Anthelmintic aza-benzothiophene and aza-benzofuran compounds

Abstract

To provide a method for treatment, control or prevention of a parasitic infestation or infection in an animal.SOLUTION: The present invention provides a compound of the formula, wherein the variables are defined herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, compositions comprising these compounds, and a method for treatment, control or prevention of a parasitic infestation or infection in an animal in need thereof by administering an effective amount of these compounds to the animal.SELECTED DRAWING: None

Description

Technical Field

[0001] This patent application relates to new anti - parasitic compounds, compositions containing the compounds, methods for their preparation, and methods of using the compounds to control parasites that harm animals. Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 820,352, filed Mar. 19, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Animals such as mammals and birds are often susceptible to parasite infestations. These parasites can be external parasites such as fleas and ticks. Animals and humans also suffer from endoparasitic infections, including helminthiasis most frequently caused by groups of parasites described as nematodes or roundworms. These parasites cause significant economic losses in pigs, sheep, horses and cattle, as well as in affected companion animals (e.g., cats and dogs) and poultry. Other parasites include those that occur in the digestive tract of animals and humans, such as Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris and Enterobius. Other parasites found in the blood or other tissues and organs include filarial worms and the extra - intestinal stages of Strongyloides and Trichinella.

[0003] One type of internal parasite that seriously harms mammals is the dog heartworm, Dirofilaria immitis, also known as heartworm. Other filarial internal parasites include Dirofilaria repens and Dirofilaria honkongensis, which can also infect humans. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected. Dog heartworms go through several life stages before becoming adult worms that infect the pulmonary arteries of the host mammal. These worms require mosquitoes as intermediate hosts to complete their life cycle. The period between the initial infection when a dog is bitten by a mosquito and the maturation of the worms into adult worms that inhabit the heart and pulmonary arteries is 6 - 7 months in dogs and is known as the "prepatent period." L3 larvae move to the tip of the mosquito's mouthparts (labium) during the mosquito's blood meal, exit the mosquito, deposit on the dog's skin, and then move into the host through the bite wound. Most L3 larvae molt into fourth-stage larvae (L4) in the dog's subcutaneous tissue within 1 - 3 days after infection. These larvae then move to the muscles of the chest and abdomen and molt into fifth-stage larvae (L5, immature adults) 45 - 60 days after infection. Then, between 75 - 120 days after infection, these immature dog heartworms enter the bloodstream, are carried through the heart, and reside in the pulmonary arteries. Approximately 7 months after infection, Dirofilaria immitis adults mature and reproduce sexually in the pulmonary arteries and right ventricle. Adult male worms are approximately 15 cm in length, female worms are approximately 25 cm in length, and their normal lifespan as adults is calculated to be about 5 years. Heartworm infection is a serious life-threatening disease. Heartworm infection in dogs is preventable, and prophylactic treatment is a priority in heartworm-endemic areas. Treatment of mature heartworm infection with adulticide (e.g., melarsomine dihydrochloride) is expensive and may cause serious side effects, so prevention by monthly administration of drugs that inhibit larval development is widely used. The goal of commercially available heartworm prophylactic therapies is to prevent the growth of the parasite into adult heartworms by interfering with the life cycle of Dirofilaria immitis after infection.

[0004] Macrocyclic lactones (MLs, such as ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemopreventives and are administered monthly or at 6-month intervals. These drugs were effective against Dirofilaria immitis infective third-stage larvae (L3) and mature fourth-stage larvae (L4) deposited by mosquitoes. When administered monthly, the MLs kill L3 and L4 larvae infected within the previous 30 days, thus preventing the diseases caused by adult worms. The MLs can also be used monthly in infected dogs to suppress the reproduction of adult worms, eliminate microfilariae, thereby reducing transmission and gradually causing a decline in adult worms (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206). In recent years, an increase in the number of cases of lack of efficacy (LOE) of dogs developing mature canine filariasis despite receiving monthly prophylactic doses of macrocyclic lactone drugs has been reported. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) have recently reported an increase in the number of cases of dogs receiving canine filariasis prophylaxis but testing positive for canine filarial antigens, suggesting that populations of Dirofilaria immitis are developing selective resistance to canine filariasis preventive drugs (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5.). Thus, there is a continuing need to develop new anthelmintics with improved activity against Dirofilaria immitis and other internal parasites.

[0005] WO 2017 / 178416 provides pyrazolopyrimidine derivatives for controlling, treating and / or preventing worms. WO 2018 / 197401 provides bicyclic pyrazole derivatives for controlling, treating and / or preventing worms. WO 2018 / 087036 provides quinoline-3-carboxamide derivatives for controlling, treating and / or preventing worms. WO 2019 / 025341 provides quinoline compounds for treating, controlling and / or preventing worm infections, and WO 2019 / 002132 provides azaquinone derivatives for controlling, treating and / or preventing worms. All of these publications are by Bayer Animal Health GmbH and are hereby incorporated by reference in their entirety into this specification. More recently, WO 2020 / 014068 (incorporated herein by reference) describes anthelmintic heterocyclic compounds that have been found to be active against Dirofilaria immitis.

[0006] It is expressly noted that the citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. The said application and all documents cited in it or during its prosecution (the "application cited documents") and all documents cited or mentioned in the application cited documents, and all documents cited or mentioned in this specification (the "documents cited in this specification"), and all documents cited or mentioned in the documents cited in this specification are hereby incorporated by reference in combination with the manufacturer's instructions, descriptions, product specifications and product sheets for any product mentioned in any document mentioned in this specification or incorporated herein by reference, and may be used in the practice of the present invention. SUMMARY OF THE INVENTION

[0007] This application provides novel anthelmintic and antiparasitic heterocyclic compounds having improved activity against endoparasites and ectoparasites. This application also relates to compositions, methods and uses of compounds for eradicating, controlling and preventing parasite infestations and / or infections in animals including humans. The compounds can be administered to animals, particularly mammals, fish and birds, to prevent or treat parasite infections.

[0008] One aspect of the invention is a compound of formula (I):

Chemical formula

[0009]

Chemical formula

[0010] The invention also includes a veterinarily acceptable composition comprising a compound of formula (I) and a veterinarily acceptable carrier, and a method of controlling parasites including helminths, the method comprising administering the compound or its veterinarily acceptable composition to an animal in need thereof. Certain embodiments of the invention also include the use of a compound of formula (I) for eradicating, controlling and preventing parasite infestations and / or infections in animals. The compounds of the invention can be administered to animals, particularly mammals, fish and birds, to prevent or treat parasite infections. Compounds and compositions containing the compounds are highly effective for the treatment and prevention of endoparasites in these hosts for the purpose of substantially removing endoparasites from mammals, fish and birds, particularly cats, dogs, horses, chickens, pigs, sheep and cows. In certain embodiments, the compounds of formula (I) and compositions containing said compounds are substantially effective against endoparasites such as filaria (e.g., Dirofilaria immitis) in the digestive tract of animals and humans, hookworms, whipworms and roundworms. In certain embodiments, the compounds of formula (I) and compositions containing said compounds are effective against Dirofilaria immitis (heartworm) isolates that are not very sensitive to treatment with macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are effective for treating and preventing animal infections by nematodes that are not very sensitive to treatment with commercially available or known active agents. In certain embodiments, the present invention includes combinations of compounds of formula (I) with at least a second active agent that can broaden the scope of protection provided to animals against endoparasites and / or ectoparasites.

[0011] Another embodiment includes a method of treating and / or preventing animal parasite infections and / or infestations, the method comprising the step of administering a compound of formula (I) to an animal. Another embodiment includes the use of a compound of formula (I) for treating and / or preventing animal parasite infections and / or infestations, as well as the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing animal parasite infections.

[0012] Thus, the present invention includes the following non-limiting embodiments: (a) A compound of formula (I) that is an active endoparasiticide and optionally also active against ectoparasites, or a pharmaceutically or veterinarily acceptable salt thereof; (b) A veterinary composition comprising a parasitocidally effective amount of a compound of formula (I), 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 of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, in combination with one or more additional active agents (i.e., active ingredients not included in formula (I)) and a pharmaceutically or veterinarily acceptable carrier or diluent; (d) A method for treating a parasitic infestation / infection in or on an animal, comprising administering to the animal in need thereof a parasiticide-effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, optionally together with one or more additional active agents (i.e., active ingredients not included in formula (I)); (e) A method for preventing a parasitic infestation / infection in an animal, comprising administering to the animal in need thereof a parasiticide-effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, optionally together with one or more additional active agents (i.e., active ingredients not included in formula (I)); (f) Use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, for treating or preventing parasitic infection and possibly also parasitic infestation in an animal; (g) Use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, for manufacturing a veterinary pharmaceutical for treating or preventing parasitic infection in an animal; and (h) A method for preparing a compound of formula (I).

[0013] Accordingly, it is an object of the present invention that the applicants hold the rights and that the present invention does not include any product, process or method known from before in any way, so as to disclose the exclusion of any product, process or method known from before. It should be further noted that the present invention is not intended to include any product, process, preparation of a product or method of using a product that does not meet the description requirements and the enablement requirements of the USPTO (35 U.S.C. § 112, paragraph 1) or the EPO (Article 83 of the EPC) within the scope of the present invention so as to disclose the exclusion of any product, process or method known from before that the applicants hold the rights. In the practice of the present invention, it may be advantageous to comply with Article 53(c) of the EPC and Rules 28(b) and (c) of the EPC. All rights are expressly reserved that expressly disclaim any embodiments that are the subject of a patent granted to the applicant in the line of this application, or any other line, or in a previously filed application of a third party. Nothing in this specification should be construed as a promise. The term "compound of formula (I)" includes any stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

[0014] These and other embodiments are disclosed by, or obvious from and included in, the following detailed description.

[0015] Definitions: In the present disclosure, particularly in the claims and / or paragraphs, terms such as "comprise", "comprised", "comprising", etc. can have the meaning ascribed by US patent law; for example, these terms can mean "includes", "included", "including", etc.; terms such as "consisting essentially of" and "consists essentially of" have the meaning given by US patent law. For example, it should be noted that these terms allow elements not explicitly recited, but exclude elements found in the prior art and elements that affect the basic or novel features of the present invention. As used herein, unless otherwise specified, terms have their ordinary meaning in the art. The organic moieties referred to in the definition of variable elements of a compound, such as a compound of formula (I), are like the term halogen - that is, a general term for the individual listings of the members of each group - fluorine, chlorine, bromine, and iodine with respect to halogen. The prefix C n -C m in each case indicates the possible number of carbon atoms in a group of an integer n to another integer m. In this specification and the claims, the term "including but not limited to" is equivalent to "included".

[0016] The term "optionally substituted" means a group that may be substituted by one or more of the following moieties: halogen, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amide, arylamino, alkoxy, aryloxy, nitro, cyano, azide, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, aryl and heteroaryl, or any other variable functional group known to those skilled in the art, unprotected or optionally protected, that does not inhibit the biological activity of the compounds of the present invention, as taught, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, which is hereby incorporated by reference. For the avoidance of doubt, "optionally substituted alkyl" includes haloalkyl.

[0017] Unless otherwise specified, "alkyl" means a saturated straight-chain, branched, primary, secondary or tertiary hydrocarbon having, alone or in combination with heteroatoms, for example alkoxy, thioalkyl, alkylamino, etc., 1 to 12 atoms. In some embodiments, the alkyl group is a C1-C 10 、C1-C8, C1-C6, C1-C4 or C1-C3 alkyl group. C1-C 10Examples of alkyl 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. C1-C4-alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0018] The cyclic alkyl group may also be referred to as "cycloalkyl" and includes those having 3 to 10 carbon atoms with single or multiple fused rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The carbocyclic group is a cyclic group composed only of carbon. The carbocyclic group includes both aromatic rings such as phenyl and non-aromatic rings such as cycloalkyl rings including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and includes those having 3 to 14 carbon atoms with single or multiple fused rings.

[0019] The term "alkenyl" refers to both straight-chain and branched-chain carbon chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group may include C2-C 12 and may include an alkenyl group. In other embodiments, alkenyl is C2-C 10, includes a C2-C8, C2-C6, C2-C4 or C3-C4 alkenyl group. In one embodiment of the alkenyl, the number of double bonds is 1 to 3; in another embodiment of the alkenyl, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the position of the alkenyl moiety on the molecule. The "alkenyl" group may contain two or more double bonds in the chain. Examples of alkenyl or specific ranges 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 are included.;

[0020] "Alkynyl" refers to both straight-chain and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is from 1 to 3; in another embodiment of alkynyl, the number of triple bonds is 1. In some embodiments, the alkynyl group contains from 2 to 12 carbon atoms. In other embodiments, the alkynyl group may contain a C2-C 10 , C2-C8, C2-C6 or C2-C4 alkynyl group. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated depending on the position of the alkenyl moiety on the molecule. For example, as used herein, the term "C2-C 10 -alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 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-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-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.

[0021] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted by one or more halogen atoms. For example, C1-C4-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 refers to an alkyl in which one or more of the hydrogen atoms are replaced by fluorine atoms, such as 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 that is substituted by one or more halogen atoms. The term "haloalkynyl" refers to an alkynyl group as defined herein that is substituted by one or more halogen atoms.

[0022] The term "alkoxy" refers to alkyl-O- (wherein alkyl is as defined above). 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- (wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl and halocycloalkenyl are as defined above), respectively. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, OCH2-C2H5, OCH(CH3)2, n-butoxy, OCH(CH3)-C2H5, OCH2-CH(CH3)2, OC(CH3)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.

[0023] The term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments, aryl includes tetrahydronaphthyl, phenylcyclopropyl, and indanyl. An aryl group may be unsubstituted or substituted by one or more moieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, -SF5, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)amino, di(alkynyl)amino, or trialkylsilyl.

[0024] The term "aralkyl" refers to an aryl group bonded to the parent compound through a diradical alkylene bridge, (-CH2-) n where n is from 1 to 12 and "aryl" is as defined above. The term "heteroaryl" refers to a monovalent aromatic group having one or more oxygen, nitrogen, and sulfur heteroatoms in the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms, and 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms. The nitrogen and sulfur heteroatoms may be oxidized. The heteroaryl group typically contains a 5- or 6-membered aromatic ring. Such a heteroaryl group can have a single ring (e.g., pyridyl or furyl) or multiple fused rings, provided that the point of attachment passes through a heteroaryl ring atom. Examples of heteroaryl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidyl, or pyrrolopyrimidyl. The heteroaryl ring may be unsubstituted or substituted by one or more of the moieties described for the aryl above.

[0025] The term "heterocyclyl", "heterocyclic" or "heterocyclo" refers to a fully saturated or unsaturated cyclic group having one or more oxygen, sulfur or nitrogen heteroatoms in the ring, preferably 1 to 4 or 1 to 3 heteroatoms, such as a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic or 10- to 15-membered tricyclic ring system. The nitrogen and sulfur heteroatoms may be oxidized and the nitrogen heteroatoms may be quaternized. The heterocyclic group may be attached by any of the heteroatoms or carbon atoms of the ring or ring system and may be unsubstituted or substituted by one or more of the moieties described for the aryl group above. Exemplary 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, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

[0026] Exemplary 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, etc.), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl, etc.), tetrahydroquinolinyl, and the like.

[0027] Bicyclic and tricyclic carbocyclic or heterocyclic ring systems include spirocyclic systems in which at least two of the rings of the system are joined through a single carbon atom. Spirocyclic ring systems include combinations of 3- to 8-membered carbocyclic and / or heterocyclic rings joined by a common carbon atom. Thus, spirocyclic ring systems can include all combinations of ring sizes from a 3-membered ring (carbocyclic or heterocyclic) attached to another 3-membered ring to an 8-membered ring attached to another 8-membered ring and all between. The heterocyclic ring component of the spirocyclic ring system contains one or two heteroatoms selected from N, O, or S. The term "alkylthio" refers to alkyl-S- (where "alkyl" is as defined above). In some embodiments, the alkyl component of the alkylthio group comprises a C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl group. For example, C1-C4-alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio.

[0028] 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" are as defined above). The term "alkylsulfinyl" refers to the group alkyl-S(=O)- (where "alkyl" is as defined above). In some embodiments, the alkyl component of the alkylsulfinyl group is C1-C 12 、C1-C 10It includes a C1-C8, C1-C6, C1-C4 or C1-C3 alkyl group. Examples include, but are not limited to, -SO-CH3, -SO-C2H5, 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.

[0029] 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)- (wherein the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" are as defined above).

[0030] The term "alkylsulfonyl" refers to the group alkyl-S(=O)2- (where the term "alkyl" is as defined above). In some embodiments, the alkyl component of the alkylsulfonyl group is C1-C 12 、C1-C 10 、C1-C8, C1-C6 or C1-C4 alkyl groups. Examples include, but are not limited to, -SO2-CH3, -SO2-C2H5, n-propylsulfonyl, -SO2-CH(CH3)2, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO2-C(CH3)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.

[0031] 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" are as defined above). The terms "alkylamino", "dialkylamino", "alkenylamino", "alkynylamino", "di(alkenyl)amino" and "di(alkynyl)amino" refer to the groups -NH(alkyl), -N(alkyl)2, -NH(alkenyl), -NH(alkynyl), -N(alkenyl)2 and -N(alkynyl)2, where the terms "alkyl", "alkenyl" and "alkynyl" are as defined above. In some embodiments, the alkyl component of an alkylamino or dialkylamino group is C1-C 12 , C1-C 10 , C1-C8, C1-C6 or C1-C4 alkyl group.

[0032] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" refer to haloalkyl-C(O)- groups, haloalkoxy-C(O)- groups, haloalkylamino-C(O)- groups and dihaloalkylamino-C(O)- groups, where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above. **DETAILED DESCRIPTION OF THE INVENTION**

[0033] One embodiment of the present invention is a compound of formula (I): **CHEMICAL STRUCTURE** (I) (wherein L is L1 or L2:

[0034] **CHEMICAL STRUCTURE** R 1 is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF5, or -NR a R b (wherein R a and R b are independently H or optionally substituted alkyl; or R a and R b may together with the nitrogen to which they are attached form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group containing 1 to 3 additional heteroatoms selected from the group consisting of N, O and S); R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 2’ is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 3 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) p(Optionally substituted alkyl), -SF5, optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbocyclyl group, spirocyclic heterocyclyl-heterocyclyl group, spirocyclic carbocyclyl-carbocyclyl group, spirocyclic carbocyclyl-heterocyclyl group or -NR a R b (Wherein R a and R b are each independently H or optionally substituted alkyl; or R a and R b may together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 4 is independently at each occurrence hydrogen, cyano, hydrogen, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (Optionally substituted alkyl or haloalkyl), -SF5, or -NR a R b (Wherein R a and R b are each independently H or optionally substituted alkyl; or R a and R bIt may combine with the nitrogen to which they are attached and contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclyl group; R 5 and R 5’ is, in each occurrence, independently hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted heteroaryl, -SF5, -SO p (optionally substituted alkyl or haloalkyl), or -NR c R d (wherein R c and R d are independently H or optionally substituted alkyl; or R c and R d may combine with the nitrogen to which they are attached and contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclyl group); R 10 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl; X is O or S; Q is O, S or N-R 2’ ; Y 1 , Y 2 and Y 3 are each independently N or -CR 4 -; Y 1’ and Y 6’ are each independently N, C or -CR 5 -; Y 2’ , Y 3’ , Y 4’ , and Y 5’ are each independently N, NR 2 , S, O, -CR5 - or CR 5 R 5’ is; W is CR 6 R 7 、O, S or N-R 8 is, Z is CR 6 R 7 、O, S or N-R 8 is, R 6 and R 7 are each occurrence independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy; R 8 is hydrogen or C1-C4-alkyl; Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ 、Y 5’ and Y 6’ Among them, the maximum 3 are heteroatoms; a is 0 or 1; q is 0 or 1; p is each occurrence independently 0, 1 or 2; Dashed bond

[0035]

Chemical formula

[0036] In another embodiment, the present invention is, R 1is hydrogen, cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, hydroxy-C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF5, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), or -NR a R b (wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 2 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl or optionally substituted phenyl; R 2’is C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl or optionally substituted phenyl; R 3 is C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SF5, -S(O) p (C1-C6-alkyl or C1-C6-haloalkyl), optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 4is, independently at each occurrence, hydrogen, cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, phenyl which may be substituted; phenyloxy which may be substituted, 5- or 6-membered heteroaryl which may be substituted, C3-C8-cycloalkyl which may be substituted, C3-C8-cycloalkyloxy which may be substituted, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), SF5, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 5 and R 5’is, independently at each occurrence, hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF5, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), or -NR c R d (wherein R c and R d are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R c and R d may together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 10 is hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C2-C6-alkenyl or C2-C6-alkynyl; L, X, Q, Y 1 , Y 2 , Y 3 , Y 1’ , Y 2’ , Y 3’ , Y 4’ , Y 5’ , Y 6’ , W, Z, R 6 , R 7 , R 8 , a, q, p and dashed bonds

[0037]

Chemical formula

[0038] In one embodiment, L is L1. In another embodiment, L is L2. In some embodiments, R 1 is hydrogen, cyano, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C1-C4-alkenyl, optionally substituted C1-C4-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted, saturated or unsaturated 5-membered, 6-membered or 7-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C1-C4-alkylcarbonyl, optionally substituted C1-C4-alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C4-alkylaminocarbonyl, optionally substituted C1-C4-dialkylaminocarbonyl, optionally substituted alkyl-SO p -, haloalkyl-SO p -, amino, -NH-optionally substituted C1-C4-alkyl, or -NR a R b (wherein R a and R b are independently optionally substituted alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterosilyl group); R 2 is hydrogen or C1-C4-alkyl; R 3 is C1-C4-alkyl, C3-C6-cycloalkyl, 4-6-membered heterosilyl, 6-10-membered aryl, 5-10-membered heteroaryl, each of which may be substituted with 1, 2 or 3 substituents; Each R 4is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, -amino, NH-optionally substituted C1-C4-alkyl, -SF5, or -NR a R b (wherein R c and R d are independently optionally substituted C1-C4-alkyl; or R a and R b together with the nitrogen to which they are attached may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group), SO p (optionally substituted C1-C4-alkyl or haloalkyl), and each R 5 is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, -amino, NH-optionally substituted C1-C4-alkyl, -SF5, or -NR c R d (wherein R c and R d are independently optionally substituted C1-C4-alkyl; or R c and R d together with the nitrogen to which they are attached may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group), SO p (optionally substituted C1-C4-alkyl or haloalkyl).

[0039] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino or di(C1-C4-alkyl)amino. In another embodiment, R 1 is halogen. In another embodiment, R 1 is C1-C4-alkyl-SO p -, C1-C4-haloalkyl-SO p - or -SF5. In other embodiments, R 1 is hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkoxy-C1-C4-alkyl or C1-C4-haloalkoxy-C1-C4-haloalkyl. In another embodiment, R 1 is methyl, ethyl, propyl, butyl, pentyl, isopropyl (i-Pr), tert-butyl (t-butyl), prop-1-en-2-yl, 2-fluoroprop-2-yl or 2-hydroxyprop-2-yl. In another embodiment, R 1 is CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 1 is C2-C4-alkenyl or C2-C4-haloalkenyl. In some embodiments, R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R 1 is an optionally substituted, saturated or unsaturated 6-membered heterocyclyl group. In one embodiment, R 1 is -NR a R b (wherein R a and R b are independently hydrogen or C1-C6 alkyl). In another embodiment, R 1 is -NR a R b (wherein R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclyl group).

[0040] In another embodiment, R 1 is C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, or di-C1-C6-haloalkylaminocarbonyl. In some embodiments, R 1 is optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, or triazinyl. In some embodiments, R 1is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, which may all be substituted by one or more halogens.

[0041] In some embodiments, R 3 is a 6- to 10-membered aryl which may be substituted with 1, 2, 3, 4 or 5 substituents. In some embodiments, R 3 is C1-C4-alkyl or C1-C4-haloalkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl, sec-butyl or isobutyl. In other embodiments, R 3 is CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 3 is optionally substituted C3-C8-cycloalkyl. In yet other embodiments, R 3 is optionally substituted C3-C6-cycloalkyl. In yet other embodiments, R 3 is optionally substituted C3-C8-cycloalkenyl or C3-C6-cycloalkenyl. In some embodiments, R 3 is optionally substituted cyclopentyl or cyclohexyl. In one embodiment, R 3 is cyclohexyl which may be substituted by one or more halo, C1-C3-alkyl or C1-C3-haloalkyl. In another embodiment, R 3 is cyclohexyl substituted by one or two fluoro, chloro or CF3.

[0042] In some embodiments, R 3 is optionally substituted piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl. In some embodiments, R 3is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more halos, C1-C6-alkyl or C1-C6-haloalkyl. In another embodiment, R 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more methyls, chloros or fluoros. In some embodiments, R 3 is a 5- to 10-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents. In one embodiment, the 5- to 10-membered heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidyl or pyrrolopyrimidyl. In other embodiments, R 3 is an optionally substituted spirocyclic heterocyclyl-carbocyclyl group, an optionally substituted spirocyclic heterocyclyl-heterocyclyl group, an optionally substituted spirocyclic carbocyclyl-carbocyclyl group or an optionally substituted spirocyclic carbocyclyl-heterocyclyl group. In other embodiments, R 3 is a 5- to 11-membered optionally substituted spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered optionally substituted spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered optionally substituted spirocyclic carbocyclyl-carbocyclyl group or a 5- to 11-membered optionally substituted spirocyclic carbocyclyl-heterocyclyl group. Non-limiting examples of spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl and spirocyclic heterocyclyl-heterocyclyl groups are shown below for illustration.

[0043]

Chemical formula

[0044] However, it will be apparent to those skilled in the art that the second ring of the spirocyclic group may be attached to any available carbon of the first ring. It will also be understood that the first ring of the spirocyclic group may be attached to the molecule by any available atom. Thus, the present invention includes 3-membered, 4-membered, 5-membered, 6-membered and 7-membered carbocyclic or heterocyclic rings as defined herein that are attached to a second 3-membered, 4-membered, 5-membered, 6-membered and 7-membered carbocyclic or heterocyclic ring by any available carbon atom of the first ring.

[0045] In some embodiments, R 3 is phenyl substituted with 1 to 4 substituents. In another embodiment, R 3 is phenyl substituted by 1 to 3 substituents. In yet another embodiment, R 3 is phenyl substituted by 1 or 2 substituents. In some embodiments, R 3 is phenyl substituted by 1, 2, 3 or 4 substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. 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 3is a haloalkoxyphenyl.

[0046] In some embodiments, R 3 is phenyl substituted with two substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. 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 2-,6-disubstituted phenyl. In some embodiments, R 3 is 3-,5-disubstituted phenyl In other embodiments, R 3 is 3-,4-disubstituted phenyl. In other embodiments, R 3 is 3-,6-disubstituted phenyl. In some embodiments, R 3 is dihalophenyl, such as dichloro; difluoro; or chloro, fluoro. In some embodiments, R 3 is 2,3-dihalophenyl. In some embodiments, R 3 is chlorophenyl. In another embodiment, R 3 is fluorophenyl. In another embodiment, R 3 is dichlorophenyl. In another embodiment, R 3 is difluorophenyl. In yet another embodiment, R 3 is 3,5-dichlorophenyl. In another embodiment, R3 is 3,5-difluorophenyl. In another embodiment, R 3 is 2,6-dichlorophenyl. In another embodiment, R 3 is 2,6-difluorophenyl. In some embodiments, R 3 is phenyl substituted with halo and haloalkyl. In some embodiments, R 3 is phenyl substituted with halo and haloalkoxy. In some embodiments, R 3 is phenyl substituted with haloalkyl and haloalkoxy.

[0047] In some embodiments, R 3 is phenyl substituted with three substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3 is trihalophenyl, such as trichloro; trifluoro; or chloro, chloro, fluoro or fluoro, fluoro, chloro. In some embodiments, R 3 is phenyl substituted with two halo and haloalkyl. In some embodiments, R 3 is phenyl substituted with two halo and haloalkoxy. In some embodiments, R 3 is phenyl substituted with one haloalkyl, one halo and one haloalkoxy. In some embodiments, R 3 is phenyl substituted with one halo and two haloalkyl. In some embodiments, R 3is a 5-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3 is a 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3 is 2-pyridyl optionally substituted with one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3 is 3-pyridyl optionally substituted with one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3is 4-pyridyl optionally substituted with one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In another embodiment, R 3 is unsubstituted or 4-pyridyl substituted with one or two chloro or fluoro. In yet another embodiment, R 3 is unsubstituted or 3-pyridyl substituted with one or two chloro or fluoro. In other embodiments, R 3 is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, R 3 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In another embodiment, R 3 may be an optionally substituted heterocyclic, bridged bicyclic group.

[0048] In some embodiments, each R 4is independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino or di-(C1-C4 alkyl)amino. In another embodiment, each R 4 is independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In another embodiment, each R 4 is independently hydrogen, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is halogen. In another embodiment, R 4 is fluoro or chloro. In another embodiment, each R 4 is independently hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) (wherein p is 0, 1 or 2). In another embodiment, R 4 is methoxy, ethoxy, propoxy or butoxy. In another embodiment, R 4 is methylthio, ethylthio, propylthio or butylthio. In another embodiment, R 4 is -OCF3 or -SCF3. In some embodiments, R 4 is C1-C4-alkenyl or C1-C4-haloalkenyl. In some embodiments, R 4 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R 4 is an optionally substituted, saturated or unsaturated 6-membered heterocyclyl group. In some embodiments, R 4is optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene or tetrahydrothiophene. In some embodiments, R 4 is optionally substituted phenyl. In other embodiments, R 4 is phenyl substituted with 1, 2 or 3 substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In another embodiment, R 4 is a 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 4Aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl, which may be substituted. In some embodiments, R 4 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, each of which may be substituted by one or more halogens.

[0049] In some embodiments, R 5 is hydrogen. In some embodiments, each R 5 is independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino or di-(C1-C4 alkyl)amino. In another embodiment, each R 5 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In another embodiment, R 5 is CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 5 is halogen. In another embodiment, R 5 is fluoro or chloro. In another embodiment, R 5is C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) (wherein p is 0, 1 or 2). In another embodiment, R 5 is methoxy, ethoxy, propoxy or butoxy. In another embodiment, R 5 is methylthio, ethylthio, propylthio or butylthio. In another embodiment, R 5 is -OCF3 or -SCF3. In some embodiments, R 5 is C1-C4-alkenyl or C1-C4-haloalkenyl. In some embodiments, R 5 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R 5 is optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene or tetrahydrothiophene. In some embodiments, R 5 is optionally substituted phenyl. In other embodiments, R 5 is phenyl substituted with 1, 2 or 3 substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In other embodiments, R 5is a 5- or 6-membered heteroaryl having one or two substituents independently selected from halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 5 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In some embodiments, R 5 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, each optionally substituted by one or more halogens.

[0050] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, Q is O. In some embodiments, Q is S. In some embodiments, Q is NR2’ is as follows. In some embodiments, W is CH2. In some embodiments, Z is CH2. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NH.

[0051] In some embodiments, the compound of formula (I) is a compound of formula (I-1):

Chemical formula

[0052] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

Chemical formula

[0053] In other embodiments, the compound of formula (I) is a compound of the following formula (I-3):

Chemical formula

[0054] In other embodiments, the compound of formula (I) is a compound of formula (I-4):

Chemical formula

[0055] In another embodiment, the compound of formula (I) is a compound of formula (I-5):

Chemical formula

[0056] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

Chemical Structure

[0057] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

Chemical Structure

[0058] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

Chemical Structure

[0059] In other embodiments, the compound of formula (I) is a compound of formula (Id):

Chemical Structure

[0060] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

Chemical Structure

[0061] In some embodiments, the compound of formula (I) is a compound of formula (If):

Chemical Structure

[0062] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

Chemical formula

[0063] In other embodiments, the compound of formula (I) is a compound of formula (Ih):

Chemical formula

[0064] In some embodiments, the compound of formula (I) is a compound of formula (Ii):

Chemical formula

[0065] Variable element R 4 and R 5 have been shown to be present as substituents on the aromatic ring (e.g., (R 4 )) n and (R 5 )) o group (wherein n is 0, 1, 2 or 3 and o is 0, 1, 2, 3 or 4)) In any of formulas (Ib) to (Ii), in the embodiment where n and o are 0, since R 4 and R 5 are absent, it will be recognized by those skilled in the art that these represent non-hydrogen substituents.

[0066] In other embodiments, the present invention includes compounds of formula (I) having the structures of formulas (Ia) to (Ii) shown above, wherein the sulfur atom corresponding to the variable element X in formula (I) is replaced by an oxygen atom. Thus, the present invention provides compounds of formulas (Ia'), (Ib'), (Ic'), (Id'), (Ie'), (If'), (Ig'), (Ih') and (Ii') corresponding to formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) and (Ii), wherein the sulfur atom in formulas (Ia) to (Ii) corresponding to the variable element X in formula (I) is replaced by oxygen.

[0067] In other embodiments, the present invention provides a compound of formula (IA) (wherein the variable elements R 1 , R 2 , R 3 , R 4 , R 5 , X, W, Z, R 10 and a are as defined for formula (I) above, and Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’is as shown in Table 1): [Chemical formula] (IA)

[0068] [Table 1-1] [Table 1-2]

[0069] In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein X is S. In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein X is O. In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein each R 4 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein each R 4 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein each R 4 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of formulas IA-1 to IA-56, wherein each R 4Provided are compounds of Formulas IA-1 to IA-56, wherein each R is independently H, -OCF3 or -SCF3.

[0070] In some embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein each R 5 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloaloxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein each R 5 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In some embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein each R 5 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein each R 5 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein each R 5 is independently H, -OCF3 or -SCF3. In other embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein R 2 and R 10 are independently H or C1-C3-alkyl. In other embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein a is 1, W is CH2 and Z is O.

[0071] In other embodiments, the present invention provides compounds of Formulas IA-1 to IA-56, wherein R 1is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group), and provides compounds of formulas IA-1 to IA-56.

[0072] In other embodiments, the present invention provides that R 3 is C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R bThese may combine with the nitrogen to which they are attached and may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered, or 6-membered heterocyclyl group), to provide a compound of formulae IA-1 to IA-56. In other embodiments, the present invention provides a compound of formulae IA-1 to IA-56, wherein X is S, and R 2 and R 10 are independently H or C1-C3-alkyl; W is CH2, Z is O, and a is 1.

[0073] In other embodiments, the present invention provides a compound of formula IA-1 as described above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by one to three halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl.

[0074] In other embodiments, the present invention provides a compound of formula IA-1 as described above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by one to three halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl.

[0075] In other embodiments, the present invention provides a compound of formula IA-1 as described above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by one to three halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2Provided is a compound of formula IA-9, wherein is H or C1-C3-alkyl. In other embodiments, the present invention provides a compound of formula IA-9, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl.

[0076] In other embodiments, the present invention provides a compound of formula IA-17, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl. In other embodiments, the present invention provides a compound of formula IA-17, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl.

[0077] In other embodiments, the present invention provides a compound of formula IA-17, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2Provided is a compound of formula IA-25 as defined above, wherein is H or C1-C3-alkyl. In other embodiments, the invention provides a compound of formula IA-25 as defined above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl. In other embodiments, the invention provides a compound of formula IA-25 as defined above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl. In other embodiments, the invention provides a compound of formula IA-49 as defined above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1-3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl.

[0078] In other embodiments, the invention provides a variable element R 1 R 2 R 4 R 5 X, W, Z, R 10 and a are as defined for formula (I) above, each R 9is cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, phenyl which may be substituted; phenyloxy which may be substituted, 5- or 6-membered heteroaryl which may be substituted, C3-C8-cycloalkyl which may be substituted, C3-C8-cycloalkyloxy which may be substituted, 3- to 7-membered heterocyclyl which may be substituted and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl) (wherein p is 0, 1 or 2), SF5, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); m is 0, 1, 2, 3 or 4; Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’ are as shown in Table 2, Provided are compounds of formula (IB) shown below:

[0079]

Chemical formula

[0080]

Table 2-1

Table 2-2

[0081] In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein X is S. In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein X is O. In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein each R 4 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein each R 4 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein each R 4 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein each R 4The present invention provides compounds of Formulas IB-1 to IB-56, wherein each R is independently H, -OCF3 or -SCF3.

[0082] In some embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein each R 5 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloaloxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein each R 5 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In some embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein each R 5 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein each R 5 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein each R 5 is independently H, -OCF3 or -SCF3.

[0083] In other embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein R 2 and R 10 are independently H or C1-C3-alkyl. In other embodiments, the present invention provides compounds of Formulas IB-1 to IB-56, wherein R 1is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b may together with the nitrogen to which they are attached form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group containing 1 to 3 additional heteroatoms selected from the group consisting of N, O and S) and provides compounds of formulae IB-1 to IB-56.

[0084] In other embodiments, the present invention provides that R 3 is C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R bThese may combine with the nitrogen to which they are attached and may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered or 6-membered heterocyclyl group), to provide compounds of formulae IB-1 to IB-56.

[0085] In other embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein a is 1, W is CH2, and Z is O. In other embodiments, the present invention provides R 9 each independently is halo, cyano, nitro, C3-C6-cycloalkyl, C1-C6-haloalkyl, C3-C6-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy or S(O) p (C1-C6-alkyl or C1-C6-haloalkyl), and m is 0, 1, 2 or 3, to provide compounds of formulae IB-1 to IB-56. In other embodiments, the present invention provides R 9 each independently is halo, and m is 1, 2 or 3, to provide compounds of formulae IB-1 to IB-56. In other embodiments, the present invention provides R 9 each independently is fluoro or chloro, and m is 1, 2 or 3, to provide compounds of formulae IB-1 to IB-56.

[0086] In other embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein X is S, R 9 each independently is halo, m is 1, 2 or 3, and R 2 and R 10 each independently is H or C1-C3-alkyl; W is CH2, Z is O, and a is 1.

[0087] In other embodiments, the present invention provides compounds of formulae IB-1 to IB-56, wherein X is S, R 9 each independently is chloro or fluoro, m is 1, 2 or 3, and R 2 and R 10Provided are compounds of formulae IB-1 to IB-56, wherein each is independently H or C1-C3-alkyl; W is CH2, Z is O, and a is 1. In another embodiment, the present invention provides a compound of formula IB-1, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0088] In another embodiment, the present invention provides a compound of formula IB-1, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. In another embodiment, the present invention provides a compound of formula IB-1, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9independently is halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-9 as described above.

[0089] In other embodiments, the present invention provides that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 independently is halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-9 as described above. In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 independently is halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-17 as described above.

[0090] In other embodiments, the present invention provides that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R9 wherein each R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-17 as described above. In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-25 as described above.

[0091] In other embodiments, the present invention provides that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IB-25 as described above. In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9Provided are compounds of formula IB-49 above, wherein each R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0092] In other embodiments, the invention provides compounds of formula (I)B-49, wherein X is O; R is optionally substituted C1-C3-alkyl; R is phenyl optionally independently substituted by 1 to 3 halos; each R is independently H or halo; each R is independently H or halo; R is H or C1-C3-alkyl; each R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. In other embodiments, the invention provides compounds of formula (IC), wherein the variable elements R, R, R, R, W and X are as defined for formula (I) above; R and m are as defined for formula IB above; o is 0, 1, 2, 3 or 4; and Y, Y and Y are as shown in Table 3: 1 R 2 R 4 R 5 R, W and X are as defined for formula (I) above; R 9 and m are as defined for formula IB above; o is 0, 1, 2, 3 or 4; Y 1 Y 2 Y 3 and Y are as shown in Table 3:

[0093]

Chemical formula

[0094]

Table 3

[0095] In some embodiments, the invention provides compounds of formulae IC-1 to IC-7, wherein X is S. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein X is O. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 4 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 4 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 4 is independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 4 is independently H, -OCF3 or -SCF3.

[0096] In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 5 is independently halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl); and o is 0, 1, 2 or 3. In some embodiments, the present invention provides compounds of Formulas IC-1 to IC-7, wherein each R 5where each R is independently chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl; and o is 0, 1, 2 or 3, there is provided a compound of formulae IC-1 to IC-7. In some embodiments, the present invention provides a compound of formulae IC-1 to IC-7, where each R 5 is independently CF3, -CH2CF3, -CHFCF3 or -CF2CF3; and o is 0, 1, 2 or 3. In some embodiments, the present invention provides a compound of formulae IC-1 to IC-7, where each R 5 is independently methoxy, ethoxy, propoxy or butoxy; and o is 0, 1, 2 or 3. In some embodiments, the present invention provides a compound of formulae IC-1 to IC-7, where each R 5 is independently -OCF3 or -SCF3; and o is 0, 1, 2 or 3.

[0097] In other embodiments, the present invention provides a compound of formulae IC-1 to IC-7, where R 2 is H or C1-C3-alkyl.

[0098] In other embodiments, the present invention provides a compound of formulae IC-1 to IC-7, where R 1 is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R bwhich, together with the nitrogen to which they are attached, may contain one to three additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group), to provide compounds of formulas IC-1 to IC-7.

[0099] In other embodiments, the invention provides R 3 is C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, an optionally substituted 3- to 7-membered heterocyclyl containing one to three heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b together with the nitrogen to which they are attached, may contain one to three additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group), to provide compounds of formulas IC-1 to IC-7.

[0100] In other embodiments, the invention provides R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide compounds of formulas IC-1 to IC-7. In other embodiments, the invention provides R 9 is independently halo and m is 1, 2 or 3, to provide compounds of formulas IC-1 to IC-7. In other embodiments, the invention provides R 9Provided are compounds of formulas IC-1 to IC-7, wherein each is independently fluoro or chloro, and m is 1, 2 or 3. In another embodiment, the present invention provides a compound of formulas IC-1 to IC-7, wherein X is S; 9 each is independently halo, m is 1, 2 or 3; 2 and each is H or C1-C3-alkyl. In another embodiment, the present invention provides a compound of formulas IC-1 to IC-7, wherein X is S; 9 each is independently chloro or fluoro, m is 1, 2 or 3; 2 and each is H or C1-C3-alkyl. In another embodiment, the present invention provides a compound of formula IC-1 above, wherein each is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. 9

[0101] In another embodiment, the present invention provides a compound of formula IC-2 above, wherein each is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. 9 In another embodiment, the present invention provides a compound of formula IC-3 above, wherein each is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. 9

[0102] In another embodiment, the present invention provides a compound of formula IC-7 above, wherein each is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. 9 In another embodiment, the present invention provides a compound wherein X is S; 1 each is optionally substituted C1-C3-alkyl; 3is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo; o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IC-1 as described above.

[0103] In other embodiments, the present invention provides a compound of formula IC-1 wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo; o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. In other embodiments, the present invention provides a compound of formula IC-1 wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo, o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide a compound of formula IC-2 as described above.

[0104] In other embodiments, the present invention provides a compound of formula IC-1 wherein X is O; R 1is C1-C3-alkyl which may be substituted; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; R 5 is halo, o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide the compound of formula IC-2 above. In other embodiments, the present invention is such that X is S; R 1 is C1-C3-alkyl which may be substituted; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo, o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide the compound of formula IC-3 above. In other embodiments, the present invention is such that X is O; R 1 is C1-C3-alkyl which may be substituted; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo, o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide the compound of formula IC-3 above.

[0105] In other embodiments, the present invention is such that X is S; R1 is C1-C3-alkyl which may be substituted; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo, and o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide the compound of formula IC-7 above.

[0106] In another embodiment, the present invention is such that X is O; R 1 is C1-C3-alkyl which may be substituted; R 3 is phenyl which may be independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently halo, and o is 0, 1 or 2; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, to provide the compound of formula IC-7 above.

[0107] In another embodiment, the present invention is such that the variable elements R 1 R 2 R 4 R 5 R 10 X, W, Z and a are as defined for formula (I) above; R 9 and m are as defined for formula IB above; b is 0 or 1; the dashed bond

Chemical formula

[0108]

Chemical formula

[0109]

Table 4-1

Table 4-2

[0110] In some embodiments, the present invention provides compounds of formulae ID-1 to ID-56, wherein X is S. In some embodiments, the present invention provides compounds of formulae ID-1 to ID-56, wherein X is O.

[0111] In some embodiments, the present invention provides compounds of formulae ID-1 to ID-56, wherein the dashed bond is a single bond. In some embodiments, the present invention provides compounds of formulae ID-1 to ID-56, wherein the dashed bond is a double bond.

[0112] In some embodiments, the present invention provides compounds of formulae ID-1 to ID-56, wherein D is CH, C-halo or N. In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein D is C, CH, C-F or N.

[0113] In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D 1 is CR 4 R 5 (wherein R 4 and R 5 together may form a 2- to 5-membered chain containing one heteroatom in the chain to form a spirocyclic group). In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D 1 is CH2, independently C-(halo)2, CH(C1-C3-alkyl) or CH(C1-C3-haloalkyl). In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D 1 is CH2, independently CF2, CH(CH3) or CH(CF3). In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D 1 is O, S, S(O) or S(O)2. In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D is CH or C-halo; and D 1 is CH2. In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D is N; and D 1 is CH2, O or S.

[0114] In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein the dashed line is a double bond; D is C; and D 1 is CH2, CF2, O or S. In some embodiments, the present invention provides a compound of Formulas ID-1 to ID-56, wherein D is N; and D 1 is CR 4 R 5 (wherein R 4 and R 5Combine to form a 2- to 4-membered chain that may contain one oxygen in the chain to form a spirocyclic group), and provide compounds of Formulas ID-1 to ID-56. In some embodiments, the present invention has D being CH; D 1 being CR 4 R 5 (wherein R 4 and R 5 Combine to form a 2- to 4-membered chain that may contain one oxygen in the chain to form a spirocyclic group), and provide compounds of Formulas ID-1 to ID-56.

[0115] In some embodiments, the present invention has D being C, and the dashed bond represents a double bond; D 1 being CR 4 R 5 (wherein R 4 and R 5 Combine to form a 2- to 4-membered chain that may contain one oxygen in the chain to form a spirocyclic group), and provide compounds of Formulas ID-1 to ID-56. In some embodiments, the present invention has R 4 independently being H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloaloxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl), and provide compounds of Formulas ID-1 to ID-56. In some embodiments, the present invention has R 4 independently being H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and provide compounds of Formulas ID-1 to ID-56. In some embodiments, the present invention has R 4 independently being H, CF3, -CH2CF3, -CHFCF3, -CF2CF3, and provide compounds of Formulas ID-1 to ID-56. In some embodiments, the present invention has R 4The present invention provides compounds of Formulas ID-1 to ID-56, wherein each R is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 4 is independently H, -OCF3 or -SCF3.

[0116] In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 5 is independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 5 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl. In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 5 is independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3. In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 5 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 5 is independently H, -OCF3 or -SCF3.

[0117] In other embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 2 is H or C1-C3-alkyl. In other embodiments, the present invention provides compounds of Formulas ID-1 to ID-56, wherein each R 1is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group), to provide compounds of formulae ID-1 to ID-56.

[0118] In other embodiments, the invention provides compounds of formulae ID-1 to ID-56, wherein R 9 are independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, m is 0, 1, 2 or 3, and b is 0 or 1. In other embodiments, the invention provides compounds of formulae ID-1 to ID-56, wherein R 9 are independently halo and m is 1, 2 or 3. In other embodiments, the invention provides compounds of formulae ID-1 to ID-56, wherein R 9 are independently fluoro or chloro and m is 1, 2 or 3.

[0119] In other embodiments, the invention provides compounds of formulae ID-1 to ID-56, wherein X is S, R 9 are independently halo, m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl. In other embodiments, the present invention provides that X is S, and R 9 is independently chloro or fluoro, m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl, and provides compounds of Formulas ID-1 to ID-56. In other embodiments, the present invention provides that X is S, and R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy; D is N or CH; D 1 is NH, O or CH2; b is 0 or 1; m is 0, 1, 2 or 3, and provides compounds of Formulas ID-1 to ID-56.

[0120] In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides the above compound of Formula ID-1. In other embodiments, the present invention provides that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides the above compound of Formula ID-1.

[0121] In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides the compound of formula ID-9 above. In other embodiments, the present invention provides that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides the compound of formula ID-9 above.

[0122] In other embodiments, the present invention provides that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides the compound of formula ID-17 above. In other embodiments, the present invention provides a compound of formula ID-17, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0123] In other embodiments, the present invention provides a compound of formula ID-25, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3. In other embodiments, the present invention provides a compound of formula ID-25, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0124] In other embodiments, the present invention is such that X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides a compound of the above formula ID-49. In other embodiments, the present invention is such that X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally independently substituted by 1 to 3 halos; each R 4 is independently H or halo; each R 5 is independently H or halo; R 2 is H or C1-C3-alkyl; R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3, and provides a compound of the above formula ID-49.

[0125] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ , Y 5’ each is CH. In any of the embodiments of Table 1, 2 or 4 above, one of Y 2’ , Y 3’ , Y 4’ and Y 5’ is CR 5 (wherein R 5 is a non-hydrogen substituent). In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y3’ and Y 4’ and Y 5’ two of which are CR 5 (where each R 5 is independently a non-hydrogen substituent). In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ three of which are CR 5 (where each R 5 is independently a non-hydrogen substituent). In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ all four of which are CR 5 (where each R 5 is independently a non-hydrogen substituent).

[0126] In any of the embodiments of Tables 1 to 4 above, each of Y 1 and Y 2 and Y 3 is CH. In any of the embodiments of Tables 1 to 4 above, one of Y 1 and Y 2 and Y 3 is CR 4 (where R 4 is a non-hydrogen substituent). In any of the embodiments of Tables 1 to 4 above, two of Y 1 and Y 2 and Y 3 are CR 4 (where each R 4 is independently a non-hydrogen substituent). In any of the embodiments of Tables 1 to 4 above, three of Y 1 and Y 2 and Y 3 are CR 4 (where each R 4 is independently a non-hydrogen substituent). In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y3’ and Y 4’ and Y 5’ One of them is C-halogen. In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ Two of them are C-halogen. In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ Three of them are C-halogen.

[0127] In any of the embodiments of Table 1-4 above, Y 1 and Y 2 and Y 3 One of them is C-halogen. In any of the embodiments of Table 1-4 above, Y 1 and Y 2 and Y 3 Two of them are C-halogen. In any of the embodiments of Table 1-4 above, Y 1 and Y 2 and Y 3 Three of them are C-halogen. In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ One of them is C-Cl or C-F. In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ Two of them are independently C-Cl or C-F. In any of the embodiments of Table 1, 2 or 4 above, Y 2’ and Y 3’ and Y 4’ and Y 5’ Three of them are independently C-Cl or C-F.

[0128] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 one of them is C-Cl or C-F. In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 two of them are independently C-Cl or C-F. In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 all three of them are independently C-Cl or C-F.

[0129] In any of the embodiments of Table 1, 2 or 4 above, a is 1, W is -CH2-, and Z is O. In any of the embodiments of Tables 1 to 4 above, R 1 is C1-C4-alkyl, C1-C4-alkenyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, morpholino, pyranyl, tetrahydropyranyl or dihydropyranyl. In any of the embodiments of Tables 1 to 4 above, one, two or three of the R 4 are hydrogen. In any of the embodiments of Tables 1 to 4 above, a certain R 4 is independently of the other R 4 halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl which may be substituted one or two times by halogen or C1-C4-alkyl. In any of the embodiments of Tables 1 to 4 above, a certain R 5 is independently of the other R 5Independently, it is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl which may be substituted one or two times by halogen or C1-C4-alkyl.

[0130] In other embodiments, the present invention is such that Y1, Y2, Y3, L, X, R1 and R3 are shown in the table; R 2 and R 2’ are both hydrogen; Q is oxygen; the group:

Chemical formula

[0131]

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0132] In Table 5, the expression "3,5-di-F-Ph" represents a 3,5-difluorophenyl group; "3,5-di-Cl-Ph" represents 3,5-dichlorophenyl; "2,3,5-tri-F-Ph" represents 2,3,5-trifluorophenyl; "3-F-Ph" represents 3-fluorophenyl; "2,6-di-F-Ph" represents 2,6-difluorophenyl; "2,3-di-Cl-Ph" represents 2,3-dichlorophenyl; "2,3,6-tri-F-Ph" represents 2,3,6-trifluorophenyl; "4-F-2,6-di-Me-Ph" represents 4-fluoro-2,6-dimethylphenyl; "2-Cl-6-F-Ph" represents 2-chloro-6-fluorophenyl; "3-Cl-5-(3,5-di-Cl-Ph)-Ph represents 3-chloro-5-(3,5-dichlorophenyl)phenyl; and so on; Prop-1-en-2-yl is the group [Chemical] represented by; 2-OH-prop-2-yl is the group [Chemical] represented by; 2-F-prop-2-yl is the group [Chemical] represented by. [Chemical] Formula (I)

[0133] [Table 5-1]

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

[0134] To avoid ambiguity, each of the compounds presented in Table 5 was prepared and tested.

[0135] Stereoisomers and polymorphic forms It is recognized by those skilled in the art that the compounds can exist and be isolated as optically active forms and racemic forms. Compounds having one or more chiral centers, including those at sulfur atoms, can exist as single enantiomers or diastereomers, or as mixtures of enantiomers and / or diastereomers. For example, it is well known in the art that sulfoxide compounds can be optically active and can exist as single enantiomers or racemic mixtures. Further, the compounds of the present invention contain one or more chiral centers and can give rise to the theoretical number of optically active isomers. In this case, the compounds of formula (I) contain at least one chiral center, and the carbon atoms are variable elements R 10 having. When the compounds herein contain n chiral centers, the compounds are up to 2 nIt may contain individual optical isomers. Thus, the compounds of the present invention include at least two enantiomers encompassed by the present invention. The present invention encompasses specific enantiomers or diastereomers of each compound having the useful properties described herein, as well as mixtures of various enantiomers and / or diastereomers of the compounds. The optically active forms can be prepared, for example, by resolution of the racemic form by selective crystallization techniques, synthesis from optically active precursors, chiral synthesis, chromatographic separation using a chiral stationary phase, or enzymatic resolution. The compounds can also exist in various solid forms such as various crystalline forms or in the form of an amorphous solid. The present invention includes various crystalline forms as well as amorphous forms of the compounds. Furthermore, the compounds can exist as hydrates or solvates in which a certain stoichiometric amount of water or solvent is associated with the molecules in the crystalline form. Hydrates and solvates of the compounds are also the subject of the present invention.

[0136] Salt In addition to the neutral compounds, the salt forms of the compounds are also active against endoparasites. The term "veterinarily acceptable salt" is used throughout this specification to describe any salt of a compound that is acceptable for administration for veterinary use and provides the active compound upon administration. If the compound is sufficiently basic or acidic to form stable, non-toxic acid or base salts, the compound can be in the form of a veterinarily or agriculturally acceptable salt. Veterinarily acceptable salts include those derived from veterinarily or agriculturally acceptable inorganic or organic bases and acids. Suitable salts include those containing alkali metals such as lithium, sodium or potassium, and alkaline earth metals such as calcium, magnesium and barium. Also suitable are salts containing transition metals including, but not limited to, manganese, copper, zinc and iron. Furthermore, salts containing the ammonium cation (NH4 + ) and substituted ammonium cations in which one or more of the hydrogen atoms are replaced by alkyl or aryl groups are encompassed by the present invention.

[0137] Salts derived from inorganic acids including, but not limited to, hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, etc. are particularly suitable. Suitable inorganic salts also include, but are not limited to, bicarbonates and carbonates. In some embodiments, examples of veterinarily and agriculturally acceptable salts include, but are not limited to, maleates, dimaleates, fumarates, tosylates, methanesulfonates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbates, α-ketoglutarates, and α-glycerophosphates, which are organic acid addition salts formed with organic acids. Of course, other acceptable organic acids may also be used. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of the compounds can also be prepared by reacting sufficiently acidic residues on the compounds with hydroxides of alkali metals or alkaline earth metals. Veterinarily acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitably acidic functional group present in the compound, or by reacting a suitable acid with a suitably basic functional group on the compound of the present invention.

[0138] Method for preparing the compound The compound of formula (I) or its pharmaceutically or veterinarily acceptable salt can be prepared by adopting one of the following Schemes 1 - 4 or Schemes 5 - 12 and the procedures of the examples: Scheme 1

[0139]

Chemical formula

[0140]

Chemical formula

[0141] [Chemistry] Scheme 4

[0142] [Chemistry]

[0143] It is well within the skill level of one of ordinary skill in the art to synthesize the specific compounds of the present invention by adapting these schemes. Furthermore, the starting materials are readily available or can be prepared via known procedures.

[0144] Veterinary compositions The compounds and compositions containing the compounds are useful for the prevention and treatment of parasitic infestations / infections in animals. The compositions of the present invention comprise an effective amount of a compound or a veterinarily acceptable salt thereof in combination with a veterinarily acceptable carrier or diluent and optionally an inert excipient. The compositions can be in various solid and liquid forms suitable for various forms of administration or dosage to animals. For example, the veterinary compositions containing the compound can be compositions suitable for oral administration, injection administration including subcutaneous and parenteral administration, and topical administration (e.g., spot-on and pour-on), skin or subcutaneous administration. The compositions are intended for administration to animals including, but not limited to, mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cows, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other domestic or bred mammals. Examples of birds include turkeys, chickens, ostriches and other domestic or bred birds. The use of the compounds for protecting companion animals such as dogs and cats from endoparasites is particularly useful.

[0145] As discussed above, the compositions of the present invention can be in a form suitable for oral use (e.g., see U.S. Patent No. 4,564,631, which is hereby incorporated by reference in its entirety), nutritional supplements, troches, lozenges, chewables, tablets, hard or soft capsules, boluses, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral liquid compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric compositions or pastes. Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more sweetening agents, bitter agents, flavoring agents, coloring agents and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets can contain the active ingredient as a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated, or tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 (all of which are hereby incorporated by reference in their entirety) to form osmotic therapeutic tablets for controlled release.

[0146] The oral composition includes hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin. The capsules can also be soft gelatin capsules in which the active ingredient is mixed with water, or a miscible solvent such as propylene glycol, PEG and ethanol, or an oil medium such as peanut oil, liquid paraffin or olive oil. In one embodiment, the compound can be administered in a chewable tablet composition or a soft chewable composition, such as those described in US Patent Application Publication No. 2013 / 0203692, US Patent Application Publication No. 2010 / 0087492, US Patent Application Publication No. 2006 / 0222684, US Patent Application Publication No. 2004 / 0151759, US Patent No. 7955632, all of which are incorporated herein by reference. The veterinary composition can be in the form of a palatable, animal-acceptable soft chewable composition (a "soft chew"). The soft chews of the present invention can include, in addition to the active ingredient, one or more of the following ingredients: a solvent or mixture of solvents, one or more fillers, 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 adjusters and one or more flavoring agents.

[0147] Solvents that can be used in the compositions of the present invention include, but are not limited to, various grades of liquid polyethylene glycol (PEG) including PEG200, PEG300, PEG400 and PEG540; 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 polyglycolized glycerides (e.g., GELUCIRE®), or combinations thereof. A variety of fillers known in the art can be used in the soft curable composition of the present invention. Fillers include, but are not limited to, corn starch, pregelatinized starch, soybean protein powder, corn cob, and corn gluten meal, etc. In some embodiments, a combination of two or more fillers can be used in the composition.

[0148] Binders that can be used in the composition of the present invention include, but are not limited to, various grades of polyethylene glycol such as polyvinylpyrrolidone (e.g., povidone), cross-linked polyvinylpyrrolidone (crospovidone), PEG3350, PEG4000, PEG6000, PEG8000, and even PEG20,000; copolymers of vinylpyrrolidone and vinyl acetate (e.g., copovidone) such as the product sold under the trade name Kollidon® VA64 by BASF, etc.; starches such as potato starch, tapioca starch, or corn starch; molasses, corn syrup, honey, maple syrup, and various types of sugars; or a combination of two or more binders. Water retention agents that can be used in the composition include, but are not limited to, glycerol (also referred to as glycerin herein), propylene glycol, cetyl alcohol, and glycerol monostearate, etc. Various grades of polyethylene glycol can also be used as water retention agents.

[0149] Surfactants may be present in the composition to improve solubility and absorption after ingestion. 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 composition include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan 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 (e.g., poloxamers such as LUTROL® F87), polyethylene glycol castor oil derivatives including polyoxy 35 castor oil (Cremophor® EL), polyoxy 40 hydrogenated castor oil (Cremophor® RH40), polyoxy 60 hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL®); glycerol caprylate / caprate (CAPMUL® MCM), polyglycolized glycerides (GELUCIRE®), PEG300 caprylic / capric glyceride (Softigen® 767), PEG400 caprylic / capric glyceride (Labrasol®), glyceride esters including PEG300 oleic acid glyceride (Labrafil® M-1944CS), PEG300 linoleic acid glyceride (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG400 monostearate), polyoxyl 40 stearate (PEG1750 monostearate), etc.

[0150] The composition may contain other inert components such as antioxidants, preservatives or pH stabilizers. These compounds are well-known in the field of the composition. Antioxidants can be added to the composition of the present invention to inhibit the decomposition of the active agent. Suitable antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylhydroxyanisole), BHT (butylhydroxytoluene), monothioglycerol, etc. The composition of the present invention may also include one or more lubricants and / or processing aids. In some cases, the lubricant / processing aid can also act as a solvent, and thus some of the components of the composition of the present invention may have a dual function. Lubricants / processing aids include, but are not limited to, polyethylene glycols of various molecular weight ranges including PEG3350 (Dow Chemical) and PEG4000, corn oil, mineral oil, hydrogenated vegetable oil (STEROTEX or LUBRITAB), peanut oil and / or castor oil.

[0151] Many flavoring agents can be used in the composition of the present invention to improve the taste of the oral veterinary composition. Preferred flavoring agents are those not derived from animal sources. In various embodiments, flavor components derived from fruits, meats (including, but not limited to, pork, beef, chicken, fish, poultry meat, etc.), vegetables, cheeses, bacon, cheese bacon and / or artificial flavors can be used. The flavor components are typically selected based on considerations related to the organism that ingests the soft chew. For example, horses may prefer apple flavor components, while dogs may prefer meat flavor components. Flavor components not derived from animal sources are preferred, but in some embodiments, natural flavoring agents containing beef or liver extracts such as steamed beef flavoring agent, artificial powdered beef flavoring agent, roasted beef flavoring agent and corned beef flavoring agent can be used. In another embodiment of the present invention, the active composition can be administered via a hydropharmaceutical, and can be administered topically or orally. The hydropharmaceutical composition is one in which the liquid-containing composition of the present invention is administered into the mouth or throat of an animal, or poured onto the skin or coat of an animal.

[0152] The composition of the present invention can also be in the form of an oil-in-water or water-in-oil emulsion. 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 naturally occurring phosphatides, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners, bitter agents, flavoring agents and / or preservatives. In one embodiment, the composition of the present invention can be in the form of a microemulsion. Microemulsions are well suited as liquid carrier vehicles. A microemulsion is a four-component system comprising an aqueous phase, an oil phase, a surfactant and a co-surfactant. These are translucent isotropic liquids. A microemulsion is composed of a stable dispersion of microdroplets of an aqueous phase into an oil phase, or conversely, a stable dispersion of microdroplets of an oil phase into an aqueous phase. The size of these microdroplets can be less than 200 nm (1000 - 100,000 nm for emulsions). The interfacial film can be composed of alternating surfactant (SA) and co-surfactant (Co-SA) molecules that allow the microemulsion to form spontaneously by reducing the interfacial tension.

[0153] In one embodiment of the oil phase, the oil phase can be formed from a mineral oil or vegetable oil, an unsaturated polyglycosylated glyceride, or a triglyceride, or a mixture of such compounds. In one embodiment of the oil phase, the oil phase can be composed of triglycerides; in another embodiment of the oil phase, the triglycerides are medium-chain triglycerides, such as C8-C 10It is capric / caprylic triglyceride. In another embodiment, the oil phase can be in the range of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v / v of the microemulsion. The aqueous phase can include, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol, or glycerol. In one embodiment, the glycol can be propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, or a mixture thereof. Generally, the aqueous phase is present in the microemulsion at a ratio of about 1 to about 4% v / v.

[0154] Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolated C8-C 10 Glycerides or polyglyceryl-6 dioleate can be included. In addition to these surfactants, co-surfactants can include short-chain alcohols such as ethanol and propanol. Some compounds are common to the three components discussed above, namely, the aqueous phase, the surfactant, and the co-surfactant. However, it is well within the skill level of one of ordinary skill in the art to use different compounds for each component of the same composition. In one embodiment regarding the amount of surfactant / co-surfactant, the ratio of co-surfactant to surfactant is about 1 / 7 to about 1 / 2. In another embodiment regarding the amount of co-surfactant, there is about 25 to about 75% v / v of surfactant and about 10 to about 55% v / v of co-surfactant in the microemulsion. The oily suspension can be formulated 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. The oily suspension may contain a thickening agent such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners such as sucrose, saccharin, or aspartame, bitter agents, and flavoring agents can be added to obtain a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid or other known preservatives.

[0155] The aqueous suspension may contain the active material as a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersing agents or wetting agents include naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecaethylene oxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening and / or bittering agents such as those shown above. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water may provide the active ingredient as a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening agents, bittering agents, flavoring agents and colorants may also be present. Syrups and elixirs may be formulated using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain demulcents, preservatives, flavoring agents and / or colorants.

[0156] In another embodiment of the present invention, the composition can be in the form of a paste. Examples of paste form embodiments include, but are not limited to, those described in U.S. Patent Nos. 6,787,342 and 7,001,889 (each incorporated herein by reference). In addition to the compounds of the present invention, the paste can further contain fumed silica; a viscosity modifier; a carrier; optionally, an absorbent; and optionally, a colorant, a stabilizer, a surfactant or a preservative. In one embodiment of the composition, the composition can be a paste containing the compound of the present invention, fumed silica, a viscosity modifier, an absorbent, a colorant; and a hydrophilic carrier that is triacetin, a monoglyceride, a diglyceride or a triglyceride. The paste can also include a viscosity modifier. Suitable viscosity modifiers include, but are not limited to, polyethylene glycols (PEGs) including PEG200, PEG300, PEG400, PEG600; monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or Tween 80) and poloxamers (e.g., Pluronic L 81); absorbents such as magnesium carbonate, calcium carbonate, starch and cellulose and its derivatives; and colorants including, but not limited to, titanium dioxide, iron oxide or FD&C Blue No. 1 aluminum lake.

[0157] In some embodiments, the composition can be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to the prior art using a suitable dispersing or wetting agent and suspending agent mentioned above. The sterile injectable preparation can also be a sterile injection solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol, glycerol formal or polyethylene glycol may be used. Preservatives such as phenol or benzyl alcohol may be used. Furthermore, a sterilized non-volatile oil can be customarily used as a solvent or a suspending medium. For this purpose, any non-irritating non-volatile oil containing synthetic mono- or diglycerides can be used. Furthermore, fatty acids such as oleic acid have found use in the preparation of injectables.

[0158] Topical skin and subcutaneous compositions can include, by way of non-limiting example, emulsions, creams, ointments, gels, pastes, powders, shampoos, pore-on compositions, ready-to-use compositions, spot-on solutions and suspensions, dips and sprays. By topical application of the composition of the present invention in the form of a compound or a spot-on, spray-on or pore-on composition containing at least one compound of the present invention among several active agents therein, the composition of the present invention can be absorbed through the skin to achieve a systemic level and distributed through the sebaceous glands or onto the surface of the skin to achieve a level through the hair coat. When the compounds are distributed through the sebaceous glands, they can act as reservoirs, thereby enabling a sustained effect (up to several months). Spot-on compositions are typically applied to a restricted area, which typically refers to an area that is not the entire animal. In one embodiment, the location can be between the shoulders. In another embodiment, the location can be a stripe, for example, a stripe from the head to the tail of the animal. Pore-on compositions are described in U.S. Patent No. 6,010,710, which is hereby incorporated by reference. Pore-on compositions are advantageously oily and can generally include a diluent or vehicle for the active ingredient and, if the active ingredient is insoluble in the diluent, a solvent (e.g., an organic solvent).

[0159] The organic solvents that can be used in the present invention include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl ester, 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 glycol, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, triacetin, C1-C 10 esters such as butyl or octyl acetate, and diethyl phthalate, or a mixture of at least two of these solvents is included.

[0160] The solvent is used according to the concentration of the active compound and its solubility in this solvent. The solvent is made to have the lowest possible volume. The vehicle constitutes a difference up to 100%. The vehicle or diluent for the composition may include dimethyl sulfoxide (DMSO), glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol or glycerol. As the vehicle or diluent, but not limited to, vegetable oils such as soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil; mineral oils such as, but not limited to, petrolatum, paraffin, silicone; aliphatic or cyclic hydrocarbons, or for example medium-chain (C8-C 12 etc.) triglycerides can also be mentioned.

[0161] In another embodiment of the present invention, a softening agent and / or spreading agent and / or film-forming agent may be added. In one embodiment, the softening agent and / or spreading agent and / or film-forming agent may be as follows: (a) Polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethyl cellulose, silicone oil, polydiorganosiloxane oil (such as polydimethylsiloxane (PDMS) oil), for example those containing silanol functional groups, or 45V2 oil, (b) Anionic surfactants, such as alkali stearates, sodium stearate, potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (for example, sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctyl sulfosuccinate; fatty acids (for example, those derived from coconut oil), (c) Cationic surfactants include water-soluble quaternary ammonium salts of the formula N + R’R’’R’’’R’’’’,Y - (wherein the group R is the same or different hydrocarbon groups which may be hydroxylated, and Y - is an anion of a strong acid such as halides, sulfates and sulfonate anions); among the cationic surfactants that can be used is cetyltrimethylammonium bromide, (d) Amine salts of the formula N + HR’R’’R’’’ (wherein the group R is the same or different hydrocarbon groups which may be hydroxylated); among the cationic surfactants that can be used is octadecylamine hydrochloride, (e) Non-ionic surfactants, such as sorbitan esters which may be polyoxyethylenated (e.g., polysorbate 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols, such as polyoxypropylene-styrene ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, (f) Amphoteric surfactants, such as substituted lauryl compounds of betaine; or (g) Mixtures of at least two of these agents.

[0162] In one embodiment of the amount of the softening agent, the softening agent used may be in a proportion of about 0.1 to 50% by volume or 0.25 to 5% by volume. In another embodiment, the softening agent used may be in a proportion of about 0.1% by volume to about 30% by volume, about 1% by volume to about 30% by volume, about 1% by volume to about 20% by volume, or about 5% by volume to about 20% by volume. In another embodiment of the present invention, the composition may be in an immediately usable solution form as described in U.S. Patent No. 6,395,765, which is incorporated herein by reference. In addition to the compounds of the present invention, the immediately usable solution may contain a crystallization inhibitor and an organic solvent or a mixture of organic solvents. In some embodiments, water may be included together with the organic solvent.

[0163] In various embodiments of the present invention, the composition may contain a crystallization inhibitor in an amount of about 1 to about 50% (w / v) or about 5 to about 40% (w / v) based on the total mass of the composition. In other embodiments, the amount of the crystallization inhibitor in the composition of the present invention may be about 1% to about 30%, about 5% to about 20%, about 1% to about 15% or about 1% to about 10% (w / w). The type of the crystallization inhibitor used in the composition of the present invention is not limited as long as it functions to inhibit the crystallization of the active agent or the inactive agent from the composition. For example, in certain embodiments of the present invention, if the solvent or co-solvent of the composition sufficiently inhibits the formation of crystals over time when the composition is administered, it may also function as a crystallization inhibitor.

[0164] Crystallization inhibitors useful in the present invention include, but are not limited to, the following: (a) Polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as acrylates or methacrylates or polymers or copolymers thereof, polyethylene glycol (PEG) or polymers containing polyethylene glycol such as glycofurol, etc.; (b) Anionic surfactants such as alkali stearates (e.g., sodium stearate, potassium stearate or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates including, but not limited to, sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzene sulfonate or sodium dioctyl sulfosuccinate; or fatty acids (e.g., coconut oil); (c) Cationic surfactants such as the water-soluble quaternary ammonium salts of the formula N + R’R’’R’’’R’’’’,Y - (wherein the R groups are the same or different hydrocarbon groups which may be hydroxylated, and Y - is an anion of a strong acid such as a halide, sulfate and sulfonate anions); cetyltrimethylammonium bromide is one of the cationic surfactants that can be used; (d) Amine salts of the formula N + HR’R’’R’’’(wherein the R groups are the same or different hydrocarbon groups which may be hydroxylated); octadecylamine hydrochloride is one of the cationic surfactants that can be used; (e) Non-ionic surfactants, such as sorbitan esters which may be polyoxyethylenated, for example, polysorbate 80, or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, 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; (g) A mixture of at least two of the compounds listed in (a) to (f) above; or (h) An organic solvent or a mixture of solvents that inhibits the formation of crystals or amorphous solids after administration of the composition.

[0165] In one embodiment of the crystallization inhibitor, a crystallization inhibitor pair is used. Such pairs include, for example, combinations of polymeric film-forming agents and surfactants. These agents are selected from the compounds mentioned above as crystallization inhibitors. In some embodiments, the organic solvent may have a dielectric constant between about 10 and about 35 or between about 20 and about 30. In other embodiments, the organic solvent may have a dielectric constant between about 10 and about 40 or between about 20 and about 30. The content of this organic solvent or mixture of solvents in the overall composition is not limited and is present in an amount sufficient to dissolve the desired components to the desired concentration. As discussed above, the organic solvent may also function as a crystallization inhibitor in the composition. In some embodiments, one or more of the organic solvents may have a boiling point of less than about 100 °C or less than about 80 °C. In other embodiments, the organic solvent may have a boiling point of less than about 300 °C, less than about 250 °C, less than about 230 °C, less than about 210 °C or less than about 200 °C.

[0166] In some embodiments where there is a mixture of solvents, i.e., a solvent and a co-solvent, the solvent can be present in the composition at a mass / mass (W / W) ratio of about 1 / 50 to about 1 / 1. Typically, the ratio of the solvent is about 1 / 30 to about 1 / 1, about 1 / 20 to about 1 / 1 or about 1 / 15 to about 1 / 1 by mass. Preferably, the two solvents are present at a mass / mass ratio of about 1 / 15 to about 1 / 2. In some embodiments, at least one of the solvents present can improve the solubility of the active agent or act as a drying accelerator. In certain embodiments, at least one of the solvents is miscible with water. The composition can also include an antioxidant intended to inhibit oxidation in air, and this agent can be present in a proportion of about 0.005 to about 1% (w / v), about 0.01 to about 0.1% or about 0.01 to about 0.05%. In one embodiment of the film-forming agent, the agent is a polymer type including, but not limited to, various grades of polyvinylpyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinyl pyrrolidone. In one embodiment of the surfactant, the agent includes, but is not limited to, those made of non-ionic surfactants; in another embodiment of the surfactant, the agent is a polyoxyethylenated sorbitan ester, and in yet another embodiment of the surfactant, the agent includes various grades of polysorbate, such as polysorbate 80.

[0167] In another embodiment of the present invention, the film-forming agent and the surfactant can be incorporated in similar or the same amounts within the limit of the total amount of the crystallization inhibitor mentioned elsewhere. The crystallization inhibitor inhibits the formation of crystals on the coat and improves the maintenance of the aesthetic appearance of the skin or fur; that is, it has no tendency to stick or to have a sticky appearance, despite the high concentration of the active material. Substances other than those mentioned herein may be used as the crystallization inhibitor in the present invention. In one embodiment, the effectiveness of the crystallization inhibitor is demonstrated by a test in which 0.3 mL of a solution containing 10% (w / v) of the active agent in a suitable solvent as defined above, and 10% (w / v) of a compound acting as the crystallization inhibitor, are placed on a slide glass at 20 °C for 24 hours, and then fewer than 10 crystals, preferably 0 crystals, are visible to the naked eye on the slide glass. In one embodiment of the antioxidant, the agent is conventional in the art and includes, but is not limited to, butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or a mixture of at least two compounds having antioxidant properties.

[0168] The composition adjuvants discussed above are well known to those skilled in the art and can be obtained commercially or through known techniques. These concentrated compositions are generally prepared by simply mixing the components as defined above; advantageously, the starting point is to mix the active material in the main solvent and then add the other components or adjuvants. The volume of the composition to be administered depends on the type of animal and the size of the animal, as well as the concentration of the composition and the potency of the active agent. In one embodiment, an amount of the composition from about 0.1 to about 20 ml can be administered to the animal. In other embodiments of the volume, the volume can 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, the administration of the spot-on composition according to the present invention can also provide sustained and wide-area effectiveness when the solution is administered to a mammal or a bird. The spot-on composition provides topical administration of a concentrated solution, suspension, microemulsion, or emulsion (spot-on type solution) for intermittent administration to a local area of the animal, generally between the two shoulders.

[0169] For spot-on compositions, the carrier can be a liquid carrier vehicle as described in U.S. Patent No. 6,426,333 (incorporated herein by reference). In one embodiment, the spot-on composition can include, but is not limited to, acetone, aliphatic alcohols such as methanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol, heptanol, octanol, nonanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, etc.; aromatic alcohols such as phenol, cresol, naphthol, benzyl alcohol, etc.; acetonitrile, butyl diglycol, organic amides such as dimethylacetamide, dimethylformamide, monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone, etc.; propylene or ethylene carbonate, dimethyl sulfoxide (DMSO), glycol polymers or their ethers such as various grades of polyethylene glycol (PEG), various grades of polypropylene glycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters such as diethyl ester or diisobutyl adipate, or a solvent or a mixture of solvents containing at least two of these solvents.

[0170] The liquid carrier vehicle may contain a crystallization inhibitor including, but not limited to, those described in (a)-(h) above, or a compound that can act as both a solvent and a crystallization inhibitor (as defined above), or a mixture of these crystallization inhibitors. The spot-on composition can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, the spot-on composition can be prepared by encapsulating the active ingredient to leave a residue of the therapeutic agent on the surface of the animal. These compositions vary with respect to the mass of the combination therapeutic agent, depending on the species of the host animal to be treated, the severity and type of the infection, and the body weight of the host. The dosage form can typically contain from about 0.1 mg to about 5 g. In other embodiments, the dosage form can contain from about 0.5 mg to about 5 mg of the active agent. In one embodiment of the dosage form, the dosage can contain from about 1 mg to about 500 mg of the active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg or about 1000 mg.

[0171] In one embodiment herein, the compound of formula (I) can be present in the composition at a concentration of about 0.05 to about 50% mass / mass. In other embodiments, the compound of formula (I) can be present at a concentration of about 0.1 to about 30% (w / w). In other embodiments, the compound of formula (I) can be present at a concentration of about 0.5 to about 30% (w / w), about 1 to about 20% (w / w) or about 0.05 to about 10% (w / w). In other embodiments, the compound of formula (I) can be present at a concentration of about 10 to about 50% (w / w), about 10 to about 30% (w / w), about 10 to about 20% (w / w). In yet another embodiment, the compound of formula (I) can be present at a concentration of about 1 to 10% (w / w) or about 5 to about 15% (w / w). In another embodiment of the present invention, the active agent can be present in the composition at a concentration of about 0.1 to about 2% w / w. In yet another embodiment of the present invention, the active agent can be present in the composition at a concentration of about 0.25 to about 1.5% w / w. In still another embodiment of the present invention, the active agent can be present in the composition at a concentration of about 1% w / w.

[0172] Treatment method As discussed above, the compounds of formula (I) are effective against endoparasites and can be used to treat and prevent parasite infections in animals. In one embodiment, the present invention provides a method of treating or preventing an endoparasite infection in an animal (e.g., a mammal or a bird), the method comprising administering to the animal an endoparasitically effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition of the present invention. In certain embodiments, the compounds of formula (I) can also be effective against ectoparasites and can be used to treat and prevent ectoparasite infestations on animals. In another embodiment, the present invention provides a method of treating or preventing an ectoparasite infestation on an animal (e.g., a mammal or a bird), the method comprising administering to the animal an ectoparasitically effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition of the present invention. In another embodiment, the present invention provides a method of treating or preventing an endoparasite infection and an ectoparasite infestation in or on an animal, the method comprising administering to the animal a composition comprising an effective amount of a compound of formula (I) in combination with an effective amount of at least a second active agent or a veterinarily acceptable salt thereof.

[0173] In yet another embodiment of the present invention, there is provided a method of treating or preventing a parasite infestation at a location, the method comprising administering or applying to the location a parasitically effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof. For purposes of the health of animals, "location" is intended to mean a habitat, breeding ground, area, material or environment in which the parasite grows or can grow, excluding within and on the animal. In another embodiment, the present invention provides methods and uses of the compounds for controlling pests of plants and crops or for protecting wood-containing structures. Mammals that can be treated include, but are not limited to, humans, cats, dogs, cows, chickens, heifers, bison, deer, goats, horses, llamas, camels, pigs, sheep and yaks. In one embodiment of the present invention, the mammal being treated is a human, a cat or a dog.

[0174] In one embodiment of the present specification, it has been found that the compound of formula (I) has excellent efficacy against endoparasites, particularly against endoparasites resistant to the active agents of the macrocyclic lactone class. In one embodiment, the compounds and compositions of the present invention are effective in controlling Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds.

[0175] In another embodiment, the present invention provides a method for treating parasitic infestations or infections in animals, comprising administering to an animal in need thereof an effective amount of an anthelmintic compound of the present invention in combination with an activator of invertebrate GABA receptors comprising an effective amount of abamectin and milbemycin. Abamectins 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. Milbemycin compounds that can be used in combination with the compounds of the present invention include, but are not limited to, milbemectin, milbemycin D, moxidectin and nemadectin. 5-oxo and 5-oxime derivatives of said abamectins and milbemycins are also included.

[0176] In one embodiment, the compounds and compositions of the invention can be used to treat or prevent endoparasitic infections of the following parasites: Anaplocephala (Anoplocephala), hookworm, Ancylostoma, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Eimeria, 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.

[0177] In a particularly preferred embodiment of the present invention, the compounds and compositions of the present invention are used for treating or preventing infection by Dirofilaria immitis. The compounds have been found to be highly effective against D. immitis microfilariae and L4 larvae. Thus, by using the compounds to kill the immature stages of D. immitis before it can develop into an adult, an animal can be prevented from developing canine filariasis. In one embodiment, the compounds and compositions containing the compounds can be used to prevent the onset of canine filariasis by killing the immature stages of D. immitis that are resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are used for treating or preventing infection by 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.

[0178] In another embodiment of the treatment for both endoparasites and ectoparasites when combined with an ectoparasiticide, the ectoparasites are one or more insects or arachnids including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.

[0179] In another embodiment of the treatment for external parasites, the external parasites are of the genus Ctenocephalides, genus Ixodes, genus Dermacentor, genus Haemaphysalis and / or genus Boophilus. The external parasites to be treated include, but are not limited to, fleas, ticks, mites, lice, flies, bed bugs, blowflies and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalides species, etc.), ticks (Ixodes species, Haemaphysalis species, Dermacentor species, Amblyomma species, etc.), and mites (Demodex species, Sarcoptes species, Notoedres species, etc.), bed bugs (Cimex species, Cheyletiella species, Polyplax species, etc.), lice (Pediculus species, Phthirus species, etc.), flies (Aedes species, Culex species, Anopheles species, etc.), and blowflies (Haematobia species, Musca species, Stomoxys species, Dermatobia species, Cochliomyia species, etc.). In yet another embodiment of the treatment for external parasites, the external parasites are fleas and / or ticks.

[0180] Examples of additional ectoparasites include, but are not limited to, ticks such as Ixodes spp., especially Ixodes ricinus (castor bean tick), Dermacentor spp., especially Dermacentor variabilis (American dog tick), Dermacentor andersoni (Rocky Mountain wood tick), Dermacentor albipictus (Winter tick), Dermacentor occidentalis (Pacific Coast tick), Dermacentor reticulatus (ornate cow tick), Dermacentor marginatus (southern cattle tick), and Dermacentor nitens (tropical cattle tick); fleas such as Ctenocephalides felis (cat flea), Ctenocephalides canis (dog flea), Pulex irritans (human flea), Tunga penetrans (chigoe flea), and Xenopsylla cheopis (rat flea); fly larvae such as myiasis, e.g., Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (screw worm fly); sheep fly larvae such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand, and South Africa). Specific flies include flies whose adults are parasites, e.g., Haematobia irritans (horn fly); lice such as Linognathus vitulorum (cattle biting louse); and mites such as Sarcoptes scabiei (itch mite) and Psoroptes ovis (sheep scab mite). The above list is not exhaustive, and it is well known in the art that other ectoparasites are harmful to animals and humans. These include, for example, mobile dipterous larvae.

[0181] In another embodiment of the invention, the compounds and compositions of the invention are suitable for controlling pests such as insects selected from the group consisting of Blattella germanica, Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitum, and combinations thereof. Plant parasitic nematodes include, for example, species of the genus Anguina, the genus Aphelenchoides, the species of the genus Belonoaimus, the species of the genus Bursaphelenchus, Ditylenchus dipsaci, the species of the genus Globodera, the species of the genus Heliocotylenchus, the species of the genus Heterodera, the species of the genus Longidorus, the species of the genus Meloidogyne, the species of the genus Pratylenchus, Radopholus similis, the species of the genus Rotylenchus, the species of the genus Trichodorus, the species of the genus Tylenchorhynchus, the species of the genus Tylenchulus, Tylenchulus semipenetrans, and the species of the genus Xiphinema.

[0182] Furthermore, with or without adding other pesticidal agents to the composition, the present invention can also be used to treat other pests including, but not limited to, the following pests: (1) Those of the order Isopoda, such as Oniscus asellus, Armadillidium vulgare, and Porcellio scaber; (2) Those of the order Diplopoda, such as Blaniulus guttulatus; (3) Those of the order Chilopoda, such as Geophilus carpophagus and species of the genus Scutigera; (4) Those of the order Symphyla, such as Scutigerella immaculata; (5) Those of Thysanura, such as Lepisma saccharina; (6) Those of Collembola, such as Onychiurus armatus; (7) Those of Blattaria, such as Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica; (8) Those of Hymenoptera, such as Diprion species, Hoplocampa species, Lasius species, Monomorium pharaonis and Vespa species; (9) Those of Siphonaptera, such as Xenopsylla cheopis and Ceratophyllus species; (10) Those of Anoplura (Phthiraptera), such as Damalinia species, Haematopinus species, Linognathus species, Pediculus species, Pthirus species;

[0183] (11) Those of the class Arachnida, such as Acarus siro, Aceria sheldoni, Aculops species, Aculus species, Bryobia praetiosa, Calacarus species, Argas species, Boophilus species, Brevipalpus species, Bryobia praetiosa, Cercopithyopsis species, Dermanyssus gallinae, Eotetranychus species, Epitrimerus pyri, Eutetranychus species, Eriophyes species, Hemitarsonemus species, Ixodes species, Leptus species, Latrodectus mactans, Metatetranychus species, Oligonychus species, Ornithodoros species, Panonychus species, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Schizotetranychus species, Tenuipalpus species, Rhizoglyphus species, Sarcoptes species, Scorpio maurus, Stenotarsonemus species, Tarsonemus species, Tetranychus species, Vasates lycopersici; (12) Those of the class Bivalva, such as Dreissena species;

[0184] (13) Those of the order Coleoptera, such as Acanthoscelides obtectus, species of the genus Adoretus, Agelastica alni, species of the genus Agriotes, Amphimallon solstitialis, Anobium punctatum, species of the genus Anoplophora, species of the genus Anthonomus, species of the genus Anthrenus, species of the genus Apogonia, species of the genus Atomaria, species of the genus Attagenus, Bruchidius obtectus, species of the genus Bruchus, species of the genus Ceuthorhynchus, Cleonus mendicus, species of the genus Conoderus, species of the genus Cosmopolites, Costelytra zealandica, species of the genus Curculio, Cryptorhynchus lapathi, species of the genus Dermestes, species of the genus Diabrotica, species of the genus Epilachna, Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, species of the genus Hypothenemus, Lachnosterna consanguinea, Colorado beetle, Lissorhoptrus oryzophilus, species of the genus Lixus, species of the genus Lyctus, Meligethesaeneus), Melolontha, Migdolus species, Monochamus species, Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga species, Popillia japonica, Premnotrypes species, Psylliodes chrysocephala, Ptinus species, Rhizobius ventralis, Rhizopertha dominica, Sitophilus species, Sphenophorus species, Sternechus species, Symphyletes species, Tenebrio molitor, Tribolium species, Trogoderma species, Tychius species, Xylotrechus species, Zabrus species;

[0185] (14) Those of the order Diptera, such as species of the genus Bibio, species of the genus Hamadryas, Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, species of the genus Chrysomyia, species of the genus Cochliomyia, Cordylobia anthropophaga, species of the genus Musca, species of the genus Cuterebra, Dacus oleae, Musca domestica, species of the genus Drosophila, species of the genus Fannia, species of the genus Gastrophilus, species of the genus Hylemyia, species of the genus Hyppobosca, species of the genus Hypoderma, species of the genus Liriomyza, species of the genus Lucilia, species of the genus Musca, species of the genus Nezara, species of the genus Oestrus, Oscinella frit, Pegomyia hyoscyami, species of the genus Phorbia, species of the genus Stomoxys, species of the genus Tabanus, species of the genus Tannia, Tipula paludosa, species of the genus Wohlfahrtia; (15) Those of the class Gastropoda, such as species of the genus Arion, species of the genus Biomphalaria, species of the genus Bulinus, species of the genus Deroceras, species of the genus Galba, species of the genus Lymnaea, species of the genus Oncomelania, species of the genus Succinea;

[0186] (16) Those of the network of worms, such as Ancylostoma duodenale, Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma species, Ascaris lubricoides, Ascaris species, Brugia malayi, Brugia timori, Bunostomum species, Caballeria species, Clonorchis species, Cooperia species, Dicrocoelium species, Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola species, Haemonchus species, Heterakis species, Hymenolepis nana, Hyostrongulus species, Loa, Nematodirus species, Oesophagostomum species, Opisthorchis species, Onchocerca volvulus, Ostertagia species, Paragonimus species, Schistosoma species, Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloides species, Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis (Trichinellapseudopsiralis), Trichostrongulus species, Trichuris trichuria, Wuchereria bancrofti;

[0187] (17) Those of the suborder Heteroptera, such as Anasa tristis, Antestiopsis species, Blissus species, Calocoris species, Campylomma livida, Cavelerius species, Cimex species, Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus species, Euschistus species, Eurygaster species, Heliopeltis species, Horchias nobiellus, Leptocorisa species, Leptoglossus phyllopus, Lygus species, Macropes excavatus, Miridae, Nezara species, Oebalus species, Pentatomidae, Piesma quadrata, Piezodorus species, Psallus seriatus, Pseudacysta persea, Rhodonius species, Sahlbergella singularis, Scotinophora species, Stephanitis nashi, Tibraca species, Triatoma species;

[0188] (18) Those of the suborder Homoptera, such as species of the genus Acyrthosipon, Aeneolamia, Agonoscena, Aleurodes, Aleurolobus barodensis, Aleurothrixus, Amrasca, Anuraphis cardui, Aonidiella, Aphanostigma piri, Aphis, Arboridia apicalis, Aspidiella, Aspidiotus, Atanus, Aulacorthum solani, Bemisia, Brachycaudus helichrysi, Brachycolus, Brevicoryne brassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes, Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus, Cryptomyzusribis), species of the genus Dalbulus, species of the genus Dialeurodes, species of the genus Diaphorina, species of the genus Diaspis, species of the genus Doralis, species of the genus Drosicha, species of the genus Dysaphis, species of the genus Dysmicoccus, species of the genus Empoasca, species of the genus Eriosoma, species of the genus Erythroneura, Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis, species of the genus Icerya, species of the genus Idiocerus, species of the genus Idioscopus, Laodelphax striatellus, species of the genus Lecanium, species of the genus Lepidosaphes, Lipaphis erysimi, species of the genus Macrosiphum, Mahanarva fimbriolata, Melanaphis sacchari, species of the genus Metcalfiella, Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, species of the genus Myzus, Nasonovia ribisnigri, species of the genus Nephotettix, Nilaparvata lugens, species of the genus Oncometopia, Orthezia praelonga, Parabemisiaspecies of Myricae, species of Paratrioza, species of Parlatoria, species of Pemphigus, Peregrinus maidis, species of Phenacoccus, Phloeomyzus passerinii, Phorodon humuli, species of Phylloxera, Pinnaspis aspidistrae, species of Planococcus, Protopulvinaria pyriformis, Pseudaulacaspis pentagona, species of Pseudococcus, species of Psylla, species of Pteromalus, species of Pyrilla, species of Quadraspidiotus, Quesada gigas, species of Rastrococcus, species of Rhopalosiphum, species of Saissetia, Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, species of Sogata, Sogatella furcifera, species of Sogatodes, Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, species of Tomaspis, species of Toxoptera, Trialeurodes vaporariorum, species of Trioza, species of Typhlocyba, species of Unaspis, Viteus vitifolii;

[0189] Those of the order Isoptera, such as species of the genus Reticulitermes and species of the genus Odontotermes; (20) Those of the order Lepidoptera, such as Acronicta major, Aedia leucomelas, Agrotis species, Alabama argillacea, Anticarsia species, Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo species, Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus species, Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa species, Feltia species, Galleria mellonella, Helicoverpa species, Heliothis species, Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella, Laphygma species, Lithocolletis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria species, Malacosoma neustria, Mamestrabrassicae), Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesia gemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia spp.;

[0190] (21) Those of the order Orthoptera, such as Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, Locusta spp., Melanoplus spp., Periplaneta americana, Schistocerca gregaria; (22) Those of the order Thysanoptera, such as Baliothrips biformis, Enneothrips flavens, species of the genus Frankliniella, species of the genus Heliothrips, Hercinothrips femoralis, species of the genus Kakothrips, Rhipiphorothrips cruentatus, species of the genus Scirtothrips, Taeniothrips cardamoni, species of the genus Thrips; (23) Those of the class Protozoa, such as species of the genus Eimeria. In each aspect of the present invention, the compounds and compositions of the present invention can be applied to a single pest or a combination thereof.

[0191] Mixtures with other active agents In another embodiment, the composition containing the compound of formula (I) may also contain other veterinary therapeutic agents. Veterinary formulations that can be included in the compositions of the present invention are well known in the art (e.g., Plumb’ Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 thEdition, (January 2005) See), but not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altretnogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide sulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, amphotericin B lipid formulation, ampicillin, amprolium antacid (oral), antivenin, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturate, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budesonide, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin salmon, calcitriol, calcium salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cephalexin, cefazolin sodium, cefixime, chlorothiazide, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, cefotiam hexetil sodium, cefotiam, ceftriaxone sodium, cephalexin, cephalosporin, cepapirin, charcoal (activated), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - clidinium bromide, chlorothiazide,Chlorpheniramine maleate, Chlorpromazine, Chlorpropamide, Chlorotetracycline, Human chorionic gonadotropin (HCG), Chromium, Cimetidine, Ciprofloxacin, Cisapride, Cisplatin, Citrate, Clarithromycin, Clemastine fumarate, Clenbuterol, Clindamycin, Clofazimine, Clomipramine, Clonazepam, Clonidine, Cloprostenol sodium, Dichlorazepate dipotassium, Chlorothiazide, Cloxacillin, Codeine phosphate, Colchicine, Corticotropin (ACTH), Cosyntropin, Cyclophosphamide, Cyclosporine, Cyproheptadine, Cytarabine, Dacarbazine, Dactinomycin / Actinomycin D, Dalteparin sodium, Danazol, Dantrolene sodium, Dapsone, Decoquinate, Deferoxamine mesylate, Delacoxib, Deslorelin acetate, Desmopressin acetate, Desoxycorticosterone pivalate, Detomidine, Dexamethasone, Dexpanthol, Dexrazoxane, Dextran, Diazepam, Diazoxide (oral), Dichlorphenamide, Diclofenac sodium, Dicloxacillin, Diethylcarbamazine citrate, Diethylstilbestrol (DES), Difloxacin, Digoxin, Dihydrotachysterol (DHT), Diltiazem, Dimenhydrinate, Dimercaprol / BAL, Dimethyl sulfoxide, Dinoprost tromethamine, Diphenhydramine, Disopyramide phosphate, Dobutamine, Doxavert / DSS, Dolasetron mesylate, Domperidone, Dopamine, Doramectin, Doxapram, Doxepin, Doxorubicin, Doxycycline, Calcium disodium edetate. Calcium EDTA, Edrophonium chloride, Enalapril / enalaprilat, Enoxaparin sodium, Enrofloxacin, Ephedrine sulfate, Epinephrine, Epoetin / erythropoietin, Eprinomectin, Epsiprantel, Erythromycin, Esmolol, Estradiol cypionate, Etacrynic acid / sodium etacrynate, Ethanol (alcohol), Sodium etidronate, Etodolac, Etomidate, Euthanasia agent w / pentobarbital, Famotidine, Fatty acids (essential / ω), Felbamate, Fentanyl, Ferrous sulfate,Filgrasitim, Finasteride, Fipronil, Florfenicol, Fluconazole, Flucytosine, Fludrocortisone Acetate, Flumazenil, Flumethasone, Flunixin Meglumine, Fluorouracil (5-FU), Fluoxetine, Fluticasone Propionate, Fluvoxamine Maleate, Hompizole (4-MP), Furazolidone, Furosemide, Gabapentin, Gemcitabine, Gentamicin Sulfate, Glimepiride, Glipizide, Glucagon, Glucocorticoid Agents, Glucosamine / Chondroitin Sulfate, Glutamine, Glyburide, Glycerin (Oral), Glycopyrrolate, Gonadorelin, Gliocladin, Guaifenesin, Halothane, Hemoglobin Glutamer-200 (OXYGLOBIN®), Heparin, Hetastarch, Sodium Hyaluronate, Hydralazine, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydromorphone, Hydroxyurea, Hydroxyzine, Ifosfamide, Imidacloprid, Imidocarb Dipropionate, Imipenem-Cilastatin Sodium, Imipramine, Inamrinone Lactate, Insulin, Interferon α-2a (Human Recombinant), Iodide (Sodium / Potassium), Tokon (Syrup), Ipodate Sodium, Iron Dextran, Isoflurane, Isoproterenol, Isotretinoin, Isoxsuprine, Itraconazole, Ivermectin, Kaolin / Pectin, Ketamine, Ketoconazole, Ketoprofen, Ketorolac Tromethamine, Lactulose, Leuprolide, Levamisole, Levetiracetam, Levothyroxine Sodium, Lidocaine, Lincomycin, Liothyronine Sodium, Lisinopril, Lomustine (CCNU), Lufenuron, Lysine, Magnesium, Mannitol, Marbofloxacin, Mechlorethamine, Mecamylamine, Mefenamic Acid, Medetomidine, Medium-Chain Triglycerides, Medroxyprogesterone Acetate, Megestrol Acetate, Melarsomine, Melatonin, Meloxicam, Melphalan, Meperidine, Mercaptopurine, Meropenem, Metformin, Methadone, Metazolamide, Methenamine Mandelate / Hippurate, Methimazole, Methionine, Methocarbamol, Methohexital Sodium, Methotrexate, Methoxyflurane, Methylene BlueMethylphenidate, Methylprednisolone, Metoclopramide, Metoprolol, Metronidazole, Mexiletine, Mibolerone, Midazolam, Milbemycin Oxime, Mineral Oil, Minocycline, Misoprostol, Mitotane, Mitoxantrone, Morphine Sulfate, Moxidectin, Naloxone, Nandrolone Decanoate, Naproxen, Narcotic (Opioid) Agonist Analgesics, Neomycin Sulfate, Neostigmine, Niacinamide, Nitazoxanide, Nitenpyram, Nitrofurantoin, Nitroglycerin, Nitroprusside Sodium, Nizatidine, Novobiocin Sodium, Nystatin, Octreotide Acetate, Orsalazine Sodium, Omeprazole, Ondansetron, Opioid Antidiarrheals, Orbifloxacin, Oxacillin Sodium, Oxazepam, Oxybutynin Chloride, Oxymorphone, Oxytetracycline, Oxytocin, Pamidronate Disodium, Pancreatic Lipase, Pancuronium Bromide, Paromomycin Sulfate, Paroxetine, Penicillamine, General Information Penicillin, Penicillin G, Penicillin V Potassium, Pentazocine, Pentobarbital Sodium, Pentosan Polysulfate Sodium, Pentoxifylline, Pergolide Mesylate, Phenobarbital, Phenoxybenzamine, Phenylbutazone, Phenylephrine, Phenylpropanolamine, Phenytoin Sodium, Pheromone, Parenteral Phosphate, Phytomenadione / Vitamin K-1, Pimobendan, Piperazine, Pyrrolnitrin, Piroxicam, Polysulfated Glycosaminoglycan, Ponazuril, Potassium Chloride, Pralidoxime Chloride, Prazosin, Prednisolone / Prednisolone, Primidone, Procainamide, Procarbazine, Prochlorperazine, Propantheline Bromide, Propionibacterium acnes Injection, Propofol, Propranolol, Protamine Sulfate, Pseudoephedrine, Psyllium Hydrophilic Mucilloid, Pyridostigmine Bromide, Pyrilamine Maleate, Pyrimethamine, Quinacrine, Quinidine, Ranitidine, Rifampin, s-Adenosyl-Methionine (SAMe), Saline / Saline Cathartics, Selamectin, Selegiline / l-Deprenyl, Sertraline, Sevelamer,Cevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachloropyridazine sodium, sulfadiazine / trimetoprim, sulfamethoxazole / trimetoprim, sulfadimethoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafine, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid stimulating hormone, thiamulin, ticarcillin disodium salt, tiletamine / zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tromethamine, telfenamic acid, topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, trimethoprim w / prednisolone tartrate, tripelennamine, tyrosine, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zileuton, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide and mixtures thereof.,

[0192] In one embodiment of the present invention, an arylpyrazole compound such as phenylpyrazole can be included in the veterinary composition of the present invention. Arylpyrazoles are known in the art and may be suitable for combination with the compound of formula (I) in the compositions herein. Examples of such arylpyrazole compounds include, but are not limited to, U.S. Patent Nos. 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 of which are incorporated herein by reference). A particularly preferred arylpyrazole active agent is fipronil.

[0193] In another embodiment of the present invention, one or more macrocyclic lactones that act as acaricides, anthelmintics and / or insecticides can be combined with the compound and included in the composition of the present invention. To avoid doubt, the term "macrocyclic lactone" as used herein includes both naturally occurring and synthetic or semi-synthetic avermectin and milbemycin compounds.

[0194] Macrocyclic lactones that can be used in the compositions of the present invention include, but are not limited to, naturally produced avermectins (e.g., including components called A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b) and milbemycin compounds, semi-synthetic avermectins and milbemycins, avermectin monosaccharide compounds and avermectin aglycone compounds. Examples of macrocyclic lactone compounds that can be used in the compositions include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, and, without limitation, milbemycin, milbemycin D, milbemycin A3, milbemycin A4, milbemycins including milbemycin oxime, moxidectin and nemadectin. Also included are 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.

[0195] Macrolide compounds are known in the art and can be readily obtained commercially or through synthetic techniques known in the art. Widely available technical and commercial literature is referenced. For avermectin, ivermectin, and abamectin, for example, see the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag. Or Albers-Schonberg et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin, one can consult “Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15. For milbemycin, in particular, Davies H.G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent No. 4,134,973, and European Patent No. 0677054, all of which are hereby incorporated by reference.

[0196] The structures of avermectin and milbemycin are closely related, for example, by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectin is disclosed in U.S. Patent No. 4,310,519, and the 22,23-dihydroavermectin compounds are disclosed in U.S. Patent No. 4,199,569. In particular, reference is also made to U.S. Patent Nos. 4,468,390, 5,824,653, European Patent No. 0007812, British Patent Specification No. 1390336, European Patent No. 0002916, and New Zealand Patent No. 237086. Naturally occurring milbemycin is described in U.S. Patent No. 3,950,360, as well as in various references cited in “The Merck Index” 12 th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Lacticidin is described in “International Nonproprietary Names for Pharmaceutical Substances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Patent Nos. 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 European Patent No. 0667054, all of which are hereby incorporated by reference in their entirety.

[0197] In one embodiment, the veterinary composition of the present invention comprises at least one of an effective amount of abamectin, doramectin, eprinomectin, emamectin, ivermectin, latidectin, lepimectin, selamectin, milbemycin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin or nemadectin, or a combination thereof. In another embodiment, the present invention provides a veterinary composition comprising at least one of an effective amount of abamectin, emamectin, eprinomectin, ivermectin, doramectin or selamectin, or a combination thereof. In yet another embodiment, the veterinary composition of the present invention comprises at least one of an effective amount of ivermectin, milbemycin, milbemycin oxime or moxidectin, or a combination thereof. In another embodiment of the present invention, there is provided a composition comprising a compound of formula (I) in combination with an acaricide or insecticide of a class known as an insect growth regulator (IGR). Compounds belonging to this group are well known to those skilled in the art and include a wide variety of chemical classes. All of these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Pat. Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, European Patent No. 0179022 or British Patent No. 2140010 and U.S. Pat. Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).

[0198] In one embodiment, the composition of the present invention may comprise an IGR compound that mimics juvenile hormone or regulates the level of insect juvenile hormone. Examples of juvenile hormone mimics include azadirachtin, diofenolan, phenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3(2H)-one. In another embodiment, the composition of the present invention comprises a compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. In another embodiment, the composition of the present invention comprises an IGR compound that is a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, tebufenozide, teflubenzuron, triflumuron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0199] In some embodiments, the composition of the present invention may comprise one or more nematicides comprising, but not limited to, activators of compounds of the benzimidazole, imidazothiazole, tetrahydropyrimidine, and organophosphorus classes. In some embodiments, benzimidazoles including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobenzendazole, febantel, thiophanate, and its o,o-dimethyl analog can be included in the composition. In other embodiments, the composition of the present invention may include imidazolethiazole compounds including, but not limited to, tetramisole, levamisole, and butamisole. In still other embodiments, the composition of the present invention may include tetrahydropyrimidine activators including, but not limited to, pyrantel, oxantel, and morantel. Suitable organophosphorus activators include, but are not limited to, coumaphos, trichlorfon, haloxon, naphthalophos, and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

[0200] In other embodiments, the composition may include, as neutral compounds and in various salt forms, the anti-nematode compounds phenothiazine, piperazine, diethylcarbamazine, phenol such as disophenol, arsenic agents such as arsenamide, ethanolamine such as bephenium, tenium croscylate, and methylidine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate, and dithiazanine iodide; isothiocyanates including bitoscanate, suramin sodium, phthalophine, and various natural products including, but not limited to, hygromycin B, α-santonin, and kainic acid. In other embodiments, the composition of the present invention may include an anti-trematode agent. Suitable anti-trematode agents include, but are not limited to, mirazine such as mirazine D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, orthopraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, hexachlorophene, bithionol, bithionol sulfoxide, and various bisphenol compounds known in the art including menichloropholan; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, nitroxynil, brotianide, bromoxanide, and closantel; triclabendazole, diamfenetide, chlorosulon, hetolin, and emetine. Anthelmintic compounds including, but not limited to, arecoline, bunamidine, niclosamide, nitrosacaine, paromomycin, paromomycin II, praziquantel and epsiprantel in various salt forms can also be advantageously used in the compositions of the present invention.

[0201] In still 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, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate, dioxathion, ethion, fanfan, fenitrothion, fenthion, fosethylate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, styrofos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrin, resmethrin, benzyl benzoate, carbon disulfide, crotonamide, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanoacetate, methoprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, Dite, dimethyl phthalate, and the 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-pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

[0202] In another embodiment, the antiparasitic agent that can be included in the veterinary composition containing the compound of formula (I) can be a bioactive peptide or protein containing a depsipeptide other than these, but not limited to these, and can be, for example, a bioactive peptide or protein containing a depsipeptide other than the present compound. These include PF1022A or its analogs and emodepside. Other cyclic depsipeptide compounds that can be included in the composition containing the compound of formula (I) are those described in International Publication No. WO 2016 / 187534 and International Publication No. WO 2017 / 116702, which are hereby incorporated by reference in their entirety. These compounds act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of parasites. In one embodiment of the depsipeptide, the depsipeptide is emodepside (see Wilson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

[0203] In another embodiment, the composition of the present invention may contain an active agent of a neonicotinoid class of antiparasitic agents. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be combined with the compound of formula (I) in the composition of the present invention is imidacloprid. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or European Patent No. 0892060 (both hereby incorporated by reference in their entirety). In another embodiment, the composition of the present invention may contain nitenpyram, another active agent of a neonicotinoid class of pest control agents. The use of nitenpyram for controlling fleas is described in U.S. Patent No. 5,750,548, which is hereby incorporated by reference in its entirety. In certain other embodiments of the present invention, the compound of formula (I) can be combined with a semicarbazone such as metaflumizone.

[0204] In another embodiment, the compositions of the present invention may advantageously include one or more isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against various ectoparasites, and the combination with the compounds of formula (I) will expand the range of effectiveness against these parasites. Particularly useful isoxazoline active agents that can be combined with the compounds include afoxolaner (including substantially pure active enantiomers), sarolaner, fluralaner (including substantially pure active enantiomers), and lotilaner. All of these active agents are incorporated herein by reference in their entirety: U.S. Patent No. 7,964,204, U.S. Patent Application Publication No. 2010 / 0254960, U.S. Patent Application Publication No. 2011 / 0159107, U.S. Patent Application Publication No. 2012 / 0309620, U.S. Patent Application Publication No. 2012 / 0030841, U.S. Patent Application Publication No. 2010 / 0069247, International Publication No. 2007 / 125984, International Publication No. 2012 / 086462, U.S. Patent No. 8318757, U.S. Patent No. 8466115, U.S. Patent No. 8618126, U.S. Patent No. 8822466, U.S. Patent No. 8383659, U.S. Patent No. 8853186, U.S. Patent No. 9221835, U.S. Patent Application Publication No. 2011 / 0144349, U.S. Patent No. 8,053,452; U.S. Patent Application Publication No. 2010 / 0137612, U.S. Patent No. 8410153, U.S. Patent Application Publication No. 2011 / 152081, International Publication No. 2012 / 089623, International Publication No. 2012 / 089622, U.S. Patent No. 8,119,671; U.S. Patent No. 7,947,715;WO 2013 / 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, US 2011 / 0118212, US 7951828 and US 7662972, US 2010 / 0137372, US 2010 / 0179194, US 2011 / 0086886, US 2011 / 0059988, US 2010 / 0179195, US 2015 / 0126523, WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236, WO 2017 / 147352, US 7897630 and US 7951828.;

[0205] In another embodiment of the present invention, nosiheptide and its derivatives can be added to the composition of the present invention. These compounds are used for treating or preventing infections in humans and animals and are described, for example, in U.S. Pat. Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, which are hereby incorporated by reference in their entirety. The composition can include one or more of the nosiheptide derivatives known in the art, including all stereoisomers such as those described in the references cited above.

[0206] In another embodiment, anthelmintic compounds of the aminoacetonitrile class (AAD), such as the compound monepantel (ZOLVIX), can be added to the composition of the present invention. These compounds are described, for example, in U.S. Pat. No. 7,084,280 to 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 composition of the present invention can also include aryloazol-2-ylcyanoethylamino compounds, such as those described in U.S. Pat. No. 8,088,801 to Soll et al. (incorporated herein by reference), and thioamide derivatives of these compounds described in U.S. Pat. No. 7,964,621 to Le Hir de Fallois (also incorporated herein by reference). Aryloazol-2-ylcyanoethylamino activators that are systemic against endoparasites can be used in combination with the compounds in the veterinary composition of the present invention.

[0207] The compositions of the present invention may also contain paraherquamides and derivatives of these compounds, including deltacantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Compounds of the paraherquamide family are a known class of compounds containing 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). Further, structurally related compounds of the mulmurthine family, such as mulmurthine 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 references to paraherquamide derivatives can be found, for example, in International Publication No. WO 91 / 09961, International Publication No. WO 92 / 22555, International Publication No. WO 97 / 03988, International Publication No. WO 01 / 076370, International Publication No. WO 09 / 004432, and U.S. Patent Application Publication No. 2010 / 0197624, U.S. Patent No. 5,703,078 and U.S. Patent No. 5,750,695, all of which are hereby incorporated by reference in their entirety.

[0208] In another embodiment of the invention, the composition can comprise a spinosyn activator produced by the soil actinomycete Saccharopolyspora spinosa (see, e.g., 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 spinosoid activator. Spinosyns are typically referred to as factor 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 combinations thereof can be used in the compositions of the invention. The spinosyn compounds can be a 5,6,5-tricyclic ring system condensed with a 12-membered macrolide, a neutral sugar (rhamnose), and an amino sugar (forosamine). These and other natural spinosyn compounds, including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which can be used in the compositions of the invention, can be produced via fermentation by conventional techniques known in the art. Other spinosyn compounds that can be used in the compositions of the invention are all disclosed in U.S. Pat. Nos. 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, which are hereby incorporated by reference in their entirety. Spinosyn compounds can include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetram, or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetram is a combination of 3'-ethoxy-5,6-dihydrospinosyn J and 3'-ethoxypinosyn L.

[0209] Generally, additional active agents (other than the compounds of formula (I) above) are included in the dosage units of the present invention in an amount between about 0.1 μg and about 1000 mg. Typically, the active agent can be included in an amount of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg or about 10 mg to about 100 mg. More typically, the additional active agent is present in the composition of the present invention in an amount of about 5 mg to about 50 mg.

[0210] The concentration of the additional active agent in the composition of the present invention will typically be between about 0.01% and about 30% (w / w), depending on the potency of the active agent. In certain embodiments of very potent active agents, including macrolide lactone active agents, without limitation, the concentration of the active agent will typically be 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 concentration of the active agent will typically be about 0.1% to about 2% (w / w) or about 0.1% to about 1% (w / w). In other embodiments, the additional active agent is typically present at a higher concentration to achieve the desired effectiveness. In some embodiments, the active agent is present at a concentration of about 1% to about 30% (w / w), about 1% to about 20% (w / w) or about 1% to about 15% (w / w). In still other embodiments, the active agent is present in the composition at a concentration of about 5% to about 20% (w / w) or about 5% to about 15% (w / w). In various embodiments of the present invention, the composition may include an additional active agent that delivers a dosage of about 0.001 mg / kg to about 50 mg / kg or about 0.5 mg / kg to about 50 mg / kg per animal body weight. In other embodiments, the active agent is present in an amount sufficient to typically deliver a dosage 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 agent is present in an amount sufficient to deliver a dosage 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 per animal body weight.

[0211] In certain embodiments of the invention where the additional active agent is a very potent compound such as a macrocyclic lactone or other potent compound, the active agent is present at a concentration providing 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. Further in other embodiments, the active agent is present in an amount sufficient to deliver a dose of from about 0.01 mg / kg to about 2 mg / kg or from about 0.1 mg / kg to about 1 mg / kg per animal body weight. Further in other embodiments, the additional active agent may be present in an amount to deliver 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 per animal body weight. In addition to the other active agents mentioned above, combinations of two or more active agents can be used in the compositions with the compounds of the invention to treat a desired range of pests and parasites. It will be well within the skill level of one of ordinary skill in the art to determine which individual compounds can be used in the compositions of the invention to treat a particular insect infestation. The invention will now be further illustrated by the following non-limiting examples.

Example

[0212] Preparation Example The compounds of formula (I) or their pharmaceutically or veterinarily acceptable salts can be prepared by employing one of the following reaction schemes. The starting materials for their preparation are commercially available or can be prepared by methods known to those skilled in the art and as described in the literature. It will be recognized that the following procedures can be modified by those skilled in the art to prepare additional compounds according to the invention. For example, one of ordinary skill in the art will understand that the preparation of various compounds of formula (I) can be made possible by replacement of certain starting materials or use of different intermediates. List of Abbreviations: ACN Acetonitrile AIBN Azobisisobutyronitrile BINAP (2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl) BSA Bovine Serum Albumin BOC tert-Butoxycarbonyl BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride DAST Diethylaminosulfur trifluoride DCC N,N’-Dicyclohexylcarbodiimide solution DCM Dichloromethane DEAD Diethyl azodicarboxylate DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMAP 4-(Dimethylamino)pyridine DMSO Dimethyl sulfoxide EDAC N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride ES Electrospray EtOAc or EA Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt or HOBT 1-Hydroxybenzotriazole KHMDS Potassium hexamethyldisilazide, more precisely potassium bis(trimethylsilyl)amide MeOH Methanol m-CPBA m-Chloroperbenzoic acid NMO N-Methylmorpholine-N-oxide o / n Overnight PE Petroleum ether Pd(dtbpf)Cl2 Dichloro[1,1’-bis(di-tert-butylphosphino)ferrocene]palladium(II) Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane TBAF tert-Butylammonium fluoride TfO triflate THF tetrahydrofuran TLC thin layer chromatography

[0213] The following compounds can be prepared using the process shown in Scheme 5: 026, 027, 028, 029, 083, 090, 092, 098, 099, 100, 101, 102, 102-1, 123, 124, 125, 126, 127, 128, 129, 130, 218, 219, 302.

[0214] In some cases for certain compounds, the process of Scheme 5 can be modified by methods known to those skilled in the art to incorporate various functional groups into the core structure. For example, using intermediate 026-E, various groups corresponding to variable element R 1 can be incorporated into the structure. Similarly, using intermediate 026-C, various groups can be incorporated at the position corresponding to variable element R 3 . Scheme 5

[0215]

Chemical formula

[0216] 1. Synthesis of methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate

Chemical formula

[0217] 2. Synthesis of methyl 7-bromo-3-hydroxybenzofuran-2-carboxylate

Chemical formula

[0218] 3. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-hydroxybenzofuran-2-carboxylate

Chemical formula

[0219] 4. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethylsulfonyloxy)benzofuran-2-carboxylate [Chemical formula] To a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere were added methyl 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylate (0.9 g, 2.67 mmol, 1.0 equivalent), TEA (0.5 g, 5.3 mmol, 2.0 equivalents), and DCM (10.0 mL). Subsequently, Tf2O (0.9 g, 3.20 mmol, 1.2 equivalents) was added at 0 °C. The resulting solution was stirred at room temperature for 2 hours. Then, 20 mL of water was added to quench the reaction. The resulting solution was extracted with 2 × 10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 1 × 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Thereby, 1.1 g (87.8%) of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethylsulfonyloxy)-1-benzofuran-2-carboxylate was obtained as a yellow solid.

[0220] 5. Synthesis of Methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)benzofuran-2-carboxylate [Chemical formula] In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate (1.10 g, 2.34 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.5 g, 2.8 mmol, 1.2 equivalents), Pd(dtbpf)Cl2 (76.4 mg, 0.12 mmol, 0.05 equivalent), H2O (2.0 mL), THF (8.0 mL), and K3PO4 (1.0 g, 4.7 mmol, 2.0 equivalents) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 8). Thereby, 400 mg (47.2%) of methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylate was obtained as a white solid.

[0221] 6. Synthesis of Methyl 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylate [Chemical formula] In a 50 mL round-bottom flask, methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylate (390 mg, 1.1 mmol, 1.0 equivalent), PtO2 (37 mg, 0.16 mmol, 0.15 equivalent), and EA (10 mL) were added. H2 gas (1 atm) was introduced thereto. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered. The resulting mixture was concentrated. Thereby, 370 mg (94.4%) of methyl 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylate was obtained as a gray solid.

[0222] Synthesis of 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylic acid [Chemical formula] Into a 25 mL round-bottom flask, methyl 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylate (350 mg, 1.0 mmol, 1.0 equivalent), NaOH (385 mg, 9.6 mmol, 10.0 equivalents), THF (1.0 mL), MeOH (4.0 mL), and H2O (1.0 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. Aqueous HCl solution (1 mol / L) was added to adjust the pH value of the solution to 4. The solid was collected by filtration. As a result, 300 mg (89.2%) of 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid was obtained as a white solid.

[0223] Synthesis of (S)-N-(chroman-4-yl)-7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxamide [Chemical formula] To a 25 mL round-bottom flask, 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid (150 mg, 0.4 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (76.9 mg, 0.52 mmol, 1.20 equiv), HATU (196 mg, 0.52 mmol, 1.20 equiv), DIEA (166.6 mg, 1.3 mmol, 3.0 equiv), and DCM (5 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was further purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, 0.05% FA in water and CH3CN (increasing from 40% CH3CN to 95% within 13 minutes); detector, UV254&220 nm. Thereby, 120 mg (58.2%) of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropyl-1-benzofuran-2-carboxamide was obtained as a white solid. (ES, m / z): 480 [M+H] + ; 1 1H-NMR (300 MHz, CDCl3): δ = 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.51 (dd, J = 7.5, 1.2 Hz, 1H), 7.45-7.32 (m, 3H), 7.27-7.18 (m, 1H), 6.96 (td, J = 7.5, 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 5.48-5.31 (m, 1H), 4.47-4.19 (m, 3H), 2.51-2.33 (m, 1H), 2.28-2.13 (m, 1H), 1.53 (dd, J = 7.1, 2.1 Hz, 6H) ppm.

[0224] Using the following reaction, methyl 7-(3,5-dichlorophenyl)-3-morpholinobenzofuran-2-carboxylate was prepared and, according to Scheme 5, R3 It can be converted to an alternative compound having a morpholine group at the corresponding position.

Chemical formula

[0225] To a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere were added methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate (500.0 mg, 1.07 mmol, 1.0 equivalent), morpholine (186 mg, 2.1 mmol, 2.0 equivalents), BINAP (133 mg, 0.21 mmol, 0.20 equivalent), Pd2(dba)3 (97.6 mg, 0.11 mmol, 0.1 equivalent), Cs2CO3 (0.69 g, 2.13 mmol, 2.0 equivalents), and toluene (10 mL). The resulting solution was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature. Then, 20 mL of water was added to quench the reaction. The resulting solution was extracted with 2 × 15 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 5). Thereby, 200 mg (46.2%) of methyl 7-(3,5-dichlorophenyl)-3-(morpholin-4-yl)-1-benzofuran-2-carboxylate was obtained as a white solid.

[0226] The following compounds can be synthesized by adopting the following Scheme 6 and the following reaction scheme: 119, 120, 122, 199, 202, 204, 205, 207, 210, 212, 212-0A, 251, 252, 253, 253-0A, 254, 256, 258, 259, 259-5, 260, 261, 262, 263, 263-8, 285, 300, 301, 309, 310, 311, 319, 336, 337, 338. Scheme 6:

[0227]

Chemical formula

[0228] Synthesis of 1.4-(3,5-difluorophenyl)-3-fluoropyridine

Chem.

[0229] Synthesis of 2. 4-(3,5-difluorophenyl)-3-fluoropyridine 1-oxide

Chem.

[0230] Synthesis of 3. 4-(3,5-difluorophenyl)-3-fluoropicolinonitrile [Chemistry] Into a 1000 mL round-bottom flask purged and maintained in an inert nitrogen atmosphere, 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-olate (21.0 g, 93.3 mmol, 1.0 eq), CH3CN (500 mL), TMSCN (23.1 g, 233.2 mmol, 2.5 eq), and TEA (19.8 g, 195.8 mmol, 2.10 eq) were added. The resulting solution was stirred at 80 °C overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (EA 0% - 30%). Thereby, 10 g (45.8%) of 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile was obtained as an off-white solid.

[0231] 4. Synthesis of Methyl 3-Amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [Chemistry] Into a 250 mL round-bottom flask, 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile (6.0 g, 25.6 mmol, 1.0 eq), CH3CN (100 mL), methyl thioglycolate (8.2 g, 76.9 mmol, 3.0 eq), and K2CO3 (10.6 g, 76.86 mmol, 3 eq) were added. The resulting solution was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature. Then, 200 mL of water was added to quench the reaction. The solid was collected by filtration and washed with water (3 × 20 mL). Thereby, 6 g (73.1%) of methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate was obtained as a pale yellow solid.

[0232] 5. Synthesis of Methyl 3-Bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [Chemistry] In a 250 mL three-necked round-bottom flask purged and maintained under an inert argon atmosphere, HBr (25.0 mL), CuBr (705.4 mg, 4.9 mmol, 1.0 equiv), and methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (1.5 g, 4.7 mmol, 1.0 equiv) were added. Subsequently, a solution of NaNO2 (388 mg, 5.6 mmol, 1.2 equiv) in H2O (5 mL) was added dropwise while stirring at 0 °C. The resulting solution was stirred at 20 °C overnight. The reaction mixture was poured into 200 mL of ice water. The precipitate was collected by filtration. The solid was dissolved in 100 mL of DCM and washed with 3 × 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. As a result, 1.5 g (83.4%) of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate was obtained as a pale yellow solid.

[0233] 6. Synthesis of methyl 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylate

Chemical formula

[0234] 7. Synthesis of Methyl 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylate

Chemical formula

[0235] 8. Synthesis of Methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

Chemical formula

[0236] 9. Synthesis of 3-(Difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid

Chemical formula

[0237] Synthesis of 10.3-(Difluoromethyl)-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide

Chem.

[0238] Compound 199-0 and 311-1 can be prepared by the process shown in Scheme 7 below and the following procedure: Scheme 7

Chem.

[0239] Synthesis of Ethyl 3-Acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

Chemical formula

[0240] Synthesis of 3-Acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic Acid

Chemical formula

[0241] Synthesis of 3-acetyl-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0242] Synthesis of 7-(3,5-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-hydroxypropan-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical Structure

[0243] Synthesis of 7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-fluoropropan-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0244] Compound 030 can be prepared by the process shown in Scheme 8 below and the following procedure: Scheme 8

Chem.

[0245] 1. Synthesis of 7-methoxy-1-benzofuran-2-carbonitrile Into a 500 mL round-bottom flask, O-vanillin (50.0 g, 328.6 mmol, 1.0 equiv), chloroacetonitrile (29.7 g, 394.3 mmol, 1.2 equiv), K2CO3 (49.9 g, 361.5 mmol, 1.1 equiv), and DMF (530 mL) were added. The resulting solution was stirred in an oil bath at 150 °C for 1 hour. Then, additional K2CO3 (49.9 g, 361.5 mmol, 1.1 equiv) was added and stirred for 20 minutes. Then, 530 mL of water was added to quench the reaction. The resulting solution was extracted with 3 × 500 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:10). Thereby, 14 g (24.6%) of 7-methoxy-1-benzofuran-2-carbonitrile was obtained as a white solid.

[0246] 2. Synthesis of 4-acetyl-7-hydroxy-1-benzofuran-2-carbonitrile

Chem.

[0247] 3. Synthesis of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile [Chemical formula] To a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, methyltriphenylphosphonium bromide (7.9 g, 22.3 mmol, 1.2 equivalents) and THF (50 mL) were added. Subsequently, while stirring at 0 °C, n-BuLi (12.6 mL, 31.6 mmol, 1.7 equivalents) in hexane was added dropwise. The resulting solution was stirred at 0 °C for 30 minutes. To this, while stirring at -78 °C, 4-acetyl-7-methoxy-1-benzofuran-2-carbonitrile (4.0 g, 18.5 mmol, 1.0 equivalent) was added dropwise. The resulting solution was stirred at room temperature for 2 hours. Then, 50 mL of water was added to quench the reaction. The resulting solution was extracted with 3 × 50 mL of ethyl acetate. The organic phase was washed with 2 × 50 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:20). Thereby, 1.6 g (40.3%) of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile was obtained as a white solid.

[0248] Synthesis of 4.7-Methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid

Chem.

[0249] Synthesis of 5.4-Isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid

Chem.

[0250] Synthesis of 6.7-Hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid

Chem.

[0251] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-hydroxy-4-isopropyl-1-benzofuran-2-carboxamide

Chemical Structure

[0252] Synthesis of 8.2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-4-isopropyl-1-benzofuran-7-yl trifluoromethanesulfonate

Chemical formula

[0253] Synthesis of 9.7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-4-isopropyl-1-benzofuran-2-carboxamide

Chemical formula

[0254] Compounds 264 and 264-0A can be prepared by the following Scheme 9 and the following detailed procedures: Scheme 9

Chemical formula

[0255] Exemplary procedures for Compounds 264 and 264-0A: 1. Synthesis of (3,5-dichlorophenyl)acetyl chloride

Chemical formula

[0256] 2. Synthesis of 1-bromo-3-(3,5-dichlorophenyl)propan-2-one

Chemical formula

[0257] Synthesis of 3,4-(3,5-dichlorophenyl)-3-oxobutanenitrile

Chemical formula

[0258] Synthesis of 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile

Chem.

[0259] 5. Synthesis of 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile

Chem.

[0260] 6. Synthesis of 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

Chem.

[0261] 7. Synthesis of ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

Chemical Structure

[0262] 8. Synthesis of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyethenyl)thieno[3,2-c]pyridine-2-carboxylate [Chemical formula] Into a 20 mL vial purged and maintained in an inert nitrogen atmosphere were placed ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (550.0 mg, 1.2 mmol, 1.0 eq), tributyl(1-ethoxyethenyl)stannane (1.4 g, 3.8 mmol, 3.0 eq), dioxane (10.0 mL) and Pd(PPh3)4 (148.0 mg, 0.1 mmol, 0.1 eq). The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:3). Thereby, 540 mg (crude product) of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyethenyl)thieno[3,2-c]pyridine-2-carboxylate was obtained as a yellow solid. MS(ESI, m / z): 422 [M+H] + 。

[0263] 9. Synthesis of ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

Chemical Structure

[0264] Synthesis of 10.3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid

Chem.

[0265] Synthesis of 11.3-acetyl-7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-c]pyridine-2-carboxamide

Chem.

[0266] 12. Synthesis of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-hydroxypropan-2-yl)thieno[3,2-c]pyridine-2-carboxamide

Chemical Structure

[0267] Synthesis of 13.7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-fluoropropan-2-yl)thieno[3,2-c]pyridine-2-carboxamide

Chemical Structure

[0268] The following compounds can be prepared by the following Scheme 10 and the following detailed procedures: 121, 226-3, 215, 227, 224, 225, 228, 225-0A, 230, 226, 234. Scheme 10

[0269]

Chemical Structure

[0270] Exemplary procedure for Compound 226-3: 1. Synthesis of 3-chloro-4-methoxypyridine

Chemical Structure

[0271] 2. Synthesis of 3-chloro-4-methoxypyridin-1-ium-1-olate

Chemical formula

[0272] 3. Synthesis of 3-chloro-4-methoxypyridine-2-carbonitrile

Chemical formula

[0273] Synthesis of Methyl 3-Amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate

Chemical Structure

[0274] Synthesis of Methyl 3-(Dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate

Chemical Structure

[0275] 6. Synthesis of 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid

Chemical formula

[0276] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0277] 8. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0278] Synthesis of 9.2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate

Chemical formula

[0279] 10. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(1-ethoxyethenyl)thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0280] Synthesis of 11.7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide [Chemical formula] To a 50 mL round-bottom flask were added THF (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(1-ethoxyethenyl)thieno[3,2-b]pyridine-2-carboxamide (350.0 mg, 0.8 mmol, 1.0 equiv), and HCl (6 M) (5.0 mL). The resulting solution was stirred at room temperature for 2 hours. Then, 10 mL of water was added to quench the reaction. The resulting solution was extracted with 3×20 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). Thereby, 180 mg (55.0%) of 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide was obtained as a yellow solid. 1 1H-NMR (300 MHz, CD3OD): δ = 8.96 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.28-7.16 (m, 1H), 6.97-6.91 (m, 1H), 6.86 (dd, J = 8.2, 1.2 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.39-4.32 (m, 1H), 4.27-4.22 (m, 1H), 2.99 (s, 6H), 2.80 (s, 3H), 2.39-2.33 (m, 1H), 2.21-2.16 (m, 1H) ppm.

[0281] 12. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpenta-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical Structure

[0282] 13. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpentan-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0283] 14. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-[(2E)-4-methylpent-2-en-2-yl]thieno[3,2-b]pyridine-2-carboxamide [Chemical formula] Into a 50 mL round-bottom flask, pyridine (3.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpentan-2-yl)thieno[3,2-b]pyridine-2-carboxamide (100.0 mg, 0.2 mmol, 1.0 equiv), and SOCl2 (0.5 mL) were added. The resulting solution was stirred at 0 °C for 1 hour. Then, water / ice was added to quench the reaction. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. Thereby, 70 mg (72.8%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-[(2E)-4-methylpent-2-en-2-yl]thieno[3,2-b]pyridine-2-carboxamide was obtained as a yellow solid.

[0284] 15. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(4-methylpentan-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0285] [Chemical formula] Into an 8 mL sealed tube were added NMP (5.0 mL), 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (200.0 mg, 0.4 mmol, 1.0 equiv), and 4,4-difluoropiperidine (400.0 mg, 3.3 mmol, 8.3 equiv). The final reaction mixture was irradiated with microwave radiation at 150 °C for 30 minutes. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O and CH3CN (increasing from 20% CH3CN to 90% within 20 minutes); detector, 254 nm. Thereby, 24.9 mg (13.3%) of 7-(4,4-difluoropiperidin-1-yl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide was obtained as a pale yellow solid. (ES, m / z): 473 [M+H] + ; 11H-NMR (300 MHz, CD3OD): δ = 8.51 (d, J = 5.4 Hz, 1H), 7.38 - 7.28 (m, 1H), 7.28 - 7.16 (m, 1H), 7.00 - 6.91 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38 - 4.32 (m, 1H), 4.27 - 4.23 (m, 1H), 3.67 - 3.58 (m, 4H), 2.97 (s, 6H), 2.44 - 2.11 (m, 6H) ppm.

[0286] The following compounds can be prepared according to Scheme 11 below: 115, 116, 117, 118, 237, 115-INT-3, 239, 239-INT-1, 237A. Scheme 11

[0287]

Chemical formula

[0288] Exemplary procedures for compounds 115 and 116: Synthesis of 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine as a white solid

Chemical formula

[0289] 1. Synthesis of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine [Chemical formula] A 250 mL round-bottom flask was charged with 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (3.50 g, 14.1 mmol, 1.0 equiv), Br2 (11.30 g, 70.6 mmol, 5.0 equiv), and AcOH (52.0 mL). The resulting solution was stirred at 70 °C for 2 days. Then, the reaction was quenched by pouring it into 500 mL of an ice aqueous solution of NaHCO3. The resulting solution was extracted with 2 × 500 mL of ethyl acetate. The EA mixture was washed with 2 × 500 mL of an aqueous solution of NaCHO3 and 1 × 500 mL of an aqueous solution of NaS2SO3. The resulting EA mixture was washed with 1 × 500 mL of brine. The EA mixture was dried over anhydrous sodium sulfate. The solid was filtered. The filtrate was concentrated. Thereby, 4 g of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine was obtained as a pale yellow solid.

[0290] 2. Synthesis of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid

Chem.

[0291] 3. Synthesis of 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide

Chem.

[0292] Synthesis of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(prop-1-en-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide

Chemical Structure

[0293] Synthesis of 5.4-(3,5-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-isopropylthieno[3,2-d]pyrimidine-6-carboxamide

Chem.

[0294] 6. Synthesis of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(dimethylamino)thieno[3,2-d]pyrimidine-6-carboxamide

Chem.

[0295] Synthesis of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(morpholin-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide

Chemical Structure

[0296] The following compounds can be prepared according to Scheme 12 below and the following detailed procedures: 201, 203, 206, 208, 209, 211, 211-0A, 213, 214, 216, 217, 220, 221, 222, 223, 229, 231, 232, 236, 238, 240, 241, 242, 243, 245, 246, 247, 248, 249, 250, 255, 255-0A, 257, 268, 268-4, 347, 348. Scheme 12

[0297]

Chem.

[0298] Exemplary procedure for Compound 201: 1. Synthesis of 3-Bromo-7-chlorothieno[3,2-b]pyridine

Chem.

[0299] 2. Synthesis of 3-Bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid

Chem.

[0300] 3. Synthesis of 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0301] 4. Synthesis of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(prop-1-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide

Chemical formula

[0302] Synthesis of 5.7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide [Chemical formula] A 1000 mL round-bottom flask was charged with 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(prop-1-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide as a yellow solid (2.50 g, 6.5 mmol, 1.0 equiv), EA (500.0 mL), and Pt2O (1.5 g). The flask was evacuated, flushed with nitrogen three times, and subsequently flushed with hydrogen. The mixture was stirred at 40 °C for 3 h under a hydrogen atmosphere (balloon). The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated. Thereby, 1.2 g (59.7%) of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide was obtained as a yellow solid.

[0303] 6. Synthesis of N-[(4S)-3,4-Dihydro-2H-1-benzopyran-4-yl]-7-(4-fluoro-2,6-dimethylphenyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide

Chem.

[0304] Exemplary procedure for Compound 255:

Chemical Structure

[0305]

Chem.

[0306]

Table 6

[0307] The following additional compounds were prepared according to the above scheme:

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Table 7-19

Table 7-20

Table 7-21

Table 7-22

Table 7-23

Table 7-24

Table 7-25

Table 7-26

Table 7-27

Table 7-28

Table 7-29

Table 7-30

Table 7-31

Table 7-32

[0308] Biological Examples The present disclosure is further illustrated by the following biological examples, which should not be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure thereby. It should be further understood that various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims are available.

[0309] (Example 1) Screening method for testing the activity of a compound against the microfilariae of Dirofilaria immitis Four to six hundred microfilariae of Dirofilaria immitis were added to the wells of a microtiter plate containing the test compound formulated in RPMI medium and 100% DMSO. The plate was kept at 37 °C and 5% CO2 for 3 days. The effectiveness of the compound was determined based on the motility of the microfilariae compared to the average motility of the control wells containing DMSO only. A dose-response assay was performed to determine the EC 50 value. Compounds 310, 228, 217, 301, 205, and 259-4 had EC 50Values were shown. Compounds 259-5, 260, 258, 220, 222, 203, 213, 199, 229, 224, 221, 247 and 214 had EC 50 values between 10 nM and 100 nM. Compounds 236, 243, 238, 256, 253, 252, 337, 212-0, 207, 120, 102, 259, 264, 211, 210, 263, 263-8, 204, 311, 309, 212, 209, 206 and 223 had EC 50 values less than 10 nM.

[0310] (Example 2) Screening method for testing the activity of compounds against Haemonchus contortus Twenty L1 Haemonchus contortus larvae were added to wells of a microtiter plate containing a nutrient medium and a test compound in DMSO. The analysis was performed on day 4 to determine the degree of development of L1-L3 larvae. Larvae exposed to DMSO only were used as a control. A dose-response assay was performed to determine the EC 50 values. Compounds 124, 090, 205, 236, 238, 256, 246, 337, 128, 207, 119, 260, 102, 338, 268-4, 268, 220, 222, 255, 255-0, 243, 213, 201, 229, 223, 115, 126, 127, 129, 102-1, 101, 130, 121, 092, 239-INT-1, 239, 240, 241, 249, 245, 242 and 123 were found to be active at EC 50 values between 100 nM and 10 μM. Compounds 263-8, 263, 210, 204, 211, 336, 259-5, 264, 309, 264-0, 259, 285, 212, 120, 258, 212-0, 310, 252, 209, 253, 206, 203 and 199 had EC 50 values less than 100 nM.

[0311] (Example 3) In vivo efficacy against Dirofilaria immitis in immunodeficient NSG mice The following in vivo tests were conducted to evaluate the efficacy of the compounds of the present invention for preventing infection by Dirofilaria immitis in mammals according to the procedure described in International Publication No. 2018 / 148392 (incorporated herein by reference). For the following tests, D. immitis was obtained from the Filariasis Research Reagent Resource Center of the University of Georgia Vet School (referred to herein as "FR3") and an in-house insectary. Generally, the helminths were recovered from the mosquitoes and shipped overnight in medium and antibiotics. The helminths were washed and counted for use in mice. Immunodeficient NSG mice susceptible to D. immitis infection were subcutaneously or intraperitoneally injected with 50 L3 D. immitis (2005 Missouri isolate or JYD-34) on day 0. The compounds of the present invention were orally administered to the NSG mice at the dosage levels indicated in the test on days 1, 15, and 30 after infection. To recover the parasites, the mice were bled for serum collection at 6 weeks post-infection, the skin was peeled off, the membranes were incised, the viscera (entrails) were removed, and the fascia was incised. All pieces were left immersed overnight at room temperature in RPMI medium supplemented with 10% FBS and penicillin / streptomycin antibiotics. The next morning, approximately 18 hours later, the helminths were counted and fixed in 95% ethanol / 5% glycerol. The helminths were placed on glycerol jelly and then measured using cellSens software.

[0312] Test No. 1 Four groups of 6 immunodeficient NSG mice were set up. One untreated group was used as a control, and the other three groups were administered compounds 211, 204, and 212 at dosage levels of 25 mg / kg body weight, 50 mg / kg, and 25 mg / kg, respectively. The compounds were formulated in a Labrasol / Labrifil® M 1944 CS (70:30) carrier at a concentration of 2.5 mg / mL and orally administered to the mice at the dosages shown in the following table. The efficacy of the compounds was evaluated against an untreated mouse control group. Table 6 below shows the percent reduction in live helminths recovered from the treated groups compared to the control group.

[0313]

Table 8

[0314] Test No. 2 Using the same protocol as Test No. 1, the efficacy of Compounds 119 and 120 was tested at two different dose levels. A control group of 6 NSG mice was assigned. Four groups of 5 NSG mice each were assigned to receive Compounds 119 and 120 at dose levels of 25 mg / kg and 50 mg / kg body weight, respectively, and tested. The compounds were formulated at a concentration of 2.5 mg / mL in a Labrasol / Labrifil® M 1944 CS (70:30) carrier as in Test No. 1 and orally administered to the mice at the doses shown in Table 7 below.

[0315]

Table 9

[0316] Test No. 3 Using the same protocol as Test No. 1, the efficacy of Compounds 210, 257, 207 and 102 was tested. A control group of 7 NSG mice was assigned. Four additional test groups were assigned to receive Compounds 210, 257, 207 and 102. The group for Compound 210 contained 7 NSG mice, and the groups for Compounds 257, 207 and 102 each contained 6 NSG mice. The compounds were formulated at a concentration of 2.5 mg / mL in a Labrasol / Labrifil® M 1944 CS (70:30) carrier as in Test No. 1 and orally administered to the mice at a level of 25 mg / kg body weight. The results of the test are shown in Table 8 below.

[0317]

Table 10

[0318] (Example 4) In Vivo Efficacy against Heligmosomoides polygyrus and Trichostrongylus colubriformis in the Striped Hamster (Meriones unguiculatus) Several in vivo tests were conducted to examine the efficacy of the compounds of the present invention against Heligmosomoides polygyrus and Trichostrongylus colubriformis in the striped hamster. Groups of five animals each were assigned to each treatment group, non-treated control group, and positive control group. Striped hamsters in the non-treated group were administered the Labrasol / Labrifil® M 1944 CS (70:30) vehicle. Animals in the positive control group were treated with levamisole (10 mg / kg in aqueous vehicle) and / or ivermectin (0.1 mg / kg in DMSO / corn oil (50% / 50% v / v)). On day 0, immunosuppressed striped hamsters were artificially infected with approximately 1,000 infectious third-stage larvae of Heligmosomoides polygyrus enclosed in sheaths. At least 4 hours later, the striped hamsters were also infected with approximately 1,000 third-stage larvae of Trichostrongylus colubriformis enclosed in sheaths. Six days after infection, the striped hamsters were treated by forced oral administration with the test compounds dissolved in a mixture of Labrasol / Labrifil® M 1944 CS (70:30) at the dose levels shown in Tables 9 - 12 below. On day 9 (3 days after treatment), the striped hamsters were euthanized and necropsied to recover the parasites from the stomach and small intestine. Efficacy was calculated as the mean percent reduction in the number of worms in each test group compared to the mean number of worms in the control group. The efficacy of the tested compounds is presented in Tables 9 - 12 below. Test 1:

[0319] [Table 11] Test 2:

[0320] [Table 12] Test 3:

[0321]

Table 13

[0322]

Table 14

[0323] Therefore, it was found that the compounds of the present invention are extremely effective against Nippostrongylus brasiliensis and Trichuris muris in a murine model.

[0324] Although the preferred embodiments of the present invention have been described in detail as above, it should be understood that the invention defined by the above paragraphs is not limited to the specific details shown in the above description, and many obvious modifications can be made without departing from the spirit or scope of the present invention.

Claims

1. A compound of formula (I): 【Chemical 1】 (I) or a pharmaceutically acceptable salt thereof (wherein, L is L1 or L2: 【Chemical Formula 2】 R 1 is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF 5 or -NR a R b (wherein R a and R b are each independently H or optionally substituted alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 2’ is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 3 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) p (optionally substituted alkyl), -SF 5 , optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbonocyclic group, spirocyclic heterocyclyl-heterocyclyl group, spirocyclic carbonocyclic-carbonocyclic group, spirocyclic carbonocyclic-heterocyclyl group, or -NR a R b (wherein R a and R b are each independently H or optionally substituted alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 4 is, independently at each occurrence, hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF 5 or -NR a R b (wherein R a and R b are independently H or optionally substituted alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 5 and R 5’ is, in each occurrence, independently, hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted heteroaryl, -SF 5 , -SO p (optionally substituted alkyl or haloalkyl), or -NR c R d (wherein R c and R d are independently H or optionally substituted alkyl; or R c and R d may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 10 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl; X is O or S; Q is O, S or NR 2’ wherein; Y 1 , Y 2 and Y 3 are each independently, -N- or -CR 4 -; Y 1’ and Y 6’ are each independently N, C or -CR 5 -; Y 2’ 、Y 3’ 、Y 4’ 、Y 5’ are each independently N, NR 2 、S, O, -CR 5 - or CR 5 R 5’ ; W is CR 6 R 7 , O, S or N-R 8 and is Z is CR 6 R 7 , O, S or N-R 8 and R 6 and R 7 is, independently at each occurrence, hydrogen, halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 3 -C 8 -cycloalkoxy; R 8 is hydrogen or C 1 -C 4 -alkyl; Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ 、Y 5’ and Y 6’ Among them, the maximum of three are heteroatoms; a is 0 or 1; q is 0 or 1; p is, independently at each occurrence, 0, 1 or 2; a dashed bond 【Chemical Formula 3】 represents a single bond or a double bond) its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts.

2. R 1 is hydrogen, cyano, halo, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 - haloalkylamino carbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C 3 - C 8 - cycloalkyl, optionally substituted C 3 - C 8 - cycloalkyloxy, optionally substituted 3 - to 7 - membered heterocyclyl, C 1 - C 6 - alkylcarbonyl, C 1 - C 6 - haloalkylcarbonyl, C 1 - C 6 - alkoxycarbonyl, C 1 - C 6 - haloalkoxycarbonyl, aminocarbonyl, C 1 - C 6 - alkylaminocarbonyl, C 1 - C 6 - haloalkylaminocarbonyl, di - C 1 - C 6 - alkylaminocarbonyl, di - C 1 - C 6 - haloalkylaminocarbonyl, - SF 5 - SO p (optionally substituted C 1 - C 6 - alkyl or C 1 - C 6 - haloalkyl), or - NR a R b (wherein R a and R b are independently H or optionally substituted C 1 - C 6 - alkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 - 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3 - membered, 4 - membered, 5 - membered, 6 - membered, 7 - membered or 8 - membered heterocyclyl group); R 2 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted phenyl; R 2’ is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted phenyl; R 3 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SF 5 、-S(O) p (C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), a 3- to 7-membered heterocyclyl optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbonocyclyl group, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered spirocyclic carbonocyclyl-carbonocyclyl group, 5- to 11-membered spirocyclic carbonocyclyl-heterocyclyl group, or -NR a R b (wherein R a and R b each independently is H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 4 is, independently at each occurrence, hydrogen, cyano, halo, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, phenyl which may be substituted; phenyloxy which may be substituted, 5- or 6-membered heteroaryl which may be substituted, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyloxy, 3- to 7-membered heterocyclyl which may be substituted and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), SF 5 or -NR a R b (wherein R a and R b are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b may together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 5 and R 5’ each occurrence is independently hydrogen, halogen, cyano, nitro, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF 5 , -SO p (optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), or -NR c R d (wherein R c and R d are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R c and R d together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 10 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, The compound of formula (I) according to claim 1.

3. R 1 is hydrogen, cyano, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 2 -C 4 -alkenyl, optionally substituted C 2 -C 4 -alkynyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted, saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, 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 p -, haloalkyl-SO p -, amino, -NH-optionally substituted C 1 -C 4 -alkyl, or -NR a R b (wherein R a and R b are independently optionally substituted alkyl; or R a and R b together with the nitrogen to which they are attached may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 2 is hydrogen or C 1 -C 4 -alkyl; R 3 is C 1 -C 4 -alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3 -C 8 -cycloalkyl, 5- to 11-membered spirocyclic heterosilyl-carbocyclic group, 5- to 11-membered spirocyclic heterosilyl-heterosilyl group, 5- to 11-membered spirocyclic carbocyclic-carbocyclic group, or a 5- to 11-membered spirocyclic carbocyclic-heterosilyl group, each of which may be substituted with one, two or three substituents; R 4 is independently hydrogen, 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, NH-optionally substituted C 1 -C 4 -alkyl, -SF 5 or -NR a R b wherein R a and R b are independently optionally substituted C 1 -C 4 -alkyl; or R a and R b together with the nitrogen to which they are attached may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group), -SO p (optionally substituted C 1 -C 4 -alkyl or haloalkyl); R 5 is independently 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, NH-optionally substituted C 1 -C 4 -alkyl, -SF 5 or -NR c R d wherein R c and R d are independently optionally substituted C 1 -C 4 -alkyl; or R c and R d together with the nitrogen to which they are attached may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); SO p (optionally substituted C 1 -C 4 -alkyl or haloalkyl), The compound of formula (I) according to claim 1 or 2.

4. The compound of formula (I) according to any one of claims 1 to 3, wherein X is S.

5. The compound of formula (I) according to any one of claims 1 to 3, wherein X is O.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein a is 1 and q is 1.

7. The compound of formula (I) according to any one of claims 1 to 5, wherein a is 0 and q is 0.

8. The compound of formula (I) according to any one of claims 1 to 5, wherein a is 1 and q is 0.

9. L is L1; R 1 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -haloalkyl, alkoxy-C 1 -C 4 -alkyl, alkoxy-C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclyl which may be substituted and contains 1 to 3 N, S or O heteroatoms, or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; or R a and R b may together with the nitrogen to which they are attached, include from 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group); R 2 is hydrogen or C 1 -C 4 -alkyl; R 3 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), -SF 5 , a 3- to 7-membered heterocyclyl optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbonocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbonocyclyl-carbonocyclyl group (each ring of the spirocyclic group contains 3, 4, 5 or 6 ring atoms); or -NR a R b (wherein R a and R b are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, include one to three additional heteroatoms selected from the group consisting of N, O and S and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group); R 4 is, independently for each occurrence, hydrogen, halo, -SF 5 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, optionally substituted C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 4 -haloalkylaminocarbonyl, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 - is a haloalkyl); R 5 is, independently at each occurrence, hydrogen, halogen, -SF 5 , C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), or -NR c R d (wherein R c and R d are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 10 is hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; Q is O or S; Z is O; W is CR 6 R 7 is that The compound of formula (I) according to any one of claims 1 to 8.

10. The compound of formula (I) according to claim 9, wherein a is 1 and q is 1.

11. The compound of formula (I) according to claim 9, wherein a is 0 or 1 and q is 0.

12. The compound of formula (I) according to claim 9, represented by the following structure of formula (IC): [Chemical Formula 4] (IC) (wherein, R 9 is independently halo, cyano, nitro, C 3 -C 8 -cycloalkyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -halocycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 1 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -alkyl, alkoxy-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, a 5- or 6-membered heterocyclyl optionally containing 1 to 3 N, S or O heteroatoms, or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; or R a and R b It may, together with the nitrogen to which they are attached, include 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered or 6-membered heterocyclyl group); R 4 is, independently at each occurrence, hydrogen, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), -SF 5 , or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 5 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), -SF 5 , or -NR c R d (wherein R c and R d are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); W is CR 6 R 7 and; R 2 is hydrogen or C 1 -C 3 -alkyl; R 10 is hydrogen; o is 0, 1 or 2; m is 0, 1, 2 or 3).

13. The compound of formula (I) according to claim 9, represented by the following structure: 【Chemical Formula 5】 (wherein, R 9 is independently halo, cyano, nitro, C 3 -C 8 -cycloalkyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -halocycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 1 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -alkyl, alkoxy-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, a 5- or 6-membered heterocyclyl which may be substituted and contains 1 to 3 N, S or O heteroatoms, or -NR a R b (wherein R a and R b are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b which, together with the nitrogen to which they are attached, may include one to three additional heteroatoms selected from the group consisting of N, O, and S and may form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclyl group); R 4 is, independently at each occurrence, hydrogen, halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), -SF 5 , or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 5 and R 5’ are each occurrence independently hydrogen, halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (optionally substituted C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl), -SF 5 , or -NR c R d (wherein R c and R d are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 2 is hydrogen or C 1 -C 3 -alkyl; R 10 is hydrogen; Z is CR 6 R 7 or O; Y 1’ and Y 6’ are each independently C, N or CR 5 ; Y 3’ 、Y 4’ 、Y 5’ is independently CR 5 、CR 5 R 5’ 、N、NR 2 、O or S; a dashed bond [Chemical Formula 6] represents a single bond or a double bond; a is 0 or 1; m is 0, 1, 2 or 3).

14. Y 1’ and Y 6’ are each C; Y 3’ and Y 4’ are each independently CR 5 ; Y 5’ is S The compound according to claim 13.

15. Y 3’ and Y 6’ is N; Y 1’ is C; Y 4’ and Y 5’ are each independently, CR 5 is The compound according to claim 13.

16. Y 1’ and Y 5’ is N; Y 6’ is C; Y 3’ and Y 4’ are each independently CR 5 is The compound according to claim 13.

17. The compound of formula (I) according to claim 9, represented by the following structure: 【Chemical Formula 7】 (wherein, R 9 is independently halo, cyano, nitro, C 3 -C 8 -cycloalkyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -halocycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or -NR a R b (wherein R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 1 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -alkyl, alkoxy-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, a 5- or 6-membered heterocyclyl optionally containing 1 to 3 N, S or O heteroatoms, or -NR a R b (wherein R a and R b are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b It may, together with the nitrogen to which these are attached, include 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, and may form an optionally substituted 3-membered, 4-membered, 5-membered, or 6-membered heterocyclyl group); R 5 is halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, -SO p (optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), -SF 5 , or -NR c R d (wherein R c and R d are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl); R 2 is hydrogen or C 1 -C 3 -alkyl; R 10 is hydrogen; D is -N- or -CH-; D 1 is -NH-, -O-, -CH 2 -; or D 1 is optionally attached to a 2- to 5-membered chain containing an N, O or S heteroatom to form a spirocyclic heteroseryl-heteroseryl group, a spirocyclic heteroseryl-carboseryl group, a spirocyclic carboseryl-carboseryl group or a spirocyclic carboseryl-heteroseryl group; m is 0, 1, 2 or 3; b is 0 or 1).

18. R 1 is C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -cycloalkyl, amino, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 4 is, independently at each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl optionally substituted one or two times by halogen or C 1 -C 4 -alkyl; R 5 is, independently at each occurrence, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl optionally substituted one or two times by halogen or C 1 -C 4 -alkyl The compound according to claim 12.

19. R 1 is C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -cycloalkyl, amino, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 4 is, independently at each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl optionally substituted one or two times by halogen or C 1 -C 4 -alkyl; R 5 is, independently at each occurrence, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl which may be substituted one or two times by halogen or C 1 -C 4 -alkyl The compound according to claim 13.

20. R 1 is C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -cycloalkyl, amino, C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 4 is, independently at each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl optionally substituted one or two times by halogen or C 1 -C 4 -alkyl; R 5 is, independently at each occurrence, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, or phenyl optionally substituted one or two times by halogen or C 1 -C 4 -alkyl The compound according to claim 17.

21. Y 1 、 Y 2 and Y 3 each of which is -C-R 4 A compound according to any one of claims 1 to 20, wherein the compound is such that.

22. Y 1 is N; Y 2 and Y 3 is -C-R 4 A compound according to any one of claims 1 to 20, wherein

23. Y 2 is N; Y 1 and Y 3 is -CR 4 The compound according to any one of claims 1 to 20, wherein

24. Y 1 and Y 3 is N; Y 2 is -CR 4 A compound according to any one of claims 1 to 20, wherein

25. Y 1 and Y 2 is N; Y 3 is -CR 4 The compound according to any one of claims 1 to 20, wherein

26. The compound according to claim 1 having the structure presented in the following table (wherein R 2 and R 2’ are both hydrogen; Q is oxygen; The group 【Chemical Formula 8】 is abbreviated as "ring system" in the table and represents the following groups: 【Chemical Formula 9】 Ring system A; 【Chemical Formula 10】 Ring system B; 【Chemical Formula 11】 Ring system C; 【Chemical 12】 Ring system D; 【Chemical 13】 Ring system E; 【Chemical 14】 Ring system F; 【Chemical Formula 15】 Ring system G; 【Chemical 16】 Ring system H; 【Chemical 17】 Ring system I; and 【Chemical Formula 18】 Ring system K: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】

27. A veterinary composition comprising the compound according to any one of claims 1 to 26 or a pharmaceutically or veterinarily acceptable salt thereof and a veterinarily acceptable carrier.

28. A veterinary composition comprising the compound according to any one of claims 1 to 26 or a pharmaceutically or veterinarily acceptable salt thereof, one or more additional active agents, and a veterinarily acceptable carrier.

29. A method for treating, controlling or preventing parasitic infestation or infection in an animal in need thereof, the method comprising administering to the animal an effective amount of the compound according to any one of claims 1 to 26 or a pharmaceutically or veterinarily acceptable salt thereof.

30. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for treating, controlling or preventing parasitic infection or infestation in an animal.

31. Use of a compound of formula (I) according to any one of claims 1 to 26 for use in the treatment, control or prevention of parasitic infection or infestation in an animal.

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