NZ613191B2 - Isoxazoline derivatives for controlling invertebrate pests - Google Patents

Abstract

Disclosed herein are isoxazoline compounds of formula (Ia), wherein the variables are as described herein in free form and in salt form, an example being N-(2-((cyanomethyl)amino)-2-oxoethyl)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylthiophene-3-carboxamide. Also disclosed are compositions comprising the compounds and the use of the compounds in the control of parasites, in particular ectoparasites, in and on warmblooded animals. o disclosed are compositions comprising the compounds and the use of the compounds in the control of parasites, in particular ectoparasites, in and on warmblooded animals.

Description

ISOXAZOLINE DERIVATIVES FOR CONTROLLING INVERTEBRATE PESTS FIELD OF THE INVENTION This invention relates to novel olines, their N-oxides and salts, processes for their manufacture, their use in the controi of ectoparasites, especiaiiy insects and acari, on non— human animals, especially productive livestock and domestic animals, and furthermore pesticidal compositions which contain one or more of these compounds.

BACKGROUND OF THE INVENTION PCT Patent ation W0 20071075459 discloses isoxazoiine derivatives of Formula (A) as plant icides (R2)n wherein, inter alia, each of A1, A2 and 81-83 are C(Rg), A3 is N, R1 is haioaikyl and Q is a heterocyciic radical.

The compounds are mainly used in the control of ebrate pests in mic environments. Many products are commercially available for these es, but the need continues for new compounds that are more effective, less costly, less toxic, environmentaiiy safer or have different modes of action. it now has been surprisingly found that novel derivatives with a modified heterocyciic side chain have superior properties in the control of pests.

SUMMARY OF THE INVENTION This present invention is directed to a compound of formula B 0‘1“! 3/ \ x\ a” BI \ /X2 2\B? X, /R5 6 (i) including all geometric and stereoisomers, N-oxides, and salts thereof, and itions containing them and their use for controlling parasites, wherein X, is S(O)m, O or NR; and X1 and X2 are each independently of the other CR3 or N, m is an integer from 0 to 2; B and B’ are each independently a group CR;’; 81, 82 and B3 are each independently selected from the group consisting of CR; and N; R2’ is H or R2; each R2 is ndently of the other halogen, Cg-CG—alkyl, Ci-Cyhaloalkyl, C1—Ce~alkoxy, Ci— Ce—haloalkoxy, C1-Cs—aikylthio, C1—C5-haloalkylthic, C1-Ca-alkyisuifinyl, C1—Cs-haloalkylsuifinyl, Ci—Ce-alkylsulfonyl, Ci-Ce-haioalkylsuifonyl, — or N,N-di-C1-C5-alkylamino, C1~Cs aikoxycarbonyl, cyano (—CN) or nitro (-NOg); R1 is halogen. cyano, Ci-Ca—alkyl, Ci~Cg—haloalkyl or C1~Cs-haloalkoxy; each R3 is independently H, halogen, C1-C5—alkyl, haloalkyl, C3-Cs-cycloalkyl, 03-05— halocycloalkyi. hydroxy, CT—Cs—alkoxy, Ci-Cs—haloalkoxy, C1—Csealkylthio, Ci—Cs—haloalkylthio, Ci-Cs-aikyl-sulfinyl, C1-CB-haloalkylsulfinyl, alkylsuifonyl, Ci-Cs-haloalkylsuifonyl, amino, N-mono- or N,N-di—Ci-Cs-alkylamino, C1—Cs-alkoxycarbonyl, cyano, nitro or unsubstituted or halogen-, Ci-Cs-alkyl-, Ci-Ce-haloaikyin hydroxy-, C1-Cs~aikoxy-, Ci-Ce- haloalkoxy—, amino-, cyano- or nitro-substituted phenyl, pyridyl or pyrimidyl; R4 is H, C1—Ce-aikyi, Cz-Ce—alkenyi, Cz—Cs—alkynyl, C3—Ce—cycloaikyl, C4~Cy—aikylcycloalkyl, C4— Cy-cycloalkylalkyl, C2—Cg-alkoxyalkyl, C1-C6-alkylcarbonyl or Ci-Ce-alkoxycarbonyl; R5 and R6 are each ndently of the other H, cyano, hydroxy, nitro, amino, aminocarbo~ nyl, a group ~N=CR7R8 or suifonamido; or are Ci~Cs~alkyl, Cz~C5~alkenyL C2~Ca-alkynyi, Cs" Ce-cycloalkyl, C4-Cy-aikylcycloalkyi, C4—C7-cycioalkyialkyl, C1—Ce—alkoxy, N-mono~ or - Ci—Ce—aikylamino, CT—Cs-alkyithic, Ci—Ce—alkylsulfinyl, Ci—Ce—alkylsulfonyl, C1-Ce-alkoxy— yl, Cg-CB-alkanoyl, C1-C5-alkylcarbonylaminc, N-mono- or N,N-di-C105-aikyiamino- yl or N—mono- or N,N, di—C1~04-alkylsulfonamido which are each tituted or are substituted in the alkyl, alkenyl or alkynyl moiety by halogen, y, CvCB—alkoxy. (31 haloalkoxy, aikylthio, Ci-Ce-haloalkyithio, Ci~Cg-alkyisulfinyl, Ci-Caéalkylsulfonyi, cyano, nitro, amino. N-mono- or N,N—di-Ci—C6~a|kylamino, Ca—Ca—cycloaikylamino. COOH, C1— Cs-alkoxycarbonyl, C2-C6-aikanoyl, 01-Ce-aikylcarbonylamino, sulfonamido, N-mono« or N,N, di—C1-C4-alkylsulfonamido, a group —C(W')NR7R3 or a l Q’; or are a radical Q; or R5 and R6 together are a group =C—NR7R8 or =C—NR7{OR3); or R5 and R5 together with the N-atom to which they are attached, form a 3- to 7-membered ring which optionally contains a r heteroatom selected from the group consisting of N, S and O. and which ring is further unsubstituted or mono- or polysubstituted by CiaCZ-alkyl, Ci-Cyhaloalkyl, Ci-Cz-alkoxy, hydroxy, halogen, cyano or nitro; Q and Q' are each independently a 4-, 5— or 6—membered heterocyclic ring, or a - carbocyclic ring system or a 8-, 9~ or bered fused -bicyclic ring , each of them being aromatic or not, and each of them being unsubstituted or mono- or polysubstituted by halogen, hydroxy, Ci—Cs-alkyl, Cg~Cs-alkenyl, Cg-Ca-alkynyl, 03-06— cycloalkyl. Ci—Cs-haloalkyi, Cl-Cs-alkoxy, Ci-Cyhaloalkoxy, Ci~Cs-alkylthio. 01 alkylsulfinyl, alkylsulfonyl, cyano, nitro. amino, ~ or N,N—di-Ci-C6‘alkylamino, C3-Cs~cycloalkylamino, COOH, C1-Ca-alkoxycarbonyl, Cg~05~alkanoyL C1-Cs-alkylcarbonyl— amino, aminocarbonyl, N—mono— or N,N—di-Cice—alkylaminocarbonyl, amido, N~mono— or N,N, di-Ci-Cralkylsulfonamido, a group —C(W’)NR7R8 or a radical Q“; Q” is a 4-, 5- or 6~membered heterocyclic ring or a C5-Cm~carbocyclic ring system, each of them being aromatic or not, and each of them being unsubstituted or mono- or polysubstituted by halogen, hydroxy, Ci-Ce—alkyl, CgaCyalkenyl, Cz-CS-alkynyl, 03 cycioalkyl, C1-Cs—haloalkyl. C1-C5—alkoxy, Ci-Ce-haloalkoxy, C1-C6-alkylthio, 01 alkylsulfinyl, Ci-Ce—alkylsulfonyl, cyano, nitro, amino, N-mono— or N,N-di—C1~C5-alkylamino, Ca~Ce-cycloalkylamino. COOH, Ci—Ce—alkoxycarbonyl, Cz-Ce-alkanoyl, C1-Ce-alkylcarbonyl- amino, sulfonamldo, N-mono— or N,N, Gil—Ci-C4—alkylsulfonamido or a group —C(W’)NR7R8; R7 and R3 are independently of the other H, cyano, hydroxy, amino, aminocarbonyl, sulfon— amido or nitro; or are Ci—Ca—alkyl, Cz~Ca~alkenyi, Cz—Cs—alkynyl, oycloalkyl, 04.07— alkylcycloalkyl or C4-Cy-cycloalkylalkyl, Ci-Cgealkoxy, N—mono— or N,N—di-C1-CS—alkylamino, C1-Cs-alkylthio, Ci-Ca-alkylsulfinyl, Cl-Cs-alkylsulfonyI‘ C1—Cs—alkoxycarbonyl, Cg-Ce-alkanoyl, 01-Cs-alkylcarbonylamino, N-mono-~ or N,N-di-CiCe-alkylaminocarbonyl, or N~mono~ or N,N, di-Ci-C4-alkylsulfonamido, which may each be unsubstituted or substituted in the alkyl, alkenyl or alkynyl moiety by halogen, hydroxy, Ci-CS-alkoxy, C1—Ce-haloalkoxy, Ci—Cae alkylthio, Ci-CS-haloalkylthio, C1-Cs-alkylsulfinyl, C1-CS-alkylsulfonyl, cyano, nitro, amino‘ N- mono- or N,N—di—C1-Cs-alkylamino, cycloalkylamino, COOH. C1-Cs-alkoxycarbonyl, Cg- Cssa‘lkanoyt, lkylcarbonylaminc, arbonyl, N-mono- or N,N—di-C.1C.5— alkylaminocarbonyl, sulfonamido, — or N,N, di-Ci-C4~alkylsulfonamido or a radical Q”; and W and W’ are each independently of the other 0 or S.

This invention also provides a composition comprising a compound of formula (i), an N-oxide or a salt thereof, and at least one onal ent selected from the group consisting of a surfactant, a solid diluent and a liquid diluent.

In one embodiment, this ion also provides a composition for controlling parasites, in particular ectoparasites, comprising a biologically effective amount of a compound of formula (i), an N»oxide or a salt thereof, and at least one additional ent selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said composition optionally further comprising a biologically ive amount of at least one additional biologically active compound or agent.

This invention r provides the composition described above in the form of a bait . composition wherein the solid diluent andlor the liquid t comprises one or more food materials, said ition optionally sing an attractant and/or a humectant.

This invention further provides a trap device for controlling parasites, in particular rasites, comprising said bait composition and a g adapted to receive said bait composition, wherein the housing has at least one opening sized to permit the parasites to pass h the opening. so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a iocus of potential or known activity for the parasites pest.

This invention also provides a method for controlling parasites sing contacting the parasites or their nment with a biologically effective amount of a compound of formula (I). an N-oxide or a salt thereof. (egi as a composition described herein). This ion also relates to such method wherein the parasites or their environment are contacted with a composition comprising a bioiogicaiiy effective amount of a compound of formula (I), an N» oxide or a salt thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a iiquid diiuent, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.

This invention also provides a composition for protecting an animal from an parasitic pest sing a parasiticidally effective amount of a compound of formula (i) an N-oxide or a salt thereof, and at least one carrier. The present invention further provides the composition described above in a form for oral administration. This invention also provides a method for protecting an animal from a parasitic pest sing administering to the animal a parasiticidally effective amount of a nd of formula (i), an N—oxide or a salt thereof.

DETAILS OF THE INVENTION In the above recitations, the term ”alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes ht—chain or branched alkyl, such as, methyl, ethyl, n— propyl, i—propyl. or the different butyl, pentyl or hexyl isomers.

The radical (alk) denotes, for example, straight~chain or branched C1—Ce—alkylene, for example methylene, 1.1- or 1,2—ethylene or straightvchaln or branched ene, butylene, pentylene cr hexylene. (elk) is preferably straight-chain or branched C1-Cq-alkylene, more preferably Cj-Cz-alkylene, most preferably methylene, or 1,2—ethylene and in particular methylene.

"Alkenyl" includes straight~chain or ed alkenes such as l, 1—propenyl, 2- propenyl, and the different butenyl, yl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and xadienyl.

"Alkynyl" includes straight—chain or branched alkynes such as ethynyl, l~propynyl, 2~propynyl and the different butynyl, pentynyl and hexynyl isomers. ”Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5~hexadlynyl.

"Alkoxy" includes, for example, methoxy, ethoxy, n—propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylthio" includes branched or straight-chain alkylthic moieties such as methylthic, ethylthio, and the different thio, butyithic, pentylthio and hexylthio isomers.

"Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of sulfinyl" include CH38(O)-, CH30H23(0)', CH3CHZCH25(O)-, CHS(O)- and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers- Examples of "alkylsulfonyl" include )2-, CHBCHQS(O)2', CH30H20H28(O)2-, (CH3)20HS(O)2-, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.

W0 201 21107533 "N—alkylamino", "N,N-di-aikyamino". and the like, are defined analogousiy to the above examples. alkyl" includes. for e, oyclopropyl. cyclobutyl, entyl and cyclohexyl. The term ”alkylcycloalkyl" denotes alkyi substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyi, i—propylcyciobutyl, 3-methylcyclopentyl and tmethylcyciohexyl.

The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety? Examples of "cycloalkylalkyl" include cyclopropylmethyi, cyclopentyiethyi, and other cycloalkyi moieties bonded to straight-chain or ed alkyi groups.

The term "halogen", either alone or in compound words such as ”haloalkyl", includes fluorine, chlorine, bromine or iodine. Further. when used in compound words such as "hatoalkyi", said aikyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haioalkyi” include F30, CICH2-, CF3CH2- and CF3CCl2—.

The terms "halocycloalkyl", "haloaikoxy", "haioalkylthio", and the like, are defined analogously to the term “haloalkyl”. Examples of “haloaikoxy” include CF30, CClSCHZO-, HCFzCHgCHzO— and CF30H20-. es of "haloalkylthio" e CCl38-. CF39, CCISCHZS- and CICHZCch H29». Examples of "haloalkylsulfinyl" include CF38(O)-, CCigS(O)-, CF3CH23(O)- and CF36F28(O)~. Examples of "haloalkylsulfonyl" e CF38(O)2~, CCIgS(O)2', CF30H28(O)2- and CFSCF28(O)2—.

"Aikylcarbonyl" denotes a straight—chain or branched alkyi moieties bonded to a C(=O) moiety. Examples of "alkylcarbonyl" include CH30(=O)—, CHSCHQCHZCFO} and (CH3}2CHC(=O)—. Exampies of "alkoxycarbonyl" include CHSOC(=O)-, CH30H200(=O), CchHZCHZOC(=O)-, CHOC(=O)— and the ent butoxy- or pentoxycarbonyl isomers, for example tert-butoxycarbonyl (Boo).

The total number of carbon atoms in a substituent group is indicated by the "Ci-Cl" prefix where i and] are integers. For example, C1—C4 alkylsulfonyl designates methylsulfonyl h butylsulfonyl; Cz-alkoxyalkyl designates CH300H2; Ca—alkoxyalkyl designates, for example, OCH3), CH300H2CH2 or CHSCHZOCHZ; and C4—alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group ning a total of four carbon atoms, examples including CH30H20H200H2 and CH30H200H20H2-.

W0 20122107533 When a compound is substituted with a substituent bearing a subscript that tes the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R2)n, n is ‘l or 2.

"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has ap— orbital perpendicular to the ring plane, and in which (4n + 2) 1T electrons, where n is a positive r, are associated with the ring to comply with Hiickel’s rule.

The terms "heterocyclic ring" or ocycie" denote a ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a cyclic ring can be a saturated, partially rated, or fully rated ring. When a fully unsaturated heterocyclic ring satisfies Hi‘J‘cKel's rule, then said ring is also called a "heteroaromatic ring", "aromatic heterocyclic ring". Unless otherwise indicated, cyclic rings and ring systems can be attached through any available carbon or en by replacement of a hydrogen on said carbon or nitrogen.

R1 is preferably C1—C4-haloalkyl or C1-C4-haloalkoxy, more ably C1—C3-haloalkyl. even more preferably C1—Cz—alkyl substituted with F, and in particuiar CF3.

Each R2 is independently of the other preferabiy haiogen, CrCyhaloalkyl, C1436 haloalkoxy or cyano, more preferably halogen, CFg, OCF3 or cyano, especially halogen, for example chlorine or fluorine, and in particular chlorine.

B and B’ are each independently preferably a radical CH or CR2, wherein R2 is halogen, in particular each a radical CH.

B1, B; and 83 are each independently of the other preferably a group CRZ', wherein R2’ is H or R2, and for R2 the above-given meanings and preferences apply. One preferred embodiment relates to a compound of formula (I), wherein one of the radicals B1, 82 and 83 is CH and the two other ones are each ndently a l CR2, wherein R2 is halogen, for example chlorine or fluorine, and in particular chlorine; within this embodiment it is particularly preferred, that B2 is CH and B1 and Ba are each independently CCI or CF.

Another preferred ment relates to a compound of formula (l), wherein all three W0 2012(107533 radicals B1. 82 and Ba are independently a l CR2, n R2 is halogen, for example chlorine or fluorine, and in particular chlorine.

Each R3 is independently of the other preferably H, halogen, hydroxy, CI—Cq-alkyl, C1—C4— kyl, Cs-Cs~cycloalkyi, alkoxy, C1—C4-haloalkoxy, N—mono- or N,N-di-C1*Cs* alkylamino, cyano or nitro, more preferably H, n, hydroxy. C1—Cz-alkyl, C1~Cz~haioalkyl, cyclopropyl or Csz—alkoxy, even more preferably H, hydroxy, C1-Cz~alkyl or C1-Cz—alkoxy, most preferably H or C1-Cz—alkyl, for e H or methyl, and especially methyl.

R4 is preferably H, C1~C4~alkyl, Cg--C4-alkenyl, Cz-C4~aikynyl, Cg-CB-cycloaikyl, Cr-Cyaikoxy- Cy~C4-alkyl or C1-C4-alkylcarbonyl. more preferably H, C1-Cg—alkyl, aikenyl, C2-C4~ alkynyl, CyCe—cycioalkyl, C1—Cz-aikoxy-Gr—Cg-aikyl or C1—CZ-alkyicarbonyl, and in particular H, Cr—Cz—alkyl, ethenyl, ethynyl, cyclopropyl, 01-Cg-alkoxy—C1-Cg—alkyl, acetyi or propionyl.

The variable m is, for example 0, 1 or 2, in particular 0.

The variable X is preferably 8 or O, for example 8, and in ular 0.

X1 or X2 are each independently of the other preferably a group CR3, wherein for R3 the above—given meanings and ences apply. X1 is most preferably the group CH. X2 is most preferably the group C(CHa).

Preferably X is S or O, and X1 and X; are each independentiy a radical CR3, wherein for R3 the above given meanings and preferences apply. More preferably, X is S or 0, X1 is CH, and X2 is CR3 wherein for R3 the above given meanings and preferences apply. in particular, X is 0, X1 is CH and X2 is C(CH3).

W and W’ are each independently of the other preferably 0.

R5 is preferably, H, C1~Cs-aikyl, Cz—Ce—alkanoylcarbonyl or C2-Ce-alkoxycarbonyl, more preferably, H, C1-C2-aikyi, 02-04—alkanoylcarbonyi or C2-C4-alkoxycarbonyl, and in particular W0 201 2H 07533 PCTIEP2012/052241 R7 and R8 are each independently of the other preferably H; C2-C4-alkenyl; CZ~C4-alkynyi; C3-Ce-cycioalkyl; or C1—CB-aikyl which is tituted or substituted by halogen, 01 alkoxy, C1—Cz-alkylthio, cyano, nitro, amino, N-mono— or N,N—di-Ci-C4alkylamino, pyridyl, pyrimidyl thiazolyl. or i, dyl or thiazolyl which is each mono— or disubstituted by halogen, cyano, C1-Cz-aikyl or C1-Cg—haloalkyi. R7 and R8 are each independently of the other especially preferably H; C1-Ce-alkyi which is tituted or substituted by n Ci-Cg-aikoxy, cyano, nitro, amino, — or —Cq-Cg-alkyiamino, pyridyl, pyrimidyi or thiazolyl; Cz-C4-alkenyl; 02alkynyl; or Cg-Cs—cycioaikyl.

R7 is most preferably H or 01-04—alkyl, in particular H, methyl or ethyl.

R8 is most preferably C1-C4-alkyl which is unsubstituted or substituted by halogen, cyano or pyridyl, or is 02alkynyl or 03cycloalkyl. ularly preferred meanings of R8 are cyclopropyl, C2-C4—alkynyl or C1-C4-alkyl which is unsubstituted or substituted by halogen or cyano, especially cyclopropyl, Ci-Cz—alkyl, C1-Cz—haloalkyt, C1—Cz—cyanoalkyl or propynyi .

According to one embodiment of the invention, 0 and 0’ each may be a CG~C1o—carbocyclic ring system, for example , naphthyl, tetrahydronaphthyl, indanyl, indenyl, hydrindanyl or dro—pentalen. in particular phenyl, which is each unsubstituted or substituted by one or more same or different substituents selected from the group of substituenis as ned above. Q and Q’ as carbocyclic ring radical are each preferably phenyi which is substituted by ’l to 4, preferably 1 to 3 and in particular 1 or 2 same or different substituents ed from the group consisting of halogen, C1-C4-alkyl, 01-04—haloalkyl, C1-C4-alkoxy, C1—C4- haloaikoxy, C1—C4-aikylthio, haioalkylthio, 01~C4—aikyisulfinyl, C1-C4-haloalkylsulfinyl, 01alkylsulfonyl, C1~C¢~haloalkylsulfonyL cyano, nitro, 01—04—atkoxycarbonyl, sulfonamido, C2-Ca-alkanoyl and unsubstituted or haiogen—, C1—C4-alkyl-, C1—C4-haloalkyln C1-C4-alkoxy-, C1-C4—haloalkoxy—, cyano- or Miro—substituted phenyl, benzyl, benzoyl and phenoxy. Q and Q‘ as carbocyclic ring radical are each more preferably phenyl, which is substituted by 1 to 3, in particular 1 or 2, same or different substituents selected from the group consisting of halogen, C1-Cg-alkyl, Ct-Cz-haioalkyi, Cq-Cz-alkoxy, C1—CZ-haloalkoxy, C1-Cz—haloalkylthio, cyano, nitro, and unsubstituted or n~, C1-Cz-alkyl-, C1-Cz-haloalkyl-, C1-C2-alkoxy-, C1— Cz-haloalkoxy-, cyano- or nitro-substituted phenyl and phenoxy.

According to another embodiment of the invention, Q and Q” are each a 4-, 5- or 6 membered heterocyclic ring, which may be saturated or preferably unsaturated, and which is PCTIEP2012/052241 unsubstituted or substituted with one or more substituents ed from the group of tuents as defined before.

Preferred tuents of the heterocyclic ring Q and Q’ are, for example, C1—C4-alkyl. C1-C4- haloalkyl, C1-C4-alkoxy, C1-C4—haloalkoxy, Cl-C4-alkylthio, C1—C4-alkylsulfinyl, C1-C4—alkyl- yl, cyano, nitro, 01alkoxycarbonyl, sulfonamido, N—mono- or N,N-di—Ci~C4— alkyiamino, aikanoyl and unsubstituted Even more red substituents of the cyclic ring Q and Q’ are each selected from the group consisting of halogen, 01-02— alkyl, C1-Cz~haloalkyl, C1-C2—alkoxy, C1—Cz—haloalkoxy, cyano, nitrc, and C1-C4—alkoxy~ carbonyl, in particular C1-Cg-alkyl, Cl-Cg-haloalkyl and C1-Cd-alkoxycarbonyl.

A suitable heterocyclic ring 0 and Q’ is, for example, a 5— or 6~membered heteroaromatlc ring having from 1 to 4. preferably from 1 to 3 same or different heteroatoms selected from the group consisting of N, O and S, which is further unsubstituted or tuted by one or more substituents as defined before for Q and Q‘ including the preferences given therefore.

The heterocyclic radical Q and Q“ is each independently ably substituted by O to 3, in particular 0, 1 or 2 substituents from the group as defined before for Q and Q’.

Examples of a 5— or 6-membered unsaturated aromatic heterocyclic ring radical Q and Q’ are thienyl‘ furanyl, pyrrolyl, yl, isoxazolyl, thiazolyl, isothiazolyl= pyrazolyl, imidazolyl, lyl, thiadiazolyl, oxadiazoiyl, i, pyrldazinyl, pyrimidinyl. pyrazinyl and triazinyl, which are each unsubstituted or substituted as mentioned before including the preferences.

Preferred unsaturated aromatic heterocyclic ring radicals Q and Q‘ are 1-. 2- or 3-pyrrolyl, 1-, 2—, 4- or 5-imidazolyl, 1~ or 4-pyrazolyl, 2—, 4- or 5—thiazolyl, 1,2,4—triazol~3~ or ~4—yl, 1,2,3~ trlazin~1- or 2-yl, 2- 3— or 4spyridyl or 4- or 5—pyrimldinyl, each unsubstituted or substituted by halogen, CT~C2~alkyL C1-Cz-haloalkyl, C1-C2-alkoxy, Ci—Cyhaloalkoxy, cyano, nitro, and C1- C4—alkoxycarbonyl.

Particularly preferred aromatic heterocyclic ring radicals Q and Q’ are 2-thiazoyl, 2— 3- or 4- l or 4— or 5-pyrimidinyi, each unsubstituted or substituted by C1-Cz-alkyl, (31 haloalkyi and Cl-Ct—alkoxycarbonyll A further group of suitable heterooyciic radicals Q and 0' comprises, for e, a 4n, 5- or 6-membered heteroaliphatic having from 1 to 4, preferably from 1 to 3 same or different heteroatoms selected from the group consisting of N, O and S, which is further unsubstituted or substituted by one or more tuents as defined before for Q and Q’ including the preferences given therefore.

Examples of heteroaliphatic rings Q and Q’ include thietanyi, tetrahy-drofuranyl, tetrahydro- thiophenyl, pyrrolidinyl, 1,3—dioxolanyl. 1,2— or 1,3-oxazolidinyi, tetrahydropyranyl. dinyl, tetrahydrothiopyranyl, morpholinyl, 1,3- or 1,4—dioxanyl, which may be substituted as mentioned before for Q and Q’ including the preferences.

A red heteroaiiphatic ring radical Q and Q' is thietanyl, or tetrahydrofuranyl, which is tituted or substituted by halogen, C1-Cz~alkyl, haloalkyl, C1-Cz-alkoxy, C1-C1;- haloalkoxy, cyano, nitro, or Cy—Cpalkoxycarbonyi.

Particularly red heteroaliphatic ring radicals Q and Q’ are thietanyi, ydrofuran— 2-yl and tetrahydrofuran-S-yl.

According to a preferred embodiment of the invention, Q and Q’ are each 1—, 2— or olyl, 1-, 2-, 4- or 5-imidazolyl, 1— or 4-pyrazolyl, 2—, 4— or 5—thiazolyl, 1,2,4—triazol~3— or -4~y|, 1,2,3w trlazin—1- or 2-yl‘, 2— 3- or 4-pyridyl, 4- or 5-pyrimidinyl, thietanyi, or tetrahydrofuranyl, which is each unsubstituted or substituted by halogen, C1—Cz-alkyl, Ct-CZ-haloalkyi, kcxy, Ct- Cz—haioalkoxy. cyano, nitro, or alkoxycarbonyl.

A particularly preferred radical Q and Q‘ is Z-thiazoyl, 2~ 3- or 4-pyridyl, 4- or 5—pyrimidlnyl, thietan—a—yl, tetrahydrofuran—Z-yl or tetrahydrofuran-s-yl, which is each unsubstituted or substituted by C1-Cz—alkyl, Ci-Cg-haioalkyl and aikoxycarbonyi.

A suitable fused hetero-bicyclic ring system comprises, for example a 5— or 6—membered heterocyclio ring having from 1 to 4, preferably from 1 to 3 same or different heteroatoms selected from the group consisting of N, O and S, to which is attached an annulated ring; in addition said fused bicyciic system is further unsubstituted or substituted by one or more substituents as defined before for Q including the preferences given. Those rings can be saturated ring or unsaturated rings.

Exampies of fused hetero-bicyclic ring systems Q and Q’ are illustrated in t 3 below.

Exhibit 3 0-96 0-97 (3-98 0-99 “2 4122 £13 ° N (R) N (R), E} (R), 52m), (.1400 mm (2.102 0-103 ~\\N. o / s / N is E (R), 1 / (R), (R), (R), Q 104 0-105 0-106 Q-107 W\N N N / N \ l‘ \ \N Vs(R), o (R), E (R), (R), 0-108 (3-109 Q 110 (3-111 / o s N (R), (R), (R), (RX 0-112 0-113 0-114 0-115 / 1 "\ I (R), (R), (R), / N / N (R). / (1-116 0—117 0-118 Q-119 \ N N\ N\ "HRL I (R), (R), (R), / N / / ‘ 3 o 0'1 2° Q~121 0—122 0423 r R R» 0-124 0-125 0-125 CF! 27 1—02) go} \ \ ' (R)‘ I (R)r 1 O (R) / ' o N 0-128 0-129 @130 0-131 0-132 0-133 W0 2012/‘107533 wherein R is any substituent as defined before for Q and (2’ including the preferences given, and r is an integer from 0 to 4, limited by the number of available positions on each Q group. in addition, when the attachment point between (R)r and the Q group is rated as floating, (R)r can be attached to any available carbon atom or nitrogen atom of the Q group.

G" independently has the meaning of Q’ as heterocyclic ring or Ce-Cm-carbocyciic ring system, with the exception that Q” is not substituted by another radical Q”, including the above-given preferences.

R5 is preferably aikyl, Cz-Cs~aikenyl, Cz-Cs-alkynyi, Ca—Cs~cycloaikyi, C4—Cy-aikylcyclo— alkyl or C4—Cy-cycloaikylaikyi, which is each unsubstituted or are substituted in the alkyl, alkenyl or alkynyl moiety by n, y, CrCralkOXY, Crcrhaioalkoxy, C1434— alkylthio, C1-C4-haioalkylthio, cyano, amino, N-mono- or N,N—di-C1—C4—alkylamino, COOH, C,- C4—alkoxycarbonyl, 4-alkylcarbonylamino, sulfonamido, N-mono- or N,N, di-C1-C4- uifonamido, a group —-C(O)NR7R5 or a radical Q’; or is a l Q; or R6 together with R5 is a group =C—NR7R3 or =C—NR7(OR8); wherein R7 is H or 01—04—aikyl; R8 is H; 02alkenyl; C2-C4-aikynyl; Ca-Cs-cycioaikyi; or C1-CG-aikyi which is unsubstituted or substituted by n, C1-C4-alkoxy, C1-C2-alkyithio, cyano, nitro, amino, N-mono- or N,N-di—C1—C4alkyiamino, pyridyl, pyrimidyi thiazoiyl, or pyridyl, pyrimidyl or thiazolyl which is each mono— or disubstituted by halogen, cyano, C1-Cz—alkyl or C1~Cz-haioalkyl; and Q and Q’ are each thienyl, turanyi, pyrroiyi, oxazoiyi, isoxazoiyi, thiazolyi, isothiazoiyl, pyrazoiyl, imidazoiyl, triazoiyi, thiadiazolyi, oxadiazoiyi, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyi and nyl, nyl, or tetrahydrofuranyi, which are each unsubstituted or substituted by halogen, C1-Cz—aikyi, C1-Cg—haloaikyl, C1—Cz—alkoxy, C1-Cg—haloaikoxy, cyano, nitro, or 01—04- aikcxycarbonyl.

R6 is even more preferably (31aikyl, which is unsubstituted or are substituted in the aikyl moiety by halogen, hydroxy, Ci-Cratkoxy, C1-C4~haloalkoxy, C1-C4-alkyithio, C1-C4- haioaikyithio, cyano, COOH, 01—84—aikoxycarbonyi, a group —C(O)NR7RB or a radical Q’; or is a radical Q; or R6 er with R5 is a group =C—NR7R3 or =C—NR7(OR8), wherein R7 is H or C1-Cz-alkyl; R3 is 02alkenyl; alkynyi; Cg-Cs-cycioalkyl; or C1-C4-alkyi which is unsubstituted or substituted by halogen, cyano or pyridyl; and Q and Q’ are each 1-, 2~ or olyi, 1-, 2-, 4- or 5-imidazoiyl, i— or 4-pyrazolyi, 2-, 4- or zolyi, 1,2,4—triazol or —4-yl, 1,2,3-triazin or 2-yl, 2— 3— or 4—pyridyl, 4- or 5-pyrimidinyi, thietanyl, or W0 20122107533 PCTIEP2012/052241 tetrahydrofuranyl, which is each unsubstituted or substituted by halogen, alkyi, 01 kyl, C1~Cz-alkoxy, haloalkoxy, cyano, nitro, or C1-C4-alkoxycarbonyl.

R5 is most preferably C1—C4-alkyl, which is unsubstituted or are substituted in the alkyl moiety by n, C1-Cz-alkoxy, C1-Cz-alkylthio, cyano, COOH, C1-Cz—aikoxycarbonyl, a group —C(O)NR7R8 or a radical Q’; or is a radical Q; or R5 together with R5 is a group =C—N(C1—Cg—alkyi)2 or =C-«NH(OC1-Czaikyi), wherein R7 is H, R5 is Cg—C4~alkynyl, 03—04— cycloalkyi or C1~C4«alkyi which is unsubstituted or substituted by halogen or cyano. and Q and Q’ are each 2athiazoiyl, 2- 3- or 4—pyridyi, 4— or 5-pyrimidinyl, tanyl, or 2— or 3- tetrahydrofuranyl, which is each unsubstituted or substituted by C1-Cyalkyl or (31-02— haloaikyl.

A preferred embodiment of the present ion relates to a compound of formula (i) above, wherein B and B’ are each CH, 81 and Ba are each independently CCI or CF, 8;; is CH, CCl or CF, R1 is CF3, X is O or S, in particular 0, X1 is CH, X2 is C(CHa), and for R5 and R5 each the above-given meanings and preferences apply.

A further preferred embodiment of the present invention relates to a compound of formula (i) above, wherein B and B‘ are each CH, 31 and Ba are each independently CCI or CF, Bz is CH, 001 or CF, R1 is CF3, X is 0, X1 is CH, X2 is C(CH3), R5 is H, and R5 is C1—C4-aikyl, which is unsubstituted or are substituted in the alkyi moiety by halogen, C1—Cz-alkoxy, 01—02- hio, cyano, COOH, Ci—ngalkoxycarbonyl, a group —C(O)NR7R8 or a radical Q’; or is a radical Q; or R3 together with R5 is a group =C~N(C1—Cz-alkyi)2 or =C—NH(OC1~C2alkyl), wherein R7 is H, R8 is 02aikynyl, 03—04-cycloalkyl or (31-04—alkyl which is unsubstituted or substituted by n or cyano. and Q and Q’ are each 2-thiazolyl, 2- 3- or dyl, 4- or »pyrimidinyl, 3-thietanyl. or 2- or 3—tetrahydrofuranyl, which is each unsubstituted or substituted by C1-Cz~alkyl or C1-Cz-haioalkyl.

According to a another preferred embodiment of the invention there is ed a compound of formula 2012/052241 (18) including all geometric and stereoisomers, N-oxides, and salts f, wherein for R1, R2, R3, R5, R5 and X each the above-given meanings and preferences apply and n is an r from O to 4, ably from 1 to 3, and in particular of 2 or 3. in particular, n is an integer from 1 to 3; R1 is Ci-Ca-haloalkyl; each R2 is independently selected from the group consisting of n, C1-Ce-haloalkyl, C1-Ce-haloalkoxy and cyano; X is S or 0; R3 is H or C1~Cg-alkyl; R5 is H or C1—Cg-alkyl; R6 is CrCs-GIKYI, Cz—Ce—alkenyl, Cz— Cs—alkynyl, Cst-cycloalkyl, C4—Cy—aikylcyclcalkyi or C4—Cy-cyclcalkylalkyl, which is each unsubstituted or are substituted in the alkyl, alkenyl or alkynyl moiety by halogen, hydroxy, C1-C4-alkoxy, C1—C4—haloalkoxy, C1~C4~alkylthio, C1-C4-haloalkylthio, cyano, amino, N—mono- or N,N-di—Ci-C4-alkylamino, COOH. C1—C4-alkcxycarbonyl. N-C1-C4-alkyicarbonylarninc, sulfonamido, N-mono- or N,N. di-C1-C4-alkyisulfonamido, a group -C(O)NR7R8 or a radical Q’; or R3 is a radical Q; or R5 er with R5 is a group =C~NR7R8 or =C—NR7(OR8); R7 is H or C1—C4-alkyl; Re is H; 02alkenyl; Cz—C4—alkynyl; Ca—Cs-cycloalkyl; or C1-Cs-alkyl which is unsubstituted or substituted by halogen, 01aikoxy, C1-Cg-alkylthio, cyano, nitro, amino, N—monc- or N,N-di—Ci—C4alkylamino, pyridyl, dyi thiazolyl, or pyridyl, pyrimidyl or thiazoiyl which is each mono- or disubstituted by halogen, cyano, C1-CZ-alkyl or C162- haloalkyl; and Q and Q’ are each thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, l, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, thietanyl, or tetrahydrofuranyl, which are each unsubstituted or substituted by halogen, aikyl, Ci-Cg—haloalkyl, C1-Cz-alkoxy, 01 haloalkoxy, cyano, nitro, or C1-C4—alkoxycarbonyl.

A ularly preferred embodiment of the invention relates to a compound of formula (la) above, wherein n is an integer of 2 or 3; R, is CFs; each R2 is independently halogen; X is S or 0; R3 is H or Cq-Cz-alkyl; R5 is H; and R5 is 01alkyl, which is unsubstituted or substituted in the alkyl moiety by halogen, hydroxy, 01alkoxy, haloalkoxy, C1-C4~ alkylthio, haloalkylthio, cyano, COOH, Cq—Cralkoxycarbonyl, a group ~C(O)NR7RB or a radical Q‘; or R5 is a radical Q; or R6 together with R5 is a group =C—NR7R3 or =C—NR7(OR5); WO 07533 2012/052241 R7 is H or C1-Cz-alkyl; R3 is CZ~C4-alkenyl, C2-C4-alkynyi, Ca-Cs-cycloalkyl, or C1«C4—alkyl which is unsubstituted or substituted by halogen, cyano or pyridyl; and Q and Q’ are each 1-, 2- or 3-pyrrolyl, 1-, 2-, 4~ or 5-imidazoiyl, 1- or 4~pyrazolyl, 24, 4- or 5-thiazotyl, 1,2,4—triazoi or yl, tn'azin or 2—yl, 2- 3— or dyl, 4— or 5—pyrimidinyl, thietanyl, or tetrahydro— furanyl, which is each unsubstituted or substituted by n, C1—Cz—alkyl, C1-Cz—haloalkyl, C1-Cg-alkoxy, haloalkoxy, cyano, nitro, or Cy-Ctraaikoxycarbonyl.

A further ularly preferred embodiment of the invention relates to a compound of formula (la) above, wherein n is an integer of 2 or 3; R1 is CFg; each R2 is independently halogen; X is S or 0; R3 is H or C1-C2-alkyl; R5 is H; R6 is C1-C4-alkyl, which is unsubstituted or are substituted in the aikyl moiety by halogen, Ci—Cz—alkoxy, Ct—Cg-alkytthio, cyano, COOH, C1—Cg—alkoxycarbonyl, a group —C(O)NR7R8 or a radical Q’; or R6 is a radical Q; or R5 er with R5 is a group =C-N(Ci—Cz—all<yi)2 or =C—NH(OC1-C2alkyl); R7 is H; R8 is 02434— aikynyl, (33—04-cycloalkyl or C1—C4—alkyt which is unsubstituted or substituted by halogen or cyano; and Q and Q’ are each 2-thiazolyl, 2- 3- or 4-pyridyl, 4- or 5-pyrimidinyl, S-thietanyl, or 2- or 3-tetrahydrofuranyl, which is each unsubstituted or substituted by C1—Cz-alkyl or 01 haloalkyl.

Still a further preferred ment of the invention relates to a compound of formula (la) above, wherein n is an integer of 2 or 3; R1 is CF3; each R2 is independently halogen; X is 0; R3 is methyl; and for R5 and R5 each the above-given meanings and preferences apply. An especially preferred embodiment of the invention s to a compound of formula (la) above, wherein n is an integer of 2 or 3; R1 is CFa; each R2 is independently halogen; X is 0; R3 is methyl; R5 is H; Re is C1-C4-alkyl, which is unsubstituted or are tuted in the alkyl moiety by halogen, Ct—Cz—atkoxy, Cf-CZ-alkylthio, oyano, COOH, C1—Cz-aikoxycarbonyi. a group R7R8 or a radical Q’; or R5 is a l Q; or R8 together with R5 is a group =C—- N(C1-Cz-alkyl)2 or =C-NH(OC1-Czalkyl); R7 is H; R3 is Cg-Crtg—alkynyl, cycloalkyl or C1- 04-alkyl which is unsubstituted or substituted by halogen or cyano; and Q and Q’ are each 2- thiazolyl, 2- 3- or 4-pyridyl, 4- or 5-pyrimidinyl, 3-thietanyi, or 2- or S-tetrahydrofuranyl, which is each unsubstituted or substituted by Ct-Cz-alkyl or Ct-Cz-haloalkyl.

Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.

One skilled in the art will appreciate that one stereoisomer may be more active andlor may exhibit beneficial effects when ed relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, , and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

One skilled in the art will appreciate that not all nitrogen containing heterocyclic rings can form N—oxides since the en requires an available lone pair for oxidation t-o the oxide; one skilled in the art will recognize those nitrogen containing heterocyclic rings which can form es. One skilled in the art will also ize that ry amines can form N- oxides. Synthetic methods for the preparation of N-oxides of cyclic rings and tertiary amines are very well known by one skilled in the art including the oxidation of heterocyclic rings and tertiary amines with peroxy acids such as peracetic and m—chioroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t—butyl hydroperoxide, sodium ate, and dioxiranes such as dimethyl dioxirane These methods for the preparation of N~oxides have been extensively described and reviewed m the literature.

One skilled in the art recognizes that e of the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of formula (l) are useful for control of invertebrate pests (Le. are veterinarily or agriculturally le). The salts of the compounds of formula (I) include acid~addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, maionic, oxalic, propionic, salicylic, tartaric, 4- toluenesulfonic "or valeric acids. When a compound of formula (l) contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, ylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. ingly, the present invention comprises compounds selected from formula (l), N—oxides and veterinary acceptable and agriculturally le salts thereof.

The compounds of the present invention made be prepared, for example, in analogy to the processes as outined in WO 2007575459 on pages 29-31. ingly, the nds of formula (I) or (la) may be prepared, for example, by cycloaddition of a compound of formula ~18— R1 H :rWH_*B 2\ /B'33/ with a nitrile oxide derived from an oxime of formula (in), wherein B, B’, 81-33, R, X, x1 and X2 each have the above~given g, Z is Br, l, COOH, Ce-alkyi or —C(W)— NR5R5, wherein W, R5 and R6 each have the given meaning, and, if 2 is Br, l, COOH or COOCrCe—alkyl, converting said radicai to a radical —C(W)— NR5R6.

The reaction lly proceeds through the intermediacy of an in situ generated hydroxamyl chloride. ln a typical procedure a chlorinating reagent such as sodium hypochlorite, N— chlorosuccinimide, or chloramine—T is combined with the oxime in the presence of the styrene, Depending on the conditions amine bases such as pyridine or triethylamine may be necessary, The reaction can be run in a wide variety of solvents including tetrahydrofuran, diethyl ether, methylene de, dioxane, and toluene with optimum temperatures ranging from room ature to the reflux temperature of the solvent.

The compounds of formula (I) or (ia) may also be prepared by a process in anaiogy of W020091025983, wherein a compound of formula (Vl) is contacted with hydroxylamine and a base to form an ole of formula (I) hydroxylamine Q_—-N (NHZOH) \ x _______..,. B \ base \ 2 solvent BII R1 2\ /Ba/ X1~< PCTfEP2012/052241 wherein B, B’, 81-83, R, X, X1 and X2 each have the above-given meaning, Z is Br, I, COOH, COOC1-Ce-alkyl or —C(W)— NRsRa, wherein W, R5 and R6 each have the above-given meaning, and, if Z is Br, i, COOH or COOC1-Cs—alkyl, converting said radical to a radical —C(W)- NRsRe.

The reaction may be performed as bed in W02009/025983 on pages 29-31. in on, synthetic routes to prepare the ediate of formula (IV) are likewise disclosed in W020091025983 on pages 31—34.

Another process for the preparation of a compound of formula (ib) above, wherein Z is COOH or Ca~aikyi, includes a functionai group transformations from a ponding compound of the formula (ib), wherein Z is Br or i, which is known in the art; a suitable method comprises haiogen-metal exchange (the metal being, for example, Li or Mg) toilowed by a quench with 002 or (CN)COQ(C1-Cs-aikyl) respectively. The on is typically carried out at low temperature, for example at a temperature of from -80°C to 0°C in a solvent such as diethylether or THF.

Another process for the preparation of a nd of formula (lb), wherein Z is a group COOH, is the hydrolysis or saponification of a corresponding compound of the formula (lb), wherein Z is COOC1—C6—alkyl or ON; the latter compound is obtainable from a corresponding nd of the formula (lb), where Z is Br or i, for example, with zinc cyanide or copper e with or without palladium catalyst.

Another process for the preparation of a compound of the formula (l) or (la), n Z is a group —~C(W)-NR5R5, includes well known functional group ormations from a corresponding compound of the formula (lb), wherein Z is Br or i, such as aminocarbony- lation with an amino compound HNRsRs and CO. The reaction is typically carried out in the presence of a palladium catalyst under CO atmosphere. Many catalysts are useful for this type of transformation, a typical catalyst being tetrakis(triphenylphosphine)palladium(0).

Solvents such as 1,2.dimethoxyethane, N,N-dimethylacetamide or toluene are suitable. The method can be conducted over a wide range of temperatures, for example from about 25°C to about 150°C, especially from 60 to 110°C.

Another process for the preparation of a compound of the formula (I) or (la), wherein Z is a group NR5R5, es well known functional group transformations from a corresponding compound of the formula (lb), wherein Z is COOH like amide coupling with well known reagents (for example EDCI, HOBT, PyBOP, ) with an amino compound HNRSRG or activation of COOH to an acyl halide (Cl for example with oxalyl chloride or thionyl chloride) and subsequent coupling with an amino compound HNRSRG, The compounds of formula (ll) are known, for example, from WO 2006149459 or may be prepared in y to the methods disclosed therein.

The compounds of formula (ill) may be prepared, for example, by first of all protecting the aldehyde group of a compound of formula llla, n X, X1 and X: are each as described above and Y is a g group, such as halogen, tosylate, triflate or nitro, for example, by converting it to a cyclic acetal, then introducing a suitable radical Z replacing Y by methods known from textbooks of organic chemistry, afterwards deprotecting the aldehyde and converting it to a hydroxyimino compound of formula ill in a manner as known from WO 2007775459.

The compounds of the formula (l) according to the invention are notable for their broad activity spectrum and are valuable active ingredients for use in pest control. They are particularly le in the control of ectoparasites and to a n extent also for controlling endoparasites on and in animals and in the hygiene field, whilst being well tolerated by warm-blooded animals. s in the context of the invention are understood to include warm-blooded animals including farm animals, such as cattle, , pigs, sheep and goats, poultry such as chickens, s, guinea fowls and geese, fur-bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as companion animals such as ferrets, guinea pigs. rats, hamster, cats and dogs, and also humans.

WO 2012/]07533 2012/052241 In the context of the present invention, rasites are understood to be in particular insects, acari (mites and ticks), and crustaceans (sea lice), These include insects of the following orders: Lepidoptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, lsoptera, Psocoptera and Hymenoptera. However, the ectoparasites which may be mentioned in ular are those which trouble humans or s and carry pathogens, for example flies such as Musca domestica, Musca vetustissima, Musca alis, Fannia canicularis, Sarcophaga carnaria, Lucilia cuprina, Lucille sericata, Hypoderma bovis, Hypoderma lineatum, myia chioropyga, Dermatobia s, Cochliomyia hominivorax, Gasterophilus intestinalis, Oestrus ovis, biting flies such as Haematobia irritans irritans, Haematobia irritans exigua, Stomoxys calcitrans, flies (Tabanids) with the subfamilies of Tabanidae such as Haematopota spp. (eg. opota pluviaiis) and Tabanus spp, abanus ittatus) and Chrysopsinae such as Chrysops spp. (eg.

Chrysops caecutiens); Hippoboscids such as Melophagus ovinus (sheep ked)‘, tsetse files, such as Glossinia spp,; other biting s like midges, such as Ceratopogonidae (biting midges), Simuliidae (Blackflies), Psychodidae (Sandflies); but also blood-sucking insects, for example mosquitoes, such as Anopheles spp, Aedes spp and Culex spp, fleas, such as ephalides tells and Ctenocephalides canis (cat and dog fleas), Xenopsylla cheopis, Pulex irritans, Ceratophyllus gallinae, Dermatophilus penetrans, blood—sucking lice (Anoplura) such as Linognathus spp, Haematopinus spp, Solenopotes spp, lus humanis; but also chewing lice (Mallophaga) such as Bovicola (Damalinia) ovis, Bovicola (Damalinia) bovis and other Bovicola spp. . Ectoparasites aiso include members of the order Acarina, such as mites (eg. Chorioptes bovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus app, Demodex canis, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp. and ticks. Known representatives of ticks are, for example, Boophilus, mma, Anocentor. Dermacentor, hysaiis, Hyalomma, lxodes, Rhipicentor, Margaropus, ephalus, Argas, Otobius and Ornithodoros and the like, which preferably infest warm- biooded animals including farm animals, such as cattle, horses, pigs, sheep and goats. poultry such as chickens, turkeys, guineafowls and geese, fur—bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as companion animals such as ferrets, guinea pigs, rats, hamster, cats and dogs, but also humans, The nds of the formula (I) according to the invention are also active against all or individual development stages of animal pests showing normal sensitivity, as well as those W0 2012!]07533 showing resistance to widely used ticides. This is especially true for resistant s and members of the order Acarina. The insecticidal, ovicidal and/or acaricidal effect of the active substances of the invention can manifest itself directly, is. killing the pests either immediately or after some time has elapsed, for example when moulting occurs, or by destroying their eggs, or indirectly, e.g. reducing the number of eggs laid andlor the hatching rate, good efficacy corresponding to a pesticidal rate (mortality) of at least 50 to 60%.

Compounds of the formula (i) can also be used against hygiene pests, ally of the order Diptera of the families Muscidae, Sarcophagidae, Anophilidae and Culicidae; the orders Orthoptera, Dictyoptera (eg. the family Blattidae (cockroaches), such as Blatella germanica, Blatta orientalis, Peripianeta americana) and Hymenoptera (eg. the famities Formicidae (ants) and Vespidae ). singly, the compounds of formula (I) are also effective against ectoparasites of fishes, especially the sub-class of Copepoda (eg. order of Siphonostomatoida (sea lice), whilst being well tolerated by fish.

The compounds of formula (i) can also be used against hygiene pests. especially of the order Diptera of the families hagidae, Anophilidae and Culicidae; the orders Orthoptera, Dictyoptera (eg. the famiiy dae) and Hymenoptera (eg. the family Formicidae).

Compounds of the formula (l) also have sustainable efficacy on parasitic mites and insects of plants. in the case of spider mites of the order Acarina, they are ive against eggs, nymphs and adults of Tetracychidae (Tetracychus app. and Panonychus spp.).

They have high activity against sucking insects of the order era, especially against pests of the families Aphididae, Delphacio'ae, Cicadeiiidae, Psyllio’ae, Loccr'dae, Diaspididae and Eriopnydia‘ae (eg. rust mite on citrus fruits); the orders Hemiptera, Heteroptera and optera, and on the plant-eating insects of the orders Lepidoptera, Coleoptera, a and Orthoptera They are similarly suitable as a soil insecticide against pests in the soil.

The compounds of formula (i) are therefore effective against all stages of development of sucking insects and eating s on crops such as cereals, cotton, rice, maize, soya, potatoes, vegetables, fruit, tobacco, hops, , avocados and other crops.

PCTIEP2012/052241 The compounds of formula l are also effective against plant des of the species Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, Rizogiyphus etc.

Certain compounds of the formula (i) seem to be also effective against certain species of helminths.

Helminths are commercially ant because they cause serious diseases in mammals and y, eg. in sheep, pigs, goats, , horses, donkeys, camels, dogs, cats, rabbits, guinea-pigs, hamsters, chicken. turkeys, guinea fowls and other farmed birds, as well as exotic birds. Typical nematodes are: Haemonchus, Trichostrongylus, agia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, ris, Strongylus, Trichonema, Dictyocaulus, Capillarla, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, Parascaris and aria. The trematodes e, in particular, the family of iideae, especially Fasciola hepatica.

The good pesticidal activity of the compounds of formula (l) according to the invention corresponds to a mortality rate of at least 50-60% of the pests mentioned, more preferably to a mortality rate over 90%, most preferably to 95-100%. The nds of formula (l) are preferably employed internally and externally in unmodified form or preferably er with the adjuvants conventionally used in the art of formulation and may therefore be processed in a known manner to give, for example, liquid formulations (eg. spot—on, pour—on, spray-on, ons, suspensions, solutions, emulsifiable concentrates, on concentrates), semi— solid formulations (e.g. creams, ointments, pastes, gels, liposomal preparations) and solid ations (e.g. food additives tablets including a. 9. capsules, powders including soluble powders, granules. or embeddings of the active ient in polymeric nces, like implants and microparticies). As with the compositions, the methods of application are selected in accordance with the intended objectives and the prevailing circumstances.

The ation, is. preparations containing the active ingredient of formula (l), or combinations of these active ingredients with other active ingredients, and ally a solid, semi-solid or liquid adjuvant, are produced in a manner known per se, for example by intimately mixing, kneading or dispersing the active ingredients with compositions of excipients, whereby the physiological compatibility of the formulation excipients must be taken into consideration.

The solvents in question may be: alcohols (aliphatic and aromatic), such as benzylalcohol, ethanol, propanol, isopropanol or butanol, fatty alcohols, such as oleyl alcohol and glycols and their ethers and esters, such as glycerin, propylene glycol, dipropylene glycol ether, W0 2012flfl7533 l ne , ethylene glycol monomethyl or -ethyl ether and butyl dioxytol, ates, such as propylene ate, ketones, such as cyclohexanone, isophorone or diacetanol alcohol and polyethylene glycols, such as PEG 300. in addition, the compositions may comprise strong polar solvents, such as N-methyi—Z-pyrrolidone, dimethyl sulfoxlde or dimethylformamide, or water, fatty acid esters. such as ethyl oleate or isopropylpalmitate, vegetable oils, such as rape, castor, coconut, or soybean oil, synthetic mono-, di-, triglycerides like eg. glyceryl monostearate and medium chain triglycerides and also, if riate, silicone oils. The mentioned ingredients may also serve as carrier for particuiate application froms.

As ointment base resp. structure building ingredients the following ents may be used: eum based substances, such as Vaseline or paraffines, bases made from wool fat, like eg. lanoiin or lanolin alcohols, polyethylene glycols like eg. macrogols and lipid bases like eg phospholipids or triglyceride, such as hydrogenated vegetable oils.

The use of emulsifiers, wetting agents and spreading agents may also be required, in general, lecithins like soy lecithin, salts of fatty acids with alkaline earth and alkali metals, alkyl sulfates like sodium cetylstearyl te, cholates, fatty alcohols like cetyl alcohol, sterols like cholestesterol, yethylene sorbitan fatty acid esters like polysorbate 20, sorbitan fatty acid esters like sorbitan mono laureate, fatty acid esters and fatty alcohol ethers of polyoxyethylene like poloxyl oleyl ether, ypropylene polyoxyethylene block copolymers as eg. PluronicTM , saccharose esters like saccharose distearate, polyglyceryl fatty acid esters like polyglycerol oleate and fatty acid esters iike e.g. ethyl oleate or isopropylmyristate.

The formulations may also include gelitying and stiffening agents, like eg. polyacrylic acid derivatives, cellulose ethers, polyvinyl aicohois, polyvinylpyrrolldons and fine disperse silicium dioxide.

As polymeric agents with controlled release properties, may be applied tives made by eg. polylactic acid, polylactic coglycolic acid, poly orthoester, polyethylene carbonate, poly anhydrids and starch and PVC based matrices.

The on of penetration enhancers like ketones, ides, amides, fatty acid esters and fatty alcohols may be necessary.

Also preservatives like sorbic acid, benzyl alcohol and parabenes, and antioxidants as eg. alpha tocopherol may be added.

The active ingredient or combinations of the active ingredient may also applied in capsules, like hard gelatine es or soft capsules.

W0 2012f107533 The binders for tablets and boil may be chemically modified polymeric l substances that are soluble in water or in alcohol, such as starch, cellulose or protein derivatives (eg. methyl ose, carboxymethyi cellulose, ethylhydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as tic polymers, such as polyvinyl alcohol, nyl pyrrolidone etc. The tablets also contain fillers (eg, starch, microcrystalline cellulose, sugar, lactose etc), ants (eg. magnesium te), glidants (eg. colloidal silicon dioxide) and disintegrants (cg. cellulose derivatives) and acid resistant gs, like eg. acrylic acid esters.

The compounds of formula (I) according to the invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same sphere of activity e.-g. to increase activity, or with substances having another sphere of ty eg. to broaden the range of activity. it can also be sensible to add led repellents. For example, in case of a nd of formula (i) having a particular efficacy as adulticicie, is since it is effective in particular against the adult stage of the target parasites, the addition of a pesticide which instead attack the juvenile stages of the parasites may be very advantageous, or vice versa. in this way, the st part of those parasites that produce great economic damage will be covered. Moreover, this action will bute substantially to avoiding the formation of resistance. Many combinations may also lead to synergistic s, is. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view. Preferred groups of ation partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of a (l).

Suitable partners in the mixture may be biocides, eg. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, eg. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broadband insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers. Non-limitative examples of suitable insecticides and acaricides are mentioned in , compounds Nos. 1-284 on pages 18-21. Non-limitative examples of suitable anthelminthics are mentioned in WC 2009;071500, compounds (A1) — (A31) on page 21. mitative examples of suitable repellents and detachers are mentioned in WO 2009/071500, compounds (R1) -(RS) on page 21 and 22. Non-limitative examples of suitable synergists are mentioned in , compounds (81) —(83) on page 22.

The said partners in the mixture are best known to specialists in this field. Most are described in various editions of the Pesticide Manual, The British Crop Protection l, London, and others in the various ns of The Merck index, Merck & Co., Inc, , New Jersey, USA or in patent literature.

As a consequence of the above s, a further aspect of the present invention s to a combination preparation for the control of parasites on warm—blooded animals, characterised in that it contains, in addition to a compound of a (l), at least one further active ingredient having the same or different sphere of activity and at least one physiologically acceptable carrier. The present invention is not cted to ld combinations.

As a rule, the insecticidal and acarioidai itions according to the invention n 0.1 to 99 % by weight, especialiy 0.1 to 95 % by weight of one or more active ingredients of formula (I), 99.9 to 1 % by weight, especially 99.8 to 5 % by weight of a solid or liquid admixture, including 0 to 25 % by weight, especially 0.1 to 25 % by weight of a surfactant.

Application of the compositions according to the invention to the animals to be d may take place topically, perorally, parenterally or subcutaneously, the composition being present, for example, in the form of solutions, emulsions, suspensions, (drenches), powders, tabtets, boli, capsules, chewable treats, collars, eartags and pour-on formulations.

Preferred topical formulations are understood to refer to a readyato-use solution in form of a spot-on, pour-on or spray-on formulation often consisting of a sion or suspoemulsion or a combination of active ingredient and spreading auxiliaries. The expression spot-on or pour-on method is understood to refer to a ready~to~use concentrate intended to be applied topically and locally on the animal. This sort of formulation is intended to be applied ly to a vely small area of the animal, preferably on the animal's back and breech or at one or several points along the line of the back and breech. It is applied as a low volume of about 0.05 to 1 ml per kg, preferably about 0.1 ml per kg, with a total volume from 0.1 to 100 ml per animal, preferably limited to a maximum of about 50 ml. However, it goes without saying that the total volume has to be adapted to the animal that is in need of the treatment and will cleariy be different, for example, in young cats and in . These pour—on and spot-on formulations are designed to spread all around the animal giving protection or treatment to almost any part of the animal. Even so the administration is carried out by ng a swab or spray of the pour-on or spot-on formulation to a relatively small area of the coat, one observes that from the active substance is dispersed almost automatically over wide areas of the fur owing to the spreading nature of the components in the formulation and assisted by the animal's movements.

Pour-on or spot-on formulations suitably contain carriers, which promote rapid dispersement over the skin surface or in the coat of the host animal, and are generally regarded as spreading oils. Suitable rs are e.g. oily solutions; alcoholic and isopropanolic solutions such as solutions of 2~ootyldodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, isopropyl palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl , decyi , capric acid esters of saturated fat alcohols of chain length 012-018; solutions of esters of dioarboxylic acids. such as dibutyl ate, ropyl isophthalate, adipio acid diisopropyl ester, di-n-butyl adipate or also soiutions of esters of aliphatic acids, eg. glycols. it may be advantageous for a dispersing agent to be onally present, such as one known from the ceutical or cosmetic industry. Examples are 2-pyrrolidone, 2-(N-alkyl)pyrrolidone, acetone, polyethylene giycol and the ethers and esters thereof, propylene glycol or synthetic triglycerides.

The oily solutions include eg. vegetable oils such as olive oil, groundnut oil, sesame oil, pine oii, linseed oil or oastor oil, The vegetable oils may also be present in epoxidised form.

Paraffins and silicone oils may also be used.

A pour—on or spot—on ation generally contains 1 to 98.9 % by weight of a compound of formula (i), 0.1 to 80 % by weight of dispersing agent and 1 to 98.9 % by weight of soivent.

The pour-on or spot-on method is especially advantageous for use on herd animals such as cattle, horses, sheep or pigs, in which it is difficult ortime-vconsuming to treat all the animals orally or by injection. Because of its simplicity, this method can of course also be used for all other animals, including individual domestic animals or pets, and is greatly favoured by the keepers of the s, as it can often be carried out t the specialist presence of the veterinarian. s it is preferred to formulate commercial products as concentrates, the end user will often use dilute formulations. However, this depends on the mode of stration. Orally administered products are most often used in diluted form or as feed additives, whereas commercial pour-on and spot-on formulations are normally ready-to—use concentrates.

W0 7533 Such compositions may also contain further additives, such as stabilisers, anti-foaming agents, viscosity regulators, binding agents or tackifiers, as well as other active ingredients, in order to achieve special effects. insecticidal and acaricidal compositions of this type, which are used by the end user, similarly form a constituent of the present invention. in each of the processes according to the invention for pest control or in each of the pest control compositions according to the invention, the active ients of a (I) can be used in all of their steric urations or in mixtures thereof.

The invention also es a method of prophylactically protecting animals, especially productive livestock, domestic animals and pets, against parasitic helminths, which is characterised in that the active ients of formula (l) or the active ingredient formulations prepared therefrom are administered to the animals as an additive to the feed, or to the drinks or also in solid or liquid form, orally or by injection or parenterally. The invention also includes the compounds of formula (l) according to the invention for usage in one of the said processes.

The following examples serve merely to rate the ion without restricting it, the term active ingredient representing any substance as described in the preparation examples. in particular, preferred formulations are made up as follows: (% = percent by weight) Formulation examples 1‘ Granulate a) b) (5) active ient 5 % 10 % kaolin 94 % - highly dispersed silicic acid 1 % - attapulgite — 90 % The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent subsequently concentrated by evaporation under . Granulates of this kind can be mixed with the animal feed.

W0 20121107533 (ii) active ingredient 3 % polyethylene glycol (mw 200) 3 “/0 kaolin 94 % (mw = molecular weight) The finely ground active ingredient is evenly applied in a mixer to the kaolin which has been moistened with polyethylene glycol. In this way, dust—free coated granules are obtained. 2. Tablets or boli l active ingredient 33.00 % methylcellulose 0.80 % silicic acid, highly dispersed 0‘80 % corn starch 8.40 % ll lactose, cryst. 22.50 % corn starch 17.00 % mlcrocryst. cellulose 16.50 % magnesium stearate 1.00 % l Methyl ose is stirred into water. After the material has swollen, silicic acid is stirred in and the mixture homogeneously suspended. The active ingredient and the corn starch are mixed. The aqueous suspension is worked into this mixture and kneaded to a dough The resulting mass is granulated h a 12 M sieve and dried. ll All 4 excipients are mixed thoroughiy. ill The preliminary mixes obtained according to l and ll are mixed and pressed into s or boli. 3. lnjectables A. Oily vehicle (slow e) (i) active ingredient 0 g groundnut oil ad 100 ml (ii) active ingredient 0.1—1.0 g sesame oil ad 100 ml Preparation: The active ingredient is dissolved in part of the oil whilst stirring and, if ed, with gentle heating, then after cooling made up to the desired volume and sterile-filtered through a suitable membrane fitter with a pore size of 0.22 pm.

W0 2012f107533 B Water-miscible solvent (average rate of release) (i) active ingredient 0.1-1.0 g 4—hydroxymethyI-1,S-dioxolane (glycerol formal) 40 g 1,2-propanediol ad 100 ml (ii) active ingredient 0 9 glycerol yl ketal 40 g 1,2—propanediol ad 100 ml Preparation: The active ingredient is dissolved in part of the solvent whilst stirring, made up to the desired volume and sterile—filtered through a le membrane filter with a pore size of 0.22 pm.

C. Aqueous solubilisate (rapid release) (i) active ingredient 0,1—i,0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g opanediol 20 g benzyl alcohol 1 g aqua ad inject, ad 100 ml (ii) active ingredient 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ne oxide units) 8 g 4—hydroxymethyl—1,3—dioxolane (glycerol formal) 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml Preparation: The active ingredient is dissolved in the solvents and the tant, and made up with water to the desired volume. Sterile filtration through an appropriate membrane filter of 0.22 pm pore size. 4. Pour on (i) active ingredient 5 g isopropyl myristate 10 g isopropanol ad 100 ml (ii) active ingredient 2 g hexyl laurate 5 g medium—chained triglyceride 15 9 ethanol ad 100 ml W0 20] 21’107533 (iii) active ingredient 2 g oleyl oleate 5 g N-methyl-pyrrolidone 40 g isopropanol ad 100 ml . Spot on (i) active ingredient 0-15 9 diethyleneglycol monoethylether ad 100 ml (ii) active ingredient 10-15 g octyl palmitate 10 g isopropanol ad 100 ml (iii) active ingredient 10-15 g panoi 20 g benzyl alcohol ad 100 ml 6. Spray on (i) active ingredient 1 g isopropanol 40 g propylene carbonate ad 100 ml (ii) active ingredient 1 g propylene glycol 10 g isopropanol ad 100 ml The aqueous systems may also ably be used for oral and/or intraruminal application.

The compositions may aiso contain further additives, such as isers, eg. where appropriate epoxidised vegetable oiis (epoxidised coconut oil, rapeseed oil, or soybean oil); ams, e.g. silicone oil, preservatives. viscosity tors, binders, tackifiers, as well as fertilisers or other active ingredients to achieve speciai effects.

Further biologically active substances or additives, which are neutral towards the compounds of formula (l) and do not have a harmful effect on the host animal to be treated, as well as mineral salts or vitamins, may also be added to the described compositions.

The following examples serve to illustrate the invention. The letter 'h’ stands for hour. The starting materials are known and partially commercially available or may be produced in y to methods known per se.

W0 20] 2n 07533 i Analysis of the purified samples is in each case done using a Waters Autopurification (HPLCIMS) system with a reversed phase column gel SP~120—ODS-AP Sum, 150X3mm) from Bischoff, Leonberg, Germany. The samples are characterized by mfz and retention time. The above—given retention times relate in each case to the use of a solvent system sing two different soivents, solvent A: H20 + 0.01% HCOOH, and solvent 8: CchN + 0.01% HCOOH). Said two soivents A and B are ed at a flow rate of 2.00 mli’min with a time—dependent gradient as given in the Table: Method A: column Daisogel -ODS—AP 5pm, 150X3mm) from Bischoff, Leonberg, Germany, flow rate of 2.00 mL/min with a time-dependent gradient as given in the Table: —E_40 Method 8: column Waters XTerra MS {:18 5pm, 5OX4.6mm (Waters), flow rate of 3.00 mLfmin with a time—dependent gradient as given in the Table: -IA% 5% Example 1 This example illustrates the ation of N-(2-((cyanomethyl)amino)oxoethyl)—5-(5-(3,5- diohlorophenyl)—5-(trifluoromethyl)—4s5-dihydroisoxazol-B-yi)—2—methyithiophene-3~carbox- amide. (Compound 1.32 in Table 1) §_t_e_p_/}t_:_ DIPEA (80 mL) and amino acetonitrile hydrochloride (11.6 g) are added to a solution of N-(tert-butoxycarbonyl)giycine (20.0 g) and TBTU (40.3 g) in dichloromethane (350 mL) at 0°C. After 18 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaH003 and a saturated aqueous solution of NaCI, dried over MgSOu and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (ethyl acetate/heptane, 3:2 than 2:1) to yield tart-butyl (2-((cyanomethyi)amino) oxoethyi)carbamate (22.2 g). §j§p_B_:_ Methanesuifonic acid (2.9 mL) is added dropwise to a solution of tart-butyi (2- ((cyanomethyi)amino)~2-oxoethyl)carbamate (8.73 g) in romethane (360 mL) and THF (90 mL). After 4 hours at room temperature, the reaction e is concentrated in vacuo.

The crude solid is suspended in diethyi ether and filtered to yield 2-amino—N— (cyanomethyl)acetamide methanesulfonate salt (7.9 g) as a white solid. §_t_e_p__(_3_:_ e (9.7 mL) is added dropwise to a solution of 1—(5-methylthiophen—2- yl)ethanone (26.8 g) and sodium acetate (17.2 g) in water (100 mL). After 18 hours at room temperature, the reaction e is quenched with sodium thiosulfate (1M) and extracted three times with ethyl acetate. The combined organic phases are washed with a saturated s solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield i-(4—bromo- —methylthiophen—Z—yl)ethanone (41.3 g) as a brownish oil. The crude product is used without further purification.

Step D: LiH (3.20 g) is added to a solution of dichloro-Z,2,2-trifluoroacetophenone (56.0 g) and romo-5—methyithiophen—Z-yi)ethanone (41.0 g) in THF (500 mL). After hours at 60°C MTBE is added (500 mL) and the reaction mixture is slowly poured onto water (500 mL) at 0°C. The phases are separated and aqueous phase is extracted twice with MTBE. The combined organic phases are washed with a ted aqueous solution of NaCl. dried over M9804 and concentrated in vacuo to yield 110 g of 1-(4Fbromo-5— methyithiophen-Z—yi)(3,5-dichlorophenyl)~4,4,4-trifluorohydroxybutan-1—one. The crude product is used without further purification.

MTrifluoroacetic anhydride (38.0 mL) is added dropwise to a solution of 1—(4-bromo—5- thiophen-2—yl)(3,5—dichlorophenyi)—4,4,4-trifiuorohydroxybutan—1—one (87.0 g) and triethylamine (53.0 mL) in dichioromethane (1000 mL) at 0°C. After 18 hours at room temperature, the reaction is diluted with a saturated aqueous soiution of NaHCOa and extracted three times with dichloromethane. The combined organic phases are washed with water, dried over M9804 and concentrated in vacuo to yieid (E/Z)-i-(4-bromo methylthiophen-Z—y|)~3—(3,5—dichlorophenyl)~4,4,4-tritluorobuten—1~one (95.0 g) as a brown oil. The crude product is used without further purification.

MNaOH (18.0 g) and hydroxylamine hydrochloride (13.0 g) are added to a solution of (E/Z)- 1—(4—bromo—5-methylthiophen-2—yl)-3—(3,5-dichlorophenyl)-4,4,4—trifluorobut—Z—en-1 -one (84.0 g) in ethanoi (1000 mL). After18 hours at room temperature the reaction mixture is trated in vacuo and diethyi ether and water are added. The phases are separated and the aqueous phase is extracted twice with l ether. The combined organic phases are washed with a saturated aqueous solution of NaCl, dried over M9804 and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (dichloromethanel heptane, 1:9, 1:4) to yield 3—(4—bromo-S-methylthi0phen—2—yl)—5v(3,5- dichiorcphenyl)(trifluoromethyi)~4,Sdihydroisoxazole (47.0 g) as a beige solid. Mp. : 110- 112°C. mg; Zinc cyanide (1.2 g) is added to Pd(PPh3)4 (1.2 g) and 3~(4~bromo methylthiophen~2—yi)~5-(3,5~dichlorcphenyl)(trifluoromethyl)—4,5~dihydroisoxazole (4.5 g) in DMF (12 mL). The on mixture is heated at 120°C in a seated tube in a microwave oven for 1 hour and then allowed to cool to room ature. Water and ethyl acetate are added and the sion is filtered through a pad of . The phases are separated and the aqueous layer is extracted twice with ethyl e. The combined organic phases are washed with a saturated aqueous soiution of NaCl, dried over M9804 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(5-(3,5~ dichiorophenyl)u5-(trifluoromethyl)-4,5~dihydroisoxazol-B-yi)methylthiophene—3—carbonitrile (2.2 g) as a beige solid.

MKOH 8 M (4.1 mL) is added to a solution of 5-(5-(3,5-dichlorophenyl)~5- uoromethyi)—4,5-dihydroisoxazol~3—yl)—2—methylthiophene-3~carbonitrite (2.2 g) in ethylene glycol (14 mL). The reaction mixture is heated at 100°C in a sealed tube in a microwave oven for 1 hour. After cooling to room temperature the mixture is diluted with water and HCl 2 M (20 mL) is added carefully- The mixture is extracted three times with ethyl acetate. The combined organic phases are washed with a ted aqueous solution of NaCl, dried over MQSO4 and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (ethyl acetate) and then crystallized with diisopropyl ether to yield 5-{5-(3,5a dichIorophenyt)—5~(trifluoromethyl)—4,5-dihydroisoxazol—3—yl)—2—methylthiophene—B-carboxylic acid (1.7 g) as a beige solid. §t§p_l: Thionyl chloride (0.1 mL) is added to a solution of 5-(5—(3,5-dichlorophenyl) (trifluoromethyi)—4,5-dihydroisoxazol—3—yl)—2—methyithiophene-3~carboxylic acid (170 mg) in toluene (1.7 mL). After 30 minutes at , the reaction mixture is cooled down and concentrated in vacuo. The crude product is dissolved in dichloromethane (3 mL) and 2- amino-N-(cyanomethyl)acetamide methanesulfonate salt (100 mg) and DlPEA (N,N— diisopropylethylamine, 0.2 mL) are added. After 18 hours at room temperature, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with water and with a ted aqueous solution of NaCi, dried over M9804 and concentrated in vacuo. The residue is crystallized with ethyl acetate to yield N-(2-((cyanomethyl)amino)oxoethy|)—5-(5- (3,5-dichlorophenyl)—5-(trifluoromethyl)—4,5~dihydroisoxazol—3-yl)-2—methylthi0phene~3- amide (130 mg) as a colorless solid. MS (HPLCIMS): 519 (MW). ion time: 1.81 min. Mp. : 158-161°C.

Example 2 This example illustrates the preparation of 5-(5-(3,5—dichlorophenyl)(trifluoromethyl)~4,5- dihydroisoxazol~3~yl)~2~methyl-N—(Z-oxo-Z-((2,2,2~trifluoroethyl)amino)ethyl)furan carboxamide. (Compound 1.19 in Table 1) mDIPEA (15 ml) is added to a solution of N—(tert-butoxycarbonyi)glycine (5.0 g), PYBOP (benzotriazol-l-yl-oxytripyrrolidinophosphonium uorophosphate, 16.3 g) and 2,2,2~trifluorethylamine (2.47 ml) in dichloromethane (48 ml). After 24 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The ed organic phases are washed with HCi (2M), Nazcoa (1M) and a ted aqueous solution of NaCl, dried over M9804 and concentrated in vacuo.

The crude product is ed by column chromatography (450 g) g with a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield —trifluoro«ethyicarbamoyl)-methyl]- carbamic acid tart-butyi ester (3.89 g).

MTrifluoracetic acid (23.4 ml) is added dropwise to a solution of [(2,2,2-trifluoro- arbamoyi)-methyli-carbamic acid tart—butyl ester (3.89 g) in dichloromethane (75 ml).

After 18 hours at room temperature, the on mixture is concentrated in vacuo. The crude oil is purified by crystallization in diethyiether to yield (2,2,2-trifiuoro-ethylcarbamoyi)- methyl-ammonium trifluoroacetate (4.12 g) as a white solid. _S_1_eg_(_3_; Hydroxylamine (50% in H20, 1.82 mL) is added to a solution of methyl 5-formyi-2— methyifuran-B—carboxylate (5.0 g) in methanol (75 mL). After 3 hours at room temperature, the reaction is concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed with water and with a saturated aqueous solution of NaCl, dried over M9804 and concentrated in vacuo to yield methyl 5—((hydroxyimino)methyi)—2—methyifuran—3- carboxyiate. The crude product is used without further purification. mAsolution of methyl 5-((hydroxyimino)methy|)methyifuran-3—carboxyiate (3.0 g) in dichloromethane (18 mL) is added to a on of 1,3-dichloro(1-trifluoromethyi-vinyl)- benzene (3.95 g), chlorox (4%, 44 mL) and triethyiamine (0.23 mi.) in dichloromethane (70 mL) at 0°C. After 2 hours, the reaction mixture is filtered and water is added. The phases are separated and the aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over M9804 and concentrated in vacuo. The crude product is purified on a semi—preparative HPLC to yield methyl 5-(5-(3,5-dichlorophenyI) (trifluoromethyl)—4,5-dihydroisoxazoi—S-yl)-2—methylfuran-B-carboxylate (3.13 g) as a light yellow solid. MS (HPLC/MS); 422 (MW). Retention time: 2.19 min. siege; LiOH (1.06 g) is added to a solution of methyl 5—(5—(3,5-dichlorophenyl)—5- (trifluoromethyl)4,5—dihydroisoxazol—3~yl)methylfuran-S-carboxylate (3.1 g) in a mixture of THF and water (75 mL. 1:1). After 18 hours at room temperature, water and HG! (2N) are added to the reaction mixture until pH 1—2 is ed. The mixture is then extracted three times with ethyl acetate. The organic phases are combined, washed with water and a saturated s solution of NaCl, dried over M9804 and concentrated in vacuo to yield 5- (5-(3,5-dichIorophenyl)-5—(trifluoromethyl)-4,5—dihydroisoxazol-S-yl)methylfuran carboxylic acid (2.8 g) as a yellow solid. The crude product is used without further purification. giggf; DIPEA (0.12 mL) is added to a solution of (2,2,2-trifluorc—ethylcarbamoyl)—methyl— ammonium trifluoroacetate (100 mg, from Step B above), PYBOP (150 mg), and 5—(5~(3,5— dichlorophenyl)-5—(trifluoromethyl)—4,5-dihydroisoxazolyl)~2—methylfuran—3—carboxylic acid (100 mg) in dichloromethane (2 mL) at 0°C. After 18 hours at room temperature the reaction e is concentrated in vacuo. The crude product is purified on a semi-preparative reversed phase HPLC to yield 5-(5-(3,5-dichIorophenyl)(trifluoromethyl)—4,5- dihydroisoxazol~3-yl)methyl~N-(2-oxo((2,2,2-trifluoroethyi)amino)ethyl)furan amide (63 mg) as a beige solid. MS (HPLC/MS): 546 (MH+). Retention time: 1.84 min. Mp. : 172—174°C.

The substances named in the following Table 1 are ed analogously to the above~ described methods. The compounds are of formula F3C 0\ Table 1: 562 4O4 507 226 oil PCT/EPZOI 21052241 ~38- -<:112\ 214 1.6 Me 534 535 4.13 1.7 Me A 423 -u Im-m -_u_10 —---m ll:-*1:an 501 502 174 148- “I'll I-IEIIII*"CH1.15 Me _ .83 484 1.03 resin 118 Me ML; 504 187 foam 1.17 . 130- . 132 1.18 546 1 72— 1 74 —nm-“ —20-—m _nm-‘-I“-—"CH”C’ W0 2012I107533 PCT/E13201 2/052241 558 1.90 ' 481 198 resm 1.81 158- [\N 500 144 foam -CH2CHZSMe £197 212 134- —-m-—~CH200NHEt—-_--- The substances named in the following Table 2 are prepared analogously to the above- described methods. The compounds are of formula W0 2012!]07533 wherein the meaning of X, R3, R5 and Re are given in Table 2.

Table 2: -IINo Anal EMcalc m/z M. p.

Method {min [°C -0H224HO‘\ :III-552 3.96 _---—-—--- -flm----26 H -—(3HZ—<O 1 87 NH\ 1112:- 2.7 Me H \CHJU‘NAS: IIIII.79 580 196 122- H F 128 I M H E 122 -uMe H -n"5-26 182-- —uMe H _-- -- -nMe H _n--- W22. H2NLMe)CH20H - —42im;—CH9_CHZOCHZCH2NHcoo‘Bu “5 W0 20122107533 Biological Examples: 1. Activity in vitro against Ctenoceghaiides felis (Cat flea).

A mixed adult population of fieas is placed the suitably formatted 96-well plate ng fleas to access and feed on treated blood via an artificial feeding system. Fleas are fed on treated blood for 24 hours, after which the compound effect is recorded. insecticidal activity is determined on the basis of the number of dead fleas red from the g system.

Compound 1.1, 1.2, 1.7, 1.10—1.14, 1.16—1.22, 1.24, 1.25, 1.28, 1.34, 1.37, 2.6—2.9, 2.12, 2.15, 2.18, 2.18 showed more than 80% (ECBO) efficacy at tOppm. 2. Activity in vitro against eghaius sanguineus {Dog tick).

A clean adult tick population is used to seed a suitabiy formatted 96—weil piate containing the test substances to be evaluated for antiparasitic activity. Each compound is tested by serial dilution in order to determine its minimal effective dose (MED). Ticks are left in contact with the test compotmd for 10 minutes and are then incubated at 28°C and 80% relative humidity for 7 days, during which the test compound effect is monitored. idal activity is confirmed if adult ticks are dead. in this test the following examples showed more than 80% (E080) cy at 640ppm: 1.2, 1.11-1.15, 1.17, 1.19~1.22,1.24, 1.25, 1274.30, 1.32.1.35, 1.37, 2.6-2.9. 2.12, 2.14, and 2.16. 3. Activity in vivo against Rhigiceghalus neus nymghs on Mongolian s (Meriones unguiculatus) (egray agglication) On day 0, s are treated with the test compound at a given dose by spray application.

On day +1 (+2), the animals are infested with nymphs of ineus. Ticks are left on the animals untii full repletion. Seven days after infestation nymphs dropped off fully engorged are coilected and counted. Efficacy in killing is expressed as a tick number reduction in comparison with a placebo treated group, using the Abbot's formula. in this test the following examples showed more than 80% (ECBO) efficacy at the dose indicated in Table 3. 4. Activity; in vivo against Ctenocegha/ides felis (cat flea) on Mongolian gerbils (Meriones un tus or oral a lication On day 0, gerbils are treated orally by gavage with the test compound formulated at a given dose. Immediately after treatment, they are infested with a mixed adult population of cat fleas. Evaluation of efficacy is performed 48h infestation by counting the numbers of live fleas recovered from the gerbils. Efficacy is expressed as comparison with a placebo d group using the Abbot’s formuia. in this test the following examples showed more than 80% (E030) efficacy at the dose indicated in Table 4.

Table 4: ——_-—‘- . Activity in vivo against eghaiides felis (cat flea) on Mongolian gerbils (Meriones un uicuiatus 5 re a on On day 0. gerbils are treated with the test compound at a given dose by spray application.

On day +1, the animals are infested with a mixed adult population of cat fleas. Evaluation of efficacy is performed 24h and 48h infestation by counting the numbers of live fleas -43” recovered from the gerbils. Efficacy is expressed as ison with a placebo treated group using the Abbot’s formula. in this test the following examples showed more than 80% (E080) efficacy at the dose indicated in Table 5-.

Table 5: Compound No. Dose mglkg Efficacy in killing %

Claims (12)

What is claimed

1. A compound of formula (R2)n (Ia), wherein n is an integer from 1 to 3; R1 is C1—C3-haloalkyl; each R2 is ndently selected from the group ting of halogen, C1-C5-haloalkyl, C1—Cg—haloalkoxy and cyano; X is S or 0; R3 is H or C1-Cg-alkyl; R5 is H or C1-Cg-alkyl; R5 is C1-Cs—alkyl, Cg-Ca-alkenyl, Cz-Cs- alkynyl, Cg-Cs-cycloalkyl, C4—C7-alkylcycloalkyl or C4-C7-cycloalkylalkyl, which is each unsubstituted or are substituted in the alkyl, alkenyl or alkynyl moiety by halogen, hydroxy, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4—alkylthio, C1-C4-haloalkylthio, cyano, amino, N-mono- or N,N-di-C1-C4-alkylamino, COOH, C1-C4-alkoxycarbonyl, N-C1-C4-alkylcarbonylamino, sulfonamido, N-mono- or N,N, di-C1-C4-alkylsulfonamido, a group -—C(O)NR7R3 or a radical Q’; or R6 is a l Q; or R6 together with R5 is a group =C—NR7R8 or =C—NR7(OR8); R7 is H or alkyl; R3 is H; Cz-C4-alkenyl; Cz—C4—alkynyl; Cg-Ce-cycloalkyl; or C1-Ce-alkyl which is unsubstituted or substituted by halogen, C1-C4-alkoxy, C1-C2-alkylthio, cyano, nitro, amino, N- mono- or N,N—di—C1-C4alkylamino, pyridyl, pyrimidyl thiazolyl, or pyridyl, pyrimidyl or thiazolyl which is each mono— or disubstituted by n, cyano, C1-C2-alkyl or C1—Cg-haloalkyl; and Q and Q’ are each thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, l, pyridazinyl, pyrimidinyl, nyl and nyl, thietanyl, or tetrahydrofuranyl, which are each unsubstituted or substituted by halogen, C1-Cz-alkyl, C1—Cg-haloalkyl, C1—Cg-alkoxy, C1—C2-haloalkoxy, cyano, nitro, or C1-C4-alkoxycarbonyl.

2. A compound of formula (la) according to claim 1, n n is an integer of 2 or 3; R1 is CF3; each R2 is independently halogen; X is S or 0; R3 is H or alkyl; R5 is H; and R5 is C1-C4-alkyl, which is unsubstituted or substituted in the alkyl moiety by halogen, hydroxy, C1- C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-haloalkylthio, cyano, COOH, C1-C4- aikoxycarbonyl, a group —C(O)NR7R8 or a l Q’; or R5 is a radical Q; or R6 together with R5 is a group =C—NR7R3 or =C—NR7(OR8); R7 is H or C1-Cg-alkyl; R8 is Cz-C4-alkenyl, 02 alkynyl, Cg-Cs—cycloalkyl, or alkyl which is unsubstituted or substituted by halogen, cyano or pyridyl; and Q and Q’ are each 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1- or 4- pyrazolyl, 2-, 4- or 5-thiazolyl, 1,2,4-triazol—3— or -4—yl, 1,2,3-triazin—1- or 2-yl, 2- 3- or 4— pyridyl, 4- or 5—pyrimidinyl, thietanyl, or tetrahydrofuranyl, which is each unsubstituted or substituted by halogen, C1-C2-alkyl, C1-Cg-haloalkyl, C1-Cz-alkoxy, C1-Cz—haloalkoxy, cyano, nitro, or C1-C4-alkoxycarbonyl.

3. A compound of formula (la) ing to claim 1, wherein n is an integer of 2 or 3; R1 is CF3; each R2 is independently halogen; X is S or 0; R3 is H or C1-Cg-alkyl; R5 is H; R; is C1- C4-alkyl, which is tituted or are substituted in the alkyl moiety by n, 01—02- alkoxy, C1-Cz-alkylthio, cyano, COOH, C1-C2-alkoxycarbonyl, a group R7R8 or a radical Q’; or R6 is a radical Q; or R6 together with R5 is a group =C—N(C1—Cg—alkyl)2 or =C— NH(OC1—Czalkyl); R7 is H; R8 is 02alkynyl, C3—C4-cycloalkyl or C1-C4-alkyl which is unsubstituted or substituted by halogen or cyano; and Q and Q’ are each 2-thiazolyl, 2- 3- or 4—pyridyl, 4- or 5-pyrimidinyl, 3-thietanyl, or 2- or 3-tetrahydrofuranyl, which is each unsubstituted or tuted by C1-C2-alkyl or Ci-CZ—haloalkyl.

4. A compound according to any one of claims 1 to 3, wherein X is O.

5. A compound according to any one of claims 1 to 4, wherein R3 is .

6. A compound according to claim 1, which is of formula F30 O\N ONHEt ,Ol' N-CHZCONHEt

7. Composition for the control of parasites, comprising as active ingredient at least one compound of the a (la) according to any one of claims 1 to 6, in on to a carrier and/or a dispersant.

8. Use of a compound of formula (Ia) according to any one of claims 1 to 6 in the preparation of a pharmaceutical composition against parasites in and on warm—blooded animals. ~48—

9. A compound according to claim 1, substantially as herein described with reference to any one of the Examples thereof.

10. A compound according to any one of claims 1 to 6, substantially as herein described.

11. A ition according to claim 7, substantially as herein described.

12. Use according to claim 8, substantialiy as herein described.