WO2012049327A2

WO2012049327A2 - Pesticidal mixtures

Info

Publication number: WO2012049327A2
Application number: PCT/EP2011/068103
Authority: WO
Inventors: Peter Maienfisch
Original assignee: Syngenta Participations Ag
Priority date: 2010-10-15
Filing date: 2011-10-17
Publication date: 2012-04-19
Also published as: WO2012049327A3

Abstract

The present invention relates to mixtures of biologically active ingredients for use in methods of therapeutic treatment, in particular for use against parasitic invertebrate pests in or on animals, including mixtures with compounds of formula (I) wherein A, B, C, X, G, R¹, R², R³, R⁴, R⁵, R⁶, m, n, o and p are as defined in the claims.

Description

PESTICIDAL MIXTURES

Invention 1

The present invention relates to mixtures of biologically active ingredients for use in methods of therapeutic treatment, in particular for use against parasitic invertebrate pests in or on animals.

WO2009/077197 discloses that certain isoxazoline compounds have insecticidal activity.

The present invention provides a combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

A¹, A², A³ and A⁴ are independently of one another C-H, C-R⁵, or nitrogen, provided that no more than two of A¹, A², A³ and A⁴ are nitrogen;

G¹ is oxygen or sulfur;

R¹ is Ci-Cealkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-Cealkoxycarbonyl-, aryl-Ci-Cealkyl- or aryl-Ci-Cealkyl- substituted by one to three R⁶, heterocyclyl-Ci-C₆alkyl- or heterocyclyl-Ci-Cealkyl- substituted by one to three R⁶; or R¹ is aryl or aryl substituted by one to three R⁶, or

R¹ is heterocyclyl or heterocyclyl substituted by one to three R⁶;

R² is hydrogen, Ci-C₆alkyl, Ci-Cealkylcarbonyl-, or Ci-Cealkoxycarbonyl-;

R³ is Ci-Cehaloalkyl;

R⁴ is aryl or aryl substituted by one to three R⁷, or heterocyclyl or heterocyclyl substituted by one to three R⁷;

each R⁵ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, or Ci-Cealkoxycarbonyl-;

each R⁶ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, Ci-C₆alkylthio-, Ci-C₆haloalkylthio-, Ci-C₆alkylsulfmyl-, Ci- Cehaloalkylsulfinyl-, Ci-Cealkylsulfonyl-, Ci-Cehaloalkylsulfonyl-, or Ci-Cealkoxycarbonyl- ; and each R⁷ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, or Ci-C₆alkoxycarbonyl-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment.

The compounds of formula I and their manufacturing processes are known from WO2009/077197.The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

Each alkyl moiety either alone or as part of a larger group (such as alkoxy, alkylcarbonyl-, alkoxycarbonyl-) is a straight or branched chain and is, for example, methyl, ethyl, ^-propyl, zso-propyl, w-butyl, sec-butyl, zso-butyl or tert-butyl. The alkyl groups are preferably Ci to C₆ alkyl groups, more preferably C₁-C4 and most preferably C₁-C3 alkyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy) are alkyl groups which are substituted with one or more of the same or different halogen atoms and are, for example, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, or 2,2- difluoroethyl.

In the context of the present specification the term "aryl" refers to a ring system which may be mono-, bi- or tricyclic. Examples of such rings include phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl. A preferred aryl group is phenyl.

The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl. Preferred heteroaryl groups are pyridyl, furanyl and thiadiazolyl, most preferably pyridyl. Examples of bicyclic groups include benzothiophenyl,

benzimidazolyl, benzothiadiazolyl, quinolinyl, cinnolinyl and quinoxalinyl.

The term "heterocyclyl" is defined to include heteroaryl and in addition their unsaturated or partially unsaturated analogues. Preferred values of A¹, A², A³, A⁴, G¹, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are, in any combination, as set out below.

Preferably A¹ is C-H or C-R⁵, more preferably C-H or C-F, most preferably C-H.

Preferably A² is C-H or C-R⁵, most preferably C-H.

Preferably A³ is C-H or C-R⁵, more preferably C-H or C-CH₃, most preferably C-H.

Preferably A⁴ is C-H or C-R⁵, more preferably C-H, C-F or C-CN, even more preferably C-F or C-CN, most preferably C-CN.

In one embodiment A¹, A², A³ and A⁴ are independently of one another C-H, C-R⁵, or nitrogen, provided that only one of A¹, A², A³ or A⁴ is C-R⁵, and the other A¹, A², A³ and A⁴ are C-H or nitrogen.

In one embodiment A¹, A², A³ and A⁴ are independently of one another C-H, C-CN, or nitrogen, provided that only one of A 1 , A2 , A 3 or A 4 is C-CN, and the other A 1 , A2 , A 3 and A⁴ are C-H or nitrogen.

In one embodiment A¹, A², A³ and A⁴ are independently of one another C-H or C- CN, provided that only one of A¹, A², A³ or A⁴ is C-CN, and the other A¹, A², A³ and A⁴ are C-H.

Preferably G¹ is oxygen.

R¹ is preferably Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, aryl-Ci-C₆alkyl- or aryl-Ci-C₆alkyl- substituted by one to three R⁶, aryl or aryl substituted by one to three R⁶, or heterocyclyl or heterocyclyl substituted by one to three R⁶, more preferably Ci-C₆alkyl, Ci-C₆haloalkoxy, aryl or aryl substituted by one to three R , or heteroaryl or heteroaryl substituted by one to three R⁶, most preferably Ci-C₆alkyl, Ci- C₆haloalkoxy, aryl or aryl substituted by one to three R⁶, or pyridyl, furanyl or thiadiazolyl or pyridyl, furanyl or thiadiazolyl substituted by one to three R⁶.

In one group of preferred compounds R¹ is Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-

Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-Cealkoxycarbonyl-, aryl-Ci-Cealkyl- or aryl- Ci-C₆alkyl- substituted by one to three R⁶, heterocyclyl-Ci-C₆alkyl- or heterocyclyl -Ci- C₆alkyl- substituted by one to three R⁶, more preferably Ci-C₆alkyl, Ci-C₆haloalkyl, Ci- C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, aryl-Ci-C₆alkyl- or aryl-Ci-C₆alkyl- substituted by one to three R⁶, most preferably «-butyl, bromomethyl, methoxym ethyl-, 2,2,2-trichloro-ethoxy, or 4-chloro-benzyl-.

In one group of preferred compounds R¹ is aryl or aryl substituted by one to three R⁶, more preferably R¹ is aryl or aryl substituted by one to three R⁶, most preferably R¹ is 2- chloro-4-cyano-phenyl, 2-chloro-4-fluoro-phenyl-, 5-chloro-2-fluoro-phenyl-, 2-chloro-4- nitro-phenyl-, 2-chloro-phenyl-, 4-cyano-phenyl-, 4-cyano-2-methyl-phenyl-, 2,3-difluoro- phenyl-, 2,4-difluoro-phenyl-, 4-fluoro-2-methyl-phenyl-, 2-fluoro-phenyl-, 4-fluoro-phenyl- , 2-fluoro-5-trifluoromethyl-phenyl-, 4-fluoro-3 -trifluoromethyl -phenyl-, 2-methoxy-phenyl-, 2-m ethyl -phenyl-, 4-methyl-phenyl-, 2-methyl-3-nitro-phenyl-, 2-methylthio-phenyl, 4-nitro- phenyl-, phenyl-, 2-trifluoromethoxy-phenyl-, 4-trifluoromethoxy-phenyl-, 2- trifluoromethyl-phenyl-, or 4-trifluoromethyl-phenyl-.

In another group of preferred compounds R¹ is heterocyclyl or heterocyclyl substituted by one to three R⁶, more preferably R¹ is heteroaryl or heteroaryl substituted by one to three R⁶, even more preferably R¹ is pyridyl or pyridyl substituted by one to three R⁶. Further examples of preferred groups for R¹ include furan-2-yl-, and 4-methyl-[l,2,3]thia- diazol-5-yl-.

Preferably R² is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, even more preferably hydrogen or methyl, most preferably hydrogen.

Preferably R³ is chlorodifluoromethyl or trifluoromethyl, most preferably trifluoromethyl.

In one group of preferred compounds R⁴ is aryl or aryl substituted by one to three R⁷, more preferably R⁴ is phenyl or phenyl substituted by one to three R⁷, even more preferably R⁴ is 3,5-dibromo-phenyl, 3,5-dichloro-phenyl, 3,4-dichloro-phenyl, or 3,4,5-trichloro- phenyl, most preferably R⁴ is 3,5-dichloro-phenyl.

In another preferred group of compounds R⁴ is heterocyclyl or heterocyclyl substituted by one to three R⁷, more preferably R⁴ is heteroaryl or heteroaryl substituted by one to three R⁷, most preferably R⁴ is pyridyl or pyridyl substituted by one to three R⁷.

Preferably each R⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, more preferably bromo, chloro, fluoro, cyano, nitro, or methyl, most preferably chloro, fluoro, cyano, or methyl.

Preferably each R⁶ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆halo- alkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-C₆alkylthio-, or Ci-C₆haloalkylthio-, most preferably chloro, fluoro, cyano, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio-, or trifluoromethylthio-.

Preferably each R⁷ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, more preferably bromo, chloro, or fluoro, most preferably chloro. A preferred embodiment are compounds of formula (la) wherein G¹, R¹ and R² are as defined for a compound of formula (I) and R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl, and A¹, A², A³, and A⁴ are C-H; or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (lb) wherein G¹, R¹ and R² are as defined for a compound of formula (I) and R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl, A¹ is C-F, and A², A³, and A⁴ are C-H; or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (Ic) wherein G¹, R¹ and R² are as defined for a compound of formula (I) and R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl, A¹, A², and A³, are C-H, and A⁴ is C-F; or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (Id) wherein G¹, R¹ and R² are as defined for a compound of formula (I) and R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl, A¹, A², and A³, are C-H, and A⁴ is C-CN; or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (Ie) wherein G¹, R¹ and R² are as defined for a compound of formula (I) and R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl, A¹, A², and A⁴, are C-H, and A³ is C-Me; or a salt or N-oxide thereof.

A further embodiment of this invention are compounds of formula (Γ) wherein A¹, A², A³ and A⁴ are independently of one another C-H, C-R⁵, or N;

G¹ is oxygen or sulfur;

R¹ is Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-C₆alkoxycarbonyl, aryl-Ci-C₆alkyl- or aryl-Ci-C₆alkyl- substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci-Cealkoxycarbonyl, heterocyclyl-Ci-Cealkyl- or heterocyclyl-Ci-C₆alkyl- substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci- C₆alkoxycarbonyl; or

R¹ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci- C₆alkoxycarbonyl, or

R¹ is heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, or Ci-Cealkoxycarbonyl;

R² is hydrogen, Ci-C₆alkyl, Ci-C₆alkylcarbonyl, or Ci-C₆alkoxycarbonyl;

R³ is Ci-C₆haloalkyl; R⁴ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci- C₆alkoxycarbonyl, or heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci-C₆alkoxycarbonyl; and

each R⁵ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci- C₆alkoxy, Ci-C₆haloalkoxy, or Ci-Cealkoxycarbonyl; or a salt or N-oxide thereof. The

1 2 3 4 1 1 2 3 4 5

preferences for A , A , A , A , G , R , R , R , R , and R are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

A further embodiment of this invention are compounds of formula (I") wherein A¹,

A², A³ and A⁴ are independently of one another C-H, C-R⁵, or nitrogen, provided that no more than two of A¹, A², A³ and A⁴ are nitrogen;

G¹ is oxygen or sulfur;

R¹ is Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-Cealkoxycarbonyl, aryl-Ci-Cealkyl- or aryl-Ci-Cealkyl- substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci-C₆alkoxycarbonyl, heterocyclyl-Ci-C₆alkyl- or heterocyclyl-Ci-C₆alkyl- substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci- C₆alkoxycarbonyl; or

R² is hydrogen, Ci-C₆alkyl, Ci-C₆alkylcarbonyl, or Ci-C₆alkoxycarbonyl;

R³ is Ci-C₆haloalkyl;

R⁴ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci- C₆alkoxycarbonyl, or heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci-C₆haloalkoxy, or Ci-C₆alkoxycarbonyl; and each R⁵ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci- C₆alkoxy, Ci-C₆haloalkoxy, or Ci-C₆alkoxycarbonyl; or a salt or N-oxide thereof. The

1 2 3 4 1 1 2 3 4 5

preferences forA,A,A,A,G,R,R,R,R, and R are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

Compounds of formula I include at least one chiral centre and may exist as compounds of formula I* or compounds of formula I**.

(I*) (I**)

Generally compounds of formula I** are more biologically active than compounds of formula I*. Component A may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1:99 to 99:1, e.g.10:1 to 1:10, e.g. a substantially 50:50 molar ratio. For example, when component A is an enantiomerically enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, when component A is an enantiomerically enriched mixture of formula I* the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. The compounds in Table 1 to Table 5 below illustrate the compounds of the invention.

Table 1 :

Table 1 provides 25 compounds of formula (la) wherein R¹ has the values listed in the table below.

Table 2:

Table 2 provides 25 compounds of formula (lb) wherein R¹ has the values listed in Table 1.

Table 3 :

Table 3 provides 25 compounds of formula (Ic) wherein R¹ has the values listed in Table 1.

Table 4:

Table 4 provides 25 compounds of formula (Id) wherein R¹ has the values listed in Table 1.

(Id)

Table 5:

Table 5 provides 25 compounds of formula (Ie) wherein R¹ has the values listed in Table 1.

O

Preferably, the combination product is for use against parasitic invertebrate pests, more preferably for use against parasitic invertebrate pests in or on an animal. Examples of pests include nematodes, trematodes, cestodes, flies, mites, tricks, lice, fleas, true bugs and maggots. The animal may be a non-human animal, e.g. an animal associated with agriculture, e.g. a cow, a pig, a sheep, a goat, a horse, or a donkey, or a companion animal, e.g. a dog or a cat.

In a further aspect the invention relates to a method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product. The administration may be for example oral administration, parenteral administration or external administration, e.g. to the surface of the animal body.

In a further aspect, the invention relates to a method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product to the environment in which an animal resides.

In a further aspect the invention provides a method of protecting an animal from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of the combination product of the invention. In a further aspect the invention provides the combination product for use in protecting an animal from a parasitic

invertebrate pest. In a further aspect the invention provides use of the combination product in the manufacture of a medicament for protecting an animal from a parasitic invertebrate pest.

In a further aspect the invention provides a method of treating an animal suffering from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of the combination product of the invention. In a further aspect the invention provides the combination product for use in treating an animal suffering from a parasitic invertebrate pest. In a further aspect the invention provides use of the combination product in the manufacture of a medicament for treating an animal suffering from a parasitic invertebrate pest.

In a further aspect, the invention provides a pharmaceutical composition comprising component A and component B and a pharmaceutically suitable excipient.

Component A may be used in combination with anthelmintic agents. Such anthelmintic agents include, compounds selected from the macrocyclic lactone class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin derivatives as described in EP- 357460, EP -444964 and EP-594291. Additional anthelmintic agents include

semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in US-5015630, WO-9415944 and WO-9522552. Additional anthelmintic agents include the benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of the class. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel. Additional anthelmintic agents include flukicides, such as triclabendazole and clorsulon and the cestocides, such as praziquantel and epsiprantel.

Component A may be used in combination with derivatives and analogues of the paraherquamide/marcfortine class of anthelmintic agents, as well as the antiparasitic oxazolines such as those disclosed in US-5478855, US- 4639771 and DE-19520936.

Component A may be used in combination with derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as described in WO-9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO-9611945, WO- 9319053, WO- 9325543, EP-626375, EP-382173, WO-9419334, EP-382173, and EP- 503538.

Component A may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron;

ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.

Component A may be used in combination with terpene alkaloids, for example those described in International Patent Application Publication Numbers W095/19363 or

WO04/72086, particularly the compounds disclosed therein. Other examples of such biologically active compounds that component A may be used in combination with include but are not restricted to the following:

Organophosphates: acephate, azamethiphos, azinphos-ethyl, azinphos- methyl, bromophos, bromophos-ethyl, cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate, isoxathion, malathion, methacriphos, methamidophos, methidathion, methyl- parathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate, phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate, phoxim, pirimiphos, pirimiphos- methyl, profenofos, propaphos, proetamphos, prothiofos, pyraclofos,

pyridapenthion, quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thimeton, triazophos, trichlorfon, vamidothion.

Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801, isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m- cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, UC-51717.

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E) -

(1 R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta -cyfluthrin, cyfluthrin, a-cypermethrin, beta -cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, ?-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t- fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide, tebufenozide; c) juvenoids: pyriproxyfen, methoprene (including S-methoprene),

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen. Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG- 505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin,

5 dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole,

ethofenprox, fenazaquin, flumite, MTI- 800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196, neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen, NC-1111, R-

10 195,RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601, silafluofen, silomadine,

spinosad, tebufenpyrad, tetradifon, tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301.

Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole, azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeaux mixture,

15 bromuconazole, bupirimate, carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole,

20 famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil,

25 metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo- asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol,

30 tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin.

Biological agents: Bacillus thuringiensis ssp aizawai, kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, virus and fungi.

Bactericides: chlortetracycline, oxytetracycline, streptomycin. Other biological agents: enrofloxacin, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, carprofen,

metaflumizone, praziquarantel, triclabendazole.

Preferably, component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide.

More preferably, component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole,

flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone.

Even more preferably, component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel.

The invention also includes the following combinations:

A compound from Tables 1-5 and imidacloprid.

A compound from Tables 1-5 and enrofloxacin.

A compound from Tables 1-5 and praziquantel.

A compound from Tables 1-5 and pyrantel embonate.

A compound from Tables 1-5 and febantel.

A compound from Tables 1-5 and penethamate.

A compound from Tables 1-5 and moloxicam. A compound from Tables 5 and cefalexin.

A compound from Tables 5 and kanamycin.

A compound from Tables 5 and pimobendan.

A compound from Tables 5 and clenbuterol.

A compound from Tables 5 and fipronil.

A compound from Tables 5 and ivermectin.

A compound from Tables 5 and omeprazole.

A compound from Tables 5 and tiamulin.

A compound from Tables 5 and benazepril.

A compound from Tables 5 and milbemycin.

A compound from Tables 5 and cyromazine.

A compound from Tables 5 and thiamethoxam

A compound from Tables 5 and pyriprole.

A compound from Tables 5 and deltamethrin.

A compound from Tables 5 and cefquinome.

A compound from Tables 5 and florfenicol.

A compound from Tables 5 and buserelin.

A compound from Tables 5 and cefovecin.

A compound from Tables 5 and tulathromycin.

A compound from Tables 5 and ceftiour.

A compound from Tables 5 and selamectin.

A compound from Tables 5 and carprofen.

A compound from Tables 5 and metaflumizone.

A compound from Tables 5 and moxidectin.

A compound from Tables 5 and methoprene (including S-methoprene).

A compound from Tables 5 and clorsulon.

A compound from Tables 5 and pyrantel.

A compound from Tables 5 and amitraz.

A compound from Tables 5 and triclabendazole.

A compound from Tables 5 and avermectin.

A compound from Tables 5 and abamectin.

A compound from Tables 5 and emamectin.

A compound from Tables 5 and eprinomectin.

A compound from Tables 5 and doramectin. A compound from Tables 1-5 and selamectin.

A compound from Tables 1-5 and nemadectin.

A compound from Tables 1-5 and albendazole.

A compound from Tables 1-5 and cambendazole.

A compound from Tables 1-5 and fenbendazole.

A compound from Tables 1-5 and flubendazole.

A compound from Tables 1-5 and mebendazole.

A compound from Tables 1-5 and oxfendazole.

A compound from Tables 1-5 and oxibendazole.

A compound from Tables 1-5 and parbendazole.

A compound from Tables 1-5 and tetramisole.

A compound from Tables 1-5 and levamisole.

A compound from Tables 1-5 and pyrantel pamoate

A compound from Tables 1-5 and oxantel.

A compound from Tables 1-5 and morantel.

A compound from Tables 1-5 and triclabendazole.

A compound from Tables 1-5 and epsiprantel.

A compound from Tables 1-5 and fipronil.

A compound from Tables 1-5 and lufenuron.

A compound from Tables 1-5 and ecdysone.

A compound from Tables 1-5 and tebufenozide.

The active ingredient combinations described above can result in a synergistic effect, e.g. the effect of the active ingredients in combination is greater than what would be expected based on the effect of the active ingredients when applied alone. Synergism may be calculated according to the Colby formula as described below. Thus the invention provides synergistic active ingredient combinations and methods in which the active ingredients are applied in a synergistically effective amount. Synergism between active ingredients can be found when applying the combinations to ectoparasites and/or endoparasites, as described in more detail below.

One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding non salt forms, salts share the biological utility of the non salt forms.

Thus a wide variety of salts of components A and B are useful for control of invertebrate pests and animal parasites. The salts of components A and B include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4- toluenesulfonic or valeric acids. Components A and B also include N-oxides. Accordingly, the invention comprises component A including N-oxides and salts thereof and component B including N-oxides and salts thereof.

Examples of ratios include 100:1 to 1:6000, 50:1 to 1:50, 20:1 to 1:20, even more especially from 10:1 to 1:10, 5:1 to 1:5, 2:1 to 1:2, 4:1 to 2:1, 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are understood to include, on the one hand, ratios by weight and also, on other hand, molar ratios.

The following paragraphs represent embodiments of invention 1

a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur;

R¹ is Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-Cealkoxycarbonyl-, aryl-Ci-Cealkyl- or aryl-Ci-Cealkyl- substituted by one to three R⁶, heterocyclyl-Ci-C₆alkyl- or heterocyclyl-Ci-Cealkyl- substituted by one to three R⁶; or

R¹ is aryl or aryl substituted by one to three R⁶, or

R¹ is heterocyclyl or heterocyclyl substituted by one to three R⁶;

R² is hydrogen, Ci-C₆alkyl, Ci-Cealkylcarbonyl-, or Ci-Cealkoxycarbonyl-;

R³ is Ci-Cehaloalkyl; R⁴ is aryl or aryl substituted by one to three R⁷, or heterocyclyl or heterocyclyl substituted by one to three R⁷;

each R⁵ is independently halogen, cyano, nitro, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci- C₆haloalkoxy, or Ci-Cealkoxycarbonyl-;

each R⁶ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, Ci-C₆alkylthio-, Ci-C₆haloalkylthio-, Ci-C₆alkylsulfinyl-, Ci- Cehaloalkylsulfinyl-, Ci-Cealkylsulfonyl-, Ci-Cehaloalkylsulfonyl-, or Ci-Cealkoxycarbonyl- ; and

each R⁷ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, or Ci-C₆alkoxycarbonyl-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹ is C-H or C-R⁵. c. A combination product according to paragraph a or paragraph b wherein A² is C-H or C-R⁵. d. A combination product according to any one of paragraphs a to c wherein A³ is C-H or C-R⁵. e. A combination product according to any one of paragraphs a to d wherein A⁴ is C-H or C-R⁵. f. A combination product according to any one of paragraphs a to e wherein G¹ is oxygen. g. A combination product according to any one of paragraphs a to f wherein R¹ is preferably Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci- C₆haloalkoxy, aryl-Ci-Cealkyl- or aryl-Ci-Cealkyl- substituted by one to three R⁶, aryl or aryl substituted by one to three R⁶, or heterocyclyl or heterocyclyl substituted by one to three R⁶. h. A combination product according to any one of paragraphs a to g wherein R² is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. i. A combination product according to any one of paragraphs a to h wherein R³ is chlorodifluoromethyl or trifluoromethyl. k. A combination product according to any one of paragraphs a to i wherein R⁴ is aryl or aryl substituted by one to three R⁷.

1. A combination product according to any one of paragraphs a to k wherein each R⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxy carbonyl. m. A combination product according to any one of paragraphs a to 1, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin,

eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole,

fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. n. A combination product according to any one of paragraphs a to m, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. o. A combination product according to any one of paragraphs a to n, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. p. A combination product according to any one of paragraphs a to o, wherein the combination product is for use against parasitic invertebrate pests. q. A combination product according to any one of paragraphs a to p, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. r. A combination product according to paragraph q, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. s. A combination product according to paragraph q or r, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. t. A method comprising administering the combination product as defined in any one of paragraphs a to o to an animal. u. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to o to the animal. v. A method according to paragraph u, wherein said administration is oral

administration, parenteral administration or external administration. w. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragraphs a to o to the environment in which an animal resides. x. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to o and a pharmaceutically suitable excipient.

Invention 2 The present invention relates to mixtures of biologically active ingredients for use in methods of therapeutic treatment, in particular for use against parasitic invertebrate pests in or on animals.

WO2009/049846 discloses that certain isoxazoline compounds have insecticidal activity.

The present invention provides a combination product comprising a component A and a component B, wherein component A is a compound of formula I

N

H

wherein

A¹, A², A³ and A⁴ are independently of one another C-H, C-R⁵, or nitrogen;

R¹ is -(D)_m-(E)_n-(D)_p-R⁶;

each D is independently Ci-C₆alkylene;

E is -0-, -(CO)- or -(CO) H-;

m, n and p are independently 0 or 1, provided that where n is 0, p is not 1 and than where n is 1, m is not 0;

R² is hydrogen, Ci-C₈alkyl, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

each R⁵ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci- C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-; and

R⁶ is hydrogen, or

R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, or R⁶ is C₂-C₈alkenyl or C₂-C₈alkenyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or R⁶ is C₂-C₈alkynyl or C₂-C₈alkynyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or

R⁶ is C₃-C₈cycloalkyl, or C₃-C₈halocycloalkyl, or

R⁶ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or

R⁶ is heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci- C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

The compounds of formula I and their manufacturing processes are known from WO2009/049846.

The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

Alkenyl and alkynyl moieties (either alone or as part of a larger group) can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl, allyl and propargyl. The alkenyl and alkynyl groups are preferably C₂ to C₆ alkenyl or alkynyl groups, more preferably C₂-C₄ and most preferably C₂-C₃ alkenyl or alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy) are alkyl groups which are substituted with one or more of the same or different halogen atoms and are, for example, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl or 2,2- difluoroethyl.

Cycloalkyl groups can be in mono- or bi-cyclic form and may optionally be substituted with one or more methyl groups. The cycloalkyl groups preferably contain 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, 1-methyl-cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halocycloalkyl groups are cycloalkyl groups which are substituted with one or more of the same of different halogen atoms and may optionally be substituted with one or more methyl groups. Examples of monocyclic halocycloalkyl groups are 2,2-dichloro-cyclopropyl, 2,2-dichloro- 1-methyl-cyclopropyl and 2-chloro-4-fluorocyclohexyl.

The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of such groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl. A preferred heteroaryl group is pyridine. Examples of bicyclic groups are benzothiophenyl, benzimidazolyl, benzothiadiazolyl, quinolinyl, cinnolinyl and quinoxalinyl.

The term "heterocyclyl" is defined to include heteroaryl and in addition their unsaturated or partially unsaturated analogues such as

6-chloro-4H-benzo[l,3]dioxin-8- l

3 ,4-dihydro-2H-benzo[b] [ 1 ,4]dioxepin-7-yl

2,3 -dihydrobenzo[ 1 ,4]dioxin-2- l

tetrahydropyran-2-yl

2,5,5-trimethyl-[l,3]dioxan-2-yl

Preferred values of A¹, A², A³, A⁴, D, E, m, n, p, R¹, R², R³, R⁴, R⁵ and R⁶ are, in any combination, as set out below.

Preferably no more than three of A¹, A², A³ and A⁴ are nitrogen.

Preferably A¹ is C-H or C-R⁵, most preferably A¹ is C-R⁵.

Preferably A² is C-H or C-R⁵, most preferably A² is C-H.

Preferably A³ is C-H or C-R⁵, most preferably A³ is C-H.

Preferably A⁴ is C-H or C-R⁵, most preferably A⁴ is C-H.

Preferably R¹ is R⁶-, R⁶-Ci-C₆alkyl-, R⁶-oxy-Ci-C₆alkyl-, R⁶-carbonyl-Ci-C₆alkyl-, R⁶-aminocarbonyl-Ci-C₆alkyl- or R⁶-Ci-C₈alkoxy-Ci-C₆alkyl-.

In one group of preferred compounds R¹ is R⁶-, more preferably R¹ is allyl-, «-butyl-, but-2-yn-l-yl-, 6-chloro-«-hexyl-, 3-cyano-«-propyl-, (E)-3-(ethoxycarbonyl)-prop-2-en-l- yl-, ethyl-, hydrogen, methyl-, 2-methyl-prop-2-en-l-yl-, propargyl-, or «-propyl-, most preferably R¹ is allyl-, «-butyl-, but-2-yn-l-yl-, 6-chloro-«-hexyl-, 3-cyano-«-propyl-, ethyl-, hydrogen, methyl-, 2-methyl-prop-2-en-l-yl-, propargyl-, or «-propyl-.

In another group of preferred compounds R¹ is R⁶-Ci-Cealkyl-, more preferably R¹ is (6-chloro-4H-benzo[l,3]dioxin-8-yl)-methyl-, (6-chloro-pyrid-3-yl)-methyl-, (2-chloro-4- trifluoromethyl-thiazol-5-yl)-methyl-, cyclohexyl-methyl-, 3,5-dichloro-benzyl-, (5,6- dichloro-pyrid-3-yl)-methyl-, 2,6-difluoro-benzyl-, (3,4-dihydro-2H-benzo[b][l,4]dioxepin- 7-yl)-m ethyl-, (2,3-dihydrobenzo[l,4]dioxin-2-yl)-methyl-, 2,4-dimethyl-benzyl-, (3,5- dimethyl-isoxazol-4-yl)-methyl-, (2,5-dimethyl-2H-pyrazol-3-yl)-methyl-, (5-ethoxy- carbonyl-furan-2-yl)-methyl-, 3-methoxy-benzyl-, 3 -phenyl -w-propyl-, (tetrahydropyran-2- yl)-methyl-, or 2-(2,5,5-trimethyl-[l,3]dioxan-2-yl)-eth-l-yl-, most preferably R¹ is (6- chloro-pyrid-3-yl)-methyl-, 3,5-dichloro-benzyl-, (5,6-dichloro-pyrid-3-yl)-methyl-, 2,6- difluoro-benzyl-, (3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-methyl-, (2,3- dihydrobenzo[l,4]dioxin-2-yl)-methyl-, 2,4-dimethyl-benzyl-, (3,5-dimethyl-isoxazol-4-yl)- methyl-, (2,5-dimethyl-2H-pyrazol-3-yl)-methyl-, 3-methoxy-benzyl-, 3-phenyl-«-propyl-, or 2-(2,5,5-trimethyl-[l,3]dioxan-2-yl)-eth-l-yl-. In a further group of preferred compounds R¹ is R⁶-oxy-Ci-C₆alkyl-, more preferably R¹ is 2-phenoxy-eth-l-yl-.

In another group of preferred compounds R¹ is R⁶-carbonyl-Ci-Cealkyl-, more preferably R¹ is (4-methoxy-benzoyl)-methyl-, or 1 -methylcarbonyl-eth-l-yl-, most preferably R¹ is 1-methylcarbonyl-eth-l-yl-.

In a further group of preferred compounds R¹ is R⁶-aminocarbonyl-Ci-C₆alkyl-, more preferably R¹ is l-(N-phenylaminocarbonyl)-eth-l-yl-.

In another group of preferred compounds R¹ is R⁶-Ci-C₆alkoxy-Ci-C₆alkyl-, more preferably R¹ is 2-benzyloxy-eth-l-yl-.

Preferably each D is independently -CH₂-, -CH₂-CH₂-, -CH(Me)-, or -CH₂-CH₂-CH₂-

, more preferably each D is independently -CH₂-, -CH₂-CH₂-, or -CH(Me)-, most preferably each D is -CH₂-.

Preferably E is -O- or -(CO)-, most preferably E is -0-.

Preferably R² is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-, more preferably R² is hydrogen, methyl or ethyl, even more preferably R² is hydrogen or methyl, most preferably R² is hydrogen.

Preferably R³ is chlorodifluoromethyl or trifluoromethyl, most preferably R³ is trifluoromethyl.

In one group of preferred compounds R⁴ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁴ is phenyl or phenyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, even more preferably R⁴ is phenyl substituted by one to three substituents independently selected from bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, yet more preferably R⁴ is phenyl substituted by one to three substituents independently selected from bromo, chloro, or fluoro, even more preferred values for R⁴ are 3,5-dibromo-phenyl, 3,5-dichloro-phenyl, 3,4- dichloro-phenyl, and 3,4,5-trichloro-phenyl, most preferably R⁴ is 3,5-dichloro-phenyl.

In another preferred group of compounds R⁴ is heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁴ is heteroaryl or heteroaryl substituted by one to three substituents

independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, even more preferably R⁴ is pyridyl or pyridyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, yet even more preferably R⁴ is pyridyl substituted by one to three substituents independently selected from bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, most preferably R⁴ is pyridyl substituted by one to three substituents independently selected from bromo, chloro, or fluoro.

Preferably each R⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, more preferably each R⁵ is independently bromo, chloro, fluoro, nitro, or methyl, most preferably each R⁵ is independently chloro, fluoro, or methyl.

In one group of preferred compounds R⁶ is hydrogen.

In another group of preferred compounds R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, or Ci-C₈haloalkoxy, even more preferably R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three substituents independently selected from halogen, or cyano, yet even more preferably R⁶ is Ci-C₈alkyl, most preferably R⁶ is methyl-, ethyl-, ^-propyl-, n- butyl-, or «-hexyl-. Further examples of preferred groups for R⁶ include 3-cyano-«-propyl- and 6-chloro-ft-hexyl-.

In a further group of preferred compounds R⁶ is C₂-C₈alkenyl or C₂-C₈alkenyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁶ is C₂- C₈alkenyl or C₂-C₈alkenyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, or Ci-C₈haloalkoxy, even more preferably R⁶ is C₂- C₈alkenyl, most preferably R⁶ is allyl- or 2-methyl-prop-2-en-l-yl-.

In another group of preferred compounds R⁶ is C₂-C₈alkynyl or C₂-C₈alkynyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁶ is C₂- C₈alkynyl or C₂-C₈alkynyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, or Ci-C₈haloalkoxy, even more preferably R⁶ is C₂- C₈alkynyl, most preferably R⁶ is propargyl- or but-2-yn-l-yl-. In a further group of preferred compounds R⁶ is C₃-C₈cycloalkyl or C₃-C₈halocyclo- alkyl, more preferably R⁶ is C₃-C₈cycloalkyl, most preferably R⁶ is cyclohexyl.

In another group of preferred compounds R⁶ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁶ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, or Ci-C₈haloalkoxy, even more preferably R⁶ is aryl or aryl substituted by one to three substituents independently selected from halogen, Ci- C₈alkyl, or Ci-C₈alkoxy, most preferably R⁶ is 3,5-dichloro-phenyl-, 2,6-difluoro-phenyl-, 2,4-dimethyl-phenyl-, 3-methoxy-phenyl-, 4-methoxy-phenyl-, or phenyl-.

In a further group of preferred compounds R⁶ is heterocyclyl or heterocyclyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, more preferably R⁶ is heteroaryl or heteroaryl substituted by one to three substituents

independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, even more preferably R⁶ is pyridyl or pyridyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, most preferably R⁶ is 6-chloro-pyrid-3-yl -, or 5,6-dichloro-pyrid-3-yl -. Further examples of preferred groups for R⁶ include 6-chloro-4H-benzo[l,3]dioxin-8-yl-, 2-chloro-4- trifluoromethyl-thiazol-5-yl -, 3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl -, 2,3- dihydrobenzo[l,4]dioxin-2-yl -, 3,5-dimethyl-isoxazol-4-yl -, 2,5-dimethyl-2H-pyrazol-3-yl - , 5-ethoxycarbonyl-furan-2-yl -, tetrahydropyran-2-yl -, and 2,5,5-trimethyl-[l,3]dioxan-2-yl A preferred embodiment are compounds of formula (la) wherein R¹ and R² are as defined for a compound of formula (I), A¹, A², A³, and A⁴ are C-H, R³ is trifluoromethyl, and R⁴ is 3,5-dichloro-phenyl.

A preferred embodiment are compounds of formula (lb) wherein R¹ and R² are as defined for a compound of formula (I), A¹ is C-Me, A², A³, and A⁴ are C-H, R³ is trifluoro- methyl, and R⁴ is 3,5-dichloro-phenyl.

A preferred embodiment are compounds of formula (Ic) wherein R¹ and R² are as defined for a compound of formula (I), A¹ is C-Cl, A², A³, and A⁴ are C-H, R³ is trifluoromethyl, and R⁴ is 3,5-dichloro-phenyl. Compounds of formula I include at least one chiral centre and may exist as compounds of formula I* or I** respectively.

Generally compounds of formula I** are more biologically active than compounds of formula I*. Component A may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10: 1 to 1 : 10, e.g. a substantially 50:50 molar ratio. For example, when component A is an enantiomerically enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, when component A is an enantiomerically enriched mixture of formula I*, the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.

The compounds in Tables 1 to 3 below illustrate the compounds of component A.

Table 1 :

Table 1 provides 34 compounds of formula (la) wherein R² is hydrogen, and R¹ has the values listed in the table below.

Compound numbers R

1.01 allyl- Compound numbers R

1.02 2-benzyloxy-eth-l-yl-

1.03 «-butyl-

1.04 but-2-yn-l-yl-

1.05 (6-chloro-4H-benzo[l,3]-dioxin-8-yl)-methyl

1.06 6-chl oro-ft-hexy 1 -

1.07 (6-chloro-pyrid-3-yl)-methyl-

1.08 (2-chloro-4-trifluoromethyl-thiazol-5-yl)-methyl-

1.09 3-cyano-«-propyl-

1.10 cyclohexyl-methyl-

1.11 3 , 5 -di chl oro-b enzy 1 -

1.12 (5,6-dichloro-pyrid-3-yl)-methyl-

1.13 2,6-difluoro-benzyl-

1.14 (3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)- methyl-

1.15 (2,3-dihydrobenzo[l,4]dioxin-2-yl)-methyl-

1.16 2,4-dimethyl-benzyl-

1.17 (3 , 5 -dimethyl-i soxazol -4-yl)-m ethyl -

1.18 (2,5-dimethyl-2H-pyrazol-3-yl)-methyl-

1.19 (5-ethoxycarbonyl-furan-2-yl)-methyl-

1.20 (E)-3 -(ethoxycarbonyl)-prop-2-en- 1 -yl-

1.21 ethyl-

1.22 hydrogen

1.23 (4-methoxy-benzoyl)-methyl-

1.24 3-methoxy-benzyl-

1.25 methyl-

1.26 1 -methylcarbonyl-eth- 1 -yl-

1.27 2-m ethyl -prop-2-en- 1 -yl-

1.28 2-phenoxy-eth-l-yl-

1.29 1 -(N-phenylaminocarbonyl)-eth- 1 -yl-

1.30 3 -phenyl -«-propy 1 -

1.31 propargyl-

1.32 «-propyl-

1.33 (tetrahydropyran-2-yl)-methyl-

1.34 2-(2,5,5-trimethyl-[l,3]dioxan-2-yl)-eth-l-yl-

Table 2:

Table 2 provides 34 compounds of formula (lb) wherein R² is hydrogen, and R¹ has the values listed in Table 1.

Table 3 :

Table 3 provides 34 compounds of formula (Ic) wherein R² is hydrogen, and R¹ has the values listed in Table 1.

invertebrate pest. In a further aspect the invention provides use of the combination product in the manufacture of a medicament for protecting an animal from a parasitic invertebrate pest. In a further aspect the invention provides a method of treating an animal suffering from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of the combination product of the invention. In a further aspect the invention provides the combination product for use in treating an animal suffering from a parasitic invertebrate pest. In a further aspect the invention provides use of the combination product in the manufacture of a medicament for treating an animal suffering from a parasitic invertebrate pest.

ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like. Component A may be used in combination with terpene alkaloids, for example those described in International Patent Application Publication Numbers W095/19363 or

WO04/72086, particularly the compounds disclosed therein.

Other examples of such biologically active compounds that component A may be used in combination with include but are not restricted to the following:

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E) - (1 R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta -cyfluthrin, cyfluthrin, a-cypermethrin, beta -cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, ?-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t- fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapaciyl, bromopropylate, BTG-504, BTG- 505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin,

dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, MTI- 800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196, neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen, NC-1111, R- 195,RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601, silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon, tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301.

bromuconazole, bupirimate, carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutnafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo- asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin. Biological agents: Bacillus thuringiensis ssp aizawai, kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, virus and fungi.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

Other biological agents: enrofloxacin, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, carprofen,

metaflumizone, praziquarantel, triclabendazole.

The invention also includes the following combinations:

A compound from Tables 1-3 and imidacloprid.

a compound from Tables 1-3 and enrofloxacin.

A compound from Tables 1-3 and praziquantel.

A compound from Tables 1-3 and pyrantel embonate. A compound from Tables 3 and febantel.

A compound from Tables 3 and penethamate.

A compound from Tables 3 and moloxicam.

A compound from Tables 3 and cefalexin.

A compound from Tables 3 and kanamycin.

A compound from Tables 3 and pimobendan.

A compound from Tables 3 and clenbuterol.

A compound from Tables 3 and fipronil.

A compound from Tables 3 and ivermectin.

A compound from Tables 3 and omeprazole.

A compound from Tables 3 and tiamulin.

A compound from Tables 3 and benazepril.

A compound from Tables 3 and milbemycin.

A compound from Tables 3 and cyromazine.

A compound from Tables 3 and thiamethoxam.

A compound from Tables 3 and pyriprole.

A compound from Tables 3 and deltamethrin.

A compound from Tables 3 and cefquinome.

A compound from Tables 3 and florfenicol.

A compound from Tables 3 and buserelin.

A compound from Tables 3 and cefovecin.

A compound from Tables 3 and tulathromycin.

A compound from Tables 3 and ceftiour.

A compound from Tables 3 and selamectin.

A compound from Tables 3 and carprofen.

A compound from Tables 3 and metaflumizone.

A compound from Tables 3 and moxidectin.

A compound from Tables 3 and methoprene (including S-methoprene).

A compound from Tables 3 and clorsulon.

A compound from Tables 3 and pyrantel.

A compound from Tables 3 and amitraz.

A compound from Tables 3 and triclabendazole.

A compound from Tables 3 and avermectin.

A compound from Tables 3 and abamectin. A compound from Tables 1-3 and emamectin.

A compound from Tables 1-3 and eprinomectin.

A compound from Tables 1-3 and doramectin.

A compound from Tables 1-3 and selamectin.

A compound from Tables 1-3 and nemadectin.

A compound from Tables 1-3 and albendazole.

A compound from Tables 1-3 and cambendazole.

A compound from Tables 1-3 and fenbendazole.

A compound from Tables 1-3 and flubendazole.

A compound from Tables 1-3 and mebendazole.

A compound from Tables 1-3 and oxfendazole.

A compound from Tables 1-3 and oxibendazole.

A compound from Tables 1-3 and parbendazole.

A compound from Tables 1-3 and tetramisole.

A compound from Tables 1-3 and levamisole.

A compound from Tables 1-3 and pyrantel pamoate

A compound from Tables 1-3 and oxantel.

A compound from Tables 1-3 and morantel.

A compound from Tables 1-3 and triclabendazole.

A compound from Tables 1-3 and epsiprantel.

A compound from Tables 1-3 and fipronil.

A compound from Tables 1-3 and lufenuron.

A compound from Tables 1-3 and ecdysone.

A compound from Tables 1-3 and tebufenozide.

The active ingredient combinations described above can result in a synergistic effect, e.g. the effect of the active ingredients in combination is greater than what would be expected based on the effect of the active ingredients when applied alone. Synergism may be calculated according to the Colby formula as described below. Thus the invention provides synergistic active ingredient combinations and methods in which the active ingredients are applied in a synergistically effective amount. Synergism between active ingredients can be found when applying the combinations to ectoparasites and/or endoparasites, as described in more detail below. One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding non salt forms, salts share the biological utility of the non salt forms.

Thus a wide variety of salts of components A and B are useful for control of invertebrate pests and animal parasites. The salts of components A and B include acid- addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. Components A and B also include N- oxides. Accordingly, the invention comprises component A including N-oxides and salts thereof and component B including N-oxides and salts thereof.

The following paragraphs represent embodiments of invention 2 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

R¹ is -(D)_m-(E)_n-(D)_p-R⁶;

each D is independently Ci-Cealkylene;

E is -0-, -(CO)- or -(CO)NH-; m, n and p are independently 0 or 1, provided that where n is 0, p is not 1 and than where n is 1, m is not 0;

R³ is Ci-Cshaloalkyl;

R⁶ is hydrogen, or

R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-, or R⁶ is C₂-C₈alkenyl or C₂-C₈alkenyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or

R⁶ is C₂-C₈alkynyl or C₂-C₈alkynyl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci- C₈alkoxycarbonyl-, or

R⁶ is C₃-C₈cycloalkyl, or C₃-C₈halocycloalkyl, or

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹ is C-H or C-R⁵. c. A combination product according to paragraph a or paragraph b wherein A² is C-H or C-R⁵. d. A combination product according to any one of paragraphs a to c wherein A³ is C-H or C-R⁵. e. A combination product according to any one of paragraphs a to d wherein A⁴ is C-H or C-R⁵. f. A combination product according to any one of paragraphs a to e wherein R¹ is R⁶-, R⁶-Ci-C₆alkyl-, R⁶-oxy-Ci-C₆alkyl-, R⁶-carbonyl-Ci-C₆alkyl-, R⁶-aminocarbonyl-Ci- C₆alkyl-, or R⁶-Ci-C₆alkoxy-Ci-C₆alkyl-. g. A combination product according to any one of paragraphs a to f wherein each D is independently -CH₂-, -CH₂-CH₂-, -CH(Me , or -CH₂-CH₂-CH₂-. h. A combination product according to any one of paragraphs a to g wherein E is -O- or -(CO)-. i. A combination product according to any one of paragraphs a to h wherein R² is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. j . A combination product according to any one of paragraphs a to i wherein R³ is chlorodifluoromethyl or trifluoromethyl. k. A combination product according to any one of paragraphs a to j wherein R⁴ is aryl or aryl substituted by one to three substituents independently selected from halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-.

1. A combination product according to any one of paragraphs a to k wherein each R⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-. m. A combination product according to any one of paragraphs a to 1, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole,

fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. n. A combination product according to any one of paragraphs a to m, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. o. A combination product according to any one of paragraphs a to n, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. p. A combination product according to any one of paragraphs a to o, wherein the combination product is for use against parasitic invertebrate pests. q. A combination product according to any one of paragraphs a to p, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. r. A combination product according to paragraph q, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. s. A combination product according to paragraph q or paragraph r, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. t. A method comprising administering the combination product as defined in any one of paragraphs a to o to an animal. u. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to o to the animal. v. A method according to paragraph u, wherein said administration is oral

administration, parenteral administration or external administration. x. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragraphs a to o to the environment in which an animal resides. y. A pharmaceutical composition comprising component A and component B as defined in any one of paragarphs a to o and a pharmaceutically suitable excipient.

Invention 3

WO2010/020521 discloses that certain isoxazoline compounds have insecticidal activity.

The present invention provides a combination product comprising a component A and a component B, wherein component A is a compound of formula (I) or (Γ)

wherein

A¹, A², A³ and A⁴, or A^1', A^2', A^3', A^4', A^5', and A^6', are independently of each other C-H, C- R⁶, or nitrogen;

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷ , aryl-Ci-C₄alkylene- or aryl-Ci- C₄alkylene- wherein the aryl moiety is substituted by one to five R⁸, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁸, C₃-Ci₀cycloalkyl, C₃-Ci₀halocycloalkyl, aryl or aryl substituted by one to five R⁸, or heterocyclyl or heterocyclyl substituted by one to five R⁸;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R⁹, or heteroaryl or heteroaryl substituted by one to five R⁹;

R^5a and R^5b are, independently of each other, hydrogen, cyano, halogen, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, arylthio- or arylthio- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfinyl- or arylsulfinyl- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfonyl- or arylsulfonyl- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclylthio- or heterocyclylthio- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, heterocyclylsulfinyl- or heterocyclylsulfinyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, or heterocyclylsulfonyl- or heterocyclylsulfonyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰ Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, Ci-C₈haloalkyl, C₂-C₈haloalkenyl, hydroxy, Ci-C₈alkoxy, C₃-C₈alkenyloxy, C₃- C₈alkynyloxy, or Ci-C₈haloalkoxy, provided that at least one of R^5a and R^5b is not hydrogen; R^5a and R^5b may also be Ci-C₈alkyl substituted by one to five R ; each R⁷ is independently halogen, cyano, nitro, C₃-Ciocycloalkyl, C₃-Ci₀halocycloalkyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; and

each R⁶, R⁸, R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₃-Ci₀cycloalkyl, C₃-Ci₀halocycloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂- C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C₄haloalkyl, Ci-C₄alkoxy, or Ci-C₄haloalkoxy, or heterocyclyl or heterocyclyl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C haloalkyl, Ci-C alkoxy, or Ci-C haloalkoxy;

or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

The compounds of formula I and Γ and their manufacturing processes are known from WO2010/020521.

The compounds of of formula (I) may contain one or more asymmetric carbon atoms, for example, at the -CR³R⁴- group and the -CR^5aR^5b- group, or at the LR²Y¹ Y³ group (see below) and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such.

Each alkyl moiety either alone or as part of a larger group (such as alkoxy, alkylthio, alkylcarbonyl, or alkoxycarbonyl) is a straight or branched chain and is, for example, methyl, ethyl, ^-propyl, prop-2-yl, «-butyl, but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are preferably Ci to C₆ alkyl groups, more preferably Ci-C , most preferably Ci-C₃ alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three

substituents.

Each alkylene moiety is a straight or branched chain and is, for example, -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(CH₃)-CH₂-, or -CH(CH₂CH₃)-. The alkylene groups are preferably Ci to C₃ alkylene groups, more preferably Ci-C₂, most preferably Ci alkylene groups.

Alkenyl moieties can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkenyl groups.

Alkynyl moieties can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy or haloalkylthio) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.

Haloalkenyl groups are alkenyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2-fluoro-vinyl.

Haloalkynyl groups are alkynyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.

Cycloalkyl groups can be in mono- or bi-cyclic form and may optionally be substituted by one or more methyl groups. The cycloalkyl groups preferably contain 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclohexyl and 2-methyl-cyclohex-l-yl. An example of a bicyclic cycloalkyl group is bicyclo[2.2.1]heptan-2-yl.

Halocycloalkyl groups are cycloalkyl groups which are substituted with one or more of the same of different halogen atoms and may optionally be substituted by one or more methyl groups. Examples of monocyclic halocycloalkyl groups are 2,2-dichloro-cyclopropyl, 2,2-dichloro-l-methyl-cyclopropyl and 2-chloro-4-fluoro-cyclohexyl.

In the context of the present specification the term "aryl" refers to a ring system which may be mono-, bi- or tricyclic. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three

substituents. The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

The term "heterocyclyl" is defined to include heteroaryl and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydro-furanyl, [l,3]dioxolanyl, piperidinyl, piperazinyl,

[l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo-thietanyl and 1, 1- dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl,

benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Preferred values of A¹, A², A³, A⁴, A^1', A^2', A^3', A^4', A^5', A^6', G¹, R¹, R², R³, R⁴, R^5a,

R^5b, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are, in any combination, as set out below.

Preferably no more than two of A¹, A², A³ and A⁴ are nitrogen.

Preferably A¹ is C-H or C-R⁶, most preferably A¹ is C-R⁶.

Preferably A² is C-H or C-R⁶, most preferably A² is C-H.

Preferably A³ is C-H or C-R⁶, most preferably A³ is C-H.

Preferably A⁴ is C-H or C-R⁶, most preferably A⁴ is C-H.

Preferably no more than two of A¹ , A² , A³ , A⁴ , A⁵ and A⁶ are nitrogen.

Preferably A^1' is C-H or C-R⁶, most preferably A^1' is C-H.

Preferably A^2' is C-H or C-R⁶, most preferably A^2' is C-H.

Preferably A^3' is C-H or C-R⁶, most preferably A^3' is C-H.

Preferably A^4' is C-H or C-R⁶, most preferably A^4' is C-H.

Preferably A^5' is C-H or C-R⁶, most preferably A^5' is C-H.

Preferably A^6' is C-H or C-R⁶, most preferably A^6' is C-H.

Preferably G¹ is oxygen. Preferably R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, even more preferably hydrogen or methyl, most preferably hydrogen.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, phenyl-Ci- C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁸, pyridyl-Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to five R⁸, C₃-Ciocycloalkyl, C₃-Ciohalocycloalkyl, oxetanyl or oxetanyl substituted by one to five R⁸, thietanyl or thietanyl substituted by one to five R⁸, oxo- thietanyl or oxo-thietanyl substituted by one to five R⁸, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁸, more preferably Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three halogen atoms, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁸, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to five R⁸, C₃-Ci₀cycloalkyl, thietanyl, oxo- thietanyl or dioxo-thietanyl, most preferably butyl-, 1-phenyl-eth-l-yl-, phenyl-methyl-, (pyrid-2-yl)-methyl-, cyclobutyl-, thietanyl-, oxo-thietanyl- or dioxo-thietanyl-. It is particularly preferred that the thietanyl, oxo-thietanyl or dioxo-thietanyl ring is linked via the 3 -position.

A group of preferred compounds are those wherein R² is Ci-C₆alkyl or Ci-C₆alkyl substituted by one to five R⁷, for example ethyl-, «-butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methoxy-ethyl-, and l-methoxy-prop-2-yl-.

A group of preferred compounds are those wherein R² is aryl-Ci-C₂alkylene- or aryl- Ci-C₂alkylene- wherein the aryl moiety is substituted by one to five R⁸, for example phenyl- methyl-, 1-phenyl-eth-l-yl-, 2-phenyl-eth-l-yl-, (3-chloro-phenyl)-methyl-, (2-fluoro- phenyl)-methyl-, (4-methoxy-phenyl)-methyl-, (2-trifluoromethyl-phenyl)-methyl-, and (2- trifluoromethoxy-phenyl)-methyl-.

A group of preferred compounds are those wherein R² is heterocyclyl-Ci-C₂alkylene- or heterocyclyl-Ci-C₂alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁸, for example (pyrid-2-yl)-methyl-, (pyrid-3-yl)-methyl-, (2-chloro-pyrid-5-yl)-methyl-, (l-methyl-lH-imidazol-4-yl)-methyl-, (furan-2-yl)-methyl-, 2-(thiophen-2'-yl)-eth-l-yl-, 2- (indol-3'-yl)-eth-l-yl-, (lH-benzimidazol-2-yl)-methyl-, (oxetan-2-yl)-methyl-, (tetrahydro- furan-2-yl)-methyl-, 2-([r,3']dioxolan-2'-yl)-eth-l-yl-, 2-(mo holin-4'-yl)-eth-l-yl-, 2- (benzo[l',3']dioxol-5'-yl)-eth-l-yl-, and (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-, more preferably R² is heteroaryl-Ci-C₂alkylene- or heteroaryl-Ci-C₂alkylene- wherein the heteroaryl moiety is substituted by one to five R⁸. A group of preferred compounds are those wherein R² is C₃-C₈cycloalkyl or C₃- C₈halocycloalkyl, for example cyclobutyl-, and 2-methyl-cyclohex-l-yl-.

A group of preferred compounds are those wherein R² is aryl or aryl substituted by one to five R⁸, for example 2-chloro-phenyl-, 3-fluoro-phenyl-, 2-methyl-phenyl-, 2-chloro- 6-m ethyl -phenyl-, 2-trifluoromethyl-phenyl-, and 2,4-dimethoxy-phenyl-.

A group of preferred compounds are those wherein R² is heterocyclyl or heterocyclyl substituted by one to five R⁸, for example 3-methyl-pyrid-2-yl-, 1,3 -dimethyl- lH-pyrazol-5- yl-, 4-methyl-thiazol-2-yl-, 5-methyl-thiadiazol-2-yl-, quinolin-2-yl-, quinolin-5-yl-, benzothiazol-6-yl-, 4-methyl-benzothiazol-2-yl-, thietan-3-yl-, l-oxo-thietan-3-yl-, 1,1- dioxo-thietan-3-yl-, and 3-methyl-thietan-3-yl-, more preferably R² is thietanyl, oxo- thietanyl or dioxo-thietanyl each optionally substituted by one to five R⁸, e.g. R² is oxo- thietanyl or dioxo-thietanyl each optionally substituted by one to five R⁸. It is particularly preferred that the thietanyl, oxo-thietanyl or dioxo-thietanyl ring is linked via the 3 -position.

Preferably R³ is chlorodifluoromethyl or trifluoromethyl, most preferably trifluoro- methyl.

A group of preferred compounds are those wherein R⁴ is aryl or aryl substituted by one to five R⁹, more preferably R⁴ is aryl substituted by two to three R⁹, even more preferably R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl-, and 3,4,5- trichloro-phenyl-, most preferably R⁴ is 3,5-dichloro-phenyl.

A group of preferred compounds are those wherein R⁴ is heteroaryl or heteroaryl substituted by one to five R⁹, most preferably R⁴ is heteroaryl substituted by two to three R⁹.

Preferably R^5a is halogen, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, Ci-C₈haloalkyl, C₂-C₈haloalkenyl, most preferably halogen, Ci- C₈alkylthio- or Ci-C₈alkyl. R^5a may also be hydroxy.

Preferably R^5b is halogen or hydrogen, most preferably hydrogen.

Preferably each R⁶ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro, or methyl.

Preferably each R⁷ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy, Ci-

C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R⁸ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, even more preferably chloro, fluoro, or methyl, most preferably methyl.

Preferably each R⁹ is independently bromo, chloro, fluoro, trifluoromethyl, methoxy, or methylthio, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably bromo or chloro.

Preferably each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro, or methyl.

In a preferred embodiment component A is a compound of formula (I); or a salt or N- oxide thereof.

In a preferred embodiment component A is a compound of formula (la) wherein A¹ is C-Me, A², A³, and A⁴ are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a is bromo, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I); or a salt or N-oxide thereof.

group (z):

(z)

wherein L is a single bond or Ci-C₆ alkylene;

R^2a is hydrogen, or Ci-C₈alkyl;

Y¹, Y² and Y³ are independently of another CR^7aR^8a, C=0, C=N-OR^9a, N-R^9a, O, S, SO, S0₂,

S=N-R^9a, or SO=N-R^9a, provided that at least one of Y¹, Y² or Y³ is not CR^7aR^8a;

R^7a and R^8a are of another independently hydrogen, halogen, Ci-C₈alkyl, or Ci-C₈haloalkyl; each R^9a is independently hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkyl- carbonyl-, Ci-C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C₄alkyl- or aryl-Ci-C₄alkyl- wherein each aryl moiety is substituted by one to three R^{l la}, or is heteroaryl-Ci-C₄alkyl- or heteroaryl-Ci-

C₄alkyl- wherein each heteroaryl moiety is substituted by one to three R^{l la};

R^lla is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci-

C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

Preferably L is a single bond or Ci-C₂alkyl, yet even more preferably a single bond or methyl, most preferably a single bond.

Preferably R^2a is hydrogen or methyl, most preferably hydrogen. Preferably Y¹, Y² and Y³ are independently of another CR^7aR^8a, C=0, C=N-OR^9a, N- R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, provided that only one of Y¹, Y² or Y³ is not CR^7aR^8a.

More preferably Y¹, Y² and Y³ are independently of another CR^7aR^8a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, provided that only one of Y¹, Y² or Y³ is not CR^7aR^8a.

More preferably Y¹, Y² and Y³ are independently of another CR⁷R⁸, O, S, SO, S0₂, S=N-R⁹, or SO=N-R⁹, provided that only one of Y¹, Y² or Y³ is not CR⁷R⁸.

Even more preferably Y¹, Y² and Y³ are independently of another CR^7aR^8a, O, S, SO, or S0₂, provided that only one of Y¹, Y² or Y³ is not CR^7aR^8a,

Even more preferably Y² is O, S, SO, or S0₂, and Y¹ and Y³ are independently of another CR^7aR^8a.

Most preferably, Y² is S, SO, or S0₂, and Y¹ and Y³ are independently of another CR^7aR^8a.

In one embodiment Y¹ is C=0, C=N-OR^9a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, and Y² and Y³ are independently of another CR^7aR^8a.

In one embodiment Y² is C=0, C=N-OR^9a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, and Y¹ and Y³ are independently of another CR^7aR^8a.

In one embodiment Y² is C=0, C=N-OR^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, and Y¹ and Y³ are independently of another CR^7aR^8a.

Preferably each R^7a and R^8a is independently hydrogen or methyl, most preferably hydrogen.

Preferably each R^9a is independently hydrogen, cyano, methyl, trifluoromethyl, methylcarbonyl-, trifluoromethylcarbonyl-, methoxycarbonyl-, trifluoromethoxycarbonyl-, methylsulfonyl-, trifluoromethylsulfonyl-, or benzyl or benzyl wherein the phenyl moiety is substituted by one to three R^10a, most preferably each R^9a is independently hydrogen, methyl, trifluoromethyl, or benzyl or benzyl wherein the phenyl moiety is substituted by one to three

_R10a

Preferably each R^10a is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, more preferably chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, or trifluoromethoxy, most preferably each R^10a is independently preferably bromo, chloro, or fluoro.

Preferably each R^{l la} is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-, more preferably chloro, fluoro, cyano, nitro, methyl, ethyl, tnfluoromethyl, methoxy, or trifluoromethoxy, most preferably each R^{l la} is independently preferably bromo, chloro, or fluoro.

Preferably, L is a single bond;

Y¹, Y² and Y³ are independently of another CR^7aR^8a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, provided that one of Y¹, Y² or Y³ is not CR^7aR^8a;

R^2a is hydrogen or methyl;

R^7a and R^8a are independently of another hydrogen, halogen C₁-C₄ alkyl or C₁-C₄ haloalkyl; and R^9a is hydrogen, halogen C₁-C₄ alkyl or C₁-C₄ haloalkyl.

In a preferred embodiment component A is a compound of formula (lb) wherein A¹ is

C-Me, A², A³, and A⁴ are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a is chloro, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Ic) wherein A¹ is C-Me, A², A³, and A⁴ are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a and R^5b are fluoro, and R¹ and R² are as defined for a compound of formula (I), preferably wherein R² is group (z); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Id.1) wherein A¹ is C-Me, A², A³, and A⁴ are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a is methylthio-, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I) preferably wherein R² is group (z); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Id.2) wherein A¹ is C-Me, A², A³, and A⁴ are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a is methylsulfonyl-, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I), preferably wherein R² is group (z); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Ie) wherein A¹

2 3 4 1 3 4

is C-Me, A , A , and A are C-H, G is oxygen, R is trifluoromethyl, R is 3,5-dichloro- phenyl, R^5a is methyl, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I), preferably wherein R² is group (z); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Ig) wherein A¹

2 , A 3 4 1 3 4

is C-Me, A , and A are C-H, G is oxygen, R is trifluoromethyl, R is 3,5-dichloro- phenyl, R^5a is fluoro, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I), preferably wherein R² is group (z); or a salt or N-oxide thereof. In a preferred embodiment component A is a compound of formula (Ih) wherein A¹ is C-Me, A 2 , A 3 , and A 4 are C-H, G 1 is oxygen, R 3 is trifluoromethyl, R 4 is 3,5-dichloro- phenyl, R^5a is hydroxy, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (I), preferably wherein R² is group (z); or a salt or N-oxide thereof.

In a preferred embodiment component A is a compound of formula (Γ); or a salt or

N-oxide thereof.

In a preferred embodiment component A is a compound of formula (I' a) wherein A¹ , A^2', A^3', A^4', A^5' and A^6' are C-H, G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro- phenyl, R^5a is bromo, R^5b is hydrogen, and R¹ and R² are as defined for a compound of formula (Γ), preferably wherein R² is group (z); or a salt or N-oxide thereof.

In one embodiment component A is a compound of formula (I)

In one embodiment component A is a compound of formula (Γ).

In one embodiment component A is a compound of formula (I^a) or (I^b):

position, and each optionally substituted by halogen, C₁-C4 alkyl or C1-C4 haloalkyl;

R³ is chlorodifluoromethyl or trifluoromethyl;

R^5a is halogen, hydroxy, C₁-C4 alkyl, C₁-C4 haloalkyl, C₁-C4 alkylthio, C₁-C4 haloalkylthio, C₁-C4 alkylsulfonyl, C₁-C4 haloalkylsulfonyl, C₁-C4 alkylsulfinyl, or C₁-C4 haloalkylsulfinyl; R^5b is hydrogen or halogen;

R¹¹ and R¹² are independently hydrogen, halogen C₁-C4 alkyl or C₁-C4 haloalkyl.

Preferably, component A is a compound of formula (I^a) or (I^b) in which R¹ is hydrogen;

R² is thietanyl, oxo-thietanyl or dioxo-thietanyl, each linked via the 3 -position, and each optionally substituted at the 3 position by methyl;

R³ is trifluorom ethyl;

R^5a is halogen, hydroxyl, methyl, methylthio, methyl sulfinyl or methylsulfonyl;

R^5a is hydrogen or halogen;

R¹¹ and R¹² are independently fluorine, chlorine or bromine.

In one embodiment component A is a compound a compound of formula (I^a).

In a preferred embodiment component A is a compound of formula (I^b).

Compounds of formula I and Γ include at least one chiral centre and may exist as compounds of formula I* or Γ * or compounds of formula I** or Γ ** respectively.

(I**)

Generally compounds of formula I** and Γ ** are more biologically active than compounds of formula I* and Γ* respectively. Component A may be a mixture of compounds I* and I** (or compounds Γ * and Γ**) in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10: 1 to 1 : 10, e.g. a substantially 50:50 molar ratio. For example, when component A is an enantiomerically enriched mixture of formula I** (or Γ **), the molar proportion of compound I** (or Γ **) compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, when component A is an enantiomerically enriched mixture of formula I* (or Γ *), the molar proportion of the compound of formula I* (or Γ *) compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. The compounds in Tables 1 to 9 below illustrate the compounds of component A. Table 1 :

Table 1 provides 50 compounds of formula (la) wherein R⁶ is methyl, and R¹ and R² have the values listed in the table below.

Compound R R

numbers

1.01 H ethyl-

1.02 H «-butyl-

1.03 H but-2-yl-

1.04 H 3-bromo-propyl-

1.05 H 2,2,2-trifluoro-ethyl-

1.06 H 3,3,3 -trifluoro-propy 1 -

1.07 H 2-methoxy-ethyl-

1.08 H 1 -methoxy-prop-2-yl-

1.09 H phenyl-methyl-

1.10 H 1 -phenyl -eth- 1 -yl-

1.11 H 2-phenyl-eth- 1 -yl-

1.12 H (3-chloro-phenyl)-methyl-

1.13 H (2-fluoro-phenyl)-m ethyl -

1.14 H (4-methoxy-phenyl)-methyl-

1.15 H (2-trifluoromethyl-phenyl)-methyl-

1.16 H (2-trifluoromethoxy-phenyl)-methyl-

1.17 H (pyrid-2-yl)-methyl-

1.18 H (pyrid-3-yl)-methyl-

1.19 H (2-chloro-pyrid-5-yl)-methyl-

1.20 H (l-methyl-lH-imidazol-4-yl)-methyl-

1.21 H (furan-2-yl)-methyl-

1.22 H 2-(thiophen-2'-yl)-eth-l-yl-

1.23 H 2-(indol-3'-yl)-eth-l-yl-

1.24 H (lH-benzimidazol-2-yl)-methyl-

1.25 H (oxetan-2-yl)-methyl-

1.26 H (tetrahydrofuran-2-yl)-methyl-

1.27 H 2-([ 1 ',3 ']dioxolan-2'-yl)-eth- 1 -yl-

1.28 H 2-(Γηο Ηο1ϊη-4'-γ1)-βίΗ- 1 -yl-

1.29 H 2-(benzo[ 1 ',3 ']dioxol-5'-yl)-eth- 1 -yl-

1.30 H (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-

1.31 H cyclobutyl- Compound R R²

numbers

1.32 H 2-methyl-cyclohex-l-yl-

1.33 H 2-chloro-phenyl-

1.34 H 3-fluoro-phenyl-

1.35 H 2-methyl-phenyl-

1.36 H 2-chloro-6-methyl-phenyl-

1.37 H 2-trifluoromethyl-phenyl-

1.38 H 2,4-dimethoxy-phenyl-

1.39 H 3-methyl-pyrid-2-yl-

1.40 H 1 ,3 -dimethyl- lH-pyrazol -5 -yl -

1.41 H 4-methyl-thiazol-2-yl-

1.42 H 5 -methyl -thi adi azol -2-yl -

1.43 H quinolin-2-yl-

1.44 H quinolin-5-yl-

1.45 H benzothiazol-6-yl-

1.46 H 4-methyl-benzothiazol-2-yl-

1.47 H thi etan-3 -yl-

1.48 H 1 -oxo-thi etan-3 -yl -

1.49 H 1 , 1 -di oxo-thi etan-3 -yl-

1.50 H 3 -methyl -thi etan-3 -yl-

Table 2:

Table 2 provides 50 compounds of formula (lb) wherein R⁶ is methyl, and R¹ and R² have the values listed in the table below.

Table 3 :

Table 3 provides 50 compounds of formula (Ic) wherein R⁶ is methyl, and R¹ and R² have the values listed in Table 1.

(Ic)

Table 4:

Table 4 provides 50 compounds of formula (Ic) wherein R⁶ is methyl, and R¹ and R² have the values listed in Table 1.

Table 5:

Table 5 provides 50 compounds of formula (Id.2) wherein R⁶ is methyl, and R¹ and R² have the values listed in Table 1.

Table 6:

Table 6 provides 50 compounds of formula (Ie) wherein R⁶ is methyl, and R¹ and R² have the values listed in Table 1.

Table 7:

Table 7 provides 50 compounds of formula (Ig) wherein R⁶ is methyl, and R¹ and R² have the values listed in the table below.

Table 8:

Table 8 provides 50 compounds of formula (Ih) wherein R⁶ is methyl, and R¹ and R² have the values listed in the table below.

Table 9:

Table 9 provides 50 compounds of formula (I'a) wherein R¹ and R² have the values listed in Table 1.

In a further aspect the invention provides a method of protecting an animal from a parasitic invertebrate pest comprising administering to the animal a pesticidally effective amount of the combination product of the invention. In a further aspect the invention provides the combination product for use in protecting an animal from a parasitic invertebrate pest. In a further aspect the invention provides use of the combination product in the manufacture of a medicament for protecting an animal from a parasitic invertebrate pest.

Component A may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron; ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.

WO04/72086, particularly the compounds disclosed therein.

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E) -

(1 R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta -cyfluthrin, cyfluthrin, a-cypermethrin, beta -cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, ?-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t- fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin. Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG- 505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin,

bromuconazole, bupirimate, carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo- asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

metaflumizone, praziquarantel, triclabendazole.

The invention also includes the following combinations:

A compound from Tables 1-9 and imidacloprid.

A compound from Tables 1-9 and enrofloxacin. A compound from Tables 1-9 and praziquantel.

A compound from Tables 1-9 and pyrantel embonate.

A compound Tables 1-9 and febantel.

A compound from Tables 1-9 and penethamate.

A compound from Tables 1-9 and moloxicam.

A compound from Tables 1-9 and cefalexin.

A compound from Tables 1-9 and kanamycin.

A compound from Tables 1-9 and pimobendan.

A compound from Tables 1-9 and clenbuterol.

A compound from Tables 1-9 and fipronil.

A compound from Tables 1-9 and ivermectin.

A compound from Tables 1-9 and omeprazole.

A compound from Tables 1-9 and tiamulin.

A compound from Tables 1-9 and benazepril.

A compound from Tables 1-9 and milbemycin.

A compound from Tables 1-9 and cyromazine.

A compound from Tables 1-9 and thiamethoxam.

A compound from Tables 1-9 and pyriprole.

A compound from Tables 1-9 and deltamethrin.

A compound from Tables 1-9 and cefquinome.

A compound from Tables 1-9 and florfenicol.

A compound from Tables 1-9 and buserelin.

A compound from Tables 1-9 and cefovecin.

A compound from Tables 1-9 and tulathromycin.

A compound from Tables 1-9 and ceftiour.

A compound from Tables 1-9 and selamectin.

A compound from Tables 1-9 and carprofen.

A compound from Tables 1-9 and metaflumizone.

A compound from Tables 1-9 and moxidectin.

A compound from Tables 1-9 and methoprene (including S-methoprene)

A compound from Tables 1-9 and clorsulon.

A compound from Tables 1-9 and pyrantel.

A compound from Tables 1-9 and amitraz.

A compound from Tables 1-9 and triclabendazole. A compound from Tables 1-9 and avermectin.

A compound from Tables 1-9 and abamectin.

A compound from Tables 1-9 and emamectin.

A compound from Tables 1-9 and eprinomectin.

A compound from Tables 1-9 and doramectin.

A compound from Tables 1-9 and selamectin.

A compound from Tables 1-9 and nemadectin.

A compound from Tables 1-9 and albendazole.

A compound from Tables 1-9 and cambendazole.

A compound from Tables 1-9 and fenbendazole.

A compound from Tables 1-9 and flubendazole.

A compound from Tables 1-9 and mebendazole.

A compound from Tables 1-9 and oxfendazole.

A compound from Tables 1-9 and oxibendazole.

A compound from Tables 1-9 and parbendazole.

A compound from Tables 1-9 and tetramisole.

A compound from Tables 1-9 and levamisole.

A compound from Tables 1-9 and pyrantel pamoate

A compound from Tables 1-9 and oxantel.

A compound from Tables 1-9 and morantel.

A compound from Tables 1-9 and triclabendazole.

A compound from Tables 1-9 and epsiprantel.

A compound from Tables 1-9 and fipronil.

A compound from Tables 1-9 and lufenuron.

A compound from Tables 1-9 and ecdysone.

A compound from Tables 1-9 and tebufenozide.

The following paragraphs represent embodiments of invention 3 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I) or (Γ)

wherein

A¹, A², A³ and A⁴, or A^1', A^2', A^3', A^4', A^5', and A^6', are independently of each other C-H, C- R⁶, or nitrogen; oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-;

R² is the group (z):

(z)

wherein L is a single bond or Ci-C₆ alkylene;

R^2a is hydrogen, or Ci-C₈alkyl;

Y¹, Y² and Y³ are independently of another CR^7aR^8a, C=0, C=N-OR^9a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, provided that at least one of Y¹, Y² or Y³ is not CR^7aR^8a;

R^7a and R^8a are independently of another hydrogen, halogen, Ci-C₈alkyl, or Ci-C₈haloalkyl; each R^9a is independently hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkyl- carbonyl-, Ci-C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C₄alkyl- or aryl-Ci-C₄alkyl- wherein each aryl moiety is substituted by one to three R^{l la}, or is heteroaryl-Ci-C alkyl- or heteroaryl -Ci- C alkyl- wherein each heteroaryl moiety is substituted by one to three R^{l la};

R^lla is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy, Ci- C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

R³ is Ci-C₈haloalkyl;

R^5a and R^5b are, independently of each other, hydrogen, cyano, halogen, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, arylthio- or arylthio- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfinyl- or arylsulfinyl- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfonyl- or arylsulfonyl- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclylthio- or heterocyclylthio- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, heterocyclylsulfinyl- or heterocyclyl sulfinyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, or heterocyclylsulfonyl- or heterocyclylsulfonyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰ Ci-C₈alkyl, Ci-C₈alkyl substituted by one to five R⁷, C₂-C₈alkenyl, C₂-C₈alkynyl, Ci-C₈haloalkyl, C₂-C₈haloalkenyl, hydroxy, Ci- C₈alkoxy, C3-C₈alkenyloxy, C₃-C₈alkynyloxy, or Ci-C₈haloalkoxy, provided that at least one of R^5a and R^5b is not hydrogen; each R⁷ is independently halogen, cyano, nitro, C₃-Ciocycloalkyl, C₃-Ci₀halocycloalkyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; and

each R⁶, R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₃- Ciocycloalkyl, C₃-Ci₀halocycloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂- C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C₄haloalkyl, Ci-C₄alkoxy, or Ci-C₄haloalkoxy, or heterocyclyl or heterocyclyl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C haloalkyl, Ci-C alkoxy, or Ci-C haloalkoxy;

or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹, A², A³ and A⁴ are independently C-H or C-R⁶. c. A combination product according to paragraph a wherein A¹ , A² , A³ , A⁴ , A⁵ and A⁶ are independently C-H or C-R⁶. d. A combination product according to any one of paragarphs a to c wherein G¹ is oxygen. e. A combination product according to any one of paragarphs a to d wherein R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. f. A combination product according to any one of paragarphs a to e wherein

L is a single bond;

Y¹, Y² and Y³ are independently of another CR^7aR^8a, N-R^9a, O, S, SO, S0₂, S=N-R^9a, or SO=N-R^9a, provided that only one of Y¹, Y² or Y³ is not CR^7aR^8a;

R^2a is hydrogen or methyl; R^7a and R^8a are independently of another hydrogen, halogen C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

R^9a is hydrogen, halogen C₁-C₄ alkyl or C₁-C₄ haloalkyl. g. A combination product according to any one of paragarphs a to f wherein R² is thietanyl, oxo-thietanyl or dioxo-thietanyl each optionally substituted by one to five R⁸. h. A combination product according to any one of paragarphs a to g wherein R² is thietanyl, oxo-thietanyl or dioxo-thietanyl, each optionally substituted by one to five R⁸, and each linked via the 3 -position. i. A combination product according to any one of paragarphs a to h wherein R³ is chlorodifluoromethyl or trifluoromethyl. j . A combination product according to any one of paragarphs a to i wherein R⁴ is aryl or aryl substituted by one to five R⁹. k. A combination product according to any one of paragarphs a to j wherein R^5a and R^5b are, independently of each other, hydrogen, cyano, halogen, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, arylthio- or arylthio- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfinyl- or arylsulfinyl- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfonyl- or arylsulfonyl- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclylthio- or heterocyclylthio- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, heterocyclylsulfinyl- or heterocyclyl sulfinyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, or heterocyclylsulfonyl- or heterocyclylsulfonyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰ Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, Ci-C₈haloalkyl, C₂-C₈haloalkenyl, hydroxy, Ci-C₈alkoxy, C₃-C₈alkenyloxy, C₃- C₈alkynyloxy, or Ci-C₈haloalkoxy, provided that at least one of R^5a and R^5b is not hydrogen.

1. A combination product according to any one of paragarphs a to k wherein R^5a is halogen, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, Ci- C₈haloalkyl, C₂-C₈haloalkenyl, most preferably halogen, Ci-C₈alkylthio- or Ci-C₈alkyl. m. A combination product according to any one of paragarphs a to 1 wherein R ^a is hydroxy. n. A combination product according to any one of paragarphs a to m wherein R^5b is halogen or hydrogen. o A combination product according to any one of paragarphs a to n, wherein each R⁶ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

each R⁷ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-,;

each R⁸ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

each R⁹ is independently bromo, chloro, fluoro, trifluoromethyl, methoxy, or methylthio; and each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy. p. A combination product wherein the compound of formula (I) or compound of formula (Γ) is a compound of formula (I^a) or a compound of formula (I^b):

R² is thietanyl, oxo-thietanyl or dioxo-thietanyl, each linked to the nitrogen atom via the 3- position, and each optionally substituted by halogen, C₁-C4 alkyl or C₁-C4 haloalkyl;

R³ is chlorodifluoromethyl or trifluorom ethyl;

R^5a is halogen, hydroxy, Ci-C₄ alkyl, Ci-C₄ haloalkyl, Ci-C₄ alkylthio, Ci-C₄ haloalkylthio, Ci-C alkylsulfonyl, Ci-C haloalkylsulfonyl, Ci-C alkylsulfinyl, or Ci-C haloalkylsulfinyl; R^5b is hydrogen or halogen;

R⁶ is Ci-C₄ alkyl or Ci-C₄ haloalkyl; and

R¹¹ and R¹² are independently hydrogen, halogen Ci-C₄ alkyl or Ci-C₄ haloalkyl. q. A combination product according to claim p, wherein

R¹ is hydrogen;

R³ is trifluorom ethyl;

R^5b is hydrogen or halogen; and

R¹¹ and R¹² are independently fluorine, chlorine or bromine. r. A combination product according to any one of paragarphs a to q, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S- methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. s. A combination product according to any one of paragarphs a to q, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. t. A combination product according to any one of paragarphs a to q, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. u A combination product according to any one of paragarphs a to t, wherein the combination product is for use against parasitic invertebrate pests. v. A combination product according to any one of paragarphs a to u, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. w. A combination product according to paragarph v, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. x. A combination product according to paragarph v or paragraph w, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. y. A method comprising administering the combination product as defined in any one of paragarphs a to q to an animal. z. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragarphs a to q to the animal. zz. A method according to paragraph z, wherein said administration is oral

administration, parenteral administration or external administration. zzz. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragarphs a to q to the environment in which an animal resides. zzzz. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to q and a pharmaceutically suitable excipient.

Invention 4

WO2010/084067 discloses that certain isoxazoline compounds have insecticidal activity.

The present invention provides a combination product comprising a component A and a component B, wherein com onent A is a compound of formula (I)

wherein

A¹, A² and A³ are independently C-R⁵, nitrogen, N-R⁶, oxygen or sulfur, provided that two of

A 1 , A2 or A 3 are C-R 5 or nitrogen and that one of A 1 , A2 or A3 is N-R6 , oxygen or sulfur; A⁴ and A⁵ are independently C-R⁵ or nitrogen;

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C3-Ciocycloalkyl or C₃-

Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene;

R³ is Ci-C₈haloalkyl; R⁴ is aryl or aryl substituted by one to five R¹⁰, or heteroaryl or heteroaryl substituted by one to five R¹⁰;

each R⁵ is independently hydrogen, halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkoxy, Ci-C₈haloalkoxy, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁶ is independently hydrogen or Ci-C₈alkyl;

each R⁷ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-; Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁸ is independently halogen or Ci-C₈alkyl;

each R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂- C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci- C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹¹, or heterocyclyl or heterocyclyl substituted by one to five R¹¹; and

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C alkoxy, or Ci-C haloalkoxy; or a salt or N-oxide thereof;

provided that -A^A^A³- is not -0-(CR⁵)=N-, -S-(CR⁵)=N-, N=(CR⁵)-0- or -N=(CR⁵)-S- irrespective of the values for A⁴ and A⁵, and

provided that -A^A^A³- is not -(CR⁵)=(CR⁵)-0-, -0-(CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-S-, -S-

(CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-( R⁶)-, -( R⁶)-(CR⁵)=(CR⁵)-, -(CR⁵)=N-( R⁶)- and -( R⁶)-

N=(CR⁵)- when A⁴ and A⁵ are both C-R⁵;

and component B is a further therapeutic agent;

The compounds of formula I and their manufacturing processes are known from

WO2010/084067.

The compounds of the invention may contain one or more asymmetric carbon atoms, for example, at the -CR³R⁴- group, and may exist as enantiomers (or as pairs of diastereo- isomers) or as mixtures of such. Alkyl groups (either alone or as part of a larger group, such as alkoxy, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl-, or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but- 2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are preferably Ci-C₆, more preferably C₁-C4, most preferably C₁-C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Alkylene groups can be in the form of a straight or branched chain and are, for example, -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(CH₃)-CH₂-, or

-CH(CH₂CH₃)-. The alkylene groups are preferably Ci-C₃, more preferably Ci-C₂, most preferably Ci alkylene groups.

Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkenyl groups.

Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluorom ethyl, trifluorom ethyl, chlorodifluorom ethyl or 2,2,2-trifluoro-ethyl.

Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2- fluoro-vinyl.

Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.

Cycloalkyl groups can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C₃-C₈, more preferably C₃-C₆ cycloalkyl groups. Where a cycloalkyl moiety is said to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Aryl groups (either alone or as part of a larger group, such as aryl-alkylene-) are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heteroaryl groups (either alone or as part of a larger group, such as heteroaryl- alkylene-) are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl.

Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heterocyclyl groups (either alone or as part of a larger group, such as heterocyclyl - alkylene-) are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo-thietanyl and 1,1-dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Preferred values of A¹, A², A³, A⁴, A⁵ _, G¹, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are, in any combination, as set out below.

For the avoidance of doubt, the ring formed by A¹, A² and A³ is an aromatic ring.

Preferably A¹ is nitrogen or N-R⁶, most preferably nitrogen or N-CH₃.

Preferably A² is C-R⁵, N-R⁶, nitrogen or sulfur, more preferably A² is C-R⁵, nitrogen or sulfur, most preferably nitrogen or sulfur.

Preferably A³ is nitrogen or N-R⁶, most preferably nitrogen or N-CH₃.

In one embodiment A¹ and A³ are nitrogen or N-R⁶ and A² is C-R⁵, N-R⁶, nitrogen or sulfur, more preferably A¹ and A³ are nitrogen or N-R⁶ and A² is N-R⁶, nitrogen or sulfur, 1 3 2 6 1 2 3 more preferably A and A are nitrogen and A is N-R or sulfur. For example, -A -A -A - may be selected from =N-S-N= -N=C(R⁵)-N(R⁶)-, -N(R⁶)-C(R⁵)=N-, =N-N(R⁶)-N=, -N=N- N(R⁶)- and -N(R⁶)-N=N-, more preferably =N-S-N= -N=C(R⁵)-N(R⁶)-, =N-N(R⁶)-N=, and -N=N-N(R⁶)-, more preferably =N-S-N= =N-N(R⁶)-N=, and -N=N-N(R⁶)-, most preferably =N-S-N=. In one embodiment two of A¹, A² and A³ are nitrogen and the other of A¹, A² and A³ is N-R⁶, oxygen or sulfur, more preferably two of A¹, A² and A³ are nitrogen and the

1 2 3 6 1 2 3

other of A , A and A is N-R or sulfur. For example, -A -A -A - may be selected from =N- S-N= -S-N=N-, -N=N-S-, =N-N(R⁶)-N=, -N=N-N(R⁶)- and -N(R⁶)-N=N-, in particular from =N-S-N= -N=N-N(R⁶)- and =N-N(R⁶)-N=. Preferably two of A¹, A² and A³ are nitrogen and

1 2 3 1 2 3

the other of A , A and A is sulfur. For example, -A -A -A - may be selected from =N-S- N=, -S-N=N-, and -N=N-S-. Most preferably -A¹-A²-A³- is =N-S-N=.

Preferably A⁴ is C-R⁵, most preferably C-H or C-CH₃, in particular C-H.

Preferably A⁵ is C-R⁵, most preferably C-H.

For example, A⁴ and A⁵ may each independently be C-H or nitrogen, more preferably A⁴ and A⁵ are both C-H.

Preferably G¹ is oxygen.

Preferably R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, even more preferably hydrogen or methyl, most preferably hydrogen.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-

Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C4alkylene- or aryl- Ci-C4alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-

C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl, pyrrolidinyl,

tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyrazolyl, benzimidazolyl, furanyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and di oxo-thietanyl.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃- Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁸, phenyl-Ci-C₄alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl- Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₄alkylene or imidazolyl-Ci-C₄alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, di oxo-thietanyl or di oxo-thietanyl substituted by one to five R⁹, Ci- C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃- C₈cycloalkyl-aminocarbonyl-Ci-C alkylene; for example Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁸, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, or di oxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one or two methyl groups, phenyl-Ci- C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C alkylene or imidazolyl-Ci-C alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo- thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹, for example Ci-C₈alkyl, C₃-Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, oxetanyl, thietanyl, oxo-thietanyl or dioxo-thietanyl.

Preferably R² is C₃-Cealkyl or C₃-Cealkyl substituted by one to five R⁷, C₄- C₈cycloalkyl or C4-C₈cycloalkyl substituted by one or two methyl groups, phenyl- Ci- C₂alkylene - or phenyl-Ci-C₂alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C₂alkylene- or pyridyl-Ci-C₂alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₂alkylene- or imidazolyl-Ci-C₂alkylene- wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo- thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹, more preferably C₃-Cealkyl or C₃-Cealkyl substituted by one to three R⁷, C4-C₈cycloalkyl, phenyl-methylene- or phenyl-methylene- wherein the phenyl moiety is substituted by one to three R⁹, imidazolyl-methylene- or imidazolyl-methylene- wherein the imidazolyl moiety is substituted by one to three R⁹, thietanyl or methylthietanyl, oxo-thietanyl or methyl-oxo-thietanyl, dioxo-thietanyl or methyl-dioxo-thietanyl, most preferably butyl, 2,2,2-trifluoroethyl, ethyl, l-methoxy-prop-2-yl, (lH-benzimidazol-2-yl)- methyl, 3,3,3-trifluoropropyl, phenyl-methyl-, (4-methoxy-phenyl)-m ethyl-, 2-methyl-l- methylthio-prop-2-yl, cyclobutyl, bicyclo[2.2.1]heptan-2-yl, thietanyl, methylthietanyl, oxo- thietanyl or dioxo-thietanyl, in particular thietanyl, oxo-thietanyl or dioxo-thietanyl.

A group of preferred compounds are those wherein R² is Ci-C₆alkyl or Ci-C₆alkyl substituted by one to five R⁷, for example ethyl-, butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methyl-l-methylthio-prop-2-yl, 2-methoxy-ethyl-, and l-methoxy-prop-2-yl-, for example ethyl-, butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methoxy-ethyl-, and l-methoxy-prop-2-yl-.

A group of preferred compounds are those wherein R² is C₃-C₈cycloalkyl or C₃- C₈cycloalkyl substituted by one to five R⁸, for example cyclobutyl-, bicyclo[2.2.1]heptan-2- yl and 2-methyl-cyclohex-l-yl-, for example cyclobutyl- and 2-methyl-cyclohex-l-yl-.

A group of preferred compounds are those wherein R² is aryl-Ci-C₂alkylene- or aryl- Ci-C₂alkylene- wherein the aryl moiety is substituted by one to five R⁹, for example phenyl- methyl-, 1 -phenyl -eth-l-yl-, 2-phenyl-eth-l-yl-, (3-chloro-phenyl)-methyl-, (2-fluoro- phenyl)-methyl-, (4-methoxy-phenyl)-methyl-, (2-trifluoromethyl-phenyl)-methyl- and (2- trifluoromethoxy-phenyl)-methyl-.

A group of preferred compounds are those wherein R² is heterocyclyl-Ci-C₂alkylene- or heterocyclyl-Ci-C₂alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, for example (pyrid-2-yl)-methyl-, (pyrid-3-yl)-methyl-, (2-chloro-pyrid-5-yl)-methyl-, (l-methyl-lH-imidazol-4-yl)-methyl-, (furan-2-yl)-methyl-, 2-(thiophen-2'-yl)-eth-l-yl-, 2- (indol-3'-yl)-eth-l-yl-, (lH-benzimidazol-2-yl)-methyl-, (oxetan-2-yl)-methyl-, (tetrahydro- furan-2-yl)-methyl-, 2-([r,3']dioxolan-2'-yl)-eth-l-yl-, 2-(morpholin-4'-yl)-eth-l-yl-, 2- (benzo[l',3']dioxol-5'-yl)-eth-l-yl-, and (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-, more preferably R² is heteroaryl-Ci-C₂alkylene- or heteroaryl-Ci-C₂alkylene- wherein the heteroaryl moiety is substituted by one to five R⁹.

A group of preferred compounds are those wherein R² is aryl or aryl substituted by one to five R⁹, for example 2-chloro-phenyl-, 3-fluoro-phenyl-, 2-methyl-phenyl-, 2-chloro- 6-m ethyl -phenyl-, 2-trifluoromethyl-phenyl-, and 2,4-dimethoxy-phenyl-.

A group of preferred compounds are those wherein R² is heterocyclyl or heterocyclyl substituted by one to five R⁹, for example 3-methyl-pyrid-2-yl-, 1,3 -dimethyl- lH-pyrazol-5- yl-, 4-methyl-thiazol-2-yl-, 5-methyl-thiadiazol-2-yl-, quinolin-2-yl-, quinolin-5-yl-, benzothiazol-6-yl-, 4-methyl-benzothiazol-2-yl-, thietan-3-yl-, l-oxo-thietan-3-yl-, 1,1- dioxo-thietan-3-yl-, and 3-methyl-thietan-3-yl-, more preferably thietan-3-yl-, 1-oxo-thietan- 3-yl-, l,l-dioxo-thietan-3-yl- and 3-methyl-thietan-3-yl-.

Preferably R⁴ is aryl or aryl substituted by one to five R¹⁰, more preferably aryl substituted by two to three R¹⁰, more preferably phenyl substituted by two to three R¹⁰, even more preferably 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl-, 4-bromo- 3,5-dichloro-phenyl or 3,4,5-trichloro-phenyl-, even more preferably 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl-, or 3,4,5-trichloro-phenyl-, most preferably R⁴ is 3 , 5 -di chl oro-pheny 1.

Preferably each R⁵ is independently hydrogen, halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, Ci-C₈alkoxy, or Ci-C₈haloalkoxy, more preferably hydrogen, bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, even more preferably hydrogen, bromo, chloro, fluoro, nitro, or methyl, more preferably hydrogen or methyl, most preferably hydrogen. Preferably each R⁶ is independently hydrogen, methyl or ethyl, more preferably hydrogen or methyl, most preferably hydrogen.

Preferably each R⁷ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy, Ci- Cshaloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methyl, methoxy, or methylthio, preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R⁸ is independently chloro, fluoro or methyl, most preferably methyl.

Preferably each R⁹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifiuoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, preferably bromo, chloro, fluoro, nitro, methoxy or methyl, preferably bromo, chloro, fluoro, nitro, or methyl, e.g. bromo, chloro, fluoro, methoxy or methyl.

Preferably each R¹⁰ is independently halogen, Ci-C₈alkoxy, Ci-C₈haloalkoxy, Ci- C₈alkylthio-, or Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably bromo or chloro.

Preferably each R¹¹ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifiuoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro, or methyl.

For example, the present invention provides compounds of formula (I) wherein A¹, A² and A³ are independently C-R⁵, nitrogen, N-R⁶, oxygen or sulfur, provided

1 2 3 5 1 2 3 6 that two of A , A or A are C-R or nitrogen and that one of A , A or A is N-R , oxygen or sulfur;

A⁴ and A⁵ are independently C-R⁵ or nitrogen;

G¹ is oxygen or sulfur;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, or heterocyclyl or heterocyclyl substituted by one to five R⁹;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R¹⁰, or heteroaryl or heteroaryl substituted by one to five R¹⁰; each R⁵ is independently hydrogen, halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, Ci-C₈alkoxy, Ci-C₈haloalkoxy, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; each R⁶ is independently hydrogen or Ci-C₈alkyl;

each R⁷ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy, Ci-

C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-; Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁸ is independently halogen or Ci-C₈alkyl;

each R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci- C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹¹, or heterocyclyl or heterocyclyl substituted by one to five R¹¹; and

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-

C₄alkoxy, or Ci-C₄haloalkoxy; or a salt or N-oxide thereof;

provided that -A^-A³- is not -0-(CR⁵)=N-, -S-(CR⁵)=N-, N=(CR⁵)-0- or -N=(CR⁵)-S- irrespective of the values for A⁴ and A⁵, and

provided that -A^-A³- is not -(CR⁵)=(CR⁵)-0-, -0-(CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-S-, -S- (CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-( R⁶)-, -( R⁶)-(CR⁵)=(CR⁵)-, -(CR⁵)=N-( R⁶)- and -(NR⁶)- N=(CR⁵)- when A⁴ and A⁵ are both C-R⁵.

For example, the present invention provides compounds of formula (I) wherein A¹ and A³ are nitrogen or N-R⁶ and A² is C-R⁵, N-R⁶, nitrogen or sulfur, provided that two of A¹, A² or A³ are C-R⁵ or nitrogen and that one of A¹, A² or A³ is N-R⁶ or sulfur;

A⁴ and A⁵ are independently C-H or nitrogen;

G¹ is oxygen;

R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C4 alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyrazolyl,

benzimidazolyl, furanyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl;

R³ is Ci-Cshaloalkyl;

R⁴ is phenyl substituted by two to three R¹⁰;

R⁵ is independently hydrogen, halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-

C₈alkoxy, or Ci-C₈haloalkoxy;

R⁶ is hydrogen or Ci-C₈alkyl;

each R⁷ is independently bromo, chloro, fluoro, methyl, methoxy, or methylthio; each R⁸ is independently chloro, fluoro or methyl;

each R⁹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-

C₈alkoxy or Ci-C₈haloalkoxy;

each R¹⁰ is independently halogen, Ci-C₈alkoxy, Ci-C₈haloalkoxy, Ci-C₈alkylthio-, or Ci-C₈haloalkylthio-.

For example, the present invention provides compounds of formula (I) wherein

1 3 6 2 5 6 2 A and A are nitrogen or N-R and A is C-R , N-R , nitrogen or sulfur, preferably A is N- R⁶, nitrogen or sulfur, and provided that two of A¹, A² or A³ are C-R⁵ or nitrogen and that one of A¹, A² or A³ is N-R⁶ or sulfur;

A⁴ and A⁵ are C-H;

G¹ is oxygen;

R¹ is hydrogen, methyl or ethyl;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁸, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₄alkylene or imidazolyl- Ci-C₄alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹, Ci- C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃- C₈cycloalkyl-aminocarbonyl-Ci-C4 alkylene;

R³ is chlorodifluoromethyl or trifluorom ethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl-, 4-bromo-3,5- dichloro-phenyl or 3,4,5-trichloro-phenyl-; R⁵ is independently hydrogen, bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R⁶ is hydrogen, methyl or ethyl;

each R⁷ is independently bromo, chloro, fluoro, methyl, methoxy, or methylthio; each R⁸ is methyl;

each R⁹ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy.

For example, the present invention provides compounds of formula (I) wherein

-A^A^A³- is selected from =N-S-N=, -N=C(R⁵)-N(R⁶)-, -N(R⁶)-C(R⁵)=N-, =N- N(R⁶)-N=, -N=N-N(R⁶)- and -N(R⁶)-N=N-, preferably N-S-N= =N-N(R⁶)-N=, -N=N-N(R⁶)- and -N(R⁶)-N=N-;

A⁴ and A⁵ are C-H;

G¹ is oxygen;

R¹ is hydrogen;

Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci- C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci- C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₄alkylene or imidazolyl-Ci-C₄alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹;

R³ is trifluoromethyl;

R⁴ is 3,5-dichloro-phenyl;

R⁵ is hydrogen or methyl;

R⁶ is hydrogen or methyl;

each R⁷ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is independently bromo, chloro, fluoro, nitro, or methyl.

For example, the present invention provides compounds of formula (I) wherein -A^A^A³- is selected from =N-S-N= -N=C(R⁵)-N(R⁶)-, =N-N(R⁶)-N=, and -N=N-

N(R⁶)-, preferably =N-S-N= =N-N(R⁶)-N=, and -N=N-N(R⁶)-;

A⁴ and A⁵ are C-H;

G¹ is oxygen;

R¹ is hydrogen; R² is C₃-C₆alkyl or C₃-C₆alkyl substituted by one to five R⁷, C -C₈cycloalkyl or C - C₈cycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₂alkylene - or phenyl-Ci- C₂alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci- C₂alkylene- or pyridyl-Ci-C₂alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₂alkylene- or imidazolyl-Ci-C₂alkylene- wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or di oxo-thietanyl substituted by one to five R⁹;

R³ is trifluorom ethyl;

R⁴ is 3,5-dichloro-phenyl;

R⁵ is hydrogen or methyl;

R⁶ is hydrogen or methyl;

each R⁷ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is independently bromo, chloro, fluoro, methoxy or methyl.

For example, the present invention provides compounds of formula (I) wherein

-A^A^A³- is =N-S-N=;

A⁴ and A⁵ are CH;

G¹ is oxygen;

R¹ is hydrogen;

R² is C₃-C₆alkyl or C₃-C₆alkyl substituted by one to three R⁷, C -C₈cycloalkyl, phenyl-methylene- or phenyl-methylene- wherein the phenyl moiety is substituted by one to three R⁹, imidazolyl-methylene- or imidazolyl-methylene- wherein the imidazolyl moiety is substituted by one to three R⁹, thietanyl or methylthietanyl, oxo-thietanyl or methyl-oxo- thietanyl, dioxo-thietanyl or methyl-dioxo-thietanyl;

R³ is trifluorom ethyl;

R⁴ is 3,5-dichloro-phenyl;

R⁶ is hydrogen or methyl;

each R⁷ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is independently bromo, chloro, fluoro, methoxy or methyl.

A preferred embodiment are compounds of formula (IA) wherein A¹ is N, A² is S and

A³ is N, A⁴ is C-H, A⁵ is C-H, and G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are as defined for a compound of formula (I); or a salt or N-oxide thereof. A preferred embodiment are compounds of formula (IB) wherein A¹ is N, A² is C-H and A³ is N-H, A⁴ is C-H, A⁵ is C-H, and G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are as defined for a compound of formula (I); or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (IC) wherein A¹ is N, A² is C-H and A³ is N-Me, A⁴ is C-H, A⁵ is C-H, and G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are as defined for a compound of formula (I); or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (ID) wherein A¹ is N, A² is N and A³ is N-H, A⁴ is C-H, A⁵ is C-H, and G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are as defined for a compound of formula (I); or a salt or N-oxide thereof.

A preferred embodiment are compounds of formula (IE) wherein A¹ is N, A² is N and

A³ is N-Me, A⁴ is C-H, A⁵ is C-H, and G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are as defined for a compound of formula (I); or a salt or N-oxide thereof.

In a further aspect, the present invention provides a compound of formula (A)

wherein

A¹, A² and A³ are independently C-R⁵, nitrogen, N-R⁶, oxygen or sulfur, provided

A⁴ and A⁵ are independently C-R⁵ or nitrogen;

G¹ is oxygen or sulfur;

R² is cyclobutyl or cyclobutyl substituted by one to five R⁸, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo- thietanyl or oxo-thietanyl substituted by one to five R⁹, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹;

R³ is Ci-C₈haloalkyl;

each R⁸ is independently halogen or Ci-C₈alkyl;

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci- C₄alkoxy, or Ci-C₄haloalkoxy; or a salt or N-oxide thereof;

Preferably A¹ is nitrogen, C-R⁵ or N-R⁶, most preferably nitrogen or N-CH₃.

Preferably A² is C-R⁵, nitrogen or sulfur.

Preferably A³ is nitrogen C-R⁵ or N-R⁶, most preferably nitrogen or N-CH₃.

Preferably -A^A^A³- is selected from =N-S-N= -S-N=N-, -N=N-S-, =N-N(R⁶)-N=, -N=N-N(R⁶)-, -N(R⁶)-N=N-, -C(R⁵)=N-N(R⁶)-, -N(R⁶)-N=C(R⁵)-, -N=C(R⁵)-N(R⁶)-, - N(R⁶)-C(R⁵)=N-, -N=C(R⁵)-0-, -0-C(R⁵)=N-, =N-0-C(R⁵)= and =C(R⁵)-0-N=, more preferably -A^A^A³- is selected from =N-S-N= -S-N=N-, -N=N-S-, =N-N(R⁶)-N=, -N=N- N(R⁶)-, -N(R⁶)-N=N-, -C(R⁵)=N-N(R⁶)-, -N(R⁶)-N=C(R⁵)-, -N=C(R⁵)-N(R⁶)-, -N(R⁶)- C(R⁵)=N-, -N=C(R⁵)-0- and -0-C(R⁵)=N-, more preferably =N-S-N= -N=C(R⁵)-N(R⁶)-, - N=N-N(R⁶)-, =N-N(R⁶)-N=, -C(R⁵)=N-N(R⁶)- and -N=C(R⁵)-0-, more preferably =N-S-N= -N=C(R⁵)-N(R⁶)-, -N=N-N(R⁶)-, =N-N(R⁶)-N= and -C(R⁵)=N-N(R⁶)-, more preferably =N- S-N=,-N=N-N(R⁶)- and =N-N(R⁶)-N=, most preferably =N-S-N=.

R² is preferably cyclobutyl or cyclobutyl substituted by one to five R⁸, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹, more preferably thietanyl or methylthietanyl, oxo-thietanyl or methyl-oxothietanyl, dioxo-thietanyl or methyl-di oxo-thietanyl, more preferably thietanyl, oxo-thietanyl or dioxo-thietanyl.

The preferred definitions for A⁴, A⁵, G¹, R¹, R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹ are as described for compounds of formula (A).

For example, the present invention provides compounds of formula (A) wherein -A^l-A²-A³- is selected from =N-S-N= -S-N=N-, -N=N-S-, =N-N(R⁶)-N=, -N=N- N(R⁶)-, -N(R⁶)-N=N-, -C(R⁵)=N-N(R⁶)-, -N(R⁶)-N=C(R⁵)-, -N=C(R⁵)-N(R⁶)-, -N(R⁶)- C(R⁵)=N-, -N=C(R⁵)-0- and -0-C(R⁵)=N-;

A⁴ and A⁵ are independently C-H or nitrogen;

G¹ is oxygen;

R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-;

R³ is Ci-Cshaloalkyl;

R⁴ is phenyl substituted by two to three R¹⁰;

R⁵ is hydrogen, bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R⁶ is hydrogen or Ci-C₈alkyl;

each R⁸ is independently chloro, fluoro or methyl;

each R⁹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkoxy, Ci-C₈haloalkoxy;

For example, the present invention provides compounds of formula (A) wherein

-A^A^A³- is selected from =N-S-N= -N=C(R⁵)-N(R⁶)-, -N=N-N(R⁶)-, =N-N(R⁶)- N=, -C(R⁵)=N-N(R⁶)- and -N=C(R⁵)-0-;

A⁴ and A⁵ are C-H;

G¹ is oxygen;

R¹ is hydrogen, methyl or ethyl;

R³ is chlorodifluoromethyl or trifluoromethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl- or 3,4,5- trichloro-phenyl-, most preferably R⁴ is 3,5-dichloro-phenyl;

R⁵ is hydrogen, bromo, chloro, fluoro, nitro, or methyl R⁶ is hydrogen, methyl or ethyl;

each R⁸ is methyl;

For example, the present invention provides compounds of formula (A) wherein

-A^-A³- is selected from =N-S-N= -N=C(R⁵)-N(R⁶)-, -N=N-N(R⁶)-, =N-N(R⁶)- N= and -C(R⁵)=N-N(R⁶)-;

A⁴ and A⁵ are C-H;

G¹ is oxygen;

R¹ is hydrogen;

R² is cyclobutyl, thietanyl or methylthietanyl, oxo-thietanyl or methyl-oxo-thietanyl, or di oxo-thietanyl or methyl-dioxo-thietanyl;

R³ is trifluoromethyl;

R⁴ is 3,5-dichloro-phenyl;

R⁵ is hydrogen or methyl;

R⁶ is hydrogen or methyl.

Any reference herein to uses and/or compositions of compounds of formula (I) also applies equally to compounds of formula (A).

Generally compounds of formula I** are more biologically active than compounds of formula I*. Component A may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10: 1 to 1 : 10, e.g. a substantially 50:50 molar ratio. For example, when component A is an enantiomerically enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, when component A is an enantiomerically enriched mixture of formula I* the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.

The compounds in Tables 1 to 8 below illustrate the compounds of the invention.

Table 1 :

Table 1 provides 51 compounds of formula (la) wherein G¹ is oxygen, R³ is trifluoromethyl, 4 is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in the table below.

Compound R R

numbers

1.01 H ethyl-

1.02 H butyl-

1.03 H but-2-yl-

1.04 H 3-bromo-propyl-

1.05 H 2,2,2-trifluoro-ethyl-

1.06 H 3,3,3 -trifluoro-propy 1 -

1.07 H 2-methoxy-ethyl-

1.08 H 1 -methoxy-prop-2-yl-

1.09 H cyclobutyl-

1.10 H 2-methyl-cyclohex-l-yl-

1.11 H phenyl-methyl-

1.12 H 1 -phenyl -eth- 1 -yl-

1.13 H 2-phenyl-eth- 1 -yl-

1.14 H (3-chloro-phenyl)-methyl-

1.15 H (2-fluoro-phenyl)-m ethyl -

1.16 H (4-methoxy-phenyl)-methyl-

1.17 H (2-trifluoromethyl-phenyl)-methyl-

1.18 H (2-trifluoromethoxy-phenyl)-methyl-

1.19 H (pyrid-2-yl)-methyl- Compound R R¹

numbers

1.20 H (pyrid-3-yl)-methyl-

1.21 H (2-chloro-pyrid-5-yl)-methyl-

1.22 H (l-methyl-lH-imidazol-4-yl)-methyl-

1.23 H (furan-2-yl)-methyl-

1.24 H 2-(thiophen-2'-yl)-eth-l-yl-

1.25 H 2-(indol-3'-yl)-eth-l-yl-

1.26 H (lH-benzimidazol-2-yl)-methyl-

1.27 H (oxetan-2-yl)-methyl-

1.28 H (tetrahydrofuran-2-yl)-methyl-

1.29 H 2-([ 1 ',3 ']dioxolan-2'-yl)-eth- 1 -yl-

1.30 H 2-(morpholin-4'-yl)-eth- 1 -yl-

1.31 H 2-(benzo[ 1 ',3 ']dioxol-5'-yl)-eth- 1 -yl-

1.32 H (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-

1.33 H 2-chloro-phenyl-

1.34 H 3-fluoro-phenyl-

1.35 H 2-methyl-phenyl-

1.36 H 2-chloro-6-methyl-phenyl-

1.37 H 2-trifluoromethyl-phenyl-

1.38 H 2,4-dimethoxy-phenyl-

1.39 H 3-methyl-pyrid-2-yl-

1.40 H 1 ,3 -dimethyl- lH-pyrazol -5 -yl -

1.41 H 4-methyl-thiazol-2-yl-

1.42 H 5 -methyl -thi adi azol -2-yl -

1.43 H quinolin-2-yl-

1.44 H quinolin-5-yl-

1.45 H benzothiazol-6-yl-

1.46 H 4-methyl-benzothiazol-2-yl-

1.47 H thietan-3-yl-

1.48 H 1 -oxo-thi etan-3 -yl -

1.49 H 1 , 1 -di oxo-thi etan-3 -yl-

1.50 H 3 -methyl -thi etan-3 -yl-

1.51 H N-(2,2,2-Trifluoro-ethyl)-acetamide-2-yl

Table 2:

Table 2 provides 51 compounds of formula (lb) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 1 above.

Table 3 :

Table 3 provides 51 compounds of formula (Ic) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 1 above.

Table 4:

Table 4 provides 51 compounds of formula (Id) wherein G¹ is oxygen, R' is trifluoromethyl, 4 is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 1 above.

Table 5:

Table 5 provides 51 compounds of formula (Ie) wherein G¹ is oxygen, R³ is trifluoromethyl, 4 is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 1 above.

(le)

Table 6:

Table 6 provides 51 compounds of formula (If) wherein G¹ is oxygen, R³ is trifluoromethyl, 4 is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 1 above.

Table 7

Table 7 provides 5 compounds of formula (Ig) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed below.

Table 8

Table 8 provides 5 compounds of formula (Ih) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, and R¹ and R² have the values listed in Table 7 above.

Component A may be used in combination with anthelmintic agents. Such

anthelmintic agents include, compounds selected from the macrocyclic lactone class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin derivatives as described in EP- 357460, EP -444964 and EP-594291. Additional anthelmintic agents include

WO04/72086, particularly the compounds disclosed therein.

pyridapenthion, quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thimeton, triazophos, trichlorfon, vamidothion. Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801, isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m- cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, 5 triazamate, UC-51717.

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E) - (1 R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta -cyfluthrin, cyfluthrin, a-cypermethrin, beta -cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin,

10 cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, ?-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t- fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.

15 Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

20 fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

25 dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole,

30 195,RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601, silafluofen, silomadine,

Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole, azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeaux mixture, bromuconazole, bupirimate, ca ropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo- asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

metaflumizone, praziquarantel, triclabendazole.

Preferably, component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. More preferably, component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole,

The invention also includes the following combinations

A compound from Tables 1-8 and imidacloprid.

A compound from Tables [-8 and enrofloxacin.

A compound from Tables 1-8 and praziquantel.

A compound from Tables 1-8 and pyrantel embonate.

A compound from Tables 1-8 and febantel.

A compound from Tables 1-8 and penethamate.

A compound from Tables [-8 and moloxicam.

A compound from Tables 1-8 and cefalexin.

A compound from Tables 1-8 and kanamycin.

A compound from Tables 1-8 and pimobendan.

A compound from Tables 1-8 and clenbuterol.

A compound from Tables [-8 and fipronil.

A compound from Tables [-8 and ivermectin.

A compound from Tables 1-8 and omeprazole.

A compound from Tables 1-8 and tiamulin.

A compound from Tables 1-8 and benazepril.

A compound from Tables [-8 and milbemycin.

A compound from Tables 1-8 and cyromazine.

A compound from Tables [-8 and thiamethoxam.

A compound from Tables 1-8 and pyriprole.

A compound from Tables 1-8 and deltamethrin. A compound from Tables 8 and cefquinome.

A compound from Tables 8 and florfenicol.

A compound from Tables 8 and buserelin.

A compound from Tables 8 and cefovecin.

A compound from Tables 8 and tulathromycin.

A compound from Tables 8 and ceftiour.

A compound from Tables 8 and selamectin.

A compound from Tables 8 and carprofen.

A compound from Tables 8 and metaflumizone.

A compound from Tables 8 and moxidectin.

A compound from Tables 8 and methoprene (including S-methoprene).

A compound from Tables 8 and clorsulon.

A compound from Tables 8 and pyrantel.

A compound from Tables 8 and amitraz.

A compound from Tables 8 and triclabendazole.

A compound from Tables 8 and avermectin.

A compound from Tables 8 and abamectin.

A compound from Tables 8 and emamectin.

A compound from Tables 8 and eprinomectin.

A compound from Tables 8 and doramectin.

A compound from Tables 8 and selamectin.

A compound from Tables 8 and nemadectin.

A compound from Tables 8 and albendazole.

A compound from Tables 8 and cambendazole.

A compound from Tables 8 and fenbendazole.

A compound from Tables 8 and flubendazole.

A compound from Tables 8 and mebendazole.

A compound from Tables 8 and oxfendazole.

A compound from Tables 8 and oxibendazole.

A compound from Tables 8 and parbendazole.

A compound from Tables 8 and tetramisole.

A compound from Tables 8 and levamisole.

A compound from Tables 8 and pyrantel pamoate.

A compound from Tables 8 and oxantel. A compound from Tables 1-8 and morantel.

A compound from Tables 1-8 and triclabendazole.

A compound from Tables 1-8 and epsiprantel.

A compound from Tables 1-8 and fipronil.

A compound from Tables 1-8 and lufenuron.

A compound from Tables 1-8 and ecdysone.

A compound from Tables 1-8 and tebufenozide.

Examples of ratios include 100: 1 to 1 :6000, 50: 1 to 1 :50, 20: 1 to 1 :20, even more especially from 10: 1 to 1 : 10, 5: 1 to 1 :5, 2: 1 to 1 :2, 4: 1 to 2: 1, 1 : 1, or 5: 1, or 5:2, or 5:3, or 5:4, or 4: 1, or 4:2, or 4:3, or 3 : 1, or 3 :2, or 2: 1, or 1 :5, or 2:5, or 3 :5, or 4:5, or 1 :4, or 2:4, or 3 :4, or 1 :3, or 2:3, or 1 :2, or 1 :600, or 1 :300, or 1 : 150, or 1 :35, or 2:35, or 4:35, or 1 :75, or 2:75, or 4:75, or 1 :6000, or 1 :3000, or 1 : 1500, or 1 :350, or 2:350, or 4:350, or 1 :750, or 2:750, or 4:750. Those mixing ratios are understood to include, on the one hand, ratios by weight and also, on other hand, molar ratios.

The following paragraphs represent embodiments of invention 4 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur;

Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R¹⁰, or heteroaryl or heteroaryl substituted by one to five R¹⁰;

each R⁶ is independently hydrogen or Ci-C₈alkyl;

each R⁸ is independently halogen or Ci-C₈alkyl; each R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂- C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci- C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹¹, or heterocyclyl or heterocyclyl substituted by one to five R¹¹; and

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C₄alkoxy, or Ci-C₄haloalkoxy; or a salt or N-oxide thereof;

provided that -A^-A³- is not -(CR⁵)=(CR⁵)-0-, -0-(CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-S-, -S-

N=(CR⁵)- when A⁴ and A⁵ are both C-R^5';

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹ and A³ are nitrogen or N-R⁶ and A² is C-R⁵, N-R⁶, nitrogen or sulfur. c. A combination product according to paragraph a or paragraph b wherein -A¹-A²-A³- is selected from =N-S-N= -N=C(R⁵)-N(R⁶)-, -N(R⁶)-C(R⁵)=N-, =N-N(R⁶)-N=, -N=N-

N(R⁶)- and -N(R⁶)-N=N-. d. A combination product according to any preceding paragraph wherein A⁴ and A⁵ are C-R⁵. e. A combination product according to any preceding paragraph wherein G¹ is oxygen. f. A combination product according to any preceding paragraph wherein R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. g. A combination product according to any preceding paragraph wherein R² is Ci- C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-Ci₀cycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁸, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to four R⁹, pyridyl-Ci-C₄alkylene- or pyridyl-Ci- C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo- thietanyl or oxo-thietanyl substituted by one to five R⁹, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹. h. A combination product according to any preceding paragraph wherein R³ is chlorodifluoromethyl or trifluorom ethyl. i. A combination product according to any preceding paragraph wherein R⁴ is aryl or aryl substituted by one to five R¹⁰. j . A combination product according to paragraph a wherein

A¹ and A³ are nitrogen or N-R⁶ and A² is C-R⁵, N-R⁶, nitrogen or sulfur, provided that two of A¹, A² or A³ are C-R⁵ or nitrogen and that one of A¹, A² or A³ is N-R⁶ or sulfur;

A⁴ and A⁵ are CH;

G¹ is oxygen;

R¹ is hydrogen, methyl or ethyl;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁸, phenyl-Ci-C₄alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₄alkylene or imidazolyl- Ci-C₄alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹, Ci- C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃- C₈cycloalkyl-aminocarbonyl-Ci-C alkylene;

R³ is chlorodifluoromethyl or trifluorom ethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,4-dichloro-phenyl-, 4-bromo-3,5- dichloro-phenyl or 3,4,5-trichloro-phenyl-;

R⁵ is independently hydrogen, bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R⁶ is hydrogen, methyl or ethyl; each R⁷ is independently bromo, chloro, fluoro, methyl, methoxy, or methylthio; each R⁸ is methyl;

each R⁹ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy. k. A combination product according to paragraph a wherein

-A^A^A³- is selected from =N-S-N=, -N=C(R⁵)-N(R⁶)-, -N(R⁶)-C(R⁵)=N-, =N- N(R⁶)-N=, -N=N-N(R⁶)- and -N(R⁶)-N=N-;

A⁴ and A⁵ are CH;

G¹ is oxygen;

R¹ is hydrogen;

R² is Ci-Csalkyl or Ci-Csalkyl substituted by one to five R⁷, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci- C₄alkylene- wherein the phenyl moiety is substituted by one to five R⁹, pyridyl-Ci- C₄alkylene- or pyridyl -Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R⁹, imidazolyl-Ci-C₄alkylene or imidazolyl-Ci-C₄alkylene wherein the imidazolyl moiety is substituted by one to five R⁹, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo-thietanyl substituted by one to five R⁹, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R⁹;

R³ is trifluoromethyl;

R⁴ is 3,5-dichloro-phenyl;

R⁵ is hydrogen or methyl;

R⁶ is hydrogen or methyl;

each R⁷ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is independently bromo, chloro, fluoro, nitro, or methyl.

1. A combination product comprising a component A and a component B, wherein component A is a compound of formula (A)

G¹ is oxygen or sulfur;

R² is cyclobutyl or cyclobutyl substituted by one to five R⁸, oxetanyl or oxetanyl substituted by one to five R⁹, thietanyl or thietanyl substituted by one to five R⁹, oxo-thietanyl or oxo- thietanyl substituted by one to five R⁹, or dioxo-thietanyl or di oxo-thietanyl substituted by one to five R⁹;

R³ is Ci-C₈haloalkyl;

each R⁶ is independently hydrogen or Ci-C₈alkyl;

each R⁸ is independently halogen or Ci-C₈alkyl;

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C alkoxy, or Ci-C₄haloalkoxy; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. m. A compound according to paragraph 1, wherein

-A^-A³- is selected from =N-S-N= -S-N=N-, -N=N-S-, =N-N(R⁶)-N=, -N=N- N(R⁶)-, -N(R⁶)-N=N-, -C(R⁵)=N-N(R⁶)-, -N(R⁶)-N=C(R⁵)-, -N=C(R⁵)-N(R⁶)-, -N(R⁶)- C(R⁵)=N-, -N=C(R⁵)-0- and -0-C(R⁵)=N-;

A⁴ and A⁵ are independently CH or nitrogen;

G¹ is oxygen; R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-;

R³ is Ci-Cshaloalkyl;

R⁴ is phenyl substituted by two to three R¹⁰;

R⁶ is hydrogen or Ci-C₈alkyl;

each R⁸ is independently chloro, fluoro or methyl;

each R¹⁰ is independently halogen, Ci-C₈alkoxy, Ci-C₈haloalkoxy, Ci-C₈alkylthio-, or Ci-C₈haloalkylthio-. n. A combination product according to any one of paragraphs a to m, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S- methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. o. A combination product according to any one of paragraphs a to m, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. p. A combination product according to any one of paragraphs a to m, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. q. A combination product according to any one of paragraphs a to p, wherein the combination product is for use against parasitic invertebrate pests. r. A combination product according to any one of paragraphs a to p, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. s. A combination product according to paragraph r, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. t. A combination product according to paragraph r or paragraph s, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. u. A method comprising administering the combination product as defined in any one of paragraphs a to p to an animal. v. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to p to the animal. w. A method according to paragraph v, wherein said administration is oral

administration, parenteral administration or external administration. x. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragrahps a to p to the environment in which an animal resides. y. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to p and a pharmaceutically suitable excipient. Invention 5

WO2010/086225 discloses that certain isoxazoline compounds have insecticidal activity.

wherein

A¹, A², A³ and A⁴ are independently of each other C-H, C-R⁵, or nitrogen;

G¹ is oxygen or sulfur;

G² is C(R^6a)(R^6b), oxygen, sulfur, or N-R⁷;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R¹¹, or heteroaryl or heteroaryl substituted by one to five R¹¹;

each R⁵ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₃- Ciocycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; R^6a and R^6b are independently of each other hydrogen, halogen, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², C₂-C₈alkenyl or C₂-C₈alkenyl substituted by one to five R¹², C₂-C₈alkynyl, C₂-C₈haloalkynyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹³, or heterocyclyl or heterocyclyl substituted by one to five R¹³, or R¹⁴R¹⁵, wherein

R¹⁴ and R¹⁵ are independently hydrogen, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, or

R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or

R^6a and R^6b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;

R⁷ is hydrogen, hydroxy, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹⁶, C₃- Ciocycloalkyl, Ci-C₈alkoxy- or Ci-C₈alkoxy- substituted by one to five R¹⁶, (Ci- C₈alkyl)amino-, di(Ci-C₈alkyl)amino-, (Ci-C₈alkylcarbonyl)amino-, or (Ci- C₈alkoxycarbonyl)amino-;

each R⁸, R¹² and R¹⁶ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-;

each R⁹ is independently halogen or Ci-C₈alkyl;

each R¹⁰, R¹¹ and R¹³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂- C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹⁷, or heterocyclyl or heterocyclyl substituted by one to five R¹⁷;

each R¹⁷ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C alkoxy-, or Ci-C haloalkoxy-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

The compounds of formula I and their manufacturing processes are known from WO2010/086225. The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

The compounds of the invention may contain one or more asymmetric carbon atoms, for example, at the -CR³R⁴- group, and may exist as enantiomers (or as pairs of diastereo- isomers) or as mixtures of such.

Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl-, alkoxycarbonyl- or alkylamino-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are preferably Ci-C₆, more preferably C₁-C4, most preferably C₁-C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkenyl groups. Where an alkenyl moiety is said to be substituted, the alkenyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluorom ethyl, trifluorom ethyl, chlorodifluorom ethyl or 2,2,2-trifluoro-ethyl.

Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2- fluoro-vinyl. Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.

Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C₃-C₈, more preferably C₃-C₆ cycloalkyl groups. Where a cycloalkyl moiety is said to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heterocyclyl groups or heterocyclic rings (either alone or as part of a larger group, such as heterocyclyl-alkylene-) are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl,

benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents. Preferred values of A¹, A², A³, A⁴, G¹, G², R¹, R², R³, R⁴, R⁵, R^6a, R^6b,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are, in any combination, as set out below.

Preferably no more than two of A¹, A², A³ and A⁴ are nitrogen.

Preferably A¹ is C-H or C-R⁵, most preferably A¹ is C-R⁵.

Preferably A² is C-H or C-R⁵, most preferably A² is C-H.

Preferably A³ is C-H or C-R⁵, most preferably A³ is C-H.

Preferably A⁴ is C-H or C-R⁵, most preferably A⁴ is C-H.

Preferably A^s C-R⁵, A² is CH, A³ is CH or nitrogen and A⁴ is CH or nitrogen.

Preferably AHs C-R⁵, A² is CH, A³ is CH and A⁴ is CH.

Preferably G¹ is oxygen.

Preferably G² is C(R^6a)(R^6b), oxygen or N-R⁷, more preferably C(H)(R^6b), oxygen or N-R⁷, more preferably C(H)(Ci-C₆alkyl), C(H)(phenyl), oxygen, N(OH), N(OCi-C₆alkyl), or N(OCi-C₆haloalkyl), more preferably C(H)(Ci-C₆alkyl), oxygen, N(OH) or N(OC

C₆alkyl), more preferably C(H)(Ci-C₆alkyl), oxygen, or N(OH), more preferably C(H)(CH₃), C(H)(phenyl), oxygen, or N(OH), most preferably C(H)(CH₃).

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, or heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl, pyrrolidinyl,

tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyrazolyl, benzimidazolyl, furanyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cyclo- alkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, phenyl-Ci-C alkylene- or phenyl-Ci- C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci- C₄alkylene- or pyridyl -Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo- thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl- Ci-C alkylene, for example Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, phenyl-Ci-C alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl- Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo- thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, more preferably Ci-C₈alkyl or Ci- C₈alkyl substituted by halogen, C₃-Ci₀cycloalkyl or C₃-Ci₀cycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl, thietanyl, oxo- thietanyl, dioxo-thietanyl, Ci-C₈alkylaminocarbonyl-methylene, Ci- C₈haloalkylaminocarbonyl-methylene, or C₃-C₈cycloalkyl-aminocarbonyl-methylene, for example Ci-C₈alkyl or Ci-C₈alkyl substituted by halogen, C₃-Ciocycloalkyl or C₃-

Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci- C alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci- C alkylene- or pyridyl -Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl,most preferably butyl-, - I l l - cyclobutyl-, 1-phenyl-eth-l-yl-, phenyl-methyl-, (pyrid-2-yl)-methyl-, thietanyl-, -(2,2,2- trifluoro-ethyl)-acetamide-2-yl, oxo-thietanyl- or dioxo-thietanyl-, for example . butyl-, cyclobutyl-, 1-phenyl-eth-l-yl-, phenyl-methyl-, (pyrid-2-yl)-methyl-, thietanyl-, oxo- thietanyl- or dioxo-thietanyl-.

A group of preferred compounds are those wherein R² is Ci-C₆alkyl or Ci-C₆alkyl substituted by one to five R⁸, for example ethyl-, butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methoxy-ethyl-, -(2,2,2-trifluoro-ethyl)-acetamide- 2-yl and l-methoxy-prop-2-yl-, for example ethyl-, butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methoxy-ethyl-, and l-methoxy-prop-2-yl-.

A group of preferred compounds are those wherein R² is C₃-C₈cycloalkyl or C₃-

C₈cycloalkyl substituted by one to five R⁹, for example cyclobutyl-, and 2-methyl-cyclohex- 1-yl-.

A group of preferred compounds are those wherein R² is aryl-Ci-C₂alkylene- or aryl- Ci-C₂alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, for example phenyl- methyl-, 1-phenyl-eth-l-yl-, 2-phenyl-eth-l-yl-, (3-chloro-phenyl)-methyl-, (2-fluoro- phenyl)-methyl-, (4-methoxy-phenyl)-methyl-, (2-trifluoromethyl-phenyl)-methyl-, and (2- trifluoromethoxy-phenyl)-methyl-.

A group of preferred compounds are those wherein R² is heterocyclyl-Ci-C₂alkylene- or heterocyclyl-Ci-C₂alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, for example (pyrid-2-yl)-methyl-, (pyrid-3-yl)-methyl-, (2-chloro-pyrid-5-yl)-methyl-, (l-methyl-lH-imidazol-4-yl)-methyl-, (furan-2-yl)-methyl-, 2-(thiophen-2'-yl)-eth-l-yl-, 2- (indol-3'-yl)-eth-l-yl-, (lH-benzimidazol-2-yl)-methyl-, (oxetan-2-yl)-methyl-, (tetrahydro- furan-2-yl)-methyl-, 2-([r,3']dioxolan-2'-yl)-eth-l-yl-, 2-(mo holin-4'-yl)-eth-l-yl-, 2- (benzo[l',3']dioxol-5'-yl)-eth-l-yl-, and (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-, more preferably R² is heteroaryl-Ci-C₂alkylene- or heteroaryl-Ci-C₂alkylene- wherein the heteroaryl moiety is substituted by one to five R¹⁰.

A group of preferred compounds are those wherein R² is aryl or aryl substituted by one to five R¹⁰, for example 2-chloro-phenyl-, 3-fluoro-phenyl-, 2-methyl-phenyl-, 2-chloro- 6-m ethyl -phenyl-, 2-trifluoromethyl-phenyl-, and 2,4-dimethoxy-phenyl-.

A group of preferred compounds are those wherein R² is heterocyclyl or heterocyclyl substituted by one to five R¹⁰, for example 3-methyl-pyrid-2-yl-, l,3-dimethyl-lH-pyrazol-5- yl-, 4-methyl-thiazol-2-yl-, 5-methyl-thiadiazol-2-yl-, quinolin-2-yl-, quinolin-5-yl-, benzothiazol-6-yl-, 4-methyl-benzothiazol-2-yl-, thietan-3-yl-, l-oxo-thietan-3-yl-, 1,1- dioxo-thietan-3-yl-, and 3-methyl-thietan-3-yl-, more preferably R² is oxetanyl, thietanyl, oxo-thietanyl or dioxo-thietanyl each optionally substituted by one to five R¹⁰, most preferably R² is thietanyl, oxo-thietanyl or dioxo-thietanyl each optionally substituted by one to five R¹⁰. It is particularly preferred that the oxetanyl, thietanyl, oxo-thietanyl and dioxo- thietanyl ring is linked via the 3-position.

Preferably R⁴ is aryl or aryl substituted by one to five R¹¹, more preferably aryl substituted by two to three R¹¹, more preferably phenyl substituted by two to three R¹¹, even more preferably 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)- phenyl-, 3,4-dichloro-phenyl- or 3,4,5-trichloro-phenyl-, most preferably R⁴ is 3,5-dichloro- phenyl.

Preferably each R⁵ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈halo- alkyl, Ci-C₈alkoxy-, or Ci-C₈haloalkoxy-, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, even more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably methyl.

Preferably R^6a is hydrogen or Ci-C₆alkyl, most preferably hydrogen.

Preferably R^6b is hydrogen, Ci-C₆alkyl or phenyl, more preferably Ci-C₆alkyl or phenyl, more preferably methyl or phenyl, most preferably methyl.

Preferably R⁷ is hydroxyl, Ci-C₆alkoxy- or Ci-C₆ haloalkoxy-, more preferably R⁷ is hydroxy or Ci-C₆alkoxy-, most preferably hydroxy.

Preferably each R⁸ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R⁹ is independently chloro, fluoro or methyl, most preferably methyl.

Preferably each R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈halo- alkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, most preferably bromo, chloro, fluoro, cyano or methyl.

Preferably each R¹¹ is independently halogen, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci- C₈alkylthio-, or Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably bromo or chloro.

Preferably each R¹² is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy. Preferably each R¹³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈halo- alkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, most preferably bromo, chloro, fluoro, nitro, or methyl.

Preferably R¹⁴ and R¹⁵ are Ci-C₈alkyl or together with the nitrogen atom to which they are attached form a 4 to 6 heterocyclic ring, more preferably R¹⁴ and R¹⁵ are methyl.

Preferably each R¹⁶ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R¹⁷ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difiuoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro, or methyl.

For example, the present invention provides compounds of formula (I) wherein

G¹ is oxygen or sulfur;

G² is C(R^6a)(R^6b), oxygen, sulfur, or N-R⁷;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci- C₈alkoxycarbonyl-;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, or heterocyclyl or heterocyclyl substituted by one to five R¹⁰;

R³ is Ci-Cshaloalkyl;

each R⁵ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₃- Ciocycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

R^6a and R^6b are independently of each other hydrogen, halogen, Ci-C₈alkyl or Ci-

C₈alkyl substituted by one to five R¹², C₂-C₈alkenyl or C₂-C₈alkenyl substituted by one to five R¹², C₂-C₈alkynyl, C₂-C₈haloalkynyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci- C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹³, or heterocyclyl or heterocyclyl substituted by one to five R¹³, or R¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently hydrogen, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or R^6a and R^6b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic or heterocyclic ring;

R⁷ is hydrogen, hydroxy, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹⁶, C₃-

Ciocycloalkyl, Ci-C₈alkoxy- or Ci-C₈alkoxy- substituted by one to five R¹⁶, (Ci- C₈alkyl)amino-, di(Ci-C₈alkyl)amino-, (Ci-C₈alkylcarbonyl)amino-, or (Ci- C₈alkoxycarbonyl)amino-;

each R⁸, R¹² and R¹⁶ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁹ is independently halogen or Ci-C₈alkyl;

each R¹⁰, R¹¹ and R¹³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci- C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci- C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹⁷, or heterocyclyl or heterocyclyl substituted by one to five R¹⁷;

each R¹⁷ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-

C₄alkoxy-, or Ci-C₄haloalkoxy-.

For example, the present invention provides compounds of formula (I) wherein

A¹ is C-R⁵, A² is C-H, A³ is C-H or nitrogen and A⁴ is C-H or nitrogen;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, sulfur, or N-R⁷;

R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyrazolyl,

benzimidazolyl, furanyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl.

R³ is Ci-Cshaloalkyl;

R⁴ is phenyl substituted by two to three R¹¹;

R⁵ is halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, or Ci-C₈halo- alkoxy-;

R^6a is hydrogen or Ci-Cealkyl;

R^6b is hydrogen, Ci-C₆alkyl or phenyl;

R⁷ is hydroxyl, Ci-C₆alkoxy- or Ci-C₆ haloalkoxy-;

each R⁸ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is independently chloro, fluoro or methyl;

each R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkoxy-, Ci-C₈haloalkoxy-;

each R¹¹ is independently halogen, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, or Ci-C₈haloalkylthio-.

For example, the present invention provides compounds of formula (I) wherein AHs C-R⁵, A² is C-H, A³ is CH and A⁴ is C-H;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen, methyl or ethyl;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene;

R³ is chlorodifluoromethyl or trifluoromethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl- or 3,4,5-trichloro-phenyl-;

R⁵ is bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy; R^6a is hydrogen or Ci-C₆alkyl;

R^6b is Ci-C₆alkyl or phenyl;

R⁷ hydroxy or Ci-C₆alkoxy-;

each R⁸ is independently chloro, fluoro, or methoxy;

each R⁹ is methyl;

each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluorom ethyl, methoxy, difluoromethoxy, or trifluoromethoxy.

For example, the present invention provides compounds of formula (I) wherein AHs C-R⁵, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by halogen, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Cr C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci- C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl;

R³ is trifluoromethyl;

R⁴ is is 3,5-dichloro-phenyl;

R⁵ is methyl;

R^6a is hydrogen;

R^6b is methyl or phenyl;

R⁷ is hydroxy;

R¹⁰ is bromo, chloro, fluoro, cyano or methyl.

For example, the present invention provides compounds of formula (I) wherein

AHs C-R⁵, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen;

R² is C₃-C₆alkyl or C₃-C₆alkyl substituted by halogen, C₄-C₆cycloalkyl, phenyl-Ci-

C₂alkylene- or phenyl-Ci-C₂alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₂alkylene- or pyridyl-Ci-C₂alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl;

R³ is trifluoromethyl; R⁴ is is 3,5-dichloro-phenyl;

R⁵ is methyl;

R^6a is hydrogen;

R^6b is methyl or phenyl;

R⁷ is hydroxy;

R¹⁰ is bromo, chloro, fluoro or methyl.

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen;

R² is C₃-C₆alkyl or C₃-C₆alkyl substituted by halogen, pyridyl-methylene- or pyridyl- methylene- wherein the pyridyl moiety is substituted by one to three R¹⁰, thietanyl, oxo- thietanyl or dioxo-thietanyl.

R³ is trifluorom ethyl;

R⁴ is is 3,5-dichloro-phenyl;

R⁵ is methyl;

R^6a is hydrogen;

R^6b is methyl or phenyl;

R⁷ is hydroxy;

R¹⁰ is bromo, chloro, fluoro or methyl.

In one embodim of formula (la)

wherein A¹, A², A³, A⁴, G¹, R¹, R², R³, R⁴, R^6a and R^6b are as defined for compounds of formula (I); or a salt or N-oxide thereof. The preferences for A¹, A², A³, A⁴, G¹, R¹, R², R³, R⁴, R^6a and R^6b are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

In another embodiment the present invention provides compounds of formula (lb)

1 2 3 4 1 1 2 3 4

wherein A , A A A G , R , R R^J and are as defined for compounds of formula (I); or a salt or N-oxide thereof. The preferences for A¹, A², A³, A⁴, G¹, R¹, R², R³ and R⁴ are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

In another embodiment the present invention provides compounds of formula (Ic)

1 2 3 4 1 1 2 3 4 1

wherein A , A A A G , R , R R R" and R' are as defined for compounds of formula (I); or a salt or N-oxide thereof. The preferences for A¹, A², A³, A⁴, G¹, R¹, R², R³, R⁴ and R are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

The compounds in Tables 1 to 5 below illustrate the compounds of the invention. Table 1 :

Table 1 provides 51 compounds of formula (la¹) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, R⁵ is methyl, R^6a is hydrogen, R^6b is methyl, and R¹ and R² have the values listed in the table below.

Compound R R

numbers

1.01 H ethyl-

1.02 H butyl-

1.03 H but-2-yl-

1.04 H 3-bromo-propyl-

1.05 H 2,2,2-trifluoro-ethyl-

1.06 H 3,3,3 -trifluoro-propy 1 -

1.07 H 2-methoxy-ethyl-

1.08 H 1 -methoxy-prop-2-yl-

1.09 H cyclobutyl-

1.10 H 2-methyl-cyclohex-l-yl-

1.11 H phenyl-methyl-

1.12 H 1 -phenyl -eth- 1 -yl-

1.13 H 2-phenyl-eth- 1 -yl-

1.14 H (3-chloro-phenyl)-methyl-

1.15 H (2-fluoro-phenyl)-m ethyl -

1.16 H (4-methoxy-phenyl)-methyl-

1.17 H (2-trifluoromethyl-phenyl)-methyl-

1.18 H (2-trifluoromethoxy-phenyl)-methyl-

1.19 H (pyrid-2-yl)-methyl- Compound R R¹

numbers

1.20 H (pyrid-3-yl)-methyl-

1.21 H (2-chloro-pyrid-5-yl)-methyl-

1.22 H (l-methyl-lH-imidazol-4-yl)-methyl-

1.23 H (furan-2-yl)-methyl-

1.24 H 2-(thiophen-2'-yl)-eth-l-yl-

1.25 H 2-(indol-3'-yl)-eth-l-yl-

1.26 H (lH-benzimidazol-2-yl)-methyl-

1.27 H (oxetan-2-yl)-methyl-

1.28 H (tetrahydrofuran-2-yl)-methyl-

1.29 H 2-([ 1 ',3 ']dioxolan-2'-yl)-eth- 1 -yl-

1.30 H 2-(morpholin-4'-yl)-eth- 1 -yl-

1.31 H 2-(benzo[ 1 ',3 ']dioxol-5'-yl)-eth- 1 -yl-

1.32 H (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-

1.33 H 2-chloro-phenyl-

1.34 H 3-fluoro-phenyl-

1.35 H 2-methyl-phenyl-

1.36 H 2-chloro-6-methyl-phenyl-

1.37 H 2-trifluoromethyl-phenyl-

1.38 H 2,4-dimethoxy-phenyl-

1.39 H 3-methyl-pyrid-2-yl-

1.40 H 1 ,3 -dimethyl- lH-pyrazol -5 -yl -

1.41 H 4-methyl-thiazol-2-yl-

1.42 H 5 -methyl -thi adi azol -2-yl -

1.43 H quinolin-2-yl-

1.44 H quinolin-5-yl-

1.45 H benzothiazol-6-yl-

1.46 H 4-methyl-benzothiazol-2-yl-

1.47 H thietan-3-yl-

1.48 H 1 -oxo-thi etan-3 -yl -

1.49 H 1 , 1 -di oxo-thi etan-3 -yl-

1.50 H 3 -methyl -thi etan-3 -yl-

1.51 H N-(2,2,2-Trifluoro-ethyl)-acetamide-2-yl

Table 2: Table 2 provides 51 compounds of formula (lb¹) wherein G¹ is oxygen, R³ is trifluoromethyl, 4 is 3,5-dichloro-phenyl-, R⁵ is methyl and R¹ and R² have the values listed in Table 1.

Table 3 :

Table 3 provides 51 compounds of formula (Ic¹) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, R⁵ is methyl, R⁷ is hydroxy, and R¹ and R² have the values listed in Table 1.

Table 4:

1 3

Table 4 provides 51 compounds of formula (Ic") wherein G is oxygen, R is

trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, R⁵ is methyl, R⁷ is 2,2-difluoroethoxy, and R¹ and R² have the values listed in Table 1.

Table 5:

1 3

Table 5 provides 51 compounds of formula (Ic' ") wherein G is oxygen, R is

trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, R⁵ is methyl, R⁷ is methoxy, and R¹ and R² have the values listed in Table 1.

Component A may be used in combination with anthelmintic agents. Such

semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in US-5015630, WO-9415944 and WO-9522552. Additional anthelmintic agents include the benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of the class. Additional anthelmintic agents include imidazothiazoles and tetrahydropynmidines such as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel. Additional anthelmintic agents include flukicides, such as triclabendazole and clorsulon and the cestocides, such as praziquantel and epsiprantel.

WO04/72086, particularly the compounds disclosed therein.

Organophosphates: acephate, azamethiphos, azinphos-ethyl, azinphos- methyl, bromophos, bromophos-ethyl, cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate, isoxathion, malathion, methacriphos, methamidophos, methidathion, methyl- parathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate, phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate, phoxim, pirimiphos, pirimiphos- methyl, profenofos, propaphos, proetamphos, prothiofos, pyraclofos, pyridapenthion, quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thimeton, triazophos, trichlorfon, vamidothion.

Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, 5 HCN-801, isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m- cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, UC-51717.

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E) - (1 R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate,

10 bifenthrin, beta -cyfluthrin, cyfluthrin, a-cypermethrin, beta -cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, ?-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins

15 (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t- fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron, buprofezin, diofenolan, hexythiazox,

20 etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide,

tebufenozide; c) juvenoids: pyriproxyfen, methoprene (including S-methoprene),

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG-

25 505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin,

dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, MTI- 800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydramethylnon, IKI-220,

30 kanemite, NC-196, neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477,

pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen, NC-1111, R- 195,RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601, silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon, tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301. Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole, azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeaux mixture,

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

metaflumizone, praziquarantel, triclabendazole.

The invention also includes the following combinations:

A compound from Tables 1-5 and imidacloprid.

A compound from Tables 1-5 and enrofloxacin.

A compound from Tables 1-5 and praziquantel.

A compound from Tables 1-5 and pyrantel embonate.

A compound from Tables 1-5 and febantel.

A compound from Tables 1-5 and penethamate.

A compound from Tables 1-5 and moloxicam.

A compound from Tables 1-5 and cefalexin.

A compound from Tables 1-5 and kanamycin.

A compound from Tables 1-5 and pimobendan.

A compound from Tables 1-5 and clenbuterol.

A compound from Tables 1-5 and fipronil.

A compound from Tables 1-5 and ivermectin.

A compound from Tables 1-5 and omeprazole.

A compound from Tables 1-5 and tiamulin.

A compound from Tables 1-5 and benazepril.

A compound from Tables 1-5 and milbemycin.

A compound from Tables 1-5 and cyromazine.

A compound from Tables 1-5 and thiamethoxam. A compound from Tables 5 and pyriprole.

A compound from Tables 5 and deltamethrin.

A compound from Tables 5 and cefquinome.

A compound from Tables 5 and florfenicol.

A compound from Tables 5 and buserelin.

A compound from Tables 5 and cefovecin.

A compound from Tables 5 and tulathromycin.

A compound from Tables 5 and ceftiour.

A compound from Tables 5 and selamectin.

A compound from Tables 5 and carprofen.

A compound from Tables 5 and metaflumizone.

A compound from Tables 5 and moxidectin.

A compound from Tables 5 and methoprene (including S-methoprene).

A compound from Tables 5 and clorsulon.

A compound from Tables 5 and pyrantel.

A compound from Tables 5 and amitraz.

A compound from Tables 5 and triclabendazole.

A compound from Tables 5 and avermectin.

A compound from Tables 5 and abamectin.

A compound from Tables 5 and emamectin.

A compound from Tables 5 and eprinomectin.

A compound from Tables 5 and doramectin.

A compound from Tables 5 and selamectin.

A compound from Tables 5 and nemadectin.

A compound from Tables 5 and albendazole.

A compound from Tables 5 and cambendazole.

A compound from Tables 5 and fenbendazole.

A compound from Tables 5 and flubendazole.

A compound from Tables 5 and mebendazole.

A compound from Tables 5 and oxfendazole.

A compound from Tables 5 and oxibendazole.

A compound from Tables 5 and parbendazole.

A compound from Tables 5 and tetramisole.

A compound from Tables 5 and levamisole. A compound from Tables 1-5 and pyrantel pamoate.

A compound from Tables 1-5 and oxantel.

A compound from Tables 1-5 and morantel.

A compound from Tables 1-5 and triclabendazole.

A compound from Tables 1-5 and fipronil.

A compound from Tables 1-5 and lufenuron.

A compound from Tables 1-5 and ecdysone.

A compound from Tables 1-5 and tebufenozide.

Examples of ratios include 100: 1 to 1 :6000, 50: 1 to 1 :50, 20: 1 to 1 :20, even more especially from 10: 1 to 1 : 10, 5: 1 to 1 :5, 2: 1 to 1 :2, 4: 1 to 2: 1, 1 : 1, or 5: 1, or 5:2, or 5:3, or 5:4, or 4: 1, or 4:2, or 4:3, or 3 : 1, or 3 :2, or 2: 1, or 1 :5, or 2:5, or 3 :5, or 4:5, or 1 :4, or 2:4, or 3 :4, or 1 :3, or 2:3, or 1 :2, or 1 :600, or 1 :300, or 1 : 150, or 1 :35, or 2:35, or 4:35, or 1 :75, or 2:75, or 4:75, or 1 :6000, or 1 :3000, or 1 : 1500, or 1 :350, or 2:350, or 4:350, or 1 :750, or 2:750, or 4:750. Those mixing ratios are understood to include, on the one hand, ratios by weight and also, on other hand, molar ratios. The following paragarphs represent embodiments of invention 5 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur;

G² is C(R^6a)(R^6b), oxygen, sulfur, or N-R⁷;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C₃-

Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C alkylene- wherein the heterocyclyl moiety is substituted by one to five

R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-

C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-Cshaloalkyl;

R¹⁴ and R¹⁵ are independently hydrogen, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic ring; or

each R⁸, R¹² and R¹⁶ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci- C₈haloalkylsulfonyl-;

each R⁹ is independently halogen or Ci-C₈alkyl;

each R¹⁰, R¹¹ and R¹³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂- C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy-, Ci-

C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-

C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci-

C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹⁷, or heterocyclyl or heterocyclyl substituted by one to five R¹⁷;

each R¹⁷ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C alkoxy-, or Ci-C₄haloalkoxy-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹ is C-R⁵, A² is C-H, A³ is C-H or nitrogen and A⁴ is C-H or nitrogen. c. A combination product according to any preceding paragarph wherein G¹ is oxygen. d. A combination product according to any preceding paragarph wherein G² is

C(R^6a)(R^6b), oxygen or N-R⁷. e. A combination product according to any preceding paragarph wherein R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. f. A combination product according to any preceding paragarph wherein R² is Ci- C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C3-Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci- C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰. g. A combination product according to any preceding paragarph wherein R³ is chlorodifluoromethyl or trifluorom ethyl. h. A combination product according to any preceding paragarph wherein R⁴ is aryl or aryl substituted by one to five R¹¹. i. A combination product according to paragarph a wherein

AHs C-R⁵, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen, methyl or ethyl;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene;

R³ is chlorodifluoromethyl or trifluoromethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl- or 3,4,5-trichloro-phenyl-; R⁵ is bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R^6a is hydrogen or Ci-Cealkyl;

R^6b is Ci-C₆alkyl or phenyl;

R⁷ hydroxy or Ci-C₆alkoxy-;

each R⁸ is independently chloro, fluoro, or methoxy;

each R⁹ is methyl;

each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy. j . A combination product according to paragarph a wherein

AHs C-R⁵, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

G² is C(R^6a)(R^6b), oxygen, or N-R⁷;

R¹ is hydrogen;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by halogen, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci- C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci- C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl;

R³ is trifluoromethyl;

R⁴ is is 3,5-dichloro-phenyl;

R⁵ is methyl;

R^6a is hydrogen;

R^6b is methyl or phenyl;

R⁷ is hydroxy;

R¹⁰ is bromo, chloro, fluoro, cyano or methyl. k. A combination product according to any one of paragarphs a to j, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin,

eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole,

fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide.

1. A combination product according to any one of paragarphs a to j, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. m. A combination product according to any one of paragarphs a to j, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. n. A combination product according to any one of paragarphs a to m, wherein the combination product is for use against parasitic invertebrate pests. o. A combination product according to any one of paragarphs a to m, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. p. A combination product according to paragraph o, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. q. A combination product according to paragraph o or paragraph p, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. r. A method comprising administering the combination product as defined in any one of paragraphs a to m to an animal. s. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to m to the animal. t. A method according to paragraph s, wherein said administration is oral

administration, parenteral administration or external administration. u. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragarphs a to m to the environment in which an animal resides. v. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to m and a pharmaceutically suitable excipient.

Invention 6

WO2010/108733 discloses that certain isoxazoline compounds have insecticidal activity.

wherein

A¹, A², A³ and A⁴ are independently of each other C-H, C-R⁷, or nitrogen;

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl- R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-C₈haloalkyl;

R^5a and R^5b are both hydrogen;

R⁶ is hydrogen, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², C₃-Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R¹³, aryl-Ci-C alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁴, heterocyclyl-Ci-C alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁴, aryl or aryl substituted by one to five R¹⁴, or heterocyclyl or heterocyclyl substituted by one to five R¹⁴;

each R⁷ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkenyl, Ci-C₈haloalkenyl, Ci-C₈alkynyl, Ci-C₈haloalkynyl, C₃-Ci₀cycloalkyl, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkyl- sulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁸ and R¹² is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci- C₈haloalkylsulfonyl-;

each R⁹ and R¹³ is independently halogen or Ci-C₈alkyl;

each R¹⁰, R¹¹ and R¹⁴ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂- C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci- C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹⁵, or heterocyclyl or heterocyclyl substituted by one to five R¹⁵;

each R¹⁵ is independently halogen, cyano, nitro, Ci-C alkyl, Ci-C haloalkyl, Ci-C alkoxy-, or Ci-C₄haloalkoxy-; or a salt or N-oxide thereof; and component B is a further therapeutic agent;

The compounds of formula I and their manufacturing processes are known from WO2010/108733.

The compounds of the invention may contain one or more asymmetric carbon atoms, for example, at the -CR³R⁴- group and at the -CR^5aR^5a- group, and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such.

Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but- 2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are preferably Ci-C₆, more preferably C₁-C4, most preferably C₁-C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluorom ethyl, trifluorom ethyl, chlorodifluorom ethyl or 2,2,2-trifluoro-ethyl. Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2- fluoro-vinyl.

Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C3-C8, more preferably C3-C6 cycloalkyl groups. Where a cycloalkyl moiety is said to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heteroaiyl groups (either alone or as part of a larger group, such as heteroaryl- alkylene-) are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl.

Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaiyl groups are preferred, pyridyl being most preferred. Where a heteroaiyl moiety is said to be substituted, the heteroaiyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Heterocyclyl groups or heterocyclic rings (either alone or as part of a larger group, such as heterocyclyl-alkylene-) are defined to include heteroaiyl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl,

[l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo-thietanyl and 1, 1- dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

Preferred values of A¹, A², A³, A⁴, G¹, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are, in any combination, as set out below.

Preferably no more than two of A¹, A², A³ and A⁴ are nitrogen.

Preferably A¹ is C-H or C-R⁷, most preferably A¹ is C-R⁷.

Preferably A² is C-H or C-R⁷, most preferably A² is C-H.

Preferably A³ is C-H or C-R⁷, most preferably A³ is C-H.

Preferably A⁴ is C-H or C-R⁷, most preferably A⁴ is C-H.

In one preferred group of compounds A¹ is C-R⁷, A² is C-H, A³ is C-H or nitrogen and A⁴ is C-H or nitrogen.

In another group of preferred compoundsA¹ is C-R⁷, A² is C-H, A³ is C-H and A⁴ is

C-H.

Preferably G¹ is oxygen.

Preferably R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, most preferably hydrogen.

Preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydrothiophenyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, oxetanyl, thietanyl, oxo-thietanyl, dioxo- thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl,

[l,4]dioxanyl, and morpholinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3- dihydro-benzo[ 1 ,4]dioxinyl .

More preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrothiophenyl, isoxazolinyl, pyridyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl.

More preferably still R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-

Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl -Ci- C alkylene- or heterocyclyl-Ci-C alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-

C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl.

Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl- Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, tetrahydrofuranyl-Ci-C alkylene- or tetrahydrofuranyl-Ci-C alkylene- wherein the tetrahydrofuranyl moiety is substituted by one to five R¹⁰, imidazolyl -Ci-C₄alkylene- or imidazolyl-Ci-C₄alkylene- wherein the imidazolyl moiety is substituted by one to three R¹⁰, pyrazolyl-Ci-C alkylene- or pyryazolyl-Ci-C alkylene- wherein the pyrazolyl moiety is substituted by one to three R¹⁰, pyrrolyl-Ci-C alkylene- or pyrrolyl-Ci-C alkylene- wherein the pyrrolyl moiety is substituted by one to four R¹⁰, thiazolyl -Ci-C alkylene- or thiazolyl- Ci-C₄alkylene- wherein the thiazolyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, for example Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cyclo- alkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci- C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci- C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, tetrahydrofuranyl-Ci-C alkylene- or tetrahydrofuranyl-Ci-C alkylene- wherein the tetrahydrofuranyl moiety is substituted by one to five R¹⁰, imidazolyl-Ci-C alkylene- or imidazolyl-Ci-C₄alkylene- wherein the imidazolyl moiety is substituted by one to three R¹⁰, pyrazolyl-Ci-C₄alkylene- or pyryazolyl-Ci-C₄alkylene- wherein the pyrazolyl moiety is substituted by one to three R¹⁰, pyrrolyl-Ci-C alkylene- or pyrrolyl-Ci-C alkylene- wherein the pyrrolyl moiety is substituted by one to four R¹⁰, thiazolyl-Ci-C alkylene- or thiazolyl- Ci-C₄alkylene- wherein the thiazolyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰.

Even more preferably R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸,

C₃-Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl- Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, dioxo- thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl- Ci-C alkylene, for example Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, phenyl-Ci-C alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl- Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo- thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, more preferably Ci-C₈alkyl or Ci- C₈alkyl substituted by one to three halogen atoms, C₃-Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, thietanyl, oxo-thietanyl, dioxo-thietanyl, Ci-C₈alkylaminocarbonyl-methylene, Ci- C₈haloalkylaminocarbonyl-methylene, or C₃-C₈cycloalkyl-aminocarbonyl-methylene, for example Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three halogen atoms, C₃- Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci- C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to four R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, thietanyl, oxo-thietanyl or dioxo-thietanyl, most preferably butyl-, cyclobutyl-, 1-phenyl-eth-l-yl-, phenyl-methyl-, (pyrid-2-yl)-methyl-, thietanyl-, oxo- thietanyl- or dioxo-thietanyl-.

A group of preferred compounds are those wherein R² is Ci-C₆alkyl or Ci-C₆alkyl substituted by one to five R⁸, for example ethyl-, butyl-, but-2-yl-, 3-bromo-propyl-, 2,2,2- trifluoro-ethyl-, 3,3,3-trifluoro-propyl-, 2-methoxy-ethyl-, and l-methoxy-prop-2-yl-.

A group of preferred compounds are those wherein R² is C₃-C₈cycloalkyl or C₃- C₈cycloalkyl substituted by one to five R⁹, for example cyclobutyl-, and 2-methyl-cyclohex- 1-yl-.

A group of preferred compounds are those wherein R² is aryl-Ci-C₂alkylene- or aryl-

Ci-C₂alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, for example phenyl- methyl-, 1-phenyl-eth-l-yl-, 2-phenyl-eth-l-yl-, (3-chloro-phenyl)-methyl-, (2-fluoro- phenyl)-methyl-, (4-methoxy-phenyl)-methyl-, (2-trifluoromethyl-phenyl)-methyl-, and (2- trifluoromethoxy-phenyl)-methyl-.

A group of preferred compounds are those wherein R² is heterocyclyl-Ci-C₂alkylene- or heterocyclyl-Ci-C₂alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰ in which the heterocyclyl group is selected from 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrothiophenyl, isoxazolinyl, pyridyl,

tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo- thietanyl and dioxo-thietanyl. A group of preferred compounds are those wherein R² is heterocyclyl-Ci-C₂alkylene- or heterocyclyl-Ci-C₂alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, for example (pyrid-2-yl)-methyl-, (pyrid-3-yl)-methyl-, (2- chloro-pyrid-5-yl)-methyl-, (l-methyl-lH-imidazol-4-yl)-methyl-, (furan-2-yl)-methyl-, 2- (thiophen-2'-yl)-eth-l-yl-, 2-(indol-3'-yl)-eth-l-yl-, (lH-benzimidazol-2-yl)-methyl-, (oxetan-2-yl)-methyl-, (tetrahydrofuran-2-yl)-methyl-, 2-([r,3']dioxolan-2'-yl)-eth-l-yl-, 2- (mo holin-4'-yl)-eth-l-yl-, 2-(benzo[l',3']dioxol-5'-yl)-eth-l-yl-, and (2,3-dihydro- benzo[l,4]dioxin-6-yl)-methyl-, more preferably R² is heteroaryl-Ci-C₂alkylene- or heteroaryl-Ci-C₂alkylene- wherein the heteroaryl moiety is substituted by one to five R¹⁰. A group of preferred compounds are those wherein R² is aryl or aryl substituted by one to five R¹⁰, for example 2-chloro-phenyl-, 3-fluoro-phenyl-, 2-methyl-phenyl-, 2-chloro-6-methyl- phenyl-, 2-trifluoromethyl-phenyl-, and 2,4-dimethoxy-phenyl-.

A group of preferred compounds are those wherein R² is heterocyclyl- or

heterocyclyl substituted by one to five R¹⁰ in which the heterocyclyl group is selected from 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,

tetrahydrothiophenyl, isoxazolinyl, pyridyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo-thietanyl.

A group of preferred compounds are those wherein R² is heterocyclyl or heterocyclyl substituted by one to five R¹⁰, for example 3-methyl-pyrid-2-yl-, l,3-dimethyl-lH-pyrazol-5- yl-, 4-methyl-thiazol-2-yl-, 5-methyl-thiadiazol-2-yl-, quinolin-2-yl-, quinolin-5-yl-, benzothiazol-6-yl-, 4-methyl-benzothiazol-2-yl-, thietan-3-yl-, l-oxo-thietan-3-yl-, 1,1- dioxo-thietan-3-yl-, and 3-methyl-thietan-3-yl-, more preferably R² is oxetanyl, thietanyl, oxo-thietanyl or dioxo-thietanyl each optionally substituted by one to five R¹⁰, most preferably R² is thietanyl, oxo-thietanyl or dioxo-thietanyl each optionally substituted by one to five R¹⁰. It is particularly preferred that the oxetanyl, thietanyl, oxo-thietanyl or dioxo- thietanyl ring is linked via the 3-position.

Preferably R⁴ is aryl or aryl substituted by one to five R¹¹, more preferably aryl substituted by one to three R¹¹, more preferably phenyl substituted by one to three R¹¹, even more preferably 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)- phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3 -trifluoromethyl -phenyl-, most preferably R⁴ is 3,5-dichloro-phenyl.

Preferably R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², aryl-Ci- C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁴, heteroaryl-Ci-C₄alkylene- or heteroaryl-Ci-C₄alkylene- wherein the heteroaryl moiety is substituted by one to five R¹⁴, more preferably Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁴, more preferably Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², phenyl-methylene- or phenyl-methylene wherein the phenyl moiety is substituted by one to five R¹⁴, more preferably Ci-C₈alkyl or phenyl-methylene, more preferably Ci- C₈alkyl, more preferably methyl.

Preferably each R⁷ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈halo- alkyl, Ci-C₈alkenyl, Ci-C₈haloalkenyl, Ci-C₈alkoxy-, or Ci-C₈haloalkoxy-, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, tnfluoromethyl, vinyl, methoxy, difluoromethoxy, or trifluoromethoxy, most preferably methyl.

Preferably each R⁸ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-Cshaloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R¹¹ is independently halogen, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, or Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, trifluoromethyl, methoxy, or methylthio, most preferably bromo or chloro.

Preferably each R¹² is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, more preferably bromo, chloro, fluoro, methoxy, or methylthio, most preferably chloro, fluoro, or methoxy.

Preferably each R¹³ is independently chloro, fluoro or methyl, most preferably methyl.

Preferably each R¹⁴ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈halo- alkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, more preferably bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, most preferably bromo, chloro, fluoro, cyano or methyl.

Preferably each R¹⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro, or methyl, most preferably chloro, fluoro, or methyl.

A group of preferred compounds are those wherein

G¹ is oxygen or sulfur;

R³ is Ci-Cshaloalkyl;

R^5a and R^5b are both hydrogen;

R⁶ is hydrogen, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R¹³, aryl-Ci-C₄alkylene- or aryl- Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁴, heterocyclyl -Ci- C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁴, aryl or aryl substituted by one to five R¹⁴, or heterocyclyl or heterocyclyl substituted by one to five R¹⁴;

each R⁷ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkenyl, Ci-C₈haloalkenyl, Ci-C₈alkynyl, Ci-C₈haloalkynyl, C₃-Ciocycloalkyl, Ci-

C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁹ and R¹³ is independently halogen or Ci-C₈alkyl;

each R¹⁰, R¹¹ and R¹⁴ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, hydroxy, Ci- C₈alkoxy-, Ci-C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-

C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, Ci- C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl substituted by one to five R¹⁵, or heterocyclyl or heterocyclyl substituted by one to five R¹⁵;

each R¹⁵ is independently halogen, cyano, nitro, Ci-C alkyl, Ci-C haloalkyl, Ci- C₄alkoxy-, or Ci-C₄haloalkoxy-.

Another group of preferred compounds are those wherein

A¹ is C-R⁷, A² is C-H, A³ is C-H or nitrogen and A⁴ is C-H or nitrogen;

G¹ is oxygen;

R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from pyridyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo-thietanyl and dioxo- thietanyl;

R³ is Ci-C₈ haloalkyl;

R⁴ is phenyl substituted by one to three R¹¹;

R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², aryl-Ci-C alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁴, heteroaryl-Ci- C₄alkylene- or heteroaryl-Ci-C₄alkylene- wherein the heteroaryl moiety is substituted by one to five R¹⁴;

R⁷ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkenyl, Ci-C₈haloalkenyl, Ci-C₈alkoxy-, or Ci-C₈haloalkoxy-;

each R⁸ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci-

C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-;

each R⁹ is independently chloro, fluoro or methyl;

each R¹¹ is independently halogen, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, Ci-

C₈haloalkoxy-, Ci-C₈alkylthio-, or Ci-C₈haloalkylthio-;

each R¹² is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-;

each R¹⁴ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci- C₈alkoxy-, Ci-C₈haloalkoxy-;

Yet another group of preferred compounds are those wherein

A¹ is C-R⁷, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

R¹ is hydrogen, methyl or ethyl; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl -Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is chlorodifluoromethyl or trifluoromethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl- R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², phenyl-Ci-C alkylene- or phenyl -Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁴,

R⁷ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl,

trifluoromethyl, vinyl, methoxy, difluoromethoxy, or trifluoromethoxy;

each R⁸ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is methyl;

each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

each R¹² is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R¹⁴ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy.

A further group of preferred compounds are those wherein

A¹ is C-R⁷, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

R¹ is hydrogen;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three halogen atoms, C₃- Ciocycloalkyl or C₃-Ciocycloalkyl substituted by one or two methyl groups, phenyl-Ci-

C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C alkylene- or pyridyl-Ci-C alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, thietanyl, oxo-thietanyl or dioxo-thietanyl;

R³ is trifluoromethyl; R⁴ is 3,5-dichloro-phenyl;

R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl;

R⁷ is methyl

each R¹⁰ is independently bromo, chloro, fluoro, cyano or methyl.

A further group of preferred compounds are those wherein

A¹ is C-R⁷, A² is CH, A³ is CH and A⁴ is CH;

G¹ is oxygen;

R¹ is hydrogen;

R² is C₂-C₆alkyl or C₂-C₆alkyl substituted by one to three halogen atoms, C -

C₈cycloalkyl or C₄-C₈cycloalkyl substituted by one or two methyl groups, phenyl-Ci- C₂alkylene- or phenyl-Ci-C₂alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₂alkylene- or pyridyl-Ci-C₂alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, thietanyl, oxo-thietanyl or dioxo-thietanyl;

R³ is trifluorom ethyl;

R⁴ is 3,5-dichloro-phenyl;

R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl;

R⁷ is methyl

each R¹⁰ is independently bromo, chloro, fluoro, cyano or methyl.

In one embodiment the present invention provides compounds of formula (la)

wherein G¹, R¹, R², R³, R⁴, R^5a, R^5b, R⁶ and R⁷ are as defined for compounds of formula (I); or a salt or N-oxide thereof. The preferences for G¹, R¹, R², R³, R⁴, R^5a, R^5b, R⁶ and R⁷ are the same as the preferences set out for the corresponding substituents of compounds of the formula (I).

Generally compounds of formula I** are more biologically active than compounds of formula I*. Component A may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99: 1, e.g. 10: 1 to 1 : 10, e.g. a substantially 50:50 molar ratio. For example, when component A is an enantiomerically enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%). Likewise, when component A is an enantiomerically enriched mixture of formula I* the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.

The compounds in Table 1 below illustrate the compounds of the invention.

Table 1 :

Table 1 provides 50 compounds of formula (la) wherein G¹ is oxygen, R³ is trifluoromethyl, R⁴ is 3,5-dichloro-phenyl-, R^5a and R^5b are both hydrogen, R⁶ and R⁷ are both methyl, and R¹ and R² have the values listed in the table below.

Compound R R

numbers

1.01 H ethyl-

1.02 H butyl-

1.03 H but-2-yl-

1.04 H 3-bromo-propyl-

1.05 H 2,2,2-trifluoro-ethyl-

1.06 H 3,3,3 -trifluoro-propy 1 -

1.07 H 2-methoxy-ethyl-

1.08 H 1 -methoxy-prop-2-yl-

1.09 H cyclobutyl-

1.10 H 2-methyl-cyclohex-l-yl-

1.11 H phenyl-methyl-

1.12 H 1 -phenyl -eth- 1 -yl-

1.13 H 2-phenyl-eth- 1 -yl-

1.14 H (3-chloro-phenyl)-methyl-

1.15 H (2-fluoro-phenyl)-m ethyl -

1.16 H (4-methoxy-phenyl)-methyl-

1.17 H (2-trifluoromethyl-phenyl)-methyl-

1.18 H (2-trifluoromethoxy-phenyl)-methyl-

1.19 H (pyrid-2-yl)-methyl-

1.20 H (pyrid-3-yl)-methyl-

1.21 H (2-chloro-pyrid-5-yl)-methyl-

1.22 H (l-methyl-lH-imidazol-4-yl)-methyl-

1.23 H (furan-2-yl)-methyl-

1.24 H 2-(thiophen-2'-yl)-eth-l-yl-

1.25 H 2-(indol-3'-yl)-eth-l-yl-

1.26 H (lH-benzimidazol-2-yl)-methyl-

1.27 H (oxetan-2-yl)-methyl-

1.28 H (tetrahydrofuran-2-yl)-methyl-

1.29 H 2-([ 1 ',3 ']dioxolan-2'-yl)-eth- 1 -yl- Compound R R¹

numbers

1.30 H 2-(morpholin-4'-yl)-eth- 1 -yl-

1.31 H 2-(benzo[ 1 ',3 ']dioxol-5'-yl)-eth- 1 -yl-

1.32 H (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-

1.33 H 2-chloro-phenyl-

1.34 H 3-fluoro-phenyl-

1.35 H 2-methyl-phenyl-

1.36 H 2-chloro-6-methyl-phenyl-

1.37 H 2-trifluoromethyl-phenyl-

1.38 H 2,4-dimethoxy-phenyl-

1.39 H 3-methyl-pyrid-2-yl-

1.40 H 1 ,3 -dimethyl- lH-pyrazol -5 -yl -

1.41 H 4-methyl-thiazol-2-yl-

1.42 H 5 -methyl -thi adi azol -2-yl -

1.43 H quinolin-2-yl-

1.44 H quinolin-5-yl-

1.45 H benzothiazol-6-yl-

1.46 H 4-methyl-benzothiazol-2-yl-

1.47 H thi etan-3 -yl-

1.48 H 1 -oxo-thi etan-3 -yl -

1.49 H 1 , 1 -di oxo-thi etan-3 -yl-

1.50 H 3 -methyl -thi etan-3 -yl-

Component A may be used in combination with derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as described in WO-9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO-9611945, WO- 9319053, WO- 9325543, EP-626375, EP-382173, WO-9419334, EP-382173, and EP- 503538. Component A may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron;

WO04/72086, particularly the compounds disclosed therein.

Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

bromuconazole, bupirimate, carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutnafol, folpet, fosetyl- aluminium, furalaxyl, furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin, metrafenone, myclobutanil, neo- asozin, nicobifen, orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, vinclozin.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

metaflumizone, praziquarantel, triclabendazole.

The invention also includes the following combinations: A compound from Table and imidacloprid.

A compound from Table and enrofloxacin.

A compound from Table and praziquantel.

A compound from Table and pyrantel embonate.

A compound from Table and febantel.

A compound from Table and penethamate.

A compound from Table and moloxicam.

A compound from Table and cefalexin.

A compound from Table and kanamycin.

A compound from Table and pimobendan.

A compound from Table and clenbuterol.

A compound from Table and fipronil.

A compound from Table and ivermectin.

A compound from Table and omeprazole.

A compound from Table and tiamulin.

A compound from Table and benazepril.

A compound from Table and milbemycin.

A compound from Table and cyromazine.

A compound from Table and thiamethoxam.

A compound from Table and pyriprole.

A compound from Table and deltamethrin.

A compound from Table and cefquinome.

A compound from Table and florfenicol.

A compound from Table and buserelin.

A compound from Table and cefovecin.

A compound from Table and tulathromycin.

A compound from Table and ceftiour.

A compound from Table and selamectin.

A compound from Table and carprofen.

A compound from Table and metaflumizone.

A compound from Table and moxidectin.

A compound from Table and methoprene (including S-methoprene).

A compound from Table and clorsulon.

A compound from Table and pyrantel. A compound from Table 1 and amitraz.

A compound from Table 1 and triclabendazole.

A compound from Table 1 and avermectin.

A compound from Table 1 and abamectin.

A compound from Table 1 and emamectin.

A compound from Table 1 and eprinomectin.

A compound from Table 1 and doramectin.

A compound from Table 1 and selamectin.

A compound from Table 1 and nemadectin.

A compound from Table 1 and albendazole.

A compound from Table 1 and cambendazole.

A compound from Table 1 and fenbendazole.

A compound from Table 1 and flubendazole.

A compound from Table 1 and mebendazole.

A compound from Table 1 and oxfendazole.

A compound from Table 1 and oxibendazole.

A compound from Table 1 and parbendazole.

A compound from Table 1 and tetramisole.

A compound from Table 1 and levamisole.

A compound from Table 1 and pyrantel pamoate

A compound from Table 1 and oxantel.

A compound from Table 1 and morantel.

A compound from Table 1 and triclabendazole.

A compound from Table 1 and epsiprantel.

A compound from Table 1 and fipronil.

A compound from Table 1 and lufenuron.

A compound from Table 1 and ecdysone.

A compound from Table 1 and tebufenozide.

The following paragraphs represent embodiments of invention 6 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, or heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-C₈haloalkyl;

R^5a and R^5b are both hydrogen;

each R⁹ and R¹³ is independently halogen or Ci-C₈alkyl;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a wherein A¹ is C-R⁷, A² is C-H, A³ is C-H or nitrogen and A⁴ is C-H or nitrogen c. A combination product according to paragraph a or paragraph b wherein G¹ is oxygen. d. A combination product according to any one of paragraphs a to c wherein R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-. e. A combination product according to any one of paragraphs a to d wherein R² is Ci- C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci- C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci- C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C₄ alkylene, or C₃- C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene, wherein each aryl group is a phenyl group and each heterocycle group is selected from 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl,

pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrothiophenyl, isoxazolinyl, pyridyl,

tetrahydrofuranyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxetanyl, thietanyl, oxo- thietanyl and dioxo-thietanyl. f. A combination product according to any one of paragraphs a to e wherein R² is Ci- C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃-Ci₀cycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci- C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo-thietanyl or dioxo- thietanyl substituted by one to five R¹⁰. g. A combination product according to any one of paragraphs a to f wherein R³ is chlorodifluoromethyl or trifluoromethyl. h. A combination product according to any one of paragraphs a to g wherein R⁴ is aryl or aryl substituted by one to five R¹¹. i. A combination product according to any one of paragraphs a to i wherein R⁶ is Ci- C₈alkyl. j . A combination product according to paragraph a, wherein

A¹ is C-R⁷, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

R¹ is hydrogen, methyl or ethyl;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C₃-Ci₀cycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, phenyl-Ci-C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, oxetanyl or oxetanyl substituted by one to five R¹⁰, thietanyl or thietanyl substituted by one to five R¹⁰, oxo-thietanyl or oxo-thietanyl substituted by one to five R¹⁰, or dioxo-thietanyl or dioxo-thietanyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci- C₈haloalkylaminocarbonyl-Ci-C4 alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C4 alkylene;

R³ is chlorodifluoromethyl or trifluoromethyl;

R⁴ is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-

R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², phenyl-Ci-C₄alkylene- or phenyl -Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁴,

R⁷ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl,

trifluoromethyl, vinyl, methoxy, difiuoromethoxy, or trifiuoromethoxy;

each R⁸ is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R⁹ is methyl;

each R¹⁰ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difiuoromethoxy, or trifiuoromethoxy; each R¹² is independently bromo, chloro, fluoro, methoxy, or methylthio;

each R¹⁴ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy. k. A combination product according to paragraph a, wherein

A¹ is C-R⁷, A² is C-H, A³ is C-H and A⁴ is C-H;

G¹ is oxygen;

R¹ is hydrogen;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to three halogen atoms, C₃- Ciocycloalkyl or C₃-Ci₀cycloalkyl substituted by one or two methyl groups, phenyl-Ci-

C₄alkylene- or phenyl-Ci-C₄alkylene- wherein the phenyl moiety is substituted by one to five R¹⁰, pyridyl-Ci-C₄alkylene- or pyridyl-Ci-C₄alkylene- wherein the pyridyl moiety is substituted by one to four R¹⁰, thietanyl, oxo-thietanyl or dioxo-thietanyl;

R³ is trifluoromethyl;

R⁴ is 3,5-dichloro-phenyl;

R^5a and R^5b are hydrogen;

R⁶ is Ci-C₈alkyl;

R⁷ is methyl

each R¹⁰ is independently bromo, chloro, fluoro, cyano or methyl. 1. A combination product according to any one of paragraphs a to k, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S- methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. m. A combination product according to any one of paragraphs a to k, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. n. A combination product according to any one of paragraphs a to k, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. o. A combination product according to any one of paragraphs a to n, wherein the combination product is for use against parasitic invertebrate pests. p. A combination product according to any one of paragraphs a to n, wherein the combination product is for use against parasitic invertebrate pests in or on an animal. q. A combination product according to paragarph p, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot. r. A combination product according to paragraph p or paragraph q, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. s. A method comprising administering the combination product as defined in any one of paragraphs a to n to an animal. t. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to n to the animal. u. A method according to paragraph t, wherein said administration

administration, parenteral administration or external administration. v. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragraphs a to n to the environment in which an animal resides. w. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to n and a pharmaceutically suitable excipient.

Invention 7

WO2010/020522 discloses that certain isoxazoline compounds have insecticidal activity.

where

A is aryl or heteroaryl;

B is a saturated or partially unsaturated heterocyclyl;

C is aryl or heteroaryl;

G is oxygen or sulfur;

m is O, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3, 4 or 5;

o is O, 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5;

each R¹ is independently Ci-C₈alkyl;

R² is hydrogen, Ci-C₈alkyl, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₃-Ci₀cycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci- C₈alkoxycarbonyl-;

each R⁴ is independently halogen, cyano, Ci-C₈alkyl, Ci-C₈haloalkyl, hydroxy, Ci-C₈alkoxy- , Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-, or

if two R⁴ are attached to the same carbon atom the two R⁴ together form =0, =N-OR⁷ or =CR⁸R⁹;

R⁵ is Ci-C₈haloalkyl;

each R⁶ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkoxycarbonyl-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; X is S, SO, S0₂, S( R¹⁰) or SO( R¹⁰);

R⁷ is hydrogen or Ci-C₄alkyl;

R⁸ and R⁹ are independently of each other hydrogen or Ci-C₄alkyl;

R¹⁰ is hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci- C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C alkylene- or aryl-Ci-C alkylene- where the aryl moiety is substituted by one to three R¹¹, or heteroaryl-Ci-C alkylene- or heteroaryl- Ci-C alkylene- where the heteroaryl moiety is substituted by one to three R¹¹, aryl or aryl substituted by one to five R¹¹, or heteroaryl or heteroaryl substituted by one to five R¹¹; and each R¹¹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy or Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

or a salt or an N-oxide thereof;

provided that if A is a group of formula (A.I), (A.II), (A.III), (A.IV) or (A.V)

(A. I) (A. I I) (A. I I I) (A. IV) (A.V) where

A¹, A², A³ and A⁴ are independently of each other C-H or nitrogen;

n is 0, 1, 2, 3, 4 or 5, and each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl,

C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₃-Ci₀cycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci-

C₈alkoxycarbonyl-,

B is not a group of formula (B.VI)

where R ^a and R are both hydrogen;

and component B is a further therapeutic agent;

The compounds of formula I and their manufacturing processes are known from WO2010/020522.

The compounds of the invention may contain one or more asymmetric carbon atoms, and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such.

Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but- 2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are, unless indicated to the contrary, preferably Ci-C₆, more preferably C₁-C4, most preferably Ci-C₃ alkyl groups.

-CH(CH₂CH₃)-. The alkylene groups are, unless indicated to the contrary, preferably Ci-C₃, more preferably Ci-C₂, most preferably Ci alkylene groups.

Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E) or (Z) configuration. Examples are vinyl and allyl. The alkenyl groups are, unless indicated to the contrary, preferably C₂-C₆, more preferably C₂-C₄, most preferably C₂-C₃ alkenyl groups. Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are, unless indicated to the contrary, preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl-, haloalkylsulfonyl-, haloalkylcarbonyl- or

haloalkoxycarbonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl,

chlorodifluorom ethyl or 2,2,2-trifluoro-ethyl.

Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups, unless indicated to the contrary, are preferably C₃-C₈, more preferably C₃-C₆ cycloalkyl groups.

Aryl groups are aromatic ring systems which can be in mono, bi or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.

Heteroaryl groups are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.

Heterocyclyl groups or heterocyclic rings are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo- thietanyl and 1,1-dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro- benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.

Preferred values for A, A¹, A², A³, A⁴, A⁵, A⁶, B, C, G, m, n, o, p, R¹, R², R³, R⁴, R⁵, R⁶, X, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are, in any combination, as set out below.

Preferably A is a phenyl or a naphthyl group, or a six-membered monocyclic heteroaryl group, or a bicyclic heteroaryl group which comprises a six-membered ring. More preferably A is a phenyl or a naphthyl group. Where A is bicyclic it is preferred that the B ring and the amide group are connected to the same six-membered ring moiety. Furthermore it is preferred that the B ring and the amide group are attached to in para-position (as shown in the groups of formula (A.I), (A. VI) and (A.VIII) below).

Preferably A is a group of formula (A.I), (A. VI), (A. VII) or (A.VIII)

(A.I) (A.VI) (A.VII) (A.VIII) where

A¹, A², A³, A⁴, A⁵ and A⁶ are independently of each other C-H or nitrogen;

n is 0, 1, 2, 3, 4 or 5, and

each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₃-Ci₀cycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci- C₈alkoxycarbonyl-.

Preferably no more than two of A¹, A², A³, A⁴, A⁵ and A⁶ are nitrogen. Preferably A¹ is C-H.

Preferably A² is C-H.

Preferably A³ is C-H.

Preferably A⁴ is C-H.

Preferably A³ is C-H.

Preferably A⁶ is C-H.

More preferably A is a group of formula (A.Ia), (A. Via), (A.Vila) or (A. Villa)

(A.Ia) (A. VI a) (A.Vila) (A.VIIIa)

Preferably B is a three- to five-membered saturated or partially unsaturated heterocyclyl group. More preferably B is a five-membered saturated or partially unsaturated heterocyclyl group.

Preferably B is a group of formula (B.I), (B.II), (B.III), (B.IV), (B.V), (B.VI) or

(B.VII)

(B.I) (B.M) (B.IM) (B.IV)

(B.V) (B.VI) (B.VII) where

R^4a, R^4b, R^4c and R^4d are independently of each other hydrogen, halogen, cyano, Ci-C₈alkyl, Ci-C₈haloalkyl, hydroxy, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci- C₈haloalkylsulfonyl-, or

R^4a and R^4b and/or R^4c and R^4d when attached to the same carbon atom together form =0, N=OR⁷ or =CR⁸R⁹.

More preferably B is a group of formula (B.Ia), (B.IIa), (B.IIIa), (B.IVa), (B.Va), (B.VIa) or (B.Vila)

(B.Ia) (B.IIa) (B.IIIa) (B.IVa)

(B.Va) (B.VIa) (B.Vila) where R is halogen.

Preferably C is a six-membered aryl or heteroaryl group.

Preferably C is a group of formula (C.I)

where

p is 1, 2, 3, 4 or 5; and

each R⁶ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkoxycarbonyl-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl- or Ci-C₈haloalkylsulfonyl-.

More preferably C is a group of formula (C.la)

(C.la)

Preferably G is oxygen.

Preferably m is 0, 1, 2, 3 or 4.

Preferably n is 0, 1 or 2.

Preferably o is 0, 1 or 2.

Preferably p is 1, 2 or 3.

Preferably each R¹ is independently methyl.

Preferably R² is hydrogen, methyl, ethyl, methylcarbonyl- or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, most preferably hydrogen.

Preferably each R³ is independently halogen, cyano, Ci-C₈alkyl, C₂-C₈alkenyl or Ci- C₈alkoxy-, more preferably each R³ is independently methyl.

Preferably each R⁴ is independently halogen, Ci-C₈alkyl, Ci-C₈alkylthio-, Ci- C₈alkylsulfinyl- or Ci-C₈alkylsulfonyl-, or

if two R⁴ are attached to the same carbon atom the two R⁴ together form =0 or =CR⁸R⁹.

Preferably R⁵ is chlorodifluoromethyl or trifluoromethyl, most preferably trifluoromethyl.

Preferably each R⁶ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci- C₈haloalkyl, Ci-C₈alkoxy-, i-C₈alkylthio-, Ci-C₈alkylsulfinyl- or Ci-C₈alkylsulfonyl-.

Preferably X is S, SO or S0₂.

Preferably R⁷ is hydrogen.

Preferably R⁸ and R⁹ are independently of each other hydrogen or methyl.

Preferably R¹⁰ is hydrogen or cyano, more preferably hydrogen.

Preferably each R¹¹ is independently fluoro, chloro, cyano, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

Table 1

Table 1 illustrates compounds of formula I

WO04/72086, particularly the compounds disclosed therein.

Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas:

fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

metaflumizone, praziquarantel, triclabendazole.

The invention also includes the following combinations:

A compound from Table 1 and imidacloprid.

A compound from Table 1 and enrofloxacin.

A compound from Table 1 and praziquantel. A compound from Table and pyrantel embonate.

A compound from Table and febantel.

A compound from Table and penethamate.

A compound from Table and moloxicam.

A compound from Table and cefalexin.

A compound from Table and kanamycin.

A compound from Table and pimobendan.

A compound from Table and clenbuterol.

A compound from Table and fipronil.

A compound from Table and ivermectin,

A compound from Table and omeprazole,

A compound from Table and tiamulin.

A compound from Table and benazepril,

A compound from Table and milbemycin.

A compound from Table and cyromazine.

A compound from Table and thiamethoxam.

A compound from Table and pyriprole.

A compound from Table and deltamethrin.

A compound from Table and cefquinome.

A compound from Table and florfenicol.

A compound from Table and buserelin.

A compound from Table and cefovecin.

A compound from Table and tulathromycin.

A compound from Table and ceftiour.

A compound from Table and selamectin.

A compound from Table and carprofen.

A compound from Table and metaflumizone.

A compound from Table and moxidectin.

A compound from Table and methoprene (including S-methoprene).

A compound from Table and clorsulon.

A compound from Table and pyrantel.

A compound from Table and amitraz.

A compound from Table and triclabendazole.

A compound from Table and avermectin. A compound from Table 1 and abamectin.

A compound from Table 1 and emamectin.

A compound from Table 1 and eprinomectin.

A compound from Table 1 and doramectin.

A compound from Table 1 and selamectin.

A compound from Table 1 and nemadectin.

A compound from Table 1 and albendazole.

A compound from Table 1 and cambendazole.

A compound from Table 1 and fenbendazole.

A compound from Table 1 and flubendazole.

A compound from Table 1 and mebendazole.

A compound from Table 1 and oxfendazole.

A compound from Table 1 and oxibendazole.

A compound from Table 1 and parbendazole.

A compound from Table 1 and tetramisole.

A compound from Table 1 and levamisole.

A compound from Table 1 and pyrantel pamoate

A compound from Table 1 and oxantel.

A compound from Table 1 and morantel.

A compound from Table 1 and triclabendazole.

A compound from Table 1 and epsiprantel.

A compound from Table 1 and fipronil.

A compound from Table 1 and lufenuron.

A compound from Table 1 and ecdysone.

A compound from Table 1 and tebufenozide.

The following paragraphs represent embodiments of invention 7 a. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

where

A is aryl or heteroaryl;

B is a saturated or partially unsaturated heterocyclyl;

C is aryl or heteroaryl;

G is oxygen or sulfur; m is O, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3, 4 or 5;

o is 0, 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5;

each R¹ is independently Ci-C₈alkyl;

each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C3-Ciocycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci- C₈alkoxycarbonyl-;

R⁵ is Ci-C₈haloalkyl;

R⁷ is hydrogen or d-C₄alkyl;

R⁸ and R⁹ are independently of each other hydrogen or Ci-C₄alkyl;

R¹⁰ is hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci- C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C alkylene- or aryl-Ci-C alkylene- where the aryl moiety is substituted by one to three R¹¹, or heteroaryl-Ci-C₄alkylene- or heteroaryl- Ci-C₄alkylene- where the heteroaryl moiety is substituted by one to three R¹¹, aryl or aryl substituted by one to five R¹¹, or heteroaryl or heteroaryl substituted by one to five R¹¹; and each R¹¹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy or Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

or a salt or an N-oxide thereof; provided that if A is a group of formula (A.I), (A.II), (A.III), (A.IV) or (A. V)

(A.I) (A.II) (A.III) (A.IV) (A.V) where

A¹, A², A³ and A⁴ are independently of each other C-H or nitrogen;

n is 0, 1, 2, 3, 4 or 5, and

each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C3-Ciocycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci- C₈alkoxycarbonyl-,

B is not a group of formula (B.VI)

where R ^a and R are both hydrogen

and component B is a further therapeutic agent;

wherein the combination product is for use in a method of therapeutic treatment. b. A combination product according to paragraph a where A is a group of formula (A.I), (A. VI), (A. VII) or (A. VIII)

(A.I) (A.VI) (A.VII) (A.VIII) where A¹, A², A³, A⁴, A⁵ and A⁶ are independently of each other C-H or nitrogen; n is 0, 1, 2, 3, 4 or 5, and

each R³ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C3-Ciocycloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, or Ci- C₈alkoxycarbonyl-. c. A combination product according to paragraph a or paragraph b where B is a group of formula (B.I), (B.II), (B ill), (B.IV), (B.V), (B.VI) or (B.VII)

(B. I) (B. I I) (B . I I I) (B. IV)

(B.V) (B.VI) (B.VI I) where

R^4a and R^4b and/or R^4c and R^4d when attached to the same carbon atom together form =0, N=OR⁷ or =CR⁸R⁹. d. A combination product according to any one of paragraphs a to c where C is a group of formula (C.I)

where p is 1, 2, 3, 4 or 5; and

each R⁶ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkoxycarbonyl-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl- or Ci-C₈haloalkylsulfonyl-. e. A combination product according to any one of paragraphs a to d, wherein each R⁵ is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or methoxycarbonyl-. f. A combination product according to any one of paragraphs a to e, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S- methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide. g. A combination product according to any one of paragraphs a to e, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone. h. A combination product according to any one of paragraphs a to e, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel. i. A combination product according to any one of paragraphs a to h, wherein the combination product is for use against parasitic invertebrate pests. j . A combination product according to any one of paragraphs a to h„ wherein the combination product is for use against parasitic invertebrate pests in or on an animal. k. A combination product according to paragraph j, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot.

1. A combination product according to paragraph j or paragraph k wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey. m. A method comprising administering the combination product as defined in any one of paragraphs a to h to an animal. m. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of paragraphs a to h to the animal. n. A method according to paragraph m, wherein said administration is oral

administration, parenteral administration or external administration. o. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of paragraphs a to h to the environment in which an animal resides. p. A pharmaceutical composition comprising component A and component B as defined in any one of paragraphs a to h and a pharmaceutically suitable excipient.

Embodiments applicable to inventions 1 to 7 The combination product may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon' s Division, The Manufacturing Confectioner Publishing Co.; and PCT

Publication WO 03/024222.

Of particular note is a combination product where component B has a different site of action from the compound of formula I. In certain instances, a combination with at least one other parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, the combination product of the invention may comprise a compound of formula I and biologically effective amount of at least one additional parasitic invertebrate pest control active ingredient having a similar spectrum of control but a different site of action.

The combination products can be applied without other adjuvants, but most often application will be of a formulation comprising one or more active ingredients with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. One method of application involves spraying a water dispersion or refined oil solution of the combination products. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy. Such sprays can be applied from spray containers such as a can, a bottle or other container, either by means of a pump or by releasing it from a pressurized container, e.g., a pressurized aerosol spray can. Such spray compositions can take various forms, for example, sprays, mists, foams, fumes or fog. Such spray compositions thus can further comprise propellants, foaming agents, etc. as the case may be. Of note is a spray composition comprising a biologically effective amount of the combination product and a carrier. One embodiment of such a spray composition comprises a biologically effective amount of a the combination product and a propellant.

Representative propellants include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrofluorocarbons, chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Of note is a spray composition (and a method utilizing such a spray composition dispensed from a spray container) used to control at least one parasitic invertebrate pest selected from the group consisting of mosquitoes, black flies, stable flies, deer flies, horse flies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, and the like, including individually or in combinations.

The controlling of animal parasites includes controlling external parasites that are parasitic to the surface of the body of the host animal (e.g., shoulders, armpits, abdomen, inner part of the thighs) and internal parasites that are parasitic to the inside of the body of the host animal (e.g., stomach, intestine, lung, veins, under the skin, lymphatic tissue).

External parasitic or disease transmitting pests include, for example, chiggers, ticks, lice, mosquitoes, flies, mites and fleas. Internal parasites include heartworms, hookworms and helminths. The combination products are particularly suitable for combating external parasitic pests. The combination products are suitable for systemic and/or non-systemic control of infestation or infection by parasites on animals.

The combination products are suitable for combating parasitic invertebrate pests that infest animal subjects including those in the wild, livestock and agricultural working animals. Livestock is the term used to refer (singularly or plurally) to a domesticated animal intentionally reared in an agricultural setting to make produce such as food or fiber, or for its labor; examples of livestock include cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens, turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and/or wool). By combating parasites, fatalities and performance reduction (in terms of meat, milk, wool, skins, eggs, etc.) are reduced, so that applying the combination product allows more economic and simple husbandry of animals.

The combination products are especially suitable for combating parasitic invertebrate pests that infest companion animals and pets (e.g., dogs, cats, pet birds and aquarium fish), research and experimental animals (e.g., hamsters, guinea pigs, rats and mice), as well as animals raised for/in zoos, wild habitats and/or circuses.

In an embodiment of this invention, the animal is preferably a vertebrate, and more preferably a mammal, avian or fish. In a particular embodiment, the animal subject is a mammal (including great apes, such as humans). Other mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Avians include Anatidae (swans, ducks and geese), Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges, grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines (e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g., ostriches).

Birds treated or protected by the combination product can be associated with either commercial or noncommercial aviculture. These include Anatidae, such as swans, geese, and ducks, Columbidae, such as doves and domestic pigeons, Phasianidae, such as partridge, grouse and turkeys, Thesienidae, such as domestic chickens, and Psittacines, such as parakeets, macaws and parrots raised for the pet or collector market, among others.

For purposes of the present invention, the term "fish" shall be understood to include without limitation, the Teleosti grouping of fish, i.e., teleosts. Both the Salmoniformes order (which includes the Salmonidae family) and the Perciformes order (which includes the Centrarchidae family) are contained within the Teleosti grouping. Examples of potential fish recipients include the Salmonidae, Serranidae, Sparidae, Cichlidae, and Centrarchidae, among others.

Other animals are also contemplated to benefit from the inventive methods, including marsupials (such as kangaroos), reptiles (such as farmed turtles), and other economically important domestic animals for which the inventive methods are safe and effective in treating or preventing parasite infection or infestation.

Examples of parasitic invertebrate pests controlled by administering a pesticidally effective amount of the combination products to an animal to be protected include ectoparasites (arthropods, acarines, etc.) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.).

The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. The term 'helminths' is meant to include nematodes, trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalent and serious economic problem with domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry.

Among the helminths, the group of worms described as nematodes causes widespread and at times serious infection in various species of animals. Nematodes that are contemplated to be treated by the combination products of the invention and by the inventive methods include, without limitation, the following genera:

Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma, Dictyocaulus,

Dioctophyme, Dipetalonema, Diphyllobothrium, Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius, Necator, Nematodirus, Oesophagostomum, Ostertagia, Oxyuris, Parafilaria, Parascaris,

Physaloptera, Protostrongylus, Setaria, Spirocerca, Stephanofilaria, Strongyloides,

Strongylus, Thelazia, Toxascaris, Toxocara, Trichinella, Trichonema, Trichostrongylus, Trichuris, Uncinaria and Wuchereria.

Of the above, the most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema,

Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia and

Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like.

Trematodes that are contemplated to be treated by the invention and by the inventive methods include, without limitation, the following genera: Alaria, Fasciola, Nanophyetus, Opisthorchis, Paragonimus and Schistosoma.

Cestodes that are contemplated to be treated by the invention and by the inventive methods include, without limitation, the following genera: Diphyllobothrium, Diplydium, Spirometra and Taenia.

The most common genera of parasites of the gastrointestinal tract of humans are Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella, Capillaria, Trichuris and

Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filarial worms such as Wuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella.

Numerous other helminth genera and species are known to the art, and are also contemplated to be treated by the combination products. These are enumerated in great detail in Textbook of Veterinary Clinical Parasitology, Volume 1, Helminths, E. J. L. Soulsby, F. A. Davis Co., Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6^thEdition of Monnig's Veterinary Helminthology and Entomology), E. J. L. Soulsby, Williams and Wilkins Co., Baltimore, Md.

The combination products are effective against a number of animal ectoparasites (e.g., arthropod ectoparasites of mammals and birds).

Insect and acarine pests include, e.g., biting insects such as flies and mosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, and the like.

Adult flies include, e.g., the horn fly or Haematobia irritans, the horse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, the black fly or Simulium spp., the deer fly or Chrysops spp., the louse fly or Me lophagus ovinus, and the tsetse fly or Glossina spp. Parasitic fly maggots include, e.g., the bot fly {Oestrus ovis and Cuterebra spp.), the blow fly or Phaenicia spp., the screwworm or Cochliomyia hominivorax, the cattle grub or

Hypoderma spp., the fleeceworm and the Gastrophilus of horses. Mosquitoes include, for example, Culex spp., Anopheles spp. and Aedes spp.

Mites include Me sostigmalphatalpha spp. e.g., mesostigmatids such as the chicken mite, Dermalphanyssus galphallinalphae; itch or scab mites such as Sarcoptidae spp. for example, Salpharcoptes scalphabiei; mange mites such as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis; chiggers e.g., Trombiculidae spp. for example the North American chigger, Trombiculalpha alphalfreddugesi .

Ticks include, e.g., soft-bodied ticks including Argasidae spp. for example Argalphas spp. and Ornithodoros spp.; hard-bodied ticks including Ixodidae spp., for example

Rhipicephalphalus sanguineus, Dermacentor variabilis, Dermacentor andersoni,

Amblyomma americanum, Ixodes scapular is and other Rhipicephalus spp. (including the former Boophilus genera).

Lice include, e.g., sucking lice, e.g., Menopon spp.

and Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.

Fleas include, e.g., Ctenocephalides spp., such as dog flea (Ctenocephalides canis) and cat flea {Ctenocephalides felis); Xenopsylla spp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. such as human flea (Pulex irritans).

True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimex lectularius); Triatominae spp. including triatomid bugs also known as kissing bugs; for example

Rhodnius prolixus and Triatoma spp. Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks and helminths cause tremendous losses to the livestock and companion animal sectors. Arthropod parasites also are a nuisance to humans and can vector disease-causing organisms in humans and animals.

Numerous other parasitic invertebrate pests are known to the art, and are also contemplated to be treated by the combination products. These are enumerated in great detail in Medical and Veterinary Entomology, D. S. Kettle, John Wiley AND Sons, New York and Toronto; Control of Arthropod Pests of Livestock: A Review of Technology, R. O.

Drummand, J. E. George, and S. E. Kunz, CRC Press, Boca Raton, Fla.

The combination products may also be effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), More Ilia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine, Gastrophilus intestinalis, Gastrophilus haemorrhoidalis and

Gastrophilus nasalis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; keds such as Me lophagus ovinus; and mites such as Psoroptes spp., Sar copies scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites).

Treatments of the invention are by conventional means such as by enteral

administration in the form of, for example, tablets, capsules, drinks, drenching preparations, granulates, pastes, boli, feed-through procedures, or suppositories; or by parenteral administration, such as, for example, by injection (including intramuscular, subcutaneous, intravenous, intraperitoneal) or implants; or by nasal administration.

The components A and B may be administered separately e.g. as separate

compositions. In this case, the components may be administered simultaneously or sequentially. Alternatively, the components A and B may be components of one

composition.

The combination products may be administered in a controlled release form, for example in subcutaneous or orally adminstered slow release formulations.

Typically a parasiticidal composition according to the present invention comprises components A and B, or N-oxides or salts thereof, with one or more pharmaceutically or veterinarily acceptable carriers comprising excipients and auxiliaries selected with regard to the intended route of administration (e.g., oral or parenteral administration such as injection) and in accordance with standard practice. In addition, a suitable carrier is selected on the basis of compatibility with the one or more active ingredients in the composition, including such considerations as stability relative to pH and moisture content. Therefore of note is a composition for protecting an animal from an invertebrate parasitic pest comprising a parasitically effective amount of the combination product and at least one carrier.

For parenteral administration including intravenous, intramuscular and subcutaneous injection, the combination product can be formulated in suspension, solution or emulsion in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents.

The combination product may also be formulated for bolus injection or continuous infusion. Pharmaceutical compositions for injection include aqueous solutions of water- soluble forms of active ingredients (e.g., a salt of an active compound), preferably in physiologically compatible buffers containing other excipients or auxiliaries as are known in the art of pharmaceutical formulation. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.

Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

In addition to the formulations described supra, the combination products may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular or subcutaneous injection.

The combination products may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a

pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.

For administration by inhalation, the combination products can be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount.

Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The combination products may have favorable pharmacokinetic and

pharmacodynamic properties providing systemic availability from oral administration and ingestion. Therefore after ingestion by the animal to be protected, parasiticidally effective concentrations of the combination products in the bloodstream may protect the treated animal from blood-sucking pests such as fleas, ticks and lice. Therefore of note is a composition for protecting an animal from an invertebrate parasite pest in a form for oral administration (i.e. comprising, in addition to a parasiticidally effective amount of a the combination products, one or more carriers selected from binders and fillers suitable for oral administration and feed concentrate carriers).

For oral administration in the form of solutions (the most readily available form for absorption), emulsions, suspensions, pastes, gels, capsules, tablets, boluses, powders, granules, rumen-retention and feed/water/lick blocks, the combination products can be formulated with binders/fillers known in the art to be suitable for oral administration compositions, such as sugars and sugar derivatives (e.g., lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch, rice starch, potato starch), cellulose and derivatives (e.g., methylcellulose, carboxymethylcellulose, ethylhydroxy cellulose), protein derivatives (e.g., zein, gelatin), and synthetic polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g., magnesium stearate), disintegrating agents (e.g., cross-linked polyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can be added. Pastes and gels often also contain adhesives (e.g., acacia, alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesium aluminum silicate) to aid in keeping the composition in contact with the oral cavity and not being easily ejected.

A preferred embodiment is a composition of the present method formulated into a chewable and/or edible product (e.g., a chewable treat or edible tablet).

Such a product would ideally have a taste, texture and/or aroma favored by the animal to be protected so as to facilitate oral administration of the combination products.

If the parasiticidal compositions are in the form of feed concentrates, the carrier is typically selected from high-performance feed, feed cereals or protein concentrates. Such feed concentrate-containing compositions can, in addition to the parasiticidal active ingredients, comprise additives promoting animal health or growth, improving quality of meat from animals for slaughter or otherwise useful to animal husbandry.

These additives can include, for example, vitamins, antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostats and hormones.

The combination product may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

The formulations for the method of this invention may include an antioxidant, such asBHT (butylated hydroxytoluene). The antioxidant is generally present in amounts of at 0.1- 5 percent (wt/vol). Some of the formulations require a solubilizer, such as oleic acid, to dissolve the active agent, particularly if spinosad is included. Common spreading agents used in these pour-on formulations include isopropyl myristate, isopropyl palmitate,

caprylic/capric acid esters of saturated C₁₂-C₁₈ fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides, silicone oils and dipropylene glycol methyl ether.

The pour-on formulations for the method of this invention are prepared according to known techniques. Where the pour-on is a solution, the parasiticide/insecticide is mixed with the carrier or vehicle, using heat and stirring if required. Auxiliary or additional ingredients can be added to the mixture of active agent and carrier, or they can be mixed with the active agent prior to the addition of the carrier. Pour-on formulations in the form of emulsions or suspensions are similarly prepared using known techniques.

Other delivery systems for relatively hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, organic solvents such as dimethyl sulfoxide may be used, if needed.

The rate of application required for effective parasitic invertebrate pest control (i.e. "pesticidally effective amount") will depend on such factors as the species of parasitic invertebrate pest to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. One skilled in the art can easily determine the pesticidally effective amount necessary for the desired level of parasitic invertebrate pest control.

In general for veterinary use, the combination products are administered in a pesticidally effective amount to an animal, particularly a homeothermic animal, to be protected from parasitic invertebrate pests. A pesticidally effective amount is the amount of active ingredient needed to achieve an observable effect diminishing the occurrence or activity of the target parasitic invertebrate pest. One skilled in the art will appreciate that the pesticidally effective dose can vary for the various compounds and compositions useful for the method of the present invention, the desired pesticidal effect and duration, the target parasitic invertebrate pest species, the animal to be protected, the mode of application and the like, and the amount needed to achieve a particular result can be determined through simple experimentation.

For oral or parenteral administration to animals, a dose of the combination product of the present invention administered at suitable intervals typically ranges from about 0.01 mg/kg to aboutlOO mg/kg, and preferably from about 0.01 mg/kg to about 30 mg/kg of animal body weight.

Suitable intervals for the administration of the combination products of the present invention to animals range from about daily to about yearly. Of note are administration intervals ranging from about weekly to about once every 6 months. Of particular note are monthly adminstration intervals (i.e. administering the compounds to the animal once every month).

The action to be expected E for a given active ingredient combination may obey the so-called COLBY formula and can be calculated as follows:

X = % action by active ingredient A)

Y = % action by active ingredient B)

Accordin to COLBY, the expected (additive) action E of active ingredients A)+B) is

If the action actually observed (O) is greater than the expected action (E), then the action of the combination is super-additive, i.e. there is a synergistic effect. In mathematical terms the synergism factor SF corresponds to O/E. In the agricultural practice an SF of > 1.2 indicates significant improvement over the purely complementary addition of activities (expected activity), while an SF of < 0.9 in the practical application routine signals a loss of activity compared to the expected activity. The skilled person is able to devise tests to determine whether a combination is synergistic.

Each invention described in this document is self-contained. This means that where tables are referred to within an invention, these references apply only to the compounds of the invention number in which the reference is made. Likewise, where compound s are referred to, e.g. "compounds of formula I", these references apply only to the compounds of the invention number in which the reference is made. In other words, compounds of formula I in invention 1 are not the same as compounds of formula I in invention 2 etc. And likewise, where substituents are referred to, these references apply only to the compounds of the invention number in which the reference is made, e.g. R¹ in invention 1 is not necessarily defined in the same was as R¹ in invention 2 etc.

Claims

1. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

where

A is aryl or heteroaryl;

B is a saturated or partially unsaturated heterocyclyl;

C is aryl or heteroaryl;

G is oxygen or sulfur;

m is O, 1, 2, 3, 4 or 5;

n is O, 1, 2, 3, 4 or 5;

o is 0, 1, 2, 3, 4 or 5;

p is 1, 2, 3, 4 or 5;

each R¹ is independently Ci-C₈alkyl;

R⁵ is Ci-C₈haloalkyl; each R⁶ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy-, Ci-C₈haloalkoxy-, Ci-C₈alkoxycarbonyl-, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; X is S, SO, S0₂, S( R¹⁰) or SO( R¹⁰);

R⁷ is hydrogen or Ci-C₄alkyl;

R⁸ and R⁹ are independently of each other hydrogen or Ci-C₄alkyl;

R¹⁰ is hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkylcarbonyl-, Ci- C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C alkylene- or aryl-Ci-C alkylene- where the aryl moiety is substituted by one to three R¹¹, or heteroaryl-Ci-C alkylene- or heteroaryl- Ci-C₄alkylene- where the heteroaryl moiety is substituted by one to three R¹¹, aryl or aryl substituted by one to five R¹¹, or heteroaryl or heteroaryl substituted by one to five R¹¹; and each R¹¹ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkoxy or Ci-C₈haloalkoxy, or Ci-C₈alkoxycarbonyl-;

or a salt or an N-oxide thereof;

provided that if A is a group of formula (A.I), (A.II), (A.III), (A.IV) or (A. V)

(A.I) (A.II) (A.III) (A.IV) (A.V) where

A¹, A², A³ and A⁴ are independently of each other C-H or nitrogen;

n is 0, 1, 2, 3, 4 or 5, and

B is not a group of formula (B.VI)

(B.VI)

where R^4a and R^4b are both hydrogen

and component B is a further therapeutic agent;

2. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

R¹ is -(D)_m-(E)_n-(D)_p-R⁶;

each D is independently Ci-C₆alkylene;

E is -0-, -(CO)- or -(CO) H-;

R³ is Ci-C₈haloalkyl;

R⁶ is hydrogen, or

R⁶ is C₃-C₈cycloalkyl, or C₃-C₈halocycloalkyl, or

and component B is a further therapeutic agent;

3 . A combination product comprising a component A and a component B, wherein component A is a compound of formula (I) or (Γ)

wherein

A¹, A², A³ and A⁴, or A¹', A²', A³', A⁴', A⁵', and A⁶', are independently of each other C-H, C-

R⁶, or nitrogen;

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is the group (z):

(^ζ) wherein L is a single bond or Ci-C₆ alkylene;

R^2a is hydrogen, or Ci-C₈alkyl;

R^7a and R^8a are independently of another hydrogen, halogen, Ci-C₈alkyl, or Ci-C₈haloalkyl; each R^9a is independently hydrogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-C₈alkyl- carbonyl-, Ci-C₈haloalkylcarbonyl-, Ci-C₈alkoxycarbonyl-, Ci-C₈haloalkoxycarbonyl-, Ci- C₈alkylsulfonyl-, Ci-C₈haloalkylsulfonyl-, aryl-Ci-C₄alkyl- or aryl-Ci-C₄alkyl- wherein each aryl moiety is substituted by one to three R^{l la}, or is heteroaryl-Ci-C₄alkyl- or heteroaryl -Ci- C₄alkyl- wherein each heteroaryl moiety is substituted by one to three R^{l la};

R³ is Ci-C₈haloalkyl;

R^5a and R^5b are, independently of each other, hydrogen, cyano, halogen, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, arylthio- or arylthio- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfinyl- or arylsulfinyl- wherein the aryl moiety is substituted by one to five R¹⁰, arylsulfonyl- or arylsulfonyl- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclylthio- or heterocyclylthio- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, heterocyclylsulfinyl- or heterocyclyl sulfinyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, or heterocyclylsulfonyl- or heterocyclylsulfonyl- wherein the heterocyclyl moiety is substituted by one to five R¹⁰ Ci-C₈alkyl, Ci-C₈alkyl substituted by one to five R⁷, C₂-C₈alkenyl, C₂-C₈alkynyl, Ci-C₈haloalkyl, C₂-C₈haloalkenyl, hydroxy, Ci- C₈alkoxy, C3-C₈alkenyloxy, C₃-C₈alkynyloxy, or Ci-C₈haloalkoxy, provided that at least one of R^5a and R^5b is not hydrogen;

each R⁷ is independently halogen, cyano, nitro, C₃-Ci₀cycloalkyl, C₃-Ci₀halocycloalkyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci- C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-; and

each R⁶, R⁹ and R¹⁰ is independently halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, C₃- Ciocycloalkyl, C₃-Ci₀halocycloalkyl, C₂-C₈alkenyl, C₂-C₈haloalkenyl, C₂-C₈alkynyl, C₂- C₈haloalkynyl, hydroxy, Ci-C₈alkoxy, Ci-C₈haloalkoxy, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, Ci- C₈haloalkylsulfonyl-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, aryl or aryl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C₄haloalkyl, Ci-C₄alkoxy, or Ci-C₄haloalkoxy, or heterocyclyl or heterocyclyl itself substituted by one to five substituents independently selected from halogen, Ci-C₄alkyl, Ci- C₄haloalkyl, Ci-C₄alkoxy, or Ci-C₄haloalkoxy;

or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

4. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

A 1 , A2 or A 3 are C-R 5 or nitrogen and that one of A 1 , A2 or A3 is N-R6 , oxygen or sulfur;

A⁴ and A⁵ are independently C-R⁵ or nitrogen;

G¹ is oxygen or sulfur;

R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁷, C₃-Ci₀cycloalkyl or C₃-

Ciocycloalkyl substituted by one to five R⁸, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R⁹, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R⁹, aryl or aryl substituted by one to five R⁹, heterocyclyl or heterocyclyl substituted by one to five R⁹, Ci-C₈alkylaminocarbonyl-Ci-C4 alkylene, Ci-C₈haloalkylaminocarbonyl-Ci-C4 alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C4 alkylene;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R¹⁰, or heteroaryl or heteroaryl substituted by one to five R¹⁰; each R⁵ is independently hydrogen, halogen, cyano, nitro, Ci-C₈alkyl, Ci-C₈haloalkyl, Ci-

C₈alkoxy, Ci-C₈haloalkoxy, Ci-C₈alkylthio-, Ci-C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci- C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci-C₈haloalkylsulfonyl-;

each R⁶ is independently hydrogen or Ci-C₈alkyl;

each R⁸ is independently halogen or Ci-C₈alkyl;

each R¹¹ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C₄alkoxy, or

Ci-C₄haloalkoxy; or a salt or N-oxide thereof;

provided that -A^A^A³- is not -(CR⁵)=(CR⁵)-0-, -0-(CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-S-, -S- (CR⁵)=(CR⁵)-, -(CR⁵)=(CR⁵)-( R⁶)-, -( R⁶)-(CR⁵)=(CR⁵)-, -(CR⁵)=N-( R⁶)- and -( R⁶)- N=(CR⁵)- when A⁴ and A⁵ are both C-R^5';

and component B is a further therapeutic agent;

5. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur; G² is C(R^6a)(R^6b), oxygen, sulfur, or N-R⁷;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C alkylene;

R³ is Ci-C₈haloalkyl;

each R⁸, R¹² and R¹⁶ is independently halogen, cyano, nitro, hydroxy, Ci-C₈alkoxy-, Ci- C₈haloalkoxy-, Ci-C₈alkylcarbonyl-, Ci-C₈alkoxycarbonyl-, mercapto, Ci-C₈alkylthio-, Ci- C₈haloalkylthio-, Ci-C₈alkylsulfinyl-, Ci-C₈haloalkylsulfinyl-, Ci-C₈alkylsulfonyl-, or Ci- C₈haloalkylsulfonyl-; each R⁹ is independently halogen or Ci-C₈alkyl;

each R¹⁷ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C₄alkoxy-, or Ci-C₄haloalkoxy-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

6. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

G¹ is oxygen or sulfur;

R¹ is hydrogen, Ci-C₈alkyl, Ci-C₈alkoxy-, Ci-C₈alkylcarbonyl-, or Ci-C₈alkoxycarbonyl-; R² is Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R⁸, C3-Ciocycloalkyl or C₃- Ciocycloalkyl substituted by one to five R⁹, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁰, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁰, aryl or aryl substituted by one to five R¹⁰, or heterocyclyl or heterocyclyl substituted by one to five R¹⁰, Ci-C₈alkylaminocarbonyl-Ci-C₄ alkylene, Ci-C₈haloalkylaminocarbonyl-Ci- C₄ alkylene, or C₃-C₈cycloalkyl-aminocarbonyl-Ci-C₄ alkylene;

R³ is Ci-C₈haloalkyl;

R⁴ is aryl or aryl substituted by one to five R¹¹, or heteroaryl or heteroaryl substituted by one to five R¹¹; R^5a and R^5b are both hydrogen;

R⁶ is hydrogen, Ci-C₈alkyl or Ci-C₈alkyl substituted by one to five R¹², C₃-Ci₀cycloalkyl or C₃-Ciocycloalkyl substituted by one to five R¹³, aryl-Ci-C₄alkylene- or aryl-Ci-C₄alkylene- wherein the aryl moiety is substituted by one to five R¹⁴, heterocyclyl-Ci-C₄alkylene- or heterocyclyl-Ci-C₄alkylene- wherein the heterocyclyl moiety is substituted by one to five R¹⁴, aryl or aryl substituted by one to five R¹⁴, or heterocyclyl or heterocyclyl substituted by one to five R¹⁴;

each R⁹ and R¹³ is independently halogen or Ci-C₈alkyl;

each R¹⁵ is independently halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄haloalkyl, Ci-C₄alkoxy-, or Ci-C₄haloalkoxy-; or a salt or N-oxide thereof;

and component B is a further therapeutic agent;

7. A combination product comprising a component A and a component B, wherein component A is a compound of formula (I)

wherein

G¹ is oxygen or sulfur;

R¹ is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C₃alkoxy-Ci-C₃alkyl-, Ci-C₆alkoxy, Ci-C₆haloalkoxy, Ci-C₆alkoxycarbonyl-, aryl-Ci-C₆alkyl- or aryl-Ci-C₆alkyl- substituted by one to three R⁶, heterocyclyl-Ci-C₆alkyl- or heterocyclyl-Ci-C₆alkyl- substituted by one to three R⁶; or R¹ is aryl or aryl substituted by one to three R⁶, or

R¹ is heterocyclyl or heterocyclyl substituted by one to three R⁶;

R² is hydrogen, Ci-C₆alkyl, Ci-C₆alkylcarbonyl-, or Ci-C₆alkoxycarbonyl-;

R³ is Ci-C₆haloalkyl;

each R⁶ is independently halogen, cyano, nitro, Ci-C₆alkyl, Ci-C₆haloalkyl, Ci-C₆alkoxy, Ci- C₆haloalkoxy, Ci-C₆alkylthio-, Ci-C₆haloalkylthio-, Ci-C₆alkylsulfmyl-, Ci- C₆haloalkylsulfinyl-, Ci-C₆alkylsulfonyl-, Ci-C₆haloalkylsulfonyl-, or Ci-C₆alkoxycarbonyl- ; and

and component B is a further therapeutic agent;

8. A combination product according to any one of claims 1 to 7, wherein component B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole,

5 fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide.

9. A combination product according to any one of claims 1 to 7, wherein component B 10 is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam,

cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, 15 oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, lufenuron or ecdysone.

10. A combination product according to any one of claims 1 to 7n, wherein component B is enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam,

20 cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel.

11. A combination product according to any one of claims 1 to 10, wherein the

25 combination product is for use against parasitic invertebrate pests.

12. A combination product according to any one of claims 1 to 10, wherein the combination product is for use against parasitic invertebrate pests in or on an animal.

30 13. A combination product according to any one of claims 1 to 10, wherein the pest is a nematode, a trematode, a cestode, a fly, a mite, a trick, a lice, a flea, a true bug or a maggot.

14. A combination product according to claim 12 or claim 13, wherein the animal to be treated is a cow, a pig, a sheep, a goat, a dog, a cat, a horse, and/or a donkey.

15 A method comprising administering the combination product as defined in any one of claims 1 to 10 to an animal.

16. A method of controlling parasitic invertebrate pests in or on an animal comprising administering an effective amount of the combination product as defined in any one of claims 1 to 10 to the animal.

17. A method according to claim 16 wherein said administration is oral administration, parenteral administration or external administration.

18. A method of controlling parasitic invertebrate pests comprising administering an effective amount of the combination product as defined in any one of claims 1 to 17 to the environment in which an animal resides.

19. A pharmaceutical composition comprising component A and component B as defined in any one of claims 1 to 18 and a pharmaceutically suitable excipient.