N-(3-(aminomethyl)-phenyl)-5-(4-phenyl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole-3-amine derivatives and similar compounds as pesticidal agents

Abstract

The present invention relates to isoxazoline compounds of formula I, wherein the variables have the meanings as defined in the description; to a composition comprising the same; to active compound combinations comprising the same; and to the use thereof for protecting growing plants and animals from infestation or infestation by invertebrate pests; furthermore, to seeds comprising such compounds. Preferred compounds are, for example, N-(3-(aminomethyl)-4-fluorophenyl)-5-(4-fluorophenyl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole-3-amine derivatives. # imgabs0 #

Description

[0001] The present invention relates to isoxazoline compounds of formula I, their N-oxides, stereoisomers and agriculturally or veterinarily acceptable salts,

[0002]

[0003] wherein

[0004] R 1 is C 1 -C 2 -haloalkyl;

[0005] W is phenyl or pyridyl; where W is unsubstituted, partially or fully substituted by R 2 substituted;

[0006] R 2 is halogen, OR 21 , NR 22 R 23 , CN, NO 2 , Si(CH 3 ) 3 , SF 5 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkyl-S(O) m , C 1 -C 3 -haloalkyl-S(O) m , C 3 -C 6 -cycloalkyl-S(O) m , C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C1 -C 3 -haloalkoxy-C 1 -C 4 -alkyl, C 1 -C 3 -alkyl-S(O) m -C 1 -C 4 -alkyl, C 1 -C 3 -haloalkyl-S(O) m -C 1 -C 4 -alkyl; these groups are unsubstituted, partially or fully substituted by R 211 substituted;

[0007] R 21 is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, Si(C 1 -C 4 -alkyl) 3 、C 1 -C 3 -alkyl-S(O) m 、C 3 -C 6 -cycloalkyl-S(O) m 、S(O) m R 24 ,these groups are unsubstituted, partially or fully substituted by R 211 substituted;

[0008] R 22 、R 23 is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy, C 1 -C 6-haloalkoxy, which is unsubstituted or partially or fully substituted by R 221 or

[0009] C 1 -C 6 -alkyl-C(=O)OR 24 、C 1 -C 6 -alkyl-C(=U)N(R 25a )R 25b ,

[0010] C 1 -C 6 -alkyl-C(=NR 25 )N(R 25a )R 25b 、S(O) m R 24 、S(O) m N(R 25a )R 25b 、C(=U)R 26 、C(=O)OR 24 、C(=U)N(R 25a )R 25b ,

[0011] C(=S)SR 24 、C(=NR 25 )R 26 ;

[0012] C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl;

[0013] R 22 and R 23 together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered fully unsaturated heterocycle, which may additionally contain a heteroatom selected from N, O and S(O) m as a ring member, and the heterocycle is unsubstituted or partially or fully substituted by R 222 ; or

[0014] R 22 and R 23 together form a group =C(R 26 ) 2 、=S(O) m (R 24 ) 2 、=S(O) m R 24 N(R 25a )R25b ;

[0015] U is O or S;

[0016] R 24 is H, Si(C 1 -C 4 -alkyl), 3 C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, which is unsubstituted or partially or fully halogenated and / or substituted by: C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo;

[0017] C 3 -C 8 -cycloalkyl, which is unsubstituted or partially or fully halogenated and / or substituted by: C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo;

[0018] phenyl, benzyl, pyridyl and phenoxy, which are unsubstituted or partially or fully halogenated and / or substituted by: C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, and (C 1 -C 6-(alkoxy)carbonyl;

[0019] R 25 is H, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C(=U)R 26 、C(=O)OR 24 、

[0020] C(=O)NH(C 1 -C 4 -alkyl),

[0021] C(=O)N(C 1 -C 4 -alkyl) 2 、S(O) m R 24 、S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -

[0022] haloalkyl, S(O) m -C 3 -C 6 -cycloalkyl, Si(C 1 -C 4 -alkyl) 3 、NR 24 C(=O)-C 1 -C 4 -alkyl, NR 24 C(=O)-C 3 -C 6 -cycloalkylalkyl, CR 24 N=OR 24 、CR 26 N=OR 24 ,

[0023] C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, which is unsubstituted or partially or fully halogenated and / or substituted by: CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C which is unsubstituted or substituted by 1 or 2 halogens and / or CN 3 -C 6 -cycloalkyl, phenyl, or a 4-, 5-, or 6-membered saturated, partially or fully unsaturated heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S(O) as ring members, these rings being unsubstituted or partially or fully substituted by: halogen, CN, C m -C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 2 -alkyl-C 1 -C 2 -alkoxy, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkylthio, C(=O)-C 1 -C 4 -alkoxy, and oxo group;

[0024] C 3 -C 8 -cycloalkyl, which is unsubstituted or partially or fully halogenated and / or substituted by: CN, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C(=O)NH(C 1 -C 4 -alkyl), C(=O)N(C 1 -C 4 -alkyl) 2, phenyl, or a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S(O) as ring members, these rings being unsubstituted or substituted in part or in full by: halogen, CN, C m -C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 2 -alkyl-C 1 -C 2 -alkoxy, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkylthio;

[0025] phenyl, benzyl, phenoxy, a 4-, 5- or 6-membered saturated, partially or fully unsaturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S(O) as ring members, m these groups being unsubstituted or substituted in part or in full by halogenation and / or by: halogen, CN, NO

[0026] , C 2 -C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, and (C 1 -C 6-alkoxy)carbonyl; and a 3-, 4-, 5- or 6-membered saturated, partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S(O) as ring members, where the heterocycle is optionally substituted with one or more R m substituents; 222

[0027] R 25a and R 25b have the meanings given for R 25 ; or

[0028] R 25a and R 25b present on the same nitrogen atom may together form =C(R 26 ) 2 , =S(O) m (R 24 ) 2 , or =S(O) m R 24 N(R 25a )R 25b ; or

[0029] R 25a and R 25b together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, where the heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O)m as ring members, and the heterocycle is unsubstituted or substituted with one or more of the following substituents: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and oxo; or R 25a and R 25b together with the nitrogen atom to which they are attached in the group C(=NR 25 )N(R 25a )R 25b form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, where the heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O) m as ring members, and the heterocycle is unsubstituted or substituted with one or more of the following substituents: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 ​- haloalkyl, C 1 - C 4 - alkoxy, C 1 - C 4 - haloalkoxy, and oxo;

[0030] R 26 is H, CN, OH, SH, C 1 - C 6 - alkyl, C 2 - C 6 - alkenyl, C 2 - C 6 - alkynyl, C 3 - C 8 - cycloalkyl, which is unsubstituted, partially or fully halogenated and / or substituted by 1, 2 or 3 of the following groups: CN, C 1 - C 4 - alkyl, C 3 - C 4 - cycloalkyl, C 1 - C 4 - haloalkyl, C 1 - C 4 - alkoxy, C 1 - C 4 - haloalkoxy, S(O) m - C 1 - C 4 - alkyl, S(O) m - C 1 - C 4 - haloalkyl, phenyl, or a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle containing 1, 2 or 3 N, O and S(O) m heteroatoms as ring members, these rings being unsubstituted or partially or fully substituted by the following: halogen, CN, C 1 - C 4 - alkyl, C 1 - C 4 - haloalkyl, C 1 - C 3 - alkoxy, C 1 - C 3 - haloalkoxy, C 1 - C 2 - alkyl - C 1 - C 2 - alkoxy, C 1 - C 3 - alkylthio, C 1 - C 3 - haloalkylthio, and oxo;

[0031] C 1 - C6 -alkoxy, C 1 -C 6 -haloalkoxy, S(O) m -C 1 -C 6 -alkyl, S(O) m -C 1 -C 6 -haloalkyl, Si(C 1 -C 4 -alkyl) 3 , C(=O)N(R 25a )R 25b ,

[0032] phenyl, benzyl, phenoxy, a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S(O) m as ring members, these rings being unsubstituted or partially or fully halogenated and / or substituted by R 222 ;

[0033] R 211 is halogen, CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 4 -alkenyloxy, C 3 -C 4 -haloalkenyloxy, C 3 -C 4 -alkynyloxy, C 3 -C 4 -haloalkynyloxy, C 1 -C 4 -alkyl-S(O) m , C 1 -C 4 -haloalkyl-S(O) m , C 3 -C 4 -alkenyl-S(O) m , C 3 -C 4 -haloalkenyl-S(O) m , C 3 -C 4 -alkynyl-S(O) m , C 3 -C 4 -haloalkynyl-S(O) m , and oxo;

[0034] C 3-C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -halocycloalkenyl;

[0035] R 221 is CN, NO 2 , OH, SH, SCN, SF 5 , Si(C 1 -C 4 -alkyl) 3 , C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkyl-S(O) m , C 1 -C 6 -haloalkyl-S(O) m , C(=O)N(R 25a )R 25b ;

[0036] C 3 -C 8 -cycloalkyl, which is unsubstituted, partially or completely halogenated and / or partially or completely substituted by: C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and oxo; or

[0037] two R's present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl 221 can together be =O, =CH(C 1 -C 4 -alkyl), =C(C 1 -C 4 -alkyl) 2 , =N(C 1 -C 6 -alkyl), or =NO(C 1 -C 6 -alkyl);

[0038] R 222 is halogen, NO 2, CN, OH, SH, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, N(R 25a )R 25b , C(=O)NR 25a R 25b , Si(C 1 -C 4 -alkyl) 3 ;

[0039] C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, which is unsubstituted or partially or completely halogenated and / or substituted by: CN, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo group;

[0040] C 3 -C 8 -cycloalkyl, which is unsubstituted or partially or completely halogenated and / or substituted by: CN, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo; or

[0041] two Rs that are present on the same atom of an unsaturated or partially unsaturated ring 222 can be =O, =S, =N(C 1 -C 6 -alkyl), =NO(C 1 -C 6 -alkyl), =CH(C 1 -C 4 -alkyl) or =C(C 1 -C 4 -alkyl)C 1 -C 4 -alkyl; or

[0042] two Rs on two adjacent carbon atoms 222 together with the carbon atoms to which they are attached form a 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring, where the ring can contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O) m as ring members, and where the ring is optionally substituted by one or more of the following groups: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and / or C 1 -C 4 -haloalkoxy;

[0043] m is 0, 1, or 2;

[0044] X is NR 3 or O;

[0045] R 3 is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, OR 21 、C1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, which is unsubstituted or partially or completely substituted by R 31 ; or

[0046] C 1 -C 6 -alkyl-C(=O)OR 24 、C 1 -C 6 -alkyl-C(=U)N(R 25a )R 25b ,

[0047] C 1 -C 6 -alkyl-C(=NR 25 )N(R 25a )R 25b 、C 1 -C 6 -alkyl-OC(=O)OR 24 、

[0048] N(R 25a )R 25b 、S(O) m R 24 、S(O) m N(R 25a )R 25b 、C(=U)R 26 、C(=O)OR 24 、

[0049] C(=U)N(R 25a )R 25b 、C(=S)SR 24 、C(=NR 25 )R 26 ;

[0050] C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, phenyl, a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O and S(O) m as ring members, or a 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S(O) m as ring members, these rings being unsubstituted or partially or completely substituted by R 32 ;

[0051] R31 is halogen, CN, NO 2 , OH, SH, SCN, SF 5 , Si(C 1 -C 4 -alkyl) 3 , N(R 25a )R 25b , C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkyl-S(O) m , C 1 -C 6 -haloalkyl-S(O) m , C(=O)N(R 25a )R 25b ;

[0052] C 3 -C 8 -cycloalkyl, which is unsubstituted, partially or completely halogenated and / or partially or completely substituted by: CN, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, and oxo;

[0053] S(O) m R 24 , S(O) m N(R 25a )R 25b , C(=U)R 26 , C(=O)OR 24 , C(=U)N(R 25a )R 25b ,

[0054] C(=S)SR 24 , C(=NR 25 )R 26 ;

[0055] phenyl, benzyl, phenoxy, or containing 1, 2 or 3 selected from N, O, S(O) m3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated, partially or fully unsaturated heterocycles having a heteroatom as a ring member, where these rings are unsubstituted or are substituted partially or fully by R 222 or

[0056] two Rs present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl 31 can together be =O, =CH(C 1 -C 4 -alkyl), =C(C 1 -C 4 -alkyl) 2 , =N(C 1 -C 6 -alkyl), or =NO(C 1 -C 6 -alkyl);

[0057] R 32 is a group as defined in R 31 or is selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl, where these groups are unsubstituted, substituted partially or fully by halogenation and / or by one or two CN, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or an oxo group;

[0058] G is phenyl, or a 6-membered heteroaryl having 1 or 2 N atoms as ring members; where G is unsubstituted, substituted partially or fully by R 4 ;

[0059] R 4 is as defined for R 2 ;

[0060] R 5 is a group as defined for R 3 ;

[0061] Y is a direct bond or C(R 4a )(R 4b );

[0062] R 4a and R 4b are H, halogen, CN, NO 2 , C 1 -C4 -alkyl, C 1 -C 4 -haloalkyl, C which is unsubstituted or substituted by CN or halogen 3 -C 6 -cycloalkyl;

[0063] R 4 and R 4a and / or R 4b together form a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle which may contain 1 or 2 heteroatoms selected from N, O and S(O) m as ring members, and wherein the ring is unsubstituted or substituted by one or more groups R 2 ;

[0064] Q is C(=U) or S(O) m ;

[0065] R 6 is as defined for R 25 ; or

[0066] R 5 and R 6 together form a 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle which may contain 1 or 2 heteroatoms selected from N, O and S(O) 5 in addition to N(R m ) as ring members, and wherein the ring is unsubstituted or substituted by one or more groups R 2 ;

[0067] The present invention also provides an agricultural composition which comprises at least one compound of formula I, its stereoisomers and / or its agriculturally acceptable salts, and at least one liquid and / or solid carrier, in particular at least one agriculturally acceptable inert liquid and / or solid carrier.

[0068] The present invention also provides a veterinary composition which comprises at least one compound of formula I, its stereoisomers and / or its veterinarily acceptable salts, and at least one liquid and / or solid carrier, in particular at least one veterinarily acceptable inert liquid and / or solid carrier.

[0069] The present invention also provides a method for controlling invertebrate pests, which comprises treating the pests, their food supply, their habitat or their breeding ground or the cultivated plants, plant propagation materials (such as seeds), soil, area, material or environment in which the pests grow or may grow, or the materials, cultivated plants, plant propagation materials (such as seeds), soil, surface or space to be protected from pest infestation or infection with a pest - controlling effective amount of a compound of formula I as defined herein or a salt thereof.

[0070] The present invention also relates to a plant propagation material, in particular a seed, comprising at least one compound of formula I and / or an agriculturally acceptable salt thereof.

[0071] The present invention further relates to a method for treating or protecting an animal from parasite infestation or infection, which comprises bringing the animal into contact with a parasiticide - effective amount of a compound of formula I or a veterinarily acceptable salt thereof. Bringing an animal into contact with the compound I, its salt or veterinary composition of the present invention means administering or giving it to the animal.

[0072] WO 2010 / 020522, WO 2010 / 135360, WO 2022 / 171472 and EP 4043444 describe structurally closely related active compounds. It is mentioned that these compounds can be used against invertebrate pests.

[0073] However, there is still a need for highly effective and versatile agents against invertebrate pests. Accordingly, it is an object of the present invention to provide compounds having good pesticidal activity against a large number of different invertebrate pests, especially against difficult - to - control pests (such as insects) and showing a broad spectrum of activity.

[0074] It has been found that these objects can be achieved by the compounds of formula I as shown and defined below, their stereoisomers, salts, tautomers and N - oxides, especially their agriculturally acceptable salts.

[0075] The compound of formula I, wherein X is NR 3 )(formula I.1) can be prepared by reacting a compound of formula IIA.1 with a compound of formula IIIA, wherein X H is a halogen, preferably bromine or iodine, in a Buchwald - Hartwig reaction [see WO 2022 / 171472 or WO 2010 / 135360].

[0076]

[0077] This transformation is typically carried out at a temperature of 20 °C to 180 °C, preferably 60 °C to 100 °C, in an inert solvent, in the presence of a base and a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) / 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Pd 2 (dba) 3 / XantPhos), [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)-phenyl)]palladium(II) chloride, etc. [see WO 2017 / 069980]. Suitable solvents are ethers such as 1,4-dioxane, THF, etc.; or alcohols such as butanol, tert-amyl alcohol, etc.; or polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), etc. Preferably, 1,4-dioxane is used. Mixtures of the solvents mentioned can also be used. Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal carbonates such as Li 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CaCO 3 , etc.; or organic compounds such as alkali metal alkoxides such as lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, etc. Cs 2 CO 3 is particularly preferred. The bases are usually used in equimolar amounts; however, they can also be used in excess. The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of IIA.1 (based on IIIA).

[0078] Compounds of formula IIA.1 are known from the literature [see INV 202944] and can be prepared as described therein.

[0079] Alternatively, the compounds of formula I can also be prepared by reacting a compound of formula IIB (where X H is a halogen, preferably bromine or chlorine) with a compound of formula IIIB in a base-promoted ipso substitution reaction [see WO 2022 / 171472].

[0080]

[0081] This transformation is usually carried out in an inert solvent in the presence of a base at a temperature of 25 °C to 200 °C, preferably 60 °C to 150 °C. Suitable solvents are DMF, DMA, NMP, DMSO, etc.; NMP and DMF are particularly preferred. Mixtures of the solvents mentioned can also be used. Suitable bases are usually 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 hydrides, such as LiH, NaH, KH, CaH 2 etc.; or alkali metal and alkaline earth metal carbonates, such as Li 2 CO 3 、K 2 CO 3 、CaCO 3 etc.; or organic bases such as N-containing heteroaromatic compounds such as pyridine, 2,6-dimethylpyridine, etc. The bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0082] The compounds of formula IIB can be prepared as described in the literature [see WO 2022 / 171472].[[]]END[]]

[0083] In addition, the compounds of formula I.1 can be prepared by reacting a compound of formula IIB (wherein X H is a halogen, preferably bromine or chlorine) with an amine of formula IIIB.1 in an acid-promoted ipso-substitution reaction [see WO 2022 / 171472].[[]]END[]]

[0084]

[0085] This transformation is usually carried out in an inert solvent in the presence of an acid at a temperature of 25 °C to 200 °C, preferably 60 °C to 150 °C. Suitable solvents are alcohols such as 2,4-dimethylpentan-3-ol, n-butanol, sec-butanol, tert-butanol, etc.; or aromatic hydrocarbons such as toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichlorobenzene, etc.; or polar aprotic solvents such as DMSO, DMF, DMA, NMP, etc.; alcohols such as 2,4-dimethylpentan-3-ol, etc. are preferably used. Mixtures of the solvents mentioned can also be used. Suitable acids and acidic catalysts are usually inorganic acids such as HCl, HBr, H 2 SO 4 、HClO 4etc.; or organic acids such as toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, etc. The acids are usually used in catalytic amounts; however, they can also be used in equimolar amounts, in excess, or, if appropriate, as solvents. The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of IIIB.1 (based on IIB).

[0086] In addition, the compounds of formula I can also be prepared by reacting an alkene of formula VI with a compound of formula V formed in situ (wherein the compound of formula V is derived from the reaction of a compound of formula IIIB with a dihaloaldoxime of formula IV) in a 1,3-dipolar cycloaddition reaction [see WO 2022 / 171472].

[0087]

[0088] This transformation is usually carried out in the presence of a base at a temperature of -78 °C to 80 °C, preferably -78 °C to 25 °C. Suitable solvents are ethers such as THF, 1,4-dioxane, Et 2 O, tert-butyl methyl ether, etc.; or esters such as EtOAc, etc.; or aromatic hydrocarbons such as benzene, toluene, o-xylene, m-xylene and p-xylene, chlorobenzene, dichlorobenzene, etc.; or halogenated hydrocarbons such as CH 2 Cl 2 、CHCl 3 、1,2-dichloroethane, etc. Mixtures of the solvents mentioned can also be used. Suitable bases are usually organic bases such as tertiary amines such as triethylamine, diisopropylethylamine, etc.; or N-containing heteroaromatic compounds such as pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, etc.; or inorganic compounds such as alkali metal and alkaline earth metal carbonates such as Li 2 CO 3 、K 2 CO 3 、CaCO 3 etc.; or alkali metal bicarbonates such as NaHCO 3 、KHCO 3 etc.; or alkali metal phosphates such as K 3 PO 4 etc. The bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0089] The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of IV and IIIB (based on VI).

[0090] Compounds of formula IV are commercially available, and the preparation of compounds of formula VI is described in the literature [see WO2022 / 171472].

[0091] Compounds of formula IIIA, where Y is a direct bond, can be prepared by reacting a compound of formula VII, where X LG is a leaving group, preferably a fluorine or chlorine atom, with an amine of formula VIII in a base-promoted nucleophilic aromatic substitution reaction.

[0092]

[0093] This reaction is typically carried out at a temperature of -20 °C to 180 °C, preferably 25 °C to 120 °C, in an inert solvent and in the presence of a base [see WO 2010 / 100189]. Suitable solvents are, for example, DMSO, DMF, DMA, NMP, etc.; or nitriles, such as acetonitrile, propionitrile, etc.; or ethers, such as 1,4-dioxane, THF, etc.; or aromatic hydrocarbons, such as toluene, o-xylene, m-xylene, p-xylene, etc.; or alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, etc.; or water. Mixtures of the solvents mentioned can also be used. Suitable bases are usually inorganic compounds, such as alkali metal and alkaline earth metal carbonates, for example, like Li 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、CaCO 3 etc.; or alkali metal and alkaline earth metal hydrides, for example, like LiH, NaH, KH, CaH 2 etc.; or organic bases, like tertiary amines, for example, like trimethylamine, triethylamine, diisopropylethylamine, N-methylpiperidine, etc.; or N-containing aromatic compounds, for example, like pyridine, collidine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, etc.; or alkali metal amides, for example, like LiN(i-Pr) 2 、LiN(SiMe 3 ) 2 、NaN(SiMe 3 ) 3 、KN(SiMe 3 ) 2 etc.; or alkali metal alkoxides, such as potassium tert-butoxide. The bases are usually used in equimolar amounts; however, they can also be used in excess, or, if appropriate, as the solvent. The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of VIII (based on VII).

[0094] Alternatively, compounds of formula IIIA can also be prepared by reacting a compound of formula VII, where X LGPreferably, it is prepared by reacting an iodine, bromine or trifluoromethanesulfonate group) with an N-heterocyclic compound of formula VIII in a palladium-catalyzed (i.e., Buchwald-Hartwig reaction) cross-coupling reaction.

[0095] The Buchwald-Hartwig reaction is generally carried out at a temperature of 25 °C to 200 °C, preferably 50 °C to 150 °C, in an inert solvent, and in the presence of a palladium catalyst and a base [see WO 2016 / 168059]. Suitable solvents are, for example, aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; or ethers such as 1,4-dioxane and THF; or nitriles such as acetonitrile and propionitrile; or polar aprotic solvents such as DMSO, DMF, DMA, NMP, etc. Suitable palladium catalysts are, for example, Pd(OAc) 2 / PPh 3 、Pd(OAc) 2 / 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), Pd(OAc) 2 / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (1,3-bis(diphenylphosphino)propane)chloropalladium(II), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)-phenyl)]chloropalladium(II), etc. Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal carbonates, such as, for example, Li 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、CaCO 3 etc.; or alkali metal phosphates such as, for example, K 3 PO 4 etc.; or organic bases such as tertiary amines such as, for example, triethylamine, diisopropylethylamine, N-methylpiperidine, N-methyl-N,N-dicyclohexylamine, and 1,4-diazabicyclo[2.2.2]octane; or amidines such as 1,8-diazabicyclo[5.4.0]undec-7-ene; or alkali metal alkoxides such as sodium tert-butoxide; or alkali metal amides such as lithium bis(trimethylsilyl)amide (LiHMDS). The bases are usually used in equimolar amounts; however, they can also be used in excess or, if appropriate, as solvents.

[0096] In addition, the compound of formula IIIA can also be prepared by reacting a compound of formula VII (where XLG Preferably iodine, bromine, B(OH) 2 , B(alkyl) 2 or B(O-alkyl) 2 ) react with the N-heterocyclic compound of formula VIII in a copper-promoted (i.e., respectively the Ullmann or Chan-Lam-Evans reaction) cross-coupling reaction for preparation.

[0097] The copper-promoted reaction is generally carried out at a temperature of 25 °C to 200 °C, preferably 50 °C to 150 °C, in an inert solvent, and in the presence of a copper catalyst and a base. Suitable solvents are, for example, N-containing aromatic compounds such as pyridine, quinoline, etc.; or polar aprotic solvents such as DMSO, DMF, DMA, N-methyl-2-pyrrolidone (NMP), etc.; or ethers such as 1,4-dioxane, bis(2-methoxyethyl) ether, etc.; or aromatic hydrocarbons such as toluene, o-xylene, m-xylene, p-xylene, etc.; or nitriles such as acetonitrile, propionitrile, etc.; or alcohols such as methanol, isopropanol, tert-butanol, etc.; and mixtures of the solvents mentioned can also be used. Suitable copper catalysts are, for example, CuI, CuBr, CuCl, Cu 2 O, Cu(OAc) 2 etc. If desired, amine- or amide-based ligands can also be used in the reaction, such as pyridine, 2,6-dimethylpyridine, 4-(dimethylamino)pyridine, quinoline, 1,10-phenanthroline, etc.; or N,N,N',N'-tetramethylethane-1,2-diamine, N,N-dimethylglycine, etc. Suitable bases are generally organic bases such as pyridine, 2,6-dimethylpyridine, etc.; or tertiary amines such as triethylamine, etc.; or inorganic compounds such as alkali metal and alkaline earth metal carbonates such as Li 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CaCO 3 etc.; or alkali metal phosphates such as K 3 PO 4 etc. The bases are generally used in equimolar amounts; however, they can also be used in excess, or, if appropriate, used as solvents.

[0098] The starting materials generally react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of VIII (based on VII).

[0099] The aromatic compound of formula VII and the N-heterocyclic compound of formula VIII are generally commercially available or known in the literature.

[0100] The compound of formula IIIA (where Y is C(R 4a )(R4b )) can be prepared by reacting a compound of formula VIIa, in which X LG is a leaving group, preferably a fluorine or chlorine atom, with an amine of formula VIII in a nucleophilic substitution reaction.

[0101]

[0102] This transformation is usually carried out at a temperature of from -78 °C to +110 °C, preferably from -20 °C to +80 °C, in an inert solvent, in the presence of a base [see Journal of the Society of Chemical Industry, London, Transactions and Communications (1947), 66, 325].

[0103] Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles such as acetonitrile and propionitrile, and dimethylformamide (DMF) and DMA, preferably aromatic hydrocarbons such as toluene; or DMF. Mixtures of the solvents mentioned can also be used.

[0104] Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal hydrides such as LiH, NaH, KH and CaH 2 , alkali metal and alkaline earth metal carbonates such as Li 2 CO 3 , K 2 CO 3 and CaCO 3 , and also alkali metal hydrogencarbonates such as NaHCO 3 , and organic bases such as tertiary amines such as trimethylamine, triethylamine, triisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Alkali metal and alkaline earth metal carbonates such as potassium carbonate or sodium carbonate are particularly preferred.

[0105] The bases are usually used in catalytic amounts; however, they can also be used in equimolar amounts, in excess, or, if appropriate, as solvents.

[0106] The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of VIII (based on VIIa).

[0107] A compound of formula IIIA, in which Y is C(R 4a )(R4b )) can be prepared in a two-step protocol via compound XIa by reacting a compound of formula VIIb with an amine of formula VIIIa in a reductive amination reaction.

[0108]

[0109] This transformation is typically carried out at a temperature of -78 °C to +120 °C, preferably -20 °C to +25 °C, in an inert solvent, in the presence of a reducing agent and an acid [see (literature) European Journal of Medicinal Chemistry (2018), 143, 390 - 401].

[0110] Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o - xylene, m - xylene and p - xylene, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert - butyl methyl ether, dioxane, anisole and THF, alcohols such as methanol, ethanol, n - propanol, isopropanol, n - butanol and tert - butanol, preferably alcohols such as methanol, ethanol. Mixtures of the solvents mentioned can also be used.

[0111] Suitable acids and acidic catalysts are usually inorganic acids such as HF, HCl, HBr, H 2 SO 4 and HClO 4 , Lewis acids such as BF 3 、AlCl 3 、FeCl 3 、SnCl 4 、TiCl 4 and ZnCl 2 , and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid. The acids are usually used in catalytic amounts; however, they can also be used in equimolar amounts, in excess, or if appropriate, as solvents.

[0112] The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of VIIIa (based on VIIb).

[0113] In the second step, the compound of formula XIa can be acylated with a compound of formula XIIa to give a compound of formula IIIA.

[0114]

[0115] This transformation is usually carried out in an inert solvent in the presence of a base at a temperature of from -78 °C to +110 °C, preferably from -20 °C to +110 °C [see WO 2007103905].

[0116] Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o - xylene, m - xylene and p - xylene, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert - butyl methyl ether, dioxane, anisole and THF, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide, DMF and DMA, preferably aromatic hydrocarbons, halogenated hydrocarbons and ethers such as toluene, dichloromethane and DMF. Mixtures of the solvents mentioned can also be used.

[0117] Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal hydrides such as LiH, NaH, KH and CaH 2 , alkali metal and alkaline earth metal carbonates such as Li 2 CO 3 , K 2 CO 3 and CaCO 3 , and also alkali metal hydrogencarbonates such as NaHCO 3 , and organic bases such as tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine and N - methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4 - dimethylaminopyridine, and also bicyclic amines. Alkali metal carbonates and organic bases such as K 2 CO 3 , triethylamine or pyridine are particularly preferred.

[0118] The bases are usually used in catalytic amounts; however, they can also be used in equimolar amounts, in excess, or, if appropriate, as the solvent.

[0119] The starting materials usually react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of XIa (based on XIIa).

[0120] Compounds of formula IIIB.1 in which X is NR 3 can be prepared by reacting a compound of formula IIIA in which X H is halogen, preferably fluorine or chlorine, with an amine R 3 NH 2 in a base - promoted nucleophilic aromatic substitution reaction under the same conditions as described above for the synthesis of IIIA from compounds of formula VII and VIII.

[0121]

[0122] Alternatively, a compound of formula IIIB.1, wherein X is NR 3 ), can be prepared by reacting a compound of formula IIIA, wherein X H is a halogen, preferably bromine or iodine, with an amine R 3 NH 2 respectively in a Buchwald-Hartwig or Ullmann cross-coupling reaction under the same conditions as described above for the synthesis of IIIA from compounds of formulas VII and VIII.

[0123] In addition, a compound of formula IIIB.1a, wherein X is NH, can be prepared from a compound of formula IX by reducing the NO 2 -group with SnCl 2 ), iron or zinc, respectively.

[0124]

[0125] These reactions are generally carried out at a temperature of 25 °C to 180 °C, preferably 25 °C to 80 °C, in an inert solvent and in the presence of an acid. Suitable solvents are, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, etc.; or esters such as EtOAc, etc.; or ethers such as THF, etc.; or H 2 O; and mixtures of the solvents mentioned can also be used. Suitable acids are generally inorganic acids such as mineral acids like HCl, etc.; or ammonium salts such as NH 4 Cl, etc.; or organic acids such as carboxylic acids like AcOH, etc. The acids are generally used in equimolar amounts; however, they can also be used in excess or, if appropriate, as a solvent. The starting materials generally react with each other in equimolar amounts. In terms of yield, it may be advantageous to use an excess of SnCl 2 ), iron or zinc (based on IX), respectively.

[0126] In addition, a compound of formula IIIB.1a, wherein X is NH, can also be prepared from a compound of formula IX by reducing the NO 2 -group with a Pd-on-carbon catalyst.

[0127] This reaction is generally carried out at a temperature of 0 °C to 100 °C, preferably 25 °C to 50 °C, in an inert solvent and in an H 2 atmosphere of 1 - 10 bar. Suitable solvents are, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, etc.; or esters such as EtOAc, etc.; or ethers such as THF, etc.; or H 2 O; and mixtures of the solvents mentioned can also be used.

[0128] A compound of formula IIIB.2, wherein X is O, can be prepared by reacting a compound of formula X, wherein X LGis a leaving group, preferably iodine, bromine, trifluoromethanesulfonate, B(OH) 2 , B(alkyl) 2 or B(O-alkyl) 2 ) and the N-heterocyclic compound of formula VIII are reacted respectively in Buchwald-Hartwig, Ullmann or Chan-Lam-Evans reaction under the same conditions as described above for the synthesis of IIIA from the compounds of formula VII and VIII to prepare.

[0129]

[0130] And the compound of formula IX can be prepared by reacting the compound of formula XI (wherein X LG is a leaving group, preferably fluorine or chlorine) with the amine of formula VIII in a base-promoted nucleophilic aromatic substitution reaction under the same conditions as described above for the synthesis of IIIA from the compounds of formula VII and VIII.

[0131]

[0132] Alternatively, the compound of formula IX can be prepared by reacting the compound of formula XI (wherein X LG is a leaving group, preferably iodine, bromine, trifluoromethanesulfonate, B(OH) 2 , B(alkyl) 2 or B(O-alkyl) 2 ) and the amine of formula VIII are reacted respectively in Buchwald-Hartwig, Ullmann or Chan-Lam-Evans reaction under the same conditions as described above for the synthesis of IIIA from the compounds of formula VII and VIII to prepare.

[0133] The compounds of formula XI are generally commercially available or known in the literature.

[0134] If desired, the compound of formula I.1 (wherein R 3 is not H) can also be prepared by alkylating or acylating the corresponding H-compound (R 3 =H), similar to that previously described in the literature [see WO 2022 / 171472].

[0135] Alternatively, the compound of formula I.1 can be prepared by reacting the compound of formula IIA.1 with the acetal of formula IIIA.1 (wherein X H is a halogen, preferably bromine or iodine) in a Buchwald-Hartwig reaction [see WO 2022 / 171472 or WO 2010 / 135360] as described at the beginning to produce the intermediate XI.1.

[0136]

[0137] This transformation is typically carried out at a temperature of from 0 °C to 150 °C, preferably 80 °C to 120 °C, in an inert solvent, in the presence of a base and a catalyst [see M.C. Harris, Journal of Organic Chemistry (1999), 64(16), 6019 - 6022].

[0138] Acetal IIIA.1 is commercially available or can be prepared by methods known in the art.

[0139] Suitable solvents are ethers such as diethyl ether, diisopropyl ether, tert - butyl methyl ether, dioxane, anisole and THF, preferably dioxane.

[0140] Acetal XIII is converted to aldehyde XIV under acidic conditions.

[0141]

[0142] This transformation is typically carried out at a temperature of from 0 °C to +80 °C, preferably 10 °C to 50 °C, in an inert solvent, in the presence of an acid [see X. Wu, Advanced Synthesis & Catalysis (2018), 360(6), 1111 - 1115].

[0143] Suitable solvents are ethers such as diethyl ether, diisopropyl ether, tert - butyl methyl ether, dioxane, anisole and THF, preferably THF. Suitable acids and acidic catalysts are typically inorganic acids such as HCl, HBr, H 2 SO 4 and HClO 4 , preferably HCl, in aqueous solution.

[0144] Under reductive conditions with ammonia, aldehyde XIV is converted to amine XV.

[0145]

[0146] This transformation is typically carried out at a temperature of from 0 °C to 120 °C, preferably 0 °C to 50 °C, in an inert solvent, in the presence of a reducing agent (e.g., NaBH 4 ) and NH 3 in the presence [see C.R. Reddy et al., Journal of Organic Chemistry (2023), 88(11), 7117 - 7127].

[0147] Suitable solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, with methanol and ethanol being preferred. Suitable alternative solvents are, for example, organic acids such as acetic acid or mixtures of acetic acid with alcohols.

[0148] The amino compound XV can be acylated with a compound of formula XIIa to give the compound I.1.

[0149]

[0150] This transformation is generally carried out under the conditions described above for the reaction of XIa with XIIa.

[0151] Alternatively, the above reaction sequence (IIIA.1 → XIII → XIV → XV → I.1) can be carried out with the compound (R 3 is H), and the introduction of R 3 can be carried out at a later stage, for example in the introduction of compound XIII or I.1.

[0152] Alternatively, the compound of formula XV can be prepared by cleavage of the compound of formula I.1 (where the group -Q-R 6 represents a protecting group such as Boc, mesyl or tosyl).

[0153]

[0154] This transformation is generally carried out under acidic proton conditions known in the art.

[0155] The starting materials required for the preparation of compound I are commercially available or known from the literature [see, for example, WO 2022 / 171472] or can be prepared according to the cited literature.

[0156] The reaction mixture is worked up in a conventional manner, for example by mixing with water, phase separation and, if appropriate, chromatographic purification of the crude product. Some of the intermediates and final products are obtained as colorless or light brown viscous oils, which are purified or the volatile components are removed under reduced pressure and at a moderately elevated temperature. If the intermediates and final products are obtained as solids, purification can also be carried out by recrystallization or digestion.

[0157] If the individual compounds I cannot be obtained by the above routes, they can be prepared by derivatization of other compounds I.

[0158] However, if the synthesis results in a mixture of isomers, separation is not generally required because in some cases the individual isomers may interconvert during work-up for use or during application (e.g. under the action of light, acids or bases). Such conversions can also occur after use, for example in the treated plant in the case of plant treatment or in the pest to be controlled.

[0159] In a preferred embodiment, compound I is present in the form of a mixture of compounds I.A and I.B, where compound I.A having an S-configuration in the isoxazoline ring is present in an amount of more than 50% by weight, in particular at least 70% by weight, more particularly at least 85% by weight, especially at least 90% by weight, based on the total weight of compounds I.A and I.B.

[0160]

[0161] In a particularly preferred embodiment of the invention, the method for protecting growing plants from infestation or infection by invertebrate pests comprises the step of bringing the plant, its parts, its propagation material, the pest, its food supply, habitat or breeding ground into contact with a pest-controlling effective amount of a compound of formula I.A.

[0162] The compounds of formulae I.A and I.B can be obtained in enantiomerically pure form by known separation methods, preferably by chiral chromatography. This preferably applies to the intermediate compounds of formulae IIA and IIB or to the compounds of formula I.

[0163] The organic moiety groups mentioned in the above definitions of the variables - like the term halogen - are collective terms for a single listing of the individual group members. The prefix Cn-Cm indicates the possible number of carbon atoms in the group in each case.

[0164] The term "partially or completely substituted" means that the group is generally substituted by the same or different groups.

[0165] The term "halogen" in each case represents fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0166] As used herein, the term "alkyl" in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and alkoxyalkyl, in each case represents a straight-chain or branched-chain alkyl group which usually has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 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.

[0167] As used herein, the term "haloalkyl" in the haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy, and haloalkoxyalkyl, in each case represents a straight-chain or branched-chain alkyl group which usually has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein some or all of the hydrogen atoms of such group are replaced by halogen atoms. Preferred haloalkyl moieties are selected from C 1 -C 4 -haloalkyl, more preferably selected from C 1 -C 3 -haloalkyl or C 1 -C 2 -haloalkyl, especially selected from C 1 -C 2 -fluoroalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

[0168] As used herein, the term "alkoxy" in each case represents a straight-chain or branched-chain alkyl group which is bonded via an oxygen atom and usually has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, tert-butoxy, and the like.

[0169] As used herein, the term "alkoxyalkyl" refers to an alkyl group typically containing from 1 to 10, often from 1 to 4, preferably 1 to 2 carbon atoms, wherein one carbon atom bears an alkoxy group typically containing from 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH 2 OCH 3 、CH 2 -OC 2 H 5 、2-(methoxy)ethyl, and 2-(ethoxy)ethyl.

[0170] As used herein, the term "haloalkoxy" in each case denotes a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of the group are partially or completely replaced by halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C 1 -C 4 -haloalkoxy, in particular C 1 -C 2 -fluoroalkoxy 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, and the like.

[0171] As used herein, the term "alkylthio" (alkylthioalkyl: alkyl-S-) refers to a straight-chain or branched saturated alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 4 carbon atoms

[0172] (=C 1 -C 4 -alkylthio), more preferably from 1 to 3 carbon atoms, attached via a sulfur atom.

[0173] 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.

[0174] As used herein, the term "alkylsulfinyl" (alkylsulfinyl: C 1 -C 6 -alkyl-S(O)-) refers to a straight-chain or branched saturated alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 4 carbon atoms (=C 1 -C 4 -alkylsulfinyl), more preferably from 1 to 3 carbon atoms, bonded at any position in the alkyl group through the sulfur atom of the sulfinyl group (as described above).

[0175] As used herein, the term "haloalkylsulfinyl" refers to an alkylsulfinyl as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.

[0176] As used herein, the term "alkylsulfonyl" (alkyl-S(O) 2 -) refers to a straight-chain or branched-chain saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (=C 1 -C 4 -alkylsulfonyl), preferably 1 to 3 carbon atoms, bonded via the sulfur atom of the sulfonyl group at any position in the alkyl group.

[0177] As used herein, the term "haloalkylsulfonyl" refers to an alkylsulfonyl as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.

[0178] The term "alkylcarbonyl" refers to an alkyl group as defined above, which is bonded to the remainder of the molecule via the carbon atom of the carbonyl group (C=O).

[0179] The term "haloalkylcarbonyl" refers to an alkylcarbonyl as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.

[0180] The term "alkoxycarbonyl" refers to an alkylcarbonyl as defined above, which is bonded to the remainder of the molecule via an oxygen atom.

[0181] The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl as described above, wherein the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.

[0182] As used herein, the term "alkenyl" in each case denotes a monounsaturated hydrocarbon group usually having 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms, such as vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en-1-yl, etc.

[0183] As used herein, the term "haloalkenyl" refers to an alkenyl as defined above, wherein the hydrogen atoms are partially or completely replaced by halogen atoms.

[0184] As used herein, the term "alkynyl" in each case denotes a monounsaturated hydrocarbon group having generally 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms, such as ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-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-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl, and the like.

[0185] As used herein, the term "haloalkynyl" means an alkynyl group as defined above, in which the hydrogen atoms are partially or completely replaced by halogen atoms.

[0186] As used herein and in the cycloalkyl moieties of cycloalkyloxy and cycloalkylthio groups, the term "cycloalkyl" in each case denotes a monocyclic alicyclic group having generally 3 to 10 or 3 to 6 carbon atoms, such as cyclopropyl (cC 3 H 5 ), cyclobutyl (cC 4 H 7 ), cyclopentyl (cC 5 H 9 ), cyclohexyl (cC 6 H 11 ), cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, or cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0187] As used herein and in the haloalkyl moieties of haloalkyloxy and haloalkylthio groups, the term "halocycloalkyl" in each case denotes a monocyclic alicyclic group having generally 3 to 10 C atoms or 3 to 6 C atoms, in which at least one (e.g., 1, 2, 3, 4, or 5) of the hydrogen atoms is replaced by halogen, especially by fluorine or chlorine. Examples are 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, and the like.

[0188] As used herein, the term "halocycloalkenyl" in the halocycloalkenyloxy and halocycloalkenylthio moieties of halocycloalkenyl groups means in each case a monocyclic monounsaturated non-aromatic group generally having from 3 to 10 (such as 3 or 4 or 5 to 10) carbon atoms, preferably from 3 to 8 carbon atoms, in which at least one (such as 1, 2, 3, 4 or 5) of the hydrogen atoms is replaced by a halogen, especially by fluorine or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.

[0189] The term "cycloalkenylalkyl" means a cycloalkenyl as defined above which is bonded to the remainder of the molecule via an alkyl group such as a C 1 -C 5 -alkyl or a C 1 -C 4 -alkyl, especially a methyl group (=cycloalkenylmethyl).

[0190] The term "carbocycle" or "carbocyclic group" generally includes 3- to 12-membered, preferably 3- to 8-membered or 5- to 8-membered, more preferably 5- or 6-membered monocyclic non-aromatic rings containing from 3 to 12, preferably from 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term "carbocycle" encompasses cycloalkyl and cycloalkenyl as defined above.

[0191] The term "heterocycle" or "heterocyclic group" generally includes 3- to 12-membered, preferably 3- to 6-membered, especially 6-membered monocyclic heterocyclic non-aromatic groups. Heterocyclic non-aromatic groups generally contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where the S atom as a ring member may be in the form of S, SO, or SO 2Exist. Examples of 5- or 6-membered heterocyclic groups include saturated or unsaturated non-aromatic heterocycles such as oxiranyl, oxetanyl, thietanyl, thietanyl-S-oxide (S-oxothietanyl), thietanyl-S-dioxide (S-dioxothietanyl), pyrrolidinyl, pyrrolinyl, pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, thiolanyl, S-oxothiolanyl, S-dioxothiolanyl, dihydrothienyl, S-oxodihydrothienyl, S-dioxodihydrothienyl, oxazolidinyl, oxazolinyl, thiazolinyl, oxathiolanyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-dioxanyl, thiopyranyl, S-oxothiopyranyl, S-dioxothiopyranyl, dihydrothiopyranyl, S-oxodihydrothiopyranyl, S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl, S-oxotetrahydrothiopyranyl, S-dioxotetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl, etc. Examples of heterocycles containing 1 or 2 carbonyls as ring members include pyrrolidin-2-oneyl, pyrrolidine-2,5-dioneyl, imidazolidin-2-oneyl, oxazolidin-2-oneyl, thiazolidin-2-oneyl, etc.

[0192] The term "heteroaryl" includes monocyclic 5- or 6-membered heteroaromatic groups containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members. Heteroaryls containing N or S can exist as positively charged ylides and together with adjacent atoms form mesoionic entities. Examples of 5- or 6-membered heteroaromatic groups include pyridyl, i.e., 2-, 3- or 4-pyridyl; pyrimidinyl, i.e., 2-, 4- or 5-pyrimidinyl; pyrazinyl; pyridazinyl, i.e., 3- or 4-pyridazinyl; thienyl, i.e., 2- or 3-thienyl; furyl, i.e., 2- or 3-furyl; pyrrolyl, i.e., 2- or 3-pyrrolyl; oxazolyl, i.e., 2-, 3- or 5-oxazolyl; isoxazolyl, i.e., 3-, 4- or 5-isoxazolyl; thiazolyl, i.e., 2-, 3- or 5-thiazolyl; isothiazolyl, i.e., 3-, 4- or 5-isothiazolyl; pyrazolyl, i.e., 1-, 3-, 4- or 5-pyrazolyl; imidazolyl, i.e., 1-, 2-, 4- or 5-imidazolyl; oxadiazolyl, e.g., 2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazolyl), 3- or 5-(1,2,4-oxadiazolyl); 2- or 5-(1,3,4-thiadiazolyl), thiadiazolyl, e.g., 2- or 5-(1,3,4-thiadiazolyl), 4- or 5-(1,2,3-thiadiazolyl), 3- or 5-(1,2,4-thiadiazolyl); triazolyl, e.g., 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H- or 4H-1,2,4-triazolyl; and tetrazolyl, i.e., 1H- or 2H-tetrazolyl. The term "heteroaryl" also includes bicyclic 8- to 10-membered heteroaromatic groups containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members, wherein a 5- or 6-membered heteroaromatic ring is fused to a benzene ring or a 5- or 6-membered heteroaromatic group. Examples of 5- or 6-membered heteroaromatic rings fused to a benzene ring or to a 5- or 6-membered heteroaromatic group include benzofuryl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridinyl, pteridinyl, pyrido[3,2d]pyrimidinyl or pyridoimidazolyl, etc. These fused heteroaryls can be bonded to the remainder of the molecule via any ring atom of the 5- or 6-membered heteroaromatic ring or via a carbon atom of the fused phenyl moiety.

[0193] The terms "heterocyclylalkyl" and "heteroarylalkyl" respectively refer to a heterocyclyl or heteroaryl as defined above bonded to the remainder of the molecule via C 1 -C 5 -alkyl or C 1 -C 4 -alkyl, especially methyl (respectively = heterocyclylmethyl or heteroarylmethyl).

[0194] The terms "arylalkyl" and "phenylalkyl" respectively refer to a phenyl or aryl bonded to the remainder of the molecule via C1 -C 5 -alkyl or C 1 -C 4 -alkyl, especially methyl (=aryl-methyl or phenyl-methyl), bonded to the rest of the molecule, of the aryl and phenyl as defined above, examples include benzyl, 1-phenylethyl, 2-phenylethyl, 2-phenoxyethyl, etc.

[0195] The terms "alkylene", "cycloalkylene", "heterocycloalkylene", "alkenylene", "cycloalkenylene", "heterocycloalkenylene" and "alkynylene" respectively refer to the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl and alkynyl as defined above, which are bonded to the rest of the molecule via two atoms of the corresponding group, preferably via two carbon atoms of the corresponding group, and thus they represent a linker between two parts of the molecule.

[0196] In certain embodiments, the variables of the compounds of formula I have the following meanings, which are specific embodiments of the compounds of formula I both per se and in combination with each other.

[0197] Embodiments and preferred compounds of the present invention for use in pest control methods and insecticidal applications are outlined in the following paragraphs.

[0198] For the variables, particularly preferred embodiments of the intermediates correspond to those of the compounds of formula I.

[0199] In one embodiment, W is the group WA,

[0200]

[0201] wherein

[0202] A 1 、A 2 、A 3 is N or CR 2 , provided that at least two are CR 2 ;

[0203] R 2 are each independently preferably H, halogen, halomethyl, halomethoxy, or halomethyl-S(O) m .

[0204] In another embodiment, W is phenyl, which is substituted with one to three of the following groups: halogen, halomethyl, halomethoxy, and / or halomethyl-S(O) m .

[0205] W is preferably the group WP:

[0206]

[0207] wherein R 2a 、R 2b and R 2c are the group R 2 , preferably selected from halogen, halomethyl, halomethoxy, and halomethyl-S(O) m .

[0208] Particularly preferably each of the following combinations of R 2a 、R 2b and R 2c , where each row of Table W represents the substitution pattern of the benzene ring (“WP”) with the R 2a 、R 2b and R 2c moieties.

[0209] Table W

[0210]

[0211]

[0212] In the compound of formula I, the W-8, W-9, W-11 and W-33 groups are more preferred patterns. W-8 and W-11 are particularly preferred.

[0213] In another embodiment, the group W is selected from W-8, W-9, W-11, W-33, and W-34.

[0214] Another embodiment of W is a 6-membered heteroaryl, such as thiophene, pyrazole, imidazole or pyridine, these rings being substituted by 1 or 2 groups R 2a or C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl.

[0215] R 1 is preferably methyl substituted by 1 to 3 atoms selected from Cl and F, such as CF 3 、CHF 2 、CClF 2 、CCl 2 F、CCl 3 、CHCl 2 、or CHFCl.

[0216] X is preferably NR 3 .

[0217] R 3 is preferably H, C 1 -C 6 -alkoxycarbonyl, or C 1 -C 6-alkyl, the alkyl being unsubstituted or substituted with CN, C 3 -C 6 -cycloalkyl, and / or C 1 -C 6 -alkoxy. R 3 is H, C 2 H 5 or CH 2 OCH 3 is particularly preferred.

[0218] In another embodiment, R 3 is OH, C 1 -C 4 -alkoxy, or C 1 -C 4 -alkoxycarbonyl.

[0219] In another embodiment, X is O.

[0220] In one embodiment, G is group GA:

[0221]

[0222] wherein

[0223] Q 1 、Q 2 、Q 3 、Q 4 is N or CR 4 ; provided that at least three are CR 4 ;

[0224] R 4 are each independently preferably H, halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -cycloalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -halocycloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, S(O) m -C 1 -C 3 -alkyl,

[0225] S(O) m -C 1 -C 3 -haloalkyl.

[0226] G is preferably group G1, G2, G3 or G4:

[0227]

[0228] where # is the bond to X, % is the bond to Y, and R 41 and R 42 are H or group R 2 , preferably H, or halogen, CN, haloalkyl, haloalkoxy. In a particularly preferred embodiment, R 41 is CN and halogen, such as Cl, and R 42 is H.

[0229] In a preferred embodiment, G is G1 and R 42 is H.

[0230] In another embodiment, G is selected from G1 and G4, where R 42 is H.

[0231] In a preferred embodiment, Y is C(R 4a )(R 4b ), preferably CH 2 .

[0232] In a preferred embodiment, Q is pyrazole, imidazole, or triazole; preferably selected from

[0233] 1-pyrazole, 1-imidazole, and 1,2,4-triazole, which are unsubstituted or substituted by the following: CN,

[0234] C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, NR 15 C(=O)R 26 、or C(=O)NR 25a R 25b , where R 25a and R 25b are preferably H, C 1 -C 4 -alkyl,

[0235] C 1 -C 4 -haloalkyl, and C 3 -C6 -cycloalkyl

[0236] In a preferred embodiment, Q is C(=O).

[0237] A preferred embodiment is a compound of formula I, wherein

[0238] R 1 is C 1 -C 2 -haloalkyl, preferably halomethyl;

[0239] W is phenyl, which is partially or fully substituted by R 2 ;

[0240] R 2 is halogen, CN, OH, C 1 -C 4 -alkoxy, OR 21 、C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkyl-S(O) m 、C 1 -C 3 -haloalkyl-S(O) m 、C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl;

[0241] X is NR 3 or O;

[0242] R 3 is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl,

[0243] G is phenyl, which is unsubstituted, partially or fully substituted by R 4 ; preferably group G1, where R 41 and R 42 are H, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy;

[0244] R 4 is H, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy; or R 4 and R 4a / R 4b together form a 5- or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring, which heterocyclic ring may contain 1 or 2 N as ring members;

[0245] Y is a direct bond or CR 4a R 4b ;

[0246] Q is C(=O) or SO 2 ;

[0247] R 5 H,

[0248] R 6 C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkenyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-S(O) m-C 1 -C 4 -alkyl, NR H C(=O)-C 1 -C 4 -alkyl, NR H C(=O)-C 3 -C 6 -cycloalkyl, CR H N=OR 24 , CR H N=OR 24 , a 4-, 5- or 6-membered saturated or partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from O, N, S as ring members, where S may be oxidized

[0249] where R H is H, CN or C 1 -C 4 -alkyl,

[0250] R 6 is unsubstituted or substituted by: CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl unsubstituted or substituted by 1 or 2 halogens and / or CN.

[0251] A preferred embodiment is a compound of formula I corresponding to formula I.A shown below, where the variables are as defined and preferred above.

[0252]

[0253] Another preferred embodiment is a compound of formula I corresponding to formula I' shown below, where the variables are as defined and preferred above.

[0254]

[0255] Another preferred embodiment is a compound of formula I corresponding to formula I.1 shown below, where the variables are as defined and preferred above.

[0256]

[0257] In particular, considering their use, preference is given to the compounds of formula I listed in the table below, which correspond to formula I.1, where R 1 is CF 3 and R 5 and R 42 represent H. In addition, each of the groups mentioned for the substituents in the table by itself (independently of the combination in which the group is mentioned) is a particularly preferred aspect of the substituents mentioned.

[0258] Table 1: Compounds of formula I.1, where Q is C=O, R 6 is CH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0259] Table 2: Compounds of formula I.1, where Q is C=O, R 6 is C 2 H 5 , and the other variables of the compound correspond to a row of Table A in each case

[0260] Table 3: Compounds of formula I.1, where Q is C=O, R 6 is CH 2 CH 2 CH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0261] Table 4: Compounds of formula I.1, where Q is CH(CH 3 ) 2 , and the other variables of the compound correspond to a row of Table A in each case

[0262] Table 5: Compounds of formula I.1, where Q is C=O, R 6 is cC 3 H 5 , and the other variables of the compound correspond to a row of Table A in each case

[0263] Table 6: Compounds of formula I.1, where Q is C=O, R 6 is (1-CN-)cC 3 H 4 , and the other variables of the compound correspond to a row of Table A in each case

[0264] Table 7: Compounds of formula I.1, where Q is C=O, R 6 is CH 2 OCH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0265] Table 8: Compounds of formula I.1, where Q is C=O, R 6 is CH 2 CH 2 OCH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0266] Table 9: Compounds of formula I.1, where Q is SO 2 , R 6 is CH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0267] Table 10: Compounds of formula I.1, where Q is SO 2 , R 6 is C 2 H 5 , and the other variables of the compound correspond to a row of Table A in each case

[0268] Table 11: Compounds of formula I.1, where Q is SO 2 , R 6 is CH 2 CH 2 CH 3 , and the other variables of the compound correspond to a row of Table A in each case

[0269] Table 12: Compounds of formula I.1, where Q is SO 2 , R 6 is CH(CH 3 ) 2 , and the other variables of the compound correspond to a row of Table A in each case

[0270] Table 13: Compounds of formula I.1, where Q is SO 2 , R 6 is cC 3 H 5 , and the other variables of the compound correspond to a row of Table A in each case

[0271] Table 14: Compounds of formula I.1, where Q is SO 2 , R 6 is (1-CN-)cC 3 H 4 , and the other variables of the compound correspond to a row of Table A in each case

[0272] Table 15: Compounds of formula I.1, where Q is SO 2 , R 6 is CH 2 OCH 3and the other variables of the compound correspond to a row of Table A in each case

[0273] Table 16: Compounds of formula I.1, where Q is SO 2 , R 6 is CH 2 CH 2 OCH 3 and the other variables of the compound correspond to a row of Table A in each case

[0274] Table A

[0275]

[0276]

[0277]

[0278] The term "one or more compounds of the invention" means one or more compounds of formula I or "one or more compounds I", and includes their salts, tautomers, stereoisomers, and N-oxides.

[0279] The invention also relates to an agrochemical composition comprising an adjuvant and at least one compound I.

[0280] The agrochemical composition comprises a pest-killing effective amount of compound I.

[0281] The agrochemical composition comprises a pest-killing effective amount of compound I.

[0282] Compound I can be converted into agrochemical compositions of common types, such as solutions, emulsions, suspensions, dusts, powders, pastes, granules, tablets, capsules, and mixtures thereof. Examples of composition types are suspensions (e.g., SC, OD, FS), emulsifiable concentrates (e.g., EC), emulsions (e.g., EW, EO, ES, ME), capsules (e.g., CS, ZC), pastes, pills, wettable powders or dusts (e.g., WP, SP, WS, DP, DS), tablets (e.g., BR, TB, DT), granules (e.g., WG, SG, GR, FG, GG, MG), insecticidal products (e.g., LN), and gel formulations (e.g., GF) for treating plant propagation materials (e.g., seeds). These and additional composition types are defined in the "Catalogue of pesticide formulation types and international coding system", Technical Monograph, Issue 2, 6th Edition, May 2008, CropLife International.

[0283] Suitable auxiliaries are solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetting agents, adjuvants, solubilizers, penetration promoters, protective colloids, adhesives, thickeners, humectants, repellents, attractants, feeding stimulants, compatibilizers, bactericides, antifreezes, defoamers, colorants, tackifiers, and binders.

[0284] Suitable solvents and liquid carriers are water and organic solvents. Suitable solid carriers or fillers are mineral earths.

[0285] Suitable surfactants are surface-active compounds, such as anionic, cationic, nonionic, and amphoteric surfactants, block polymers, polyelectrolytes. Such surfactants can be used as emulsifiers, dispersants, solubilizers, wetting agents, penetration enhancers, protective colloids, or adjuvants. Surfactants are listed in McCutcheon's, Volume 1: Emulsifiers & Detergents, McCutcheon's Directories, Glen Rock, USA, 2008 (International Edition or North American Edition). Suitable anionic surfactants are alkali metal salts, alkaline earth metal salts, 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, polymeric surfactants. Suitable cationic surfactants are quaternary surfactants.

[0286] Agrochemical compositions generally contain an active substance in an amount between 0.01% and 95% by weight, preferably between 0.1% and 90% by weight, and most preferably between 0.5% and 75% by weight. The active substance is used with a purity of 90% to 100%, preferably 95% to 100%.

[0287] Various types of oils, wetting agents, adjuvants, or fertilizers can be added as a premix or (if appropriate) added until immediately before use (tank mixing) to the active substance or the composition containing them. These reagents can be mixed with the composition according to the invention in a weight ratio of 1:100 to 100:1.

[0288] The user generally applies the composition according to the invention by means of a pre - dosing device, a knapsack sprayer, a spray tank, a spray aircraft, or an irrigation system. Generally, the agrochemical composition is made up with water, a buffer, and / or additional adjuvants to the desired application concentration, and thus a ready - to - use spray liquid or agrochemical composition according to the invention is obtained. Generally, 20 to 2000 liters of the ready - to - use spray liquid are applied per hectare of agricultural use area.

[0289] Compound I is suitable for protecting crops, plants, plant propagation materials (such as seeds), or the soil or water body in which plants grow from infestation or infection by animal pests. Accordingly, the present invention also relates to a method for plant protection, which comprises bringing into contact a crop, a plant, a plant propagation material (such as a seed), or the soil or water body in which plants grow, which is to be protected from infestation or infection by animal pests, with a pest - killing effective amount of Compound I.

[0290] Compound I is also suitable for combating or controlling animal pests. Accordingly, the present invention also relates to a method for combating or controlling animal pests, which comprises bringing into contact an animal pest, its habitat, breeding ground, or food supply, or a crop, a plant, a plant propagation material (such as a seed), or the soil, or the area, material, or environment in which the animal pest grows or may grow, with a pest - killing effective amount of Compound I.

[0291] Compound I is effective for any and all developmental stages, such as eggs, larvae, pupae, and adults, by both contact and ingestion.

[0292] Compound I can be applied as such or in the form of compositions containing them.

[0293] Application can be carried out both before and after the crop, plant, plant propagation material is infested by pests.

[0294] The term "contact" includes both direct contact (applying the compound / composition directly to the animal pest or the plant) and indirect contact (applying the compound / composition to the site).

[0295] The term "animal pest" includes arthropods, gastropods, and nematodes. Preferred animal pests according to the invention are arthropods, preferably insects and arachnids, especially insects.

[0296] The term "plant" includes cereals such as durum wheat and other wheat, rye, barley, triticale, oats, rice, or maize (forage maize and sweet maize / sweet corn as well as field corn); sugar beet such as sugar beet or fodder beet; fruits such as pomes, stone fruits, or soft fruits such as apples, pears, plums, peaches, nectarines, almonds, cherries, papayas, strawberries, raspberries, blackberries, or gooseberries; leguminous plants such as kidney beans, lentils, peas, alfalfa, or soybeans; oil plants such as rapeseed (oilseed rape), Brassica rapa var. oleifera, mustard, olives, sunflowers, coconuts, cocoa beans, castor oil plants, oil palms, peanuts, or soybeans; cucurbitaceous plants such as squashes, pumpkins, cucumbers, or melons; fiber plants such as cotton, flax, hemp, or jute; citrus fruits such as oranges, lemons, grapefruits, or tangerines; vegetables such as eggplants, spinach, lettuce (such as iceberg lettuce), chicory, cabbages, asparagus, cabbages, carrots, onions, garlic, leeks, tomatoes, potatoes, cucurbits, or sweet peppers; laurel plants such as avocados, cinnamon, or camphor; energy and raw material plants such as maize, soybeans, rapeseed, sugar cane, or oil palms; tobacco; nuts such as walnuts; pistachios; coffee; tea; bananas; vines; hops; stevia (Stevia rebaudiana); natural rubber plants or ornamental and forest plants, shrubs, broad-leaved trees or evergreens, eucalypts; turf; lawns; grasses. Preferred plants include potatoes, sugar beet, tobacco, wheat, rye, barley, oats, rice, maize, cotton, soybeans, rapeseed, leguminous plants, sunflowers, coffee, or sugar cane; fruits; vines; ornamental plants; or vegetables such as cucumbers, tomatoes, kidney beans, or squashes.

[0297] The term "seed" includes seeds and plant propagules, including true seeds, seed pieces, suckers, corms, bulbs, fruits, tubers, grains, cuttings, cut shoots, and preferably means true seeds.

[0298] "Pest - killing effective amount" means the amount of the active ingredient required to achieve an observable effect on growth, the effect including necrosis, death, retardation, prevention and elimination, destruction or otherwise reducing the occurrence and activity of the target organism. For the various compounds / compositions used in the present invention, the pest - killing effective amount can vary. The pest - killing effective amount of a composition will also vary according to main conditions such as the desired pest - killing effect and duration, climate, target species, location, and application method.

[0299] For use, for example, in the treatment of crop plants by foliar application, the application rate of the active ingredient of the invention can range from 0.0001 g to 4000 g per hectare, for example from 1 g to 2 kg or from 1 g to 750 g per hectare, preferably from 1 g to 100 g per hectare.

[0300] Compound I is also suitable for combating non-crop insect pests. For use in combating said non-crop pests, Compound I can be used as a bait composition, gel, general insect spray, aerosol, ultra-low volume application, and mosquito net (impregnated or surface applied).

[0301] The term "non-crop insect pest" refers to pests that are particularly relevant to non-crop targets, such as ants, termites, wasps, flies, ticks, mosquitoes, bed bugs, crickets, or cockroaches, such as: Aedes aegypti, Musca domestica, Tribolium spp.; termites, such as Reticulitermes flavipes, Coptotermes formosanus; cockroaches, such as Blattella germanica, Periplaneta Americana; ants, such as Solenopsis invicta, Linepithema humile, and Camponotus pennsylvanicus.

[0302] The bait can be a liquid, solid or semi-solid preparation (such as a gel). For use in a bait composition, the typical content of the active ingredient is 0.001 wt% to 15 wt%, desirably 0.001 wt% to 5 wt% of the active compound.

[0303] Compound I and its compositions can be used to protect wood materials, such as trees, wooden fences, sleepers, frames, works of art, etc., as well as buildings, and building materials, furniture, leather, fibers, vinyl products, wires and cables, etc., from ants, termites and / or beetles that damage wood or textiles, and for controlling ants and termites from causing harm to crops or humans (for example when pests invade houses and public facilities or nest in yards, orchards or parks).

[0304] Conventional application rates in material protection are, for example, 0.001 g to 2000 g or 0.01 g to 1000 g of active compound / m 2 of the material to be treated, desirably 0.1 g to 50 g of active compound / m 2 of the material to be treated.

[0305] Insecticidal compositions for use in impregnating materials typically contain from 0.001 wt% to 95 wt%, preferably from 0.1 wt% to 45 wt%, and more preferably from 1 wt% to 25 wt% of at least one repellent and / or insecticide.

[0306] The compounds of the present invention are particularly suitable for effectively combating animal pests, such as arthropods and nematodes, including:

[0307] Insects from: Auchenorrhyncha, such as Amrasca biguttula, Empoasca spp., Nephotettix virescens, Sogatella furcifera, Mahanarva spp., Laodelphax striatellus, Nilaparvata lugens, Diaphorina citri;

[0308] Lepidoptera, such as Helicoverpa spp., Heliothis virescens, Lobesia botrana, Ostrinia nubilalis, Plutella xylostella, Pseudoplusia includens, Scirpophaga incertulas, Spodoptera spp., Trichoplusia ni, Tuta absoluta, Cnaphalocrocis medialis, Cydia pomonella, Chilo suppressalis, Anticarsia gemmatalis, Agrotis ipsilon, Chrysodeixis includens;

[0309] True bugs, such as Lygus spp.; stink bugs, such as Euschistus spp., Halyomorpha halys, Nezara viridula, Piezodorus guildinii, Dichelops furcatus;

[0310] Thrips, such as Frankliniella spp., Thrips spp., Dichromothrips corbettii;

[0311] Aphids, such as Acyrthosiphon pisum, Aphis spp., Myzus persicae, Rhopalosiphum spp., Schizaphis graminum, Megoura viciae;

[0312] Whiteflies, such as Trialeurodes vaporariorum, Bemisia spp.;

[0313] Coleoptera, such as Phyllotreta spp., Melanotus spp., Meligethes aeneus, Leptinotarsa decimlineata, Ceutorhynchus spp., Diabrotica spp., Anthonomus grandis, Atomaria linearia, Agriotes spp., Epilachna spp.;

[0314] Flies, such as Delia spp., Ceratitis capitate, Bactrocera spp., Liriomyza spp.;

[0315] Mosquitoes (Diptera), such as Aedes aegypti, Aedes albopictus, Aedes vexans, Anastrepha ludens, Anopheles maculipennis, Anopheles crucians, Anopheles albimanus, Anopheles gambiae, Anopheles freeborni, Anopheles leucosphyrus, Anopheles minimus, Anopheles quadrimaculatus;

[0316] Scale insects (Coccoidea), such as Aonidiella aurantia, Ferrisia virgate;

[0317] Arachnid arthropods (mites), such as Penthaleus major, Tetranychus spp.;

[0318] Nematodes, such as Heterodera glycines, Meloidogyne spp., Pratylenchus spp., Caenorhabditis elegans.

[0319] Compound I is suitable for treating or protecting animals against parasite infestation or infection. Accordingly, the present invention also relates to the use of the compounds of the invention for the manufacture of a medicament for treating or protecting animals against parasite infestation or infection. In addition, the present invention relates to a method for treating or protecting animals against parasite infestation and infection, which comprises orally, topically or parenterally administering or applying to the animal a parasitically effective amount of Compound I.

[0320] The present invention also relates to the non-therapeutic use of the compounds of the invention for treating or protecting animals against parasite infestation and infection. In addition, the present invention relates to a non-therapeutic method for treating or protecting animals against parasite infestation and infection, which comprises applying to the premises a parasitically effective amount of Compound I.

[0321] The compounds of the present invention are further suitable for use in combating or controlling parasites in and on animals. In addition, the present invention relates to a method for combating or controlling parasites in and on animals, which comprises bringing the parasites into contact with a parasitically effective amount of Compound I.

[0322] The present invention also relates to the non-therapeutic use of Compound I for preventing or combating parasites. In addition, the present invention relates to a non-therapeutic method for combating or preventing parasites, which comprises applying to a locus a parasiticidally effective amount of Compound I.

[0323] Compound I can be effective by both contact (via soil, glass, walls, mosquito nets, carpets, rugs, or animal parts) and ingestion (e.g., bait). In addition, Compound I can be applied to any and all developmental stages.

[0324] Compound I can be applied as such or in the form of compositions containing them.

[0325] The term "locus" means a habitat, a food supply, a breeding ground, an area, material or environment in which a parasite grows or may grow outside an animal.

[0326] As used herein, the term "parasite" includes endoparasites and ectoparasites. In some embodiments of the present invention, endoparasites may be preferred. In other embodiments, ectoparasites may be preferred. Infestations in warm-blooded animals and fish include lice, biting lice, ticks, Oestrus ovis, Melophagus ovinus, Stomoxys calcitrans, Musca domestica, flies, fly larvae, chiggers, blackflies, mosquitoes and fleas.

[0327] The compounds of the present invention are particularly useful for combating the following parasites: Cimex lectularius, Rhipicephalus sanguineus, and Ctenocephalides felis.

[0328] As used herein, the term "animal" includes warm-blooded animals (including humans) and fish. Preferred mammals are, for example, cattle, sheep, pigs, camels, deer, horses, pigs, poultry, rabbits, goats, dogs and cats, water buffalo, donkeys, fallow deer and reindeer, and also fur animals such as mink, chinchilla and raccoon, birds such as hens, geese, turkeys and ducks, and fish such as freshwater fish and saltwater fish such as salmon, carp and eels. Particularly preferred are domestic animals such as dogs or cats.

[0329] Compound I can be administered in a total amount of from 0.5 mg / kg to 100 mg / kg per day, preferably from 1 mg / kg to 50 mg / kg per day.

[0330] For oral administration to warm-blooded animals, Compound I can be formulated as animal feed, animal feed premix, animal feed concentrate, boluses, solutions, pastes, suspensions, infusions, gels, tablets, dragees and capsules. For oral administration, the dosage form selected should provide the animal with from 0.01 mg / kg to 100 mg / kg of animal body weight per day, preferably from 0.5 mg / kg to 100 mg / kg of animal body weight per day, of Compound I.

[0331] Alternatively, Compound I can be administered to an animal parenterally, e.g., by intracoelomic, intramuscular, intravenous or subcutaneous injection. For subcutaneous injection, Compound I can be dispersed or dissolved in a physiologically acceptable carrier. Alternatively, Compound I can be formulated into an implant for subcutaneous administration. Additionally, Compound I can be administered transdermally to an animal. For parenteral administration, the selected dosage form should provide the animal with Compound I at 0.01 mg / kg to 100 mg / kg of animal body weight per day.

[0332] Compound I can also be administered topically to an animal in the form of dips, dusts, powders, collars, medallions, sprays, shampoos, spot-ons and pour-ons, as well as in the form of ointments or oil-in-water or water-in-oil emulsions. For topical administration, dips and sprays typically contain 0.5 ppm to 5,000 ppm and preferably 1 ppm to 3,000 ppm of Compound I. Additionally, Compound I can be formulated into ear tags for animals, especially quadrupeds (e.g., cattle and sheep).

[0333] The oral solution is administered directly.

[0334] The solution for use on the skin is dropped, applied, rubbed, sprinkled or sprayed.

[0335] The gel is applied or spread on the skin or introduced into a body cavity.

[0336] The pour-on formulation is poured or sprayed onto a defined skin area, and the active compound penetrates the skin and acts systemically. The pour-on formulation is prepared by dissolving, suspending, or emulsifying the active compound in a suitable skin-compatible solvent or solvent mixture.

[0337] The emulsion can be administered orally, transdermally or as an injection.

[0338] The suspension can be administered orally or topically / transdermally.

[0339] The semi-solid preparation can be administered orally or topically / transdermally.

[0340] To produce a solid preparation, the active compound is mixed with a suitable excipient, and if appropriate, additives are added, and the desired dosage form is made.

[0341] The compositions that can be used in the present invention can generally contain from about 0.001% to 95% of Compound I.

[0342] The ready-to-use preparation contains a compound which acts against parasites, preferably ectoparasites, at a concentration of from 10 ppm to 80% by weight, preferably from 0.1% to 65% by weight, more preferably from 1% to 50% by weight, most preferably from 5% to 40% by weight.

[0343] The preparation to be diluted before use contains a compound which acts against ectoparasites at a concentration of from 0.5% to 90% by weight, preferably from 1% to 50% by weight.

[0344] In addition, the preparation contains the compound of formula I which acts against endoparasites at a concentration of from 10 ppm to 2% by weight, preferably from 0.05% to 0.9% by weight, very particularly preferably from 0.005% to 0.25% by weight.

[0345] Solid formulations which release the compounds of the invention in a total amount of from 10 mg / kg to 300 mg / kg, preferably from 20 mg / kg to 200 mg / kg, most preferably from 25 mg / kg to 160 mg / kg of the body weight of the treated animal within three weeks can be administered.

[0346] A. Preparation examples

[0347] By appropriately varying the starting materials, further compounds I are obtained using the procedures given in the synthesis description. The compounds obtained in this way are listed in the table below together with their physical data.

[0348] The products shown below are characterized by melting point determination, NMR spectroscopy or the mass ([m / z]) or retention time (RT; [min.]) determined by HPLC-MS or HPLC spectroscopy.

[0349] HPLC-MS = mass spectrometry coupled with high performance liquid chromatography;

[0350] HPLC method A: Shimadzu LC2010, column: Waters XBridge C18, 150 mm × 4.6 mm ID × 5 μ; mobile phase: A: water + 0.1% TFA; B: acetonitrile + 0.1% TFA; temperature: 40 °C; 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.

[0351] Example 1: Synthesis of N-(3-(aminomethyl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0352] Step 1: At 0 °C, n-BuLi (79.5 mL, 178.6 mmol) was added dropwise to a solution of i-PrMgCl (98 mL, 196.4 mmol) in THF (450 mL), and the mixture was stirred additionally for 30 min at 0 °C. At 0 °C, a solution of 5-bromo-1,3-dichloro-2-fluorobenzene (40 g, 180 mmol) in THF (150 mL) was added dropwise to the mixture and stirred at 0 °C under N 2 2. At 0 °C, a mixture of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (42 g, 270 mmol) in THF (100 mL) was added dropwise to this mixture. Then, it was stirred at 0 °C under N 2 2 for 3 h. TLC (PE / EtOAc = 5 / 1) indicated complete conversion. The resulting mixture was poured into an aqueous solution of NH 4 Cl (500 mL) and extracted with MTBE (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one as a yellow oil (20 g, yield: 45.9%).

[0353] Step 2: At 25 °C under N 2 2, diethyl (cyanomethyl)phosphonate (33.6 g, 189.8 mmol), triethylamine (70 mL) and LiBr (16.5 g, 189.7 mmol) were added to a solution of 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one (49.4 g, 189.3 mmol) in THF (500 mL). Then, the reaction mixture was heated to 70 °C and stirred for 3 h. TLC (PE / EtOAc = 5 / 1) indicated complete conversion. The resulting reaction mixture was filtered, the filtrate was poured into water (200 mL) and extracted with EtOAc (500 mL x 2). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to give (Z)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enenitrile as a yellow oil (50 g, yield: 96.7%).

[0354] 1 1H-NMR (400 MHz, CDCl 3 3): δ = 7.50 (d, J = 5.9 Hz, 2H), 6.28 - 6.26 (m, 1H).

[0355] Step 3: Note: Set two batches simultaneously. At 25 °C, 1-hydroxyurea (10.4 g, 137.4 mmol) was added to a solution of NaOMe (15.6 g, 302 mmol) in MeOH (306 mL). At 0 °C, a solution of 3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enenitrile (25 g, 91.6 mmol) in MeOH (100 mL) was added dropwise to the reaction mixture and stirred at 50 °C for 3 h. LCMS indicated complete conversion. The resulting reaction mixture was poured into water (300 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 dried and concentrated to give 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (33 g, crude yield) as a white solid and used in the next step without prior purification.

[0356] 1 1H-NMR (400 MHz, CD 3 OD) δ = 7.65 (d, J = 6.3 Hz, 2H), 3.78 - 3.71 (m, 1H), 3.50 - 3.44 (m, 1H).

[0357] Step 4: At 25 °C, ethylene glycol (45.8 g, 739 mmol) and TsOH (4.23 g, 24.6 mmol) were added to a solution of 5-bromo-2-fluorobenzaldehyde (50 g, 246 mmol) in toluene (500 mL). The reaction mixture was stirred at 130 °C under N 2 2. TLC (PE:EtOAc = 10:1) indicated complete conversion. The reaction was quenched with NaHCO 3 (800 mL) and extracted with EtOAc (400 mL x 2). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE / EtOAc = 1:0 to 10:1) to afford 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (35 g, yield: 57.6%) as a white oil.

[0358] 1 1H-NMR (400 MHz, CDCl 3) δ = 7.67 (dd, J = 2.6, 6.2 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.00 - 6.92 (m, 1H), 6.06 - 6.03 (m, 1H), 4.16 - 4.09 (m, 2H), 4.08 - 3.99 (m, 2H).

[0359] Step 5: To a solution of 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (5 g, 15.77 mmol) and 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (4.3 g, 17.35 mmol) in dioxane (100 mL) was added Pd(dba) 2 (907 mg, 1.577 mmol), XantPhos (1.83 g, 3.15 mmol), K 3 PO 4 (6.695 g, 31.5 mmol), and the mixture was stirred at 120 °C under N 2 for 16 h. TLC (PE:EtOAc = 3:1) indicated complete conversion of the starting materials. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated to give the crude product, which was further purified by column chromatography (PE:EtOAc = 1:0 to 0:1) to afford N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a yellow solid (3.5 g, yield: 46%).

[0360] 1 1H-NMR (400 MHz, CD 3 OD) δ = 7.72 - 7.68 (m, 2H), 7.65 (d, J = 6.3 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.44 - 7.38 (m, 1H), 7.03 (dd, J = 9.1, 9.8 Hz, 1H), 6.02 - 5.98 (m, 1H), 4.17 - 4.06 (m, 2H), 4.06 - 3.98 (m, 2H), 3.97 - 3.90 (m, 1H), 3.68 (d, J = 16.8 Hz, 1H)

[0361] Step 6: At 25 °C, an aqueous HCl solution (35 mL, 4 N) was added to a solution of N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (3.5 g, 7.25 mmol) in THF (35 mL). The reaction mixture was stirred at 40 °C for 2 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The reaction mixture was quenched with an aqueous NaHCO 3 aqueous solution (240 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated to dryness. The crude product was purified by column chromatography (PE / EtOAc = 1:0 to 1:1) to afford 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-fluorobenzaldehyde as a yellow oil (3 g, yield: 94.2%).

[0362] 1 1H-NMR (400 MHz, DMSO-d 6 ) δ = 10.22 - 10.19 (m, 1H), 9.62 - 9.54 (m, 1H), 7.96 - 7.90 (m, 1H), 7.87 - 7.81 (m, 2H), 7.69 - 7.62 (m, 1H), 7.41 - 7.33 (m, 1H), 4.00 - 3.93 (m, 1H), 3.90 - 3.82 (m, 1H)

[0363] Step 7: At 25 °C, NH 4 OAc (6.3 g, 82.2 mmol) and NH 3 (60 mL, 7 N, in MeOH) were added to a solution of 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-fluorobenzaldehyde (3 g, 6.8 mmol) in EtOH (120 mL). The reaction mixture was stirred at 25 °C for 1 h. Then, at 0 °C, NaBH 4 (1 g, 27.2 mmol) was added to the reaction mixture and stirred at 0 °C - 25 °C for 2 h. TLC (EtOAc:MeOH = 1:1) indicated complete conversion. The reaction mixture was quenched with NH 4The reaction mixture was quenched with an aqueous solution of HCl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated to dryness and purified by column chromatography (PE / EtOAc = 1:0 to 0:1) to give N-(3-(aminomethyl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (1.6 g, yield: 53.3%) as a white solid.

[0364] 1 1H-NMR (400 MHz, CD 3 OD) δ = 7.75 - 7.66 (m, 2H), 7.50 - 7.41 (m, 1H), 7.30 - 7.21 (m, 1H), 7.06 - 6.96 (m, 1H), 3.98 - 3.92 (m, 1H), 3.86 - 3.81 (m, 2H), 3.73 - 3.65 (m, 1H), 2.05 - 2.02 (m, 1H)

[0365] Example 2: Synthesis of N-(3-(aminomethyl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-N-ethyl-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0366] Step 1: At 0 °C, NaH (368 mg, 9.2 mmol) was added to a solution of N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (3.7 g, 7.7 mmol) in THF (120 mL). The reaction mixture was stirred at 0 °C under N 2 for 0.5 h. Then, at 0 °C, EtOTf (1.64 g, 9.2 mmol) was added dropwise to the mixture and stirred at 0 °C - 25 °C for 4 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting solution was quenched with an aqueous solution of NH 4 Cl (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-N-ethyl-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (4 g, yield: crude) as a yellow oil.

[0367] Step 2: At 25 °C, an aqueous HCl solution (40 mL, 4 N) was added to a solution of N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-N-ethyl-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (4 g, 7.8 mmol) in THF (40 mL). The reaction mixture was stirred at 40 °C for 3 h. TLC (PE:EtOAc = 3:1) indicated complete conversion of the starting material. The reaction was quenched with an aqueous NaHCO 3 solution (200 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to afford 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)(ethyl)amino)-2-fluorobenzaldehyde as a yellow oil (3 g, yield: 82.1%).

[0368] 1 H-NMR (400 MHz, CDCl 3 ) δ = 10.38 - 10.36 (m, 1H), 7.64 (dd, J = 2.9, 5.9 Hz, 1H), 7.48 - 7.45 (m, 2H), 7.43 - 7.37 (m, 1H), 7.27 (s, 1H), 3.64 (br s, 2H), 3.54 - 3.47 (m, 1H), 3.14 - 3.05 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H)

[0369] Step 3: At 0 °C, NH 4 OAc (3.4 g, 43.8 mmol) and NH 3 (50 mL, 7 N, in MeOH) were added to a solution of 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)(ethyl)amino)-2-fluorobenzaldehyde (1.7 g, 3.65 mmol) in EtOH (60 mL). The reaction mixture was stirred at 25 °C for 1 h. Then, NaBH 3 CN (920 mg, 14.6 mmol) was added at 0 °C and the mixture was stirred at 50 °C for 16 h. TLC (PE:EtOAc = 1:1) indicated complete conversion of the starting material. The resulting solution was treated with NH 4The reaction mixture was quenched with aqueous HCl solution (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to give N-(3-(aminomethyl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-N-ethyl-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (1.5 g, yield: 87.6%) as a yellow oil.

[0370] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.66 - 7.61 (m, 2H), 7.33 - 7.26 (m, 1H), 7.11 (s, 2H), 3.85 (s, 2H), 3.69 - 3.64 (m, 2H), 3.64 - 3.61 (m, 1H), 3.46 - 3.40 (m, 1H), 1.17 - 1.12 (m, 3H)

[0371] Example 3: Synthesis of N-(3-(aminomethyl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-N-(ethoxymethyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0372] Step 1: At 0 °C, NaH (392 mg, 9.79 mmol) was added to a solution of 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-fluorobenzaldehyde (3.8 g, 8.15 mmol) in THF (120 mL). The reaction mixture was stirred at 0 °C under N 2 for 1 h. Then, at 0 °C, (chloromethoxy)ethane (925 mg, 9.79 mmol) was added dropwise to the mixture and stirred at 0 °C - 25 °C for 4 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting solution was quenched with aqueous NH 4 Cl solution (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)(ethoxymethyl)amino)-2-fluorobenzaldehyde (2.79 g, yield: 68.22%) as a yellow oil.

[0373] 1 H-NMR (400 MHz, CD3 OD) δ = 7.66 (d, J = 6.3 Hz, 2H), 7.52 (dd, J = 2.6, 6.1 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.13 (t, J = 9.3 Hz, 1H), 5.75 (s, 1H), 4.92 (s, 2H), 4.02 - 3.87 (m, 1H), 3.87 - 3.71 (m, 1H), 3.61 - 3.56 (m, 2H), 1.18 (t, J = 6.6 Hz, 3H).

[0374] Step 2: At 0 °C, add NH 4 OAc (6 g, 77.9 mmol) and NH 3 (60 mL, 7N, in MeOH) to a solution of 5 - ((5 - (3,5 - dichloro - 4 - fluorophenyl) - 5 - (trifluoromethyl) - 4,5 - dihydroisoxazol - 3 - yl)(ethoxymethyl)amino) - 2 - fluorobenzaldehyde (2.76 g, 5.56 mmol) in EtOH (90 mL) and stir for 2 h. Then, at 0 °C, add NaBH 3 CN (1.4 g, 22.24 mmol) to the reaction and stir at 50 °C for 16 h. TLC (PE:EtOAc = 0:1) indicates complete conversion. Quench the resulting solution with aqueous NH 4 Cl (100 mL) and extract with EtOAc (50 mL x 2). Wash the combined organic layers with brine (100 mL), dry over sodium sulfate and concentrate to dryness. Purify the residue by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to afford N - (3 - (aminomethyl) - 4 - fluorophenyl) - 5 - (3,5 - dichloro - 4 - fluorophenyl) - N - (ethoxymethyl) - 5 - (trifluoromethyl) - 4,5 - dihydroisoxazol - 3 - amine as a yellow oil (2.5 g, yield: 90.29%).

[0375] 1 H - NMR (400 MHz, CD 3 OD) δ = 7.67 (d, J = 6.1 Hz, 2H), 7.38 (dd, J = 2.7, 6.6 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.18 - 7.10 (m, 1H), 4.94 - 4.91 (m, 2H), 3.93 - 3.88 (m, 1H), 3.83 (br s, 1H), 3.69 - 3.64 (m, 1H), 3.61 - 3.55 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0376] Example 4: Synthesis of Ethyl (4-(aminomethyl)-3-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate

[0377] Step 1: At 20 °C under N 2 To a solution of 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (10 g, 31.5 mmol) in dioxane (150 mL) was added 2-bromo-1-fluoro-4-iodobenzene (11.3 g, 37.8 mmol), Pd 2 (dba) 3 (1.4 g, 1.57 mmol), XantPhos (1.8 g, 3.15 mmol), Cs 2 CO 3 (20 g, 63 mmol) and the mixture was stirred at 80 °C under N 2 for 16 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting reaction mixture was quenched with H 2 O (200 mL), extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated to dryness. The crude product was purified by silica gel column chromatography (PE:EtOAc = 100:0 to 17:83) to afford N-(3-bromo-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a yellow solid (8.2 g, yield: 52.9%).

[0378] 1 1H-NMR (400 MHz, CDCl 3 ) δ = (dd, J = 5.75, 2.75 Hz, 1H) 7.56 (d, J = 6.00 Hz, 2H) 7.20 - 7.26 (m, 1H) 7.01 - 7.16 (m, 1H) 5.85 (s, 1H) 3.90 (d, J = 16.01 Hz, 1H) 3.50 (d, J = 16.01 Hz, 1H).

[0379] Step 2: At 0 °C, to a solution of N-(3-bromo-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (4 g, 8.16 mmol) in THF (40 mL) was added NaH (490 mg, 12.2 mmol). The reaction mixture was stirred at 0 °C under N 2Stir for 0.5 h. Then, at 0 °C, ethyl chloroformate (2.67 g, 24.5 mmol) in THF (4 mL) was added dropwise to the reaction and stirred additionally for 2 h at 0 °C. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting solution was quenched with aqueous NH 4 Cl solution (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to afford ethyl (3-bromo-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (4 g, yield: 86.9%) as a yellow oil.

[0380] 1 H-NMR (400 MHz, CDCl 3 ) δ = 7.51 (d, J = 6.00 Hz, 2H), 7.43 (dd, J = 5.94, 2.31 Hz, 1H), 7.13 - 7.23 (m, 2H), 4.40 (d, J = 18.26 Hz, 1H), 4.21 (q, J = 7.05 Hz, 2H), 4.03 (d, J = 18.39 Hz, 1H), 1.25 - 1.29 (m, 3H).

[0381] Step 3: At 25 °C, to a solution of ethyl (3-bromo-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (4 g, 7.1 mmol) in toluene (40 mL) was added (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (2.1 g, 10.65 mmol), tBu 3 P-Pd-G2 (386 mg, 0.71 mmol), K 2 CO 3 (2 M, 7.1 ml, 14.2 mmol). The reaction mixture was stirred at 80 °C for 12 h. HPLC indicated 51% conversion to the desired product. The reaction mixture was quenched with H 2 O (40 ml), the filtrate was extracted with EtOAc (40 mL x 3), the combined organic layers were washed with brine (40 mL), and dried over Na 2 SO 4Dry, concentrate to dryness, and further purify the crude product by silica gel column chromatography (PE:EtOAc = 100:0 to 95:5) to obtain ethyl (3-(((tert-butoxycarbonyl)amino)methyl)-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (4 g, yield 91.9%) as a white solid.

[0382] 1 H-NMR(400MHz, CDCl 3 ) δ = 7.51 (d, J = 6.00Hz, 2H), 7.21 (br d, J = 5.38Hz, 1H), 7.05 - 7.14 (m, 2H), 4.31 - 4.47 (m, 3H), 4.18 (q, J = 7.00Hz, 2H), 4.04 (d, J = 18.39Hz, 1H), 1.44 (s, 9H), 1.19 (t, J = 7.13Hz, 3H).

[0383] Step 4: Stir a solution of ethyl (3-(((tert-butoxycarbonyl)amino)methyl)-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (4 g, 6.5 mmol) in HCl / EtOAc (50 mL) at 25 °C for 2 h. TLC (PE:EtOAc = 1:1) indicates complete conversion. Pour the resulting reaction mixture into NaHCO 3 (100 mL) and extract with EtOAc (50 mL x 2). Wash the combined organic layers with brine (100 mL), dry over Na 2 SO 4 and concentrate to dryness to obtain the crude product, which is further purified by column chromatography (PE:EtOAc = 1:0 to 0:1) to obtain ethyl (3-(aminomethyl)-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (2.015 g, yield: 60.3%) as a white solid.

[0384] 1 H-NMR(400MHz, CDCl 3)δ = 7.51 (d, J = 6.02 Hz, 2H), 7.25 (dd, J = 6.53, 1.76 Hz, 1H), 7.05 - 7.12 (m, 2H), 4.41 (d, J = 18.32 Hz, 1H), 4.19 (q, J = 7.07 Hz, 2H), 4.04 (d, J = 18.32 Hz, 1H), 3.94 (s, 2H), 1.20 (t, J = 7.09 Hz, 3H).

[0385] Example 5: Synthesis of N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0386] Step 1: At 20 °C under N 2 To a solution of 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (10 g, 31.53 mmol) in dioxane (150 mL) was added 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (12 g, 37.9 mmol), Pd 2 (dba) 3 (2 g, 3.15 mmol), Xantphos (2.74 g, 4.7 mmol), K 3 PO 4 (13.4 g, 63 mmol) and the mixture was stirred at 80 °C under N 2 for 16 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting reaction mixture was quenched with H 2 O (200 mL), and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated to dryness. The crude product was further purified by MPLC to give N-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a yellow solid (1.82 g, yield: 11.96%).

[0387] 1 1H-NMR (400 MHz, CDCl 3) δ = 7.55 (d, J = 6.00 Hz, 2H), 7.39 - 7.47 (m, 2H), 7.02 (t, J = 9.19 Hz, 1H), 6.05 (s, 1H), 6.02 (s, 1H), 4.11 - 4.20 (m, 2H), 4.00 - 4.10 (m, 2H), 3.86 (d, J = 16.01 Hz, 1H), 3.45 (d, J = 16.13 Hz, 1H).

[0388] Example 6: Synthesis of 5-(3,5-Dichloro-4-fluorophenyl)-N-(4-fluoro-3-((methylamino)methyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0389] Step 1: At 25 °C, MeNH 2 (7.3 g, approximately 30%, in EtOH, 70.8 mmol) was added to a solution of 5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-fluorobenzaldehyde (3.1 g, 7.08 mmol) in MeOH (120 mL), and the mixture was stirred at 65 °C for 16 h. Then, at 0 °C, NaBH 4 (1.1 g, 28.3 mmol) was added to the reaction mixture. The reactants were stirred for 4 h. TLC (EtOAc:MeOH = 1:1) indicated complete conversion. The resulting reaction mixture was quenched with aqueous NH 4 Cl (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to give 5-(3,5-dichloro-4-fluorophenyl)-N-(4-fluoro-3-((methylamino)methyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a white solid (2.4 g, yield: 74.9%).

[0390] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.78 - 7.73 (m, 1H), 7.71 (d, J = 6.3 Hz, 2H), 7.44 (s, 1H), 7.19 (t, J = 9.2 Hz, 1H), 4.27 - 4.22 (m, 2H), 4.02 - 3.95 (m, 1H), 3.78 - 3.70 (m, 1H), 2.76 - 2.73 (m, 3H).

[0391] Example 7: Synthesis of N-(3-(Aminomethyl)-4-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0392] Step 1: At 0 °C under N 2 under, BH 3 ·THF (77.94 mL, 77.94 mmol) was added dropwise to a solution of 2-bromo-5-iodobenzonitrile (10 g, 32.48 mmol) in THF (100 mL), and after complete addition, the mixture was stirred additionally at 70 °C for 16 hours. TLC (PE:EA = 5:1) indicated complete conversion. At 0 °C, the mixture was poured into aqueous HCl solution (1 M, 50 mL), and stirred at 20 °C for 20 min. The pH of the mixture was adjusted to 10 with NaOH to obtain (2-bromo-5-iodophenyl)methanamine (10 g, yield: crude) in the solution. It was used directly without further purification.

[0393] Step 2: At 0 °C under N 2 under, Boc 2 O (20.99 g, 96.17 mmol) was added to a solution of (2-bromo-5-iodophenyl)methanamine (10 g, 32.06 mmol) in MeCN (100 mL), and after warming to 20 °C, the mixture was stirred additionally for 16 hours. TLC (PE:EA = 5:1) indicated complete conversion. The reaction mixture was poured into H 2 O (200 mL) and extracted with EtOAc (90 ml x 3). The combined organic phases were washed with brine (180 ml x 3), dried over Na 2 SO 4 dried, filtered and concentrated to obtain the crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to obtain tert-butyl (2-bromo-5-iodobenzyl)carbamate (10 g, yield: 75.7%) as a white solid.

[0394] 1 H-NMR (400 MHz, CD 3 OD) δ = 1.47 (s, 9H), 4.23 (s, 2H), 7.31 (d, J = 8.38 Hz, 1H), 7.49 (dd, J = 8.25, 1.50 Hz, 1H), 7.63 (s, 1H).

[0395] Step 3: At 25 °C under N 2 under, 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (5.92 g, 18.67 mmol), K 3 PO 4(11.89 g, 56 mmol), Pd 2 (dba) 3 (1.71 g, 1.87 mmol) and XantPhos (2.16 g, 3.74 mmol) were stirred at 120 °C for 16 h. LCMS indicated complete conversion. The mixture was poured into H 2 O (200 mL) and extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine (150 ml x 3), dried over Na 2 SO 4 , filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to afford tert-butyl (2-bromo-5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (5.27 g, yield: 36.1%).

[0396] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 1.46 (s, 9H), 3.41 (br d, J = 16.38 Hz, 1H), 3.82 (br d, J = 16.38 Hz, 1H), 4.25 (d, J = 6.24 Hz, 2H), 5.25 (br s, 1H), 7.00 (br s, 1H), 7.14 - 7.23 (m, 2H), 7.32 (br d, J = 7.95 Hz, 1H), 7.53 (d, J = 5.99 Hz, 2H).

[0397] Step 4: At 25 °C under N 2 , to a mixture of tert-butyl (2-bromo-5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (5.26 g, 8.75 mmol) in dioxane (55 mL) and H 2 O (11 mL) was added methylboronic acid (1.57 g, 26.25 mmol), Na 2 CO 3 (2.78 g, 26.25 mmol), PdCl 2 (dppf) (0.64 g, 0.88 mmol), and the mixture was stirred at 110 °C for 16 h. LCMS indicated complete conversion. The mixture was poured into H 2 O (200 mL), extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine (150 ml x 3), dried over Na 2 SO4 Dry, filter and concentrate to obtain the crude product. The product was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to give tert-butyl (5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-methylbenzyl)carbamate (5.1 g, yield: crude) as a brown solid.

[0398] 1 H-NMR (400 MHz, CDCl 3 ) δ = 1.47 (s, 10H), 2.23 (s, 3H), 3.44 (br d, J = 16.13 Hz, 1H), 3.85 (br d, J = 16.13 Hz, 1H), 4.17 - 4.30 (m, 2H), 4.83 (br s, 1H), 6.45 (br s, 1H), 7.04 (d, J = 8.13 Hz, 1H), 7.12 - 7.21 (m, 2H), 7.54 (d, J = 6.00 Hz, 2H).

[0399] Step 5: At 25 °C under N 2 To a solution of tert-butyl (5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-methylbenzyl)carbamate (2.0 g, 3.73 mmol) in EtOAc / HCl (25 mL) was added and stirred at 25 °C for 16 h. TLC (PE:EA = 5:1) indicated complete conversion. The mixture was filtered, washed with MTBE (25 mL) and concentrated to give N-(3-(aminomethyl)-4-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine hydrochloride (2.0 g, purity: 99%, 1.9 g delivered as the hydrochloride) as a white solid.

[0400] 1 H-NMR (400 MHz, CD 3 OD) δ = 2.35 (s, 3H), 3.74 (d, J = 16.81 Hz, 1H), 3.99 (d, J = 16.81 Hz, 1H), 4.12 (s, 2H), 7.17 - 7.26 (m, 2H), 7.56 (d, J = 2.13 Hz, 1H), 7.71 (d, J = 6.15 Hz, 2H).

[0401] Example 8: Synthesis of N-(3-(aminomethyl)-4-chlorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0402] Step 1: At 0 °C under N 2 To a solution of 5-bromo-2-chlorobenzonitrile (15.0 g, 69.30 mmol) in THF (150 mL) was added dropwise BH 3 ·THF (166.32 mL, 166.32 mmol). Then, the mixture was stirred at 70 °C for 16 h. LCMS indicated complete conversion of the starting material. The mixture was poured into HCl (1 M, 50 mL) and stirred at 20 °C for 20 min. The pH of the mixture was adjusted to 10 with NaOH to obtain (5-bromo-2-chlorophenyl)methanamine (15 g) as a white liquid, which was used directly without further purification.

[0403] Step 2: At 0 °C under N 2 To a mixture of (5-bromo-2-chlorophenyl)methanamine (15 g, 68.03 mmol) in MeCN (150 mL) was added Boc 2 O (44.55 g, 204.9 mmol), and the mixture was stirred additionally at 20 °C for 16 h. LCMS indicated complete conversion of the starting material. The mixture was poured into H 2 O (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 dried, filtered and concentrated to obtain a crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to yield tert-butyl (5-bromo-2-chlorobenzyl)carbamate (10 g, yield: 45.8%) as a white solid.

[0404] 1 ¹H-NMR (400 MHz, CDCl 3 ) δ = 1.47 (s, 9H), 4.37 (br d, J = 5.75 Hz, 2H), 5.01 (br s, 1H), 5.30 (s, 1H), 7.15 - 7.25 (m, 1H), 7.34 (dd, J = 8.50, 2.25 Hz, 1H), 7.51 (d, J = 2.25 Hz, 1H).

[0405] Step 3: At 25 °C under N 2 To a mixture of tert-butyl (5-bromo-2-chlorobenzyl)carbamate (5.6 g, 17.47 mmol) in dioxane (57 mL) was added 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (3.73 g, 11.65 mmol), K 3 PO 4(7.47 g, 34.94 mmol), Pd 2 (dba) 3 (1.07 g, 1.17 mmol) and Xantphos (1.36 g, 2.33 mmol), and the mixture was stirred at 110 °C for 16 h. LCMS indicated complete conversion. The mixture was poured into H 2 O (200 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (150 mL x 3), dried over Na 2 SO 4 and filtered and concentrated to give the crude product. The product was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 2:1) to give tert-butyl (2-chloro-5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (4.3 g, yield: 44.4%) as a brown oil.

[0406] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 1.38 (s, 8H), 3.37 (br d, J = 16.26 Hz, 1H), 3.78 (br d, J = 16.13 Hz, 1H), 4.24 (d, J = 6.38 Hz, 2H), 5.06 (br s, 1H), 7.15 (br d, J = 8.50 Hz, 2H), 7.22 - 7.28 (m, 1H), 7.47 (d, J = 6.00 Hz, 2H).

[0407] Step 4: At 25 °C under N 2 , was added to a solution of tert-butyl (2-chloro-5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (3.6 g, 6.47 mmol) in EtOAc / HCl (36 mL). Then, the mixture was stirred at 25 °C for 3 h. TLC (PE:EA = 2:1) indicated complete conversion. The mixture was concentrated to give N-(3-(aminomethyl)-4-chlorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (2.5 g, yield: 47%) as a white solid.

[0408] 1 1H-NMR (400 MHz, DMSO-d 6) δ = 3.85 - 3.91 (m, 1H), 4.01 (s, 1H), 4.05 (br s, 2H), 7.45 (s, 2H), 7.65 (s, 1H), 7.82 (d, J = 6.27 Hz, 2H), 8.47 (br s, 3H), 9.91 (s, 1H).

[0409] Example 9: Synthesis of N-(3-(aminomethyl)-4-(trifluoromethoxy)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0410] Step 1: At 0 °C under N 2 To a solution of 5-bromo-2-(trifluoromethoxy)benzonitrile (10 g, 37.59 mmol) in THF (100 mL) was added dropwise BH 3 ·THF (90.22 mL, 90.22 mmol), and the mixture was stirred for an additional 16 h at 70 °C. LCMS indicated complete conversion. The mixture was poured into HCl (1 M, 50 mL) and stirred at 20 °C for 20 min. The pH of the mixture was adjusted to 10 with NaOH. Then, (5-bromo-2-(trifluoromethoxy)phenyl)methanamine, obtained as a white liquid (10 g), was used directly without further purification.

[0411] Step 2: At 0 °C under N 2 To a solution of (5-bromo-2-(trifluoromethoxy)phenyl)methanamine (8 g, 29.62 mmol) in MeCN (80 mL) was added Boc 2 O (19.40 g, 88.87 mmol), and the mixture was stirred at 20 °C for 16 h. LCMS indicated complete conversion. The mixture was poured into H 2 O (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 and filtered and concentrated to give a crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to yield (5-bromo-2-(trifluoromethoxy)benzyl)carbamic acid tert-butyl ester as a brown oil (12 g, crude yield).

[0412] 1 1H-NMR (400 MHz, CDCl 3) δ = 1.39 - 1.45 (m, 9H), 2.00 (s, 1H), 4.33 (br d, J = 6.15 Hz, 2H), 7.07 (dd, J = 8.72, 1.32 Hz, 1H), 7.38 (dd, J = 8.72, 2.32 Hz, 1H), 7.52 (d, J = 2.38 Hz, 1H).

[0413] Step 3: At 25 °C under N 2 To a mixture of tert-butyl (5-bromo-2-(trifluoromethoxy)benzyl)carbamate (10.2 g, 27.64 mmol) in dioxane (102 mL) was added 5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (5.84 g, 18.43 mmol), K 3 PO 4 (11.72 g, 55.28 mmol), Pd 2 (dba) 3 (1.69 g, 1.84 mmol) and Xantphos (2.13 g, 3.69 mmol), and the mixture was stirred at 110 °C for 16 h. LCMS indicated complete conversion. The mixture was poured into H 2 O (200 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (150 mL), dried over Na 2 SO 4 and filtered and concentrated to dryness to give a crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to yield tert-butyl (5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-(trifluoromethoxy)benzyl)carbamate (8.5 g, yield: crude) as a brown oil.

[0414] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 1.47 (s, 9H), 3.48 (d, J = 16.13 Hz, 1H), 3.83 - 3.95 (m, 1H), 4.33 (d, J = 6.38 Hz, 2H), 7.16 (br d, J = 8.88 Hz, 1H), 7.29 - 7.41 (m, 2H), 7.56 (d, J = 6.00 Hz, 2H).

[0415] Step 4: A solution of tert-butyl (5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-(trifluoromethoxy)benzyl)carbamate (5.1 g, 8.41 mmol) in EtOAc / HCl (51 mL) was stirred at 25 °C for 3 h. LCMs indicated complete conversion. The mixture was poured into H 2 O (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (60 mL), dried over Na 2 SO 4 and filtered and concentrated to dryness to afford the crude product. The crude product was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to yield N-(3-(aminomethyl)-4-(trifluoromethoxy)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (2.8 g, yield: 65%) as a white solid.

[0416] 1 H-NMR (400 MHz, CD 3 OD) δ = 3.67 - 3.74 (m, 1H), 3.84 (s, 2H), 3.93 - 4.00 (m, 1H), 7.21 (dd, J = 8.94, 1.44 Hz, 1H), 7.35 (dd, J = 8.88, 2.75 Hz, 1H), 7.56 (d, J = 2.75 Hz, 1H), 7.71 (d, J = 6.25 Hz, 2H).

[0417] Example 10: Synthesis of N-(4-(aminomethyl)-3-chlorophenyl)-5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0418] At 0 °C, i-PrMgCl (39.5 mL, 78.95 mmol) and n-BuLi (28.7 mL, 71.77 mmol) were added to a solution of THF (150 mL). The reaction mixture was stirred at 0 °C for 0.5 h. Then, 4-bromo-2-chloro-1-fluorobenzene (15 g, 71.77 mmol) was added and the mixture was stirred an additional 0.5 h at 0 °C. Then, a solution of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (16.9 g, 107.66 mmol) in THF (150 mL) was added dropwise at 0 °C and the mixture was stirred an additional 2 h at 0 °C - 25 °C. TLC (PE:EtOAc = 5:1) indicated complete conversion. The resulting mixture was quenched with NH 4The reaction was quenched with an aqueous solution of Cl (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to obtain 1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one as a yellow oil (9.4 g, yield: 58.3%).

[0419] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.68 (dd, J = 2.1, 7.2 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.28 (t, J = 8.9 Hz, 1H).

[0420] Step 2: At 25 °C, diethyl (cyanomethyl)phosphonate (7.3 g, 41.4 mmol) and TEA (11.5 mL, 82.8 mmol) were added to a mixture of 1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one (9.4 g, 41.4 mmol) in THF (50 mL). At 0 °C, a mixture of LiBr (3.6 g, 41.4 mmol) in THF (50 mL) was added to the reaction, and the mixture was stirred at 70 °C for 4 h. TLC (PE:EtOAc = 5:1) indicated complete conversion. The resulting reaction mixture was poured into H 2 O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to obtain 3-(3-chloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enenitrile as a yellow oil (9.1 g, yield: 88.07%).

[0421] 1 H-NMR (400 MHz, CDCl 3 ) δ = 7.60 (dd, J = 2.1, 6.6 Hz, 1H), 7.45 (ddd, J = 2.3, 4.3, 8.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.24 - 6.20 (m, 1H).

[0422] Step 3: Add 1-hydroxyurea (4.15 g, 54.6 mmol) to a solution of MeONa (6.5 g, 120.12 mmol) in MeOH (100 mL). Then, a solution of 3-(3-chloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enenitrile (9.1 g, 36.4 mmol) in MeOH (100 mL) was added dropwise at 0 °C. The solution was stirred at 50 °C for 3 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The resulting reaction mixture was poured into H 2 O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to give 5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a white solid (6 g, yield: 58.2%).

[0423] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.67 (dd, J = 2.2, 6.9 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.32 (t, J = 8.8 Hz, 1H), 3.78 - 3.70 (m, 1H), 3.45 (d, J = 16.9 Hz, 1H).

[0424] Step 4: Add Pd 2 (dba) 3 (1.62 g, 1.77 mmol), Xantphos (2.05 g, 3.53 mmol) and K 3 PO 4 (11.24 g, 53.01 mmol) to a solution of tert-butyl (5-bromo-2-chlorobenzyl)carbamate (8.5 g, 26.5 mmol) and 5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (5 g, 17.67 mmol) in dioxane (100 mL), and stir at 110 °C under N 2 for 16 h. TLC (PE:EtOAc = 3:1) indicated complete conversion. The reaction mixture was poured into H 2 O (200 mL), extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4Dry and concentrate to dryness to obtain the crude product, which is further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to obtain tert-butyl (2-chloro-5-((5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (6 g, yield: 65%) as a yellow solid.

[0425] 1 H-NMR (400 MHz, CDCl 3 ) δ = 7.65 (dd, J = 2.1, 6.8 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.36 (br d, J = 8.5 Hz, 1H), 7.27 - 7.24 (m, 2H), 7.20 (t, J = 8.6 Hz, 1H), 6.19 - 6.12 (m, 1H), 5.12 - 5.01 (m, 1H), 4.37 - 4.29 (m, 2H), 3.91 - 3.82 (m, 1H), 3.54 - 3.45 (m, 1H), 1.46 (s, 9H).

[0426] Step 5: Stir a solution of tert-butyl (2-chloro-5-((5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (5 g, 9.6 mmol) in HCl / EtOAc (50 mL) at 25 °C for 2 h. TLC (PE:EtOAc = 1:1) indicates complete conversion. Pour the resulting mixture into an aqueous NaHCO 3 solution (100 mL) and extract with EtOAc (50 mL x 2). Wash the combined organic layers with brine (100 mL), dry over Na 2 SO 4 and concentrate to dryness to obtain the crude product, which is further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to yield N-(3-(aminomethyl)-4-chlorophenyl)-5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (3.01 g, yield: 74.3%) as a white solid.

[0427] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.73 (dd, J = 2.1, 6.9 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 3.94 (d, J = 16.6 Hz, 1H), 3.84 (s, 2H), 3.68 (d, J = 16.6 Hz, 1H).

[0428] Example 11: Synthesis of N-(4-(aminomethyl)-3-chlorophenyl)-5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine

[0429] At -25 °C to -10 °C, diethylaminosulfur trifluoride (DAST) (124.7 g, 774.7 mmol) was added dropwise to a solution of diisopropylamine (90.85 g, 704.2 mmol) in DCM / EtOAc (1333 mL / 667 mL), and the mixture was stirred additionally for 10 min at -20 °C to -10 °C. Then, trimethyl(trifluoromethyl)silane (100 g, 704.2 mmol) was added dropwise at -25 °C to -10 °C. The reaction mixture was stirred at -20 °C to -10 °C for 1 hour. Then, solid TsNH 2 (120.4 g, 704.23 mmol) was added at -25 °C to -10 °C, and the mixture was stirred at -20 °C for 1 hour, warmed to 25 °C and stirred additionally for 16 hours. TLC (PE:EtOAc = 3:1) indicated complete conversion. The reaction mixture was poured into H 2 O (1 L), and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO 4 and concentrated to dryness to obtain the crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to obtain N-((diethylamino)fluoro(trifluoromethyl)-l4-thio) -4-methylbenzenesulfonamide as a brown oil (220 g, yield: 91%).

[0430] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.76 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.36 (td, J = 7.2, 14.4 Hz, 2H), 3.31 - 3.20 (m, 2H), 2.39 (s, 3H), 2.03 (s, 1H), 1.17 (t, J = 7.3 Hz, 6H).

[0431] Step 2: At 0 °C, H 2 SO 4(94 g, 959.3 mmol), and the temperature was raised to 25 °C and stirred for an additional 2 hours. TLC (PE:EtOAc = 5:1) indicated complete conversion. The reaction mixture was poured into H 2 O (0.5 L), and extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO 4 and concentrated to dryness to obtain the crude product as a white solid, 4-methyl-N-((trifluoromethyl)thio)benzenesulfonamide, which was used directly without prior purification.

[0432] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.82 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.24 (brs, 1H), 2.46 (s, 3H).

[0433] Step 3: At 0 °C, DIEA (31.42 g, 243.5 mmol) was added dropwise to a solution of 4-methyl-N-((trifluoromethyl)thio)benzenesulfonamide (60 g, 221.4 mmol) in DCM (600 mL), and stirred for an additional 5 min. At 0 °C to 5 °C, MeOTf (38.1 g, 232.47 mmol) was added dropwise to the reaction mixture, and stirred for an additional 2 hours at 0 °C to 5 °C. TLC (PE:EtOAc = 5:1) indicated complete conversion. The resulting reaction mixture was poured into H 2 O (0.6 L), and extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO 4 and concentrated to obtain the crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 3:1) to yield N,4-dimethyl-N-((trifluoromethyl)thio)benzenesulfonamide as a white oil (100 g, yield: 79.2%).

[0434] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.78 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 3.33 (s, 3H), 2.46 (s, 3H).

[0435] Step 4: At 25 °C, B(OCH 3 ) 3(36 g, 244.8 mmol). Then, at 0 °C, Mg (8.3 g, 344.8 mmol) was added to the mixture. It was stirred at 0 °C to 25 °C for 4 h. TLC (PE:EtOAc = 10:1) indicated complete conversion. The resulting mixture was poured into aqueous HCl (1 N) and extracted with MTBE (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO 4 and concentrated to dryness to afford (3,3,3-trifluoroprop-1-en-2-yl)boronic acid as a black oil (65 g).

[0436] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 6.49 - 6.29 (m, 2H).

[0437] Step 5: At 25 °C, to a solution of (5-bromo-2-fluorophenyl)boronic acid (25 g, 114.16 mmol) in DME (250 mL) was added N,4-dimethyl-N-((trifluoromethyl)thio)benzenesulfonamide (42.3 g, 148.4 mmol), K 2 2CO 3 (31.5 g, 228.32 mmol), 4,4'-dimethylbipyridine (4.2 g, 22.83 mmol) and CuI (2.17 g, 11.42 mmol), and the mixture was stirred at 25 °C for 16 h. TLC (PE:EtOAc = 10:1) indicated complete conversion. The resulting reaction mixture was poured into H 2 2O (250 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 2SO 4 and concentrated to dryness to give a crude product, which was further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to yield (5-bromo-2-fluorophenyl)(trifluoromethyl) sulfane as a colorless oil (50 g, yield: 79.6%).

[0438] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.81 (dd, J = 2.3, 6.2 Hz, 1H), 7.63 (ddd, J = 2.6, 4.4, 8.7 Hz, 1H), 7.12 (t, J = 8.4 Hz, 1H).

[0439] Step 6: At 25 °C, to (5-bromo-2-fluorophenyl)(trifluoromethyl) sulfane (8 g, 29.09 mmol) in dioxane / H2 To the solution in O (60 mL / 12 mL), add (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (12.2 g, 87.27 mmol), Cs 2 CO 3 (28.4 g, 87.27 mmol) and Pd(dppf)Cl 2 . DCM (2.38 g, 2.9 mmol), and stir at 100 °C under N 2 for 16 h. TLC (PE:EtOAc = 10:1) indicates complete conversion. Pour the resulting reaction mixture into H 2 O (150 mL) and extract with MTBE (150 mL x 2). Wash the combined organic layers with brine (200 mL), dry over Na 2 SO 4 and concentrate to dryness to obtain the crude product, which is further purified by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to yield (3,3,3-trifluoroprop-1-en-2-yl)boronic acid as a yellow oil (13.5 g, yield: 79.6%).

[0440] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.96 (dd, J = 2.0, 6.4 Hz, 1H), 7.82 (td, J = 2.2, 4.4 Hz, 1H), 7.31 (t, J = 8.5 Hz, 1H), 6.24 (d, J = 1.0 Hz, 1H), 6.00 (br d, J = 1.5 Hz, 1H).

[0441] Step 7: Under vigorous stirring at -78 °C under N 2 dropwise add a solution of dibromoformaldoxime (10.9 g, 53.79 mmol) in THF (20 mL) to a solution of NH(PMB) 2 (11.54 g, 44.83 mmol) in THF (80 mL). Then, at -78 °C under N 2 dropwise add diisopropylethylamine (DIEA, 5.7 g, 44.83 mmol) within 20 min. Then, at -78 °C, dropwise add a solution of (2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)(trifluoromethyl)sulfane (13 g, 44.83 mmol) in THF (30 mL). Add DIEA (11.4 g, 89.66 mmol) at -78 °C, and under N 2Heat it to 20 °C - 25 °C below and keep it for 16 hours. TLC (PE:EtOAc = 5:1) indicates complete conversion of the starting material. Pour the resulting solution into water (200 mL) and extract with EtOAc (2100 mL x 3). Wash the combined organic layers with brine (200 mL), dry over sodium sulfate and concentrate to dryness. Purify the residue by silica gel column chromatography (PE / EtOAc = 1:0 to 3:1) to obtain 5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a yellow oil (10 g, yield: 37.9%).

[0442] 1 H-NMR(400MHz, CDCl 3 ) δ = 7.83 (dd, J = 2.1, 6.3 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.27 - 7.24 (m, 1H), 7.07 (d, J = 8.6 Hz, 4H), 6.87 - 6.83 (m, 4H), 4.29 - 4.26 (m, 4H), 3.83 (br d, J = 6.0 Hz, 1H), 3.81 - 3.80 (m, 6H), 3.42 (d, J = 16.0 Hz, 1H).

[0443] Step 8: Stir a solution of 5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (10 g, 17.0 mmol) in TFA (20 mL) at 25 °C for 16 hours. TLC (PE:EtOAc = 3:1) indicates complete conversion. Quench the resulting mixture with an aqueous NaHCO 3 solution (800 mL), extract with EtOAc (200 mL x 3), wash the combined organic layers with brine (200 mL), dry over Na 2 SO 4 and concentrate to dryness to obtain the crude product, which is further purified by silica gel column chromatography (PE / EtOAc = 1:0 to 0:1) to yield 5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine as a yellow oil (5 g, yield: 84.47%).

[0444] 1 H-NMR(400MHz, CDCl 3) δ = 7.83 (dd, J = 2.0, 6.4 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.30 - 7.25 (m, 1H), 3.74 (d, J = 16.4 Hz, 1H), 3.37 (d, J = 16.4 Hz, 1H).

[0445] Step 9: Add Pd 2 (dba) 3 (2.6 g, 2.87 mmol), Xantphos (3.3 g, 5.75 mmol) and K 3 PO 4 (18.27 g, 86.19 mmol) to a solution of 5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (10 g, 28.74 mmol) and tert-butyl (5-bromo-2-chlorobenzyl)carbamate (13.75 g, 43.1 mmol) in dioxane (100 mL), and stir at 110 °C under N 2 for 16 h. TLC (PE:EtOAc = 3:1) indicates complete conversion. Pour the resulting mixture into H 2 O (200 mL), and extract with EtOAc (100 mL x 2). Wash the combined organic layers with brine (100 mL), dry over Na 2 SO 4 and concentrate to dryness to obtain the crude product, which is further purified by column chromatography (PE:EtOAc = 5:1 to 0:1) to yield tert-butyl (2-chloro-5-((5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (7 g, yield: 41.4%) as a yellow solid.

[0446] 1 1H-NMR (400 MHz, CDCl 3 ) δ = 7.88 - 7.83 (m, 1H), 7.79 - 7.72 (m, 1H), 7.36 (br d, J = 8.4 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.25 (br d, J = 6.0 Hz, 1H), 6.21 (s, 1H), 5.07 (br s, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.89 (d, J = 16.0 Hz, 1H), 3.52 (d, J = 16.1 Hz, 1H), 1.46 (s, 9H).

[0447] Step 10: A solution of tert-butyl (2-chloro-5-((5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)carbamate (7 g, 11.9 mmol) in HCl / EtOAc (70 mL) was stirred at 25 °C for 2 h. TLC (PE:EtOAc = 1:1) indicated complete conversion. The resulting mixture was poured into NaHCO 3 (1 L) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 and concentrated to dryness to give the crude product, which was further purified by preparative HPLC (H 2 O-MeCN, TFA) to afford N-(3-(aminomethyl)-4-chlorophenyl)-5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (2.29 g, yield: 39.5%) as a white solid.

[0448] 1 H-NMR (400 MHz, CD 3 OD) δ = 7.96 (dd, J = 1.9, 6.4 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 3.98 (d, J = 16.6 Hz, 1H), 3.85 (s, 2H), 3.71 (d, J = 16.8 Hz, 1H).

[0449] Example 12: Ethyl (3-(cyclopropanecarboxamidomethyl)-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate

[0450] To a solution of ethyl (3-(aminomethyl)-4-fluorophenyl)(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)carbamate (250 mg, 0.49 mmol) in ethyl acetate (3.8 mL) was added cyclopropanecarboxylic acid (46.2 mg, 0.54 mmol), a solution of propanephosphonic anhydride in EtOAc (50%, 1.41 ml, 2.44 mmol) and pyridine (0.20 ml, 2.44 mmol). The reaction mixture was stirred at 20 °C until TLC indicated complete conversion. All volatile compounds were evaporated under reduced pressure and the residue was then purified by silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 100% EtOAc) to afford the title compound as a colorless solid (250 mg, 51%).

[0451] 1 H-NMR (500 MHz, MeOD) δ 7.66 (d, J = 6.1 Hz, 2H), 7.24 (dd, J = 6.6, 2.6 Hz, 1H), 7.22–7.18 (m, 1H), 7.18–7.13 (m, 1H), 4.85 (s, 2H), 4.47 (d, J = 18.4 Hz, 1H), 4.43 (sbr, 2H), 4.20–4.14 (m, 3H), 1.60 (tt, J = 8.0, 4.7 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H), 0.84 (dt, J = 4.5, 3.0 Hz, 2H), 0.75 (dt, J = 8.0, 3.2 Hz, 2H).

[0452] Example 13: N-(2-Chloro-5-((5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)cyclopropanecarboxamide

[0453] To a solution of N-(3-(aminomethyl)-4-chlorophenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (400 mg, 0.88 mmol) in dichloromethane (10 mL) was added cyclopropanecarboxylic acid (75.4 mg, 0.88 mmol), a solution of propanephosphonic anhydride in EtOAc (50%, 3.34 g, 5.26 mmol), and 4-dimethylaminopyridine (321 mg, 2.63 mmol). The reaction mixture was stirred at 20 °C for 16 h. TLC indicated complete conversion. The reaction was quenched by the addition of water, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to dryness to afford the crude product, which was further purified by flash silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 60% EtOAc) to give the title product as a colorless solid (300 mg, 65%).

[0454] 1 H-NMR (400 MHz, MeOD) δ 7.70 (d, J = 6.2 Hz, 2H), 7.42 (d, J = 2.5 Hz, 1H), 7.34–7.26 (m, 2H), 4.88 (sbr, 1H), 4.42 (s, 2H), 3.93 (d, J = 16.7 Hz, 1H), 3.67 (d, J = 16.7 Hz, 1H), 1.69 (tt, J = 8.0, 4.7 Hz, 1H), 0.91 (dt, J = 4.7, 3.1 Hz, 2H), 0.81 (dt, J = 8.0, 3.1 Hz, 2H).

[0455] Example 14: N-(2-Chloro-5-((5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)cyclopropanecarboxamide

[0456] To a solution of N-(3-(aminomethyl)-4-chlorophenyl)-5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (200 mg, 0.47 mmol) in ethyl acetate (3.9 mL) was added cyclopropanecarboxylic acid (44.9 mg, 0.52 mmol), a solution of propanephosphonic anhydride in EtOAc (50%, 1.37 mL, 2.37 mmol), and pyridine (0.19 mL, 2.37 mmol). The reaction mixture was stirred at 20 °C for 16 h. TLC analysis indicated complete conversion. The reaction was quenched by the addition of water, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to dryness to afford the crude product, which was further purified by flash silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 100% EtOAc) to give the title product as a colorless solid (98 mg, 42%).

[0457] 1 H-NMR (500 MHz, MeOD) δ 7.72 (dd, J = 6.9, 2.3 Hz, 1H), 7.56 (ddd, J = 8.8, 4.4, 2.3 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.36–7.25 (m, 3H), 4.86 (sbr, 2H), 4.42 (s, 2H), 3.92 (d, J = 16.6 Hz, 1H), 3.65 (d, J = 16.6 Hz, 1H), 1.69 (tt, J = 8.0, 4.6 Hz, 1H), 0.91 (dt, J = 4.7, 3.3 Hz, 2H), 0.81 (dt, J = 8.1, 3.3 Hz, 2H).

[0458] Example 15: N-(2-Chloro-5-((5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)amino)benzyl)cyclopropanecarboxamide

[0459] To a solution of N-(3-(aminomethyl)-4-chlorophenyl)-5-(4-fluoro-3-((trifluoromethyl)thio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine (250 mg, 0.51 mmol) in pyridine (3.9 mL) was added cyclopropanecarboxylic acid (48.5 mg, 0.56 mmol), a solution of propanephosphonic anhydride in EtOAc (50%, 1.78 mL, 3.07 mmol), and 4-dimethylaminopyridine (63.0 mg, 0.51 mmol). The reaction mixture was stirred at 20 °C for 16 h. TLC analysis indicated complete conversion. The reaction was quenched by the addition of water, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to dryness to afford the crude product, which was further purified by flash silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 100% EtOAc) to give the title product as a colorless solid (134 mg, 47%).

[0460] 1H-NMR (400 MHz, MeOD) δ 8.51 (t, J = 5.9 Hz, 1H), 7.95 (dd, J = 6.6, 2.4 Hz, 1H), 7.88–7.81 (m, 1H), 7.44–7.37 (m, 2H), 7.31–7.20 (m, 2H), 4.86 (s, 1H), 4.42–4.38 (s, 2H), 3.95 (d, J = 16.6 Hz, 1H), 3.67 (d, J = 16.6 Hz, 1H), 1.69 (tt, J = 8.3, 4.6 Hz, 1H), 0.90 (dt, J = 6.2, 3.2 Hz, 2H), 0.80 (dt, J = 8.1, 3.3 Hz, 2H).

[0461] Example 16: N-(5-((5-(3-chloro-4-fluorophenyl)-5-(dichloromethyl)-4,5-dihydroisoxazol-3-yl)amino)-2-methoxybenzyl)acetamide

[0462] To a solution of N-(3-(aminomethyl)-4-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)-5-(dichloromethyl)-4,5-dihydroisoxazol-3-amine (459 mg, 1.06 mmol) in THF (16 mL) was added acetic anhydride (130 mg, 1.27 mmol), diisopropylethylamine (822 mg, 6.37 mmol), and 4-dimethylaminopyridine (13.0 mg, 0.11 mmol). The reaction mixture was stirred at 20 °C for 20 h. LC-MS indicated complete conversion. The reaction was quenched by the addition of water, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to dryness to afford the crude product, which was further purified by flash silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 100% EtOAc) to give the title product as a colorless solid (373 mg, 74%).

[0463] 1 H-NMR (400 MHz, MeOD) δ 7.73 (dd, J = 7.0, 2.3 Hz, 1H), 7.56 (ddd, J = 8.7, 4.5, 2.4 Hz, 1H), 7.32–7.24 (m, 2H), 7.20 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.39 (s, 1H), 4.84 (sbr, 2H), 4.31 (s, 2H), 3.89 (d, J = 16.4 Hz, 1H), 3.80 (s, 3H), 3.54 (d, J = 16.4 Hz, 1H), 1.99 (s, 3H).

[0464] Example 17: N-((4-((5-(3-chloro-4-fluorophenyl)-5-(dichloromethyl)-4,5-dihydroisoxazol-3-yl)amino)pyridin-2-yl)methyl)cyclopropanecarboxamide

[0465] To a solution of N-(2-(aminomethyl)pyridin-4-yl)-5-(3-chloro-4-fluorophenyl)-5-(dichloromethyl)-4,5-dihydroisoxazol-3-amine (90 mg, 0.22 mmol) in THF (4 mL) was added cyclopropanecarboxylic anhydride (41.3 mg, 0.27 mmol), diisopropylethylamine (173 mg, 1.34 mmol) and 4-dimethylaminopyridine (2.72 mg, 0.02 mmol). The reaction mixture was stirred at 20 °C for 18 h. LC-MS indicated complete conversion. The reaction was quenched by the addition of water, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to dryness to afford the crude product, which was further purified by flash silica gel column chromatography (cyclohexane / EtOAc; gradient 0 to 100% EtOAc) to give the title product as a colorless solid (72 mg, 68%).

[0466] 1 H-NMR (500 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.29 (d, J = 5.7 Hz, 1H), 7.72 (dd, J = 6.9, 2.3 Hz, 1H), 7.56–7.46 (m, 1H), 7.24 (t, J = 8.6 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 6.03 (s, 1H), 5.37 (s, OH), 4.51 (dd, J = 5.4, 2.3 Hz, 2H), 3.94 (d, J = 16.6 Hz, 1H), 3.61 (d, J = 16.6 Hz, 1H), 2.43 (s, 1H), 1.66 (tt, J = 8.1, 4.6 Hz, 1H), 1.06–0.97 (m, 2H), 0.97–0.85 (m, 2H).

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474] Biological examples

[0475] Unless otherwise stated, the test solution was prepared as follows:

[0476] The active compound was dissolved in a 1:1 (v / v) mixture of distilled water:acetone at the desired concentration. The test solution was prepared on the day of use.

[0477] The test solution was generally prepared at a concentration of 2500 ppm (w / v).

[0478] B.1. Boll weevil

[0479] To evaluate the control of boll weevils, the test unit consisted of a 96-well microtiter plate containing insect feed and 5 - 10 boll weevil eggs.

[0480] The compounds were formulated using a solution containing 75% v / v water and 25% v / v DMSO. Different concentrations of the formulated compounds were sprayed onto the insect feed at 5 μl using a custom-made microatomizer, and repeated twice.

[0481] After application, the microtiter plate was incubated at approximately 25°C ± 1°C and approximately 75% ± 5% relative humidity for 5 days. Then, the mortality of the eggs and larvae was visually evaluated.

[0482] In this test, compared with the untreated control, Compounds I-2, I-3, I-4, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-25, I-26, I-28, I-29, I-32, I-33, I-34, I-38, I-40, 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-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-69, I-70, I-71, I-72, I-75, I-76, I-78, I-79, I-80, I-81, I-82, I-84, and III-1 showed at least 75% mortality at 800 ppm, respectively.

[0483] B.2. Green peach aphid (mixed life stages)

[0484] To evaluate the control of Myzus persicae through a systematic method, the test unit consisted of a 96-well microtiter plate containing liquid artificial diet under an artificial membrane. Compounds were formulated using a solution containing 75% v / v water and 25% v / v DMSO. Different concentrations of the formulated compounds were pipetted onto the aphid diet using a customized pipette, and repeated twice. After application, 5 - 8 adult aphids were placed on the artificial membrane inside the microtiter plate wells. Then the aphids were allowed to suck the treated aphid diet and incubated at approximately 23°C ± 1°C and approximately 50% ± 5% relative humidity for 3 days. Then the aphid mortality and fecundity were visually evaluated.

[0485] In this test, compared with the untreated control, Compounds I-2, I-3, I-4, I-5, I-6, I-8, I-9, I-12, I-13, I-14, I-15, I-16, I-18, I-19, I-20, I-21, I-22, I-23, I-25, I-26, I-28, I-29, I-31, I-32, I-40, 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-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-77, I-78, I-79, I-80, I-82, I-83, and III-1 showed at least 75% mortality at 800 ppm, respectively.

[0486] B.3. Tobacco budworm (Heliothis virescens)

[0487] To evaluate the control of Heliothis virescens, the test unit consisted of a 96-well microtiter plate containing insect diet and 15 - 25 Heliothis virescens eggs. Compounds were formulated using a solution containing 75% v / v water and 25% v / v DMSO. Different concentrations of the formulated compounds were sprayed onto the insect diet at 10 μl using a customized microatomizer, and repeated twice. After application, the microtiter plate was incubated at approximately 28°C ± 1°C and approximately 80% ± 5% relative humidity for 5 days. Then the egg and larval mortalities were visually evaluated.

[0488] In this test, compared with the untreated control, Compounds I-1, I-2, I-3, I-4, I-6, I-8, I-9, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-42, I-73, I-74, I-78, I-79, I-80, I-82, and I-84 showed at least 75% mortality at 2500 ppm, respectively.

[0489] In this test, compared with the untreated control, Compounds I-2, I-3, I-4, I-6, I-8, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-25, I-28, I-32, I-42, I-43, I-45, I-48, I-50, I-53, I-54, I-55, I-59, I-60, I-62, I-64, I-66, I-70, I-72, and III-1 showed at least 75% mortality at 800 ppm, respectively.

[0490] B.4. Yellow fever mosquito (Aedes aegypti)

[0491] To evaluate the control of yellow fever mosquitoes, the test unit consisted of 96-well microtiter plates containing 200 μl of tap water and 5 - 15 newly hatched Aedes aegypti larvae per well. The active compounds were formulated using a solution containing 75% (v / v) water and 25% (v / v) DMSO. Different concentrations of the formulated compounds or mixtures were sprayed onto the insect feed at 2.5 μl using a custom-made microatomizer, and repeated twice.

[0492] After application, the microtiter plates were incubated at 28 °C ± 1 °C and 80% ± 5% RH for 2 days. Then, the larval mortality was visually evaluated.

[0493] In this test, compared with the untreated control, Compounds I-3, I-4, I-5, I-6, I-7, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-42, I-73, I-74, I-78, I-79, I-80, I-81, I-82, and I-84 showed at least 75% mortality at 2500 ppm, respectively.

[0494] In this test, compared with the untreated control, Compounds I-3, I-4, I-6, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-25, I-26, I-27, I-28, I-29, I-31, I-32, I-33, I-34, I-37, I-38, I-40, 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-58, I-59, I-60, I-62, I-63, I-65, I-66, I-68, I-69, I-70, I-71, I-72, I-75, I-76, I-77, I-83, II-1, and III-1 showed at least 75% mortality at 800 ppm, respectively.

[0495] B.5. Diamond back moth (Plutella xylostella)

[0496] To evaluate the control of tobacco cutworm larvae (Plutella xylostella), the test setup consisted of 96-well microtiter plates containing insect feed and 15 - 25 Plutella xylostella eggs.

[0497] Compounds or mixtures were formulated using a solution containing 75% water and 25% DMSO. Different concentrations of the formulated compounds or mixtures were sprayed onto the insect feed at 5 μl using a custom-made micro-nebulizer, and repeated twice.

[0498] After application, the microtiter plates were incubated at 28°C ± 1°C and 80% ± 5% RH for 5 days. Then, egg and larval mortality were visually evaluated.

[0499] In this test, compared with the untreated control, Compounds I-2, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-42, I-73, I-74, I-78, I-79, I-80, I-81, and I-82 showed at least 75% mortality at 2500 ppm, respectively.

[0500] In this test, compared to the untreated control, Compounds I-2, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-25, I-26, I-28, I-29, I-32, I-33, I-34, I-37, I-38, I-40, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-50, I-51, II-1, III-1, and III-2 showed at least 75% mortality at 800 ppm, respectively.

[0501] The beneficial activity of the compounds according to the invention compared to structurally close compounds known from WO 2022 / 171472 was demonstrated by the following comparative experiments:

[0502] C.1. Western flower thrips (Frankliniella occidentalis)

[0503] The active compounds were formulated as 10,000 ppm solutions in tubes in 100% cyclohexanone by a Tecan liquid handler. This 10,000 ppm solution was serially diluted in 100% cyclohexanone to prepare intermediate solutions. These were used as stock solutions and were made into final dilutions in 50% acetone:50% water (v / v) in 10 ml or 20 ml glass vials by Tecan. A non-ionic surfactant was included at 0.01% (v / v) by volume in the solutions. The vials were then inserted into an automated electrostatic sprayer equipped with a nebulizing nozzle for application to the plants / insects. Small (ca. 2” tall) cotton plants were sprayed with the test compounds at concentrations ranging from 300 ppm to 0.01 ppm in acetone / water by an automated VPS. After drying, cotton leaves were removed and circular leaf discs (ca. 1 cm in diameter) were punched from the treated surfaces and transferred to clean 20 mL scintillation vials. Ten western flower thrips (FRANOC) were aspirated into each scintillation vial. The vials containing the leaf discs and thrips were kept in a vertical incubator at 25 °C and 50% relative humidity with a 14:10 light:dark photoperiod. Each treatment was repeated twice. Thrips mortality was evaluated at 2 DAT (days after treatment) and all dead and surviving thrips were counted.

[0504]

[0505] In this test, compared to the untreated control, Compound I-8 showed 100% mortality at 100 ppm, while Compound I-30 of WO 2022 / 171472 showed 19% mortality at 100 ppm.

[0506] C.2. Southern armyworm (Spodoptera eridania), 2nd instar larvae

[0507] The active compound was formulated in 100% cyclohexanone as a 10,000-ppm solution supplied in tubes by a Tecan liquid handler. This 10,000-ppm solution was serially diluted in 100% cyclohexanone to prepare intermediate solutions. These were used as stock solutions and were made into final dilutions in 50% acetone:50% water (v / v) in 10-ml or 20-ml glass vials by Tecan. A non-ionic surfactant was included at 0.01% (v / v) by volume in the solutions. The vials were then inserted into an automated electrostatic sprayer equipped with a nebulizing nozzle for application to the plants / insects. Two lima bean plants (variety: Sieva) were planted in pots and were selected for treatment at the first true leaf stage. The test solutions were sprayed onto the leaf surfaces by an automated electrostatic plant sprayer equipped with a nebulizing nozzle. The plants were dried in the spray booth of the sprayer and were then removed from the sprayer. Each pot was placed in a perforated plastic bag with a zip closure. Ten to eleven armyworm larvae were placed in the bag and the bag was zipped closed. The test plants were kept in a growth chamber at approximately 25 °C and approximately 20%-40% relative humidity for 4 days, avoiding direct exposure to fluorescence (14:10 light:dark photoperiod) to prevent heat build-up inside the bag. Mortality and feeding reduction were evaluated 4 days after treatment compared to untreated control plants.

[0508] In this test, compared to the untreated control, Compound I-8 showed 80% mortality at 1 ppm, while Compound I-30 of WO 2022 / 171472 showed 0% mortality at 1 ppm.

Claims

1. A compound of formula I, its N-oxides, stereoisomers and agriculturally or veterinarily acceptable salts, wherein R 1 is C 1 -C 2 -haloalkyl; W is phenyl or pyridyl; where W is unsubstituted, partially or fully substituted by R 2 substituted; R 2 is halogen, OR 21 、NR 22 R 23 、CN, NO 2 、Si(CH 3 ) 3 、SF 5 、C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkyl-S(O) m 、C 1 -C 3 -haloalkyl-S(O) m 、C 3 -C 6 -cycloalkyl-S(O) m 、C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 3 -haloalkoxy-C 1 -C 4 -alkyl, C 1 -C 3 -alkyl-S(O) m -C 1 -C 4 -alkyl, C 1 -C 3 -haloalkyl-S(O) m -C 1 -C 4 -alkyl; these groups are unsubstituted, partially or fully substituted by R 211 substituted; R 21 is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, Si(C 1 -C 4 -alkyl) 3 、C 1 -C 3 -alkyl-S(O) m 、C 3 -C 6 -cycloalkyl-S(O) m 、S(O) m R 24 , and these groups are unsubstituted, partially or fully substituted by R 211 ; R 22 、R 23 is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, which is unsubstituted or partially or completely substituted by R 221 ; or C 1 -C 6 -alkyl-C(=O)OR 24 、C 1 -C 6 -alkyl-C(=U)N(R 25a )R 25b 、C 1 -C 6 - alkyl-C(=NR 25 )N(R 25a )R 25b , S(O) m R 24 、S(O) m N(R 25a )R 25b 、C(=U)R 26 、C(=O)OR 24 、 C(=U)N(R 25a )R 25b 、 C(=S)SR 24 、C(=NR 25 )R 26 、 C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl; R 22 and R 23 together with the nitrogen atom to which they are bonded form a 3-, 4-, 5- or 6-membered fully unsaturated heterocycle which may additionally contain a heteroatom selected from N, O and S(O) m as a ring member, and the heterocycle is unsubstituted or is substituted in part or in full by R 222 or R 22 and R 23 together form a group =C(R 26 ) 2 、=S(O) m (R 24 ) 2 、=S(O) m R 24 N(R 25a )R 25b ; U is O or S; R 24 is H, Si(C 1 -C 4 -alkyl) 3 、C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, which is unsubstituted or partially or fully halogenated and / or substituted by: C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo group; C 3 -C 8 -cycloalkyl, which is unsubstituted or partially or completely halogenated and / or substituted by: C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo group; Phenyl, benzyl, pyridyl and phenoxy, which are unsubstituted or partially or fully halogenated and / or substituted by: C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, and (C 1 -C 6 -alkoxy)carbonyl; R 25 is H, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C(=U)R 26 、C(=O)OR 24 、 C(=O)NH(C 1 -C 4 -alkyl), C(=O)N(C 1 -C 4 -alkyl) 2 、S(O) m R 24 、S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, S(O) m -C 3 -C 6 -cycloalkyl, Si(C 1 -C 4 -alkyl) 3 、NR 24 C(=O)-C 1 -C 4 -alkyl, NR 24 C(=O)-C 3 -C 6 -cycloalkylalkyl, CR 24 N=OR 24 、CR 26 N=OR 24 , C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, which is unsubstituted or is partially or fully halogenated and / or substituted by: CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C which is unsubstituted or substituted by 1 or 2 halogens and / or CN 3 -C 6 -cycloalkyl, phenyl, or a 4-, 5-, or 6-membered saturated, partially or fully unsaturated heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S(O) m as ring members, these rings being unsubstituted or partially or fully substituted by: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 2 -alkyl-C 1 -C 2 -alkoxy, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkylthio, C(=O)-C 1 -C 4 -alkoxy, and oxo; C 3 -C 8 - cycloalkyl, which is unsubstituted or partially or fully halogenated and / or substituted by: CN, C 1 -C 4 - alkyl, C 1 -C 4 - alkoxy, C 1 -C 4 - haloalkyl, C 1 -C 4 - haloalkoxy, S(O) m -C 1 -C 4 - alkyl, S(O) m -C 1 -C 4 - haloalkyl, C(=O)NH(C 1 -C 4 - alkyl), C(=O)N(C 1 -C 4 - alkyl) 2 , phenyl, or a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S(O) m as ring members, these rings being unsubstituted or partially or fully substituted by: halogen, CN, C 1 -C 4 - alkyl, C 1 -C 4 - haloalkyl, C 1 -C 3 - alkoxy, C 1 -C 3 - haloalkoxy, C 1 -C 2 - alkyl - C 1 -C 2 - alkoxy, C 1 -C 3 - alkylthio, C 1 -C 3 - haloalkylthio; phenyl, benzyl, phenoxy, a 4-, 5- or 6-membered saturated, partially or fully unsaturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S(O) m as ring members, These groups are unsubstituted or are partially or completely halogenated and / or substituted by: halogen, CN, NO 2 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, and (C 1 -C 6 -alkoxy)carbonyl; and 3-, 4-, 5- or 6-membered saturated, partially or completely unsaturated heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S(O) m as ring members, where the heterocycle is optionally substituted by one or more R 222 substituents; R 25a and R 25b has the meaning given to R 25 ; or R groups attached to the same nitrogen atom 25a and R 25b can together form =C(R 26 ) 2 , =S(O) m (R 24 ) 2 , or =S(O) m R 24 N(R 25a )R 25b ; or R 25a and R 25b together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O)m as ring members, and which heterocycle is unsubstituted or substituted by one or more of the following substituents: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and oxo; or R 25a and R 25b together with the nitrogen atom to which they are attached in the group C(=NR 25 )N(R 25a )R 25b form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O) m as ring members, and which heterocycle is unsubstituted or substituted by one or more of the following substituents: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and oxo; R 26 is H, CN, OH, SH, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, which is unsubstituted, partially or completely halogenated and / or substituted by one, two or three of the following groups: CN, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, phenyl, or a 3-, 4-, 5-, 6- or 7-membered saturated, partially or completely unsaturated heterocycle containing one, two or three N, O and S(O) m heteroatoms as ring members, these rings being unsubstituted or partially or completely substituted by the following: halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 2 -alkyl-C 1 -C 2 -alkoxy, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkylthio, and oxo; C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, S(O) m -C 1 -C 6 -alkyl, S(O) m -C 1 -C 6 -haloalkyl, Si(C 1 -C 4 -alkyl) 3 、C(=O)N(R 25a )R 25b , phenyl, benzyl, phenoxy, a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S(O) m as ring members, these rings being unsubstituted or partially or fully halogenated and / or substituted by R 222 ; R 211 is halogen, CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 4 -alkenyloxy, C 3 -C 4 -haloalkenyloxy, C 3 -C 4 -alkynyloxy, C 3 -C 4 -haloalkynyloxy, C 1 -C 4 -alkyl-S(O) m 、C 1 -C 4 -haloalkyl-S(O) m 、C 3 -C 4 -alkenyl-S(O) m 、C 3 -C 4 -haloalkenyl-S(O) m 、C 3 -C 4 -alkynyl-S(O) m 、C 3 -C 4 -haloalkynyl-S(O) m 、and oxo group; C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -halocycloalkenyl; R 221 is CN, NO 2 , OH, SH, SCN, SF 5 , Si(C 1 -C 4 -alkyl) 3 , C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkyl-S(O) m , C 1 -C 6 -haloalkyl-S(O) m , C(=O)N(R 25a )R 25b ; C 3 -C 8 -cycloalkyl, which is unsubstituted, partially or completely halogenated and / or partially or completely substituted by: C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and oxo; or Two Rs on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl 221 may together be =O, =CH(C 1 -C 4 -alkyl), =C(C 1 -C 4 -alkyl) 2 , =N(C 1 -C 6 -alkyl), or =NO(C 1 -C 6 -alkyl); R 222 is halogen, NO 2 , CN, OH, SH, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, N(R 25a )R 25b , C(=O)NR 25a R 25b , Si(C 1 -C 4 -alkyl) 3 ; C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, which is unsubstituted or partially or completely halogenated and / or substituted by: CN, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo group; C 3 -C 8 -cycloalkyl, which is unsubstituted or partially or fully halogenated and / or substituted by: CN, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, and oxo group; or Two Rs that are present together on the same atom of an unsaturated or partially unsaturated ring 222 can be =O, =S, =N(C 1 -C 6 -alkyl), =NO(C 1 -C 6 -alkyl), =CH(C 1 -C 4 -alkyl) or =C(C 1 -C 4 -alkyl)C 1 -C 4 -alkyl; or Two Rs on two adjacent carbon atoms 222 together with the carbon atoms to which they are bonded form a 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or fully unsaturated ring, where the ring may contain 1 or 2 heteroatoms or heteroatom groups selected from N, O and S(O) m as ring members, and where the ring is optionally substituted by one or more of the following groups: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and / or C 1 -C 4 -haloalkoxy; m is 0, 1, or 2; X is NR 3 or O; R 3 is H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, OR 21 、C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, which is unsubstituted or partially or completely substituted by R 31 ; or C 1 -C 6 -alkyl-C(=O)OR 24 、C 1 -C 6 -alkyl-C(=U)N(R 25a )R 25b , C 1 -C 6 -alkyl-C(=NR 25 )N(R 25a )R 25b 、C 1 -C 6 -alkyl-OC(=O)OR 24 、 N(R 25a )R 25b 、S(O) m R 24 、S(O) m N(R 25a )R 25b 、C(=U)R 26 、C(=O)OR 24 、 C(=U)N(R 25a )R 25b 、C(=S)SR 24 、C(=NR 25 )R 26 ; C 3 -C 8 -cycloalkyl, C 3 -C 8 -halocycloalkyl, phenyl, a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O and S(O) m as ring members, or a 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S(O) m as ring members, these rings being unsubstituted or substituted in part or in full by R 32 ; R 31 is halogen, CN, NO 2 , OH, SH, SCN, SF 5 , Si(C 1 -C 4 -alkyl) 3 , N(R 25a )R 25b , C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkyl-S(O) m , C 1 -C 6 -haloalkyl-S(O) m , C(=O)N(R 25a )R 25b ; C 3 -C 8 -cycloalkyl, which is unsubstituted, partially or fully halogenated and / or partially or fully substituted by: CN, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, and oxo group; S(O) m R 24 、S(O) m N(R 25a )R 25b 、C(=U)R 26 、C(=O)OR 24 、 C(=U)N(R 25a )R 25b 、C(=S)SR 24 、C(=NR 25 )R 26 ; phenyl, benzyl, phenoxy, or a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from N, O, S(O) m as ring members, where these rings are unsubstituted or are partially or fully substituted by R 222 ; or Two Rs on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group 31 may together be =O, =CH(C 1 -C 4 -alkyl), =C(C 1 -C 4 -alkyl) 2 , =N(C 1 -C 6 -alkyl), or =NO(C 1 -C 6 -alkyl); R 32 is a group as defined in R 31 or is selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl, where these groups are unsubstituted, partially or fully halogenated and / or substituted by one or two CN, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or an oxo group; G is phenyl, or a 6-membered heteroaryl containing 1 or 2 N atoms as ring members; wherein G is unsubstituted, partially or completely substituted by R 4 substituted; R 4 is as defined for R 2 as defined; R 5 is a group as defined for R 3 as defined; Y is a direct bond or C(R 4a )(R 4b ); R 4a and R 4b is H, halogen, CN, NO 2 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C unsubstituted or substituted by CN or halogen 3 -C 6 -cycloalkyl; R 4 and R 4a and / or R 4b together form a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocycle which may contain one or two heteroatoms selected from N, O and S(O) m as ring members, and wherein the ring is unsubstituted or substituted by one or more groups R 2 substituted; Q is C(=U) or S(O) m ; R 6 is as defined for R 25 or R 5 and R 6 together form a 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle which may contain, in addition to N(R 5 ), one or two heteroatoms selected from N, O and S(O) m as ring members and in which the ring is unsubstituted or substituted by one or more groups R 2 substituents.

2. The compound of formula I according to claim 1, wherein, W is phenyl which is substituted by one to three of the following groups: halogen, halomethyl, halomethoxy and / or halomethyl-S(O) m .

3. The compound of formula I according to claim 1 or 2, wherein, Y is C(R 4a )(R 4b ), preferably CH 2 .

4. The compound of formula I according to any one of claims 1 to 3, wherein, Q is C(=O).

5. The compound of formula I according to any one of claims 1 to 4, wherein, X is NR 3 and R 3 is H, alkoxycarbonyl, C 1 -C 6 -alkyl, where the alkyl is unsubstituted or substituted with CN, cycloalkyl, alkoxy.

6. The compound of formula I according to any one of claims 1 to 5, wherein, X is O.

7. The compound of formula I according to any one of claims 1 to 6, wherein, G is group G1, G2, G3 or G4, where # is a bond with X, % is a bond with Y, and R 41 and R 42 are H or a group R 2 , preferably H, or halogen, CN, halomethyl, or haloalkoxy.

8. The compound of formula I according to claim 7, wherein, G is G1 and R 42 is H.

9. The compound of formula I according to any one of claims 1 to 8, wherein, R 1 is a halomethyl group; W is phenyl which is partially or fully substituted by R 2 substituted; R 2 is halogen, CN, OH, C 1 -C 4 -alkoxy, OR 21 、C 1 -C 4 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkyl-S(O) m 、C 1 -C 3 -haloalkyl-S(O) m 、C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl; X is NR 3 or O; R 3 is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, G is phenyl, which is unsubstituted, partially or fully substituted by R 4 ; preferably group G1, where R 41 and R 42 are H, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy; R 4 is H, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy; or R 4 and R 4a / R 4b together form a 5- or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring, which heterocyclic ring may contain 1 or 2 N's as ring members; Y is a direct key or CR 4a R 4b ; Q is C(=O) or SO 2 ; R 5 H, R 6 C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkenyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-S(O) m -C 1 -C 4 -alkyl, NR H C(=O)-C 1 -C 4 -alkyl, NR H C(=O)-C 3 -C 6 -cycloalkyl, CR H N=OR 24 ,CR H N=OR 24 a 4-, 5- or 6-membered saturated or partially or fully unsaturated heterocycle containing 1, 2 or 3 heteroatoms selected from O, N, S as ring members, where S may be oxidized wherein R H is H, CN or C 1 -C 4 -alkyl, R 6 unsubstituted or substituted by: CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, S(O) m -C 1 -C 4 -alkyl, S(O) m -C 1 -C 4 -haloalkyl, C unsubstituted or substituted by 1 or 2 halogens and / or CN 3 -C 6 -cycloalkyl.

10. The compound of formula I according to any one of the preceding claims, wherein, R 1 is CF 3 .

11. The compound of formula I according to any one of the preceding claims, which compounds correspond to formula I.A 12. An agricultural or veterinary composition comprising at least one compound according to any one of claims 1 to 11 and / or at least one of its agriculturally or veterinarily acceptable salts, and at least one agriculturally or veterinarily acceptable inert liquid and / or solid carrier.

13. An agricultural composition for combating animal pests, comprising at least one compound according to any one of claims 1 to 11 and at least one acceptable inert liquid and / or solid carrier and - if desired - at least one surfactant.

14. A method for combating or controlling invertebrate pests, which method comprises bringing the pests or their food supply, habitat or breeding ground into contact with a pesticidal effective amount of at least one compound according to any one of claims 1 to 11.

15. A method for protecting growing plants against infestation or infection by invertebrate pests, which method comprises bringing the plant, or the soil or water body in which the plant grows, into contact with a pesticidal effective amount of at least one compound according to any one of claims 1 to 11.

16. A seed comprising a compound according to any one of claims 1 to 11, or its enantiomers, diastereomers or salts, in an amount of 0.1 g to 10 kg / 100 kg of seed.

17. A method for treating or protecting animals against infestation or infection by invertebrate pests, which comprises bringing the animal into contact with a pesticidal effective amount of at least one compound of formula I according to any one of claims 1 to 11, its stereoisomers and / or at least one of its veterinarily acceptable salts.

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