RU2798093C2 - Antihelminthic heterocyclic compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: compound of formula (I), (IA) or formula (II), or a composition containing a compound of formula (I), (IA) or formula (II), in complex with a veterinarily acceptable carrier is described. The invention relates to new anthelminthic compounds of formula (Ia) or (Ib), where R1-R4, X and Y, o and q are defined in the claims, compositions containing these compounds, and methods of using the compounds to combat helminths.

EFFECT: obtaining antihelminthic heterocyclic compounds.

16 cl, 1 tbl, 16 ex

Description

The present application relates to new anthelminthic compounds, compositions containing these compounds, and methods of using these compounds to control helminths.

Cross-references to related applications

This application claims the priority claimed in Provisional Application for US Patent No. 62/695,656, filed July 9, 2019, which is incorporated herein in its entirety by reference.

The field of technology to which the invention belongs

The present application concerns novel anthelminthic heterocyclic compounds with improved activity against endoparasites and/or ectoparasites. The present application also relates to compositions containing said compounds, methods and uses of said compounds to rid, control and prevent parasite infestation and/or parasitic infections in animals. The compounds of the present invention can be administered to animals, in particular mammals, fish and birds, to prevent or treat parasitic infections.

Prior Art

Animals such as mammals and birds are often prone to parasitic infestations and infections. These parasites may be ectoparasites such as fleas and ticks. Animals and humans also suffer from endoparasitic infections, including, for example, helminthiasis, which is most often caused by a group of parasitic worms called nematodes or roundworms. These parasites cause great economic losses in pig, sheep, horse and cattle breeding, as well as infecting companion animals (eg cats and dogs) and birds. Other parasites found in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and parasites found in the blood or other tissues and organs such as filarial worms and extraintestinal stages of Strongyloides and Trichinella.

One type of endoparasite that seriously harms mammals is Dirofilaria immitis, also known as heartworm. Other filarial endoparasites include Dirofilaria repens and Dirofilaria honkongensis, which also infect humans. Cats and dogs are the most common hosts, but other mammals such as ferrets and raccoons may also be affected. The heartworm goes through several life stages before becoming an adult, infecting the pulmonary artery of a mammalian guest. Worms require a mosquito as an intermediate host to complete their life cycle. The period between initial infection, when the dog is bitten by a mosquito, and the transformation of the worms into adults living in the heart and pulmonary arteries, is six to seven months in dogs, and is known as the "pre-patent period." L3 larvae migrate during the mosquito's blood sucking to the tip of the mosquito's mouthparts (labium), leave the mosquito and remain on the skin of the dog, where they then migrate into the host through the bite wound. Most L3 larvae develop into fourth stage (L4) larvae in the subcutaneous tissues of the dog within 1-3 days of infection. They then migrate to the muscles of the chest and abdomen, and 45-60 days after infection, they enter the fifth stage (L5, immature adult). Approximately 75-20 days after infection, these immature heartworms then enter the bloodstream and pass through the heart, lingering in the pulmonary artery. Approximately seven months after infection, adults of Dirofilaria immitis reach maturity and begin sexual reproduction in the pulmonary arteries and right ventricle. Adult males are about 15cm long and females are about 25cm, and their normal adult lifespan is about 5 years.

Heartworm infection is a severe and life-threatening disease. Heartworm infection in dogs is preventable, and preventive treatment is a priority in areas where heartworm disease is endemic. Treatment of adult heartworm infection with drugs that kill adult helminths (eg, melarsomine dihydrochloride) is expensive and can cause serious side effects, so prevention of infection by monthly administration of drugs that interrupt larval development is widely used. The goal of available therapies for canine heartworm is to prevent the development of the parasite into adult worms by interrupting the life cycle of Dirofilaria immitis after infection.

Macrocyclic lactones (ML, eg, ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most widely used chemopreventive agents and are administered monthly or every six months. These drugs are effective against infective third stage (L3) larvae of Dirofilaria immitis, spread by mosquitoes, as well as against maturing fourth stage (L4) larvae. When administered monthly, ML kills L3 and L4 larvae ingested during the previous 30 days and thus prevents disease caused by adult worms. ML can also be used monthly in infected dogs to inhibit adult worm reproduction and remove microfilariae, thereby reducing transmission and progressively eliminating adult worms (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206).

In recent years, an increasing number of cases of lack of efficacy (LOE) have been reported in which dogs develop mature heartworm infections despite monthly prophylactic doses of macrocyclic lactone drugs. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) recently reported an increasing number of cases of dogs that were positive for heartworm antigen when receiving heartworm prophylactic therapy, suggesting that some Dirofilaria immitis populations have developed selective resistance to heartworm preventives (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5.). Thus, there is an urgent need to develop new anthelmintic agents with improved activity against Dirofilaria immitis and other endoparasites.

It should be noted that the citation or reference to any document in this application is not an admission that such document is part of the prior art for the present invention. All prior applications and all documents cited in or at the time of their consideration (“application documents cited”), and all documents cited or referred to in documents cited in applications, and all documents cited or referred to in this text (“applications cited”). documents in this text"), and all documents cited or referred to in documents cited in this text, together with all manufacturer's instructions, descriptions, product specifications and product data sheets for all products mentioned in this text, or in any document included in the present text by reference, are incorporated herein by reference, and may be used in the practice of the present invention.

Brief description of the invention

In one embodiment, the present invention describes a compound, for example, having formula (I):

Where:

W ¹ W ² , W ³ and W ⁴ independently represent CH or N;

R ¹ represents a hydrogen atom, a cyano group, an optionally substituted alkoxy group, an optionally substituted haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted C ₃ -C ₈ -cycloalkyl, an optionally substituted alkenyl , optionally substituted haloalkenyl, optionally substituted alkynyl, optionally substituted haloalkynyl, optionally substituted aryl; optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-SO _n , amino group, NH-optionally substituted alkyl, or NR ^a R ^b , where R ^a and R ^b independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ² is hydrogen, halogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, or SO _m (optionally substituted alkyl);

R ³ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

each R ⁴ is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, -amino, NH-optionally substituted alkyl, SF ₅ or NR ^c R ^d , where R ^c and R ^d are independently optionally substituted alkyl; or R ^c and R ^d may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which may optionally be substituted, SO _p (optionally substituted C ₁ -C ₄ -alkyl);

o is 0, 1, 2, 3 or 4;

m, n and p are independently 0, 1 or 2;

q is 0 or 1;

X and Y are independently CR ⁵ R ⁶ , O, S or NR ⁷ where at least one of X and Y is CR ⁵ R ⁶ ;

R ⁵ and R ⁶ independently represent a hydrogen atom, fluorine or C ₁ -C ₄ -alkyl;

R ⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In another embodiment, the present invention describes a compound having the following formula (IA), where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I ), and W ⁵ , W ⁶ and W ⁷ are independently CH, N or S.

The present invention includes, for example, a compound having the formula (I-1):

Where:

R ¹ represents a hydrogen atom, a cyano group, an optionally substituted alkoxy group, an optionally substituted haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted C ₃ -C ₈ -cycloalkyl, an optionally substituted alkenyl , optionally substituted haloalkenyl, optionally substituted alkynyl, optionally substituted haloalkynyl, optionally substituted aryl; optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-SO _n , amino group, NH-optionally substituted alkyl, or NR ^a R ^b , where R ^a and R ^b independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ² is hydrogen, halogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, or SO _m (optionally substituted alkyl);

R ³ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

each R ⁴ is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, -amino, NH-optionally substituted alkyl, SF ₅ or NR ^c R ^d , where R ^c and R ^d are independently optionally substituted alkyl; or R ^c and R ^d may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which may optionally be substituted, SO _p (optionally substituted C ₁ -C ₄ -alkyl);

o is 0, 1, 2, 3 or 4;

m, n, and p are independently 0, 1, or 2;

q is 0 or 1;

X and Y are independently CR ⁵ R ⁶ , O, S or NR ⁷ where at least one of X and Y is CR ⁵ R ⁶ ;

R ⁵ and R ⁶ independently represent a hydrogen atom, fluorine or C ₁ -C ₄ -alkyl;

R ⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

The present invention also includes a veterinarily acceptable composition comprising a compound of the present invention and a veterinarily acceptable carrier, and a method of helminth control comprising administering a compound of the present invention or a veterinarily acceptable composition thereof to an animal in need thereof. The present invention also includes the use of a compound of the present invention for the elimination, control or prevention of infestation and/or parasitic infections in animals. The compound of the present invention can be administered to animals, in particular mammals, fish and birds, to prevent or treat parasitic infections.

The compound of the present invention and compositions containing this compound are highly effective in the treatment and prevention of endoparasites in mammals, fish and birds, in particular in cats, dogs, horses, chickens, pigs, sheep and cattle, carried out to rid the listed host animals from endoparasites.

In one embodiment, the compounds and compositions of the present invention have significant efficacy against endoparasites such as filariae (eg, heartworm), hookworms, whipworms, and roundworms in the digestive tract of animals and humans. In some embodiments, the compounds and compositions of the present invention are effective against Dirofilaria immitis (heartworm), which is less responsive to treatment with macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are effective in treating and preventing infection in animals with roundworms that are less responsive to treatment with commercially available or known active ingredients.

In one embodiment, the present invention describes a combination of a compound of the present invention with at least one second active ingredient that enhances the protection of animals against endoparasites and/or ectoparasites.

The present invention also includes a method for treating and preventing a parasitic infection or infestation in an animal, comprising administering to a mammal a compound, for example a compound having formula (I). Also included in the present invention is the use of a compound, for example a compound having formula (I), for the treatment and/or prevention of parasitic infections and infestations in animals, and the use of said compounds in the preparation of a medicament for the treatment and/or prevention of parasitic infection in an animal.

Thus, the present invention includes at least the following features:

(a) In one embodiment, a compound, for example a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof, which is active against endoparasites, and in some cases also against ectoparasites;

(b) a veterinary composition comprising a parasiticide effective amount of a compound, for example a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof, in combination with a pharmaceutically or veterinarily acceptable carrier or diluent;

(c) a veterinary composition comprising a parasiticide effective amount of a compound, e.g. a compound having formula (I) or (IA) etc., or a pharmaceutically or veterinarily acceptable salt thereof, in combination with one or more other active ingredients and pharmaceutically or a veterinarily acceptable carrier or diluent;

(d) a method of treating infestations/infections with parasites in or on the body of an animal, comprising administering a parasiticide effective amount of a compound, e.g., a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof , optionally with one or more other active ingredients, to the mammal in need;

(e) a method of preventing infestations/infections in an animal, which comprises administering a parasiticide effective amount of a compound, e.g., a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof, optionally with one or more additional active substances, in need of this mammal;

(f) the use of a compound, for example a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof, for the treatment or prevention of parasite infections and possibly infestation in an animal;

(g) the use of a compound, for example a compound having formula (I) or (IA), etc., or a pharmaceutically or veterinarily acceptable salt thereof, for the manufacture of a veterinary medicinal product for the treatment or prevention of a parasitic infection in an animal; And

(h) a method for producing a compound, for example, a compound having formula (I) or (IA), etc.

Definitions:

The terms used in this text have the generally accepted meaning in this field, unless otherwise indicated. The organic moieties indicated in the definitions of the variables present in compounds, for example compounds having formula (I), are - like the term "halogen" - collective terms for lists of individual group members - in the case of "halogen" these are fluorine, chlorine, bromine and iodine. The prefix C _n -C _m in each case indicates the possible number of carbon atoms in the group from the number n to another number m.

In the present description and in the claims, the term "including (but not limited to)" is equivalent to the term "including".

By "optionally substituted" is meant a radical which is optionally substituted by one or more of the following moieties: halogen, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl or dialkylamino, amido, arylamino, alkoxy group, aryloxy group, nitro group, cyano group, azide group, thiol, imino group, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester group, phosphonyl, phosphinyl, phosphoryl, phosphine, thioether group, acyl halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, aryl and heteroaryl, or any other stable functional group which does not inhibit the biological activity of the compounds of the present invention, in an unprotected or, if appropriate, protected form, as known to those skilled in the art. those skilled in the art, for example as described in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, which is incorporated herein by reference..

Unless otherwise indicated, the term "alkyl", alone or in combination with a heteroatom, for example, alkoxy, thioalkyl, alkylamino, and the like, refers to saturated linear, branched, primary, secondary, or tertiary hydrocarbons, including hydrocarbons containing from 1 to 12 atoms. In some embodiments, the alkyl groups include C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₃ alkyl groups. Examples of C ₁ -C ₁₀ alkyls include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl , 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl , 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2 ,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl, and their isomers. C ₁ -C ₄ -alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups may be referred to as "cycloalkyl" and include groups containing 3 to 10 carbon atoms having one or more fused rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

Carbocyclic groups are cyclic groups composed entirely of carbon. Carbocyclic groups include both aromatic rings such as phenyl and non-aromatic rings such as cyclohexyl and include groups containing 3-14 carbon atoms having one or more fused rings.

The term "alkenyl" refers to straight and branched carbon chains containing at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C ₂ -C ₁₂ alkenyl groups. In other embodiments, "alkenyl" includes C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C _{4 ,} or C ₃ -C ₄ alkenyl groups. In one version of alkenyl, the number of double bonds is 1-3, in another version of alkenyl, the number of double bonds is one. Other numbers of carbon-carbon double bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkenyl fragment in the molecule. "C ₂ -C ₁₀ -alkenyl" groups may contain more than one double bond in the chain. Examples of alkenyl, or a specific range thereof, include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2- methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2- pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3- butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2- butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3- butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2- methyl-1-propenyl; and 1-ethyl-2-methyl-2-propenyl.

The term "alkynyl" refers to straight and branched carbon chains containing at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another variant of alkynyl, the number of triple bonds is one. In some embodiments, the alkynyl groups include C ₂ -C ₁₂ alkynyl groups. In other embodiments, alkynyl groups may include C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₄ alkynyl groups. Other numbers of carbon-carbon triple bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkynyl moiety in the molecule. "C ₂ -C ₁₀ alkynyl" as used herein refers to linear or branched unsaturated hydrocarbon groups containing from 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1 -yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n -but-2-in-1-yl, n-pent-1-in-1-yl, n-pent-1-in-3-yl, n-pent-1-in-4-yl, n-pent -1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1 -yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn -4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4 -yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl , 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4 -methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl, and the like.

The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halogen atoms. For example, C ₁ -C ₄ haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2 -fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2 -trichloroethyl, pentafluoroethyl, and the like.

The term "fluoroalkyl" as used herein means alkyl in which one or more carbon atoms have been replaced by fluorine atoms, e.g. difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl , 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

The term "haloalkenyl" refers to an alkenyl group, as defined herein, which is substituted by one or more halogen atoms.

The term "haloalkynyl" refers to an alkynyl group, as defined herein, which is substituted by one or more halogen atoms.

The term "alkoxy" refers to the group alkyl-O-, where alkyl has the above meaning. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "halocycloalkoxy", and "halocycloalkenyloxy" refer to the groups alkenyl-O-, alkynyl-O- , haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O- and halocycloalkenyl-O-, respectively, where alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl , cycloalkenyl, halocycloalkyl and halocycloalkenyl are as defined above. Examples of C ₁ -C ₆ -alkoxy include (but are not limited to) methoxy, ethoxy, OCH ₂ -C ₂ H ₅ , OCH(CH ₃ ) ₂ , n-butoxy, OCH(CH ₃ )-C ₂ H ₅ , OCH ₂ -CH (CH ₃ ) _2, OC (CH ₃ ) ₃ , n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl -propoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy , 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2 -methylpropoxy and the like.

The term "aryl" refers to a monovalent carbocyclic group containing from 6 to 14 carbon atoms, having one ring or more fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments, aryl includes tetrahydronaphthyl, phenylcyclopropyl, and indanyl. Aryl groups may be unsubstituted or be substituted with one or more substituents selected from the following: halogen atom, cyano group, nitro group, hydroxy group, mercapto group, amino group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group, haloalkenyloxy group, haloalkenyloxy group, cycloalkoxy group, cycloalkenyloxy group, halocycloalkoxy group, halocycloalkenyloxy group, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfone yl, -SF ₅ , alkylamino- group, alkenylamino group, alkynylamino group, di(alkyl)amino group, di(alkenyl)amino group, di(alkynyl)amino group or trialkylsilyl.

The term "aralkyl" refers to an aryl group that is linked to the remainder of the compound via a diradical alkylene bridge, (-CH ₂ -) _n , where n is 1-12 and where "aryl" has the meaning given above. The term "heteroaryl" refers to a monovalent aromatic group containing 1-15 carbon atoms, preferably 1 to 10 carbon atoms, containing one or more oxygen, nitrogen and sulfur heteroatoms in the ring, preferably 1-4 heteroatoms or 1-3 heteroatoms. The nitrogen and sulfur heteroatoms can optionally be oxidized. Such heteroaryl groups may have one ring (eg, pyridyl or furyl) or multiple fused rings, provided that the point of attachment is on a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothy onenil, imidazopyridyl, imidazopyrimidyl or pyrrolopyrimidyl. Heteroaryl rings may be unsubstituted or substituted with one or more of the moieties defined above for the term "aryl".

The terms "heterocyclyl", "heterocyclic", or "heterocyclo" refers to fully saturated or unsaturated cyclic groups, for example, 3-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic systems, which may contain at least at least one heteroatom in a ring containing at least one carbon atom. Each cycle of a heterocyclic group containing a heteroatom may contain 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 quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom in the ring or ring system, and may be unsubstituted or substituted with one or more substituents as described above for aryl groups.

Examples of monocyclic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinil, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl , morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Examples of bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 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 3,4- dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.

The term "alkylthio" refers to the group alkyl-S-, where alkyl has the above meaning. In some embodiments, the alkyl component of the alkylthio group includes C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ C ₁ -C ₄ , or C ₁ -C ₃ alkyl groups. For example, C ₁ -C ₄ -alkylthio groups include (but are not limited to) methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 1-methylpropylthio group, 2-methylpropylthio - group or 1,1-dimethylethylthio group.

Similarly, the terms "haloalkylthio", "cycloalkylthio", "halocycloalkylthio" refer to the groups -S-haloalkyl, -S-cycloalkyl and -S-halocycloalkyl, respectively, where the terms "haloalkyl", "cycloalkyl" and "halocycloalkyl" have the above values.

The term "alkylsulfinyl" means an alkyl-S(=O)- group, where "alkyl" has the same meaning as above. In some embodiments, the alkyl component of the alkylsulfinyl groups includes C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ , or C ₁ -C ₃ alkyl groups. Examples include (but are not limited to) -SO-CH ₃ , -SO-C ₂ H ₅ , n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n -pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3 -methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl , 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

Similarly, the terms "alkenylsulfinyl", "alkynylsulfinyl", "haloalkylsulfinyl", "haloalkenylsulfinyl" and "haloalkynylsulfinyl" refer to the groups alkenyl-S(=O)-, alkynyl-S(=O)- and haloalkyl-S(=O) -, haloalkenyl-S(=O)- and haloalkynyl-S(=O)-, where the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" have the meanings indicated above.

The term "alkylsulfonyl" means a group of alkyl-S(=O) ₂ -, where the term "alkyl" has the above meaning. In some embodiments, the alkyl component in the alkylsulfonyl groups includes C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , or C ₁ -C ₄ alkyl groups. Examples include (but are not limited to) -SO ₂ -CH ₃ , -SO ₂ -C ₂ H ₅ , n-propylsulfonyl, -SO ₂ -CH(CH ₃ ) ₂ , n-butylsulfonyl, 1-methylpropylsulfonyl, 2- methylpropylsulfonyl, -SO ₂ -C (CH ₃ ) ₃ , n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl , n-hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl , 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl and the like .

The terms "alkenylsulfonyl", "alkynylsulfonyl", "haloalkylsulfonyl", "haloalkenylsulfonyl", and "haloalkynylsulfonyl" refer to the groups alkenyl-S(=O) ₂ -, alkynyl-S(=O) ₂ - and haloalkyl-S(=O) ₂ -, haloalkenyl-S(=O) ₂ - and haloalkynyl-S(=O) ₂ -, where the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" have the meanings indicated above.

The terms "alkylamino group", "dialkylamino group", "alkenylamino group", "alkynylamino group", "di(alkenyl)amino group", and "di(alkynyl)amino group" refer to -NH( alkyl), -N(alkyl) ₂ , -NH(alkenyl), -NH(alkynyl), -N(alkenyl) ₂ and -N(alkynyl) ₂ , where the terms "alkyl", "alkenyl" and "alkynyl" have the above values. In some embodiments, the alkyl component in alkylamino or dialkylamino groups includes C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , or C ₁ -C ₄ alkyl groups.

The term "compound", unless otherwise indicated, means a compound having formula (I), or a compound having formula (II), or another compound which may be an anthelmintic heterocyclic compound.

Detailed description of the invention

In one embodiment, the present invention includes a compound having formula (I):

W ¹ W ² , W ³ and W ⁴ independently represent CH or N;

R ¹ represents a hydrogen atom, a cyano group, an optionally substituted alkoxy group, an optionally substituted haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted C ₃ -C ₈ -cycloalkyl, an optionally substituted alkenyl , optionally substituted haloalkenyl, optionally substituted alkynyl, optionally substituted haloalkynyl, optionally substituted aryl; optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-SO _n , amino group, NH-optionally substituted alkyl, or NR ^a R ^b , where R ^a and R ^b independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ² is hydrogen, halogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, or SO _m (optionally substituted alkyl);

R ³ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

each R ⁴ is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, -amino, NH-optionally substituted alkyl, SF ₅ or NR ^c R ^d , where R ^c and R ^d are independently optionally substituted alkyl; or R ^c and R ^d may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally be substituted, SO _p (optionally substituted C ₁ -C ₄ -alkyl);

o is 0, 1, 2, 3 or 4;

m, n and p are independently 0, 1 or 2;

q is 0 or 1;

X and Y are independently CR ⁵ R ⁶ , O, S or NR ⁷ where at least one of X and Y is CR ⁵ R ⁶ ;

R ⁵ and R ⁶ independently represent a hydrogen atom, fluorine or C ₁ -C ₄ -alkyl;

R ⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In another embodiment, the present invention includes a compound having the following formula (IA), where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I) , and W ⁵ , W ⁶ and W ⁷ are independently CH, N or S.

In one embodiment, the present invention includes a compound having the formula (I-1):

Where:

R ¹ is hydrogen atom, cyano, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted alkenyl, optionally substituted haloalkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-S(O) _n , amino group, NH-optionally substituted alkyl, or NR ^a R ^b , where R ^a and R ^b are independently optionally substituted alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ² is hydrogen, halogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, or SO _m (optionally substituted alkyl);

R ³ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

each R ⁴ is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, -amino, NH-optionally substituted alkyl, SF ₅ or NR ^c R ^d , where R ^c and R ^d are independently optionally substituted alkyl; or R ^c and R ^d may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which may optionally be substituted, SO _p (optionally substituted alkyl);

o is 0, 1, 2, 3 or 4;

m, n and p are independently 0, 1 or 2;

q is 0 or 1;

X and Y are independently CR ⁵ R ⁶ , O, S or NR ⁷ where at least one of X and Y is CR ⁵ R ⁶ ;

R ⁵ and R ⁶ independently represent a hydrogen atom, fluorine or C ₁ -C ₄ -alkyl;

R ⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In some embodiments, R ¹ is a hydrogen atom, a cyano group, an optionally substituted C ₁ -C ₄ alkoxy group, an optionally substituted C ₁ -C ₄ haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₄ alkenyl, optionally substituted C ₁ -C ₄ haloalkenyl, optionally substituted C ₁ - C ₄ alkynyl, optionally substituted aryl; optionally substituted C ₁ -C ₄ alkylcarbonyl, optionally substituted C ₁ -C ₄ alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C ₁ -C ₄ alkylaminocarbonyl, optionally substituted C ₁ -C ₄ dialkylaminocarbonyl, optionally substituted alkyl-SO _n , halo-C ₁ -C ₄ -alkyl-S(O) _n , amino group, NH-optionally substituted C ₁ -C ₄ -alkyl or NR ^a R ^b , where R ^a and R ^b independently represent optionally substituted alkyl ; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ² is hydrogen, halogen, cyano, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl or SO _m (optionally substituted C ₁ -C ₄ alkyl);

R ³ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

each R ⁴ is independently hydrogen atom, halogen, cyano, nitro, -OH, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₈ -cycloalkyl, -amino group, NH-optionally substituted C ₁ -C ₄ -alkyl, SF ₅ or NR ^c R ^d , where R ^c and R ^d independently represent optionally substituted C ₁ -C ₄ -alkyl; or R ^c and R ^d may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which may optionally be substituted, SO _p (optionally substituted C ₁ -C ₄ -alkyl);

o is 0, 1, 2, 3 or 4;

m, n and p are independently 0, 1 or 2;

q is 0 or 1;

X and Y are independently CR ⁵ R ⁶ , O, S or NR ⁷ where at least one of X and Y is CR ⁵ R ⁶ ;

R ⁵ and R ⁶ independently represent a hydrogen atom, fluorine or C ₁ -C ₄ -alkyl;

R ⁷ represents a hydrogen atom or C ₁ -C ₄ -alkyl; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In some embodiments, R ¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, amino, C ₁ -C ₄ alkylalkylamino, or di-(C ₁ -C ₄ alkyl)amino -group.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ alkylthio group.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ alkylsulfinyl.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ alkylsulfonyl.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ haloalkylthio group.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ haloalkylsulfinyl.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ haloalkylsulfonyl.

In some embodiments, R ¹ is an optionally substituted C ₁ -C ₄ haloalkynyl.

In some embodiments, R ¹ is a hydrogen atom, a cyano group, an optionally substituted C ₁ -C ₄ alkoxy group, an optionally substituted C ₁ -C ₄ haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₄ alkenyl, optionally substituted C ₁ -C ₄ haloalkenyl, optionally substituted C ₁ - C ₄ alkynyl, optionally substituted aryl; optionally substituted C ₁ -C ₄ alkylcarbonyl, optionally substituted C ₁ -C ₄ alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-S(O) _n , amino group , NH-optionally substituted alkyl or NR ^a R ^b , where R ^a and R ^b are independently optionally substituted alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

In some embodiments, R ¹ is secondary C ₁ -C ₄ alkyl.

In some embodiments, R ¹ is heterocyclyl.

In some embodiments, R ¹ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiadiazolidinyl, isothiazolyl, isothiadiazolidinyl, furyl , tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thia morpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl.

In some embodiments, R ¹ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which may be optionally substituted with one or more halogens.

In some embodiments, R ² is hydrogen, alkyl, or haloalkyl.

In some embodiments, R ² is alkyl or haloalkyl.

In some embodiments, R ² is alkyl.

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ alkylthio group.

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ alkylsulfinyl.

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ alkylsulfonyl.

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ haloalkylthio group.

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ haloalkylsulfinyl.

In some embodiments, R ² is hydrogen, halogen, cyano, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₈ -cycloalkyl or SO _m (optionally substituted C ₁ -C ₄ -alkyl).

In some embodiments, R ² is an optionally substituted C ₁ -C ₄ haloalkylsulfonyl. In some embodiments, R ³ is 6- or 10-membered aryl, optionally substituted with 1, 2, 3, 4, or 5 substituents.

In some embodiments, R ³ is 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 substituents.

In some embodiments, R ³ is phenyl substituted with 1 substituent, which is halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group or a haloalkenyloxy group.

In some embodiments, R ³ is para-substituted phenyl.

In some embodiments, R ³ is meta-substituted phenyl.

In some embodiments, R ³ is ortho-substituted phenyl.

In some embodiments, R ³ is halophenyl.

In some embodiments, R ³ is haloalkylphenyl.

In some embodiments, R ³ is haloalkoxyphenyl.

In some embodiments, R ³ is phenyl substituted with 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl , a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group, or a haloalkenyloxy group.

In some embodiments, R ³ is 2,3-disubstituted phenyl.

In some embodiments, R ³ is 2,4-disubstituted phenyl.

In some embodiments, R ³ is 2,5-disubstituted phenyl.

In some embodiments, R ³ is dihalophenyl, eg dichloro; difluoro; or chlorine, fluorine.

In some embodiments, R ³ is phenyl substituted with halo and haloalkyl.

In some embodiments, R ³ is phenyl substituted with halogen and a haloalkoxy group.

In some embodiments, R ³ is phenyl substituted with haloalkyl and haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 3 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl , a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group, or a haloalkenyloxy group.

In some embodiments, R ³ is trihalophenyl, eg trichlor; trifluoro; or chlorine, chlorine, fluorine, or fluorine, fluorine, chlorine.

In some embodiments, R ³ is phenyl substituted with 2 halo and haloalkyl.

In some embodiments, R ³ is phenyl substituted with 2 halogens and a haloalkoxy group.

In some embodiments, R ³ is phenyl substituted with 1 haloalkyl, 1 halo, and 1 haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 1 halo and 2 haloalkyl.

In some embodiments, R ³ is a 5-membered heteroaryl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl , haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ³ is a 6-membered heteroaryl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl , haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ³ is 2-pyridyl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ³ is 3-pyridyl with 1 or 2 substituents that are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ³ is 4-pyridyl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, X is CH ₂ .

In some embodiments, X is O.

In some embodiments, X is S.

In some embodiments, X is S=O.

In some embodiments, X is SO ₂ .

In some embodiments, X is NH.

In some embodiments, X is NCOalkyl.

In some embodiments, X is N aryl.

In some embodiments, Y is CH ₂ .

In some embodiments, Y is CHalkyl.

In some embodiments, Y is CHaryl.

In some embodiments, a compound having formula (I) is a compound having formula (Ia):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ib):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ic):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Id):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ie):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, the compound having formula (I) is a compound having formula (If):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, the compound having formula (I) is a compound having formula (Ig):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ih):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ii):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, the compound having formula (I) is a compound having formula (Ij):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ik):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Il):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Im):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (In):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Io):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (I).

In some embodiments, a compound having formula (I) is a compound having formula (Ip), (Iq), or (Ir):

where the values of the variables R ¹ , R ² , R ³ , R ⁴ , X, Y, q and o are the same as in the case of formula (IA)

In some embodiments, o is 0.

In some embodiments, o is 1.

In some embodiments, o is 2.

In some embodiments, o is 3.

In some embodiments, o is 4.

In some embodiments, R ⁴ is, independently of the other R ⁴ , halo.

In some embodiments, R ⁴ is, independently of other R ⁴ , optionally substituted C ₁ -C ₄ alkyl.

In some embodiments, R ⁴ is, independently of other R ⁴ , haloalkyl.

In one embodiment, the present invention includes a compound having formula (II):

Where:

R ⁸ is hydrogen atom, cyano, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted alkenyl , optionally substituted haloalkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-S(O) _n , amino group, NH-optionally substituted alkyl, or NR ^a' R ^{b '} where R ^a' and R ^b' independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a' and R ^b' may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ⁹ is hydrogen, halogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, or SO _m (optionally substituted alkyl);

R ¹⁰ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

R ^e and R ^f independently represent a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R ^e and R ^f may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents; and m and m are 0, 1, or 2; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In some embodiments, R⁸ is a hydrogen atom, a cyano group optionally substituted with C₁-C₄-alkoxy optionally substituted with C₁-C₄-haloalkoxy group, optionally substituted aryloxy group, optionally substituted C₁-C₄-alkyl optionally substituted with C₁-C₄- haloalkyl, optionally substituted with C₃-C₈-cycloalkyl optionally substituted with C₁-C₄-alkenyl optionally substituted with C₁-C₄-haloalkenyl optionally substituted with C₁-C₄-alkynyl, optionally substituted aryl; optionally substituted C₁-C₄-alkylcarbonyl optionally substituted with C₁-C₄-alkoxycarbonyl optionally substituted with C₁-C₄-aminocarbonyl optionally substituted with C₁-C₄-alkylaminocarbonyl optionally substituted with C₁-C₄-dialkylaminocarbonyl optionally substituted with C₁-C₄-alkyl-SO_n, C₁-C₄-haloalkyl-S(O)n, amino group, NH-optionally substituted with C₁-C₄-alkyl or NR^a'R^b', where R^a' and R^b' are independently an optionally substituted C₁-C₄ alkyl; or R^a' and R^b' may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

R ⁹ is hydrogen, halogen, cyano, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₆ cycloalkyl or SO _m (optionally substituted C ₁ -C ₄ alkyl);

R ¹⁰ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4 or 5 substituents;

R ^e and R ^f independently represent a hydrogen atom, optionally substituted C ₁ -C ₄ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R ^e and R ^f may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents; and m and m are 0, 1, or 2; or

its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt.

In some embodiments, R ⁸ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, amino, C ₁ -C ₄ alkylalkylamino, or di-(C ₁ -C ₄ alkyl) amino -group.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ alkylthio group.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ alkylsulfinyl.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ alkylsulfonyl.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ haloalkylthio group.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ haloalkylsulfinyl.

In some embodiments, R ⁸ is an optionally substituted C ₁ -C ₄ haloalkylsulfonyl.

In some embodiments, R ⁸ is secondary C ₁ -C ₄ alkyl.

In some embodiments, R ⁸ is heterocyclyl.

In some embodiments, R ⁸ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiadiazolidinyl, isothiazolyl, isothiadiazolidinyl, furyl , tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thia morpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl.

In some embodiments, R ⁸ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which may be optionally substituted with one or more halogens.

In some embodiments, R ⁸ is a hydrogen atom, a cyano group, an optionally substituted C ₁ -C ₄ alkoxy group, an optionally substituted C ₁ -C ₄ haloalkoxy group, an optionally substituted aryloxy group, an optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₄ alkenyl, optionally substituted C ₁ -C ₄ haloalkenyl, optionally substituted C ₁ -C ₄ alkynyl, optionally substituted aryl; optionally substituted C ₁ -C ₄ alkylcarbonyl, optionally substituted C ₁ -C ₄ alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, optionally substituted alkyl-SO _n , haloalkyl-S(O)n, amino group , NH-optionally substituted alkyl or NR ^a R ^b , where R ^a' and R ^b' independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a' and R ^b' may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents;

In some embodiments, R ⁹ is hydrogen, halogen, cyano, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₃ -C ₆ -cycloalkyl or SO _m (optionally substituted C ₁ -C ₄ -alkyl);

In some embodiments, R ¹⁰ is selected from the group consisting of 6- or 10-membered aryl and 5-10-membered heteroaryl, each of which may have 1, 2, 3, 4, or 5 substituents;

In some embodiments, R ^e and R ^f are independently hydrogen, optionally substituted C ₁ -C ₄ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R ^e and R ^f may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents.

In some embodiments, R ⁹ is hydrogen, alkyl, or haloalkyl.

In some embodiments, R ⁹ is alkyl or haloalkyl.

In some embodiments, R ⁹ is alkyl.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ alkylthio group.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ alkylsulfinyl.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ alkylsulfonyl.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ haloalkylthio group.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ haloalkylsulfinyl.

In some embodiments, R ⁹ is an optionally substituted C ₁ -C ₄ haloalkylsulfonyl.

In some embodiments, R ¹⁰ is a 6- or 10-membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents

In some embodiments, R ¹⁰ is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents.

In some embodiments, R ¹⁰ is phenyl substituted with 1 substituent, which is halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group or a haloalkenyloxy group.

In some embodiments, R ¹⁰ is para-substituted phenyl.

In some embodiments, R ¹⁰ is meta-substituted phenyl.

In some embodiments, R ¹⁰ is ortho-substituted phenyl.

In some embodiments, R ¹⁰ is halophenyl.

In some embodiments, R ¹⁰ is haloalkylphenyl.

In some embodiments, R ¹⁰ is haloalkoxyphenyl.

In some embodiments, R ³ is phenyl substituted with 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl , a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group, or a haloalkenyloxy group.

In some embodiments, R ¹⁰ is 2,3-disubstituted phenyl.

In some embodiments, R ¹⁰ is 2,4-disubstituted phenyl.

In some embodiments, R ¹⁰ is 2,5-disubstituted phenyl.

In some embodiments, R ¹⁰ is dihalophenyl, eg dichloro; difluoro; or chlorine, fluorine.

In some embodiments, R ¹⁰ is phenyl substituted with halo and haloalkyl.

In some embodiments, R ¹⁰ is phenyl substituted with halogen and a haloalkoxy group.

In some embodiments, R ¹⁰ is phenyl substituted with haloalkyl and haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 3 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl , a halocycloalkenyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a haloalkoxy group, or a haloalkenyloxy group.

In some embodiments, R ³ is trihalophenyl, eg trichlor; trifluoro; or chlorine, chlorine, fluorine, or fluorine, fluorine, chlorine.

In some embodiments, R ¹⁰ is phenyl substituted with 2 halo and haloalkyl.

In some embodiments, R ¹⁰ is phenyl substituted with 2 halogens and a haloalkoxy group.

In some embodiments, R ¹⁰ is phenyl substituted with 1 haloalkyl, 1 halo, and 1 haloalkoxy.

In some embodiments, R ¹⁰ is phenyl substituted with 1 halo and 2 haloalkyl.

In some embodiments, R ¹⁰ is a 5-membered heteroaryl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl , haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ¹⁰ is a 6-membered heteroaryl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl , haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ¹⁰ is 2-pyridyl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ¹⁰ is 3-pyridyl with 1 or 2 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ¹⁰ is 4-pyridyl with 1 or 2 substituents that are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, a haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group or haloalkenyloxy group.

In some embodiments, R ^e is a hydrogen atom.

In some embodiments, R ^f is a hydrogen atom.

In some embodiments, R ^f is an optionally substituted alkyl.

In some embodiments, R ^f is alkyl substituted with aryl.

In some embodiments, R ^f is alkyl substituted with heteroaryl.

In some embodiments, a compound having formula (II) is a compound having formula (IIa):

where the variables R ⁸ , R ⁹ , R ¹⁰ , R ^e and R ^f have the meanings indicated for the compound having formula (II).

In some embodiments, the compound having formula (II) is a compound having formula (IIb):

where the variables R ⁸ , R ⁹ , R ¹⁰ , R ^e and R ^f have the meanings indicated for the compound having formula (II).

In some embodiments, the compound having formula (II) is a compound having formula (IIc):

where the variables R ⁸ , R ⁹ , R ¹⁰ , R ^e and R ^f have the meanings indicated for the compound having formula (II).

Stereoisomers and polymorphic forms

Those skilled in the art will appreciate that the compounds of the present invention may exist and be isolated as optically active and racemic forms enantiomers and/or diastereomers. For example, it is well known that sulfoxide compounds may be optically active and may exist as single enantiomers or racemic mixtures. In addition, the compounds of the present invention may include one or more chiral centers, which lead to the existence of a theoretical number of optically active isomers. Where the compounds of the present invention include n chiral centers, the compounds may have up to ²ⁿ optical isomers. The present invention encompasses the particular enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the present invention that have the useful properties described herein. Optically active forms can be obtained, for example, by resolution of racemic forms by selective crystallization, synthesis from optically active precursors, chiral synthesis, chromatographic separation using a chiral stationary phase, or by enzymatic resolution.

The compounds of the present invention may also be present in various solid forms, such as various crystalline forms, or in the form of an amorphous solid. The present invention encompasses various crystalline forms as well as amorphous forms of the compounds of the present invention.

In addition, the compounds of the present invention may exist as hydrates or solvates in which certain stoichiometric amounts of water or solvent are associated with the molecule in crystalline form. Hydrates and solvates of compounds having formula (I) are also the object of the invention.

salt

In addition to neutral compounds, salts of these compounds also have activity against endoparasites. The term "veterinarily acceptable salt" is used herein to describe any salts of compounds that are acceptable for veterinary administration and that upon administration provide delivery of the active compound.

In cases where the compounds are sufficiently basic or acidic to form stable non-toxic salts with acids or bases, the compounds may be in the form of a veterinarily acceptable salt or an agriculturally acceptable salt. Veterinary acceptable salts include salts derived from veterinary or agriculturally acceptable inorganic or organic bases and acids. Suitable salts include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium, magnesium and barium. Transition metal salts may also be used, including (but not limited to) magnesium, copper, zinc, and iron. In addition, salts containing ammonium cations (NH ₄ ⁺ ), as well as substituted ammonium cations in which one or more hydrogen atoms are replaced by alkyl or aryl groups, are also within the scope of the present invention.

Particularly well suited are salts derived from inorganic acids including, but not limited to, hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable inorganic salts also include, but are not limited to, the bicarbonate and carbonate salts. In some embodiments, examples of veterinary and agriculturally acceptable salts are organic acid salts formed with organic acids, including (but not limited to) maleate, dimaleate, fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Of course, other suitable organic acids can be used.

Salts of the described compounds with alkali metals (eg sodium, potassium or lithium) or alkaline earth metals (eg calcium) can also be prepared by reacting a sufficiently acidic residue of the compounds with an alkali or alkaline earth metal hydroxide.

Veterinary acceptable salts may be prepared by conventional procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with an appropriate sufficiently acidic functional group contained in the compound, or by reacting an appropriate acid with a sufficiently basic functional group of the compound of the present invention.

Methods for obtaining compounds:

In some embodiments, a compound having formula I can be prepared by reacting a compound having formula III:

with a compound having the formula (IV):

in the presence of a coupling agent. Suitable coupling reagents include, but are not limited to, diimide reagents, eg dicyclohexylcarbodiimide, and phosphonium or uronium reagents, eg BOP, PyBOP and/or HBTU, as is known to those skilled in the art.

In some embodiments, a compound having formula (II) can be prepared by reacting a compound having formula III:

with an amine having the formula HNR ^e R ^f in the presence of a coupling reagent such as dicyclohexylcarbodiimide.

In some embodiments, a compound having formula (III) can be obtained by acidic or basic hydrolysis of a compound having formula (V):

In some embodiments, a compound having formula (V) wherein R ¹ is an optionally substituted alkyl, an optionally substituted C ₃ -C ₈ cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted alkylcarbonyl, an optionally substituted alkoxycarbonyl and optionally substituted alkyl-SO _n can be obtained by reacting a compound having formula (VI):

where X is a halogen, preferably Br or I, with a borane having the formula R ¹¹ -BOR ^g OR ^h , where R ¹¹ contains an alkene directly bonded to the borane, and R ^g and R ^h are alkyl or a hydrogen atom, in the presence of palladium(0) catalyst; and then the R ¹¹ group is hydrogenated. In some embodiments, R ¹ -BOR ^g OR ^h may directly react with a compound having formula (VI).

In some embodiments, a compound having formula (V) wherein R ¹ is an amino group, NH-optionally substituted C ₁ -C ₄ alkyl, or NR ^a R ^b , where R ^a and R ^b are independently optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents, may be obtained by a compound reaction having formula (VI), with ammonia, NH ₂ -optionally substituted C ₁ -C ₄ -alkyl or HNR ^a R ^b where R ^a and R ^b independently represent optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may optionally have substituents.

In some embodiments, a compound having formula (VI) may be prepared by reacting a compound having formula (VII):

with a strong base, eg lithium diisopropylamide, and then with a halogenating agent, eg carbon tetrabromide or carbon tetraiodide.

In some embodiments, a compound having formula (VII) can be prepared by reacting a compound having formula (VIII):

where X is halogen, preferably Br or I, with a borane having the formula R ³ -BOR ^g OR ^h , where R ^g and R ^h are alkyl or a hydrogen atom, in the presence of a palladium(0) catalyst.

In some embodiments, a compound having formula (VIII) can be prepared by reacting a compound having formula (IX):

with a halogenating compound, for example PBr ₃ or N-bromosuccinimide, or with N-chlorosuccinimide.

In some embodiments, a compound having formula (IX) may be a compound having formula (IXa), (IXb), or (IXc):

In some embodiments, compound (IXa) or (IXb) can be prepared by a salt reaction having the formula X ⁺ Y ^- where X ⁺ is:

and where Y ^- represents an anionic counterion, with a compound having the formula (XI):

In some embodiments, a compound having formula (IXc) may be prepared by reacting a compound having formula (XI) with a salt having formula Xc ⁺ Y ^- , where Xc ⁺ is:

to obtain a compound having formula XII:

and subsequent reaction of a compound having formula XII under dihydroxylation conditions in a manner known to those skilled in the art, for example, as described in US Patent 4,451,356.

In some embodiments, a compound having formula (I) wherein R ¹ is a cyano group, an optionally substituted alkoxy group, or an optionally substituted aryloxy group may be prepared by reacting a compound having formula (I) where R ¹ is is a halogen, with a cyanide ion, an optionally substituted alkoxide anion, and an optionally substituted aryloxide anion, respectively.

In some embodiments, a compound having formula (I) where R ¹ is halogen can be prepared by reacting a compound having formula (I) where R ¹ is hydroxyl with a halogenating agent, e.g., PBr ₃ , PCl ₃ or Vilsmeier's reagent.

In some embodiments, a compound having formula (I) wherein R ¹ is hydroxyl can be prepared by reacting a salt having formula X ⁺ Y ^- or a salt having formula Xc ⁺ Y ^- with a compound having formula alkylOCOCH ₂ R ³ .

The provisions described above are general and can be adapted by a person skilled in the art.

Veterinary Compositions:

The compound of the present invention and compositions containing said compound can be used to prevent and treat parasitic infestations/infections in animals. Compositions of the present invention contain an effective amount of a compound, or a veterinarily acceptable salt thereof, in combination with a veterinarily acceptable carrier or diluent and, optionally, an inactive auxiliary compound. The compositions may take the form of various solid or liquid formulations suitable for various routes of administration or administration to animals. For example, veterinary compositions containing a compound of the present invention may be in the form of compositions suitable for oral administration, administration by injection, including subcutaneous and parenteral administration, and topical application (for example, topical application or pour-on preparation), dermal or subcutaneous administration. . The compositions are intended for administration to an animal, including (but not limited to) mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other agricultural or domestic mammals. Examples of birds include turkeys, chickens, ostriches, and other farm or domestic birds. The use of a compound of the present invention is particularly useful in protecting companion animals such as dogs and cats from endoparasites.

As described above, the compositions of the present invention may be in a suitable oral form (see, for example, US Patent No. 4,564,631 incorporated herein by reference), nutritional supplements, lozenges, lozenges, chewable tablets, tablets, hard or capsules, boluses, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral infusion compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric compositions or pastes. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and these compositions may contain one or more sweeteners, bitters, flavors, colors, and preservatives to provide pharmaceutically superior and visually appealing formulations.

Tablets may contain the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Such fillers may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binders, such as starch, gelatin or acacia gum, and lubricants, such as magnesium stearate, stearic acid or talc, tablets may be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract, thereby providing prolonged action over a longer period of time. For example, materials to increase the duration of action, such as glyceryl monostearate or glyceryl distearate, can be used. Tablets can also be coated as described in US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 (incorporated herein by reference) to produce controlled release osmotic therapeutic tablets.

Compositions for oral use include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Capsules can also be soft gelatin capsules in which the active ingredient is mixed with water or a water-miscible solvent such as propylene glycol, polyethylene glycols (PEG) and ethanol, or an oily vehicle such as peanut oil, liquid paraffin or olive oil. .

In one embodiment, a compound of the present invention may be administered as soft tablet formulations or soft chewable formulations such as those described in US 2013/0203692 A1, US 2010/0087492, US 2006/0222684, US 2004/0151759, US 7955632, all incorporated into this text by reference. Veterinary compositions may be in the form of soft chewable compositions ("soft gum") that are attractive and acceptable to mammals. In addition to the active ingredient(s), the soft chews of the present invention may include one or more of the following: a solvent or mixture of solvents, one or more excipients, one or more binders, one or more surfactants, one or more humectants, one or more lubricants, one or more disintegrants, one or more colorants, one or more antimicrobial agents, one or more antioxidants, one or more pH modifiers, and one or more flavors.

Solvents that can be used in the compositions of the present invention include, without limitation, various categories of liquid polyethylene glycol (PEG), including PEG 200, PEG 300, PEG 400 and PEG 540; propylene carbonate; propylene glycol; triglycerides, including, but not limited to, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride (e.g. ^MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride, propylene glycol dicaprylate/dicaprate, etc.; water, sorbitol solution , glycerol caprylate/caprate and polyglycosylated glycerides ( ^GELUCIRE® ), or combinations thereof.

Various excipients known in the art may be used in the soft chewable compositions of the invention. Fillers include, but are not limited to, corn starch, pregelatinized corn starch, finely ground soy protein, corn cob meal, corn gluten meal, and the like. In some embodiments, a combination of two or more excipients may be used in the compositions.

Binders that can be used in the compositions of the invention include, but are not limited to, polyvinylpyrrolidone (e.g., povidone), cross-linked polyvinylpyrrolidone (crospovidone), polyethylene glycols of various categories, including PEG 3350, PEG 4000, PEG 6000, PEG 8000, and even PEG 20,000, copolymers of vinylpyrrolidone and vinyl acetate (eg, copovidone) such as those sold by BASF under the trademark ^Kollidon® VA 64 and the like, starch such as potato starch, tapioca starch, and corn starch; molasses, corn syrup, honey, maple syrup and sugars of various types; or a combination of two or more binders.

Humectants that can be used in the compositions include, but are not limited to, glycerol (also referred to herein as glycerol), propylene glycol, cetyl alcohol, or glycerol monostearate, and the like. Polyethylene glycols of various grades can also be used as humectants.

Surfactants may be present in the compositions to improve solubility and absorption after digestion. Surfactants are typically present at a concentration of about 1 to 10% (w/w), more typically about 1 to about 5% (w/w). Examples of surfactants that can be used in the compositions include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, including sorbitol monooleate ( ^Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide (for example, poloxomers such as LUTROL ^® F87, etc.), polyethylene glycol derivatives of castor oils including polyoxyl 35 castor oil ( ^Cremophor® EL), polyoxyl 40 hydrogenated castor oil ( ^Cremophor® RH 40), polyoxyl 60 castor oil ( ^Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL ^® ); glycerol esters including glycerol caprylate/caprate ( ^CAPMUL® MCM), polyglycolized glycerides ( ^GELUCIRE® ), PEG 300 caprylic/capric triglycerides ( ^Softigen® 767), PEG 400 caprylic/capric triglycerides ( ^Labrasol® ), PEG 300 oleic glycerides (Labrafil ^® M-1944CS), PEG 300 linoleic glycerides (Labrafil ^® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl stearate 40 (PEG 1750 monostearate), and the like.

The compositions of the present invention may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are also well known in the formulation art. Antioxidants may be added to the compositions of the invention to inhibit degradation of the active agents. Suitable antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol, etc. P.

The compositions of the present invention may also include one or more lubricants/auxiliaries. In some cases, the lubricant may also act as a solvent, and, accordingly, some components of the original compositions may perform dual functions. Lubricants/auxiliaries include, but are not limited to, polyethylene glycols in various molecular weight ranges including PEG 3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenated vegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil .

Many flavoring agents can be used in the compositions of the invention to improve the palatability of oral veterinary compositions. Preferred flavoring agents are those that are not derived from animal sources. In various embodiments, flavor components derived from fruit, meat (including, but not limited to, pork, beef, chicken, fish, poultry, and the like), vegetables, cheese, bacon, bacon cheese, and/ or artificial flavoring flavors. The flavor component is typically selected based on consideration of the organism that will ingest the soft chew. For example, a horse may prefer an apple flavor component and a dog may prefer a meat flavor component. While flavors derived from non-animal sources are preferred, in some embodiments, natural flavors containing beef or liver extracts and the like can be used, such as stew flavor, artificial beef flavor powder, fried beef flavor, and corned beef flavor supplement, among others.

In another embodiment of the present invention, the active composition may be administered as liquid formulations and may be applied either topically or orally. Liquid formulations are liquid-containing compositions of the present invention and are administered by mouth or throat to an animal, or poured onto the animal's skin or integument.

The compositions of the present invention may also take the form of oil-in-water or water-in-oil emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural phosphatides, eg soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, eg sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, eg polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners, bitters, flavors and/or preservatives.

In one embodiment, the composition of the present invention may be in the form of a microemulsion. Microemulsions are well suited as a liquid carrier. Microemulsions are four component systems containing an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are transparent and isotropic liquids.

Microemulsions consist of stable dispersions of microdroplets of an aqueous phase in an oil phase, or vice versa, microdroplets of an oil phase in an aqueous phase. The size of such microdroplets can be less than 200 nm (from 1000 to 100,000 nm for emulsions). The interfacial film may consist of an alternation of surfactant and co-surfactant molecules which, by reducing the surface tension coefficient, allow the spontaneous formation of a microemulsion.

In one embodiment of the oil phase, the oil phase may be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides, or from triglycerides, or alternatively from mixtures of these compounds. In one embodiment of the oil phase, the oil phase is formed by triglycerides; in another embodiment of the oil phase, the triglycerides are medium chain triglycerides, eg C ₈ -C ₁₀ caprylic/capric triglyceride. In another embodiment, the percentage (v/v) of the oil phase is selected from the group consisting of the following ranges: from about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% (v/v) microemulsion.

The aqueous phase includes, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol or glycerol. In one embodiment of the glycol derivative, the glycol may be propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. In general, the aqueous phase makes up about 1 to about 4% (v/v) of the microemulsion.

Microemulsion surfactants include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolized C ₈ -C ₁₀ glycerides, or polyglyceryl-6-dioleate. In addition to the surfactants listed, co-surfactants include short chain alcohols such as ethanol and propanol.

Some substances are common to the three components discussed above, ie. an aqueous phase, a surfactant and an auxiliary surfactant. However, one skilled in the art may use different materials for each component in a single composition. In one variation of the surfactant/co-surfactant ratio, the ratio of co-surfactant to surfactant is from about 1/7 to about 1/2. In another embodiment, the amount of co-surfactant, the specified ratio is from about 25 to about 75% (v/v) of surfactant and from about 10 to about 55% (v/v) of co-surfactant in the microemulsion.

Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as sucrose, saccharin or aspartame, bitters and flavors may be added to prepare a palatable oral preparation. The described compositions can be preserved by the addition of an antioxidant such as ascorbic acid or other known preservatives.

Aqueous suspensions may contain the active ingredient in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia; dispersing or wetting agents can be natural phosphatides, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids. acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may contain one or more preservatives, for example, ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavors, and one or more sweeteners and/or bitters, such as described above.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents, as well as suspending agents, are already listed above. Additional excipients may also be present, such as sweeteners, bitters, flavors and colors.

Syrups and elixirs may contain sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such compositions may also contain an emollient, preservative, sweetener(s) and/or color(s).

In another embodiment of the present invention, the composition may be in the form of a paste. Examples of pasty formulation options include, but are not limited to, those described in US Patent Nos. 6,787,342 and 7,001,889, both of which are incorporated herein by reference. In addition to the compounds of the present invention, the paste may also contain highly dispersed silicon dioxide; viscosity modifier; carrier; optional, adsorbent; and, optionally, a coloring agent, a stabilizing agent, a surfactant, or a preservative.

In one version of the composition, the composition may be a paste containing the compounds of the present invention, highly dispersed silicon dioxide, viscosity modifier, adsorbent, dye; and a hydrophilic carrier which is a triacetin, a monoglyceride, a diglyceride or a triglyceride.

The paste may also include a viscosity modifier. Suitable viscosity modifiers include, but are not limited to, polyethylene glycols (PEGs) including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerin, propylene glycol, polyoxyethylene (20) sorbitan mono -oleate (polysorbate 80 or Tween 80), and polyoxamers (eg Pluronic L 81); an adsorbent such as magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives; and a colorant including (but not limited to) titanium dioxide, iron oxide, FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of sterile injectable aqueous or oily suspensions. Such a suspension can be prepared according to art-known procedures using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or vehicle, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents suitable for use are water, Ringer's solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol, formal glycerol or polyethylene glycols can also be used. Preservatives such as phenol or benzyl alcohol may be used.

In addition, sterile fatty oils can be used as a solvent or suspending medium. Any brand of fixed oil can be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable compositions.

Compositions for topical, dermal, and subcutaneous use may include, but are not limited to, emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, ready-to-use formulations, spot-on solutions and suspensions, dipping solutions, and sprays. Topical application of an innovative compound or a composition containing at least one innovative compound among other active substances, in the form of a composition for spot application, spraying or pouring, allows absorption of the innovative compositions through the skin and achieves systemic concentration, distribution through the sebaceous glands or over the surface of the skin , providing achievement of desirable concentration on all area of covers. When the compound is distributed through the sebaceous glands, they can act as a reservoir, so that a long-term (up to several months) effect can be achieved. Spot application compositions are typically applied to a localized area constituting an area distinct from the animal as a whole. In one embodiment, the localized area may be the area between the shoulder blades. In another embodiment, it may be a stripe, such as a stripe from the head to the tail of the animal.

Pouring compositions are described in US Patent 6,010,710, which is also incorporated herein by reference. The pour-on formulations may advantageously be oily and typically contain a diluent or carrier, as well as a solvent (eg an organic solvent) for the active ingredient if it is insoluble in the diluent.

Organic solvents that can be used in the present invention include, but are not limited to, acetyl butyl citrate, fatty acid esters such as dimethyl ether, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, ethyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, triacetin, C ₁ -C ₁₀ esters of carboxylic acids such as butyl or octyl acetate, and diethyl phthalate, or a mixture of at least two of these solvents.

The solvent is used in proportion to the concentration of the active substance and its solubility in this solvent. The smallest possible volume should be used. The carrier makes up the remaining up to 100% amount.

Carriers or diluents for these compositions may include dimethyl sulfoxide (DMSO), glycol derivatives such as, for example, propylene glycol, glycol ethers, polyethylene glycols or glycerin. As a carrier or diluent, vegetable oils can also be mentioned, such as (but not limited to) soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, mineral oils such as (but not limited to) petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or, alternatively, for example, medium chain (such as C ₈ - C ₁₂ ) triglycerides.

In another embodiment of the present invention, a softener and/or a spreader and/or a film former may be added. In one embodiment, the softener and/or spreader and/or film-forming agent may be:

(a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate-vinylpyrrolidone copolymers, polyethylene glycols, benzyl alcohol, mannitol, glycerin, sorbitol, polyoxyethylene sorbitan esters, lecithin, sodium carboxymethyl cellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example containing silanol functional groups, or 45V2 oil,

(b) anionic surfactants such as alkali metal stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (eg sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (for example, coconut oil derivatives),

(c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N ⁺ R'R"R"'R""Y ^- , in which the radicals R are optionally hydroxylated hydrocarbon radicals, and Y ^- is a strong acid anion, such as halide, sulfate and sulfonate anions; among suitable cationic surfactants is also cetyltrimethylammonium bromide,

(d) amine salts of the formula N ⁺ R'R"R'" wherein the R radicals are, if desired, hydroxylated hydrocarbon radicals; among suitable cationic surfactants is also octadecylamine hydrochloride,

(e) nonionic surfactants such as esters of sorbitan, which are optionally polyoxyethylenated (eg polysorbate 80), polyoxyethylene alkyl ethers; polyoxypropylene fatty alcohols such as polyoxypropylene styrene ether; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, ethylene oxide-propylene oxide copolymers,

(f) amphoteric surfactants such as substituted lauryl compounds of betaine, and

(g) a mixture of at least two of the listed agents.

In one embodiment, the amount of softener is about 0.1 to 50%, or 0.25 to 5%, by volume. In another embodiment, the amount of softener is from about 0.1% to about 30%, from about 1% to about 30%, from about 1% to about 20%, or from about 5% to about 20%, by volume.

In another embodiment of the present invention, the compositions may be a ready-to-use solution as described, for example, in U.S. Patent no. 6,395,765, which is incorporated herein by reference. In addition to the compounds of the present invention, the ready-to-use solution may contain a crystallization inhibitor, an organic solvent or an organic co-solvent. In some embodiments, water may be included along with the organic solvent.

In various embodiments, implementation of the present invention, the compositions may include a crystallization inhibitor in an amount of from about 1 to about 50% (w/v) or from about 5 to about 40% (w/v) based on the total weight of the composition. In other embodiments, the amount of crystallization inhibitor in the novel compositions can be from about 1% to about 30%, from about 5% to about 20%, from about 1% to about 15%, or from about 1% to about 10% ( weight/weight). The type of crystallization inhibitor used in the innovative compositions is not limited, provided that it inhibits the crystallization of active or inert substances from the formulation. For example, in some embodiments, implementation of the present invention, the solvent or co-solvent in the composition can also act as a crystallization inhibitor, if it sufficiently inhibits the formation of crystals after the introduction of the composition.

Crystallization inhibitors that can be used in the present invention include (but are not limited to):

(a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate-vinylpyrrolidone copolymers, polyethylene glycols, benzyl alcohol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, sorbitol, or polyoxyethylene esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as acrylates or methacrylates or polymers or copolymers thereof, polyethylene glycols (PEG) or polymers containing polyethylene glycols such as glycofurols and the like, and others;

(b) anionic surfactants such as alkali metal stearates (eg sodium, potassium or ammonium stearates); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include (but are not limited to) sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids (like coconut oil),

(c) cationic surfactants, such as water-soluble quaternary ammonium salts of the formula N ⁺ R'R"R"'R""Y ^- , in which the R radicals are the same or different, if desired, hydroxylated hydrocarbon radicals, and Y ^- is a strong anion acids such as halide sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants suitable for use,

(d) amine salts of the formula N ⁺ R'R"R'", in which the R radicals are the same or different, if desired, hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one suitable cationic surfactant for use;

(e) nonionic surfactants, such as, if desired, polyoxyethylene esters of sorbitan, for example polysorbate 80, or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, or copolymers of ethylene oxide and propylene oxide;

(f) amphoteric surfactants such as substituted lauryl compounds of betaine, or

(g) a mixture of at least two of the compounds listed in points (a)-(f) above, or

(h) an organic solvent or mixture of solvents that inhibits the formation of crystals or amorphous solids after administration of the composition.

In one embodiment of the crystallization inhibitor, a pair of inhibitors may be used. Such pairs include, for example, a combination of a polymer type film former and a surfactant. These agents may be selected from the compounds listed above as crystallization inhibitors.

In some embodiments, the organic solvent(s) may have a dielectric constant from about 10 to about 35, or from about 20 to about 30. In other embodiments, the organic solvent may have a dielectric constant from about 10 to about 40, or from about 20 up to about 30. The content of the organic solvent or mixture of solvents in the composition is not limited, and it is present in an amount sufficient to dissolve the target components at the desired concentration. As discussed above, the organic solvent may also play the role of a crystallization inhibitor in the composition.

In some embodiments, one or more organic solvents may have a boiling point below about 100°C, or below about 80°C. In other embodiments, the organic solvent(s) may have a boiling point below about 300°C, below about 250°C, below about 230°C, below about 210°C, or below about 200°C.

In some embodiments, when a mixture of solvents is present, i. solvent and co-solvent, the solvents may be present in the composition in a weight/weight ratio of from about 1/50 to about 1/1. Typically, the solvents are present in a ratio of about 1/30 to about 1/1, about 1/20 to about 1/1, or about 1/15 to about 1/1 by weight. Preferably, the two solvents are present in a weight/weight ratio of about 1/15 to about 1/2. In some embodiments, at least one of the solvents present may improve the solubility of the active ingredient or act as a drying accelerator. In private embodiments, at least one of the solvents is miscible with water.

The composition may also contain an antioxidant designed to inhibit oxidation in air, and this antioxidant may be present in an amount of from about 0.005 to about 1% (w/v), from about 0.01 to about 0.1%, or from about 0.01 to about 0.05%.

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

In one embodiment of surfactants, these substances include (but are not limited to) substances made from nonionic surfactants; in another embodiment of surfactants, these substances are polyoxyethylene sorbitan ester. In another embodiment of surfactants, these substances include various grades of polysorbate, such as Polysorbate 80.

In another embodiment of the present invention, the film-forming agent and surfactant may be present in similar or equal amounts, within the limits of the total amount of crystallization inhibitor indicated above.

The crystallization inhibitor inhibits the formation of crystals on the integument and improves the cosmetic appearance of the skin or fur; without creating a sticky feeling or sticky appearance, despite the high concentration of the active ingredient. Substances other than those mentioned herein can also be used as crystallization inhibitors in the present invention. In one embodiment, the effectiveness of a crystallization inhibitor can be demonstrated by a test in which 0.3 ml of a solution containing 10% (w/v) of the active substance in the above appropriate solvent and 10% (w/v) of the compound acting as a crystallization inhibitor , placed on a glass plate at 20° C. for 24 hours, after which less than 10 crystals, preferably 0 crystals, are visible to the naked eye on the glass surface.

In one embodiment of antioxidants, these agents are known in the art and include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or a mixture of at least two compounds having antioxidant properties.

Formulation auxiliaries are well known to those of skill in the art and can be purchased from commercial suppliers or prepared by known methods. The concentrated compositions described are generally prepared by simply mixing the components described above; preferably, the starting point is the mixing of the active substance with the main solvent, followed by the addition of other ingredients or excipients.

The volume of the composition used depends on the type of animal, the size of the animal, as well as the strength of the composition and the activity of the active substances. In one embodiment, an amount of about 0.1 to about 20 ml of the composition can be applied to a mammal. In another embodiment, the volume may be from about 0.1 to about 10 ml, from about 0.1 to about 5 ml, from about 0.5 ml to about 10 ml, or from about 0.3 to about 3 ml.

In another embodiment of the present invention, application of the spot application composition of the present invention may also provide a long lasting broad spectrum effect when the solution is applied to an animal or bird. Spot application compositions provide topical application of a concentrated solution, suspension, microemulsion, or intermittent emulsion to a specific area of the animal, usually between two arms (spot solution).

In the case of spot application compositions, the carrier may be a liquid carrier as described in US Patent 6,426,333 (incorporated herein by reference), which in one embodiment of the topic application composition may contain a solvent or mixture of solvents, including (but not limited to them) acetone, an aliphatic alcohol such as methanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol, heptanol, octanol, nonanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, and the like; an aromatic alcohol such as phenol, cresol, naphthol, benzyl alcohol, and the like; acetonitrile, butyl diglycol, an organic amide such as dimethylacetamide, dimethylformamide, monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone, and the like; propylene or ethylene carbonate, dimethyl sulfoxide (DMSO), polymer glycol or its ether, such as various grades of polyethylene glycol (PEG), various grades of polypropylene glycols, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, diethylene glycol monoethyl an ether, ethylene glycol, diethyl phthalate, fatty acid esters such as diethyl or diisobutyl adipate, or a mixture of at least two of these solvents.

The liquid carrier may optionally contain a crystallization inhibitor, including (but not limited to) those described in paragraphs (a)-(h) above, or a compound that can simultaneously act as a solvent and a crystallization inhibitor (as described above), or a mixture of these inhibitors crystallization.

Topical compositions can be prepared by dissolving the active ingredients in a pharmaceutically or veterinarily acceptable carrier. Alternatively, a topical composition may be prepared by encapsulating the active ingredient so that the remainder of the therapeutic agent remains on the integument of the animal. The composition of such compositions may vary with respect to the content of the therapeutic agent in combination, depending on the species of animal being treated, the degree and type of infection, and the weight of the animal.

Dosage forms typically contain from about 0.1 mg to about 5 g of the active ingredient. In other embodiments, the dosage form may contain from about 0.5 mg to about 5 g of the active ingredient. In one dosage form, the dosage may be from about 1 mg to about 500 mg of the active ingredient, 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 mg.

In one embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.05 to about 10% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.1% to about 2% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of from about 0.25 to about 1.5% w/v. In another embodiment of the present invention, the active ingredient may be present in the composition at a concentration of about 1% w/v.

II. Treatment methods:

As described above, the compound of the present invention is effective against endoparasites and can be used to treat or prevent parasitic infections in or on animals. In one embodiment, the present invention describes a method of treating or preventing an endoparasitic infection in or on an animal body (e.g., a mammal or bird), comprising administering to the animal an endoparasitically effective amount of a compound having formula (I), or veterinarily acceptable salts thereof, or compositions of the present invention.

The compound of the present invention is also effective against ectoparasites and can be used to treat or prevent infestation of animals with ectoparasites. In another embodiment, the present invention describes a method of treating or preventing an infestation of an animal (e.g., a mammal or a bird) with ectoparasites, comprising administering to the animal an ectoparasiticidally effective amount of a compound having formula (I), or veterinarily acceptable salts thereof, or a composition of the present invention.

In another embodiment, the present invention describes a method of treating or preventing an endoparasitic infection in the body of animals or on their integument, or preventing infection of animals with ectoparasites, comprising administering to a mammal a composition containing an effective amount of a compound having formula (I), in combination with an effective amount of at least one second active ingredient, or a veterinarily acceptable salt thereof.

In another embodiment of the present invention, a method for treating or preventing infestation in a lesion is described which comprises administering or applying to the lesion a parasiticide effective amount of a compound having formula (I) or a veterinarily acceptable salt thereof. In the context of animal health, "locus" means a habitat, breeding area, area, material or environment in which a parasite grows or may grow, excluding the body of an animal or its integument.

In another embodiment, the present invention describes methods and uses of a compound of the present invention to control plant or cereal pests, or to protect tree-containing structures.

Mammals that may be treated include, but are not limited to, humans, cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep, and yaks. In one embodiment of the present invention, the treated animals are humans, cats or dogs.

In one embodiment of the present invention, the compound of the present invention has improved efficacy against endoparasites, and in particular against endoparasites resistant to active substances from the class of macrocyclic lactones. In one embodiment, the compounds and compositions of the present invention are effective against Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds.

In another embodiment, the present invention describes a method of treating a parasitic infection or infestation in an animal, comprising administering an effective amount of an anthelmintic compound of the present invention in combination with an effective amount of invertebrate GABA receptor activators, including avermectin or milbemycin, to a mammal in need thereof. Avermectins that can be used in combination with the compounds of the present invention include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Milbemycins that can be used in combination with the compounds of the present invention include, but are not limited to, milbemictin, milbemycin D, moxidectin, and nemadctin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.

In one embodiment, the compounds and compositions of the present invention can be used to treat or prevent endoparasitic infection of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus , Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris , Schistosoma, Strongylus, Taenia , Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus, Uncinaria, Wuchereria, and combinations thereof.

In a particularly preferred embodiment of the present invention, the compounds and compositions of the present invention are used to treat or prevent Dirofilaria immitis infection. The compound of the present invention has been found to be highly effective against microfilariae and L4 larvae of D. immitis. Thus, the compound of the present invention can be used to protect animals from developing heartworm disease by killing the immature stages of D. immitis before they develop into mature worms. In one embodiment, a compound of the present invention and compositions containing these compounds can be used to prevent the development of heartworm disease by eradicating immature stages of D. immitis resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are used to treat or prevent infection with Dirofilaria repens or Dirofilaria hongkongensis.

In another embodiment of the present invention, the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, and combinations thereof.

In another treatment option against endoparasites and ectoparasites, when combined with ectoparasiticidal agents, the ectoparasite is one or more insects or arachnids, including members of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola.

In another treatment option against endoparasites and ectoparasites, when combined with ectoparasiticidal agents, the ectoparasite is one or more insects or arachnids, including members of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola.

In another embodiment of treating ectoparasites, the ectoparasite is from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and/or Boophilus. Ectoparasites treated include, but are not limited to, fleas, parasitiform mites, acariform mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp., and the like), parasitiform mites (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp., and the like). ), and mites (Demodex sp., Sarcoptes sp., Otodectes sp., etc.), lice (Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.), mosquitoes (Aedes spp. , Culex spp., Anopheles spp., etc.) and flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.). In another embodiment of the treatment of ectoparasites, the ectoparasite is a flea and/or a tick.

Additional examples of ectoparasites include, but are not limited to, the tick genus Boophilus, especially microplus (ringed tick), decoloratus, and annulatus species; myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (green carrion); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as the carrion fly in Australia, New Zealand and South Africa), flies proper, namely those whose adult forms are parasitic, such as Haematobia irritans (small cow's stallion); lice such as Linognathus vituli and the like; and acariform mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be dangerous to animals and humans. They include, for example, migrating Diptera larvae.

In another embodiment of the present invention, the compounds and compositions of the present invention are suitable for controlling pests selected from the group consisting of Blatella germanica, Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitum, and combinations thereof.

Phytoparasitic nematodes include, for example, species of the genera Anguina, Aphelenchoides, Belonoaimus, Bursaphelenchus, Ditylenchus dipsaci, Globodera, Heliocotylenchus, Heterodera, Longidorus, Meloidogyne, Pratylenchus, Radopholus similis, Rotylenchus, Trichodorus, Tylenchorhynchus, Tylenchulus, Tylenchulu s semipenetrans and Xiphinema.

In addition, with or without the addition of other pesticides to the composition, the present invention can also be used to control other pests, which include (but are not limited to) the following pests:

(1) from the order Isopoda, such as Oniscus asellus, Armadillidium vulgare and Porcellio scaber;

(2) from the order Diplopoda, such as Blaniulus guttulatus;

(3) from the order Chilopoda, such as Geophilus carpophagus and Scutigera spp.;

(4) from the order Symphyla, eg Scutigerella immaculata;

(5) from the order Thysanura, eg Lepisma saccharina;

(6) from the order Collembola, such as Onychiurus armatus;

(7) from the order Blattaria, such as Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica;

(8) from the order Hymenoptera, for example, species of the genera Diprion, Hoplocampa, Lasius, Monomorium pharaonis and Vespa;

(9) from the order Siphonaptera, eg Xenopsylla cheopis and species of the genera Ceratophyllus;

(10) from the order Anoplura (Phthiraptera), for example, species of the genera Damalinia, Haematopinus, Linognathus, Pediculus, Trichodectes;

(11) from the class Arachnida, e.g. Acarus siro, Aceria sheldoni, species of the genera Aculops, Aculus, Amblyomma, Argas, Boophilus, Brevipalpus, Bryobia praetiosa, Chorioptes, Dermanyssus gallinae, Eotetranychus, Epitrimerus pyri, Eutetranychus, Eriophyes, Hemitarsonemus, Hyalomma, Ixodes, Latrodectus mactans, Metatetranychus, Oligonychus, Ornithodoros, Panonychus, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes, Rhipicephalus, Rhizoglyphus, Sarcoptes, Scorpio maurus, Stenotarsonemus, Tarsonemus, Tetranychus, Vasates lycopersici;

(12) from the class Bivalva, for example, species of the genus Dreissena;

(13) From the Coleoptera detachment, for example, Acanthoscelides Obtectus, Types of Birth Adoretus, Agelastica Alni, Agriotes, Amphimallon Solstitialis, Anobium Punstatum, Anoplophora, Anthonomus, Anthrenus, A Anthrenus, A Pogonia, Atomaria, Attagenus, Bruchidius Obtectus, Bruchus, Ceuthorhynchus, Cleonus Mendicus, Conoderus , Cosmopolites, Costelytra zealandica, Curculio, Cryptorhynchus lapathi, Dermestes, Diabrotica, Epilachna, Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus, Lachnosterna consanguinea, Leptinotarsa decemlineata , Lissorhoptrus oryzophilus, Lixus, Lyctus, Meligethes aeneus, Melolontha melolontha, Migdolus, Monochamus, Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Popillia japonica, Premnotry pes, Psylliodes chrysocephala, Ptinus, Rhizobius ventralis, Rhizopertha dominica , Sitophilus, Sphenophorus, Sternechus, Symphyletes, Tenebrio molitor, Tribolium, Trogoderma, Tychius, Xylotrechus, Zabrus;

(14) from the order Diptera, e.g., species of the genera Aedes, Anopheles, Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia, Cochliomyia, Cordylobia anthropophaga, Culex, Cuterebra, Dacus oleae, Dermatobia hominis, Drosophila, Fannia, Gastrophilus, Hylemyia, Hyppobosca , Hypoderma, Liriomyza, Lucilia, Musca, Nezara, Oestrus, Oscinella frit, Pegomyia hyoscyami, Phorbia, Stomoxys, Tabanus, Tannia, Tipula paludosa, Wohlfahrtia;

(15) from the class Gastropoda, for example, species of the genera Arion, Biomphalaria, Bulinus, Deroceras, Galba, Lymnaea, Oncomelania, Succinea;

(16) from the class of helminths, e.g. Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, species of the genera Ancylostoma, Ascaris lubricoides, Ascaris, Brugia malayi, Brugia timori, Bunostomum, Chabertia, Clonorchis, Cooperia, Dicrocoelium Dictyocaulus filaria, Diphyllobothrium latum, D racunculus medinensis , Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola, Haemonchus, Heterakis, Hymenolepis nana, Hyostrongulus, Loa Loa, Nematodirus, Oesophagostomum, Opisthorchis, Onchocerca volvulus, Ostertagia, Paragonimus, Schistosomen, Strongyloides fuelleborni, Strongyloides stercoralis, Stronyloides, Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus, Trichuris trichuria, Wuchereria bancrofti;

(17) from the order Heteroptera, e.g. Anasa tristis, species of the genera Antestiopsis, Blissus, Calocoris, Campylomma livida, Cavelerius, Cimex, Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus, Euschistus, Eurygaster, Heliopeltis, Horcias nobilellus, Leptocorisa, Leptoglossus phyllopus, Lygus, Macropes excavatus, Miridae, Nezara, Oebalus, Pentomidae, Piesma quadrata, Piezodorus, Psallus seriatus, Pseudacysta persea, Rhodnius, Sahlbergella singularis, Scotinophora, Stephanitis nashi, Tibraca, Triatoma;

(18) from the order Homoptera, e.g., species of the genera Acyrthosipon, Aeneolamia, Agonoscena, Aleurodes, Aleurolobus barodensis, Aleurothrixus, Amrasca, Anuraphis cardui, Aonidiella, Aphanostigma piri, Aphis, Arboridia apicalis, Aspidiella, Aspidiotus, Atanus, Aulacorthum solani, Bemisia, Brachycaudus helichrysii, Brachycolus, Brevicoryne brassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes, Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coc comytilus halli, Coccus, Cryptomyzus ribis, Dalbulus, Dialeurodes , Diaphorina, Diaspis, Doralis, Drosicha, Dysaphis, Dysmicoccus, Empoasca, Eriosoma, Erythroneura, Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis, Icerya, Idiocerus, Idioscopus, Laodelphax striatellus, Lecanium, Lepidosaphes, Lip aphis erysimi, Macrosiphum, Mahanarva fimbriolata, Melanaphis sacchari, Metcalfiella, Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzus, Nasonovia ribisnigri, Nephotettix, Nilaparvata lugens, Oncometopia, Orthezia praelonga, Parabemisia myricae, Paratrioza, Parlatoria, Pemphigus, Peregrinus maidis, Phenacoccus, Phloeomyzus passerinii, Phorodon humuli , Phylloxera, Pinnaspis aspidistrae, Planococcus, Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus, Psylla, Pteromalus, Pyrilla, Quadraspidiotus, Quesada gigas, Rastrococcus, Rhopalosiphum, Saissetia, Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata, Sogatella furcifera, Sogatodes, Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis, Toxoptera, Trialeurodes vaporariorum, Trioza, Typhlocyba, Unaspis, Viteus vitifolii;

(19) from the order Isoptera, for example, species of the genera Reticulitermes, Odontotermes;

(20) from the order Lepidoptera, e.g. Acronicta major, Aedia leucomelas, species of the genera Agrotis, Alabama argillacea, Anticarsia, Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo, Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus, Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa, Feltia, Galleria mellonella, Helicoverpa, Heliothis, Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella, Laphygma, Lithocolletis blancardella, Lithophane antennata, Loxagro tis albicosta, Lymantria, Malacosoma neustria, Mamestra brassicae, Mocis repanda, Mythimna separata, Oria, Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris, Plutella xylostella, Prodenia spp., Pseudaletia, Pseudoplusia includens, Pyrausta nubilalis, Spodoptera, Thermesia gemmatalis , Tinea pellionella, Tineola bisselliella , Tortrix viridana, Trichoplusia;

(21) from the order Orthoptera, e.g. Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, species of the genera Locusta, Melanoplus, Periplaneta americana, Schistocerca gregaria.;

(22) from the order Thysanoptera, eg Baliothrips biformis, Enneothrips flavens, species of the genera Frankliniella, Heliothrips, Hercinothrips femoralis, Kakothrips, Rhipiphorothrips cruentatus, Scirtothrips, Taeniothrips cardamoni, Thrips;

(23) from the class Protozoa, for example, species of the genus Eimeria.

In each aspect of the present invention, the compounds and compositions of the present invention may be used against a single pest or a combination thereof.

III. Mixtures with other active ingredients

In another embodiment, compositions containing cyclic depsipeptides having formula (I) may also include other veterinary therapeutic agents. Veterinary pharmaceutical agents that can be included in the compositions of the present invention are well known in the art (see, for example, Plumb' Veterinary Drug Handbook, ^5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, ^9th Edition, (January 2005)) and include (but are not limited to) acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitrecin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, potassium clavulanate, amphotre Cin B deoxycholate, lipid-based amphotrecin B , ampicillin, amprolium, antacids (oral), antivenin, apomorphion, apramycin sulfate, ascorbic acid, aspraginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, a zithromycin, baclofen, barbiturates, benazepril, betamethasone, betanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromides, bromocriptine mesylate, budenoside, buprenorphine, busiron, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril , carbenicillin indanyl sodium , carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon. cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cefapirin, activated charcoal, chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinium bromide, chlorthiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (hCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam, clonidine, c loprostenol sodium, dipotassium clorazepate, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropine, cyclophosphamide, cyclosporine, cycloheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, de slorelin acetate , desmopressin acetate, deoxycortioxterone pivalate, detomidine, dexamethasone, dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (D HT), diltiazem, dimenhydrinate, dimercaprol/BAL, dimethylsulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, disodium calcium edate, calcium EDTA, edrophonium chloride , enalapril /enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/sodium ethacrynate, ethanol (alcohol), sodium etidronate, etodolac, etomidate, euthanasia with pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepisol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerol (oral), glycopyrro lat, gonadorelin , grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (oxyglobin®), heparin, hydroxyethyl starch, sodium hyaluronate, hydrazalin, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, impenem-cilastat in sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, levprolide, levamisole, levitiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, m eclofenamic acid, medetomidine , medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate/hippurate, methimazole, methionine, methocarbamol, methohexital sodium, metho treksat, methoxyflurane, methylene blue , methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxol, mexiletine, mibolerlon, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic (opiate) ) agonistic analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium, oxaz epam, oxybutynin chloride, oxymorphone , oxytetracycline, oxytocin, disodium pamidronate, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, penicillamine, well-known penicillins, penicillin g, penicillin V potassium, pentazocine, sodium pentobarbital, sodium pentosan polysulfate, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, sodium phenytoin, pheromones, parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone/prednisone, primidone, procainamide, procarbazine, Prochlorperazine, Propantheline Bromide, Acne Propionobacteria Injection, Propofol, Propranolol, Protamine Sulfate, Pseudoephedrine, Psyllium Bulk Laxative, Pyridostigmine Bromide, Pyrylamine Maleate, Pyrimethamine, Quinacrine, Quinidine, Ranitidine, Rifampin, s-Adenosyl Methionine (SAMe), Ph. solution /hyperosmotic laxative, selamectin, selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin , succimer, succinylcholine chloride, sucralfate, sufentanyl citrate, sulfachloropyridazine sodium, sulfadiazine/trimetroprim, sulfamethoxazole/trimethoprim, sulfadimentoxin, sulfadimentoxin/ormethroprim, sulfasalazine, taurine, tepoxalin, terbinaflin, terbutaline sulfate, testosterone, tetracycline, thiabedazole, thiacetarsamide sodium, thiamine, thioguanine, sodium thiopental, thiotepa, thyrotropin, tiamulin, ticarcilin disodium, tiletamine/zolazepam, tilmoxin, thiopronin, tobramycin sulfate, tocainide, tolazolone, telfenamic acid, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxine tar spending with prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisami d and their mixtures.

In one embodiment of the present invention, arylpyrazole compounds, such as phenylpyrazoles, can be included in the veterinary compositions of the present invention. Arylpyrazoles are known in the art and are suitable for combination with cyclic depsipeptides having formula (I) in the compositions of the present invention. Examples of such arylpyrazole compounds include (but are not limited to) those described in US Patents 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954, 6,998,131 and 7,759,381 (all incorporated herein by reference). A particularly preferred arylpyrazole active ingredient is fipronil.

In another embodiment of the present invention, one or more macrocyclic lactones that function as an acaricide, anthelmintic and/or insecticide can be included in the compositions of the present invention in combination with a compound of the present invention. For the avoidance of doubt, the term "macrocyclic lactone" as used herein includes both natural and synthetic or semi-synthetic avermectin and milbemycin.

Macrocyclic lactones that can be used in the compositions of the present invention include, but are not limited to, natural avermectins (for example, including components designated as A ₁ a, A ₁ b, A ₂ a, A ₂ b, B ₁ a, B ₁ b, B ₂ a and B ₂ b) and milbemycins, semi-synthetic avermectins and milbemycins, monosaccharide avermectins and aglycone avermectins. Examples of macrocyclic lactone compounds that can be used in the compositions of the present invention include (but are not limited to) abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ml-1,694,554, and milbemycins, including (but not limited to) milbemectin, milbemycin D, milbemycin A ₃ , milbemycin A ₄ , milbemycin oxime, moxidectin, and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.

Macrocyclic lactones are known in the art and can be readily obtained from commercial sources or by known synthetic methods. Technical and commercial literature on the subject is widely available. For avermectins, ivermectin and abamectin, for example, the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., or Albers-Schönberg et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. In the case of doramectin, the work "Veterinary Parasitology", vol. 49, no. 1, July 1993, 5-15. In the case of milbemycins, reference may be made, among others, to Davies H.G. et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synhesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US Pat. links.

The structures of avermectins and milbemycins are closely related, for example they all contain a complex 16-membered macrocyclic lactone ring. Natural avermectins are described in US Patent 4,310,519 and 22,23-dihydro avermectin compounds are described in US Patent 4,199,569. It should also be mentioned, among others, US patents 4,468,390, 5,824,653, EP 0 007 812 A1, British patent 1 390 336, EP 0 002 916, and New Zealand Patent 237 086. Natural Milbemicins are described in the US patent 3.950.360, as well as in numerous publications cited in “The Merck Index” ^12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in “International Nonproprietary Names for Pharmaceutical Substances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in US Patents 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569 , 5,055,596, 4,973,711, 4,978,677, 4,920,148, and in EP 0 667 054 , all incorporated herein by reference.

In one embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of the following: abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin A ₃ , milbemycin A ₄ , milbemycin oxime, moxidectin and nemadectin, or combinations thereof. In another embodiment, the present invention describes a veterinary composition containing an effective amount of at least one of the following substances: abamectin, emamectin, eprinomectin, ivermectin, doramectin and selamectin, or combinations thereof. In another embodiment, the veterinary compositions of the present invention contain an effective amount of at least one of the following: ivermectin, milbemectin, milbemycin oxime, or moxidectin, or combinations thereof.

In one embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of the following: abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin A ₃ , milbemycin A ₄ , milbemycin oxime, moxidectin and nemadectin, or combinations thereof. In another embodiment, the present invention describes a veterinary composition containing an effective amount of at least one of the following substances: abamectin, emamectin, eprinomectin, ivermectin, doramectin and selamectin, or combinations thereof. In another embodiment, the veterinary compositions of the present invention contain an effective amount of at least one of the following: ivermectin, milbemectin, milbemycin oxime, or moxidectin, or combinations thereof.

In some embodiments, the compositions of the present invention may include one or more anti-nematode agents, including (but not limited to) active substances from the classes of benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organic phosphates. In some embodiments, the compositions may include benzimidazoles, including (but not limited to) thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and its o,o-dimethyl analogs .

In other embodiments, the compositions may include imidazothiazole compounds, including (but not limited to) tetramizole, levamisole, and butamisole.

In other embodiments, the compositions of the present invention may include tetrahydropyrimidine active compounds, including (but not limited to) pyrantel, oxanthel and morantel.

Suitable organophosphate active compounds include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalophos and dichlorphos, heptenophos, mevinphos, monocrotophos, tetraethyl pyrophosphate, and tetrachlorvinphos.

In other embodiments, the compositions may include the antinematode compounds phenothiazine, piperazine as neutral compounds and as various salts, diethylcarbamazine, phenols such as disophenol, arsenic compounds such as arsenamide, ethanolamines such as bephenia, tenium closylate and methyridine; cyanine dyes including pyrvinium chloride, pirvinium pamoate and dithiazanin iodide, isothiocyanates including bitoscanate, sodium suramin, phthalofin, and various natural substances including (but not limited to) hygromycin B, α-santonine and kainic acid.

In other embodiments, the compositions of the present invention may include anti-trematode agents. Suitable anti-trematodose agents include, but are not limited to, miracils such as miracil D and mirazan, praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, gycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenolic compounds known in the art. the art, including hexachlorophene, bithionol, bithionol sulfoxide, and menichlorofolane; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide, and closantel; triclabendazole, diamphenetide, clorsulon, getolin and emetine.

The compositions of the present invention may also usefully employ anticestodotic agents including, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin, paromomycin II, praziquantel, and epsiprantel.

In other embodiments, the compositions of the present invention may include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclene, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothione, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthione, diemtoate, dioxathion, ethion , famfur, fenitrothion, fenthion, phosphopyrate, iodophenphos, malathion, naled, fosalon, phosmet, phoxim, propetamphos, ronnel, styrophos, alletrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucitrinate, permethrin, phenothrin, pyrethrins, resmethrin, ben zylbenzoate, disulfide carbon, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornylthiocyanatoacetate, methoprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DETA, dimethyl phthalate and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)- dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl- 2,5-pyridine dicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

In another embodiment, the antiparasitic agent that can be included in a veterinary composition containing a compound having formula (I) may be a biologically active peptide or protein, including (but not limited to) depsipeptides other than the compound of the present invention. They include PF1022A or its equivalents, and emopeside. These compounds work at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of the parasites. In one embodiment of the depsipeptide, the depsepeptide is an emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

In another embodiment, the compositions of the present invention may contain an active ingredient from the neonicotinoid class of parasiticides. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be combined with a compound having formula (I) in a composition of the present invention is imidacloprid. Means from this class are described, for example, in US Patent 4,742,060 or in EP 0 892 060 (both incorporated herein by reference). In another embodiment, the compositions of the present invention may contain nitenpyram, another active ingredient in the neonicotinoid class of pesticides. The use of nitenpyram in flea control is described in US Pat. No. 5,750,548, which is incorporated herein by reference in its entirety.

In some other embodiments of the present invention, cyclic depsipeptides having formula (I) can be combined with compositions of the present invention containing semicarbazone, such as metaflumizone.

In another embodiment, the compositions of the present invention may preferably contain a mixture of one or more other isoxazoline compounds known in the art, in addition to or instead of the isoxazoline active ingredients described above. Isoxazoline active ingredients are highly effective against various ectoparasites and combination with cyclic depsipeptides of formula (I) would broaden the spectrum of effectiveness against these parasites. Particularly preferred isoxazoline active ingredients that can be combined with a compound of the present invention include afoxolaner (including the substantially pure active enantiomer), sarolaner, fluralaner (including the substantially pure active enantiomer) and lotilaner. These active substances are described in US7,964,204, US 2010/0254960 A1, US2011/0159107, US2012/0309620, US2012/0030841, US2010/0069247, WO 2007/125984, WO 2012/086462, US 8318757, US 8466115, US 8618126, US 8822466, US8383659, US8853186, US 9221835, US 2011/0144349, US 8,053,452; US 2010/0137612, US 8410153, US 2011/152081, WO 2012/089623, WO 2012/089622, US 8,119,671; US 7,947,715; WO 2102/120135, WO 2012/107533, WO 2011/157748, US 2011/0245274, US 2011/0245239, US 2012/0232026, US 2012/0077765, US 2012/0035122, US 2011/0251247, WO 2011/154433, WO 2011/154434, US 2012/0238517, US 2011/0166193, WO 2011/104088, WO 2011/104087, WO 2011/104089, US 2012/015946, US 2009/0143410, WO 2007/123855 A2, US 2011/0118212 . 2010/003923, WO2010/003877, WO 2010/072602, WO 2014/134236, US 7897630 and U.S. 7951828, which are all incorporated herein in their entirety by reference.

In another embodiment of the present invention, nodulisporic acid and its derivatives can be added to the compositions of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in US Patent Nos. The compositions may include one or more nodulisporic acid derivatives known in the art, including all stereoisomers such as those described in the literature cited above.

In another embodiment, anthelmintic compounds from the aminoacetonitrile (AAD) class such as monepantel (ZOLVIX) and the like can be added to the compositions of the present invention. These compounds are described, for example, in US Patent 7,084,280 issued by Ducray et al. (incorporated herein by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13 March 2008, 176-181.

The compositions of the present invention may also include aryloazol-2-yl cyanoethylamine compounds such as those described in U.S. Patent 8,088,801 to Soll et al., which is incorporated herein by reference, and thioamide derivatives of these compounds as described in U.S. Patent 7,964,621 to Soll et al. Le Hir de Fallois, which is also incorporated herein by reference. Arylazol-2-yl cyanoethylamine active ingredients which have a systemic effect against endoparasites can be used in combination with the compound of the present invention in the veterinary compositions of the present invention.

Compositions of the present invention may also include parahercamides and derivatives of these compounds, 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 is a known class of compounds that contain a spirodioxepinoindole core with activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492 ). In addition, a structurally related family of marcfortines, such as marcfortines A-C, are also known and can be combined with the compositions of the present invention (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977 ). Further information on paraherquamid derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432 and US 2010/0197624, US Patent 5,703,078 and US Patent 5,750,69 5 who all are incorporated herein in their entirety by reference.

In another embodiment of the present invention, the compositions may include a spinosyn active ingredient produced by the soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado V.L. and Sparks T.C., “The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance,” in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosyn active ingredient. Spinosyns are commonly referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or a combination of them can be used in the compositions of the present invention. The spinosyn compound may be a 5,6,5-tricyclic ring system fused with a 12-membered macrocyclic lactone, a neutral sugar (rhamnose) and an amino sugar (forosamine). These and other naturally occurring spinosyn compounds, including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which can be used in the compositions of the present invention, can be prepared by fermentation according to techniques known in the art. Other spinosyn compounds that can be used in the compositions of the present invention are described in US Patents 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861; 5,670,486; 5,631,155 and 6,001,981, all of which are incorporated herein in their entirety by reference. Spinosyn compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydro spinosyn J and 3'-ethoxy spinosyn L.

In general, additional active ingredients (other than the compound of formula (I) described above) are included in the dosage forms of the present invention in an amount of from about 0.1 μg to about 1000 mg. Typically, the active ingredient may be included in an amount of from about 10 μg to about 500 mg, from about 10 μg to about 400 mg, from about 1 mg to about 300 mg, from about 10 mg to about 200 mg, or from about 10 mg to about 100 mg. More typically, the additional active ingredient is present in the compositions of the present invention in an amount of from about 5 mg to about 50 mg.

The concentration of additional active ingredient in the compositions of the present invention is typically from about 0.01% to about 30% (w/w), depending on the activity of the active ingredient. In some embodiments, for highly active active ingredients, including but not limited to macrocyclic lactones, the active ingredient concentration is typically about 0.01% to about 10% (w/w), about 0.01 to about 1% ( w/w), about 0.01% to about 0.5% (w/w), about 0.1% to about 0.5% (w/w), or about 0.01% to about 0.1% (w/w). In other embodiments, the active ingredient concentration is typically from about 0.1% to about 2% (w/w), or from about 0.1% to about 1% (w/w).

In other embodiments, the additional active ingredient is typically present at higher concentrations to achieve the desired efficacy. In some embodiments, the active ingredient is present at a concentration of from about 1% to about 30% (w/w), from about 1% to about 20% (w/w), or from about 1% to about 15% (w/w). weight). In other embodiments, the active ingredient is present in the composition at a concentration of from about 5% to about 20% (w/w), or from about 5% to about 15% (w/w).

In various embodiments of the present invention, the additional active ingredient may be included in the composition in such an amount to provide a dose of from about 0.001 mg/kg to about 50 mg/kg, or from about 0.5 mg/kg to about 50 mg/kg of body weight. animal body. In other embodiments, the active ingredient is typically present in an amount sufficient to create a dose of about 0.05 mg/kg to about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments, the active ingredient is present in an amount sufficient to create a dose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1 mg/kg, or about 0.5 mg/kg to about 50 mg/kg animal body weight.

In some embodiments of the present invention, when the additional active ingredient is a very active compound, such as a macrocyclic lactone or other active compounds, the active ingredient is present at a concentration sufficient to create a dose of from about 0.001 mg/kg to about 5 mg/kg, from about 0.001 mg/kg to about 0.1 mg/kg, or from about 0.001 mg/kg to about 0.01 mg/kg. In other embodiments, the active ingredient is present at a concentration sufficient to create a dose of about 0.01 mg/kg to about 2 mg/kg, or about 0.1 mg/kg to about 1 mg/kg of the animal's body weight. In other embodiments, the additional active ingredient is present in an amount sufficient to create a dose of from about 1 μg/kg to about 200 μg/kg, or from about 0.1 mg/kg to about 1 mg/kg of animal weight.

In addition to the other active ingredients mentioned above, combinations of two or more active ingredients with the compounds of the present invention can be used in a composition for the treatment of a target spectrum of pests and parasites. The decision as to which particular compound can be used in innovative compositions to treat a particular insect infestation is within the purview of one skilled in the art to practice the present invention.

The present invention is further described in more detail with the involvement of private non-limiting examples.

Examples

The present invention is further illustrated by the examples below, which should not be construed as limiting the scope of the present invention to the particular particular techniques described therein. It should be understood that the examples are provided only to illustrate certain embodiments, and that they do not limit the scope of the present invention in any way. It should also be understood that various other embodiments, modifications and equivalents are possible, which will be apparent to those skilled in the art without departing from the gist of the present description and/or the scope of the Claims.

Abbreviations

ACN acetonitrile AIBN azabisisobutyroniril BSA bovine serum albumin BOC tert-butoxycarbonyl BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphine chloride DCC N,N'-Dicyclohexylcarbodiimide solution DXM dichloromethane DEAD diethyl azodicarboxylate DIEA diisopropylethylamine DMF N,N-dimethylformamide DMAP 4-(Dimethylamino)pyridine DMSO dimethyl sulfoxide EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride ES electrospray EtOAc or EA ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate HOBt or HOBT 1-hydroxybenzotriazole
KHMDS potassium hexamethyldisilazide, i.e. potassium bis(trimethylsilyl)amide MeOH methanol PE petroleum ether TBAF tert-butylammonium fluoride THF tetrahydrofuran TLC thin layer chromatography rt room temperature LDA lithium diisopropylamide M.W. microwave radiation

Example 1

Methyl 3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (B)

Into a 500 ml round-bottom flask, in which an inert atmosphere was created by purging with nitrogen, were placed THF (0.23 ml, 2.839 mmol, 0.15 eq.), H ₂ O (0.02 ml, 1.115 mmol, 0.06 eq.), methyl 3-bromo- 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate ((A) 5 g, 18.581 mmol, 1 eq.), (2-chloro-6-fluorophenyl)boronic acid (4.86 g, 27.871 mmol, 1.50 eq. .), Pd(dtBpf)Cl2 (1.27 g, 1.949 mmol, 0.10 equiv.), K ₃ PO ₄ (11.8 g, 55.591 mmol, 2.99 equiv.). The resulting solution was stirred overnight at 70°C. The resulting mixture was evaporated in vacuo. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:5) as eluent. This gave 4.6 g (77.67%) of methyl 3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 319 [M+H] ⁺ .

Example 2

Methyl 7-bromo-3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (C)

Into a 250 ml three-necked round-bottom flask, in which an inert atmosphere was created by purging with nitrogen, was placed THF (30.00 ml, 416.118 mmol, 29.51 eq.), methyl 3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1.5 -a]pyridine-6-carboxylate ((B) 4 g, 12.550 mmol, 1 eq.). Then LDA (7.79 ml, 15.580 mmol, 1.24 eq.) was added dropwise with stirring at -70°C for 30 minutes. Then CBr ₄ (6.24 g, 18.816 mmol, 1.50 eq.) was added dropwise with stirring at -70°C. The resulting solution was stirred for 1 hour at room temperature. The reaction was quenched by adding NH ₄ Cl (aq.). The resulting solution was extracted with 3x20 ml of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:3) as eluent. This gave 3.2 g (64.13%) of methyl 7-bromo-3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 397 [M+H] ⁺ .

Example 3

Methyl 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (D)

Morpholine (4 ml, 0.046 mmol, 0.04 equiv.), methyl 7-bromo-3-(2-chloro-6-fluorophenyl)-2-methylpyrazolo[1,5-a]pyridine- 6-carboxylate ((C) 500 mg, 1.257 mmol, 1 eq.). The reaction mixture was kept under microwave irradiation for 20 minutes at 120°C. The reaction was quenched by adding a mixture of water and ice. The resulting solution was extracted with 3x15 ml of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate and evaporated in vacuo. As a result, 450 mg (88.62%) of methyl 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylate was obtained in the form yellow solid. (ES, m/z): 404 [M+H] ⁺ .

Example 4

3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid (E)

H ₂ O (1 ml, 0.056 mmol, 0.05 equiv.), MeOH ((D) 5 ml, 0.156 mmol, 0.13 equiv.), THF (2 ml, 0.028 mmol, 0.02 equiv.) , methyl 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (480 mg, 1.189 mmol, 1 eq. ), LiOH (143 mg, 5.971 mmol, 5.02 equiv.). The resulting solution was stirred for 2 hours at 80°C. The reaction was quenched by adding 10 ml of water. The pH value of the solution was adjusted to 4 by adding HCl (3M solution). The resulting solution was extracted with 3x20 ml of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate and evaporated in vacuo. This gave 400 mg (crude) of 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid as yellow solid. (ES, m/z): 390 [M+H] ⁺ .

Example 5

3-(2-chloro-6-fluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-7-(morpholin-4-yl)pyrazolo [1,5-a]pyridine-6-carboxamide (F)

DCM (5 ml, 0.059 mmol, 0.06 equiv.), 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(morpholin-4-yl)pyrazolo[1.5 -a]pyridine-6-carboxylic acid (400 mg, 1.026 mmol, 1 eq.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (225 mg, 1.508 mmol, 1.47 eq. ), HATU (782.8 mg, 2.059 mmol, 2.01 equiv.), DIEA (398.6 mg, 3.084 mmol, 3.01 equiv.). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was evaporated in vacuo. The crude product was purified by preparative flash chromatography under the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H ₂ O:CH ₃ CN=70:30 rising to H ₂ O:CH ₃ CN=15:85 over 25 minutes; Detector, UV 254 nm. The result was 185 mg (34.60%) 3-(2-chloro-6-fluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-7 -(morpholin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxamide as yellow solid, (ES, m/z): 521 [M+H] ⁺ ; ¹ H NMR (300 MHz, CD ₃ OD, ppm): δ 7.67 (d, J = 9.3 Hz, 1H), 7.47-7.43 (m, 2H), 7.35 (d, J = 7.5 Hz, 2H) , 7.27-7.21 (m, 2H), 7.07 (d, J = 9.3 Hz, 1H), 6.98-6.93 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.29-5.25 (m, 1H ), 4.37-4.22 (m, 2H), 3.67-3.57 (m, 8H), 2.36 (s, 3H), 2.32-2.24 (m, 2H).

Example 6

3-ethyl 6-methyl 2-methylpyrazolo[1,5-a]pyridine-3,6-dicarboxylate (H)

1-amino-3-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzene-1-sulfonate ((G) 90 g, 255.384 mmol, 1 equiv.), CH ₃ CN (200 ml), K ₂ CO ₃ (105.89 g, 766.178 mmol, 3.00 eq.), ethyl but-2-inoate (42.95 g, 383.077 mmol, 1.5 eq.). The resulting solution was stirred overnight at room temperature. The resulting mixture was evaporated. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:10) as eluent. This gave 19 g (28.37%) of 3-ethyl 6-methyl 2-methylpyrazolo[1,5-a]pyridine-3,6-dicarboxylate as a yellow solid. (ES, m/z): 263 [M+H] ⁺ .

Example 7

Methyl 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (I)

In a 1 L round bottom flask was placed 3-ethyl 6-methyl 2-methylpyrazolo[1,5-a]pyridine-3,6-dicarboxylate ((H) 34 g, 129.640 mmol, 1 eq.), HBr (300 ml, 48%). The resulting solution was stirred for 2 hours at 120°C in an oil bath. The resulting mixture was evaporated. This gave 30 g (crude) of methyl 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 177 [M+H] ⁺ .

Example 8

Methyl 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (J)

Into a 1 liter round bottom flask, in which an inert atmosphere was created by purging with nitrogen, was placed 2-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid (30 g, 170.285 mmol, 1 eq.), MeOH (100 ml) . SOCl ₂ (40 g, 551.400 mmol, 3.24 eq.) was then added dropwise with stirring at 0°C. The resulting solution was stirred overnight at 70° C. in an oil bath. The resulting mixture was evaporated. The pH value of the solution was adjusted to 8 by adding NaHCO ₃ (50%). The resulting solution was extracted with 3x100 ml of ethyl acetate. The combined organic layer was washed with 3 x 50 ml NaCl solution and evaporated. This gave 21 g (crude) of methyl 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 191 [M+H] ⁺ .

Example 9

Methyl 3-bromo-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (K)

Methyl 2-methylpyrazolo[1,5-a]pyridine-6-carboxylate ((J) 21 g, 110.409 mmol, 1 equiv.), DMF (100 ml), NBS (21.62 g, 121.472 mmol, 1.10 equiv.). The resulting solution was stirred for 2 hours at room temperature. The reaction was quenched by adding 300 ml of water. The resulting solution was extracted with 3x100 ml of ethyl acetate. The organic layer was collected and washed with 3 x 100 ml NaCl solution. The combined organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:5) as eluent. This gave 27 g (90.88%) of methyl 3-bromo-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a white solid. (ES, m/z): 269 [M+H] ⁺ .

Example 10

Methyl 3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (L)

Methyl 3-bromo-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate ((K) 8 g, 0.03 mol, 1 equiv.) , DCM (160 ml), (2,6-difluorophenyl)boronic acid (7.04 g, 0.045 mol, 1.50 equiv.), H ₂ O (80 ml), K ₃ PO ₄ (18.9 g, 0.090 mol, 3.00 equiv. ), Xphos-Pd-G ₃ (2.56 g, 0.32 mmol, 0.1 equiv.). The resulting solution was stirred for 2 hours at 25°C. The resulting solution was stirred overnight at 70°C. The resulting mixture was evaporated in vacuo. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:5) as eluent. This gave 4.2 g (47%) of methyl 3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 303 [M+H] ⁺ .

Example 11

Methyl 7-bromo-3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (M)

Methyl 3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate ((L) 4.1 g , 13.564 mmol, 1 eq.), THF (41 ml), LDA (1.60 g, 0.015 mmol, 1.1 eq.) at -78°C and stirred for 30 minutes. CBr ₄ (6.75 g, 0.020 mmol, 1.5 equiv.) was added to the resulting mixture. The reaction mixture was stirred for another 1 hour at room temperature. The reaction was quenched by adding water. The resulting solution was extracted with 300 ml of ethyl acetate. The organic phase was collected and evaporated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate/hexane (1/10) as eluent. This gave 1.4 g (87.04%) of methyl 7-bromo-3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate as a yellow solid. (ES, m/z): 381 [M+H] ⁺ .

Example 12

Methyl 3-(2,6-difluorophenyl)-2-methyl-7-(prop-1-en-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (N)

Methyl 7-bromo-3-(2,6-difluorophenyl)-2-methylpyrazolo[1,5-a]pyridine-6-carboxylate (( M) 1000 mg, 2.623 mmol, 1 eq.), dioxane (10 ml), H ₂ O (1 ml), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl) -1,3,2-dioxaborolane (1322.54 mg, 7.870 mmol, 3.00 equiv.), Pd(PPh ₃ ) ₄ (303.16 mg, 0.262 mmol, 0.1 equiv.), K ₃ PO ₄ (1670.61 mg, 7.870 mmol, 3.0 equiv.). The resulting solution was stirred for 1 hour at 100°C. The reaction mixture was cooled to room temperature and quenched by adding 10 ml of water. The resulting solution was extracted with 30 ml of ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate/hexane (1/15) as eluent. As a result, 805 mg (89.63%) of methyl 3-(2,6-difluorophenyl)-2-methyl-7-(prop-1-en-2-yl) pyrazolo[1,5-a]pyridine-6-carboxylate was obtained as a yellow solid. (ES, m/z): 343 [M+H] ⁺ .

Example 13

Methyl 3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (O)

Methyl 3-(2,6-difluorophenyl)-2-methyl-7-(prop-1-en-2-yl)pyrazolo[1, 5-a]pyridine-6-carboxylate ((N) 805 mg, 2.351 mmol, 1 equiv.), EA (16 ml), PtO ₂ (240.29 mg, 1.058 mmol, 0.45 equiv.), then H ₂ (gas ). The resulting solution was stirred for 4 hours at 55°C. The solid precipitate was separated by filtration. The filtrate was evaporated in vacuo. This gave 657 mg (81.14%) of methyl 3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylate as a solid . (ES, m/z): 345 [M+H] ⁺ .

Example 14

3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid (O)

Methyl 3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylate ((P) 650 mg, 1.888 mmol, 1 equiv.), MeOH (8 ml), THF (8 ml), H ₂ O (2.5 ml), NaOH (377.48 mg, 9.438 mmol, 5.00 equiv.). The resulting solution was stirred for 6 hours at 80°C. The residue was diluted with water. The pH of the mixture was adjusted to 4 by adding HCl (1M solution). The resulting solution was extracted with 3x20 ml of ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and evaporated in vacuo. This gave 617 mg (98.95%) of 3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid as a yellow solid substances. (ES, m/z): 331 [M+H] ⁺ .

Example 15

3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-7-(propan-2-yl)pyrazolo[1 ,5-a]pyridine-6-carboxamide (Q)

3-(2,6-difluorophenyl)-2-methyl-7-(propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid ((P) 325 mg, 0.984 mmol, 1 eq.), DCM (10 ml), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (220.18 mg, 1.476 mmol, 1.50 eq.), HATU (748.18 mg, 1.968 mmol, 2.0 equiv.), DIEA (381.47 mg, 2.952 mmol, 3.0 equiv.). The resulting solution was stirred for 2 hours at room temperature. The mixture was evaporated in vacuo. The crude product was purified by preparative flash chromatography under the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, H ₂ O:CH ₃ CN=60:40 growing to H ₂ O:CH ₃ CN=15:85 over 25 minutes; Detector, UV 254 nm. As a result, 180 mg (39.64%) of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-7-( propan-2-yl)pyrazolo[1,5-a]pyridine-6-carboxamide as a white solid. (ES, m/z): 462 [M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ , ppm): δ 7.38-7.14 (m, 4H), 7.10-6.94 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 5.72 (d , J = 7.8 Hz, 1H), 5.38-5.36 (m, 1H), 4.37-4.34 (m, 1H), 4.25-4.09 (m, 2H), 2.45 (s, 3H), 2.43-2.36 (m, 1H ), 2.27–2.24 (m, 1H), 1.69 (d, J = 6.3 Hz, 3H), 1.67 (d, J = 6.3 Hz, 3H).

While the subject matter of the present invention has been described above with some examples for purposes of illustration for clarity of understanding, those skilled in the art will appreciate that certain changes and modifications are possible in practice within the scope of the description and examples. Table 1 includes compounds obtained according to the present description.

Table 1

Example 16

4-6 hundreds of Dirofilaria immitis microfilariae were placed in microplate wells containing RPMI medium and test compound in 100% DMSO. Tablets kept three days at 37°C and 5% CO ₂ . Compound potency was determined by microfilarial motility compared to mean motility in control wells containing DMSO alone. Dose-effect analysis was performed to determine the EC ₅₀ value. The following compounds from Table 1 showed activity against Dirofilaria immitis: 2-4, 8-10, 14, 15, 20, 25, 32-39, 113, 124, 156-159, 161, 162, 164, 165, 168, 170 and 172.

Claims (29)

1. Compound having formula (Ia) or (Ib):

Where: R ¹ is an optionally substituted C ₁ -C ₄ alkyl, an optionally substituted C ₂ -C ₄ alkenyl, an amino group, an NH-optionally substituted C ₁ -C ₄ alkyl, or NR ^a R ^b , where R ^a and R ^b are independently is an optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, or 6-membered heterocyclyl group, which may contain 1 additional nitrogen or oxygen heteroatom, which may optionally have substituents; where, independently of each other, optional substituents are in each case selected from the group consisting of: halogen, hydroxyl or C ₁ -C ₃ alkoxy; R ² is C ₁ -C ₄ alkyl optionally substituted with halogen; R ³ is phenyl which may have 1, 2, or 3 substituents selected from the group consisting of: halo and C ₁ -C ₃ haloalkyl; each R ⁴ is independently halogen, and a C ₁ -C ₄ alkoxy group optionally substituted with halogen; o is 0, 1 or 2; q is 0 or 1; X and Y are independently CH ₂ or O, where at least one of X and Y is CH ₂ ; or his salt. 2. The compound according to claim 1, where R ₁ represents a secondary C ₁ -C ₄ -alkyl. 3. A compound according to claim 1, wherein R ¹ is heterocyclyl. 4. The compound of claim 3 wherein R ¹ is aziridinyl, azetidinyl, or morpholinyl, all of which may be optionally substituted with one or more halogens. 5. A compound according to any one of the preceding claims, wherein R ² is methyl. 6. A compound according to any one of the preceding claims, wherein R ³ is phenyl substituted with 1 substituent which is halogen. 7. A compound according to any one of the preceding claims, wherein R ³ is dihalophenyl. 8. Connection according to any one of paragraphs. 1-5, where R ³ is trihalophenyl. 9. Connection according to any of the preceding paragraphs, where q is equal to 1. 10. Connection according to any one of paragraphs. 1-8 where q is 0. 11. A compound according to any one of the preceding claims, wherein X is CH ₂ . 12. A compound according to any one of the preceding claims, wherein Y is CH ₂ . 13. A compound according to any one of the preceding claims, wherein X is O. 14. A compound selected from the group consisting of: Structure Connection #

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173 or its salt. 15. Anthelmintic veterinary composition containing an effective amount of a compound according to any one of paragraphs. 1-14, or salts thereof, and a veterinarily acceptable carrier. 16. A method of combating helminths, including the introduction of a parasiticide-effective amount of a compound according to any one of paragraphs. 1-14, or a veterinarily acceptable composition according to claim 15, to a mammal in need thereof.