H), 2.89 (s, 1H), 2.20 (s, 3H), 2.05 (s, 4H).

[0597] The product can then be further converted into, for example, compound I-156, similar to the examples above.

[0598] Example 39: Synthesis of 2-[5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso [Azol-3-yl]amino]-2-methylphenyl]-2,2-difluoroethyl acetate

[0599] Step 1 : 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-isocyanate under an Ar atmosphere at 20-25℃ Azolium-3-amine (400 mg, 1.26 mmol) in 1,4-dioxane 2-(5-bromo-2-methylphenyl)-2,2-difluoroethyl acetate (370 mg, 1.26 mmol), K₂CO₃ (523 mg, 3.78 mmol), Pd₂(dba)₃ (58 mg, 0.063 mmol), and Xantphos (88 mg, 0.15 mmol) were added to a solution of cyclohexane (10 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was then quenched with NH₄Cl solution (15 mL saturated aqueous solution), and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with NaCl solution (1 × 15 mL saturated aqueous solution), dried over Na₂SO₄, filtered, and concentrated. The solution was purified by column chromatography (cyclohexane / EtOAc = 100:0-60:40) to give the title 2-[5-[[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4H-iso Ethyl 2,2-difluoroacetate [azol-3-yl]amino]-2-methylphenyl]-2,2-difluoroacetate (267 mg, 40%).

[0600] HPLC-MS (Method A): Retention time = 1.483 min, m / z = 529 ([M+H]). + ).

[0601] The product can then be further converted into, for example, compounds III-3 and III-4, similar to the examples above.

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[0603]

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[0605]

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[0608]

[0609]

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[0611]

[0612]

[0613]

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[0615]

[0616]

[0617]

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[0621]

[0622]

[0623] Biological Examples

[0624] Unless otherwise specified, prepare the test solution as follows:

[0625] Dissolve the active compound at the desired concentration in a 1:1 (volume ratio) mixture of distilled water and acetone. Prepare the test solution on the day of use.

[0626] Test solutions are typically prepared at a concentration of 2500 ppm (weight / volume).

[0627] B.1. Cotton Boll Weevil (Mexican Cotton Boll Weevil)

[0628] To evaluate the control of the boll weevil, the experimental unit consisted of a 96-well microtiter plate containing insect food and 5-10 Mexican boll weevil eggs.

[0629] The compound was prepared using a solution containing 75% by volume water and 25% by volume DMSO. Different concentrations of the prepared compound were sprayed onto the insect diet at 5 μl using a custom microneedler, repeated twice.

[0630] After application, the microtiter plates were incubated for 5 days at approximately 25±1°C and approximately 75±5% relative humidity. The mortality rates of eggs and larvae were then visually evaluated.

[0631] In this test,compared to the comparison,compound I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-1 1、I-12、I-13、I-14、I-15、I-16、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I -25、I-26、I-27、I-28、I-30、I-31、I-32、I-33、I-34、I-35、I-37、I-38、I-3 9、I-40、I-41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-52、I -53、I-55、I-56、I-57、I-58、I-59、I-60、I-61、I-63、I-65、I-66、I-67、I-6 8、I-69、I-70、I-71、I-72、I-74、I-75、I-76、I-77、I-78、I-79、I-81、I-84、I -85、I-87、I-88、I-89、I-90、I-91、I-95、I-97、I-98、I-99、I-100、I-101、I -102、I-103、I-104、I-105、I-106、I-107、I-108、I-109、I-110、I-111、I-11 2、I-114、I-115、I-116、I-117、I-118、I-120、I-121、I-122、I-123、I-124、 I-125、I-126、I-127、I-128、I-131、I-132、I-133、I-134、I-135、I-136、I-1 37、I-139、I-140、I-141、I-142、I-143、I-145、I-146、I-147、I-148、I-149 、I-150、I-151、I-152、I-153、I-154、I-155、I-157、I-158、I-159、I-160、I- 161、I-162、I-163、I-164、I-165、I-167、I-168、I-169、I-170、I-171、I-17 2、I-173、I-174、I-175、I-177、I-181、I-183、I-184、I-188、I-189、I-190、I -191、I-192、I-194、I-196、I-197、I-198、I-199、I-200、I-204、I-205、I-2 06、I-207、I-208、I-209、I-210、I-211、I-212、I-214、I-215、I-216、I-219、I-220, I-221, I-222, I-223, I-226, I-227, I-228, I-230, I-231, I-232, I-233, I-234, I-235, I-236, I-238, I-240, I-242, I-243, I-244 , I-246, I-248, I-249, I-250, I-251, I-252, II-1, II-4, II-5, II-6, II-7, II-8, II-9, II-11, III-1 and III-4 respectively showed at least 75% mortality at 2500 ppm. ,

[0632] B.2. Greenhouse whitefly (Greenhouse whitefly)

[0633] To evaluate the control of greenhouse whiteflies, the experimental unit consisted of a 96-well microtiter plate containing eggplant leaves and whitefly eggs. Compounds or mixtures were prepared using a solution containing 75% v / v water and 25% v / v DMSO. Different concentrations of the formulation were sprayed onto the insect diet at 2.5 μl using a custom-made microneedler, repeated twice. After application, the microtiter plates were incubated for 6 days at approximately 23 ± 1 °C and approximately 65 ± 5% RH. The mortality rate of hatched reptiles was then visually assessed.

[0634] In this experiment, compounds I-21, I-25, I-34, I-37, I-38, I-42, I-47, I-63, I-67, I-108, I-174 and II-4 showed a mortality rate of at least 75% at 2500 ppm, compared with the untreated control.

[0635] B.3. Green Peach Aphid (Peach Aphid) (Mixed Life Stages)

[0636] To evaluate the control of the green peach aphid via systemic absorption, the experimental unit consisted of a 96-well microtiter plate containing a liquid artificial diet under an artificial membrane. The compound was prepared using a solution containing 75% (v / v) water and 25% (v / v) DMSO. Different concentrations of the prepared compound were transferred to the aphid diet using custom-made pipettes, repeated twice. After application, 5–8 adult aphids were placed on the artificial membrane within the wells of the microtiter plate. The aphids were then allowed to feed on the treated aphid diet and incubated for 3 days at approximately 23 ± 1 °C and approximately 50 ± 5% relative humidity. Aphid mortality and fertility were then visually assessed.

[0637] In this experiment, compared to the unprocessed counterpart, compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-17, I-19, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-31, I-32, I-33, I-34, I-35, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-45, I-46, I-48, I-49, I-50, I-52, I-55, I-56, I-59, I- 61, I-63, I-65, I-66, I-67, I-68, I-69, I-71, I-72, I-74, I-75, I-76, I -77, I-78, I-81, I-84, I-85, I-87, I-88, I-90, I-95, I-97, I-98, I-102 , I-103, I-104, I-105, I-106, I-107, I-108, I-110, I-112, I-114, I-11 5, I-116, I-120, I-121, I-122, I-123, I-125, I-126, I-127, I-128, I-13 1, I-132, I-133, I-135, I-137, I-138, I-140, I-142, I-145, I-146, I-1 47, I-148, I-150, I-152, I-153, I-154, I-155, I-159, I-164, I-165, I- 167, I-168, I-169, I-170, I-173, I-174, I-177, I-181, I-183, I-184, I -188, I-190, I-191, I-192, I-194, I-196, I-197, I-200, I-206, I-210, I -211, I-212, I-215, I-216, I-219, I-220, I-221, I-222, I-226, I-227, I-228, I-230, I-231, I-232, I-233, I-235, I-236, I-238, I-240, I-242, I-243, I-244, I-246, I-248, I-249, I-250, I-251, I-252, II-1, II-4, II-5, II-6, II-7, II-8, II-9, II-11 and III-4 show a mortality rate of at least 75% under 2500 ppm.

[0638] B.4.Sweet night moth (Sweet night moth)

[0639] To evaluate the control effect on the tobacco budworm, the experimental unit consisted of a 96-well microtiter plate containing insect feed and 15–25 tobacco budworm eggs. The compound was prepared using a solution containing 75% v / v water and 25% v / v DMSO. Different concentrations of the prepared compound were sprayed onto the insect feed at 10 μl intervals using a custom-made microneedler, repeated twice. After application, the microtiter plates were incubated for 5 days at approximately 28 ± 1 °C and approximately 80 ± 5% relative humidity. Egg and larval mortality rates were then visually assessed.

[0640] In this test,compared to the comparison,compound I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-1 1、I-12、I-13、I-14、I-15、I-16、I-18、I-19、I-21、I-22、I-23、I-24、I-25、I -26、I-27、I-28、I-30、I-31、I-32、I-33、I-34、I-35、I-37、I-38、I-39、I-4 0、I-41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-52、I-53、I -55、I-56、I-57、I-58、I-59、I-60、I-61、I-63、I-65、I-66、I-67、I-68、I-6 9、I-70、I-71、I-72、I-74、I-75、I-76、I-77、I-78、I-79、I-81、I-84、I-85、I -87、I-88、I-89、I-91、I-94、I-95、I-97、I-98、I-99、I-100、I-101、I-102、 I-103、I-104、I-105、I-106、I-107、I-108、I-110、I-111、I-112、I-114、I-1 15、I-116、I-117、I-118、I-120、I-121、I-122、I-123、I-124、I-125、I-126 、I-127、I-128、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I- 139、I-140、I-142、I-143、I-145、I-146、I-147、I-148、I-149、I-150、I-15 1、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I -163、I-164、I-165、I-167、I-168、I-169、I-170、I-171、I-172、I-173、I-1 74、I-181、I-183、I-184、I-188、I-189、I-190、I-191、I-192、I-194、I-196、 I-197、I-198、I-199、I-200、I-204、I-205、I-206、I-207、I-208、I-209、I-2 10、I-211、I-212、I-214、I-215、I-216、I-219、I-220、I-221、I-222、I-223、I-226, I-227, I-228, I-230, I-231, I-232, I-233, I-234, I-235, I-236, I-238, I-240, I-242, I-243, I-244, I-246, I-248, I- 249, I-250, I-251, I-252, II-1, II-4, II-5, II-6, II-7, II-8, II-9, II-11, III-1, III-3 and III-4 each showed at least 75% mortality at 2500 ppm. ,

[0641] B.5. Yellow fever mosquito (Aedes aegypti)

[0642] To evaluate the control effect on yellow fever mosquitoes, the experimental unit consisted of a 96-well microtiter plate containing 200 μl of tap water and 5–15 newly hatched yellow fever mosquito larvae per well. The active compound was prepared using a solution containing 75% (v / v) water and 25% (v / v) DMSO. Different concentrations of the prepared compound or mixture were sprayed onto the insect diet at 2.5 μl using a custom-made microatomizer, repeated twice.

[0643] After application, the microtiter plates were incubated at 28±1℃ and 80±5%RH for 2 days. The larval mortality rate was then visually evaluated.

[0644] In this test, compared to the comparison, compound I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-9、I-10、I-11、I- 13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-23、I-24、I-25、I-26、 I-27、I-28、I-30、I-31、I-32、I-33、I-34、I-35、I-37、I-39、I-40、I-41、I- 42、I-43、I-45、I-46、I-48、I-49、I-50、I-55、I-57、I-59、I-60、I-61、I-63、 I-65、I-66、I-67、I-68、I-69、I-70、I-71、I-72、I-74、I-75、I-76、I-78、I- 79、I-84、I-85、I-86、I-87、I-89、I-90、I-94、I-95、I-97、I-98、I-99、I-100 、I-101、I-102、I-103、I-104、I-106、I-107、I-108、I-110、I-111、I-114、I -115、I-116、I-117、I-118、I-120、I-121、I-122、I-123、I-124、I-126、I-12 7、I-128、I-130、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、 I-140、I-142、I-143、I-144、I-145、I-146、I-147、I-148、I-149、I-150、I-1 52、I-154、I-155、I-157、I-158、I-160、I-161、I-162、I-163、I-164、I-165 、I-168、I-169、I-170、I-172、I-173、I-174、I-177、I-181、I-183、I-184、I- 188、I-189、I-190、I-191、I-192、I-194、I-196、I-197、I-198、I-199、I-20 0、I-204、I-205、I-206、I-207、I-208、I-209、I-210、I-211、I-212、I-214、I -215、I-216、I-219、I-220、I-221、I-222、I-223、I-226、I-227、I-228、I-2 30、I-231、I-232、I-233、I-234、I-235、I-236、I-238、I-240、I-242、I-243、Cholesterols I-244, I-246, I-248, I-249, I-250, I-251, I-252, II-1, II-4, II-5, II-6, II-7, II-8, II-9, II-11, III-1, III-2, and III-3 each showed a mortality rate of at least 75% at 2500 ppm.

[0645] B.6. Diamondback moth (small diamondback moth)

[0646] The active compound was dissolved at the desired concentration in a 1:1 (v / v) mixture of distilled water and acetone. A surfactant (kinetic) was added at a ratio of 0.01 v / v. The test solution was prepared on the day of use. Cabbage leaves (60 mm in diameter) were immersed in the test solution and air-dried. The treated leaves were placed in Petitves dishes lined with damp filter paper and inoculated with 10 third-instar larvae. Mortality was recorded 72 hours after treatment. Feeding damage was also recorded using a 0–100% scale.

[0647] In this experiment, compared with the untreated control,Compound I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-1 4、I-15、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、I-28、 I-29、I-30、I-31、I-32、I-33、I-34、I-35、I-36、I-37、I-38、I-39、I-40、I- 41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-51、I-52、I-54、 I-55、I-56、I-58、I-59、I-60、I-61、I-62、I-63、I-64、I-65、I-66、I-67、I- 68、I-69、I-70、I-71、I-72、I-73、I-74、I-75、I-76、I-77、I-78、I-79、I-80 、I-81、I-82、I-84、I-85、I-86、I-87、I-88、I-89、I-90、I-91、I-92、I-93、I -94、I-95、I-96、I-97、I-98、I-99、I-100、I-101、I-102、I-103、I-104、I-10 5、I-106、I-107、I-108、I-109、I-110、I-111、I-112、I-113、I-114、I-115、 I-116、I-117、I-118、I-119、I-120、I-121、I-122、I-123、I-124、I-125、I- 126、I-127、I-128、I-129、I-130、I-131、I-132、I-133、I-134、I-135、I-13 6、I-137、I-138、I-139、I-140、I-141、I-142、I-143、I-144、I-145、I-146、I -147、I-148、I-149、I-150、I-151、I-152、I-153、I-154、I-155、I-156、I-1 57、I-158、I-159、I-160、I-161、I-162、I-163、I-164、I-165、I-166、I-167 、I-168、I-169、I-170、I-171、I-172、I-173、I-174、I-175、II-1、II-3、II-4、II-5、II-6、II-7、II-8、III-2、III-3、III-4 respectively show at least 75% mortality at 300ppm。,

[0648] B.7. Orchid Thrips

[0649] Orchid thrips adults used for bioanalysis were obtained from a population continuously maintained under laboratory conditions. For testing purposes, the test compounds were diluted in a 1:1 mixture (volume ratio) of acetone and water with 0.01 vol% Kinetic added.

[0650] The thrips control efficacy of each compound was evaluated using a flower dip technique. Orchid petals were immersed in the treatment solution and dried in Petit-British dishes. The treated petals were placed in resealable plastic containers along with approximately 20 adult thrips. All test sites were maintained in darkness and at approximately 28°C throughout the analysis. Mortality rates were recorded 72 hours post-treatment.

[0651] In this test, compared to the comparison, compound I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23 、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-32、I-33、I-34、I-3 5、I-36、I-37、I-38、I-39、I-40、I-41、I-42、I-43、I-44、I-45、I-46、I- 47、I-48、I-49、I-50、I-51、I-52、I-53、I-54、I-55、I-56、I-58、I-59、I -60、I-61、I-62、I-63、I-64、I-65、I-66、I-67、I-68、I-69、I-70、I-71、 I-72、I-73、I-74、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-83、I-84 、I-85、I-86、I-87、I-88、I-89、I-91、I-92、I-93、I-94、I-95、I-97、I-9 8、I-99、I-100、I-101、I-102、I-103、I-104、I-105、I-106、I-107、I-10 8、I-110、I-111、I-112、I-113、I-114、I-115、I-116、I-117、I-118、I-1 19、I-120、I-121、I-122、I-123、I-124、I-125、I-126、I-127、I-128、I- 130、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I-140、I -142、I-144、I-145、I-146、I-147、I-148、I-149、I-150、I-151、I-152、 I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I-163 、I-164、I-165、I-166、I-167、I-168、I-169、I-170、I-171、I-173、I-174、I-175、II-1、II-4、II-5、II-6、II-7、II-8 respectively show at least 75% mortality rate at 300ppm。

[0652] B.8. Nezara viridula

[0653] Dissolve the active compound at the desired concentration in a 1:1 (v / v) mixture of distilled water and acetone. Add a surfactant (kinetic) at a ratio of 0.01 vol%. Prepare the test solution on the day of use. Place the pods in 90 × 50 mm glass petri dishes lined with moist filter paper and inoculate 10 late-stage third-instar green rice bugs. Spray approximately 2 mL of the solution into each petri dish using a handheld nebulizer. Maintain the treated apparatus at approximately 25–26 °C and approximately 65–70% relative humidity. Record the mortality percentage after 5 days.

[0654] In this test, compounds I-1, I-2, I-3, I-4, I-9, I-12, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I- 32. I-38, I-55, I-60, I-63, I-65, I-66, I-67, I-68, I-72, I-76, I-98, I-102, I-104, I-108, I-110, I-1 11. I-115, I-116, I-119, I-120, I-132, I-135, I-137, I-140, I-145, I-146, I-147, I-150, I-154, I-15 7. I-158, I-159, I-165, I-166, I-168, I-174, II-4, II-5, II-6, II-7 and II-8 respectively showed at least 75% mortality at 300 ppm.

[0655] B.9. Black-tailed Leafhopper (Two-spotted Black-tailed Leafhopper)

[0656] Clean and wash 4-5 week old rice seedlings with cut upper leaves 24 hours before spraying. Prepare the active compound in a 1:1 acetone:water (volume ratio) and add 0.01 vol% surfactant (kinetic). Spray potted rice seedlings with 5-6 ml of the test solution, air dry, cover with Mylar cages, and inoculate with 10 adults. Maintain the treated rice plants at approximately 28-29°C and approximately 50-60% relative humidity. Record the mortality percentage after 72 hours.

[0657] In this experiment, compounds I-24, I-25, I-28, I-32, I-60, I-63, I-75, I-101, I-108, I-115, I-116, I-118, I-119, I-120, I-126, I-137, I-146, I-170, I-173, I-174, I-175, II-4, II-6, II-7, and II-8 showed a mortality rate of at least 75% at 300 ppm, compared to the untreated control.

[0658] B.10. Red spider mite (Tetranychus kanzawai)

[0659] Dissolve the active compound at the desired concentration in a 1:1 (volume ratio) mixture of distilled water and acetone. Add a surfactant (kinetic) at a ratio of 0.01% (volume). Prepare the test solution on the day of use. Clean potted cowpeas aged 4-5 days with tap water and use pneumatic... Spray 1-2 mL of test solution using a handheld nebulizer at 20-30 psi (≈1.38-2.07 bar). Air-dry the treated plants and then inoculate them with 30 or more mites by cutting cassava leaves from the rearing population. Place the treated plants in a holding chamber at approximately 25-26°C and approximately 65-70% relative humidity. Evaluate the mortality percentage 72 hours after treatment.

[0660] In this experiment, compounds I-9, I-27, I-61, I-98, I-104, I-111, I-132, I-145, I-146, I-150, I-174, II-1, II-4, II-5, II-6, II-7 and II-8 showed a mortality rate of at least 75% at 300 ppm, compared with the untreated control.

[0661] B.11. Southern Grey-winged Noctuid Moth (Spodoptera eridania), second instar larvae

[0662] The active compound was formulated into a 10,000 ppm solution in 100% cyclohexanone using a Tecan liquid processor and supplied in tubes. This 10,000 ppm solution was serially diluted in 100% cyclohexanone to prepare transition solutions. These were used as stock solutions, and the final dilution was prepared by diluting the latter in 50% acetone:50% water (v / v) using a Tecan solution and placed in 10 or 20 ml glass vials. Nonionic surfactant The solution was added at 0.01% (by volume). The vial was then inserted into an automated electrostatic sprayer equipped with a misting nozzle for application to the plants / insects. Two lima bean plants (Sieva cultivar) were planted in pots and selected for treatment at the first true leaf stage. The test solution was sprayed onto the leaves using an automated electrostatic plant sprayer equipped with a misting nozzle. The plants were dried in a sprayer fume hood and then removed from the sprayer. Each pot was placed in a perforated plastic bag with a zip closure. Ten to eleven gray-winged noctuid moth larvae were placed in the bag, and the bag was zipped shut. The test plants were kept in a growth chamber at approximately 25°C and approximately 20–40% relative humidity for four days, avoiding direct exposure to fluorescence (14:10 bright:dark photocycle) to prevent heat trapping inside the bag. Four days after treatment, mortality and reduced feeding were evaluated compared to the untreated control plants.

[0663] In this test, compared to the unprocessed counterpart, compounds I-7, I-12, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-52, I-53, I-55, I- 56, I-57, I-58, I-59, I-60, I-61, I-63, I-64, I-65, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I- 77, I-78, I-79, I-80, I-81, I-82, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-93, I-94, I-95, I-97, I-98, I-99, I- 100, I-101, I-102, I-103, I-104, I-105, I-106, I-107, I-108, I-109, I-110, I-111, I-114, I-115, I-126, I-127, I -128, I-129, I-130, I-131, I-137, I-138, I-139, I-140, I-141, I-143, I-144, I-145, I-146, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-156, I-157, I-159, I-160, I-161, I-162, I-163, I-164, I-165, I-167, I-169, I-170, I-171, I-173, I-174, I-175, I-176, II-1, II-4, II-5, II-6, II-7 and II-8 show a mortality rate of at least 75% under 300 ppm.

[0664] B.12. Bemisia argentifolii (adult)

[0665] Contains 100% environmentally friendly active compounds in Tecan's liquid processing equipment and contains 10,000ppm solution. Contains 100% environmentally friendly 10,000ppm solution. In general, Tecan contains 50% alcohol: 50% water (body ratio), and the final solution is poured into a 5 or 10ml glass bottle. non-reactive surface active Include the solution at 0.01% (by volume). Then insert the vial into an automatic electrostatic sprayer equipped with a misting nozzle for application to the plants / insects. Spray the cotyledon stage cotton plants (one plant per pot) using an automatic electrostatic plant sprayer equipped with a misting nozzle. Dry each plant in the sprayer fume hood, then remove it from the sprayer. Place each pot in a plastic cup and introduce approximately 10-12 adult whiteflies (approximately 3-5 days old). Use a suction device and a non-toxic pipette tip connected to a protective pipette. Insects were collected in tubes. The tube containing the collected insects was then gently inserted into the soil containing the treated plants, allowing the insects to crawl out of the tube and reach the leaves to feed. The cups were covered with reusable sieve lids. The test plants were kept in a growth chamber at approximately 25°C and approximately 20–40% relative humidity for 3 days, avoiding direct exposure to fluorescence (14:10 bright:dark photocycle) to prevent heat trapping inside the cups. Mortality was evaluated after 3 days of treatment compared to untreated control plants.

[0666] In this test, compounds I-21, I-24, I-25, I-32, I-47, I-63, I-65, I-69, I-75, I-77, I-78, I-79, I-80, I-87, I-93, I-98, I-100, I-109, I-110, I-111, I-11 4. I-126, I-128, I-130, I-137, I-140, I-143, I-145, I-153, I-156, I-157, I -160, I-162, I-174, II-1, II-4, II-6, II-7 and II-8 each showed at least 75% mortality at 300 ppm.

Claims

1. Compounds of Formula I and their agricultural or veterinary salts: in R 1 Ci-C2haloalkyl; W is a phenyl group or a 5- or 6-membered heteroaryl group containing one heteroatom selected from N, O, and S as a ring member; wherein W is unsubstituted, partially or completely replaced by R. 2 replace; R 2 For halogen, OR 21 C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl-S(O) m C1-C3 haloalkyl-S(O) m C1-C3 alkoxy-C1-C4 alkyl, C1-C3 haloalkoxy-C1-C4 alkyl, C1-C3 haloalkyl-S(O) m -C1-C4 alkyl groups; these groups are optionally R 211 replace; m is 0, 1, or 2; R 21 Ci-C6-alkyl, which groups are unsubstituted or partially or completely substituted by R 211 substituted; R 211 R is halogen; X is NR 3 O or S(O) m ; R 3 H, C1-C4 alkyl, the latter being unsubstituted or surrounded by one or two groups CN, C3-C4 cycloalkyl, C1-C2 alkoxy, containing N, O, and S(O). m The heteroatom is substituted as a 4-membered heterocyclic group of the ring member; G is phenyl or a 5- or 6-membered heteroaryl comprising 1 heteroatom selected from N, O and S as a ring member; wherein G is unsubstituted, partially or fully substituted by R 4 substituted; R 4 R 2 is a group as defined for R 4 ; U is O; R 5 H, C1-C6 alkyl, C1-C6 haloalkyl, which is unsubstituted or partially or completely replaced by R 51 Replace; or N(R 12a )R 12b 、S(O) m R 13 、C(=O)OR 13 、C(=U)N(R 12a )R 12b , C3-C8 cycloalkyl, C3-C8 halocycloalkyl, phenyl, containing 1, 2, 3 or 4 atoms selected from N, O and S(O). m The heteroatom is a 3, 4, 5, 6, or 7-member saturated or partially unsaturated heterocycle, or contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S(O). m The heteroatoms are 5- or 6-membered heteroaryl groups that are ring members, and these rings are either unsubstituted or partially or completely replaced by R. 52 replace; R 51 Halogen, CN, N(R) 12a )R 12b C(=O)N(R) 12a )R 12b ; Unsubstituted, partially halogenated and / or CN-substituted C3-C8 cycloalkyl groups; S(O) m R 13 C(=U)N(R) 12a )R 12b ; Phenyl or containing 1, 2 or 3 atoms selected from N, O, S(O). m The heteroatom is a 3, 4, 5, 6, or 7-member saturated, partially, or fully unsaturated heterocycle; or R 52 R is as defined in R 51 ; R 6 It is H or C1-C4 alkyl, C3-C4 cycloalkyl-C1-C2 alkyl, C1-C4 alkyl carbonyl or C1-C4 alkoxycarbonyl; or R 5 and R 6 together with the nitrogen to which they are bound form a zwitterionic entity; Y at G has one or two ring atoms of G between the point of attachment of G to X and Y; Y is a direct bond or CR 7 R 8 ; R 7 R 8 All are H or halogen, or R 7 and R 8 Together, they form a 3- or 4-membered saturated carbon ring; R 12a and R 12b is H, C1-C6alkoxy, C1-C6haloalkoxy, S(O) m -C1-C4alkyl, S(O) m -C1-C4haloalkyl, C1-C6 alkyl groups that are unsubstituted or partially or completely halogenated and / or converted to Cn, C1-C4 alkoxy, C1-C4 haloalkoxy, or S(O) groups. m -C1-C4 alkyl groups, S(O) m -C1-C4 haloalkyl, unsubstituted or C3-C6 cycloalkyl and oxosubstituted with one or two halogens and / or CN; Unsubstituted or partially or completely halogenated and / or substituted with CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C3-C4 cycloalkyl, C3-C4 cycloalkyl-C1-C4 alkyl—these rings may be substituted with one or two halogens and / or CN—and oxosubstituted C3-C8 cycloalkyl; Phenyl, benzyl, pyridyl, phenoxy, unsubstituted or partially or completely substituted with halogen and / or substituted with halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C3-C6 cycloalkyl, C3-C6 halocycloalkyl and (C1-C6 alkoxy)carbonyl; and comprising 1, 2 or 3 selected from N, O and S(O). m The heteroatom is a 3, 4, 5, or 6-member saturated, partially, or fully unsaturated heterocycle, wherein the heterocycle is optionally composed of one or more R atoms. 14 replace; R 13 It is H, C1-C6 alkyl, which is unsubstituted or partially or completely halogenated and / or converted to C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O) m -C1-C4 alkyl and oxo-substituted; Unsubstituted or partially or completely halogenated and / or converted to C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S(O) m -C1-C4 alkyl and oxo-substituted C3-C8 cycloalkyl; Phenyl, benzyl, pyridyl and phenoxy compounds that are not substituted or are partially or completely substituted with halogenated and / or substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy and (C1-C6 alkoxy)carbonyl; R 14 is halogen.

2. A compound of formula I according to claim 1, wherein X is NR 3 .

3. The compound of formula I according to claim 1, wherein X is O.

4. The compound of formula I according to claim 1, wherein Y is a direct bond.

5. The compound of formula I according to claim 2, wherein Y is a direct bond.

6. The compound of formula I according to claim 3, wherein Y is a direct bond.

7. The compound of formula I according to any one of claims 1-6, wherein W is a compound surrounded by 1-3 halogen groups, a halomethyl group, a halomethoxy group, a halomethyl group, or a -S(O) group. m Substituted phenyl groups.

8. The compound of formula I according to any one of claims 1-6, wherein X is NR. 3 And R 3 The alkyl group is H or C1-C4 alkyl, wherein the alkyl group is unsubstituted or substituted by one or two groups CN, C3-C4 cycloalkyl, or C1-C2 alkoxy.

9. Compounds of formula I according to claim 7, wherein X is NR 3 and R 3 is H, C1-C4alkyl, which alkyl is unsubstituted or substituted by one or two groups CN, C3-C4cycloalkyl, C1-C2alkoxy.

10. The compound of formula I according to any one of claims 1-6, wherein G is a group G1, G2, G3 or G4: wherein # is a bond to X, % is a bond to Y and R 41 and R 42 is H or a group R 4 .

11. The compound of formula I according to claim 7, wherein G is a group G1, G2, G3 or G4: wherein # is a bond to X, % is a bond to Y and R 41 and R 42 is H or a group R 4 .

12. The compound of formula I according to claim 8, wherein G is a group G1, G2, G3 or G4: wherein # is a bond to X, % is a bond to Y and R 41 and R 42 is H or a group R 4 .

13. Compounds of formula I according to claim 10, wherein R 41 and R 42 are H, halogen, halogenmethyl or halogenmethoxy.

14. The compound of claim 10, wherein G is G1 and R 42 is H.

15. The compound of formula I according to any one of claims 1-6, wherein R 5 H, C1-C6 alkyl, C1-C6 haloalkyl, which is unsubstituted or partially or completely replaced by R 51 Replace; or N(R) 12a )R 12b S(O) m R 13 C(=O)OR 13 C(=U)N(R) 12a )R 12b C3-C8 cycloalkyl, C3-C8 halocycloalkyl, phenyl, or containing 1, 2, 3 or 4 atoms selected from N, O and S(O). m The heteroatoms are 4, 5, or 6-member saturated, partially or completely unsaturated heterocycles, which are either unsubstituted or partially or completely replaced by R. 52 replace; R 51 halogen, CN, N(R 12a )R 12b , C(=O)N(R 12a )R 12b ; C3-C8 cycloalkyl groups that are unsubstituted, partially and / or partially substituted with CN; S(O) m R 13 , C(=U)N(R 12a )R 12b ; phenyl or a 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O, S(O) m as ring members; R 52 R is as defined in R 51 and R is as defined in R R 6 is H, C1-C4alkyl, C3-C4cycloalkyl-C1-C2alkyl or C1-C4alkoxycarbonyl.

16. The compound of formula I according to claim 7, wherein R 5 H, C1-C6 alkyl, C1-C6 haloalkyl, which is unsubstituted or partially or completely replaced by R 51 Replacement; or N(R) 12a )R 12b S(O) m R 13 C(=O)OR 13 C(=U)N(R) 12a )R 12b C3-C8 cycloalkyl, C3-C8 halocycloalkyl, phenyl, or containing 1, 2, 3 or 4 atoms selected from N, O and S(O). m The heteroatoms are 4, 5, or 6-member saturated, partially or completely unsaturated heterocycles, which are either unsubstituted or partially or completely replaced by R. 52 replace; R 51 halogen, CN, N(R 12a )R 12b , C(=O)N(R 12a )R 12b ; C3-C8 cycloalkyl groups that are unsubstituted, partially and / or partially substituted with CN; S(O) m R 13 , C(=U)N(R 12a )R 12b ; phenyl or a 5-, 6-, or 10-membered saturated, partially or fully unsaturated heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, S(O) m as ring members; or R 52 R is as defined in R 51 and R is as defined in R R 6 is H, C1-C4alkyl, C3-C4cycloalkyl-C1-C2alkyl or C1-C4alkoxycarbonyl.

17. The compound of formula I according to any one of claims 1-6, corresponding to formula IA: 。 18. The compound of formula I according to claim 7, corresponding to formula IA: 。 19. The compound of formula I according to claim 8, corresponding to formula IA: 。 20. The compound of formula I according to claim 10, corresponding to formula IA: 。 21. The compound of formula I according to claim 15, corresponding to formula IA: 。 22. An agricultural or veterinary composition comprising at least one compound according to any one of claims 1-21 and / or at least one of its agricultural or veterinary salts and at least one agricultural or veterinary inert liquid and / or solid carrier.

23. An agricultural composition for controlling animal pests, comprising at least one compound as defined in any one of claims 1-21, at least one inert liquid and / or solid acceptable carrier, and, if necessary, at least one surfactant.

24. A method for the prevention or control of invertebrate pests for purposes other than disease diagnosis and treatment, the method comprising contacting the pest or its food source, habitat or breeding ground with an effective amount of at least one compound as defined in any one of claims 1-21.

25. A method of protecting growing plants from attack by, or infestation with, invertebrate pests which comprises contacting the plants, or the soil or water in which the plants are growing, with a pesticidally effective amount of at least one compound as defined in any of claims 1 to 21.

26. A method of treating seed which comprises using a compound as defined in any of claims 1 to 21, or an enantiomer, diastereomer or salt thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.

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