NZ619552B2 - Amido-pyridyl ether compounds and compositions and their use against parasites - Google Patents

Abstract

The disclosure relates to amido-pyridyl ether compounds of formula I wherein R1 – R11, Ra, a, b and d are as described in the disclosure, compositions comprising the compounds of formula I, methods for preparing them and their use against parasites. The parasite may be an ectoparasite or an endoparasite, and may further be fleas, ticks, mites, mosquitoes, flies, fly larvae or lice. site, and may further be fleas, ticks, mites, mosquitoes, flies, fly larvae or lice.

Description

AMIDO-PYRIDYL ETHER COMPOUNDS AND COMPOSITIONS AND THEIR USE AGAINST PARASITES FIELD OF THE INVENTION The subject matter disclosed herein is directed to 2-amido-pyridyl ether compounds of formula I: R2 0 R1%7(0R4R5)a\NRa / R10 R3 | I (CR6R7)b—O—(CR8R9)d \ / /\R11 wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, Ra, a, b and d are as described herein, compositions comprising the nds of formula 1, methods for their preparation and methods for their uses against tes.

BACKGROUND Animals such as mammals and birds are often tible to parasite infestations. These parasites may be ectoparasites, such as insects, and endoparasites such as fllariae and worms.

Domesticated animal, such as cats and dogs, are often infested with one or more of the following ectoparasites: cat and dog fleas (Ctenocephalz’desfelz’s, Ctenocephalz’des Sp. and the like), ticks (hapz'cephalus Sp., IxodeS Sp., Dermacem‘or Sp. , Amblyoma Sp. and the like), and mites (Demodex Sp., SarcopteS Sp., OtOdecteS Sp. and the like), lice (Trichodectes Sp., Cheyletz'ella Sp., athus Sp., and the like), toes (AedeS Sp., Culex Sp., les Sp., and the like) and flies obl'a Sp., Musca Sp., StomoxyS Sp., Dermatobz'a Sp., Coclyomz'a Sp., and the like).

Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals, such as dog tapeworm lz'dz'um caninum), and humans.

Similarly, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem ated with ticks is that they are the vector of pathogenic agents, agents which cause diseases in both humans and animal. Major diseases which are caused by ticks include borrelioses (Lyme disease caused by Borrelz'a burgdorferz’), babesioses (or piroplasmoses caused by Babesz'a sp.) and rickettsioses (also known as Rocky Mountain spotted . Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.

Moreover, mites and lice are particularly difficult to combat since there are very few active substances which act on these parasites and they require frequent treatment.

Likewise, farm s are also susceptible to parasite infestations. For example, cattle are affected by a large number of tes. A parasite which is very prevalent among farm s is a tick genus Boophilus, especially those of the species microplus (cattle tick), decoloratus and anulatus. Ticks, such as lus lus, are particularly difficult to control because they live in the pasture where the farm animals graze. Other ant parasites of cattle and sheep are listed as follows in order of sing ance: myiases such as Dermatobz'a hominis (known as Beme in Brazil) and Cochlyomz'a hominivorax (greenbottle); sheep myiases such as Lucilz’a sericata, Lucilz'a cuprz’na (known as blowfly strike in Australia, New Zealand and South Africa). These are flies whose larva constitutes the animal parasite; flies , namely those whose adult constitutes the parasite, such as Haematobz'a irritans (horn fly); lice such as Linognathus vitulorum, etc.; and mites such as Sarcoptes scabiez’ and Psoroptes 0vz's. The above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example migrating dipterous larvae.

Animals and humans also suffer from endoparasitical infections ing, for example, thiasis which is most frequently caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry. Other parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius and parasites which are found in the blood or other tissues and organs such as fllarial worms and the extra intestinal stages of Strogyloides, Toxocara and Trichinella.

Many icides exist in the art for treating parasites. These insecticides vary in their effectiveness against a particular parasite as well as their cost. However the results of these insecticides are not always satisfactory because of, for example, the development of resistance by the parasite to the therapeutic agent, as is the case, for example, with ates, organophosphorus compounds and pyrethroids. Thus, there is a need in the art for more ive rasitic formulation treatment and protection of animal, e.g. mammals, fish and birds for a wide range of parasites. Moreover, there is a need in the art for an antiparasitic formulation which is easy to use on any type of domestic animal, irrespective of its size and the nature of its coat, and which does not need to be sprinkled over the entire body of the mammal, fish or bird. What is needed are compounds that are effective against a range pests, particularly for controlling endoparasites or ectoparasites in or on animals.

Any sion of documents, acts, als, devices, articles or the like which has been included in the present specification is not to be taken as an ion that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present sure as it existed before the priority date of each claim of this application.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

In a first , there is provided a compound of Formula I wherein, Ra is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, koxyalkyl, carbonyl and haloalkoxycarbonyl; R1 is hydrogen or alkyl; R2 and R3 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, alkylthio, alkylamino, dialkylamino, lkyl, alkylaminoalkyl, dialkylaminoalkyl, and cyano, or R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted 3- to 7-member cyclic, heterocyclic or heteroaromatic ring, wherein the tuents may each be independent of one another cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino; a is an integer from zero to four, b is an integer from zero to four, d is an r from zero to four, R4, R5, R6 , R7, R8 and R9 are each independently hydrogen, halogen, alkyl, alkenyl, hydroxyalkyl, alkylthioalkyl, haloalkyl, alkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylsulfonyloxyalkyl, nitro, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and diamino; R10 and R11 are each independently selected from the group ting of hydrogen, hydroxy, amino, cyano, nitro, halogen, thiol, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, , phenoxy, alkoxyalkoxy, cycloalkyloxy, koxy, formyl, alkylcarbonyl, alkoxycarbonyl, yl, sulfinyl, and unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted arylthio, unsubstituted or substituted aryloxy, or unsubstituted or substituted heteroaryl, wherein the substituents, independent of one another, may be one or more of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylaminoalkoxy, laminoalkoxy, and alkylaminoalkyl, provided that, at least one of b and d is other than zero, and at least one of R10 and R11 is other than hydrogen.

In another aspect, there is provided a parasiticidal composition comprising a compound of Formula 1 and a carrier.

BRIEF Y The present disclosure is based, in part, on unexpected results that compounds of a I have efficacy t a range of pests including ectoparasites or endoparasites or both.

In an embodiment, the subject matter sed herein is directed to compounds of formula I.

In an embodiment, the subject matter disclosed herein is directed to solid state forms of the compounds of the invention which consists of crystalline forms including single crystals, nanocrystals, co-crystals, molecular complexes, hydrates, anhydrates, solvates, desolvates, clathrates and ion complexes and non-crystalline forms including non-crystalline glass and non-crystalline amorphous forms.

In an embodiment, the subject matter disclosed herein is directed to pesticidal compositions comprising a compound of formula I.

In an embodiment, the subject matter disclosed herein is directed methods of ng a pest infestation by contacting the site of ation or its surroundings with a compound of formula I or a composition thereof.

In an embodiment, the subject matter sed herein is directed to preventing or protecting an area from pest infestation by contacting the site in need of prevention or protection or its surroundings with a compound of formula I or a composition thereof.

In an embodiment, the subject matter disclosed herein is directed to a method of preventing or protecting an animal from pest or its habitat from pest ation by ting the animal or its habitat with a compound of formula I or a composition f.

In an embodiment, the subject matter disclosed herein is directed to methods of preparing the compounds and compositions disclosed herein.

DETAILED DESCRIPTION The 2-Amido-pyridyl ether compounds and itions thereof disclosed herein have been found to have activity against pests, particularly endoparasites or ectoparasites or both. The compounds of formula I disclosed herein are useful against pests directly or can be used in the areas that pests infest or are likely to infest. The compounds are also useful for applying to animals to treat or prevent parasite infestations or infections. This includes methods for ting and/or treating a parasitic infestation or infection in an animal, and the use of the compounds in treating a parasitic infestation or infection in an animal or the use in the manufacture of a medicament for treating a tic infestation or infection in an animal.

I. Definitions The compounds of the invention are intended to encompass racemic mixtures, specific isomers and tautomeric forms of the compound. Another aspect of the invention is a salt form of the compound of the invention.

The term “subject” or “animal” as used herein includes warm-blooded and cold-blooded animals such as mammals, birds and fish. Examples ofmammals e but are not limited to humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, ns, ostriches and other livestock or domestic birds.

As referred to in this disclosure, the term "pest" or “parasite” includes arthropods, gastropods and nematodes. The term "arthropod" includes insects, mites, spiders, scorpions, centipedes, millipedes; pill bugs and symphylans. The term opod" includes snails, slugs and other Stylommatophora. The term "helminthsg" includes worms in the phyla of Nemathelminthes, Platyhelminthes and Acanthocephala such as: round worms, heartworms, and phytophagous nematodes (Nematoda), flukes (Trematoda), tape worms (Cestoda) and thomy- headed worms. Also specifically included are endoparasites and rasites.

For the purposes of this application, unless otherwise stated in the cation, the following chemical terms have the ology cited below: (1) Alkyl refers to both ht, branched carbon chains and cyclic arbon groups; nces to individual alkyl groups are specific for the straight chain (e.g. butyl = n-butyl). In one embodiment of alkyl, the number of carbons atoms is 1-20, in other embodiments of alkyl, WO 03505 the number of carbon atoms is 1-12, 1-10 or 1-8 carbon atoms. In yet another embodiment of alkyl, the number of carbon atoms is 1-4 carbon atoms. Other ranges of carbon numbers are also contemplated depending on the location of the alkyl moiety on the molecule; Examples of C1-C10 alkyl include, but are not limited to, methyl, ethyl, propyl, lmethylethyl , butyl, l-methylpropyl, 2-methylpropyl, l,l-dimethylethyl, pentyl, l-methylbutyl, 2- methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, l-ethylpropyl, hexyl, l,l-dimethylpropyl, 1,2- dimethylpropyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, l,l- dimethylbutyl, l,2-dimethylbutyl, methylbutyl, methylbutyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, l-ethylbutyl, 2-ethylbutyl, trimethylpropyl, 1,2,2-trimethylpropyl, l- l-methylpropyl, l-ethylmethylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C1-C4-alkyl means for example methyl, ethyl, propyl, l-methylethyl, butyl, l- methylpropyl, 2-methylpropyl or l,l-dimethylethyl.

Cyclic alkyl , which are encompassed by alkyls, may be ed to as alkyl” and include those with 3 to 10 carbon atoms haVing single or multiple fiJsed rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The alkyl and cycloalkyl groups described herein can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulf1nyl, sulfamonyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, ine, ate, phosphonic acid, phosphate, phosphonate, or any other Viable onal group that does not inhibit the biological actiVity of the compounds of the invention, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in c sis, John Wiley and Sons, Third Edition, 1999, hereby incorporated by reference. (2) Alkenyl refers to both straight and branched carbon chains which have at least one carbon-carbon double bond. In one embodiment of alkenyl, the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one. In one embodiment of alkenyl, the number of carbons atoms is 2-20, in other embodiments of alkenyl, the number of carbon atoms is 2-12, 2-10 or 2-8. In yet r embodiment of alkenyl, the number of carbon WO 03505 atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule; “C2-C10-alkenyl” groups may e more than one double bond in the chain. Examples include, but are not limited to, ethenyl, l-propenyl, 2-propenyl, l-methyl-ethenyl, l-butenyl, 2- butenyl, 3-butenyl, l-methyl- l -propenyl, 2-methyl-l-propenyl, ylpropenyl, 2-methyl- 2-propenyl; l-pentenyl, 2-pentenyl, enyl, 4-pentenyl, l-methyl- l -butenyl, 2-methyl- l - butenyl, 3-methyl-l-butenyl, l-methylbutenyl, 2-methylbutenyl, 3-methylbutenyl, l- methylbutenyl, 2-methylbutenyl, 3-methylbutenyl, l,l-dimethylpropenyl, 1,2- dimethyl- l -propenyl, l ,2-dimethylpropenyl, l -ethyl- l -propenyl, l-ethylpropenyl, l - hexenyl, nyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, l-methyl-l-pentenyl, 2-methyl-l-pentenyl, 3 -methylpentenyl, 4-methyl- l -pentenyl, l -methylpentenyl, 2-methylpentenyl, 3-methyl- 2-pentenyl, 4-methylpentenyl, l-methylpentenyl, 2-methylpentenyl, yl pentenyl, 4-methylpentenyl, l-methylpentenyl, 2-methylpentenyl, 3-methylpentenyl, ylpentenyl, l,l-dimethylbutenyl, l,l-dimethyl-3 yl, l,2-dimethyl-l-butenyl, l,2-dimethylbutenyl, l,2-dimethylbutenyl, l,3-dimethyl-l-butenyl, l,3-dimethylbutenyl, methylbutenyl, 2,2-dimethylbutenyl, 2,3-dimethyl-l-butenyl, 2,3-dimethylbutenyl, 2,3 -dimethyl-3 -butenyl, 3 ,3 -dimethyl- l -butenyl, 3 ,3 -dimethylbutenyl, l -ethyl- l -butenyl, l - ethylbutenyl, l-ethylbutenyl, 2-ethyl-l-butenyl, 2-ethylbutenyl, 2-ethylbutenyl, l,l,2- trimethylpropenyl, l -ethyl- l -methylpropenyl, l -ethylmethyl- l -propenyl and l -ethyl methylpropenyl. (3) Alkynyl refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of l, the number of triple bonds is one. In one embodiment of l, the number of carbons atoms is 2-20, in other ments of alkynyl, the number of carbon atoms is 2-l2, 2-lO or 2-8. In yet another embodiment of alkynyl, the number of carbon atoms is 2-4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the l moiety on the molecule; For example, the term ”C2-C10-all<ynyl” as used herein refers to a straight-chain or branched unsaturated hydrocarbon group haVing 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop- l -yn- l -yl, propyn- l -yl, n-but- l -yn- l -yl, n-but- l -yn-3 -yl, n- butynyl, n-butyn- l -yl, n-pent- l -yn- l -yl, - l -yn-3 -yl, n-pent- l -ynyl, n-pent- l - ynyl, n-pentyn-l-yl, n-pentynyl, n-pentynyl, 3-methylbut-l-yn-3 -yl, 3- methylbut- l -ynyl, n-hex- l -yn- l -yl, n-hex- l -yn-3 -yl, n-hex- l -ynyl, n-hex- l -yn-5 -yl, n-hexl-ynyl , n-heXyn-l-yl, n-heXynyl, n-heXynyl, 2-ynyl, n-heXyn-l-yl, n-heXynyl, 3-methylpent- l -yn- l -yl, 3 -methylpent- l -yn-3 -yl, 3 -methylpent- l -ynyl, 3 - methylpent-l -yn-5 -yl, ylpent- l -yn- l -yl, 4-methylpentynyl or 4-methylpentyn-5 - yl and the like. (4) Aryl refers to a C6-C14 aromatic carbocyclic ring structure having a single ring or multiple fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments aryl es tetrahydronapthyl, phenylcyclopropyl and indanyl. Aryl groups may be unsubstituted or tuted by one or more moieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, kynyl, halocycloalkyl, cloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, arylthio, cycloalkylthio, halocycloalkylthio, alkylsulfmyl, alkenylsulfmyl, l-sulfmyl, haloalkylsulfmyl, kenylsulfmyl, haloalkynylsulfmyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkylamino, alkenylamino, lamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or SFS. In one embodiment of aryl, the moiety is phenyl, naphthyl, tetrahydronapthyl, cyclopropyl and indanyl; in another embodiment of aryl, the moiety is phenyl. Arylo refers to an aryl substituted at two adjacent sites. (5) Alkoxy refers to -O-alkyl, wherein alkyl is as defined in (l); (6) Alkoxycarbonyl refers to -C(=O)-O-alkyl, wherein alkoxy is as defined in (5); (7) Cyclo as a prefix (e.g. cycloalkyl, cycloalkenyl, cycloalkynyl) refers to a ted or unsaturated cyclic ring structure haVing from three to eight carbon atoms in the ring the scope of which is intended to be separate and distinct from the definition of aryl above. In one embodiment of cyclo, the range of ring sizes is 4-7 carbon atoms; in another ment of cyclo the range of ring sizes is 3-4. Other ranges of carbon numbers are also contemplated depending on the on of the cyclo- moiety on the molecule; (8) Halogen means the atoms fluorine, chlorine, bromine and iodine. The designation of “halo” (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (-CH2Cl), dichloromethyl 2), oromethyl (-CC13)); (9) Heterocycle, heterocyclic or cyclo refers to fully saturated or unsaturated cyclic groups, for e, 4 to 7 membered monocyclic, 7 to 11 ed bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, Where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. (10) Heteroaryl refers to a monovalent aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, haVing one or more , nitrogen, and sulfur heteroatoms Within the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple fiased rings provided that the point of attachment is through a heteroaryl ring atom. red heteroaryls include pyridyl, piridazinyl, pyrimidinyl, triazinyl, pyrrolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thienyl, furyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, and benzothienyl.

Heteroaryl rings may be unsubstituted or substituted by one or more es as described for aryl above.

Exemplary monocyclic cyclic or heteroaryl groups also include, but are not limited to, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, zepinyl, azepinyl, 4-piperidonyl, pyridinyl, nyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, rpholinyl sulfone, oxolane and tetrahydro-l , l -dioxothienyl, triazolyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to, l, benzothiazolyl, azolyl, benzodioxolyl, benzothienyl, quinuclidinyl, tetra- hydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl]or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as hydrooxo-quinazolinyl), tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include, but are not limited to, carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, thridinyl, xanthenyl and the like.

Unless otherwise specifically noted or nt by context, “active agent” or “active ingredient” or “therapeutic agent” as used in this specification, means a 2-amidopyridyl ether compound as disclosed herein or r active in combination with one or more 2-amidopyridyl ether nds.

It is further noted that the invention does not intend to encompass within the scope of the invention any previously disclosed product, process of making the product or method of using the product, which meets the written description and enablement requirements of the USPTO (35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC), such that applicant(s) e the right and hereby se a disclaimer of any previously described product, method of making the product or s of using the product.

It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in US. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in US. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention. 11. Compounds In an embodiment, the subject matter sed herein is directed to a compound of Formula I: R‘%7<CR4R5)a\NRa / R10 R3 I I (CR6R7)b—O—(CR8R9)d \ / /\R11 wherein, Ra is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, haloalkyl, hio, haloalkylthio, alkoxy, haloalkoxyalkyl, alkoxycarbonyl and haloalkoxycarbonyl; R1 is hydrogen or alkyl; R2 and R3 are each independently selected from the group consisting of hydrogen, hydroxy, amino, alkyl, haloalkyl, alkoxyalkyl, alkenyl, l, alkylthio, alkylamino, dialkylamino, lkyl, alkylaminoalkyl, dialkylaminoalkyl, and cyano, or R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted 3- to 7-member , heterocyclic or heteroaromatic ring, wherein the substituents may each be independent of one r cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino; a is an integer from zero to four, b is an integer from zero to four, d is an integer from zero to four, R4, R5, R6 R8 and R9 are each ndently hydrogen, halogen, alkyl, alkenyl, , R7, hydroxyalkyl, alkylthioalkyl, haloalkyl, alkyloxyalkyl, ulfinylalkyl, ulfonylalkyl, alkylsulfonyloxyalkyl, nitro, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and diamino; R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, thiol, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, haloalkyl, hio, haloalkylthio, arylthio, alkoxy, phenoxy, alkoxy, cycloalkyloxy, haloalkoxy, formyl, alkylcarbonyl, carbonyl, sulfonyl, sulfinyl, and unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted arylthio, unsubstituted or substituted aryloxy, or unsubstituted or substituted heteroaryl, wherein the substituents, independent of one another, may be one or more of cyano, nitro, halogen, alkyl, kyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylaminoalkoxy, dialkylaminoalkoxy, and alkylaminoalkyl, provided that, at least one of b and d is other than zero, and at least one of R10 and R11 is other than hydrogen.

Preferred compounds of formula I include those where: Ra is selected from the group consisting of hydrogen, C1_6 alkyl, C1_6 alkoxy(C1_6)alkyl, C1_6 alkylcarbonyl, halo(C1_6)alkylcarbonyl, C1_6 carbonyl, halo(C1_6)alkoxycarbonyl, C1_6 alkylthiocarbonyl, halo(C1_6)alkyl, C1_6 alkylthio, halo(C1_6)alkylthio, C1_6 alkoxy, halo(C1_ 6)alkoxy(C1_6)alkyl, C1_6 alkoxycarbonyl and halo(C1-6)alkoxycarbonyl; R1 is hydrogen or C1_6 alkyl; R2 and R3 are each independently selected from the group consisting of hydrogen, hydroxy, amino, C1_6 alkyl, halo(C1_6)alkyl, alkoxy(C1_6)alkyl, C1_6 alkenyl, C1_6 alkynyl, C1_6 alkylthio, C1_6 alkylaniino, di(C1_6 alkyl)an1ino, aminoalkyl, alkylaniinoalkyl, dialkylaniinoalkyl, and cyano, or R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted 3- to 7-men1ber cyclic, heterocyclic or heteroaromatic ring, wherein the substituents may each be independent of one another cyano, nitro, halogen, C1_6 alkyl, 1_ l, C1_6 alkylthio, halo(C1_6)alkylthio, C1_6 alkoxy, halo(C1_6)alkoxy, amino, C1_6 alkylaniino, and di(C1_6 alkyl)an1ino; a is an integer from zero to four, b is an integer from zero to four, d is an integer from zero to four, R4, R5, R6 R8 and R9 are each independently hydrogen, halogen, C1_6 alkyl, C1_6 , R7, alkenyl, hydroxy(C1_6)alkyl, C1_6 alkylthio(C1_6)alkyl, halo(C1_6)alkyl, C1_6 alkyloxy(C1_6)alkyl, C1_6 alkylsulfinyl(C1_6)alkyl, C1_6 alkylsulfonyl(C1-6)alkyl, C1_6 alkylsulfonyloxy(C1-6)alkyl, nitro, C1_6 hio, halo(C1_6)alkylthio, C1_6 , halo(C1_6)alkoxy, amino, alkylaniino, and di(C1_6 alkyl)an1ino; R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, thiol, alkylaniino, dialkylaniino, C1_6 alkyl, C1_6 l, C1_6 alkynyl, C3_7 cycloalkyl, hydroxy(C1_6)alkyl, halo(C1_6)alkyl, C1_6 alkylthio, halo(C1_ 6)alkylthio, arylthio, C1_6 alkoxy, phenoxy, alkoxy(C1_6)alkoxy, C3_7 cyclo(C1_6)alkyloxy, halo(C1_6)alkoxy, forniyl, alkylcarbonyl, alkoxycarbonyl, sulfonyl, sulfinyl, and unsubstituted or tuted phenyl, unsubstituted or tuted , unsubstituted or substituted arylthio, unsubstituted or substituted aryloxy, or unsubstituted or substituted aryl, wherein the substituents, ndent of one another, may be one or more of cyano, nitro, halogen, C1_6 alkyl, halo(C1_6)alkyl, C1_6 alkylthio, halo(C1_6)alkylthio, C1_6 alkoxy, halo(C1_6)alkoxy, amino, 2012/044476 alkylamino, di(C1_6 alkyl)amino, C1_6 alkylamino(C1_6)alkoxy, C1_6 dialkylamino(C1-6)alkoxy, and C1_6 alkylamino(C1_6)alkyl, provided that, at least one of b and d is other than zero, and at least one of R10 and R11 is other than hydrogen.

Combinations of substituents and/or variables the the s embodiments bed herein are permissible only if such combinations result in stable compounds.

Preferred nds of formula I include those where b is one and d is zero, b is two and d is zero, b is one and d is one, b is zero and d is one, or b is zero and d is two. In these preferred compounds, it is more preferable that a is one or two.

Preferred compounds of formula I include any compound of formula I where a is one or two. Also preferred are compounds where a is zero, provided that when R10 and R11 are both selected from the group consisting of chloro and methyl, then: i) d is other than zero, or ii) R81 is other than C1_6 alkyl, or iii) R2 and R3 when taken together with the carbon to which both are bound form a ring other than entyl or cyclohexyl.

Preferred compounds of formula I include those where R10 and R11 are each independently selected from the group consisting of hydrogen, halogen, branched or straight- chain C1_6 alkyl, C1_6 alkenyl, C1_6 alkynyl, hydroxy(C1_6)alkyl, halo(C1_6)alkyl, C1_6 alkoxy, halo(C1_6)alkoxy and unsubstituted or substituted phenyl, wherein the substituents, independent of one another, may be one or more of halogen, C1_6 alkyl, 1_6)alkyl, C1_6 alkoxy, or halo(C1_6)alkoxy. More preferably, R10 and R11 are each independently selected from the group consisting of hydrogen, bromo, chloro, fluoro, methyl, ethyl, trifluoromethyl and romethoxy.

Preferred compounds of formula I include those where a is one, R4 and R5 are both hydrogen, b is zero, one or two, and d is zero, one or two. In these preferred compounds, it is also preferred that b is one or two, d is zero, and R6 and R7 in each instance are both hydrogen.

In these preferred compounds, it is also red that d is one or two, b is zero, and R8 and R9 in each instance are both hydrogen. In these red compounds, it is also preferred that b is one or two, R6 and R7 in each instance are both hydrogen, d is one or two, and R8 and R9 in each instance are both hydrogen.

Preferred compounds of formula I include those where R1 is hydrogen or methyl, R2 and R3 are each independently selected from the group consisting of hydrogen, C1_6 alkenyl, cyano, C1_6 alkyl, C1_6 alkoxy, amino, C1_6 alkylamino, di(C1_6 alkyl)amino and C1_6 alkylthio, or R2 and R3 taken together with the carbon to which both are bound form a substituted or tituted 3- to 7-member cyclic, heterocyclic or heteroaromatic ring. In these preferred compounds, it is also preferred that R2 and R3 are each independently selected from the group consisting of hydrogen, C1_6 alkenyl, C1_6 alkyl and C1_6 alkylthio. In these preferred compounds, it is preferable that R2 and R3 taken er with the carbon to which both are bound form a substituted or unsubstituted 3- to 7-member cyclic, heterocyclic or pyridine. More preferably, R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted pyrrolidinyl, tetrahydrofilranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, rpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, nyl, 2-pyrrolinyl, 3-pyrrolinyl, anyl, 4H-pyranyl, dioxanyl, l,3-dioxolanyl, dithianyl, dithiolanyl and othienyl. Most ably, R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted ropyl or 4- morpholinyl.

Preferred compounds of formula I include those where Ra is hydrogen.

Preferred compounds of formula I include those where R1 is hydrogen or methyl.

Preferred compounds of formula I include those where R2 and R3 are each independently selected from the group consisting of hydrogen, C1_6 alkenyl, cyano, C1_6 alkyl, C1_6 alkoxy, amino, C1_6 alkylamino, di(C1_6 alkyl)amino and C1_6 alkylthio, or R2 and R3 taken together with the carbon to which both are bound form a substituted or tituted 3- to 7-member cyclic, heterocyclic or heteroaromatic ring. When R2 and R3 are taken together with the carbon to which both are bound, preferred rings are substituted or unsubstituted pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, ydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dinyl, morpholinyl, rpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, 2- pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, l,3-dioxolanyl, dithianyl, dithiolanyl 2012/044476 and dihydrothienyl. Preferred compounds include those where R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted cyclopropyl or 4- linyl. Preferred compounds include those where R2 and R3 are each independently selected from the group consisting of hydrogen, C1_6 alkenyl, C1_6 alkyl and C1_6 alkylthio.

Preferred compounds of formula I include the following: WO 03505 YVfijw/g“? WO 03505 2012/044476 S’\/N-| / 70 N / 0 Br 107 WO 03505 N / 0 Br 108 K 124 NH —— \ / O—Q Y“ I : K/éj 132 WO 03505 WO 03505 WO 03505 To 0%; 227 H I O\'<FF F 240 WO 03505 RH ' N N/ ROCKF 241 WO 03505 H I N / OVO/ F 279 Other useful compounds of a I are described elsewhere herein.

III. Compositions Various methods of formulating antiparasitical formulations are known in the art. These include oral formulations, baits, dietary supplements, powders, shampoos, concentrated solution, suspension, microemulsion, emulsion, oral drench formulation, le formulation, transdermal or transmucosal patch or liquid, gel or paste, solution for inhalation and inj e formulation. Formulations for localized topical applications of antiparasitical formulations are also known in the art, such as ready-to-use ons, pour-on solutions, spot-on formulations, paste formulations, shampoos, s, etc. are well known in the art.

The formulations are ed to be administered to an animal which includes but is not limited to mammals, birds and fish. Examples ofmammals include but are not limited to humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. es of birds include s, ns, ostriches and other livestock or domestic birds.

The ition may be in a form suitable for oral use, for example, as baits (see, e.g., US. Patent No. 4,564,631), y supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral drench formulations, dispersible powders or granules, premixes, syrups or elixirs, enteric formulations or pastes. itions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, ng agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium ate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, ium stearate, stearic acid or talc, the tablets may be uncoated or they may be coated by known techniques to delay disintegration and tion in the gastrointestinal tract and thereby e a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in US. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 (incorporated herein by reference) to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, m carbonate, m phosphate or kaolin.

Capsules may also be soft gelatin capsules, wherein the active ient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

The compositions may also be in the form of oil-in-water or water-in-oil emulsions. The oily phase may be a ble oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring phosphatides, for example, n, lecithin, and esters or partial esters derived from fatty acids and hexitol ides, for example, sorbitan ate, and condensation products of the said partial esters with ethylene oxide, for e, polyoxyethylene sorbitan eate.

The emulsions may also contain sweetening agents, bittering agents, flavoring agents, and/or preservatives.

In one embodiment of the formulation, the composition of the invention is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase.

The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co- SA) molecules which, by lowering the interfacial tension, allows the mulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. In one embodiment of the oily phase, the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example Cg-Clo caprylic/capric triglyceride. In another embodiment of the oily phase will represent a % v/v range ed from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the mulsion.

The s phase includes, for example water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivatives, the glycol is selected from the group consisting of ene glycol, lene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropyelene glycol monomethyl ether, polyglycolyzed C8-C10 glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, the cosurfactants include chain alcohols, such as ethanol and propanol.

Some compounds are common to the three ents discussed above, i.e., s phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment for the amount of surfactant/cosurfactant, the cosurfactant to surfactant ratio will be from about 1/7 to about 1/2. In another embodiment for the amount of cosurfactant, there will be from about 25 to about 75% v/v of surfactant and from about 10 to about 55% v/v of cosurfactant in the microemulsion.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl l. ning agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to e a palatable oral ation. These compositions may be ved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.

Aqueous suspensions may contain the active al in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-ocurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic ls, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters d from fatty acids and a hexitol such as polyoxyethylene sorbitol eate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene an monooleate. The s suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. le dispersing or wetting agents and suspending agents are exemplified by those y mentioned above. onal excipients, for example, sweetening, ing, flavoring and coloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent(s) and/or ng agent(s).

In another embodiment, the composition can be in paste form. Examples of embodiments in a paste form include but are not limited to those described in US. Patent Nos. 6,787,342 and 7,001,889 (each of which are incorporated herein by reference). The paste can also contain filmed ; a viscosity modifier; a carrier; ally, an absorbent; and optionally, a colorant, izer, tant, or preservative.

The process for preparing a paste ation comprises the steps of: (a) dissolving or dispersing at least one 2-amido-pyridyl ether compound(s) described herein into the carrier by mixing; WO 03505 (b) adding the filmed silica to the carrier above, and mixing until the silica is dispersed in the carrier; (c) allowing the ediate formed in (b) to settle for a time sufficient in order to allow the air entrapped during step (b) to escape; and (d) adding the viscosity modifier to the intermediate with mixing to produce a uniform paste.

The above steps are illustrative, but not limiting. For example, step (a) can be the last step.

The paste may also include, but is not limited to, a viscosity modifier selected from the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (POLYSORBATE 80 or TWEEN 80), and polyoxamers (e. g., PLURONIC L 81); an absorbent selected from the group consisting of magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives; and a colorant ed from the group consisting of titanium dioxide iron oxide, and FD&C Blue #1 ALUMINUM LAKE.

The compositions may be in the form of a e inj ectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable ation may also be a e inj e solution or sion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in l,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's on and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol glycerol formal or polyethylene glycols may also be used. Preservatives, such as phenol or benzyl alcohol, may be used.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including tic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.

Topical, dermal and subdermal formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on ations, ready-to-use formulations, spot-on solutions and suspensions, dips and sprays. Topical application of an inventive compound or of a composition including at least one inventive nd among active agent(s) therein, a spot- on or pour-on composition, can allow for the inventive compound to be ed through the skin to achieve systemic levels, distributed through the ous glands or on the surface of the WO 03505 skin achieving levels throughout the haircoat. When the nd is distributed through the sebaceous glands, they can act as a reservoir, whereby there can be a long-lasting effect (up to several months) effect. Spot-on formulations are typically applied in a zed region which refers to an area other than the entire animal. In one embodiment of a localized region, the location is between the shoulders. In another embodiment of a localized region it is a stripe, e.g. a stripe from head to tail of the animal.

Pour-on formulations are described in US. Patent No. 6,010,710, incorporated herein by reference. The pour-on formulations may be advantageously oily, and generally comprise a diluent or vehicle and also a solvent (e.g. an organic solvent) for the active ingredient if the latter is not soluble in the diluent.

Organic solvents that can be used in the invention include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, thylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene , 2-pyrrolidone including N—methylpyrrolidone, diethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, ethylene glycol, diisobutyl adipate, diisopropyl e (also known as CERAPHYL 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethylsufoxide, organic amides ing dimethylformamide and dimethylacetamide, and diethyl ate, or a mixture of at least two of these solvents.

In one embodiment of the invention, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises C1-C10 alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), Clo-C18 ted fatty acids or esters thereof, Clo-C18 saturated fatty acids or esters f, ters or diesters of aliphatic diacids, glycerol ters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), glycerol triesters (e.g. cerides such as triacetin), glycols, glycol ethers, glycol esters or glycol carbonates, polyethylene s of various grades (PEGs) or monoethers, diethers, monoesters or diesters thereof (e. g. diethylene glycol monoethyl ether), or mixtures thereof.

As vehicle or diluent, mention may be made of plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, coconut oils etc.; mineral oils such as, but not limited to, petrolatum, paraff1n, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C8 to C12) triglycerides.

In another embodiment of the invention, an emollient and/or spreading and/or fllm- forming agent can be added. One embodiment of the emollient and/or spreading and/or filmforming agent are those agents ed from the group consisting of: (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, hylene glycols, benzyl alcohol, 2—pyrrolidones including, but not limited to N-methylpyrrolidone, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, organosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example those containing silanol functionalities, or a 45V2 oil, (b) anionic surfactants such as ne stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetyl sulphate); sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids (e.g. those derived from t oil), (c) cationic surfactants such as water-soluble quaternary ammonium salts of formula N+R'R"R"'R"", Y" in which the radicals R are optionally hydroxylated hydrocarbon radicals and Y" is an anion of a strong acid such as the halide, te and sulphonate ; cetyltrimethylammonium e is among the cationic surfactants which can be used, (d) amine salts of formula N+ '" in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used, (e) nonionic surfactants such as sorbitan esters, which are optionally yethylenated (e.g. POLYSORBATE 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty ls such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol , polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, (f) amphoteric surfactants such as the substituted lauryl compounds of betaine; or (g) a mixture of at least two of these agents.

The solvent will be used in proportion with the concentration of the 2-amido-pyridyl ether compound(s) and its solubility in this solvent. It will be sought to have the lowest possible volume. The vehicle makes up the difference to 100%.

In one embodiment of the amount of emollient, the emollient is used in a proportion of from 0.1 to 50% and 0.25 to 5%, by volume.

In another embodiment, the composition can be in ready-to-use solution form as is described in US. Patent No. 6,395,765, incorporated herein by reference. These formulations may be in the form of spot-on or pour-on formulations to be applied to a localized area on an . In addition to the o-pyridyl ether compound(s), the ready-to-use solution can contain a crystallization inhibitor, an organic t and an c co-solvent.

In one ment of the amount of crystallization inhibitor, the crystallization inhibitor can be present in a proportion of about 1 to about 30% (w/v) in the composition. In other embodiments, the crystallization inhibitor may be t in a proportion of about 1 to about % (w/v) and about 5 to about 15%. Acceptable inhibitors are those whose addition to the formulation inhibits the formation of crystals when the formulation is applied. In some embodiments, formulations may include compounds that function as llization tors other than those listed herein. In these embodiments, the suitability of a crystallization inhibitor may be ined by a the test in which 0.3 ml of a solution comprising 10% (w/v) of the 2- amido-pyridyl ether compound(s) in the liquid carrier and 10% of the inhibitor are deposited on a glass slide at 20°C and d to stand for 24 hours. The slide is then observed with the naked eye. Acceptable inhibitors are those whose addition es for few (e.g. less than ten crystals) or no l.

In one embodiment, the organic solvent has a dielectric constant of a range selected from the group consisting of between about 2 to about 35, about 10 to about 35 or about 20 to about 30. In other embodiments, the solvent will have a dielectric constant of between about 2 and about 20, or between about 2 and about 10. The content of this organic solvent in the overall composition representing the complement to 100% of the composition.

As discussed above, the solvent may comprise a mixture of solvents including a mixture of an organic solvent and an organic co-solvent. In one embodiment, and the organic co-solvent has a boiling point of less than about 300° C or less than about 250° C. In other embodiments, the co-solvent has a boiling point of below about 200° C, or below about 130° C. In still another embodiment of the invention, the organic co-solvent has a boiling point of below about 1000 C, or below about 800 C. In still other ments, the organic co-solvent will have a dielectric constant of a range selected from the group consisting of about 2 to about 40, about 10 to about 40, or typically about 20 to about 30. In some embodiments of the invention, this co-solvent may be present in the composition in a organic co-solvent/organic solvent weight/weight (W/W) ratio of about 1/15 to about 1/2. In some embodiments, the co-solvent is le so as to act as a drying promoter, and is miscible with water and/or with the organic solvent.

The formulation can also comprise an antioxidizing agent intended to inhibit oxidation in air, this agent being present in a proportion selected from a range consisting of about 0.005 to about 1% (w/v) and about 0.01 to about 0.05%.

Crystallization inhibitors which are useful for the invention include but are not limited to: (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols of various grades, benzyl alcohol, 2-pyrrolidones including, but not limited to N—methylpyrrolidone, dimethylsufoxide, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; a solvent as described herein that is capable of inhibiting crystal formation; acrylic tives, such as acrylates and methacrylates or other rs derived from acrylic monomers, and others; (b) anionic surfactants, such as alkaline stearates (e. g. , ium or um te); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulphates, which include but are not limited to sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids (e.g. t oil); (c) cationic surfactants, such as water-soluble quaternary ammonium salts of formula NlR'R"R"'R""Y_, in which the R ls are identical or different optionally hydroxylated hydrocarbon radicals and Y_ is an anion of a strong acid, such as halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is one ofthe cationic surfactants which can be used; (d) amine salts of formula "R'", in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; cylamine hydrochloride is one of the cationic surfactants which can be used; (e) non-ionic surfactants, such as optionally yethylenated esters of sorbitan, e.g.

POLYSORBATE 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty ls, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide; (f) amphoteric surfactants, such as substituted lauryl compounds of e; or (g) a mixture of at least two of the compounds listed in (a)—(f) above.

In one embodiment of the crystallization inhibitor, a crystallization inhibitor pair will be used. Such pairs e, for example, the combination of a film-forming agent of polymeric type and of a surface-active agent. Other mixtures of crystallization inhibitors are also contemplated, including mixtures of two or more, three or more, four or more or even five or more, of the individual crystallization inhibitors bed herein. These agents will be selected from the compounds mentioned above as crystallization inhibitors, or equivalent compounds.

In one embodiment of the film-forming agent, the agents are of the polymeric type which include but are not limited to the various grades of polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinyl acetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents e but are not d to those made of non-ionic surfactants; in another embodiment of the surface active agents, the agent is a polyoxyethylenated esters of sorbitan and in yet r embodiment of the surface- active agent, the agents e the various grades of POLYSORBATE, for example POLYSORBATE 80. In yet another embodiment, the crystallization inhibitor comprises a polyoxyethylenated derivatives of castor oil, including polyoxyethylenated hydrogenated castor oil derivatives. In still another embodiment, the crystallization inhibitor comprises a polyethylene glycol.

In another embodiment, the film-forming agent and the surface-active agent can be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.

The pair thus constituted secures, in a noteworthy way, the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the skin or filr, that is to say without a cy towards sticking or towards a sticky appearance, despite the high concentration of active material.

In one ment of the antioxidizing agents, the agents are those conventional in the art and include but is not limited to ted hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate or a mixture of not more than two of them.

The ation adjuvants discussed above are well known to the practitioner in this art and may be obtained commercially or through known techniques. These concentrated itions are generally prepared by simple mixing of the constituents as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added.

The volume applied is not restricted as long as the amount of substance administered is shown to be safe and efficacious. Typically, the volume applied depends on the size and weight of the animal as well as the concentration of active, the extent of infestation by parasites and the type of administration. In some embodiments, the volume applied can be of the order of about 0.3 to about 5 ml or about 0.3 ml to about 1 ml. In one embodiment for the volume, the volume is on the order of about 0.5 ml, for cats and on the order of about 0.3 to about 3 ml for dogs, depending on the weight of the animal.

In another embodiment, ation of a spot-on formulation according to the present invention can also e long-lasting and broad-spectrum eff1cacy when the solution is applied to the mammal or bird. The spot-on formulations provide for topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to a spot on the animal, lly between the two shoulders (solution of spot-on type).

For n formulations, the carrier can be a liquid carrier vehicle as described in US.

Patent No. 333 (incorporated herein by reference), which in one embodiment of the spot- on formulation ses a solvent and a cosolvent wherein the solvent is selected from the group ting of acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, diisobutyl adipate, diisopropyl e (also known as YL 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, ne carbonate, dimethylsufoxide, organic amides including dimethylformamide and dimethylacetamide, ethanol, panol, methanol, ethylene glycol monoethyl ether, ne glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone including N—methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters, such as the l ester or diisobutyl adipate, and a mixture of at least two of these solvents and the cosolvent is selected from the group consisting of absolute ethanol, isopropanol or methanol.

In one embodiment, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises C1-C10 alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), Clo-C18 saturated fatty acids or esters thereof, 8 monounsaturated fatty acids or esters f, monoesters or rs of aliphatic diacids, glycerol monoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), ol triesters (e.g. triglycerides such as triacetin), s, glycol , glycol esters or glycol carbonates, polyethylene glycols of various grades (PEGs) or monoethers, diethers, monoesters or diesters thereof (e. g. diethylene glycol monoethyl ether), or mixtures thereof.

The liquid r vehicle can optionally contain a crystallization inhibitor including an anionic surfactant, a cationic surfactant, a non-ionic surfactant, an amine salt, an amphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, 2-pyrrolidone including N—methylpyrrolidone (NMP), dimethylsulfoxide, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, solvents as defined herein that can t the formation of crystals, and acrylic derivatives such acrylates or rylates as well as other polymers derived from acrylic monomers, or a mixture of these crystallization inhibitors.

Spot-on ations may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle. Alternatively, the spot-on formulation can be prepared by ulation of the active ient to leave a residue of the therapeutic agent on the surface of the animal. These formulations will vary with regard to the weight of the eutic agent in the combination depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.

Dosage forms may contain from about 0.5 mg to about 5 g of the 2-amido-pyridyl ether compound(s) present. In one embodiment of the dosage form, the dosage is from about 1 mg to about 500 mg of an active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 In one embodiment, the 2-amido-pyridyl ether compound(s) is present in the formulation at a concentration of about 0.05% to about 50% weight/volume. In other embodiments, the 2- WO 03505 amido-pyridyl ether compound(s) may be present in the formulation at a concentration of about 0.1% to about 30%, about 0.5% to about 20% (w/v) or about 1% to about 10% (w/v). In another embodiment, the 2-amido-pyridyl ether compound(s) is present in the formulation as a concentration from about 0.1 to 2% weight/volume. In yet r embodiment, the 2-amido- pyridyl ether compound(s) is present in the formulation as a concentration from about 0.25 to about 1.5% weight/volume. In still another embodiment, the 2-amido-pyridyl ether nd(s) is present in the ation as a concentration about 1% weight/volume.

In a particular advantageous embodiment of the invention, the dose of the 2-amido- pyridyl ether compound(s) is about 0.1 mg/kg to about 100 mg/kg. In other embodiments, the dose of the 2-amido-pyridyl ether compound(s) is about 0.5 mg/kg to about 70 mg/kg, about 0.5 mg/kg to about 50 mg/kg or about 0.5 mg/kg to about 30 mg/kg. In other preferred ments, the dose is 0.5 mg/kg to about 30 mg/kg, 0.5 mg/kg to about 20 mg/kg or 0.5 mg/kg to about 10 mg/kg. More lly, in some embodiments the dose of the 2-amido-pyridyl ether compound(s) is about 0.1 mg/kg to 5 mg/kg, 0.1 mg/kg to about 3 mg/kg, or about 0.1 mg/kg to 1.5 mg/kg. In still other embodiments, the dose may be as low as 0.1 mg/kg (0.02 mg/ml), about 0.2 mg/kg (0.04 mg/ml), about 0.3 mg/kg (0.06 mg/ml), about 0.4 mg/kg (0.08 mg/ml), about 0.5 mg/kg (0.1 mg/ml), about 0.6 mg/kg (0.12 mg/ml), about 0.7 mg/kg (0.14 mg/ml), about 0.8 mg/kg (0.16 mg/ml), about 0.9 mg/kg (0.18 mg/ml), about 1.0 mg/kg (0.2 mg/ml).

The compounds of formula I or their salts can be employed as such or in the form of their preparations (formulations) as combinations with other active substances, such as, for example, insecticides, attractants, sterilants, acaricides, nematicides, herbicides, fiangicides, and with safeners, fertilizers and/or growth regulators, for example as a premix/readymix.

Classifications of ides are well-known in the art and include classifications by FRAC (Fungicide Resistance Action Committee). Fungicides which may ally be admixed include, but are not limited to, methyl benzimidazole carbamates, such as benzimidazoles and thiophanates; oximides; demethylation inhibitors, such as imidazoles, piperazines, pyridines, pyrimidines, and triazoles; phenylamides, such as acylalanines, oxazolidinones, and butyrolactones; amines, such as morpholines, piperidines, and spiroketalamines; phosphorothiolates; dithiolanes; carboxamides; hydroxy-(2-amino-)pyrimidines; anilino- dines; N—phenyl carbamates; quinone outside inhibitors; pyrroles; quinolines; aromatic hydrocarbons; aromatics; melanin thesis inhibitors-reductase; melanin biosynthesis inhibitors-dehydratase; hydroxyanilides (SBI class 111), such as fenhexamid; SBI class IV, such as thiocarbamates and allylamines; polyoxins; phenylureas; quinone inside inhibitors; benzamides; enopyranuronic acid antibiotic; hexopyranosyl antibiotic; glucopyranosyl antibiotic; yranosyl antibiotic; cyanoacetamideoximes; carbamates; uncoupler of oxidative phosphorylation; organo tin compounds; carboxylic acids; heteroaromatics; phosphonates; phthalamic acids; benzotriazines; benzenesulfonamides; pyridazinones; carboxylic acid ; ycline otic; thiocarbamate; thiadiazole BTH; benzisothiazole; thiadiazolecarboxamide; thiazolecarboxamides; benzamidoxime; quinazolinone; henone; acylpicolide; inorganic compounds, such as copper salts and sulphur; dithiocarbamates and relatives; phthalimides; chloronitriles; sulphamides; guanidines; triazines; quinones.

Other fungicides that may optionally be admixed may also be from the classes of compounds described in US. Patent Nos. 7,001,903 and 7,420,062.

Herbicides that are known from the literature and classified by HRAC (Herbicide ance Action Committee) and may be combined with the compounds of the invention are, for e: aryloxyphenoxy-propionate; cyclohexanedione; phenylpyrazoline; sulfonylurea; imidazolinone, such as imazapic and imazethapyr; triazolopyrimidine; pyrimidinyl(thio)benzoate; sulfonylaminocarbonyl-triazolinone; triazine, such as atrazine; triazinone; linone; uracil; pyridazinone; phenyl-carbamate; urea; amide; nitrile; benzothiadiazinone; phenyl-pyridazine; bipyridylium, such as paraquat; diphenylether; phenylpyrazole; N—phenylphthalimide; thiadiazole; thiadiazole; triazolinone; oxazolidinedione; pyrimidindione; pyridazinone; pyridinecarboxamide; triketone; ole; pyrazole; triazole; isoxazolidinone; urea, such as n; diphenylether; glycine, such as glyphosate; phosphinic acid, such as glufosinate-ammonium; carbamate; dinitroaniline, such as pendimethalin; phosphoroamidate; pyridine; benzamide; benzoic acid; chloroacetamide; metolachlor; acetamide; oxyacetamide; tetrazolinone; nitrile; benzamide; triazolocarboxamide; quinoline carboxylic acid; dinitrophenol; thiocarbamate; phosphorodithioate; benzofuran; -carbonic-acid; phenoxy- carboxylic-acid, such as 2,4-D; benzoic acid, such as dicamba; pyridine carboxylic acid, such as clopyralid, triclopyr, fluroxypyr and picloram; quinoline carboxylic acid; phthalamate semicarbazone; qrylaminopropionic acid; qrylaminopropionic acid; organoarsenical.

Other herbicides that may optionally be admixed are compounds bed in US. Patent Nos. 7,432,226, 7,012,041, and 7,365,082.

Appropriate ide safeners include but are not limited to benoxacor, cloquintocet, cyometrinil, cyprosulfamide, dichlormid, dicyclonon, dietholate, fenchlorazole, fenclorim, flurazole, fluxofenim, filrilazole, isoxadifen, mefenpyr, mephenate, naphthalic anyhydride and oxabetrinil.

Bactericides include, but are not limited to, bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, arboxylic acid, oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulphate and other copper ations.

Insecticides/acaricides/nematicides include those compounds mentioned in US. Patent Nos. 7,420,062 and 7,001,903, US. Patent publication 2008/0234331, each incorporated herein by reference, the literature known to the person skilled in the art, and the compounds classified by IRAC (Insecticide Resistance Action Committee). Examples of insecticides/acaricides/nematicides include, but are limited to, carbamates; triazemate; organophosphates; cyclodiene organochlorines; phenylpyrazoles; DDT; methoxychlor; pyrethroids; pyrethrins; neonicotinoids; nicotine; tap; cartap hydrochloride; nereistoxin analogues; spinosyns; avermectins and milbemycins; juvenile hormone ues; fenoxycarb; fenoxycarb; alkyl halides; chloropicrin; yl fluoride; cryolite; pymetrozine; flonicamid; clofentezine; hexythiazox; etoxazole; Bacillus sphaerz'cus; diafenthiuron; organotin miticides; propargite; tetradifon; chlorfenapyr; DNOC; benzoylureas; buprofezin; cyromazine; diacylhydrazines; azadirachtin; amitraz; hydramethylnon; acequinocyl; pyrim; METI acaricides; rotenone; indoxacarb; metaflumizone; tetronic acid tives; aluminium ide; cyanide; phosphine; bifenazate; fluoroacetate; P450-dependent monooxygenase inhibitors; esterase inhibitors; diamides; benzoximate; chinomethionat; dicofol; pyridalyl; borax; tartar emetic; filmigants, such as methyl e; ditera; clandosan; sincocin.

The compounds of formula I can be formulated in s ways, ing on the prevailing biological and/or chemico-physical parameters. Examples of le ations which are le are: le powders (WP), water-soluble s (SP), water-soluble concentrates, emulsifiable concentrates (EC), emulsions (EW) such as oil-in-water and water-in- oil emulsions, sprayable solutions, suspension concentrates (SC), dispersions on an oil or water basis, solutions which are miscible with oil, capsule suspensions (CS), dusts (DP), seed-dressing products, granules for broadcasting and soil application, granules (GR) in the form of microgranules, spray es, coated granules and adsorption granules, water-dispersible granules (WG), water-soluble granules (SG), ULV formulations, microcapsules and waxes.

Solid state forms of the compounds of formula (I) can be prepared by methods known in the art, e.g. Bym et al., “Solid-State Chemistry of Drugs”, 2Ild Edition, SSCI Inc., (1999); Glusker et al., “Crystal ure Analysis — A ”, 211d Edition, Oxford sity Press, (1 985).

The formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one solvent or diluent, emulsifier, dispersant and/or binder or fixative, water repellent and optionally one or more of a ant, UV stabilizer, a colorant, a pigment and other processing auxiliaries.

These indiVidual formulation types are known in principle and described, for e, in: Winnacker—Kiichler, "Chemische Technologie" [Chemical Technology], Volume 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wade van Valkenburg, "Pesticide Formulations", Marcel Dekker, N.Y., 1973; K. Martens, "Spray Drying Handbook", 3rd Ed. 1979, G. Goodwin Ltd.

London.

The necessary formulation auxiliaries such as inert materials, surfactants, solvents and other additives are also known and described, for example, in: Watkins, "Handbook of Insecticide Dust Diluents and Carriers", 2nd Ed., Darland Books, Caldwell N.J.; H.V. Olphen, "Introduction to Clay Colloid Chemistry", 2nd Ed., J. Wiley & Sons, N.Y.; C. Marsden, "Solvents , 2nd Ed., Interscience, NY. 1963; McCutcheon's "Detergents and Emulsifiers Annual", MC Publ. Corp., Ridgewood N.J.; Sisley and Wood, lopedia of Surface Active Agents", Chem. Publ. Co. Inc., NY. 1964; Schonfeldt, flachenaktive Athylenoxidaddukte" [Surface-active ethylene oxide adducts], Wiss. Verlagsgesell., Stuttgart 1976; Winnacker-Kiichler, "Chemische Technologie" [Chemical Technology], Volume 7, C.

Hauser Verlag, Munich, 4th Ed. 1986.

Wettable powders are ations which are uniformly dispersible in water and which, besides the compounds of formula I, also se ionic and/or nonionic tants (wetters, dispersants), for example, polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxyethylated fatty , fatty alcohol polyglycol ether es, alkanesulfonates or alkylbenzenesulfonates, sodium lignosulfonate, sodium 2,2'-dinaphthylmethane-6,6'-disulfonate, sodium dibutylnaphthalenesulfonate or else sodium oleoylmethyltaurinate, in addition to a diluent or inert substance. To prepare the le powders, the compounds of formula I are, for example, ground finely in conventional apparatuses such as hammer mills, blower mills and airjet mills and mixed with the formulation auxiliaries, either concomitantly or thereafter.

Emulsifiable concentrates are prepared, for example, by dissolving the compounds of formula I in an organic solvent, for example l, cyclohexanone, dimethylformamide, xylene or else higher-boiling aromatics or hydrocarbons or mixtures of these, with addition of one or more ionic and/or nonionic surfactants (emulsifiers). Emulsifiers which can be used are, for example: calcium salts of alkylarylsulfonic acids, such as calcium dodecylbenzenesulfonate or nonionic emulsif1ers, such as fatty acid polyglycol , alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide/ethylene oxide sates, alkyl polyethers, sorbitan esters such as sorbitan fatty acid esters or polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan fatty acid esters.

Dusts are ed by grinding the active substance with finely divided solid substances, for example talc or l clays, such as , bentonite or yllite, or diatomaceous earth.

Suspension concentrates may be water- or oil-based. They can be prepared, for example, by wet grinding by means of commercially available bead mills, if appropriate with on of surfactants, as they have already been mentioned above for example in the case of the other formulation types. ons, for example oil-in-water emulsions (EW), can be prepared for example by means of stirrers, colloid mills and/or static mixtures using aqueous organic solvents and, if appropriate, surfactants as they have already been ned above for example in the case of the other formulation types. es can be prepared either by spraying the compounds of formula I onto adsorptive, granulated inert material or by applying active substance concentrates onto the surface of rs such as sand, kaolinites or of granulated inert material, by means of binders, for example polyvinyl alcohol, sodium polyacrylate or alternatively mineral oils. Suitable active substances can also be granulated in the manner which is tional for the production of fertilizer granules, if desired in a mixture with fertilizers.

Water-dispersible granules are prepared, as a rule, by the customary processes such as spray-drying, fluidized-bed granulation, disk granulation, mixing in high-speed mixers and extrusion without solid inert material. To prepare disk, fluidized-bed, extruder and spray granules, see, for example, processes in -Drying Handbook" 3rd ed. 1979, G. Goodwin Ltd., London; J.E. Browning, "Agglomeration", Chemical and Engineering 1967, pages 147 et seq.; "Perry's Chemical Engineer's Handbook", 5th Ed., McGraw-Hill, New York 1973, p. 8-57.

In general, the agrochemical ations comprise a range selected from the group consisting of about 0.1 to about 99% by weight and about 0.1 to about 95% by weight, of compounds of formula I.

The concentration of compounds of formula I in wettable powders is, for example, about to about 90% by weight, the remainder to 100% by weight being composed of customary ation components. In the case of emulsif1able concentrates, the concentration of compounds of formula I can amount to ranges ed from the group consisting of about 1% to about 90% and about 5% to about 80% by weight. Formulations in the form of dusts usually se in the range selected from the group consisting of about 1% to about 30% by weight of compounds of formula I and about 5% to about 20% by weight of compounds of formula I. For sprayable ons comprise a range selected from the group consisting of about 0.05% to about 80% by weight of compounds of formula I and about 2% to about 50% by weight of compounds of formula I. In the case of water-dispersible granules, the content of compounds of a I depends partly on whether the compounds of formula I are in liquid or solid form and on which granulation auxiliaries, fillers and the like are being used. The water-dispersible granules, for example, comprise a range selected from the group ting of between about 1 and about 95% and between about 10% and about 80% by .

In addition, the ations of compounds of formula I mentioned comprise, if appropriate, the adhesives, wetters, dispersants, emulsifiers, penetrants, preservatives, eeze , solvents, fillers, carriers, colorants, antifoams, evaporation inhibitors, pH regulators and viscosity regulators which are conventional in each case.

Additional pharmaceutically or veterinarily active ingredients may also be added to the compositions of the invention. In some ments, the additional active agents may be one or more parasiticidal nds including acaricides, anthelmintics, endectocides and insecticides.

Anti-parasitic agents can include both ectoparasiticisal and endoparasiticidal agents.

Veterinary pharmaceutical agents that may be included in the compositions of the invention are nown in the art (see e.g. Plumb ’ Veterinary Drag Handbook, 5th Edition, ed.

Donald C. Plumb, ell hing, (2005) or The Merck Veterinary Manual, 9th Edition, ry 2005)) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide , acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, in sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitraz, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, clavulanate potassium, amphotericin B desoxycholate, ericin B lipid-based, ampicillin, amprolium, antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbic acid, asparaginase, ng, atenolol, atipamezole, atracurium besylate, atropine e, aumofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbituates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol te, cabergoline, calcitonin salmon, calcitrol, calcium salts, captopril, carbenicillin indanyl , carbimazole, latin, camitine, carprofen, carvedilol, oxil, cefazolin sodium, cefixime, chlorsulon, cefoperazone , cefotaXime , cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, idime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), um, cimetidine, ciprofloxacin, cisapride, cisplatin, e salts, clarithromycin, clemastine filmarate, clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), ropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexraazoxane, n, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), cin, digoxin, otachysterol (DHT), diltiazem, ydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, idone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium.calcium EDTA, edrophonium chloride, ril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasia agents W/pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, f1pronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (S-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), lidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine, ide, glycerine (oral), glycopyrrolate, relin, ofulVin, guaifenesin, halothane, hemoglobin glutamer-200 (oxyglobin®), heparin, hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, ortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, impenem—cilastatin , imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium, iron dextran, ane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, racetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine , lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone e, megestrol acetate, melarsomine, melatonin, meloxican, melphalan, meperidine, mercaptopurine, nem, metformin, methadone, methazolamide, amine mandelate/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, olol, metronidaxole, mexiletine, mibolerlone, midazolam milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, ne sulfate, ctin, naloxone, lone decanoate, naproxen, narcotic (opiate) agonist sics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, in, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, pencillamine, general information penicillins, llin G, penicillin V ium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, ide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone, ephrine, phenypropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione/Vitamin K-l, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone/prednisone, primidone, procainamide, bazine, prochlorperazine, propantheline bromide, propionibacterium acnes injection, propofol, propranolol, protamine sulfate, ephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin, selegiline /l- deprenyl, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, olol, streptokinase, streptozocin, succimer, ylcholine chloride, sucralfate, sufentanil citrate, hlorpyridazine sodium, sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim, sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine, tepoxaline, terbinafline, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, ntal sodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium, tiletamine /zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tolazoline, telfenamic acid, topiramate, tramadol, trimcinolone acetonide, ine, trilostane, trimepraxine tartrate nisolone, ennamine, tylosin, urdosiol, ic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, Vinblastine sulfate, Vincristine e, n E/selenium, warfarin sodium, ne, yohimbine, zafirlukast, zidovudine (AZT), zinc e/zinc sulfate, zonisamide and es thereof.

In one embodiment, arylpyrazole compounds such as pyrazoles (eg. f1pronil, pyriprole), may be suitable for combination with the aryloazol-2—yl cyanoethylamino compounds of the invention. Examples of such arylpyrazole compounds include but are not limited to those described in US. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 329; 6,174,540; 6,685,954 and 6,998,131 - each assigned to Merial, Ltd., , GA.

In another embodiment, nodulisporic acid and its derivatives (a class of known acaricidal, anthelminitic, anti-parasitic and insecticidal agents) can be added to the compositions of the ion. These nds are used to treat or prevent infections in humans and s and are described, for e, in US. Patent No. 5,399,582, 5,962,499, 6,221,894 and 6,399,786.

The composition can include one or more of the known nodulisporic acid derivatives in the art, including all stereoisomers, such as those described in the literature cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrile class (AAD) of compounds such as monepantel X) and the like may be added to the compositions of the invention. These compounds are described, for example, in ; Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13 March 2008, 176-181.

In another embodiment, the compositions may advantageously include one or more compounds of the isoxazoline class of compounds. These active agents are described in WO 2007/079162, and US 2009/0133319, and US 2009/0143410, , , WO 24541, WO 85216 and US 2007/0066617 and , all of which are incorporated herein by reference in their entirety.

In another embodiment, the compositions may advantageously include at least one compound of formula I in combination with paraherquamide nds and derivatives of these nds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherquamide family of compounds are known class of compounds that include a spirodioxepino indole core with actiVity against n parasites (see Tet. Lett. 1981, 22, 135; J.

Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, the structurally related marcfortine family of compounds, such as marcfortines A-C, are also known and may be combined with the formulations of the invention (see J. Chem. Soc. — Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to the paraherquamide derivatives can be found, for e, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, W0 09/004432, US. Patent 5,703,078 and US. Patent 5,750,695, all of which are hereby orated by reference in their entirety.

In another embodiment, the compositions may be combined with cyclo-depsipeptide anthelmintic compounds including emodepside (see Willson et al., Parasitology, Jan. 2003, l26(Pt l):79-86).

In some embodiments, the itions may include one or more antinematodal agents including, but not limited to, active agents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates class of compounds. In some embodiments, benzimidazoles including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, azole, fenbendazole, oxfendazole, albendazole, endazole, febantel, thiophanate and its o,o-dimethyl analogue may be included in the compositions.

In other embodiments, the compositions may include an imidazothiazole compounds including, but not limited to, tetramisole, levamisole and sole. In still other embodiments, the compositions may include tetrahydropyrimidine active agents including, but not limited to, pyrantel, l, and el. Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos.

In other embodiments, the compositions may e the antinematodal compounds phenothiazine, piperazine as the neutral compound and in various salt forms, lcarbamazine, phenols such as disophenol, arsenicals such as arsenamide, ethanolamines such as bephenium, thenium closylate, and idine; cyanine dyes including pyrvinium chloride, ium pamoate and dithiazanine iodide; isothiocyanates including bitoscanate, suramin , phthalofyne, and various natural products including, but not limited to, hygromycin B, santonin and kainic acid.

In other embodiments, the compositions may include antitrematodal agents. Suitable antitrematodal agents include, but are not limited to, the miracils such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, zole, nitroxynil, various bisphenol compounds known in the art ing hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan; various salicylanilide compounds including msalan, oxyclozanide, clioxanide, rafoxanide, nide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

Anticestodal compounds may also be advantageously used in the itions ing, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.

In yet other embodiments, the compositions may e other active agents that are effective against arthropod parasites. le active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, ychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, on, dichlorenthion,, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, nphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, os, carbaryl, promacyl, propoxur, allethrin, cyhalothrin, cypermethrin, ethrin, fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins, resmethrin, amitraz, benzyl benzoate, carbon disulf1de, crotamiton, diflubenzuron, diphenylamine, disulf1ram, isobomyl thiocyanato acetate, methroprene, monosulf1ram, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, deet, dimethyl phthalate, and the compounds 1,5a,6,9,9a,9b- hexahydro-4a(4H)—dibenzofurancarboxaldehyde (MGK-l 1), 2-(2-ethylhexyl)-3a,4,7,7atetrahydro-4 ,7-methano-1H-isoindole-1,3(2H)dione 64), dipropyl-2,5- pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

In another embodiment of the invention, one or more macrocyclic lactones, which act as an acaricide, anthelmintic agent and insecticide, can be added to the compositions of the invention. The macrocyclic lactones also include, but are not limited to, avermectins, such as abamectin, dimadectin, ctin, emamectin, eprinomectin, ctin, latidectin, lepimectin, selamectin and milbemycins, such as milbemectin, milbemycin D, moxidectin and nemadectin.

Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.

Examples of combinations of macrocyclic lactones with other active agents are described in US.

Patent Nos. 6,426,333; 6,482,425; 6,962,713 and 6,998,131 - each assigned to Merial, Ltd., , GA, all incorporated herein by nce.

The macrocyclic lactone compounds are known in the art and can be ed commercially or through synthesis techniques known in the art. Reference is made to the widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference may be made, for example, to the work ectin and Abamectin”, 1989, by M.H.

Fischer and H. Mrozik, m C. Campbell, hed by Springer ., “Macrocyclic Lactones in Antiparasitic Therapy”, 2002, by J Vercruysse and RS Rew published by CABI Publishing or Albers-Schonberg et al. (1981), “Avermectins Structure Determination”, J. Am.

Chem. Soc., 103, 4216-4221. For doramectin, inary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may be consulted. For milbemycins, reference may be made, inter alia, to Davies H.G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US.

Patent No. 4,134,973 and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-synthetic derivatives f.

The structures of the avermectins and milbemycins are y related, e. g., by sharing a complex 16-membered macrocyclic lactone ring; milbemycins lack the glycosidic moiety of the avermectins. The natural products avermectins are disclosed in US. Patent No. 519 to Albers-Schonberg et al., and the 22,23-dihydro avermectin compounds are disclosed in Chabala et al., US. Patent No. 4,199,569. Mention is also made of Kitano, US. Patent No. 4,468,390, Beuvry et al., US. Patent No. 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP 0 002 916, and Ancare New Zealand Patent No. 237 086, inter alia. Naturally ing milbemycins are described in Aoki et al., US. Patent No. 3,950,360 as well as in the various references cited in “The Merck Index” 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in the “International Nonproprietary Names for Pharmaceutical Substances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263- 286, (2003). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in US. Patent No. 5,077,308, US. Patent No. 4,859,657, US. Patent No. 582, US. Patent No. 4,855,317, US. Patent No. 4,871,719, US. Patent No. 4,874,749, US. Patent No. 4,427,663, US. Patent No. 4,310,519, US. Patent No. 4,199,569, US. Patent No. 5,055,596, US. Patent No. 4,973,711, US. Patent No. 4,978,677, US. Patent No. 148 and EP 0 667 054.

In another embodiment, the class of acaricides or insecticides known as insect growth regulators (IGRs) can also be added to the compositions of the invention. Compounds belonging to this group are well known to the practitioner and represent a wide range of ent al classes. These compounds all act by interfering with the development or growth of the insect pests. Insect growth regulators are described, for example, in US. Patent No. 3,748,356; US.

Patent No. 3,8 1 8,047; US. Patent No. 4,225,598; US. Patent No. 4,798,837; US. Patent No. 4,751,225, EP 0 179 022 or UK. 2 140 010 as well as US. Patent Nos. 6,096,329 and 6,685,954 (both assigned to Merial Ltd., , GA). Examples of IGRs suitable for use include but are not limited to methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron, novaluron, pyrethroids, formamidines and l-(2, 6-difluorobenzoyl)(2-fluoro oromethyl)phenylurea.

A parasiticidal agent that can be combined with at least one compound of formula I to form a composition can be a biologically active peptide or protein ing, but not limited to, depsipeptides, which act at the neuromuscular on by stimulating presynaptic receptors belonging to the secretin receptor family resulting in the paralysis and death of parasites. In one embodiment of the depsipeptide, the depsipeptide is side.

An insecticidal agent that can be combined at least one compound of formual I to form a composition can be a spinosyn (e.g. spinosad) or a tuted pyridylmethyl derivative compound such as imidacloprid. Agents of this class are described above, and for example, in US. Patent No. 4,742,060 or in EP 0 892 060. It would be well within the skill level of the tioner to decide which individual compound can be used in the inventive formulation to treat a particular parasitic ion/infestation. For ectoparasites, active agents that can be combined also include but are not limited to pyrethoids, organophosphates and neonicotinoids such as loprid, as well as compounds such as metaflumizone, amitraz and ryanodine receptor antagonists.

Where riate the mintic, parasiticidal and insecticial agent may also be selected from the group of compounds described above as suitable for agrochemical use.

In general, at least one compound of formula I is included in a dose of between about 0.1 ug and about 500 mg. In some embodiments, the additional active agent may be present in a dose of about 1 mg to about 500 mg, about 1 mg to about 300 mg, or about 1 mg to about 100 mg. In other embodiments, the additional active agent may be present in a dose of about 1 mg to about 50 mg or about 1 mg to about 20 mg. In other embodiment of the invention, the additional active agent is included in a dose of about 1 ug to about 10 mg.

In another embodiment, the additional active agent is included in a dose of about 5 ug/kg to about 50 mg/kg. In other embodiments, the additional active agent may be included in a dose of about 5ug/kg to about 30 mg/kg, about 5ug/kg to about 20 mg/kg or about 5ug/kg to about 10 mg/kg. In still other embodiments, the additional active agent may be included in a dose of about 10 ug/kg to about 1 mg/kg or about 50 ug/kg to about 500 ug/kg of weight of the animal.

In yet another embodiment, the additional active agent is included in a dose between about 0.1 mg/kg to about 10 mg/kg of weight of animal. In still another embodiment, the additional active agent is included in a dose between about 0.5 mg/kg to 50 mg/kg.

The proportions, by weight, of the at least one compound of formula I and the additional active agent are for example between about 5/ 1 and about 10,000/ 1. However, one of ordinary skill in the art would be able to select the appropriate ratio of 2-amido-pyridyl ether compound(s) and the additional active agent for the intended host and use f.

The subject matter disclosed herein is also directed to a treated seed comprising a compound of formula Iin an amount of from about 0.0001 to 1% by weight of the seed before treatment.

IV. Methods ofUse In another embodiment, the subject matter described herein is directed to a method of treating endoparasitic infestation or infection in an , sing administering an effective amount of at least one 2-amido-pyridyl ether compound(s) as described herein to an animal or subject in need thereof The nds of the invention have been shown to have excellent cy against rasites, rasites or both.

In one embodiment, the compounds and compositions of the invention may be used for treating endoparasiticidal infection or ation by helminth species including, but is not limited to, Anaplocephala (Anoplocephala), Ancylostoma, Anecator, Ascarz's, Brugz'a, omum, Capillaria, Chabertz'a, Cooperl'a, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, caulus, Dz'petalonema, Dl'pylz'dz'um, Dirofilarz'a, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroz'des, Habronema, Haemonchus, Metastrongylus, z'a, Necator,Nemat0dirus, Nl'ppostrongylus, Oesophagostumum, erca, Ostertagz'a, Oxyuris, Paracarz's, Schistosoma, Strongylus, Taenz'a, Toxocara, Strongyloz'des, Toxascaris, Trichl'nella, Trichurl's, Trichostrongylus, Triodontophorous, Uncz'narz'a, Wuchereria, and combinations thereof In a preferred embodiment, the helminth is chus contortus, Ostertagz'a circumcincta, Trichostrongylus axez', Trichostrongylus z’formz’s, Cooperz'a curticei, Nematodirus battus and combinations thereof In another embodiment, the subject matter sed herein is directed toward a method of treating ectoparasitic infestation or infection in an animal in need thereof which comprises administering an ive amount of the nd of the invention to the animal in need thereof. In an embodiment, the ectoparasite is an arthropod. Preferably, the pod is selected from the group consisting of houseflies (Musca domestica), Musca hervez’, Musca bezzz', Haematobz'a irritans, Simulz'um iwatens, Culicoz'des oxystoma, Tabanus chrysurus, common mosquito (Culex pl’piens), Aedes albopictus; lice pests (Anoplura), cattle lice (Haematopinus eurysternus), sheep lice (Damalz'nz'a ovis); tick pests (Acarl'na), Haemaphysalis longicom's, 'lus microplus; fleas (Sz'phonaptera), cat fleas (Ctenocephalidesfelis), dog fleas (Ctenocephalides canis) and oriental rat flea (Xenopsylla cheapz’s).

In one embodiment, the infection or infestation is caused by fleas, ticks, mites, mosquitoes, flies, lice, blowfly, fly larvae and combinations f Preferably, the pest or parasite is selected from the group consisting of flies, including homfly and stable fly, fleas, ticks and mosquitos.

In one emodiment, the subject matter disclosed herein is directed to a method for treating an ectoparasitic infestation or infection in an animal, comprising administering an effective amount of at least one 2-amido-pyridyl ether compound(s) as described herein in combination with a second active ingredient to an animal.

In one embodiment, the parasite is an ectoparasite or an endoparasite or a ation thereof.

The methods include contacting a pest or parasite with at least one 2-amido-pyridyl ether compound as described herein. The methods also e contacting the areas and ties where the pests or parasites infest or reside. In a prophylactic treatment, the methods include contacting the areas or Vicinities susceptible to pest or parasitic infestation or residence.

The subject of the present invention is also a process for the elimination of parasites in mammals and birds, ally dogs and cats, using a composition according to the t invention.

In one embodiment of the invention, direct pour-on skin formulation according to the present invention can obtain long-lasting and broad-spectrum efficacy when the solution is d to the animal's back, preferably along the line of the back at one or more points.

According to an embodiment for administering direct pour-on formulations, the process consists in applying the solution to the animals in pasture and/or before they arrive in pasture, the application preferably being repeated every month, preferably every two months.

According to another embodiment for administering direct pour-on formulation, the process consists in applying the solution to livestock s before they arrive in the "Feed Lot", it being le for this ation to be the final one before the animals are slaughtered.

This method can serve to cleanse the skin and the hairs of the animals by eliminating the parasites which are present thereon, as well as their es and dejections. The result of this is that the animals are no longer stressed by the parasites and their bites, this having ve consequences, for e on their growth and on the use of their food .

In another embodiment, application of spot-on formulation can also obtain long-lasting and broad-spectrum eff1cacy when the solution is applied to the mammal or bird.

Administration of the spot-on formulation may be intermittent in time and may be administered daily, weekly, biweekly, y, bimonthly, quarterly, or even for longer durations of time. The time period between treatments depends upon factors such as the parasite(s) being treated, the degree of infestation, the type ofmammal or bird and the environment where it resides. It is well within the skill level of the tioner to determine a specific administration period for a particular ion. This invention contemplates a method for permanently combating a parasite in an environment in which the animal is subjected to strong parasitic pressure where the administration is at a frequency far below a daily administration in this case. For example, it is preferable for the treatment according to the invention to be carried out monthly on dogs and on cats.

The administration of spot-on formulations also provides for a method for cleaning the coats and the skin of animals by l of the parasites which are present and of their waste and excreta. The s treated thus exhibit a coat which is more pleasing to the eye and more pleasant to the touch. 2012/044476 In an embodiment, the present subject matter is ed to a method for protecting a seed from a pest comprising contacting the seed with a biologically effective amount of a compound of formula I.

V. Articles of Manufacture In an ment, the present subject matter is directed to a deVice for controlling a pest comprising a bait composition containing at least one 2-amido-pyridyl ether compound and a housing adapted to receive the bait composition, wherein the housing has at least one opening sized to permit the pest to pass through an opening that allows the pest access to the bait ition from a location outside the g, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the pest.

VI. Examples A. Methods of Preparing Compounds of Formula I The compounds of formula I may be prepared according to the processes described herein or by the application or adaptation of known methods (i.e. s heretofore used or described in the chemical literature).

All temperatures are given in degrees rade; room temperature means 20 to 25°C.

Reagents were purchased from cial sources or prepared following literature procedures.

Proton and fluorine magnetic resonance (respectively 1H NMR and 19F NMR) spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (1H) and 377 MHz (19F)], Bruker NMR spectrometer [400 MHz (1H) and 377 MHz (19F)] and Bruker NMR ometer [300 MHz (lH)]. All spectra were determined in the solvents indicated. Chemical shifts are ed in ppm downfield of tetramethylsilane (TMS), referenced to the residual proton peak of the tive solvent peak for 1H NMR. LC-MS spectra were obtained using: Shimadzu SP-20A 2010EV using a Shim-pack XR—ODS 2.2 micron C18 50 x 3.0 mm column and a linear gradient from 10% acetonitrile with 0.1% formic acid in water with 0.1% formic acid to 100% acetonitrile with 0.1% formic acid over 2 minutes; 100% acetonitrile with 0.1% formic acid was held for 1 minute. Waters Acquity HPLC system using an Ascentis® Express C18 HPLC Column, 75 X 2.1 mm, 2.7u. Column temperature was held at 400 C. Solvent A: 10 mMol Ammonium Acetate in 5% Acetonitrile/Water with 0.1% v/v Acetic acid. Solvent B: Acetonitrile. Method ran from 0%B to 100%B over 0.7 min holding at 100%B for 0.15 min then returning to initial conditions for 0.15 min at a flow rate of 1.5 . Agilent 12OOSL LC equipped with a 6130 single quadrupole mass spectrometer and SofTa (Westminster, CO) 300s ELSD using a Shimadzu Shim-pack XR-ODS, 3.0 x 30 mm, 2.2 um, was used at a temperature of 50°C and at a flow rate of 1.5 , 2 uL injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) methanol with 0.1% formic acid; retention time given in minutes. Method details: (1) runs on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion ospray mode with UV-detection at 220 and 254 nm with a gradient of 15-95% (B) in a 2.2 min linear gradient (11) hold for 0.8 min at 95% (B) (111) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15% (B).

Schemes 1-5 depict tic routes to yield carboxylic acid and ester containing derivatives Via moethyl)chloropyridine. The derivatives are useful for preparing compounds of formula 1.

Example 1. sis of nd I-4 rflc‘fl ,HKIEO er “I:I In: BPflfifl.) m/fljfl»;ml | 5 Ell ml er a.» at: mm 1—1 I42 “UH” Pam-Tm:Eta" ”off:40,» Mflj-fififl Scheme 1. A synthetic route for preparing compound I-4.

Example 2. Synthesis of compound I-1. Into a 1000-mL round-bottom flask, was placed 2-chloromethylpyridine (44 g, 344.83 mmol, 1.00 equiv), perchloromethane (500 mL), 1- bromopyrrolidine-2,5-dione (60 g, 337.08 mmol, 0.98 equiv), and benzoic peroxyanhydride (1 g). The resulting solution was heated to reflux for overnight. The solids were removed by filteration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :20). This resulted in 22 g (31%) of 5- methyl)chloropyridine as a white solid.

LC—MS: (ES, m/Z): 208 [M+H]+ li/ NBS . mm} or H” CCl, CI113”“ mlhx II- 1 Scheme 2. A synthetic route for preparing compound I-l.

Example 3. Synthesis of compound I-2. Into a 1000-mL round-bottom flask, was placed -(bromomethyl)chloropyridine (22 g, 106.54 mmol, 1.00 , 4- (trifluoromethoxy)phenol (22 g, 123.53 mmol, 1.16 equiv), acetonitrile (300 mL), and potassium carbonate (22 g, 159.19 mmol, 1.49 equiv). The resulting solution was heated at reflux overnight. The ing mixture was concentrated under vacuum. The residue was dissolved in 300 mL of romethane. The solids were removed by filtration. The filtrate was concentrated under vacuum. This resulted in 25 g (77%) of 2-chloro((4- (trifluoromethoxy)phenoxy)methyl)pyridine as a light yellow solid.

LC—MS: (ES, m/Z): 304 [M+H]+ Scheme 3. A synthetic route for preparing nd I-2. e 4. Synthesis of compound I-3. Into a 1000-mL pressure tank reactor, was placed 2-chloro((4-(trifluoromethoxy)phenoxy)methyl)pyridine (25 g, 82.32 mmol, 1.00 equiv), methanol (300 mL), triethylamine (16.7 g, 165.02 mmol, 2.00 equiv), and Pd(dppl)C12 (2 g). To the above CO (g) was introduced at 20 atm pressure. The ing solution was d for 1 hr overnight at 100°C. The resulting mixture was cooled and concentrated under vacuum. The residue was d onto a silica gel column with dichloromethane/petroleum ether (1 :1). This resulted in 15 g (56%) of methyl 5-((4- (trifluoromethoxy)phenoxy)methyl)picolinate as a light yellow solid LC—MS: (ES, m/Z): 328 [M+H]+ Human. E's" QmD‘F 1;we. AGHQTO‘CF, "20H " AH/(j/mD» mm}2mm 1mm: Scheme 4. Synthetic route for preparing compound 1-3.

Example 5. Synthesis of L4. Into a 500-mL round-bottom flask, was placed a solution of methyl 5-((4-(trifluoromethoxy)phenoxy)methyl)picolinate (15 g, 45.83 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), and a solution of lithium hydroxide (2.2 g, 92.05 mmol, 2.01 equiv) in water (100 mL). The resulting solution was heated to reflux for 1 hr. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6 with acetic acid. The solids were collected by filtration and dried in an oven under reduced pressure. This ed in 9.6 g (67%) of 5-((4-(trifluoromethoxy)phenoxy)methyl)picolinic acid as a white solid.

LC-MS: (ES, m/Z): 314 [M+H]+ 1H-NMR: (400MHz, DMSO-d6, ppm): 55.29(s, 2H), 7.15(m, 2H), 7.33(m, 2H), , 2H), 8.79(s, 1H). 19F-NMR: (376 MHz; DMSO-d6, ppm): -57.25 (s, 3F) ,[flj/mJ/EMHFWH of) HCFE (IE/(f0 Scheme 5. A synthetic route for preparing compound 1-4.

Schemes 6-19 depict synthetic routes to yield carboxylic acid and ester containing derivatives via 5-(bromoethyl)picolinate. The derivatives are useful for preparing compounds of a 1. e 6. Synthesis of 10.

I?“ E #9:“ch_ a: flaw” a$.22» D x“ I- 5:33-10:33 Miss-1:321 LIJHH-p MElip/“Olav" —"‘ AD/[SEX LES-1m 15.1.3-3 Scheme 6. A synthetic route for preparing compound 10.

Example 7. Synthesis of 100. Into a 2-L pressure tank reactor was placed a solution of 2-chloromethylpyridine (100 g, 783.70 mmol, 1.00 equiv) in methanol (1000 mL), triethylamine (158.6 g, 1.57 mol, 2.00 equiv), and Pd(dppf)Clz(5 g). To the above CO (g) was introduced at 20 atm pressure and heated to reflux overnight. The resulting mixture was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :50-1 :5). This resulted in 50 g (41%) of methyl 5-methylpicolinate as an off-white solid.

LC-MS: (ES, m/Z): 152 [M+H]+ a Putdpmclz Eta" I I “j u If" " (:0 Mann I 113-0 Scheme 7. A synthetic route for ing compound I100.

Example 8. sis of I101. Into a 2000-mL 4-necked round-bottom flask, was placed a solution of methyl 5-methylpicolinate (85 g, 539.68 mmol, 1.00 equiv, 96%) in CCl4 (1000 mL), N—bromosuccinimide (110 g, 617.98 mmol, 1.10 equiv), and benzoyl peroxide (3.5 g, 14.45 mmol, 0.03 equiv). The resulting solution was heated to reflux overnight. The solids were d by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl e/petroleum ether (1 :30-1 :5). This resulted in 15 g (11%) of methyl 5-(bromomethyl)picolinate as a light-yellow solid.

LC-MS: (ES, m/Z): 232 [M+H]+ rerfifigV“ Liam-10¢} II—Sifi-CMI.

Scheme 8. A synthetic route for preparing compound I101.

Example 9. Synthesis of 102. Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(bromomethyl)picolinate (500 mg, 2.09 mmol, 1.00 equiv, 96%) in acetonitrile (20 mL), 3-ethylphenol (280 mg, 2.29 mmol, 1.05 equiv), and potassium ate (900 mg, 6.51 mmol, 3.00 equiv). The ing solution was stirred for 2 h at 85°C. The mixture was concentrated under vacuum. The residue was diluted with 30 mL of water and extracted with 2x20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.6 g (92%) of methyl 5-((3- ethylphenoxy)methyl)picolinate as a brown solid.

LC-MS: (ES, m/Z): 272 [M+H]+ 1- 5:38-1:11 1-5113— 103 Scheme 9. A synthetic route for preparing compound 1102.

Example 10. Synthesis of 10. Into a 500-mL round-bottom flask, was placed a on of methyl 5-((3-ethylphenoxy)methyl)picolinate (8 g, 25.65 mmol, l.00 equiv, 87%) in tetrahydrofilran/water (2:1) (200 mL) and lithium hydroxide hydrate (4.95 g, ll7.86 mmol, 4.00 equiv). The resulting solution was stirred for 45 min at 40°C. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. The pH value of the solid was adjusted to 6 with acetic acid. The solids were collected by filtration and dried in an oven under reduced pressure. This resulted in 4.55 g (67%) of ethylphenoxy)methyl)picolinic acid as a light yellow solid.

LC-MS: (ES, m/Z): [M+H]+ 258 lH-NMR: (400MHz, DMSO-d6, ppm) 5 8.78(s, lH), , 2H), 7.21(m, lH), 6.83(m, 3H), 5.24(s, 2H), 2.54(m, 2H), l.l6(m, 3H).

DEE?'1, a (“W x x" JD‘H/ H” 11:20 Hum/ETTH o 0 I— 543-163 H433 Scheme 10. A tic route for preparing nd 10.

Example ll. Synthesis of I0.

I— 513-101 Scheme 11. A synthetic route for preparing compound I0.

Example 12. Synthesis of 11. Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(bromomethyl)picolinate (500 mg, 2.17 mmol, 1.00 equiv) in CH3CN (25 mL), m-cresol (250 mg, 2.31 mmol, 1.05 equiv), and potassium carbonate (900 mg, 6.52 mmol, 3.00 equiv). The solution was heated to reflux for 2 h in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 50 mL of H20. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined and dried over ous sodium sulfate and concentrated under vacuum. This resulted in 0.6 g (89%) of methyl 5-(m- tolyloxymethyl)picolinate as a brown solid.

LC-MS: (ES, m/Z): [M+H]+ 258 “/0”pincana. Low pa 15453-181 155-44 Scheme 12. A synthetic route for ing compound I1.

Example 13. Synthesis of 0. Into a 250-mL bottom flask, was placed a solution of methyl 5-(m-tolyloxymethyl)picolinate (8.7 g, 33.85 mmol, 1.00 equiv) in tetrahydrofuran/HZO (50ml/50 mL), and LiOH.HzO (5.6 g, 133.33 mmol, 4.00 equiv). The resulting solution was stirred for 30 min at 50°C in an oil bath. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. The pH value of the solid was adjusted to 2~3 with acetic acid (30 %). The solids were collected by filtration and dried in an oven under reduced pressure. This resulted in 4.85 g (57%) of 5-(m-tolyloxymethyl)picolinic acid as a white solid.

LC—MS: (ES, m/Z): 244 [M+H]+ 1H-NMR: (300MHz, CDClg, ppm) 5 2.370(s, 3H), s, 2H), 6.829(m, 3H), 7.224(1, 1H), 8.045(m, 1H), 8.263(d, 1H), 8.720(s, 1H) 0 ML"- 15541-1 1-55;-.{3 Scheme 13. A synthetic route for preparing compound I0.

Example 14. Synthesis of 0.

Br 3' fr B‘ ,2 “R Bi l HUN.'120 !5 59 a JW I ”OWN” If! n” “5A0 XF | “”120 K + crlzcn I 0’ T/LF a l /0 DH 1191 1-5.1111 I—S-i'fi-G Scheme 14. A tic route for preparing compound I0.

Example 15. Synthesis of I1. Into a 50-mL bottom flask, was placed methyl 5-(bromomethyl)picolinate (500 mg, 2.17 mmol, 1.00 equiv), ofluorophenol (440 mg, 2.30 mmol, 1.06 equiv), CH3CN (6 mL), and potassium carbonate (900 mg, 6.52 mmol, 3.00 equiv). The resulting solution was stirred for 60 min at 85°C. The mixture was concentrated under vacuum and the residue was diluted with 20 mL of H20. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.62 g (77%) of methyl 5-((3-bromo henoxy)methyl)picolinate as a yellow solid.

LC-MS: (ES, m/Z): 342 [M+H]+ I-S‘fi-E—lm 15456—1 Scheme 15. A synthetic route for preparing compound 11.

Example 16. Synthesis of 10. Into a 250-mL round-bottom flask, was placed methyl -((3-bromofluorophenoxy)methyl)picolinate (9.2 g, 27.05 mmol, 1.00 equiv), tetrahydrofilran (100 mL), water (30 mL), and LiOH.HzO (3.41 g, 81.19 mmol, 3.00 equiv). The ing solution was stirred for 60 min at 45°C. The resulting e was concentrated under . The residue was diluted with 200 mL of H20. The pH value of the solution was adjusted to 5-6 with acetic acid. The solids were collected by filtration and washed with 2x100 mL ofpetroleum ether. The solid was dried in an oven under reduced pressure. This resulted in 7.37 g (82%) of 5-((3 -bromofluorophenoxy)methyl)picolinic acid as a yellow solid.

LC—MS: (ES, m/Z): 326 [M+H]+ lH-NMR: z, CDClg, ppm) 5 5.186 (s, 2H), 6.687 (m, 1H), 6.962 (m, 2H), 8.030(m, 1H), 8.316(d, 1H), 8.716(s, 1H) WO 03505 i A | LiUHJ-lzfl “WE; ° F :““m I-Séfi—l I-Sfifi-Q Scheme 16. A synthetic route for preparing compound I0.

Example 17. Synthesis of I0.

W“-5mgrfl testis—1&1 1549—1 “x fl a, fix“ o OCF ljDHJ-Izfl' N HUI r Tl-FJ'HIO T H LEW-fi- Scheme 17. A synthetic route for preparing compound I0.

Example 18. sis of Il. Into a 50-mL round-bottom flask, was placed methyl -(bromomethyl)picolinate (500 mg, 2.17 mmol, l.00 equiv), 3-(trifluoromethoxy)phenol (410 mg, 2.30 mmol, 1.06 equiv), CH3CN (6 mL), and potassium carbonate (900 mg, 6.52 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at 85°C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of H20 and extracted with 2x20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium e. The solids were filtered out. The e was concentrated under vacuum. This resulted in 0.56 g (74%) of methyl 5-((3- (trifluoromethoxy)phenoxy)methyl)picolinate as a yellow-tan solid. 2012/044476 x0 T/E/"j/ xtFa “20% 0QUCF3 + I 0 [ET “a. CHEW H 1—543—101 I- 53349-1 Scheme 18. A synthetic route for preparing compound Il.

Example 19. Synthesis of 10. Into a 500-mL round-bottom flask, was placed methyl 5-((3-(trifluoromethoxy)phenoxy)methyl)picolinate (8.2 g, 25.05 mmol, l.00 equiv), tetrahydrofuran (100 mL), water (20 mL) and LlOH.H20 (4.20 g, 4.00 equiv). The resulting on was stirred for l h at 45°C. The reaction mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H20. The pH value of the solution was adjusted to -6 with acetic acid. The solids were collected by filtration and washed with 2x100 mL of petroleum ether. The solid was dried in an oven under reduced pressure. This ed in 7.09 g (90%) of 5-((3-(trifluoromethoxy)phenoxy)methyl)picolinic acid as a light yellow solid.

LC-MS: (ES, m/Z): 314 [M+H]+ 1H-NMR: (300MHz, CDClg, ppm) 5 5.200(s, 2H), 6.904(t, 3H), 7.351(t, lH), 8.028(d, lH), 8.297(d, lH), 8.735(s, 1H). mm3530f “3WFMZO IES-‘ifi-l Ii-Szai-Q-Q Scheme 19. A synthetic route for preparing compound 0.

Schemes 20-23 depict synthetic routes to yield carboxylic acid I0and ester 13 containing derivatives Via 6-chloropyridinemethanol. The derivatives are useful for preparing compounds of formula I.

WO 03505 Example 20. Synthesis of 10.

[H'I I F x“ \IIF mam OQFF mommaflau Cir” -H FHIBIDIADTI‘F OILj» CO,” 1WT,ZHEIIII .20 F nuaoHmay:maummm :flrfiJ F U 0 141753‘ 14:54} Scheme 20. A synthetic route for preparing compound 10.

Example 21. Synthesis of 14. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (6-chloropyridin- 3-yl)methanol (10 g, 69.64 mmol, 1.00 equiv) in tetrahydrofuran (50 mL), 3- (trifluoromethyl)phenol (13.55 g, 83.59 mmol, 1.20 equiv), and triphenylphosphine (21.93 g, 83.61 mmol, 1.20 equiv). This was followed by the addition of DIAD (16.90 g, 83.58 mmol, 1.20 equiv) dropwise with stirring at 0°C. The resulting solution was d overnight at room ature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/50-1/10). This resulted in 11.6 g (58%) of 2-chloro((3- (trifluoromethyl)phenoxy)methyl)pyridine as a white solid. ,r if urn/Ln manmnnr from I---ai-.':S-i 2012/044476 Scheme 21. A synthetic route for preparing compound 14.

Example 22. Synthesis of 13. A 250-mL autoclave vessel was charged with a solution of 2-chloro((3-(trifiuoromethyl)phenoxy)methyl)pyridine (8.63 g, 30.00 mmol, 1.00 equiv), Pd(dppf)Cl2 (1.30 g, 1.81 mmol, 0.06 , and triethylamine (6.07 g, 60.10 mmol, 2.00 equiv) in ol(150 mL). The vessel was purged with nitrogen three times and carbon monoxide three times. The vessel was pressurized to 20 atm with carbon monoxide and heated to 100 0C. The resulting on was stirred for 5 h. The reaction mixture was cooled. The solids were filtered out. The filtrate was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20-1/10). This resulted in 6 g (64%) of methyl 5-((3-(trifiuoromethyl)phenoxy)methyl)picolinate as a white solid. {’13.

ADFFP‘KMCE.E13" u, ”noif) F“a l \H 1:°c.anaim(:0, "90H ‘1. "f F ’5 If 14:54- 14"“ Scheme 22. A synthetic route for preparing compound 13.

Example 23. Synthesis of 10. Into a 500-mL round-bottom flask, was placed a solution of methyl 5-((3-(trifiuoromethyl)phenoxy)methyl)picolinate (6.2 g, 19.92 mmol, 1.00 equiv) in tetrahydrofuran/H20(1 :1) (100 mL). To this solution was added sodium hydroxide (925 mg, 23.12 mmol, 1.20 equiv). The resulting solution was stirred for 10 min at room temperature. The reaction mixture was concentrated under vacuum to remove THF. The resulting solution was extracted with 2x50 mL of ethyl acetate and the aqueous layer combined was ed pH value to 5-6 with hydrogen chloride aqueous (4.5 mL, 6 mol/L). White solid was formed. The suspension was stirred for 1 h further. The solids were ted by filtration. The solid was dried in an oven under reduced pressure. This resulted in 5.75 g (97%) of 5-((3- (trifiuoromethyl)phenoxy)methyl)picolinic acid as a white solid.

LC-MS (ES, m/Z): 298 [M+H]+ 1H-NMR: (400 MHz, DMSO, ppm): 6 13.36(s,1H),8.82(s,1H),8.11-8.06(m,2H),7.59- , 1H), 7.39-7.33(m, 3H), 5.37(s, 2H) 19F-NMR: (376 MHz; DMSO-d6, ppm): -61.10 (s, 3F) if,“ ,1 i F‘@ F \l/F 1} HaflII-l,11l:fl120 L1x” a - F flan/LN»!raj/«D I am F 2} 5 H HCI mm“ HI)”; F D 0 L35? 5—3 I— i?5-—=§ Scheme 23. A synthetic route for preparing compound 10.

Example 24. Synthesis of Compound 125. To a solution of EDAC-HCl (1.5 eq, 0.15 mmol, 28 mg), HOBt (20 mg, 1.5 eq, 1.5 mmol), and NMM (19 uL, 1.5 eq, 0.15 mmol) were dissolved in DMF (0.5 mL) was added a solution of Ph-SN—546-0 (32 mg, 0.1 mmol) in DMF (0.5 mL). This e was added to a solution of isobutylamine (7.13 mg, 0.15 mmol, 1.5 eq ) in DMF (0.5 mL). The reaction mixture was agitated ght at room temperature. DMSO (500 uL) was added to the reaction mixture which was then concentrated. Additional DMSO (500 uL) was added to the reaction mixture which was then purified on a Gilson Prep HPLC system using Varian Pursuit XRs, C18, 50 x 21.4 mm, 10u. t A: HPLC Water, Solvent B: 10 mMol Ammonium Acetate in Methanol with 0.1% v/v Ammonium ide. Method ran from 40%B to 100%B over 5 minutes holding at 100%B for 1 minute at 28 mL/min.

Br\ ; , F O \f EDAC HoBt NMM I DMF \ N Scheme 24. A synthetic route for preparing compound 125.

The above synthetic route can be used to prepare nds of formula 1. Using this route, the following compounds of formula I were prepared: 4, 5, 10, 24, 28, 33, 37, 41, 44, 47, 49, 54, 56, 63, 65, 68, 70, 73, 76, 77, 78, 124, 125, 127, 129, 130 and 132.

Example 25. Synthesis of ethylene-type linker compounds.

Pd(dppf)c'2 o \ LiBH-CMeOH | MeOH 70°C THF TEA co 90 % O 0 °C to RT MeOH 100PSi OH RHN2 N H I —, N / —> N / 40% DEAD microwave in toluene std 130 °C OH PPh3 55-75% toluene, RT 60-85% Scheme 25 depicts a tic route to prepare compounds of formula I having an ethylene-type linker.

Example 26. Synthesis of ic-type linker compounds.

CI CI \ \ | CI,|midazole | Pd(dppf)CI2,NEt3 MeO \ N / OH | N / OTBDMS —’ N / OTBDMS DCM CO,MeOH 100°C NaOH,THF/HZO HO \ EDAC-HC|,HOBt I R1\N \ —’ —’ N / OTBDMS | I NMM,DMF.rt R2 N / OTBDMS 6NHC|(aq) TBAF THF NaH, DMF —>i RR” R1 WJHGV\ ' I R2 N / OH R2 N / o 0-25°C Br‘ 3R3 \Gm 0-25 °C Scheme 26 depicts a synthetic route to prepare compounds of formula I having an benzylic-type linker.

Example 27. Synthesis of 5-(2-hydroxyethyl)pyridineacetic acid methyl ester (1-087). 1—83? Scheme 27 s a tic route to prepare intermediate compounds useful for the preparation of compounds of formula 1.

Example 28. Synthesis of K002. To a suspension of 6-cholropyridineacetic acid methyl ester (10 g, 58.2 mmol) was added conc. sulfuric acid (30 mL) and the reaction was heated to 70 0C for 4 hr. The reaction mixture was cooled to room temperature and concentrated and the resulting residue was suspended in H20 (1L) and pH was adjusted to pH = 9 with sodium carbonate. The solution was extracted with ethyl acetate. The organics were washed with brine, dried over Na2S04, filtered and concentrated to give the crude product that was purified by flash column chromatography (30% EtOAC: 70% heptanes) to give the desired product 8.58 g, 79%.

LC—MS: (ES, m/Z): 186 [M+H]+ 1H-NMR: (400MHz, MeCN—d3, ppm): 5 3.66 (m, 5H), 7.36(d, 1H), 7.67(d, 1H), 8.26(s, 1H).

Example 29. Synthesis of I-054. A solution of K002 (19.34 g, 104.17 mmol) in THF/MeOH (100 mL/10 mL) was cooled to 0 0C and LiBH4 (4.76 g, 215.64 mmol) was added.

The reaction mixture was warmed to room temperature and allowed to stir overnight. To quench, the reaction was cooled to 0C and sat. NH4C1 on (500mL) was added. The pH was adjusted to pH = 7 h addition of solid NH4Cl. The aqueous mixture was extracted with ethyl acetate and the organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography to give the desired t (1.51 g, 70%) as a clear oil. 1H-NMR: (400MHz, CDClg, ppm): 5 2.78 (t, 2H), 3.81 (m, 2H), 7.2 (d, 1H), 7.48 (d, 1H), 8.17 (s, 1H).

Example 30. sis of I-066. To a solution of I-054 (1.0 g, 6.33 mmol) in DMF (2 mL) was added imidazole (0.94 g, 13.8 mmol) and tert—butyldimethylsilyl chloride (1.25 g, 8.28 mmol). The reaction mixture was stirred at room temperature overnight and the concentrated.

The resulting residue was partitioned between ethyl acetate and water and extracted. The organics were dried (MgSO4), filtered and trated. The crude al was purified by flash column chromatography to give the desired compound (1.80 g, 99%) as a clear oil. : (400MHz, CDClg, ppm): 8 0.1 (s, 6H), 0.88 (s, 9H) 2.83 (t, 2H), 3.81 (t, 2H), 7.28 (d, 1H), 7.54 (d, 1H), 8.27 (s, 1H).

Example 31. Synthesis of I-087. Into a 40-mL high pressure reactor, was placed I-066 (4.28 g, 15.79 mmol), methanol (14 mL), triethylamine (3.3 mL, 23.69 mmol), and Pd(dppf)C12 (1.16 g). To the above CO (g) was introduced at 300 psi pressure. The resulting on was stirred overnight at 96°C. The ing mixture was cooled and filtered through a pad of Celite® and the e was concentrated under vacuum. The residue was applied onto a silica gel pad with heptanes/ethyl acetate. This resulted in 4.6g (99%) of desired t. 1H—NMR: (400MHz, CDC13, ppm): 8 0.1 (s, 6H), 0.89 (s, 9H) 2.93 (t, 2H), 3.89 (t, 2H), 4.05 (s, 3H), 7.73 (d, 1H), 8.10 (d, 1H), 8.65 (s, 1H).

Example 32. Synthesis of compound 206.

Scheme 28 depicts a synthetic route to prepare nd 206.

Example 33. Synthesis of I-013. A solution of I-087 (3.54 g, 12 mmol) in O/HOAc (20 mL/20 mL/60 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to give the desired product 1.92 g, (91%). lH-NMR: z, CDClg, ppm): 8 2.88 (t, 2H), 3.85 (t, 2H), 3.93 (s, 3H), 7.68 (d, 1H), 7.99 (d, 1H), 8.54 (s, 1H).

Example 34. Synthesis of I-008. A 100 mL bottom flask was charged with 4- trifluoromethylphenol (0.17 g, 1.05 mmol), triphenylphosphine (0.18 g, 1.05 mmol) and toluene (3 mL). A solution of I-013 (0.19 g, 1.05 mmol) in toluene/THF (2 mL/7 mL) was added and stirred for 10 mins at which time a solution of diethyl azodicarboxylate (0.53 mL of 40% (v/v) solution in toluene, 1.15 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue purified by reverse phase HPLC using a Gilson Prep HPLC system using Varian Pursuit XRs, C18, 50 x 21.4 mm, 10u. t A: HPLC Water, Solvent B: Methanol. The method ran from 40%B to 100%B over 5 minutes holding at 100%B for 2 minute at 28 mL/min. The appropriate fractions were concentrated to give the desired t, 200 mg (59%). : (400MHz, coon, ppm): 8 3.13 (t, 2H), 3.94 (s, 3H), 4.19 (t, 2H), 6.86 (d, 2H), 7.45 (d, 2H), 7.73 (d, 1H), 8.04 (d, 1H), 8.63 (s, 1H).

Example 35. Synthesis of compound 206. A microwave vial was charged with I-008 (0.032 g, 0.1 mmol) and iso-butylamine (1 mL). The reaction mixture was heated for 3 hrs at 120 WO 03505 0C and 75W. The reaction mixture was concentrated, re-dissovled in methanol (3 mL) and purified by reverse phase HPLC using a Gilson Prep HPLC system using Varian Pursuit XRs, C18, 50 X 21.4 mm, 10u. Solvent A: HPLC Water, Solvent B: Methanol. The method ran from 40%B to 100%B over 5 minutes holding at 100%B for 2 minute at 28 mL/min. The riate fractions were concentrated to give the desired product, 27 mg (74%).

LC-MS (ES, m/Z): 367 [M+H]+ 1H—NMR: (400MHz, CDC13, ppm): 5 0.93 (d, 6H), 1.85 (m, 1H), 3.11 (t, 2H), 3.23 (t, 2H), 4.18 (t, 2H), 6.88 (d, 2H) 7.71 (d, 2H), 8.01 (br. t, 1H), 8.42 (s, 1H).

These specific compounds of formula I, as well as other compounds of formula I, were prepared using the chemistry described above: 47, 219, 220, 221, 209, 9, 12, 13, 14, 15, 132, 133, 134, 135, 140, 205, 47, 138, 222, 225, 223, 237, 238, 240, 241, 242, 243, 275, 278, and 279.

Example 36. Synthesis of compounds useful for preparing nds of formula I.

Scheme 29 depicts a synthetic route for nds useful for preparing compounds of formula e 37. Synthesis of J-025. In a 200 mL round-bottom flask, was placed a solution of 2-chlorohydroxymethyl pyridine (10 g, 69.6 mmol, 1.00 equiv) in anhydrous dimethylformamide (70 mL). Imidazole (11.85 g, 174 mmol, 2.5 equiv) was added all at once as a solid. Once dissolved a dropping funnel was added and a solution of tert—butyldimethylsilyl chloride (15.75 g, 104 mmol, 1.5 equiv) in anhydrous dimethylformamide (30 mL) was added over a 5 minute . The solution was stirred 16hr at ambient temperature. The resulting mixture was poured into water (250 mL), stirred 5 minutes and extracted into ethyl acetate (3 x 200 mL). The c layers were ed, washed with brine (100 mL), dried (NaZSO4), filtered and trated to a clear oil. The oil was dried under d pressure to yield the desired product (J-025, 17.9 g, quantitative).

LC-MS-J-025: (ES, m/Z): 257 [M+H]+ 1H-NMR-J-025: (400 MHz, CDClg, ppm): 8 8.23(s, 1H), 7.53-7.51(m, 1H), .18(m, 1H), , 2H), 0.83(s, 9H), 0.00(s, 6H) I c M. J. lirrzix'pesele KIT I f and,“ fl ._ ,x .F-r! 0-?:K 3-035 Scheme 30 depicts a synthetic route for compounds useful for preparing compounds of formula 1.

Example 38. Synthesis of J-086. An oven dried 500-mL 3-neck flask in a heating mantle equipped with stir bar, condenser, rubber septa and closable gas inlet attached to a vacuum line was cooled under N2 atmosphere. The apparatus was d with a degassed solution of J-025 (17.9 g, 69.6 mmol, 1.00 equiv) and NEtg (19.38 mL, 139 mmol, 2 equiv) in anhydrous methanol (100 mL). Pd(dppf)Clz was added as a solid and the system degassed again using vacuum and nitrogen. Two balloons were charged with CO and the atmosphere was switched to CO via vacuum. The red suspension was stirred at 60°C 16 hrs. The reaction mixture was filtered h celite and washed with methanol. The ted palladium waste was discarded and the eluant concentrated under reduced pressure. The residue was slurried in warm toluene (15 mL) and loaded onto a large (350g) silica plug in a glass fritted filnnel inserted into an erlenmeyer flask attached to vaccuum. The desired product was purified by collecting 500 mL fractions from the following sequence passing over the plug using vacuum (500 mL heptanes, 1L x 10% EtOAc-Heptanes, 2L x 15% EtOAc-Heptanes, 1L x 20% EtOAc-Heptanes, 1L x 20% EtOAc- es). After concentrating the oil was dried under reduced pressure to yield the d product (J-086, 16.4g, 84%).

LC-MS-J-086: (ES, m/Z): 283 [M+H]+ 1H-NMR-J-086: (400MHz, CDC13,ppm): 5 8.75(s, 1H), 8.01-7.99(m, 1H), 7.70-7.69(m, 1H), 4.72(s, 2H), , 3H), 0.83(s, 9H), 0.00(s, 6H) | K | ' " _ ,-' _0_|fix _ . 0-5;,”- . ITE $4025 11—0136 Scheme 31 depicts a synthetic route for compound J-086, a useful compound for preparing compounds of formula 1.

Example 39. Synthesis of J-093. In a 200 mL round-bottom flask, was placed a on of J-086 (16.4 g, 58.2 mmol, 1.00 equiv) in acetonitrile (40 mL). Isobutylamine (25 mL, 251 mmol, 4 equiv) was added and the solution heated at 50°C 48 hrs. The solution was concentrated to a yellow oil under reduced pressure, diluted with toluene (10 mL) and loaded onto a silica column (120g, 05-20% EtOAc- heptanes gradient over 26 minutes). The desired fractions were combined, concentrated and the oil was dried under reduced pressure to yield the desired product as a white low melting solid (J-093, 15.92 g, 85%).

LC-MS-J-093: (ES, m/Z): 323 [M+H]+ 1H-NMR-J-O93: z, CDC13,ppm): 5 8.38(s, 1H), 8.06-8.04(m, 1H), 7.99(b, 1H), 7.67- 7.65(m, 1H), 4.69(s, 2H), 3.18(m, 3H), 1.81(m, 1H), 0.87-0.83(m, 15H), 0.00(s, 6H) ALI ‘1 III :35:15: mine \r/WIH' "4:: ,r 0 .-' .. Si —J-- ’ 0 I I \IQ ._~.=: "w”?Lx 5i I 2“ a.“ v1“ 3-13235 J-fl=93 Scheme 32 depicts a synthetic route for compound J-086, a useful compound for preparing compounds of formula 1.

Example 40. sis of J-096. In a 200-mL round-bottom flask, was placed a solution of J-096 (15.92 g, 49.44 mmol, l.00 equiv) in tetrahydrofuran (20 mL). Acetic acid (40 mL) and water (20mL) were added and the solution stirred at ambient temperature l6hrs. The solution was concentrated to a yellow oil under d pressure. Then oped 6x with toluene/methanol (100 mL (1 : l)) and placed on a high vacuum pump to yield the desired product as an oil , 10.2 g, quantitative).

LC-MS-J-093: (ES, m/Z): 209 [M+H]+ 1H-NMR-J-093: (400 MHz, CDClg, ppm): 5 8.50(s, 1H), 8.10-8.08(m, 2H), 7.80-7.78(m, 1H), 4.77(s, 2H), 3.27(t, J=6.5 x 2, 2H), l.89(m, 1H), 0.96(d, J: 6.6, 6H) - JL \l/‘H :lII H“ 12 MFA—15:3 “a. ”“1“0 arr-"1 Jim.“ "—fiom 3—093 3—096 Scheme 33 depicts a synthetic route for compound J-096, a useful compound for preparing compounds of formula 1.

Example 41. Synthesis of compound 227. ous dimethylformamide (1 mL) was placed in a 40 mL vial with stir bar and cooled in a metal reaction block in the refrigerator. A solution of J-096 (80 mg, 0.38 mmol, 1.00 equiv) in anhydrous dimethylformamide (2 mL) was placed in a vial and cooled in the refrigerator. (4-Chlorotrifluoromethoxy)benzylbromide (143 mg, 0.50 mmol, 1.3 equiv) was ved in ous dimethylformamide (1 mL) and cooled in the refrigerator. NaH (12 mg, 0.50 mmol, 1.3 equiv) was added to the cold 40 mL vial via a glass pipette. The contents were swirled and the alcohol solution was added via pipette.

The suspension was swirled again and the reaction block returned to the refrigerator. After 30 minutes, the block was removed, the bromide solution added via pipette and the reaction block placed at ambient temperature on a stir plate 16 hrs. Water was added (4 mL) to quench the reaction. The product was extracted into EtOAc and concentrated under reduced pressure.

Heptanes (1 mL) and acetonitrile/methanol (3 mL (1 :l)) were added and shook and the methanolic layer removed and shot onto the chromeleon HPLC (UV detector, MeOH/HZO, method: 607-28). Concentration of the desired peaks resulted in the desired product (compound 227, 47 mg, 30%). 227: (ES, m/Z): 414 [M+H]+ lH-NMR-227: (400 MHz, CDClg, ppm): 5 8.49(m, 1H), 8.17(dd, J=8 and 0.6, 1H), 8.08(b, 1H), 7.80(dd, J=8 and 2.1, 1H), 7.43(d, J=8.2, 1H), 7.3l(s, 1H), 7.2l(m, 1H), 4.6l(s, 2H), , 2H), 3.28(t, J=6.5 x 2, 2H), l.89(m, 1H), 0.96(d, J: 6.6, 6H). flAm0" Ha H 3-5;:TI win... cc”? 3-696 lib—(:34:F 2“}? m. - ”‘1‘ n m- _.,:-. v2.1.2 “L.- Scheme 34 depicts a synthetic route for compound 227.

These specific compounds of formula I, as well as other compounds of formula I, were prepared using the try described above: 227, 228, 229, 232, 234, 216, 228, 256, 257, 258, 259, 260, 263, 264, 266, 268 and 270.

It will be iated by persons skilled in the art that, within aspect of the processes described above; the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups t in a particular ate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted (see e.g. “Protective Groups in Organic Synthesis h Edition)”, eds. Peter G. M. Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007)). Clearly, such factors will also influence the choice of ts for use in the said synthetic steps.

The invention fiarther contemplates separating the enantioners in whole or in part of the present invention or synthesizing enantiomerically enriched compounds of the invention. The composition may be ed by separating the enantioners in whole or in part by standard methods, for example by chemical resolution using optically active acid or by use of column chromatography or reverse-phase column chromatography using a ntially optically active (or “chiral”) stationary phase as known to those skilled in the art. The formation and/or isolation of specific enantiomers of a compound is not routine, and there are no general methods that may be used to obtain specific enantiomers of all compounds. The methods and conditions used to obtain c enantiomers of a compound must be determined for each specific nd.

Table 1 below shows specific compounds of formula I.

Table l \ \ N / /R2 Linker [Inventor: The application must be what is meant in the table below by “Chemistry 7,” “Chemistry 22” etc. Also we will format all the subscripts in the chemical formula.] Comound No. 11-1311 3-CF3Ph CHZO l-naohthalenemeth l 3-CF3Ph 3-C30Ph NNl—‘b—‘b—‘b—‘b—‘l—‘b—‘b—‘b—‘HHooooqomhwmwooooflou‘fiwwh‘ 2-CF30Ph CHZO i-B—u 4-CF30Ph CH2CH20 CH2THP Ph CH2CH20 —2-MePh CH2CH2CH20CH3 4-CF30Ph CHZO Me 4-CF30Ph CHZO CH2CH20Et Ph 22 CH2CH2CH20Et 4-CF3OPh CHZO WO 03505 23 Et Ph CHzO 24 CH2THP 4-CF3OPh CHZO 3-rneth lene o ridine 4-CF3OPh CHZO 26 4-Meth lene o ridine 4-CF3OPh 29 2-methylenepyridine 4-CF3OPh CHzO CH2CH2SMe 4-CF3OPh CHZO 31 i-Pr 4-CF3OPh CHzO 32 CH2furan 4-CF3OPh CHZO 33 C 010 oro o anemeth 1 4-CF3OPh 34 4—CF3OPh C clobut 1 4-CF3OPh 36 —_——.ro o1 4-CF3OPh CHZO 37 —_——.ro o1 4-CF3OPh CHZO 38 2-meth 12111 1 4-CF3OPh 39 4—CF3OPh 40 Ph 41 2-Methy1buty1 4-CF3OPh CHZO 42 2-trifluor0rneth lbenz 1 4-CF3OPh CHzO 43 4-pheny1— 1 -buty1 4-CF3OPh CHZO 44 Dimethl acetal 3-CF3OPh CHZO 45 Ph 46 3-CF3OPh 47 CH2THP 3-CF3OPh 48 CH2THP 3-CF3OPh CHZO 49 2- Meth 1thio eth 1 3-CF3OPh CHZO 50 i-Pr 3-CF3OPh CHZO 51 4-Eth leneo ridine 3-CF3OPh CHZO 52 C c10or0 o anemeth 1 3-CF3OPh 56 2-Meth lbu 1 3-CF3OPh CHZO 59 2- Meth 1thi0 eth 1 3-MePh CH2O 60 Methylfuran 3-MePh CH2O 61 C clomoanemeth 1 3-MePh CH2O 63 i-Bu 3-MePh CH2O 2012/044476 66 2-eth0x eth 1 3-EtPh CH20 67 CH2THP 3-EtPh CH20 68 CH2THP 3-EtPh CH20 69 3-meth lene o ridine 3-EtPh CH20 70 2- Meth 1thio eth 1 3-EtPh CH20 71 2- Meth 1thio ooro 1 3-EtPh CH20 72 Methylfuran 3-EtPh CH20 73 C c100r0 o anemeth 1 3-EtPh CH20 74 n-Pr 3-EtPh CH20 75 C clobut 1 3-EtPh CH20 80 N,N,2,2-Tetrarneth 1-1,3- oro o ane 2-CF3Ph CH20 84 2-ethoxyethy1 4-CF3Ph CH20 85 2-Meth0x iso oro o 1 4-CF3Ph CH20 86 3-Eth0xypropy1 h CH20 87 Et 4-CF3Ph CH20 88 CH2THP 4-CF3Ph CH20 89 4—CH2. rid 1 4-CF3Ph CH20 90 4-CF3Ph CH20 91 2-(Methy1thio)ethy1 4-CF3Ph CH20 92 3-ISOooroox ooro 1 4-CF3Ph CH20 93 2-(Methy1thio)propy1 4-CF3Ph CH20 94 i-Pr 4-CF3Ph CH20 95 C c100r0 o anemeth 1 4-CF3Ph CH20 99 iBu 4-CF3Ph CH20 103 4-F1u0r0pheny1 4-CF3Ph CH20 104 n-Bu 2-OCF3Ph CH20 105 0CH3 3-BrFPh CH20 106 3-Meth0x ooro 1 3-BrFPh CH20 1 10 3-Eth0xypropy1 3-BrFPh CH20 1 1 1 Et 3-BrFPh CH2O 1 12 CH2THP 3-BrFPh CH2O 1 13 3-Meth lene o ridine 3-BrFPh CH2O 1 14 4-Meth lene o ridine 3-BrFPh CH2O 115 2- Meth 1thio eth 1 3-BrFPh CH2O 116 3-BrFPh CHZO 1 17 hy1thio)propy1 3-BrFPh CH2O 1 18 4-CH2CH2 . rid 1 3-BrFPh CH2O 1 19 Cyclopropanernethyl 3 -BrFPh CH2O 120 n-Pr 3-BrFPh CH2O 121 2-CH2CH2o rid 1 3-BrFPh CH2O 122 C clobut 1 3-BrFPh CH2O 123 CH2CF3 3-BrFPh CH2O 3 -dirnethy1arnino-2,2-dirnethy1— 124 oro o 1 3-BrFPh CH2O 125 i-Bu 3-BrFPh CH2O 126 Pro o_ar 1 3-BrFPh CH2O 131 4-CF30- .hen 1 3-BrFPh CH2O 138 CH2THP Bn CH2O 141 C c10or0 o anemeth 1 3-CF3Ph OCH2CH2 142 Cyclopropanernethyl Ph OCH2CH2 143 i-Bu 4-CF3OPh OCH2CH2 144 i-Bu 3-CF3Ph OCH2 145 C ClOllI'OflIlel’Ileth 1 3-CF3Ph OCH2 146 2-Meth 12111 1 3-CF3OPh CH2O 147 4-CF30-ohen 1 Ph CH2O 148 4- CF3 2FCPhen 1 3-CF3OPh CH2O 149 Cyclopropanernethyl 3-OCH3Ph CH2O 150 2-Meth 12111 1 3-OCH3Ph CH2O 154 2-(Methy1thio)ethy1 3,4-th CH20 155 i-Bu 3,4FPh CH20 157 Acetaldeh de dimeth 1 acetal 3-PrPh CH20 160 2- Meth 1thio eth 1 3-PrPh CH20 161 (CH2)2Ryridy1 3-PrPh CH20 162 N,N,2,2-Tetrarneth 1-1,3- oro o ane 3-PrPh CH20 163 2-Methy1a11y1 3-PrPh CH20 164 3- 1H-irnidaz01 1 0ane 3- 3-FPh Ph CH20 169 Me 3- 3-FPh Ph CH20 172 3-rneth leneo ridine 3- 3-FPh Ph CH20 173 CH2Ryridy1 3-(3-FPh)Ph CH20 174 2— Meth 1thio eth 1 3— 3-FPh Ph CH20 175 (CH2)2Ryridy1 3-(3-FPh)Ph CH20 176 C clomoanemeth 1 3- 3-FPh Ph CH20 177 3- 3-FPh Ph CH20 178 2-Tetrarneth 1-1,3-oor0ane 3- 3-FPh Ph CH20 179 2-Meth 12111 1 3- 3-FPh Ph CH20 180 1-1311 3-(3-FPh)Ph CH20 181 2-Meth lbu 1 3- 3th Ph CH20 182 2-CF3Pheny1 3-(3-FPh)Ph CH20 183 CH2CH20CH3 3— Ph Ph CH20 184 CH2CH2CH2OCH3 3- Ph Ph CH20 188 Et 3- Ph Ph CH20 192 2-(Methy1thio)ethy1 3-(Ph)Ph CH20 193 CH2 2. rid 1 3- Ph Ph CH20 194 Cyclopropanernethyl 3-(Ph)Ph CH20 195 2-CH2CH2. rid 1 3- Ph Ph CH20 196 N,N,2,2-Tetrarneth 1-1,3-oor0ane 3- Ph Ph CH20 197 2-Meth 12111 1 3- Ph Ph CH20 198 3- Ph Ph CH20 199 i-Bu 3-EtOPh CH20 2012/044476 200 4-CF30-hen 1 3-EtOPh CH20 202 4-CF3-.hen 1 3,3-Dirneth lbutane CH20 205 ——.- 206 i-Bu 4-CF3Ph CH2CH20 207 C c10or0 o anemeth 1 4-CF3Ph CH2CH20 208 Cyclopropanernethyl 3-CF3Ph CH2CH20 209 i-Bu 3-CF3Ph CH2CH20 214 \Iement 1 2-MeOCF3OBn CH20 219 2-\/Ieth lbut 1 4-CF3Ph CH2CH20 221 2-\/Ieth lbut 1 3-CF3Ph CH2CH20 222 3-0CF3-4F-Ph CH2CH20 223 C1PH CH2CH20 224 i-Bu 3,4-FPh CH2CH20 225 i-Bu 3 ,5-C1Ph CH2CH20 226 i-Bu 3-BrFPh 0 227 i-Bu 3-CF30C1Bn CH20 228 i-Bu 3-CF30FBn CH20 229 i-Bu 230 i—Bu 232 i-Bu 2-FCF3Bn 233 i-Bu 3-C1Bn CH20 235 i-Bu 237 i-Bu 3-CF30BrPh CH2CH20 238 i-Bu 3-acet lenePh 0 239 i-Pr 3-CF3OPh CH2CH20 240 i-Arn 3-CF3OPh CH2CH20 244 CH(Me)THP 3-CF3OPh CH2CH20 3 -dirnethylarnino-2,2-dirnethy1— 245 proRyl 3-CF3OPh CH2CH20 246 S - - -3,3-dirneth nobutane 3-CF3OPh CH2CH20 247 S - - -3,3-dirneth l2-aminobutane Ph CH2CH20 ,4S) 248 aminobic clo[2.2.1]heotane 3-CF3OPh CH2CH20 249 3-BrFPh C CH3 20 250 CH2THP 3-BrFPh C CH3 2CH20 251 1—13.11 3-CF3OPh )CH20 252 CH2THP 3-CF3OPh CH CH3 CH20 254 CH2THP 2-FCF3Bn CH20 259 CH2THP 4-C1Bn CH20 263 CH2THP 4-MeBn CH20 264 CH2THP 2-MeBn CH20 265 CH2THP 3-IBn CH20 266 CH2THP 2-CF3Bn CH20 267 CH2THP CH20 268 CH2THP CH20 269 CH2THP CH20 270 CH2THP 3,4-FBn CH20 271 i-Bu 3-BrFPh CH CH3 CH20 272 CH2THP 3-BrFPh C(CH3)2CH20 273 i-Bu 3-CF3Ph C CH3 2CH20 274 C clomoanemeth 1 3-CF3OPh C CH3 2CH20 278 i-Bu 3-FCF3Ph CH2CH20 3-dirnethy1arnino-2,2-dirnethy1— 282 r0 5 1 3-CF3FPh CH2CH20 283 i-Bu 3FCF3Bn CH20 284 i-Bu 3C1—4-CF3Bn CH20 285 i-Bu 2-Ban CH20 286 i-Bu 3-Ban CH20 WO 03505 2012/044476 287 i-Bu 3 ,S-Ban CH2O i-Bu 3-BrFBn CH2O i-Bu 3-BrFBn CH2O B. Biological Assays Example 42. Screening method to test contact activity of nds against ticks.

A solution of the test compound was used to coat the inner wall of glass vials and to treat two filter papers. Once dried, one filter paper was placed in the cap of the vial and the other in the bottom of the vial. Each treated vial was infested with 10 adult cephalus sanguineus (Brown Dog Tick). Contact of the ticks with residues was induced by holding the vials in a controlled nment (24°C, 90-95% relative humidity) and assessment was performed at 24, 48 hours after application in comparison with ted controls.

Example 43. Screening method to test ty of compounds against fleas following ingestion.

A cylindrical test container was filled with 10 adult Ctenocephalidesfelis. A cylindrical well was closed on one end with a self-sealing flexible film and placed on top of the test container in such a position that the fleas could pierce the film and feed on the contents of the cylinder. The test compound on was then pipetted into bovine blood and added to the well.

The container part with the Ctenocephalz’desfelz’s was held at 20-22°C and 40-60% relative humidity while the well part containing the treated blood was held at 37°C and 40-60% relative humidity. Assessment was performed at 72 hours after application in comparison with untreated controls.

Example 44. Screening method to test contact activity of compounds against flies A solution of the test compound was used to treat a filter paper contained within a Petri dish and the filter paper was allowed to evaporate to dryness. A small piece of absorbent cotton moistened with 10% sucrose and ten adult flies (Haematobz'a irritans or Stomoxys calcitrans) were added to each dish. Dishes were capped and held at room ature. Assessments were performed at 4 and 24 hours after infestation in comparison with untreated controls.

Example 45. Screening method to test activity of compounds against to Ten neonate Aedes aegypti larvae were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. The microtitre plate was then held at 22°C where the L1 larvae were allowed to develop. An analysis was conducted at 2 days to determine the inhibition of motility of the treated larvae relative to control larvae.

Example 46. ing method to test activity of compounds t H. tus Twenty Ll Haemonchus contortus larvae were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. The microtitre plate was then held at 27°C where the L1 larvae were allowed to develop. An analysis was conducted at 3 days to determine successful development to the L3 stage. Larvae exposed to DMSO and no test compound served as controls Example 47. Screening method to test activity of compounds against D. 's microfilaria Four hundred to six hundred microfilaria of Dirofilarz'a immitz's were added to wells of a microtitre plate containing RPMI media and the test compound in DMSO. The microtitre plate was then held at 37°C in an environment containing 5% C02. An assessment was conducted at 5 days to determine survival of the microfilaria. laria exposed to DMSO and no test compound served as controls.

Assay: AHHTSCS Organism: A. aegyptz' Test Param: EC50 Compound No. Timepoint: 2 day 243 0.098 WO 03505 108 0 6 0.696 194 2.3015 WO 03505 171 4.0 WO 03505 WO 03505 195 7.5885 7.6085 7.624 144 7.754 61 7.834 7.9575 90 8.06 273 8.1315 8.634 8.784 141 8.7915 116 8.992 9.2895 162 9.397 86 9.434 157 9.5735 9.709 9.774 50 9.808 Tick Contact EC50 DMSO Fly Contact EC50 Tick Contact EC50 ephalus sanguineus Paramater: EC50 DMSO Paramater: EC50 Timepoint: (below in hrs.) Rhipicephalus Timepoint: (below in hrs.) sanguineus Paramater: EC50 Timepoint: (below in >200.0 197.8 52.4 46.3 200.0 181.7 ~50.0 ~20.9 1.25 1.25 190.5 46.9 31.5 15.8 1.1 1.2 117.0 92.2 >200.0 79.1 1.2 1.2 >200.0 92.2 1.4 1.4 14.7 63.4 ~46.3 0.5 1.4 >200.0 ~195.4 ~50.0 36.8 0.5 0.73 ~200.0 100.0 117.0 ~100.0 4.8 2.5 51.8 39.3 4.8 2.9 197.8 177.4 ~184.9 117.0 4.6 4.6 ~188.2 51.8 2.1 0.9 >200.0 72.8 ~47-0 ~190-5 ~55-0 ~188.2 ~90.4 1.4 1.31 79.1 62.3 2.1 1.35 ~54.0 ~50.0 1.4 1.3 ~193.1 108.1 126.0 ~56.2 1.4 14 —— ~13.5 127 ~181.7 ~53.2 1.4 1.3 ~197.8 72.8 50.4 4.8 1.35 58.2 34.3 ~5 1.84 100.0 >200.0 181.7 4.6 1.4 40.5 25.0 2.1 2.5 >200.0 197.8 197.8 100.2 4.8 1.2 >200.0 193.1 >200.0 190.5 1.4 2.5 >200.0 184.9 4.8 2.9 56.7 44.1 ~48.9 ~197.8 ~195.4 ~184.9 44.1 ~1oo.o ~100.0 ~55.0 ~188.2 ~1oo.o Assay: 5 Cmpd A. aegypti N0. Paramater: EC50 Timepoint: (below in da 5 2 da 5 4 5.0 3.5 9 3.9 2.3 12 2.1 13 8.0 14 >10.0 8.8 24 2.3 28 1.1 33 1.5 41 6.4 44 4.3 WO 03505 47 10.0 49 2.2 54 >10.0 63 2.5 65 7.0 70 6.0 73 3.2 76 2.5 77 5.0 124 10.0 125 0.6 127 1.6 129 5.6 130 2.0 132 4.3 133 >100 134 4.5 135 >100 138 >100 140 >100 205 >100 206 1.5 209 0.7 216 >100 219 7.7 220 9.4 221 3.9 222 0.8 225 0.6 227 2.4 228 3.5 229 4.0 232 7.1 234 5.1 2012/044476 Contact SP Contact EC50 Stable Fly Stable Fly PCT Mortality EC50 lag/cm2 Timepoint: (below in hrs) Timepoint: (below Comoound No. ' —-o_108 0% 0% 0.1 63 80 % 80 % 1.3 =_60% 1.4 90% ~14 52 60 % 80 % 1.4041 33 80 % 80 % 1.8 90 % ~4.6 LDA SP LDA DR Mf sp Mf sp H. cont. H. cont. D.immitis D.immitis PCT Mot M MIC 90 PCT Motili EC50 ppm 5 ppm 5 ppm Timepoint: Timepoint: Timepoint: Timepoint: Com 0ound No. 206 100 % 219 90 % ————_ ————_ ————_ 207 100 % 136 89.2655 Assay: Minilnge Assay: Minilnge Organism: C. felis Organism: C. felis Test ter: PCT Mortal Test Parameter: EC50 Dose: 200 ppm Comoound No. Timeooint: 72 hr Timeooint: 72 hr WO 03505 185 90 % 185 “Horn Fly” Contact SP Fly Contact EC50 Horn Fly Horn Fly PCT Mortality (%) EC50 Mg/crn2 Timepoint: (below in hrs) Timepoint: (below Corn oound No. ' —_—— 33 100 100 0.53 0.73 ——_— 100 2.14 —m100 1-1 70 1'2 2 129 40 40 4.8 1 .2 "n-207 80 1 .2217 —_-— —-=fi- 90 1 .25 —“60 47654 114 1.3 —“0——38 50 1.35423 1 .3122 —“_— 24 500 700 0.53 1 . —_H—107 1. —-_— —_—5— &_ 4.7654 2.1372 70 2 14 —-§- 60 48 100 135 552 100 18000 ~28 80 2.885805 2.8805 44 80 2.9 133 80 80 4.786 2.9 29253 —“40 2.8805 2.9253 251 80 18000 ~4.8843 4.4449 50 70 4.8843 4.4449 63 100 18000 4.6 4 6. 49 60 800 4.6 —-i5- 21371 46252 121 4.8843 “Tick” Contact SP Tick Contact EC50 DMSO Rhicz'cep ha’pz’cephalus sanguineus PCT Mortality EC50 (%) Timcpoint: (below in hrs) 200 ppm Compound No. Timcpoint: (below in hrs) 4 24 48 240 90 90 48.861 11.0217 228 90 18.3654 11.7142 221 .sfi-_ 19.9406 12.1746 —__—_ —__126-0 14-7 "n“-134 56.7 ~14.6 ——___ —_—_-=fi- —_—_“ 206 100 100 47.6205 6 225 90 100 27.1261 22.6041 127 90 100 40.5 25.0 177 80 90 5 25 58-8325 2012/044476 90 100 49.4465 27.6499 59.5661 33.876 34.3 “ 44.0869 36.3885 100 100 ~50.0 36.8 100 100 51.8 39.3 90 100 58.1848 42.8922 .sfi-Isfi- 46.9949 46.2591 _m—46-3 100 2 46.2591 63.4 ~46.3 171.5279 46.2591 80 ~53.2 ~48.3 __—~48-9 6 49.4465 ~50.0 0 80 72.8 50.4 .sfi-_ 51.7921 50.5463 mm- 115.6016 50.5463 54.9508 51.186 90 100 ~100.0 ~51.2 60 70 ~197.8 ~51.2 100 100 115.6016 51.7921 0 60 117.013 51.7921 _Isfi- 67.8106 51.8142 n— ~188-2 51-8 __—52-4342 40 60 ~181.7 ~53.2 60 100 ~100.0 ~54.0 50 90 190.5 53.9616 54.4434 54.4434 _~55-0 ~100-0 ~55-0 70 126.0 ~56.2 _62-3 —-=r-— 62-2528 63-3747 72-8 77-9043 >200.0 79.1 257 80 90 171.5279 83.5861 —-=fi-_—83-5861 ~184-9 85-5 —““ 110-5989 90-417 23 ~188.2 ~90.4 14 >200.0 92.2 —mm 100-2134 92-7385 Having thus described in detail preferred embodiments of the present invention, it is to be tood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible Without departing from the spirit or scope of the t invention.

Claims (28)

WHAT IS CLAIMED IS:

1. A compound of Formula I wherein, Ra is ed from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, kylcarbonyl, alkoxycarbonyl, koxycarbonyl, hiocarbonyl, haloalkyl, alkylthio, haloalkylthio, , haloalkoxyalkyl, alkoxycarbonyl and haloalkoxycarbonyl; R1 is hydrogen or alkyl; R2 and R3 are each independently selected from the group ting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, alkylthio, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and cyano, or R2 and R3 taken er with the carbon to which both are bound form a substituted or unsubstituted 3- to 7-member cyclic, cyclic or heteroaromatic ring, wherein the substituents may each be independent of one another cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino; a is an integer from zero to four, b is an integer from zero to four, d is an integer from zero to four, R4, R5, R6 , R7, R8 and R9 are each independently hydrogen, n, alkyl, alkenyl, hydroxyalkyl, alkylthioalkyl, haloalkyl, alkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylsulfonyloxyalkyl, nitro, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and diamino; R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, thiol, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, lkyl, hydroxyalkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, phenoxy, alkoxyalkoxy, cycloalkyloxy, haloalkoxy, formyl, alkylcarbonyl, alkoxycarbonyl, sulfonyl, sulfinyl, and unsubstituted or substituted phenyl, tituted or substituted benzyl, unsubstituted or substituted arylthio, unsubstituted or substituted aryloxy, or unsubstituted or tuted heteroaryl, wherein the substituents, ndent of one another, may be one or more of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylaminoalkoxy, dialkylaminoalkoxy, and minoalkyl, provided that, at least one of b and d is other than zero, and at least one of R10 and R11 is other than hydrogen.

2. The compound of claim 1, wherein b is one and d is zero, b is two and d is zero, b is one and d is one, b is zero and d is one, or b is zero and d is two.

3. The compound of claim 2, wherein a is one or two.

4. The compound of claim 1, wherein a is zero, provided that when R10 and R11 are both selected from the group consisting of chloro and methyl, then: i) d is other than zero, or ii) Ra is other than C1-6 alkyl, or iii) R2 and R3 when taken together with the carbon to which both are bound form a ring other than cyclopentyl or cyclohexyl.

5. The compound of claim 1, wherein R10 and R11 are each independently selected from the group consisting of hydrogen, halogen, ed or straight-chain C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, hydroxy(C1-6)alkyl, halo(C 1-6)alkyl, C1-6 alkoxy, halo(C1-6)alkoxy and unsubstituted or substituted phenyl, wherein the substituents, independent of one another, may be one or more of halogen, C1-6 alkyl, halo(C1- 6)alkyl, C1-6 alkoxy, or halo(C1-6)alkoxy.

6. The compound of claim 5, wherein R10 and R11 are each independently selected from the group ting of hydrogen, bromo, chloro, fluoro, methyl, ethyl, trifluoromethyl and trifluoromethoxy.

7. The compound of claim 1, wherein a is one, R4 and R5 are both hydrogen, b is zero, one or two, and d is zero, one or two.

8. The compound of claim 7, wherein b is one or two, d is zero, and R6 and R7 in each ce are both en.

9. The compound of claim 7, wherein d is one or two, b is zero, and R8 and R9 in each instance are both hydrogen.

10. The compound of claim 7, wherein b is one or two, R6 and R7 in each instance are both hydrogen, d is one or two, and R8 and R9 in each instance are both en.

11. The compound of claim 1, wherein R1 is hydrogen or methyl, R2 and R3 are each independently ed from the group ting of hydrogen, C1-6 alkenyl, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di(C1-6 alkyl)amino and C1-6 alkylthio, or R2 and R3 taken together with the carbon to which both are bound form a substituted or tituted 3- to 7-member cyclic, heterocyclic or heteroaromatic ring; wherein the substituents may each be independent of one another cyano, nitro, halogen, alkyl, haloalkyl, hio, haloalkylthio, alkoxy, haloalkoxy, amino, alkylamino, and dialkylamino.

12. The compound of claim 11, n R2 and R3 taken together with the carbon to which both are bound form a tuted or unsubstituted 3- to 7-member cyclic, heterocyclic or pyridine.

13. The compound of claim 12, wherein R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, perazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, 2-pyrrolinyl, olinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl and dihydrothienyl.

14. The compound of claim 13, wherein R2 and R3 taken together with the carbon to which both are bound form a substituted or unsubstituted cyclopropyl or 4-morpholinyl.

15. The compound of claim 11, wherein R2 and R3 are each ndently selected from the group consisting of hydrogen, C1-6 alkenyl, C1-6 alkyl and C1-6 alkylthio.

16. The compound of claim 1, wherein Ra is hydrogen.

17. The compound of claim 1, wherein a is one or two.

18. The nd of claim 1, having one of the following structures: N F 4 F F , N F O 5 F F , H F F F O O 9 N O O 10 F F , O O F H 12 O , O F N F O , 13 O F H 14 O N F O , O O F H 15 O N O , O F O 24 N O O , H O 28 S N O , H O N 33 O , F 37 H O O , O 41 N O O , O 44 H F O N O , O O 47 H F N F O , O 49 S N F N F O , O 54 N F N F O , O 56 H F N F O , NH 63 O N NH O 65 O N O 68 O , S O NH 70 O N NH 73 O N NH O 76 O N NH O 77 O N O 78 O , N Br O N F NH O O N F , NH O O N F , NH O O N F , NH 130 O N F , O O F H 132 N O , O F H 133 N O F , O F N F H F 134 N O , F F O F N O O F H 138 O N O F , O F N F H F 140 O N O , F F O F O N O , NH F O F 206 O , NH F F 209 O , N 216 N O NH N O 219 F , O N 220 F , N 221 F , N 222 F F F F , O 223 Cl F F F , N 225 Cl Cl , O O 227 N O , O O H 228 N O F 229 N O O F N F 232 H F N O F , Cl 234 N O O O F H F N F N Br 237 O , N 238 O , O O F H F N F 240 O , O O F H F N F 241 O , O O F H F N F 242 O , O O F H F N F 243 O , O F 256 N F H F N O , O F N F H F N O O Cl 258 N O , O 259 N O , Cl 260 N O N O N O H 266 N O F F , O F N O , O F F 270 N O N F 275 F , NH F 278 F and NH F 279 F .

19. A parasiticidal composition comprising a compound of claim 1 and a carrier.

20. The composition of claim 19, further sing one or more additional active agents.

21. A method of ng or preventing infection or ation of a non-human animal by one or more parasites, said method comprising administering an effective amount of a compound of claim 1.

22. The method of claim 21, wherein said one or more parasites is selected from the group consisting of fleas, ticks, mites, mosquitoes, flies, fly larvae and lice and combinations thereof.

23. The method of claim 21, wherein said one or more parasites is selected from the group consisting of fleas and ticks and combinations thereof.

24. The method of claim 21, n said one or more tes is an ectoparasite or an endoparasite or a combination thereof.

25. The method of claim 24, n said ectoparasite is an arthropod.

26. The method of claim 25, wherein said pod is selected from the group consisting of houseflies (Musca domestica), Musca hervei, Musca bezzi, Haematobia irritans, Simulium iwatens, Culicoides oxystoma, Tabanus chrysurus, common mosquito (Culex pipiens), Aedes albopictus; lice pests (Anoplura), cattle lice (Haematopinus eurysternus), sheep lice (Damalinia ovis); tick pests (Acarina), Haemaphysalis longiconis, Boophilus microplus; fleas (Siphonaptera), cat fleas (Ctenocephalides felis), dog fleas (Ctenocephalides canis) and oriental rat flea (Xenopsylla cheopis).

27. The method of claim 24, wherein said endoparasite is a helminth.

28. The method of claim 24, wherein said endoparasite is selected from the group consisting of Anaplocephala (Anoplocephala), Ancylostoma, Anecator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, ides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum, erca, Ostertagia, s, Paracaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, ntophorous, Uncinaria, Wuchereria, chus contortus, agia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus and combinations thereof.