Anthelmintic azabenzothiophene and azabenzofuran compounds

Abstract

The present invention provides compounds of the formulae in which the variables are defined herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, compositions comprising these compounds, and methods for treating, controlling or preventing parasitic infestation or infection in animals by administering an effective amount of these compounds to an animal in need thereof. JPEG2022526901000215.jpg54106(I)

Description

[Technical Field]

[0001] This patent application relates to new antiparasitic compounds, compositions containing the compounds, methods for their preparation, and methods for using the compounds to control parasites that harm animals. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 820,352, filed March 19, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Animals, such as mammals and birds, are often susceptible to parasitic infestations. These parasites can be ectoparasites, such as fleas and ticks. Animals and humans also suffer from endoparasitic infections, including helminthiasis, which is most frequently caused by a group of parasites described as nematodes or roundworms. These parasites cause serious 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 gastrointestinal 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 extraintestinal stages of Strongyloides and Trichinella.

[0003] One type of internal parasite that seriously infects mammals is 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. Heartworms undergo several life stages before becoming adult worms that infect the pulmonary arteries of mammalian hosts. These worms require a mosquito as an intermediate host to complete their life cycle. The period between initial infection by a mosquito bite and maturation of the worms into adult worms that inhabit the heart and pulmonary arteries is 6 to 7 months in dogs, known as the "pre-occurring stage." During a blood meal, L3 larvae migrate to the tip of the mosquito's mouthparts (lower lip), exit the mosquito, and deposit themselves on the dog's skin, then migrate into the host through the bite wound. Most L3 larvae molt into fourth-stage nymphs (L4) in the dog's subcutaneous tissue within one to three days after infection. These larvae then migrate to the thoracic and abdominal muscles, where they molt into fifth-stage nymphs (L5, immature adults) 45 to 60 days after infection. Between 75 and 120 days after infection, these immature heartworms enter the bloodstream, are transported through the heart, and reside in the pulmonary artery. Approximately seven months after infection, Dirofilaria immitis adult worms mature and sexually reproduce in the pulmonary artery and right ventricle. Adult males are approximately 15 cm long, and females are approximately 25 cm long. Their normal adult lifespan is estimated to be approximately five years. Heartworm infection is a serious, life-threatening disease. Heartworm infection in dogs is preventable, and preventive treatment is a priority in heartworm-endemic areas. Treatment of mature heartworm infection with adulticides (e.g., melarsomine dihydrochloride) is expensive and can cause serious side effects, so prevention with monthly administration of drugs that inhibit larval development is widely used. The goal of commercially available heartworm preventative therapy is to prevent the parasite from developing into adult heartworms by interrupting the Dirofilaria immitis life cycle after infection.

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

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

[0006] It is expressly noted that 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 application and all documents cited therein or during its prosecution ("application cited documents") and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein ("documents cited herein"), and all documents cited or referenced in the documents cited herein, together with manufacturer's instructions, descriptions, product specifications and product sheets for any products referenced in this specification or any document incorporated by reference herein, are hereby incorporated by reference and may be used in the practice of this invention. Summary of the Invention

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

[0008] One aspect of the present invention is a compound of formula (I): [ka] (I) its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, where variable R 1 , R 3 , R 10 , Y 1 , Y 2 , Y 3 , X, L, W, Z, Y 1’ , Y 2’ , Y 3’ , Y 4’ , Y 5’ , Y 6’ , a and q are as defined herein; and the dashed bond

[0009] [ka] indicates a single or double bond) Includes.

[0010] The present invention also includes veterinarily acceptable compositions comprising a compound of formula (I) and a veterinarily acceptable carrier, and methods for controlling parasites, including helminths, comprising administering the compound or a veterinarily acceptable composition thereof to an animal in need thereof. Some embodiments of the present invention also include the use of compounds of formula (I) to eradicate, control, and prevent parasitic infestations and / or infections in animals. The compounds of the present invention can be administered to animals, particularly mammals, fish, and birds, to prevent or treat parasitic infections. The compounds and compositions containing the compounds are highly effective in the treatment and prevention of endoparasites in mammals, fish and birds, particularly cats, dogs, horses, chickens, pigs, sheep and cattle, with the aim of substantially eliminating endoparasites from these hosts. In one embodiment, compounds of formula (I) and compositions comprising the compounds are substantially effective against endoparasites of the gastrointestinal tract of animals and humans, such as filariae (e.g., heartworms), hookworms, whipworms, and roundworms. In certain embodiments, compounds of formula (I) and compositions comprising the compounds are effective against Dirofilaria immitis (heartworm) isolates that are less susceptible to treatment with macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are effective in treating and preventing infections in animals with nematodes that are less susceptible to treatment with commercially available or known active agents. In certain embodiments, the present invention comprises a combination of a compound of formula (I) and at least a second active agent that can broaden the scope of protection afforded to an animal against endoparasites and / or ectoparasites.

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

[0012] Thus, the present invention includes the following non-limiting embodiments: (a) a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, which is an active endoparasiticidal agent and, optionally, is also active against ectoparasites; (b) a veterinary composition comprising a parasiticidally 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 parasiticidally 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 encompassed by 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 an animal in need thereof a parasiticidally 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 encompassed by formula (I)); (e) a method for preventing parasitic infestation / infection in an animal, comprising administering to an animal in need thereof a parasiticidally 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 encompassed by formula (I)); (f) the use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, for treating or preventing parasitic infections and possibly also parasitic infestations in animals; (g) use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, for the manufacture of a veterinary medicament for the treatment or prevention of parasitic infections in animals; and (h) A method for preparing a compound of formula (I).

[0013] Therefore, it is the object of the present invention not to encompass any previously known products, processes for preparing products, or methods for using products, so as to disclose the exclusion of any previously known products, processes, or methods to which the applicants have reserved rights. It is further noted that the present invention is not intended to encompass within its scope any product, process, preparation of a product, or method for using a product that does not meet the description and enablement requirements of the USPTO (35 U.S.C. § 112, first paragraph) or the EPO (Article 83 EPC). In implementing the present invention, it may be advantageous to comply with Article 53(c) of the EPC and Articles 28(b) and (c) of the EPC Rules. All rights are expressly reserved to explicitly disclaim any embodiment that is the subject of the applicant's granted patents in this or any other line, or in a previously filed application of a third party. Nothing herein should be construed as a promise. The term "compounds of formula (I)" includes any stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof.

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

[0015] Definition: In this disclosure, and particularly in the claims and / or paragraphs, terms such as "comprise," "comprised," "comprising," and the like can have the meaning ascribed to them in U.S. patent law; for example, these terms can mean "includes," "included," "including," and the like; and terms such as "consisting essentially of" and "consists essentially of" have the meaning ascribed to them in U.S. patent law, for example, it should be noted that these terms permit elements not expressly recited, but exclude elements found in the prior art or that affect a basic or novel characteristic of the invention. Terms used herein have their conventional meaning in the art unless otherwise specified. The organic moieties referred to in the definitions of the variables of compounds, such as compounds of formula (I), are like the term halogen - i.e., members of the individual groups - a generic term for the individual enumerations of fluoro, chloro, bromo, and iodo for halogen. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group from an integer n to another integer m. As used in this specification and claims, the term "including but not limited to" is equivalent to "included."

[0016] The term "optionally substituted" refers to a group that is optionally substituted with one or more of the following moieties: halogen, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, 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, unprotected or optionally protected, known to those skilled in the art that does not interfere with the biological activity of the compounds of the invention, for example, as taught 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," alone or in combination with heteroatoms, refers to a saturated straight-chain, branched, primary, secondary, or tertiary hydrocarbon, including those having 1 to 12 atoms, such as alkoxy, thioalkyl, alkylamino, etc. In some embodiments, the alkyl group is C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. 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 isomers thereof. C1-C4-Alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0018] Cyclic alkyl groups, which may also be referred to as "cycloalkyl," include those having 3 to 10 carbon atoms with single or multiple condensed rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Carbocyclic groups are ring groups composed solely of carbon. Carbocyclic groups include both aromatic rings, such as phenyl, and non-aromatic rings, such as cycloalkyl rings, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and include those having 3 to 14 carbon atoms with single or multiple condensed rings.

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

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

[0021] The term "haloalkyl" refers to an alkyl group, as defined herein, 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, etc. The term "fluoroalkyl," as used herein, refers to an alkyl in which one or more of the hydrogen atoms have been replaced by a fluorine atom, 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-, where 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-, respectively, where alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. 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-methylpent ... butyloxy, 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 condensed rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments, aryl includes tetrahydronaphthyl, phenylcyclopropyl, and indanyl. Aryl groups can be unsubstituted or include any of the following radicals: 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. and optionally substituted by one or more moieties selected from alkylsulfinyl, alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, -SF5, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.

[0024] The term "aralkyl" refers to the diradical alkylene bridge, (-CH2-) n where n is 1-12 and "aryl" is defined above. The term "heteroaryl" refers to a monovalent aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms, within the ring. The nitrogen and sulfur heteroatoms may be oxidized. Heteroaryl groups typically contain a 5- or 6-membered aromatic ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings, provided that the point of attachment is 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. Heteroaryl rings can be unsubstituted or substituted with one or more moieties as described for aryl above.

[0025] The terms "heterocyclyl," "heterocyclic," or "heterocyclo" refer to a fully saturated or unsaturated cyclic group, e.g., a 3- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or a 10- to 15-membered tricyclic ring system, having one or more oxygen, sulfur, or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, within the ring. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more moieties as described above for aryl groups. 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, pi These include peridinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl and the like.

[0026] Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.

[0027] Bicyclic and tricyclic carbocyclic or heterocyclic ring systems include spirocyclic ring systems in which at least two of the rings in the system are bonded through a single carbon atom. Spirocyclic ring systems include combinations of 3- to 8-membered carbocyclic and / or heterocyclic ring systems bonded at a common carbon atom. Thus, spirocyclic ring systems can include anything from a 3-membered ring bonded to another 3-membered ring (carbocyclic or heterocyclic) to an 8-membered ring bonded to another 8-membered ring, and all combinations of ring sizes in between. The heterocyclic ring component of a 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 is C-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. 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", and "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 defined above. In some embodiments, the alkyl component of the alkylsulfinyl group is C-C 12 , C1-C 10, C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. 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, Examples include 1,1-dimethylbutylsulfinyl, 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, and 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)-, where the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are defined above.

[0030] The term "alkylsulfonyl" refers to the group alkyl-S(=O)2-, where the term "alkyl" is 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 1-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, and 1-ethyl-2-methylpropylsulfonyl.

[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), -NH(alkenyl), -NH(alkynyl), -N(alkenyl), and -N(alkynyl), where the terms "alkyl," "alkenyl," and "alkynyl" are as defined above. In some embodiments, the alkyl component of an alkylamino or dialkylamino group is C-C 12 , C1-C 10 , C1-C8, C1-C6 or C1-C4 alkyl groups.

[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)-, haloalkoxy-C(O)-, haloalkylamino-C(O)-, 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): [ka] (I) (In the formula, L is L1 or L2:

[0034] [ka] 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 (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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), -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 (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 is independently in 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 (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R bmay contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 5 and R 5’ is independently in each occurrence 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 (In the formula, R c and R d are independently H or optionally substituted alkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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’ and; Y 1 , Y 2 and Y 3 are each independently N or -CR 4 - and; Y 1’ and Y 6’ are each independently N, C, or -CR 5 - and; Y 2’ , Y 3’ , Y 4’ , and Y 5’ are independently N, NR 2 ,S,O,-CR5 - or CR 5 R 5’ and; W is CR 6 R 7 , O, S or NR 8 and Z is CR 6 R 7 , O, S or NR 8 and R 6 and R 7 is independently at each occurrence hydrogen, halo, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy or cycloalkoxy; R 8 is hydrogen or C1-C4-alkyl; Y 1’ , Y 2’ , Y 3’ , Y 4’ , Y 5’ and Y 6’ up to three of which are heteroatoms; a is 0 or 1; q is 0 or 1; p is independently in each occurrence 0, 1, or 2; Dashed bond

[0035] [ka] indicates a single or double bond); This includes stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof.

[0036] In another embodiment, the present invention provides R 1are 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-C 6-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 (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4are independently in 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, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cyclo Alkyl, optionally substituted C3-C8-cycloalkyloxy, 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 (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 5 and R 5’are independently in 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 (In the formula, R c and R d are independently H, C-C-alkyl or C-C-haloalkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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 bond

[0037] [ka] is as defined above for compounds of formula (I), A compound of formula (I) is provided.

[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-, 6- 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 (In the formula, R a and R b are independently optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 2 is hydrogen or C1-C4-alkyl; R 3 is C1-C4-alkyl, C3-C6-cycloalkyl, 4- to 6-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, each of which may be substituted by 1, 2 or 3 substituents; Each R 4are 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 (In the formula, R c and R d are independently optionally substituted C1-C4-alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group), SO p (optionally substituted C1-C4-alkyl or haloalkyl), Each R 5 are 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 (In the formula, R c and R d are independently optionally substituted C1-C4-alkyl; or R c and R d may be taken together with the nitrogen to which they are attached to 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 a halogen. In another embodiment, R 1 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 Ga-NR a R b (In the formula, R a and R b are independently hydrogen or C1-C6 alkyl. In another embodiment, R 1 Ga-NR a R b (In the formula, R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- 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, 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 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 thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, or triazinyl. In some embodiments, R 1is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be substituted by one or more halogens.

[0041] In some embodiments, R 3 is a 6- to 10-membered aryl optionally 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, iso-propyl, tert-butyl, sec-butyl or iso-butyl. In other embodiments, R 3 is CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 3 is optionally substituted C-C-cycloalkyl. In yet another embodiment, R 3 is optionally substituted C-C-cycloalkyl. In yet another embodiment, R 3 is an optionally substituted C-C-cycloalkenyl or C-C-cycloalkenyl. In some embodiments, R 3 is optionally substituted cyclopentyl or cyclohexyl. In one embodiment, R 3 is cyclohexyl optionally substituted by one or more halo, C-C-alkyl or C-C-haloalkyl. 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 halo, C-C-alkyl or C-C-haloalkyl. 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more methyl, chloro or fluoro. In some embodiments, R 3 is a 5- to 10-membered heteroaryl optionally substituted by 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. 3 is an optionally substituted 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, an optionally substituted 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, an optionally substituted 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, or an optionally substituted 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group. Non-limiting examples of spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl, and spirocyclic heterocyclyl-heterocyclyl groups are shown below for illustrative purposes.

[0043] [ka]

[0044] However, it will be apparent to those skilled in the art that the second ring of the spirocyclic group may be attached at any available carbon atom of the first ring. It will also be understood that the first ring of the spirocyclic group may be attached to the molecule at any available atom. Thus, the present invention includes 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic rings as defined herein that are attached to a second 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic ring at 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 with 1 to 3 substituents. 3 is phenyl substituted with 1 or 2 substituents. In some embodiments, R 3 is phenyl substituted by 1, 2, 3, or 4 substituents which 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 a para-substituted phenyl. In some embodiments, R 3 is a meta-substituted phenyl. In some embodiments, R 3 is an ortho-substituted phenyl. In some embodiments, R 3 is halophenyl. In some embodiments, R 3 is haloalkylphenyl. In some embodiments, R 3is haloalkoxyphenyl.

[0046] In some embodiments, R 3 is phenyl substituted by two substituents which 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 a 2,3-disubstituted phenyl. In some embodiments, R 3 is a 2,4-disubstituted phenyl. In some embodiments, R 3 is a 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 a 3-,4-disubstituted phenyl. In other embodiments, R 3 is a 3-,6-disubstituted phenyl. In some embodiments, R 3 is dihalophenyl, for example 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 by three substituents which 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, for example 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 by 1 or 2 substituents which 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 a 6-membered heteroaryl optionally substituted by 1 or 2 substituents which 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-pyridyl optionally substituted by one or two substituents which 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 3-pyridyl optionally substituted by 1 or 2 substituents which 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 3is 4-pyridyl optionally substituted by 1 or 2 substituents which are independently 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 4-pyridyl that is unsubstituted or substituted with one or two chloro or fluoro. 3 is 3-pyridyl which is unsubstituted or substituted by one or two chloro or fluoro. In other embodiments, R 3 is an optionally substituted 3- to 7-membered heterocycle. In some embodiments, R 3 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, piperidinyl, Razinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In another embodiment, R 3 may be an optionally substituted heterocyclic, bridged bicyclic group.

[0048] In some embodiments, each R 4are independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino or di-(C1-C4 alkyl)amino. In another embodiment, each R 4 are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In another embodiment, each R 4 are independently hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen. In another embodiment, R 4 is fluoro or chloro. In another embodiment, each R 4 are 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 which are independently 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 which 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 4optionally 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, piperidinyl, Razinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In some embodiments, R 4 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be substituted by one or more halogens.

[0049] In some embodiments, R 5 is hydrogen. In some embodiments, each R 5 are 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 a 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 which are independently 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 1 or 2 substituents which 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 5 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, piperidinyl, Razinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In some embodiments, R 5 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be 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. 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): [ka] (I-1) (wherein the variables L, R 1 , R 3 , Y 1 , Y 2 , Y 3 , Y 1’ , Y 3’ , Y 4’ , Y 5’ , Y 6’ , X, W, Z, R 10 and a is as defined for formula (I). is.

[0052] In some embodiments, the compound of formula (I) is a compound of formula (I-2): [ka] (I-2) where variable R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ , Y 5’ , X, Q, W, Z, R 10 and a is as defined for formula (I). is.

[0053] In another embodiment, the compound of formula (I) is a compound of formula (I-3): [ka] (I-3) where variable R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ , Y 5’ , X, Q, W, Z, R 10 and a is as defined for formula (I). is.

[0054] In other embodiments, the compound of formula (I) is a compound of formula (I-4): [ka] (I-4) where variable R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 1’ , Y 3’ , Y 4’ , Y 5’ , Y 6’ , X, Q, W, Z, R 10 and a is as defined for formula (I). is.

[0055] In another embodiment, the compound of formula (I) is a compound of formula (I-5): [ka] (I-5) where variable R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 1’ , Y3’ , Y 4’ , Y 5’ , Y 6’ , X, Q, W, Z, R 10 and a is as defined for formula (I). is.

[0056] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): [ka] (Ia) where variable Y 1 , Y 2 , Y 3 , R 1 , R 2 , R 3 , W, Z, Y 2’ , Y 3’ , Y 4’ , Y 5’ , R 10 and a is as defined for formula (I). is.

[0057] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib): [ka] (Ib) where variable Y 1 , Y 2 , Y 3 , R 1 , R 2 , R 3 , R 5 , W, Z, R 10 and a is as defined for formula (I), and o is 0, 1, 2, 3, or 4. is.

[0058] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] (I C) where variable R1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); n is 0, 1, or 2; and o is 0, 1, 2, 3, or 4. is.

[0059] In other embodiments, the compound of formula (I) is a compound of formula (Id): [ka] (Id) where variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); n is 0, 1, or 2; and o is 0, 1, 2, 3, or 4. is.

[0060] In some embodiments, the compound of Formula (I) is a compound of Formula (Ie): [ka] (Ie) where variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); o is 0, 1, 2, 3, or 4. is.

[0061] In some embodiments, the compound of formula (I) is a compound of formula (If): [ka] (If) where variable R 1 , R 2 , R3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); o is 0, 1, 2, 3, or 4. is.

[0062] In some embodiments, the compound of Formula (I) is a compound of Formula (Ig): [ka] (Ig) where variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); n is 0, 1, or 2; and o is 0, 1, 2, 3, or 4. is.

[0063] In other embodiments, the compound of formula (I) is a compound of formula (Ih): [ka] (Ih) where variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a is as defined for formula (I); o is 0, 1, 2, 3, or 4. is.

[0064] In some embodiments, the compound of Formula (I) is a compound of Formula (Ii): [ka] (II) where variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R10 and a is as defined for formula (I); n is 0, 1, 2, or 3; and o is 0, 1, 2, 3, or 4. is.

[0065] Variable Element R 4 and R 5 It has been shown that (R 4 ) n and (R 5 ) o In any of formulas (Ib)-(Ii), in embodiments where n and o are 0, R 4 and R 5 It will be recognized by those skilled in the art that these represent non-hydrogen substituents since there is no

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

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

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

[0069] In some embodiments, the invention provides compounds of formulas IA-1 through IA-56, wherein X is S. In some embodiments, the invention provides compounds of formulas IA-1 through IA-56, where X is O. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4is independently H, —OCF 3 or —SCF 3 .

[0070] In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, —OCF 3 or —SCF 3 . In another embodiment, the present invention provides a compound comprising R 2 and R 10 is independently H or C1-C3-alkyl. In other embodiments, the invention provides compounds of formulas IA-1 through IA-56, where a is 1, W is CH 2 , and Z is O.

[0071] In another embodiment, the present invention provides a compound comprising 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 (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b and 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0072] In another embodiment, the present invention provides a compound comprising R 3 is optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R band 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group. In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 2 and R 10 is independently H or C1-C3-alkyl; W is CH2, Z is O, and a is 1.

[0073] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl.

[0074] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl.

[0075] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl.

[0076] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl.

[0077] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl.

[0078] In another embodiment, the present invention provides Variable Element R 1 , R 2 , R 4 , R 5 , X, W, Z, R 10 and a is 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, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, Optionally substituted C3-C8-cycloalkyloxy, 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) (wherein p is 0, 1 or 2), SF5, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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’ is as shown in Table 2. A compound of formula (IB) shown below is provided:

[0079] [ka] (IB)

[0080] [Table 2-1] [Table 2-2]

[0081] In some embodiments, the invention provides compounds of formulas IB-1 through IB-56, wherein X is S. In some embodiments, the invention provides compounds of formulas IB-1 through IB-56, where X is O. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4is independently H, —OCF 3 or —SCF 3 .

[0082] In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently H, —OCF 3 or —SCF 3 .

[0083] In another embodiment, the present invention provides a compound comprising R 2 and R 10 is independently H or C1-C3-alkyl. In another embodiment, the present invention provides a compound comprising 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 (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b and 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0084] In another embodiment, the present invention provides a compound comprising R 3 is optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R band 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0085] In other embodiments, the invention provides compounds of formulas IB-1 through IB-56, where a is 1, W is CH 2 , and Z is O. In another embodiment, the present invention provides a compound comprising R 9 are independently 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. In another embodiment, the present invention provides a compound comprising R 9 is independently halo; and m is 1, 2, or 3. In another embodiment, the present invention provides a compound comprising R 9 is independently fluoro or chloro; and m is 1, 2, or 3.

[0086] In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 9 is independently halo, m is 1, 2 or 3, and R 2 and R 10 is independently H or C1-C3-alkyl; W is CH2, Z is O, and a is 1.

[0087] In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 9 is independently chloro or fluoro, m is 1, 2 or 3, and R 2 and R 10is independently H or C1-C3-alkyl; W is CH2, Z is O, and a is 1. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl; R 9is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy; and m is 0, 1, 2, or 3.

[0089] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0090] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl; R9 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 method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0091] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are independently H or halo; R 2 is H or C1-C3-alkyl; R 9is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy; and m is 0, 1, 2, or 3.

[0092] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for determining whether the variable R 1 , R 2 , R 4 , R 5 , W and X are as defined above for formula (I); R 9 and m is as defined above for formula IB; o is 0, 1, 2, 3, or 4; Y 1 , Y 2 and Y 3 is as shown in Table 3:

[0093] [ka] (I C)

[0094] [Table 3]

[0095] In some embodiments, the invention provides compounds of formulas IC-1 to IC-7, wherein X is S. In some embodiments, the invention provides compounds of formulas IC-1 to IC-7, where X is O. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 4 is independently H, —OCF3, or —SCF3.

[0096] In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 are 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 a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5is 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. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently CF3, -CH2CF3, -CHFCF3, or -CF2CF3; and o is 0, 1, 2, or 3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently methoxy, ethoxy, propoxy, or butoxy; and o is 0, 1, 2, or 3. In some embodiments, the present invention provides a method for treating a cancer, comprising administering to a patient a cancer treatment ... a method for treating a cancer, or a cancer 5 is independently -OCF3 or -SCF3; and o is 0, 1, 2, or 3.

[0097] In another embodiment, the present invention provides a compound comprising R 2 is H or C1-C3-alkyl.

[0098] In another embodiment, the present invention provides a compound comprising 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 (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R band 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 to form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclyl group.

[0099] In another embodiment, the present invention provides a compound comprising 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, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b and 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 to form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclyl group.

[0100] In another embodiment, the present invention provides a compound comprising 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 comprising R 9 is independently halo; and m is 1, 2, or 3. In another embodiment, the present invention provides a compound comprising R 9is independently fluoro or chloro; and m is 1, 2, or 3. In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 9 is independently halo, m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein 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. In another embodiment, the present invention provides a compound comprising R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy; and m is 0, 1, 2, or 3.

[0101] In another embodiment, the present invention provides a compound comprising 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 comprising R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy; and m is 0, 1, 2, or 3.

[0102] In another embodiment, the present invention provides a compound comprising 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 method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0103] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0104] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are 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. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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. In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0105] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0106] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0107] In another embodiment, the present invention provides a method for determining whether the variable R 1 , R 2 , R 4 , R 5 , R 10 , X, W, Z and a are as defined above for formula (I); R 9 and m is as defined above for formula IB; b is 0 or 1; and the dashed bond [ka] is a single or double bond; D is N, C, or CR 4 And ;D 1 N, O, -CR4 R 5 , S(O) p (wherein p is 0, 1 or 2), or D 1 is CR 4 R 5 (In the formula, R 4 and R 5 are taken together to form a 2- to 5-membered chain which may contain one heteroatom in the chain to form a spirocyclic group; Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’ is as shown in Table 4:

[0108] [ka] (ID)

[0109] [Table 4-1] [Table 4-2]

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

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

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

[0113] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CR 4 R 5 (In the formula, R 4 and R 5 together form a 2- to 5-membered chain which may contain one heteroatom in the chain to form a spirocyclic group). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CH2, independently C-(halo)2, CH(C1-C3-alkyl) or CH(C1-C3-haloalkyl). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CH2, independently CF2, CH(CH3) or CH(CF3). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is O, S, S(O) or S(O)2. In some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: 1 is CH2. In some embodiments, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein D is N; D 1 is CH2, O or S.

[0114] In some embodiments, the present invention provides a compound in which the dashed line is a double bond; D is C; 1 is CH2, CF2, O or S. In some embodiments, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein D is N; D 1 is CR 4 R 5 (In the formula, R 4 and R 5together form a 2- to 4-membered chain which may contain one oxygen atom in the chain to form a spirocyclic group), providing compounds of formulae ID-1 to ID-56. In some embodiments, the present invention provides a method for treating cancer wherein D is CH; D 1 is CR 4 R 5 (In the formula, R 4 and R 5 together form a 2- to 4-membered chain which may contain one oxygen atom in the chain to form a spirocyclic group), providing compounds of formulae ID-1 to ID-56.

[0115] In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein D is C and the dashed bond represents a double bond; 1 is CR 4 R 5 (In the formula, R 4 and R 5 together form a 2- to 4-membered chain which may contain one oxygen atom in the chain to form a spirocyclic group), providing compounds of formulae ID-1 to ID-56. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 4 are 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 a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 4 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 a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 4 is independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 4is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 4 is independently H, —OCF3 or —SCF3.

[0116] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 5 are 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 a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 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 a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 5 is independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 5 is independently H, methoxy, ethoxy, propoxy or butoxy. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 5 is independently H, —OCF3 or —SCF3.

[0117] In another embodiment, the present invention provides a compound comprising R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a compound comprising 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 (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b and 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0118] In another embodiment, the present invention provides a compound comprising R 9 is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy; m is 0, 1, 2 or 3; and b is 0 or 1. In another embodiment, the present invention provides a compound comprising R 9 is independently halo; and m is 1, 2, or 3. In another embodiment, the present invention provides a compound comprising R 9 is independently fluoro or chloro; and m is 1, 2, or 3.

[0119] In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 9 is independently halo, m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl. In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein 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. In another embodiment, the present invention provides a method for producing a compound of formula (I) wherein X is S and R 9 are 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; and m is 0, 1, 2 or 3.

[0120] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0121] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0122] In another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 another embodiment, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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 method for producing a medicament for the treatment of psoriasis, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted independently by 1 to 3 halo; 4 are independently H or halo; each R 5 are 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.

[0125] In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ , Y 5’ Each of these is CH. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ One of them is CR 5 (In the formula, R 5 is a non-hydrogen substituent). In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y3’ , Y 4’ and Y 5’ Two of them are CR 5 (In the formula, each R 5 are independently non-hydrogen substituents). In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Three of them are CR 5 (In the formula, each R 5 are independently non-hydrogen substituents). In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ All four of them are CR 5 (In the formula, each R 5 are independently non-hydrogen substituents).

[0126] In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Each of these is CH. In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One of them is CR 4 (In the formula, R 4 is a non-hydrogen substituent). In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Two of them are CR 4 (In the formula, each R 4 are independently non-hydrogen substituents). In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Three of them are CR 4 (In the formula, each R 4 are independently non-hydrogen substituents). In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y3’ , Y 4’ and Y 5’ One of them is a C-halogen. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Two of them are C-halogens. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Three of them are C-halogens.

[0127] In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One of them is a C-halogen. In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Two of them are C-halogens. In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Three of them are C-halogens. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ One of the groups is C-Cl or CF. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ two of which are independently C—Cl or CF. In any of the embodiments of Tables 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ three of which are independently C—Cl or CF.

[0128] In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One of the groups is C-Cl or CF. In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 two of which are independently C—Cl or CF. In any of the embodiments in Tables 1 to 4 above, Y 1 , Y 2 and Y 3 three of which are independently C—Cl or CF.

[0129] In any of the embodiments of Tables 1, 2 or 4 above, a is 1, W is -CH2- and Z is O. In any of the embodiments in Tables 1-4 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 in Tables 1-4 above, one, two, or three R 4 is hydrogen. In any of the embodiments in Tables 1-4 above, a certain R 4 Other R 4 and independently are halogen, cyano, C-C-alkyl, C-C-haloalkyl, C-C-cycloalkyl, amino, C-C-alkylamino, di(C-C-alkyl)amino, or phenyl optionally substituted once or twice by halo or C-C-alkyl. In any of the embodiments in Tables 1-4 above, a certain R 5 Other R 5and independently are halogen, cyano, C-C-alkyl, C-C-haloalkyl, C-C-cycloalkyl, amino, C-C-alkylamino, di(C-C-alkyl)amino, or phenyl optionally substituted once or twice by halo or C-C-alkyl.

[0130] In another embodiment, the present invention provides a compound in which Y1, Y2, Y3, L, X, R1, and R3 are as shown in the Table; 2 and R 2’ are both hydrogen; Q is oxygen; and the group: [ka] is abbreviated in the table as "ring system" and represents the following group:

[0131] [ka] Ring system A; [ka] Ring system B; [ka] Ring system C; [ka] ring system D; [ka] Ring system E; [ka] ring system F; [ka] ring system G; [ka] Ring system H; [ka] Ring System I; and [ka] Ring system K

[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; and "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 the same applies below; Prop-1-en-2-yl is a group [ka] represents; 2-OH-prop-2-yl is a group [ka] represents; 2-F-prop-2-yl is a group [ka] Represents. [ka] 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] For the avoidance of doubt, each of the compounds presented in Table 5 has been prepared and tested.

[0135] Stereoisomers and polymorphic forms Those skilled in the art will recognize that compounds can exist and be isolated in optically active and racemic forms. Compounds with 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. Furthermore, the compounds of the present invention can contain one or more chiral centers, resulting in a theoretical number of optically active isomers. In this case, the compound of formula (I) contains at least one chiral center, and the carbon atom is connected to the variable R 10 When the compounds herein contain n chiral centers, the compounds have up to 2 nThe compounds of the present invention may contain two optical isomers. Thus, the compounds of the present invention include at least two enantiomers encompassed by the present invention. The present invention encompasses the 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. Optically active forms can be prepared, for example, by resolution of racemic forms by selective crystallization techniques, synthesis from optically active precursors, chiral synthesis, chromatographic separation using chiral stationary phases, or enzymatic resolution. The compounds may also exist in various solid forms, such as various crystalline forms, or in amorphous solid form. The present invention includes various crystalline forms of the compounds as well as amorphous forms. Furthermore, the compounds may exist as hydrates or solvates in which a stoichiometric amount of water or solvent is associated with the molecule in crystalline form. Hydrates and solvates of the compounds are also the subject of the present invention.

[0136] salt In addition to the neutral compounds, 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 that provides an active compound upon administration. If the compound is sufficiently basic or acidic to form stable non-toxic acid or base salts, the compound may 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, alkaline earth metals such as calcium, magnesium, and barium. Salts containing transition metals, including, but not limited to, manganese, copper, zinc, and iron, are also suitable. Additionally, salts containing ammonium cations (NH4 + ) as well as salts containing substituted ammonium cations in which one or more of the hydrogen atoms have been replaced by alkyl or aryl groups are encompassed by the present invention.

[0137] Particularly suitable are salts derived from inorganic acids, including, but not limited to, hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable inorganic salts also include, but are not limited to, bicarbonates and carbonates. In some embodiments, examples of veterinarily and agriculturally acceptable salts include, but are not limited to, organic acid addition salts formed with organic acids, including, but not limited to, maleate, dimaleate, fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Of course, other 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 a sufficiently acidic residue on the compound with an alkali or alkaline earth metal hydroxide. 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 an appropriately acidic functional group present in the compound, or by reacting a suitable acid with an appropriately basic functional group on a compound of the invention.

[0138] Methods for preparing compounds Compounds of formula (I) or pharmaceutically or veterinarily acceptable salts thereof may be prepared by employing the procedures of one of the following Schemes 1-4 or Schemes 5-12 and the Examples: Scheme 1

[0139] [ka] Scheme 2

[0140] [ka] Scheme 3

[0141] [ka] Scheme 4

[0142] [ka]

[0143] Adapting these schemes to synthesize specific compounds of the invention is well within the level of skill of one of ordinary skill in the art. Additionally, 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 the compound or a veterinarily acceptable salt thereof in combination with a veterinarily acceptable carrier or diluent and, optionally, inactive excipients. The compositions may be in various solid and liquid forms suitable for various modes of application or administration to animals. For example, veterinary compositions containing the compounds may be suitable for oral administration, injection administration, including subcutaneous and parenteral administration, and topical administration (e.g., spot-on and pour-on), dermal 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, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other domestic or farmed mammals. Examples of birds include turkeys, chickens, ostriches, and other domestic or farmed birds. The use of the compounds to protect companion animals, such as dogs and cats, from internal parasites is particularly useful.

[0145] As discussed above, the compositions of the present invention may be in a form suitable for oral use (see, e.g., U.S. Pat. No. 4,564,631, hereby incorporated by reference in its entirety), dietary supplement, troche, lozenge, chewable, tablet, hard or soft capsule, bolus, emulsion, aqueous or oily suspension, aqueous or oily solution, oral drench composition, dispersible powder or granule, premix, syrup or elixir, enteric composition, or paste. 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, bittering agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as cornstarch or alginic acid; binders, such as starch, gelatin, or acacia; and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, may be used. Tablets may also be coated by techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 (all of which are incorporated herein by reference in their entireties) to form osmotic therapeutic tablets for controlled release.

[0146] Oral compositions include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Capsules can also be soft gelatin capsules in which the active ingredient is mixed with water, or a 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 may be administered in a chewable tablet composition or soft chew composition, such as those described in U.S. Patent Application Publication Nos. 2013 / 0203692, 2010 / 0087492, 2006 / 0222684, 2004 / 0151759, and U.S. Patent No. 7,955,632, all of which are incorporated herein by reference. The veterinary composition may be in the form of a palatable, animal-acceptable soft chewable composition ("soft chew"). The soft chew of the present invention may contain, 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 may be used in the compositions of the present invention include various grades of liquid polyethylene glycol (PEG), including, but not limited to, PEG 200, PEG 300, PEG 400, and PEG 540; propylene carbonate; propylene glycol; triglycerides, including, but not limited to, caprylic / capric triglyceride, caprylic / capric / linoleic triglyceride (e.g., MIGLYOL® 810 and 812, caprylic / capric / succinic triglyceride, propylene glycol dicaprylate / dicaprate, and the like; water, sorbitol solution, glycerol caprylate / caprate, and polyglycolized glycerides (e.g., GELUCIRE®), or combinations thereof. Various fillers known in the art can be used in the soft chewable compositions of the present invention.Fillers include, but are not limited to, corn starch, pregelatinized starch, soy protein powder, corn cob and corn gluten meal.In some embodiments, a combination of two or more fillers can be used in the composition.

[0148] Binders that may be used in the compositions of the present invention include, but are not limited to, polyvinylpyrrolidone (e.g., povidone), cross-linked polyvinylpyrrolidone (crospovidone), various grades of polyethylene glycol, including PEG 3350, PEG 4000, PEG 6000, PEG 8000, and even PEG 20,000; copolymers of vinylpyrrolidone and vinyl acetate (e.g., copovidone), such as the product sold under the trade name Kollidon® VA64 by BASF; starches, such as potato starch, tapioca starch, or corn starch; molasses, corn syrup, honey, maple syrup, and various types of sugars; or combinations of two or more binders. Humectants that may be used in the compositions include, but are not limited to, glycerol (also referred to herein as glycerin), propylene glycol, cetyl alcohol, and glycerol monostearate. Various grades of polyethylene glycol may also be used as humectants.

[0149] A surfactant may be present in the composition to improve solubility and absorption after ingestion, typically at a concentration of about 1 to 10% (w / w), more typically about 1 to about 5% (w / w). Examples of surfactants that may be used in the compositions 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 polyoxyethylene 35 castor oil (Cremophor® EL), polyoxyethylene 40 hydrogenated castor oil (Cremophor® RH40), polyoxyethylene 60 hydrogenated castor oil (Cremophor® RH60); Glyceride esters including glycerol caprylate / caprate (CAPMUL® MCM), polyglycolized glycerides (GELUCIRE®), PEG 300 caprylic / capric glyceride (Softigen® 767), PEG 400 caprylic / capric glyceride (Labrasol®), PEG 300 oleic glyceride (Labrafil® M-1944CS), PEG 300 linoleic glyceride (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), and the like.

[0150] The composition may contain other inactive ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the field of composition. Antioxidants can be added to the compositions of the present invention to inhibit the decomposition of active agents. Suitable antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylhydroxyanisole), BHT (butylhydroxytoluene), monothioglycerol, etc. The compositions of the present invention may also contain one or more lubricants and / or processing aids. In some cases, the lubricants / processing aids can also act as solvents, thus some of the components of the compositions of the present invention may have dual functions. Lubricants / processing aids include, but are not limited to, polyethylene glycols of various molecular weight ranges, including PEG 3350 (Dow Chemical) and PEG 4000, 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 compositions of the present invention to improve the palatability of the oral veterinary composition. Preferred flavoring agents are those not derived from animal sources. In various embodiments, flavoring ingredients derived from fruit, meat (including, but not limited to, pork, beef, chicken, fish, poultry, etc.), vegetables, cheese, bacon, cheese bacon, and / or artificial flavors can be used. Flavoring ingredients are typically selected based on considerations related to the organism that will consume the soft chew. For example, horses may prefer apple flavoring ingredients, while dogs may prefer meat flavoring ingredients. While flavoring ingredients derived from non-animal sources are preferred, in some embodiments, natural flavorings containing beef or liver extracts, such as braised beef flavor, artificial powdered beef flavor, roast beef flavor, and corned beef flavor, can be used. In another embodiment of the present invention, the active composition may be administered via a drench, which may be administered topically or orally. A drench composition is one in which the liquid-containing composition of the present invention is administered into the animal's mouth or throat or poured onto the animal's skin or coat.

[0152] The compositions of the present invention can also be in the form of oil-in-water or water-in-oil emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring phosphatides, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions can also contain sweeteners, bittering 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.Microemulsions are four-component systems that include an aqueous phase, an oil phase, a surfactant and a co-surfactant.They are translucent isotropic liquids. Microemulsions consist of a stable dispersion of minute droplets of aqueous phase in an oil phase, or vice versa. These droplets can be less than 200 nm in size (1000-100,000 nm for emulsions). The interfacial film can consist of alternating surface-active (SA) and co-surface-active (Co-SA) molecules, which lower the interfacial tension, allowing the microemulsion to form spontaneously.

[0153] In one embodiment of the oil phase, the oil phase may be formed from a mineral 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 may be composed of a triglyceride; in another embodiment of the oil phase, the triglyceride is a medium-chain triglyceride, for example, C8-C 10Caprylic / capric triglyceride. In other embodiments, the oil phase can be in the % v / v range of about 2 to about 15% of the microemulsion; about 7 to about 10%; and about 8 to about 9% v / v. The aqueous phase can comprise, for example, water or a glycol derivative, such as propylene glycol, glycol ether, 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. Typically, the aqueous phase comprises about 1 to about 4% v / v of the microemulsion.

[0154] Surfactants for microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, and polyglycolized C8-C 10 Glycerides or polyglyceryl-6 dioleate may be included. In addition to these surfactants, co-surfactants may include short chain alcohols such as ethanol and propanol. Some compounds are common to the three components discussed above, i.e., aqueous phase, surfactant, and 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 of the surfactant / co-surfactant amount, the co-surfactant to surfactant ratio is about 1 / 7 to about 1 / 2. In another embodiment of the co-surfactant amount, the microemulsion contains about 25 to about 75% v / v of surfactant and about 10 to about 55% v / v of co-surfactant. Oily suspensions can be prepared by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil, such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, solid paraffin or cetyl alcohol.Sweeteners, bittering agents, and flavoring agents, such as sucrose, saccharin or aspartame, can be added to obtain a palatable oral preparation.These compositions can be preserved by adding antioxidants, such as ascorbic acid or other known preservatives.

[0155] Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents include naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening and / or bitter agents, such as those set out above. Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water can provide the active ingredient in admixture 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 sweeteners, bittering agents, flavoring agents, and coloring agents, can also be present. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain a demulcent, preservative, flavoring and / or coloring agent.

[0156] In another embodiment of the present invention, composition can be paste form.The example of paste form embodiment includes but is not limited to those described in United States Patent No. 6,787,342 and United States Patent No. 7,001,889 (each of which is incorporated herein by reference).In addition to the compound of the present invention, paste can further contain fumed silica; viscosity adjuster; carrier; optionally absorbent; and optionally colorant, stabilizer, surfactant or preservative. In one embodiment of the composition, the composition may be a paste containing a 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 may also contain a viscosity modifier. Suitable viscosity modifiers include, but are not limited to, polyethylene glycols (PEGs), including PEG200, PEG300, PEG400, and 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 may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the prior art using the appropriate dispersing or wetting agent and suspending agent mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol, glycerol formal, or polyethylene glycol may also be used. Preservatives such as phenol or benzyl alcohol may also be used. In addition, sterile, fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0158] Topical skin and subcutaneous compositions may include, by way of non-limiting example, emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on compositions, ready-to-use compositions, spot-on solutions and suspensions, dips, and sprays. Topical application of the compounds of the present invention or compositions containing at least one compound of the present invention, among other active agents, in the form of a spot-on, spray-on, or pour-on composition may allow the compositions of the present invention to 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. When the compound is distributed through the sebaceous glands, they can act as a reservoir, thereby allowing for a prolonged effect (up to several months). Spot-on compositions are typically applied to a localized area, which refers to an area that is not the entire animal. In one embodiment, the location may be between the shoulders. In another embodiment, the location may be a stripe, such as a stripe from the head to the tail of the animal. Pour-on compositions are described in U.S. Patent No. 6,010,710, also incorporated herein by reference. Pour-on compositions are advantageously oil-based and generally may also include a diluent or vehicle for the active ingredient, and a solvent (e.g., organic solvent) if the active ingredient is insoluble in the diluent.

[0159] 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 esters, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, ethyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, triacetin, C1-C2 carboxylic acids, 10 Esters such as butyl or octyl acetate, and diethyl phthalate, or a mixture of at least two of these solvents, are included.

[0160] The solvent is used according to the concentration of the active agent compound and its solubility in this solvent. The solvent is made to have the lowest possible volume. The vehicle makes up the difference to 100%. Vehicles or diluents for the compositions may include dimethyl sulfoxide (DMSO), glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol, or glycerol. Vehicles or diluents include, but are not limited to, vegetable oils such as soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grapeseed oil, and sunflower oil; mineral oils such as, but not limited to, petrolatum, paraffin, and silicone; aliphatic or cyclic hydrocarbons, or medium-chain (C8-C9) hydrocarbons. 12 Triglycerides such as glycerides of glycerol, glycerols of glycerol, and glycerols of ... may also be mentioned.

[0161] In another embodiment of the present invention, softeners and / or spreading agents and / or film-forming agents may be added. In one embodiment, the softeners and / or spreading agents and / or film-forming agents may be: (a) polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example, those containing silanol functional groups, or 45V2 oil; (b) anionic surfactants, such as alkali metal stearates, sodium stearates, potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietic acid; alkyl sulfates (e.g., sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctyl sulfosuccinate; fatty acids (e.g., those derived from coconut oil), (c) Cationic surfactants include those of formula N + R'R''R'''R'''',Y - (wherein the groups R are the same or different optionally hydroxylated hydrocarbon groups, and Y - are the anions of strong acids such as halides, sulfates, and sulfonates; among the cationic surfactants that can be used is cetyltrimethylammonium bromide. (d) Formula N + Amine salts of HR'R''R''', where the groups R are the same or different, optionally hydroxylated hydrocarbon groups; among the cationic surfactants that can be used is octadecylamine hydrochloride, (e) nonionic surfactants, such as optionally polyoxyethylated sorbitan esters (e.g., polysorbate 80), polyoxyethylated alkyl ethers; polyoxypropylated fatty alcohols, such as polyoxypropylene-styrene ether; polyethylene glycol stearates, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids, copolymers of ethylene oxide and propylene oxide, (f) amphoteric surfactants, such as substituted lauryl compounds of betaine; or (g) A mixture of at least two of these drugs.

[0162] In one embodiment, the amount of the softener used may be about 0.1 to 50% by volume or 0.25 to 5% by volume, or in another embodiment, about 0.1 to 30% by volume, about 1 to 30% by volume, about 1 to 20% by volume, or about 5 to 20% by volume. In another embodiment of the present invention, composition can be in the form of a ready-to-use solution, as described in U.S. Patent No. 6,395,765, which is incorporated herein by reference.In addition to the compound of the present invention, the ready-to-use solution can contain crystallization inhibitor and organic solvent or a mixture of organic solvent.In some embodiments, water can be included together with 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 weight of the composition. In other embodiments, the amount of 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 / v). The type of 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 inactive agent from the composition. For example, in certain embodiments of the present invention, a solvent or cosolvent in the composition may also function as a crystallization inhibitor if it sufficiently inhibits the formation of crystals over time when the composition is administered.

[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, polyoxyethylenated esters of sorbitol or 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; (b) anionic surfactants, such as alkaline stearates (e.g., sodium stearate, potassium stearate, or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietic acid; alkyl sulfates, including, but not limited to, sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids (e.g., coconut oil); (c) cationic surfactants, such as those of formula N + R'R''R'''R'''',Y - (wherein R groups are the same or different, optionally hydroxylated hydrocarbon groups; Y - Water-soluble quaternary ammonium salts of (wherein is an anion of a strong acid such as a halide, sulfate, or sulfonate anion); cetyltrimethylammonium bromide is one cationic surfactant that can be used; (d) Formula N + Amine salts of HR'R''R''', where the R groups are the same or different, optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride is one cationic surfactant that can be used; (e) nonionic surfactants, such as sorbitan esters which may be polyoxyethylated, for example, polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearates, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated 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) through (f) above; or (h) An organic solvent or mixture of solvents that inhibits the formation of crystalline or amorphous solids after administration of the composition.

[0165] In one embodiment of the crystallization inhibitor, a crystallization inhibitor pair is used. Such a pair includes, for example, a combination of a polymeric film-forming agent and a surfactant. 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 amount of the 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 solvents 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 a mixture of solvents, i.e., a solvent and a co-solvent, is present, the solvents may be present in the composition in a weight / weight (W / W) ratio of about 1 / 50 to about 1 / 1. Typically, the solvents are present in a weight ratio of about 1 / 30 to about 1 / 1, about 1 / 20 to about 1 / 1, or about 1 / 15 to about 1 / 1. Preferably, the two solvents are present in a weight / weight ratio of about 1 / 15 to about 1 / 2. In some embodiments, at least one of the solvents present may improve the solubility of the active agent or act as a drying accelerator. In certain embodiments, at least one of the solvents is miscible with water. The composition may also contain an antioxidant intended to inhibit oxidation in air, which may 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 of the polymeric type, including, but not limited to, various grades of polyvinylpyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinylpyrrolidone. 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, e.g., polysorbate 80.

[0167] In another embodiment of the present invention, the film-forming agent and surfactant may be incorporated in similar or identical amounts within the limits of the total amount of the other mentioned crystallization inhibitors. Crystallization inhibitors inhibit the formation of crystals on the coat and improve the maintenance of the aesthetic appearance of the skin or fur; that is, despite high concentrations of active material, they do not tend to stick or have a sticky appearance. Substances other than those mentioned herein may be used as crystallization inhibitors in the present invention. In one embodiment, the effectiveness of a crystallization inhibitor can be demonstrated by placing 0.3 mL of a solution containing 10% (w / v) of an active agent in a suitable solvent as defined above and 10% (w / v) of a compound acting as a crystallization inhibitor on a glass slide at 20°C for 24 hours, after which less than 10 crystals, preferably 0 crystals, are visible on the glass slide with the naked eye. In one embodiment of the antioxidant, the agent is one 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 defined above; advantageously, the starting point is to mix the active material in the main solvent, and then add other components or adjuvants. The volume of composition applied depends on the species and size of the animal, as well as the concentration of the composition and the potency of the active agent. In one embodiment, about 0.1 to about 20 ml of the composition may be applied to the animal. In other volume embodiments, the volume may be about 0.1 to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, or about 0.3 to about 3 ml. In another embodiment of the present invention, application of a spot-on composition according to the present invention can also provide sustained, broad-spectrum effectiveness when the solution is applied to a mammal or bird. The spot-on composition provides local administration of a concentrated solution, suspension, microemulsion or emulsion (a spot-on solution) for intermittent application to a local area on the animal, typically between the two shoulders.

[0169] For spot-on compositions, the carrier may 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 may be a liquid carrier vehicle, including but not limited to, acetone, aliphatic alcohols such as methanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol, heptanol, octanol, nonanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, and the like; aromatic alcohols such as phenol, cresol, naphthol, benzyl alcohol, and the like; acetonitrile, butyl diglycol, organic amides such as dimethylacetamide, dimethylformamide, monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone, and the like; propylene glycol, The solvent may comprise a solvent or a mixture of solvents including ethylene glycol or ethylene carbonate, dimethyl sulfoxide (DMSO), a glycol polymer or its ether, 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 the diethyl ester or diisobutyl adipate, or a mixture of 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. Spot-on compositions can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, spot-on compositions 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 in terms of the mass of the combined therapeutic agent, depending on the species of the host animal being treated, the severity and type of infection, and the body weight of the host. Dosage forms may typically contain from about 0.1 mg to about 5 g. In other embodiments, dosage forms may contain from about 0.5 mg to about 5 mg of active agent. In one embodiment of the dosage form, the dosage may contain from about 1 mg to about 500 mg of 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 of the present specification, the compound of formula (I) may be present in the composition at a concentration of about 0.05 to about 50% w / w. In another embodiment, the compound of formula (I) may be present at a concentration of about 0.1 to about 30% (w / w). In another embodiment, the compound of formula (I) may 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 another embodiment, the compound of formula (I) may be present at a concentration of about 10 to about 50% (w / w), about 10 to about 30% (w / w), or about 10 to about 20% (w / w). In yet another embodiment, the compound of formula (I) may 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 invention, the active agent may be present in the composition at a concentration of about 0.1 to about 2% w / w. In yet another embodiment of the invention, the active agent may be present in the composition at a concentration of about 0.25 to about 1.5% w / w. In yet another embodiment of the invention, the active agent may 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 parasitic infections in animals. In one embodiment, the present invention provides a method for treating or preventing an endoparasitic infection in or on an animal (e.g., a mammal or a bird), comprising administering to the animal an endoparasiticidally 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) may also be effective against ectoparasites and may be used to treat and prevent ectoparasite infestations on animals. In another embodiment, the present invention provides a method of treating or preventing ectoparasite infestations on an animal (e.g., a mammal or a bird), comprising administering to the animal an ectoparasiticidally effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition of the invention. In another embodiment, the present invention provides a method for treating or preventing endoparasitic infections and ectoparasitic infestations in or on an animal, 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 parasitic infestation of a locus, the method comprising administering or applying to the locus a parasiticidally effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof. For animal health applications, "locus" is intended to mean a habitat, breeding ground, area, material or environment in which a parasite is growing or may grow, excluding in and on an animal. In another embodiment, the present invention provides methods and uses of compounds for controlling plant and crop pests or protecting wood-containing structures. Mammals that can be treated include, but are not limited to, humans, cats, dogs, cows, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep, and yaks. In one embodiment of the present invention, the mammal being treated is a human, cat, or dog.

[0174] In one embodiment herein, the compounds of formula (I) have been found to have excellent efficacy against endoparasites, particularly against endoparasites resistant to the macrocyclic lactone class of active agents. 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 a parasitic infestation or infection in an animal, comprising administering to an animal in need thereof an effective amount of an anthelmintic compound of the present invention in combination with an effective amount of an invertebrate GABA receptor activator, including avermectins and milbemycins. Avermectins that can be used in combination with the compounds of the present invention include, but are not limited to, abamectin, zimadectin, 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 the avermectins and milbemycins are also included.

[0176] In one embodiment, the compounds and compositions of the present invention may be used to treat or prevent endoparasitic infections of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Ancylostoma, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Silicocyclus, licocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Genus Ae, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, American hookworm, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia rtagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Tridonothorus, 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 to treat or prevent infection with Dirofilaria immitis. The compounds have been found to be highly effective against D. immitis microfilariae and L4 larvae. Thus, the compounds can be used to prevent animals from developing heartworm disease by killing immature stages of D. immitis before they can mature into adults. In one embodiment, the compounds and compositions containing the compounds can be used to prevent the development of heartworm disease by killing immature stages of D. immitis that are resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are used to treat or prevent infection with Dirofilaria repens or Dirofilaria hongkonensis. In another embodiment of the invention, the parasite is Haemonchus contortus, Ostertagia circumcinctus, 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 selected from the group consisting of Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, one or more insects or arachnids including those of the genera Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalini, Linognathus, Haematopinus, Solenopotes, Trichodectes, and Felicola.

[0179] In another embodiment of the ectoparasite treatment, the ectoparasite is of the genus Rhipicephalus, Rhizopus, Dermacentor, Ixodes, and / or Rhipicephalus. Ectoparasites to be treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Dolichorax spp.), ticks (such as Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp.), and mites (such as Demodex spp., Sarcoptes spp., Otodectes spp.), lice (such as Dermoptera spp., Cheyletiella spp., Otodectes spp.), mosquitoes (such as Aedes spp., Culex spp., Anopheles spp.), and flies (such as Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp.). In yet another embodiment of the treatment for ectoparasites, the ectoparasites are fleas and / or ticks.

[0180] Additional examples of ectoparasites include, but are not limited to, ticks, Boophilus genus, particularly the species Boophilus microplus (cattle tick), decoloratus and annulatus; myiasis, such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (blood fly); sheep myiasis, such as Lucilia sericata, Lucilia cuprina (known as blowfly myiasis in Australia, New Zealand and South Africa). Indigenous flies include flies whose adult forms are parasitic, such as Haematobia irritans (horn flies); lice, such as Linognathus vitulorum (cattle lice); and mites, such as Sarcoptes scabiei (scabie mites) and Psoroptes ovis (sheep mite). The above list is not exhaustive, and other ectoparasites are known in the art to be harmful to animals and humans. These include, for example, migratory dipteran larvae.

[0181] In another embodiment of the present invention, the compounds and compositions of the present invention are suitable for controlling pests such as insects selected from the group consisting of the German cockroach (Blattella germanica), the tobacco budworm (Heliothis virescens), the Colorado potato beetle (Leptinotarsa ​​decemlineata), the brown ant (Tetramorium caespitum), and combinations thereof. Plant parasitic nematodes include, for example, Anguina spp., Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, and the like. similis, Rotylenchus species, Trichodorus species, Tylenchorhynchus species, Tylenchulus species, Tylenchulus semipenetrans, and Xiphinema species.

[0182] Additionally, the present invention may also be used to treat other pests, with or without other pesticides added to the composition, including but not limited to the following pests: (1) Isopoda, such as Oniscus asellus, Armadillidium vulgare, and Porcellio scaber; (2) Diplopoda, e.g., Blaniulus guttulatus; (3) Chilopoda, e.g., Geophilus carpophagus and Scutigera species; (4) Order Symphyla, e.g., Scutigerella immaculata; (5) Thysanura, e.g., Lepisma saccharina; (6) Collembola, e.g., Onychiurus armatus; (7) Blattaria, such as the Asian cockroach (Blatta orientalis), the American cockroach (Periplaneta americana), the Madera cockroach (Leucophaea maderae) and the German cockroach; (8) Hymenoptera, such as Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis spp., and Vespa spp.; (9) Siphonaptera, such as Xenopsylla cheopis and Ceratophyllus species; (10) From the suborder Anoplura (order Phthiraptera), for example, Damarinia spp., Piglice spp., Piglice spp., Pediculus spp., Piglice spp.;

[0183] (11) From the class of Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Rhipicephalus spp., Brevipalpus spp., Bryobia praetiosa, Dermanyssus spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pili pyri, Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhizoglyphus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus maurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici; (12) From the class of Bivalva, for example, Dreissena species;

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

[0185] (14) From the order Diptera, for example, Aedes spp., Anopheles spp., Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus spp., oleae, human flies, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia spp., Hypobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxis spp., Tabanus spp., Tannia spp., Tipula paludosa paludosa), Wohlfahrtia species; (15) From the class of Gastropoda, for example, Arion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.;

[0186] (16) From the class of the Helminths, for example, Ancylostoma duodenale, Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma spp., Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Cavertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp., Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa, Nematogyrus spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosoma spp., Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloides spp., Taenia spp. saginata), Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsillarispseudopsiralis), Trichostrongulus species, Trichuris trichuria, Wuchereria bancrofti;

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

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

[0189] (19) Isoptera, such as Reticulitermes species and Odontotermes species; (20) Lepidoptera, such as Acronicta major, Aedia leucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp., Choristoneura fumiferana, Grapevine moth (Clysia ambiguella), Cnaphalocerus spp., Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp., Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padera, 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 gemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia species;

[0190] (21) Orthoptera, such as Acheta domesticus, the Asian cockroach, the German cockroach, Gryllotalpa species, the Madeira cockroach, Locusta species, Melanoplus species, the American cockroach, and the desert locust (Schistocerca gregaria); (22) Thysanoptera, for example, Baliothrips biformis, Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips cardamoni, Thrips spp.; (23) Protozoa, such as Eimeria species. In each aspect of the present invention, the compounds and compositions of the present invention may be applied to a single pest or a combination thereof.

[0191] Mixtures with other activators In another embodiment, the composition comprising the compound of formula (I) may also contain other veterinary therapeutic agents. Veterinary preparations that may be included in the compositions of the invention are well known in the art (e.g., Plumb's Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 thEdition, (January 2005)), including, but not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline / theophylline, Amiodarone, amitriptyline, amlodipine besilate, 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 besilate , atropine sulfate, auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin, calcitrol, calcitonin sodium salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiafur, ceftriaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal (active), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - clidinium bromide, chlorothiazideChlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin ( ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), diclofenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium. Calcium EDTA, edrophonium chloride, enalapril / enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid / sodium ethacrynate, ethanol (alcohol), sodium etidronate, etodolac, etomidate, euthanasia agents with pentobarbital, famotidine, fatty acids (essential / omega), felbamate, fentanyl, ferrous sulfate,Filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / chondroitin sulfate, glutamine, glyburide, glycerol Phosphate (oral), glycopyrrolate, gonadorelin, griseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin, hetastarch, sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, imipenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alpha-2 a (human recombinant), iodide (sodium / potassium), ipecac (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, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate / hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue,Methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole, mexiletine, mibolerlone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate decanoate), naproxen, narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin hydrochloride, oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, penicillamine, general information penicillin, penicillin G, penicillin Phosphate V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisolone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes acnes) injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilage, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline / saline laxatives, selamectin, selegiline / l-deprenyl, sertraline, sevelamer,Sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succinimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadiazine Menthoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafrine, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, tiamulin, ticarcillin disodium salt, tiletamine / zolazepam, tilmicosin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid acid), topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, trimepraxin tartrate with prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide, and mixtures thereof.

[0192] In one embodiment of the present invention, arylpyrazole compounds such as phenylpyrazole can be included in the veterinary compositions of the present invention.Arylpyrazoles are known in the art and may be suitable for combining with the compound of formula (I) in the compositions herein.Examples of such arylpyrazole compounds include, but are not limited to, those described in 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 included in the compositions of the present invention in combination with compounds. For the avoidance of 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 occurring avermectins (e.g., containing components designated as 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, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, and milbemycins, including, but not limited to, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, and nemadectin. 5-oxo and 5-oxime derivatives of the avermectins and milbemycins are also included.

[0195] Macrocyclic lactone compounds are known in the art and can be easily obtained commercially or through synthetic techniques known in the art. Reference is made to widely available technical and commercial literature. For avermectins, ivermectins, and abamectins, see, for example, 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 doramectins, see "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15. For milbemycins, see, in particular, Davies HG 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. Pat. No. 4,134,973; and European Patent No. 0677054, all of which are incorporated herein by reference.

[0196] The structures of the avermectins and milbemycins are closely related, for example, by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519, and the 22,23-dihydroavermectin compounds are disclosed in U.S. Pat. No. 4,199,569. See also, inter alia, U.S. Pat. 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 milbemycins are disclosed in U.S. Pat. No. 3,950,360, as well as in "The Merck Index" 12. th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is listed in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. 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 incorporated herein by reference.

[0197] In one embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of abamectin, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, 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 an effective amount of at least one of abamectin, emamectin, eprinomectin, ivermectin, doramectin, or selamectin, or a combination thereof. In yet another embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of ivermectin, milbemectin, milbemycin oxime, or moxidectin, or a combination thereof. In another embodiment of the present invention, a composition is provided that includes a compound of formula (I) in combination with a miticide or insecticide from the class known as insect growth regulators (IGRs). Compounds belonging to this group are well known to those skilled in the art and represent 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. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179022 or GB 2140010, and U.S. Patent Nos. 6,096,329 and 6,685,954 (all of which are incorporated herein by reference).

[0198] In one embodiment, the composition of the present invention may contain an IGR compound that mimics juvenile hormone or regulates the level of juvenile hormone in insects. Examples of juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, 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 contains a compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. In another embodiment, the compositions of the present invention comprise an IGR compound that is a chitin synthesis inhibitor, including chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumorone, lufenuron, tebufenozide, teflubenzuron, triflumolone, 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, compositions of the present invention may include one or more anti-nematic agents, including but not limited to active agents from the benzimidazole, imidazothiazole, tetrahydropyrimidine, and organophosphate classes of compounds. In some embodiments, benzimidazoles, including but not limited to thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, and its o,o-dimethyl analogs, may be included in the composition. In other embodiments, the compositions of the present invention may include imidazothiazole compounds, including, but not limited to, tetramisole, levamisole, and butamisole. In yet other embodiments, the compositions of the present invention may include tetrahydropyrimidine active agents, including, but not limited to, pyrantel, oxantel, and morantel. Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naphthalophos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP and tetrachlorvinphos.

[0200] In other embodiments, the compositions may include the nematicidal compounds phenothiazine, piperazine, diethylcarbamazine, both as neutral compounds and in various salt forms, phenols such as disophenol, arsenicals such as arsenamide, ethanolamines such as bephenium, thenium closylate, and methylidine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate, and dithiazanine iodide; isothiocyanates including bitoscanate, sodium suramin, phthalophine, and various natural products including, but not limited to, hygromycin B, α-santonin, and kainic acid. In other embodiments, the compositions of the present invention can comprise anti-fluke agents.Suitable anti-fluke agents include, but are not limited to, miracil, such as miracil D and mirasan; various bisphenol compounds known in the art, including praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, hexachlorophene, bithionol, bithionol sulfoxide and meniclofolan; various salicylanilide compounds, including tribromsalan, oxyclozanide, clioxanide, lafoxanide, nitroxynil, brothianide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetrin and emetine. Anti-taenid compounds, including but not limited to arecoline, bunamidine, niclosamide, nitroscanate, paromomycin, paromomycin II, praziquantel, and epsiprantel in various salt forms, may also be advantageously used in the compositions of the present invention.

[0201] In yet other embodiments, the compositions of the present invention may contain other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate, dioxathion, ethion, fenfen, fenitrothion, fenthion, phospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stylophos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, fenothrin, pyrethrin, thiazolinone ... These include benzotriazole, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, methoprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, 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 biologically active peptide or protein, including, but not limited to, 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 WO 2016 / 187534 and WO 2017 / 116702, both of which are incorporated herein by reference. These compounds act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of the parasite. In one depsipeptide embodiment, the depsipeptide is emodepside (see Wilson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

[0203] In another embodiment, the compositions of the present invention may contain an active agent of a neonicotinoid class of parasiticide. 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 compositions of the present invention is imidacloprid. This class of agent is described, for example, in U.S. Pat. No. 4,742,060 or European Patent No. 0892060 (both of which are incorporated herein by reference). In another embodiment, the compositions of the present invention may contain nitenpyram, another active agent of a neonicotinoid class of pesticide. The use of nitenpyram to control fleas is described in U.S. Pat. No. 5,750,548, the entire contents of which are incorporated herein by reference. In certain other embodiments of the present invention, the compound of formula (I) may be combined with a semicarbazone, such as metaflumizone.

[0204] In another embodiment, the compositions of the present invention may advantageously contain one or more isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against a variety of ectoparasites, and combination with a compound of formula (I) will expand the spectrum of effectiveness against these parasites. Particularly useful isoxazoline active agents that can be combined with the compound include afoxolaner (including a substantially pure active enantiomer), sarolaner, fluralaner (including a substantially pure active enantiomer), and lotilaner. These active agents are disclosed in U.S. Pat. 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, WO 2007 / 125984, WO 2012 / 086462, U.S. Pat. No. 8,318,757, U.S. Pat. No. 8,466,115, U.S. Pat. No. 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, WO 2012 / 089623, WO 2012 / 089622, U.S. Patent No. 8,119,671; U.S. Patent No. 7,947,715;WO 2102 / 120135, WO 2012 / 107533, WO 2011 / 157748, U.S. Patent Application Publication No. 2011 / 0245274, U.S. Patent Application Publication No. 2011 / 0245239, U.S. Patent Application Publication No. 2012 / 0232026, U.S. Patent Application Publication No. 2012 / 0077765, U.S. Patent Application Publication No. 2012 / 0035122, U.S. Patent Application Publication No. No. 2011 / 0251247, International Publication No. 2011 / 154433, International Publication No. 2011 / 154434, U.S. Patent Application Publication No. 2012 / 0238517, U.S. Patent Application Publication No. 2011 / 0166193, International Publication No. 2011 / 104088, International Publication No. 2011 / 104087, International Publication No. 2011 / 104089, U.S. Patent Application Publication No. 2012 / 015946, U.S. Patent No. Publication No. 2009 / 0143410, International Publication No. 2007 / 123855, U.S. Patent Application Publication No. 2011 / 0118212, U.S. Patent No. 7,951,828 and U.S. Patent No. 7,662,972, U.S. Patent Application Publication No. 2010 / 0137372, U.S. Patent Application Publication No. 2010 / 0179194, U.S. Patent Application Publication No. 2011 / 0086886, U.S. Patent Application Publication No. 2011 / 00599 88, U.S. Patent Application Publication No. 2010 / 0179195, U.S. Patent Application Publication No. 2015 / 0126523, WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236, WO 2017 / 147352, U.S. Patent No. 7,897,630, and U.S. Patent No. 7,951,828;

[0205] In another embodiment of the present invention, nodulisporic acid and its derivatives can be added to the compositions of the present invention.These compounds are used to treat or prevent infections in humans and animals, and are described, for example, in U.S. Patent Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference in their entirety.The compositions can contain one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above-cited documents.

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

[0207] The compositions of the present invention may also contain paraherquamide compounds and derivatives of these compounds, including delquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds containing a spirodioxepinoindole core that have activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380 and J. Antibiotics 1991, 44, 492). Additionally, structurally related compounds of the marcfortine family, such as marcfortines A-C, are known and can be combined with the compositions of the 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 WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, 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 entireties.

[0208] In another embodiment of the present invention, the compositions may include spinosyn active agents produced by the soil actinomycete Saccharopolyspora spinosa (see, e.g., Salgado VL and Sparks TC, "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance," in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or semisynthetic spinosoid active agents. Spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or combinations thereof may be used in the compositions of the present invention. Spinosyn compounds can be a 12-membered macrocyclic lactone, a 5,6,5-tricyclic ring system fused with a neutral sugar (rhamnose) and an amino sugar (forosamine). These and other naturally occurring spinosyn compounds, including the 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 present invention are disclosed in U.S. Patent 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, all of which are incorporated herein by reference in their entireties. Spinosyn compounds can include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydrospinosyn J and 3'-ethoxyspinosyn L.

[0209] Generally, the additional active agent (other than the compound of Formula (I) above) is included in the dosage unit of the present invention in an amount between about 0.1 μg and about 1000 mg. Typically, the active agent may 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 additional active agents in the compositions of the present invention will typically be about 0.01% to about 30% (w / w), depending on the potency of the active agent. In certain embodiments of highly potent active agents, including but not limited to macrocyclic lactone active agents, 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 present, typically at a higher concentration to achieve the desired efficacy. In some embodiments, the active agent is present in 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 yet 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 to deliver a dose of about 0.001 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 50 mg / kg of animal body weight. In other embodiments, the active agent is present in an amount sufficient to deliver a dose of typically about 0.05 mg / kg to about 30 mg / kg, or 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 dose of about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.5 mg / kg to about 50 mg / kg of animal body weight.

[0211] In certain embodiments of the invention where the additional active agent is a highly potent compound, such as a macrocyclic lactone or other potent compound, the active agent is present in a concentration that provides a dose of about 0.001 mg / kg to about 5 mg / kg, about 0.001 mg / kg to about 0.1 mg / kg, or about 0.001 mg / kg to about 0.01 mg / kg. In yet other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.01 mg / kg to about 2 mg / kg, or about 0.1 mg / kg to about 1 mg / kg of animal body weight. In yet other embodiments, the additional active agent may be present in an amount that delivers a dose of about 1 μg / kg to about 200 μg / kg, or about 0.1 mg / kg to about 1 mg / kg of animal body weight. In addition to the other active agents mentioned above, combinations of two or more active agents can be used in compositions with the compounds of the present 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 present invention to treat a particular insect infestation. The invention will now be further illustrated by the following non-limiting examples. [Example]

[0212] Preparation Examples The compound of formula (I) or its pharmaceutically or veterinarily acceptable salt can be prepared by employing one of the following reaction schemes. The starting materials for the 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 appreciated that the following procedures can be modified by those skilled in the art to prepare additional compounds according to the present invention. For example, those skilled in the art will understand that by replacing certain starting materials or using different intermediates, various compounds of formula (I) can be prepared. 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 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, intermediate 026-E can be used to incorporate variable R 1 Similarly, intermediate 026-C can be used to incorporate various groups corresponding to variable R 3 A variety of groups can be incorporated at positions corresponding to: Scheme 5

[0215] [ka]

[0216] 1. Synthesis of methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate [ka] A 100 mL round-bottom flask was charged with methyl 3-bromo-2-hydroxybenzoate (5.0 g, 21.6 mmol, 1.0 equiv.), ethyl bromoacetate (3.6 g, 21.6 mmol, 1 equiv.), acetone (50 mL), and K2CO3 (8.97 g, 64.9 mmol, 3.0 equiv.). The resulting solution was stirred at 60 °C overnight. The reaction mixture was cooled. The solid was filtered. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 2). This afforded 7 g of methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate (crude product) as a pale yellow solid.

[0217] 2. Synthesis of methyl 7-bromo-3-hydroxybenzofuran-2-carboxylate [ka] A 50 mL round-bottom flask was charged with methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate (5.0 g, 15.7 mmol, 1.0 equiv.), CHOH (20.0 mL, 315.3 mmol), and CHONa (1.7 g, 31.5 mmol, 2.0 equiv.). The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 3). This afforded 3.5 g (81.9%) of methyl 7-bromo-3-hydroxy-1-benzofuran-2-carboxylate as a white solid.

[0218] 3. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-hydroxybenzofuran-2-carboxylate [ka] A 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere was charged with methyl 7-bromo-3-hydroxy-1-benzofuran-2-carboxylate (1.50 g, 5.53 mmol, 1.00 equiv.), 3,5-dichlorophenylboronic acid (1.1 g, 6.1 mmol, 1.1 equiv.), Pd(dtbpf)Cl2 (180 mg, 0.28 mmol, 0.05 equiv.), HO (2.0 mL), THF (8.0 mL), and K3PO4 (2.3 g, 11.0 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 3). This afforded 1 g (53.6%) of methyl 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylate as a white solid.

[0219] 4. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethylsulfonyloxy)benzofuran-2-carboxylate [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with methyl 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylate (0.9 g, 2.67 mmol, 1.0 equiv.), TEA (0.5 g, 5.3 mmol, 2.0 equiv.), and DCM (10.0 mL). This was followed by the addition of TfO (0.9 g, 3.20 mmol, 1.2 equiv.) at 0 °C. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 20 mL of water. 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. This gave 1.1 g (87.8%) of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate as a yellow solid.

[0220] 5. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)benzofuran-2-carboxylate [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate (1.10 g, 2.34 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.5 g, 2.8 mmol, 1.2 equiv.), Pd(dtbpf)Cl (76.4 mg, 0.12 mmol, 0.05 equiv.), HO (2.0 mL), THF (8.0 mL), and KPO (1.0 g, 4.7 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 8). This gave 400 mg (47.2%) of methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylate as a white solid.

[0221] 6. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylate [ka] A 50 mL round-bottom flask was charged with methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylate (390 mg, 1.1 mmol, 1.0 equiv), PtO (37 mg, 0.16 mmol, 0.15 equiv), and EA (10 mL). H gas (1 atm) was introduced into the flask. The resulting solution was stirred at room temperature for 30 min. The solid was filtered. The resulting mixture was concentrated. This afforded 370 mg (94.4%) of methyl 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylate as a gray solid.

[0222] 7. Synthesis of 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylic acid [ka] A 25 mL round-bottom flask was charged with methyl 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylate (350 mg, 1.0 mmol, 1.0 equiv), NaOH (385 mg, 9.6 mmol, 10.0 equiv), THF (1.0 mL), MeOH (4.0 mL), and HO (1.0 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. Aqueous HCl (1 mol / L) was added to adjust the pH of the solution to 4. The solid was collected by filtration. This afforded 300 mg (89.2%) of 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid as a white solid.

[0223] 8. Synthesis of (S)-N-(chroman-4-yl)-7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxamide [ka] A 25 mL round-bottom flask was charged with 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). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated. The crude product was further purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, 0.05% FA and CH3CN in water (increasing from 40% CH3CN to 95% within 13 min); detector, UV 254 & 220 nm. This gave 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 as a white solid. (ES, m / z): 480 [M+H] + ; 1 H-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] The following reaction was used to prepare methyl 7-(3,5-dichlorophenyl)-3-morpholinobenzofuran-2-carboxylate, which was then reacted with R according to Scheme 5:3 can be converted into an alternative compound having a morpholine group at the position corresponding to: [ka]

[0225] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate (500.0 mg, 1.07 mmol, 1.0 equiv.), morpholine (186 mg, 2.1 mmol, 2.0 equiv.), BINAP (133 mg, 0.21 mmol, 0.20 equiv.), Pd2(dba)3 (97.6 mg, 0.11 mmol, 0.1 equiv.), Cs2CO3 (0.69 g, 2.13 mmol, 2.0 equiv.), and toluene (10 mL). The resulting solution was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2 × 15 mL of ethyl acetate, and 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), which gave 200 mg (46.2%) of methyl 7-(3,5-dichlorophenyl)-3-(morpholin-4-yl)-1-benzofuran-2-carboxylate as a white solid.

[0226] The following compounds can be synthesized by employing Scheme 6 below and the following reaction schemes: 119, 120, 122, 199, 202, 204, 205, 207, 210, 212, 212-0A, 251, 252, 253, 253-0A, 254, 256, 2 58, 259, 259-5, 260, 261, 262, 263, 263-8, 285, 300, 301, 309, 310, 311, 319, 336, 337, 338. Scheme 6:

[0227] [ka]

[0228] Synthesis of 1,4-(3,5-difluorophenyl)-3-fluoropyridine [ka] A 1000 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 3-fluoro-4-iodopyridine (30.0 g, 134.5 mmol, 1.0 equiv.), dioxane (20 mL), 3,5-difluorophenylboronic acid (25.5 g, 161.4 mmol, 1.2 equiv.), Pd(dppf)Cl2 (4.92 g, 6.7 mmol, 0.05 equiv.), K2CO3 (37.2 g, 269.0 mmol, 2.0 equiv.), and HO (4 mL). The resulting solution was stirred at 7°C for 2 h. The resulting solution was extracted with 3 x 500 mL of ethyl acetate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (0% to 30%). This afforded 26 g (92.4%) of 4-(3,5-difluorophenyl)-3-fluoropyridine as a white solid.

[0229] Synthesis of 2,4-(3,5-difluorophenyl)-3-fluoropyridine 1-oxide [ka] A 1000 mL round-bottom flask was charged with 4-(3,5-difluorophenyl)-3-fluoropyridine (26.0 g, 124.3 mmol, 1.0 equiv.), DCM (500 mL), and m-CPBA (42.9 g, 248.6 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (EA 0% to 100%) to EA / MeOH (1 / 2). This afforded 21 g (75.0%) of 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-olate as a white solid.

[0230] Synthesis of 3,4-(3,5-difluorophenyl)-3-fluoropicolinonitrile [ka] A 1000 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-olate (21.0 g, 93.3 mmol, 1.0 equiv.), CH3CN (500 mL), TMSCN (23.1 g, 233.2 mmol, 2.5 equiv.), and TEA (19.8 g, 195.8 mmol, 2.10 equiv.). 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%). This afforded 10 g (45.8%) of 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile as an off-white solid.

[0231] 4. Synthesis of methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [ka] A 250 mL round-bottom flask was charged with 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile (6.0 g, 25.6 mmol, 1.0 equiv.), CHCN (100 mL), methyl thioglycolate (8.2 g, 76.9 mmol, 3.0 equiv.), and KCO (10.6 g, 76.86 mmol, 3 equiv.). The resulting solution was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 200 mL of water. The solid was collected by filtration and washed with water (3 × 20 mL). This afforded 6 g (73.1%) of methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a pale yellow solid.

[0232] 5. Synthesis of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [ka] A 250 mL three-necked round-bottom flask purged and maintained with an inert argon atmosphere was charged with 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.). This was followed by the dropwise addition of a solution of NaNO (388 mg, 5.6 mmol, 1.2 equiv.) in HO (5 mL) with stirring at 0 °C. The resulting solution was stirred overnight at 20 °C. The reaction 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 in vacuo. This gave 1.5 g (83.4%) of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a pale yellow solid.

[0233] 6. Synthesis of methyl 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylate [ka] A 40 mL vial purged and maintained under an inert nitrogen atmosphere was charged with methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (500 mg, 1.3 mmol, 1.0 equiv.), THF (10 mL), potassium ethenyltrifluoroboranide (523 mg, 3.9 mmol, 3.0 equiv.), HO (2 mL), Pd(PPh3)2Cl2 (91.4 mg, 0.1 mmol, 0.1 equiv.), and Cs2CO3 (1.27 g, 3.9 mmol, 3.0 equiv.). 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%). This gave 350 mg (81.2%) of methyl 7-(3,5-difluorophenyl)-3-ethenylthieno[3,2-b]pyridine-2-carboxylate as a yellow solid.

[0234] 7. Synthesis of methyl 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylate [ka] A 100 mL round-bottom flask was charged with KOsO.2HO (200.2 mg, 0.5 mmol, 0.6 equiv.), acetone (10 mL), HO (10 mL), NMO (636.4 mg, 5.4 mmol, 6.0 equiv.), NaIO (1.2 g, 5.4 mmol, 6 equiv.), and methyl 7-(3,5-difluorophenyl)-3-ethenylthieno[3,2-b]pyridine-2-carboxylate (300 mg, 0.90 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (EA 0%–30%). This gave 170 mg (56.3%) of methyl 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylate as a yellow solid.

[0235] 8. Synthesis of methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [ka] A 50 mL round-bottom flask was charged with methyl 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylate (170 mg, 0.5 mmol, 1.0 equiv.), DCM (5 mL), and DAST (0.5 mL, 0.001 mmol, 0.04 equiv.). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was added dropwise to 30 mL of water / ice. The resulting solution was extracted with 3 × 10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 3 × 20 mL of brine. The resulting mixture was concentrated. The residue was applied to silica gel pre-TLC using ethyl acetate / petroleum ether (1 / 3). This afforded 130 mg (71.7%) of methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a white solid.

[0236] 9. Synthesis of 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid [ka] A 25 mL round-bottom flask was charged with methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (110 mg, 0.3 mmol, 1.0 equiv.), i-PrOH (2.0 mL, 0.1 mmol), NaOH (200 mg, 5.0 mmol, 16.1 equiv.), and HO (2.0 mL, 0.3 mmol). The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature. Aqueous HCl (2 mol / L) was added to adjust the pH of the solution to 5. The resulting solution was extracted with 3 × 10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 100 mg (94.6%) of 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid as a white solid.

[0237] 10. Synthesis of 3-(difluoromethyl)-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide [ka] A 50 mL round-bottom flask was charged with 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (80 mg, 0.2 mmol, 1.0 equiv.), DMF (3 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (70 mg, 0.5 mmol, 2.0 equiv.), DIEA (91 mg, 0.7 mmol, 3.0 equiv.), and HATU (133.7 mg, 0.3 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The residue was applied to a C18 column using 0.05% FA and CH3CN in HO (40% CH3CN to 80% in 10 min). This gave 82.4 mg (74.4%) of 3-(difluoromethyl)-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide as an off-white solid. (ES, m / z): 479 [M+H] + ; 1 H-NMR (300 MHz, CDCl3): δ = 8.88 (d, J = 4.8 Hz, 1H), 7.63 (t, J = 54.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39-7.19 (m, 5H), 7.15 (d, J = 8.0 Hz, 1H), 7.09-6.86 (m, 3H), 5.40 (q, J = 5.9 Hz, 1H), 4.39-4.22 (m, 2H), 2.43-2.24 (m, 2H) ppm.

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

[0239] Synthesis of ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate [ka] A 40 mL vial purged and maintained under an inert nitrogen atmosphere was charged with ethyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (1.0 g, 2.5 mmol, 1.0 equiv.), dioxane (20 mL), tributyl(1-ethoxyethenyl)stannane (2.7 g, 7.5 mmol, 3.0 equiv.), and Pd(PPh3)4 (290.2 mg, 0.2 mmol, 0.1 equiv.). The resulting solution was stirred at 115 °C overnight. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of aqueous HCl (10 mL, 2 mol / L). The resulting solution was extracted with 3 × 20 mL of ethyl acetate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (10%–30%). This gave 800 mg (88.2%) of ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a pale yellow solid.

[0240] Synthesis of 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid [ka] A 25 mL round-bottom flask was charged with ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (300 mg, 0.8 mmol, 1.0 equiv.), i-PrOH (10 mL, 0.2 mmol, 0.2 equiv.), HO (10 mL), and NaOH (300 mg, 7.5 mmol, 9.0 equiv.). The resulting solution was stirred at 60 °C for 3 h. The reaction mixture was cooled to room temperature. Aqueous HCl (2 mol / L) was added to adjust the pH of the solution to 5. The resulting solution was extracted with 3 × 20 mL of ethyl acetate. The resulting mixture was washed with 3 × 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This afforded 270 mg (97.6%) of 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid as a yellow oil.

[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 [ka] A 25 mL round-bottom flask was charged with 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (270 mg, 0.81 mmol, 1.00 equiv.), DMF (5 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (242 mg, 1.62 mmol, 2.00 equiv.), DIEA (314 mg, 2.4 mmol, 3.0 equiv.), and HATU (462 mg, 1.2 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 2 h. The residue was applied to a C18 column using 0.05% FA and CH3CN in HO (40% CH3CN to 90% in 10 min). This gave 180 mg (47.8%) of 3-acetyl-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide as a white solid.

[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 [ka] A 40 mL vial purged and maintained under an inert nitrogen atmosphere was charged with 3-acetyl-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide (160 mg, 0.3 mmol, 1.0 equiv.) and DCM (10 mL). This was followed by the dropwise addition of AlMe3 (0.2 mL, 1.7 mmol, 5.0 equiv.) with stirring at 0 °C. The resulting solution was stirred at 0–10 °C for 1 h. The reaction mixture was added dropwise to 20 mL of ice water. The resulting solution was extracted with 3 × 10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 3 × 20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 2). This gave 35.3 mg (21.3%) 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 as a pale yellow solid. (ES, m / z): 447 [M+H] + ; 1 H-NMR (300 MHz, CDCl3): δ = 8.79 (d, J = 4.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06-6.92 (m, 2H), 6.88 (dd, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.16 (s, 1H), 5.33 (q, J = 5.5 Hz, 1H), 4.38-4.32 (m, 1H), 4.25-4.17 (m, 1H), 2.46-2.16 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H) ppm.

[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 [ka] An 8 mL vial was charged with 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 (108 mg, 0.2 mmol, 1.0 equiv.) and DCM (3 mL). This was followed by the dropwise addition of DAST (72.5 mg, 0.4 mmol, 2.0 equiv.) while stirring at 0°C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 3 × 5 mL of dichloromethane, and the organic layers were combined and concentrated. The crude product was purified by prep-HPLC. This gave 23.1 mg (21.3%) 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 as a yellow solid. (ES, m / z): 483 [M+H] + ; 1 H-NMR (300 MHz, DMSO-d6): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 7.66-7.46 (m, 4H), 7.28 (d, J = 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 6.90 (td, J = 7.5, 1.3 Hz, 1H), 6.78 (dd, J = 8.2, 1.2 Hz, 1H), 5.24-5.13 (m, 1H), 4.29-4.17 (m, 2H), 2.24-2.03 (m, 2H), 1.98 (d, J = 9.9 Hz, 3H), 1.90 (d, J = 9.8 Hz, 3H) ppm.

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

[0245] Synthesis of 1,7-methoxy-1-benzofuran-2-carbonitrile A 500 mL round-bottom flask was charged with 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). The resulting solution was stirred in an oil bath at 150 °C for 1 h. Additional K2CO3 (49.9 g, 361.5 mmol, 1.1 equiv.) was then added and stirred for 20 min. The reaction was then quenched by adding 530 mL of water. 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). This afforded 14 g (24.6%) of 7-methoxy-1-benzofuran-2-carbonitrile as a white solid.

[0246] Synthesis of 2,4-acetyl-7-hydroxy-1-benzofuran-2-carbonitrile [ka] A 100 mL round-bottom flask was charged with 7-methoxy-1-benzofuran-2-carbonitrile (14.0 g, 80.8 mmol, 1.00 equiv.), acetyl chloride (19.0 g, 242.5 mmol, 3.0 equiv.), and DCM (300 mL). This was followed by the addition of AlCl (43.1 g, 323.3 mmol, 4.0 equiv.) in several batches at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 500 mL of water / ice. The resulting solution was extracted with 3 × 400 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). This afforded 9 g (51.7%) of 4-acetyl-7-methoxy-1-benzofuran-2-carbonitrile as a white solid.

[0247] Synthesis of 3.7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile [ka] A 250 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with methyltriphenylphosphonium bromide (7.9 g, 22.3 mmol, 1.2 equiv.) and THF (50 mL). This was followed by the dropwise addition of n-BuLi (12.6 mL, 31.6 mmol, 1.7 equiv.) in hexanes with stirring at 0°C. The resulting solution was stirred at 0°C for 30 minutes. To this was added 4-acetyl-7-methoxy-1-benzofuran-2-carbonitrile (4.0 g, 18.5 mmol, 1.0 equiv.) with stirring at -78°C. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3 x 50 mL of ethyl acetate. The organic phase was washed with 2 x 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), which gave 1.6 g (40.3%) of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile as a white solid.

[0248] 4. Synthesis of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid [ka] A 100 mL round-bottom flask was charged with 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile (1.6 g, 7.5 mmol, 1.0 equiv.) and 50.0 mL of 10 M aqueous NaOH solution. The resulting solution was stirred in an oil bath at 100 °C for 1.5 h. The pH of the solution was adjusted to 3-4 with 6 M aqueous HCl. The solid was collected by filtration. This afforded 1.4 g (80.3%) of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid as a white solid.

[0249] 5. Synthesis of 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid [ka] A 250 mL round-bottom flask was charged with 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid (2.2 g, 9.4 mmol, 1.0 equiv.), EA (50.0 mL), and PtO2 (0.4 g, 1.8 mmol, 0.2 equiv.). H2 (g) was introduced. The resulting solution was stirred at room temperature for 2 h. The solid was filtered. The resulting mixture was concentrated. This afforded 2.2 g (99.1%) of 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid as a yellow solid.

[0250] 6. Synthesis of 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid [ka] A 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid (500.0 mg, 2.1 mmol, 1.0 equiv.) and DCM (50 mL). This was followed by the dropwise addition of BBr3 (10.6 mL, 10.6 mmol, 5.0 equiv.) with stirring at -70 °C. The resulting solution was stirred at 5 °C for 4 h. The reaction was then quenched by the addition of NH4Cl (aqueous solution, 50 mL). The resulting solution was extracted with 3 x 50 mL of DCM and concentrated. This afforded 500 mg of 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid (crude product) as a colorless oil.

[0251] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-hydroxy-4-isopropyl-1-benzofuran-2-carboxamide [ka] A 100 mL round-bottom flask was charged with 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid (500.00 mg, 2.270 mmol, 1.00 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (508.1 mg, 3.4 mmol, 1.5 equiv.), HATU (1726.5 mg, 4.5 mmol, 2.0 equiv.), DIEA (880.3 mg, 6.8 mmol, 3.0 equiv.), and DCM (20.0 mL). The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 x 30 mL of DCM, and the organic layer was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). This gave 250 mg (31.3%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-hydroxy-4-isopropyl-1-benzofuran-2-carboxamide as a colorless oil.

[0252] 8. Synthesis of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-4-isopropyl-1-benzofuran-7-yl trifluoromethanesulfonate [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-hydroxy-4-isopropyl-1-benzofuran-2-carboxamide (240.0 mg, 0.6 mmol, 1.0 equiv.), DCM (10.0 mL), and TEA (138.2 mg, 1.3 mmol, 2.0 equiv.). This was followed by the dropwise addition of TfO (231.2 mg, 0.8 mmol, 1.2 equiv.) with stirring at -70 °C. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 20 mL of NHCl (aq.). The resulting solution was extracted with 3 × 20 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. This gave 290 mg (87.8%) of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-4-isopropyl-1-benzofuran-7-yl trifluoromethanesulfonate as a colorless oil.

[0253] 9. Synthesis of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-4-isopropyl-1-benzofuran-2-carboxamide [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-4-isopropyl-1-benzofuran-7-yl trifluoromethanesulfonate (280.0 mg, 0.5 mmol, 1.0 equiv.), 3,5-dichlorophenylboronic acid (143.6 mg, 0.7 mmol, 1.3 equiv.), Pd(dtbpf)Cl2 (37.7 mg, 0.058 mmol, 0.1 equiv.), K3PO4 (245.8 mg, 1.1 mmol, 2.0 equiv.), THF (12.00 mL), and water (3.00 mL). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC (Waters-2767) under the following conditions: column, X-bridge RP18, 5 μm, 19 * 100 mm; mobile phase, 0.03% aqueous ammonia and CH3CN (50% CH3CN to 80% in 13 min); detector, UV 254 nm. This gave 87 mg (31.27%) of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-4-isopropyl-1-benzofuran-2-carboxamide as a white solid. (ES, m / z): 480 [M+H] + ; 1 H-NMR (300 MHz, DMSO-d6): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.05-7.87 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.28-7.14 (m, 2H), 6.96-6.87 (m, 1H), 6.86-6.79 (m, 1H), 5.28 (q, J = 6.7 Hz, 1H), 4.30 (dt, J = 6.7, 3.8 Hz, 2H), 2.25-1.97 (m, 2H), 1.35 (d, J = 6.9 Hz, 6H) ppm.

[0254] Compounds 264 and 264-0A can be prepared according to Scheme 9 below and the detailed procedures below: Scheme 9 [ka]

[0255] Exemplary Procedure for Compounds 264 and 264-0A: 1. Synthesis of (3,5-dichlorophenyl)acetyl chloride [ka] A 1 L round-bottom flask was charged with (3,5-dichlorophenyl)acetic acid (20.00 g, 97.547 mmol, 1.0 equiv.), toluene (120.0 mL), and thionyl chloride (50.0 g, 420.3 mmol, 4.3 equiv.). The resulting solution was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo to afford 19 g of (3,5-dichlorophenyl)acetyl chloride as a yellow oil (crude product).

[0256] Synthesis of 2.1-bromo-3-(3,5-dichlorophenyl)propan-2-one [ka] A 2 L three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with (3,5-dichlorophenyl)acetyl chloride (20 g, 89.4 mmol, 1.0 equiv.) and ACN (400.0 mL). Subsequently, TMSCHN2 (83 mL, 116.3 mmol, 2.0 equiv., 2 M) was added dropwise with stirring at 0 °C. The resulting solution was stirred at 0 °C for 1 h. To this was added HBr (40.0 mL, 547.7 mmol, 6.1 equiv., 40%) dropwise with stirring at 0 °C. The resulting solution was allowed to react at room temperature for an additional 2 h with stirring. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of ethyl acetate, and the resulting mixture was washed with 3 × 200 mL of water. The mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). This gave 19 g (crude) of 1-bromo-3-(3,5-dichlorophenyl)propan-2-one as a yellow oil. MS (ESI, m / z): 281 [M+H] + .

[0257] Synthesis of 3,4-(3,5-dichlorophenyl)-3-oxobutanenitrile [ka] A 500 mL round-bottom flask was charged with 1-bromo-3-(3,5-dichlorophenyl)propan-2-one (22.0 g, 78.0 mmol, 1.0 equiv.), MeOH (120.0 mL), and KCN (10.0 g, 153.5 mmol, 1.9 equiv.). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3 x 200 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This afforded 5 g (28.1%) of 4-(3,5-dichlorophenyl)-3-oxobutanenitrile as an off-white solid. MS (ESI, m / z): 228 [M+H] + .

[0258] Synthesis of 4,5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile [ka] A 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 4-(3,5-dichlorophenyl)-3-oxobutanenitrile (2.0 g, 8.7 mmol, 1.0 equiv.) and (dimethoxymethyl)dimethylamine (5.2 g, 43.9 mmol, 5.0 equiv.). The resulting solution was stirred at 122 °C for 1 h. Subsequently, CH3COONH4 (5.0 g, 64.9 mmol, 7.4 equiv.) and AcOH (50.0 mL) were added. The resulting solution was reacted at 80 °C for an additional 1 h with stirring. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using MeOH / DCM (1:10). This afforded 1.6 g (68.8%) of 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile as a yellow solid. MS (ESI, m / z): 265 [M + H] + .

[0259] 5. Synthesis of 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile [ka] A 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile (1.6 g, 6.0 mmol, 1.0 equiv) and POCl3 (20.00 mL). The resulting solution was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. This afforded 1.6 g (93.5%) of 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile as a brown oil. MS (ESI, m / z): 283 [M+H] + .

[0260] 6. Synthesis of 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate [ka] A 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile (1.6 g, 5.6 mmol, 1.0 equiv.), ethyl thioglycolate (1.0 g, 8.5 mmol, 1.5 equiv.), acetonitrile (20.0 mL), and triethylamine (2.0 g, 19.7 mmol, 3.5 equiv.). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 100 mL of ethyl acetate, and the solid was collected by filtration. This afforded 660 mg (31.8%) of ethyl 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate as a yellow solid. MS (ESI, m / z): 367 [M+H] + .

[0261] 7. Synthesis of ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate [ka] A 100 mL round-bottom flask was charged with ethyl 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (300.0 mg, 0.8 mmol, 1.0 equiv.), acetonitrile (10.0 mL), and HBr (10.0 mL). This was followed by the addition of CuBr2 (365.6 mg, 1.6 mmol, 2.0 equiv.) at 0 °C. To this was added NaNO2 (85.0 mg, 1.2 mmol, 1.5 equiv.) at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of 100 mL of 1 M HCl. The resulting solution was extracted with 3 × 200 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:2). This gave 400 mg (crude) of ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate as a yellow solid. MS (ESI, m / z): 430 [M+H] + .

[0262] 8. Synthesis of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyethenyl)thieno[3,2-c]pyridine-2-carboxylate [ka] A 20 mL vial purged and maintained under an inert nitrogen atmosphere was charged with ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (550.0 mg, 1.2 mmol, 1.0 equiv.), tributyl(1-ethoxyethenyl)stannane (1.4 g, 3.8 mmol, 3.0 equiv.), dioxane (10.0 mL), and Pd(PPh3)4 (148.0 mg, 0.1 mmol, 0.1 equiv.). The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:3). This gave 540 mg (crude) of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyethenyl)thieno[3,2-c]pyridine-2-carboxylate 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 [ka] A 50 mL round-bottom flask was charged with ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyethenyl)thieno[3,2-c]pyridine-2-carboxylate (530.0 mg, 1.2 mmol, 1.0 equiv), THF (6.00 mL), and HCl (0.2 mL, 12 M). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The reaction was then quenched by adding 50 mL of 2 M aqueous NaHCO3. The resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. This afforded 500 mg of ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (crude product) as a yellow solid. MS (ESI, m / z): 394 [M+H] + .

[0264] 10. Synthesis of 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid [ka] A 40 mL vial was charged with ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (500.0 mg, 1.2 mmol, 1.0 equiv.), THF (5.0 mL), water (5.0 mL), and LiOH.HO (160.0 mg, 3.8 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The pH of the solution was adjusted to 3 with aqueous HCl (1 M). The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This afforded 330 mg (71.0%) of 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid as a white solid. MS (ESI, m / z): 366 [M+H] + .

[0265] 11. Synthesis of 3-acetyl-7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-c]pyridine-2-carboxamide [ka] A 50 mL round-bottom flask was charged with 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid (330.0 mg, 0.9 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (202.0 mg, 1.3 mmol, 1.5 equiv.), DMF (3.00 mL), HATU (687.0 mg, 1.8 mmol, 2.0 equiv.), and DIEA (350.0 mg, 2.7 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: 18The mobile phase was increased from 20% CHCN:HO to 90% CHCN:HO within 20 min. This afforded 320 mg (71.4%) of 3-acetyl-7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-c]pyridine-2-carboxamide as a yellow solid. MS (ESI, m / z): 497 [M+H] + .

[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 [ka] A 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere was charged with AlMe3 (5 mL, 2 M in hexane). Subsequently, at 0 °C, 3-acetyl-7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-c]pyridine-2-carboxamide (140.0 mg, 0.2 mmol, 1.0 equiv.) was added. The resulting solution was stirred at room temperature for 1 hour. The pH value of the solution was adjusted to 2 with aqueous HCl (3 M). The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C 18 Silica gel; mobile phase: CHCN:HO = 20% increasing to CHCN:HO = 50% within 20 min. This gave 5.4 mg (3.7%) 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 as a white solid. MS (ESI, m / z): 513 [M+H] + ; 1H-NMR (300 MHz, CDCl3): δ = 9.58 (s, 1H), 9.40 (d, J = 7.8 Hz, 1H), 8.45 (s, 1H), 7.71 (s, 3H), 7.20-7.13 (m, 2H), 6.90-6.86 (m,1H), 6.76 (d, J = 9.0 Hz, 1H), 5.14-5.13 (d, J = 1.8 Hz, 1H), 4.18 (s, 2H), 2.11-2.10 (m, 1H), 2.00-1.95 (m, 1H), 1.68 (s, 6H) ppm.

[0267] 13. Synthesis of 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 [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 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 (35.0 mg, 0.06 mmol, 1.0 equiv.), DCM (5.0 mL), and DAST (21.0 mg, 0.1 mmol, 1.9 equiv.). The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3 × 5 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C 18Silica gel; mobile phase, increasing from 45% CHCN:HO to 65% CHCN:HO within 20 min. This afforded 22.7 mg (64.6%) of 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 as a white solid. MS (ESI, m / z): 515 [M+H] + ; 1 H-NMR (300 MHz, CDCl3): δ = 9.37 (s, 1H), 8.50 (s, 1H), 7.54-7.50 (m, 3H), 7.31 (s, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.99-6.90 (m, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 7.5 Hz, 1H), 5.33-5.25 (m, 1H), 4.39-4.32 (m, 1H), 4.25-4.17 (m, 1H), 2.37-2.34 (m, 1H), 2.27-2.22 (m, 1H), 2.07 (d, J = 7.1 Hz, 3H), 1.99 (d, J = 7.1 Hz, 3H) ppm.

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

[0269] [ka]

[0270] Exemplary Procedure for Compound 226-3: Synthesis of 1,3-chloro-4-methoxypyridine [ka] A 1000 mL round-bottom flask was charged with 3-chloro-4-nitropyridine (30.00 g, 189.2 mmol, 1.0 equiv), MeOH (400.0 mL), and CHONa (56.7 mL, 5 mol / L, 1.50 equiv). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was dissolved in 500 mL of EA. The resulting mixture was washed with 3 x 500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 25 g (92.0%) of 3-chloro-4-methoxypyridine as a yellow oil.

[0271] Synthesis of 2.3-chloro-4-methoxypyridin-1-ium-1-olate [ka] A 1000 mL round-bottom flask was charged with 3-chloro-4-methoxypyridine (25.00 g, 174.131 mmol, 1.00 equiv.), DCM (500.0 mL), and m-CPBA (60.1 g, 348.2 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (EA 0% to 100%) to EA / MeOH (1 / 2). This afforded 30 g of crude 3-chloro-4-methoxypyridin-1-ium-1-olate as an off-white solid.

[0272] Synthesis of 3-chloro-4-methoxypyridine-2-carbonitrile [ka] A 1000 mL round-bottom flask was charged with 3-chloro-4-methoxypyridin-1-ium-1-olate (30.00 g, 188.0 mmol, 1.0 equiv.), CHCN (600.0 mL), TMSCN (46.6 g, 470.0 mmol, 2.5 equiv.), and TEA (39.95 g, 394.8 mmol, 2.1 equiv.). The resulting solution was stirred at 80 °C for 6 h. The resulting mixture was concentrated in vacuo to afford 35 g of crude 3-chloro-4-methoxypyridine-2-carbonitrile as a brown solid.

[0273] 4. Synthesis of methyl 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate [ka] A 500 mL round-bottom flask was charged with 3-chloro-4-methoxypyridine-2-carbonitrile (16.00 g, 94.9 mmol, 1.0 equiv.), CHCN (300.0 mL), methyl thioglycolate (40.30 g, 379.6 mmol, 4.0 equiv.), and KCO (52.47 g, 379.6 mmol, 4.0 equiv.). 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%-70%). This afforded 2.7 g (11.9%) of methyl 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate as a yellow solid.

[0274] 5. Synthesis of methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate [ka] A 250 mL round-bottom flask was charged with methyl 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate (1.00 g, 4.1 mmol, 1.0 equiv.), HOAc (40.0 mL), HCHO (1260.2 mg, 41.9 mmol, 10.0 equiv.), and NaBH3CN (2637.5 mg, 41.9 mmol, 10.0 equiv.). The resulting solution was stirred at 35 °C for 3 h. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3 × 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 100 mL of NaHCO3 (aq.) and 3 × 100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (EA 0%-50%). This gave 1.1 g (98.4%) of methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate as a pale yellow solid.

[0275] 6. Synthesis of 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid [ka] A 100 mL round-bottom flask was charged with methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate (130.0 mg, 0.4 mmol, 1.0 equiv), THF (3.0 mL), NaOH (130.00 mg, 3.2 mmol, 6.6 equiv), and HO (3.0 mL). The resulting solution was stirred at 55 °C for 3 h. The resulting mixture was concentrated in vacuo to afford 150 mg of crude 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid as a yellow solid.

[0276] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxamide [ka] A 100 mL round-bottom flask was charged with 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid (900.0 mg, 3.5 mmol, 1.0 equiv.), DMF (20.0 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (532.2 mg, 3.5 mmol, 1.0 equiv.), DIEA (1383.1 mg, 10.7 mmol, 3.0 equiv.), and HATU (2034.60 mg, 5.3 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (0% to 50%). This gave 530 mg (38.7%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxamide as a yellow semi-solid.

[0277] 8. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide [ka] A 40 mL vial was charged with N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxamide (500.0 mg, 1.3 mmol, 1.0 equiv.), DMF (10.0 mL, 0.014 mmol), and LiCl (300.1 mg, 7.0 mmol, 5.4 equiv.). The resulting solution was stirred at 140 °C for 6 h. The reaction mixture was cooled to room temperature. The residue was applied to a silica C18 column using 0.05% TFA and CH3CN in HO (20% CH3CN to 60% in 12 min). This gave 200 mg (41.5%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide as a pale yellow solid.

[0278] 9. Synthesis of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide (180.0 mg, 0.4 mmol, 1.0 equiv.), DCM (5.0 mL), TEA (493.0 mg, 4.8 mmol, 10.0 equiv.), and TfO (687.3 mg, 2.4 mmol, 5.0 equiv.). The resulting solution was stirred at 10 °C for 2 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3 × 10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 20 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to silica gel pre-TLC using ethyl acetate / petroleum ether (1 / 3). This gave 150 mg (61.3%) of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate as a yellow oil.

[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 [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (500.0 mg, 1.0 mmol, 1.0 equiv.), tributyl(1-ethoxyethenyl)stannane (1 g, 2.7 mmol, 2.7 equiv.), Pd(dppf)Cl2 (160.00 mg, 0.2 mmol, 0.2 equiv.), and K2CO3 (250.0 mg, 1.8 mmol, 1.8 equiv.). The resulting solution was stirred at 100 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:4). This gave 350 mg (82.8%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(1-ethoxyethenyl)thieno[3,2-b]pyridine-2-carboxamide as a brown solid.

[0280] 11. Synthesis of 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide [ka] A 50 mL round-bottom flask was charged with 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. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and 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). This gave 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 as a yellow solid. 1 H-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-methylpent-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide [ka] A 50 mL three-necked round-bottom flask was charged with THF (5.0 mL) and 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide (300.0 mg, 0.7 mmol, 1.0 equiv.). Following this, bromo(2-methylprop-1-en-1-yl)magnesium (1.0 mL, 0.006 mmol, 0.01 equiv.) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and 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 (1:4). This gave 150 mg (43.7%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpent-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide as a yellow solid.

[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 [ka] A 50 mL round-bottom flask was charged with EtOH (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpent-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide (150.0 mg, 0.3 mmol, 1.0 equiv.), and Pd / C (30.0 mg, 0.2 mmol, 0.8 equiv.). H2(g) was introduced. The resulting solution was stirred at 50 °C for 2 h. The solid was filtered. The resulting mixture was concentrated in vacuo. This gave 100 mg (66.3%) 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 as a white solid.

[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 [ka] A 50 mL round-bottom flask was charged with 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 SOCl (0.5 mL). The resulting solution was stirred at 0 °C for 1 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. This gave 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 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 [ka] A 50 mL round-bottom flask was charged with EtOH (5.0 mL), 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 (70.0 mg, 0.16 mmol, 1.0 equiv.), and Pd / C (20.0 mg, 0.19 mmol, 1.2 equiv.). H2(g) was introduced. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, HO and CH3CN (increasing from 20% CH3CN to 90% within 20 min); detector, 220 nm. This afforded 12.2 mg (17.3%) 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 as a white solid. (ES, m / z): 438 [M+H] + ; 1H-NMR (300 MHz, CDCl3): δ = 8.65 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 (m, 1H), 6.97-6.94 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.38-4.36 (m, 1H), 4.27-4.24 (m, 1H), 3.24-2.22 (m, 1H), 2.99 (s, 6H), 2.45-2.28 (m, 1H), 2.27-2.11 (m, 1H), 1.90-1.75 (m, 1H), 1.66-1.35 (m, 6H), 0.99- 0.90 (m, 6H) ppm.

[0285] [ka] An 8 mL sealed tube was charged with 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 (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, HO and CH3CN (increasing from 20% CH3CN to 90% within 20 minutes); detector, 254 nm. This gave 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 as a pale yellow solid. (ES, m / z): 473 [M+H] + ; 1H-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] [ka]

[0288] Exemplary Procedure for Compounds 115 and 116: Synthesis of 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine as a white solid [ka] A 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere was charged with 4-chlorothieno[3,2-d]pyrimidine (5.0 g, 29.3 mmol, 1.0 equiv.), 3,5-difluorophenylboronic acid (6.0 g, 38.0 mmol, 1.3 equiv.), Pd(dppf)Cl2 (2.1 g, 3.0 mmol, 0.1 equiv.), K3PO4 (12.4 g, 59.0 mmol, 2 equiv.), dioxane (100.0 mL), and HO (10.0 mL). The resulting solution was stirred at 80 °C overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 10 to 1 / 4). This afforded 7.8 g of 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (crude product) as a white solid. (ES, m / z): 249 [M + H] + .

[0289] Synthesis of 1,7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine [ka] 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. The reaction was then quenched by pouring into 500 mL of ice-water NaHCO3. The resulting solution was extracted with 2 × 500 mL of ethyl acetate. The EA mixture was washed with 2 × 500 mL of aqueous NaCHO3 and 1 × 500 mL of aqueous 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. This gave 4 g of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine as a pale yellow solid.

[0290] Synthesis of 2,7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid [ka] A 250 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (1.3 g, 1.0 equiv.) and THF (130.0 mL). Subsequently, LDA (4.0 mL, 1.5 equiv.) was added dropwise with stirring at −78°C. The resulting solution was stirred at −78°C for 30 minutes. It was then flushed with CO at −50°C. The resulting solution was allowed to react with stirring for an additional 2 hours at −50°C. The resulting solution was allowed to react with stirring at room temperature for an additional 2 hours. The reaction was then quenched by the addition of 100 mL of water. The solid was collected by filtration. This yielded 500 mg of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid as a pale yellow solid.

[0291] Synthesis of 3,7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide [ka] A 250 mL round-bottom flask was charged with 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid (1.6 g, 4.3 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (707.4 mg, 4.7 mmol, 1.1 equiv.), HATU (3278.2 mg, 8.6 mmol, 2 equiv.), DIEA (1392.8 mg, 10.7 mmol, 2.5 equiv.), and DMF (50.0 mL). The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 50 mL of water. The solid was collected by filtration. This gave 1.1 g (50.8%) of 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide as a yellow solid. (ES, m / z): 502 [M+H] + ; 1 H-NMR (300 MHz, DMSO-d6): δ = 9.49 (s, 1H), 9.40 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 6.6 Hz, 2H), 7.65 (t, J = 9.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.29 (d, J = 6.6 Hz, 1H), 4.29 (s, 2H), 42.25-2.13 (m, 2H) ppm.

[0292] 4. 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 [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide (57.0 mg, 0.1 mmol, 1.0 equiv.), potassium trifluoro(prop-1-en-2-yl)-lambda 4-borane (38.0 mg, 0.3 mmol, 2.0 equiv.), Pd(dppf)Cl (15.0 mg, 0.02 mmol, 0.2 equiv.), KPO (48.0 mg, 0.3 mmol, 2.0 equiv.), dioxane (3.0 mL), and HO (0.3 mL). The resulting solution was stirred at 80 °C overnight. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from ACN / HO = 20 / 80 to ACN / HO = 100 / 0 within 15 min; detector, 254 nm. This afforded 27.8 mg 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 as an off-white solid. (ES, m / z): 464 [M+H] + ; 1 H-NMR (300 MHz, CD3OD): δ = 9.34 (s, 1H), 7.81-7.78 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.02 (m, 1H), 6.97-6.87 (m, 2H), 5.60 (t, J = 1.5 Hz, 1H), 5.38-5.35 (m, 1H), 5.27 (s, 1H), 4.34-4.31 (m, 1H), 4.19-4.12 (m, 1H), 2.39-2.36 (m, 1H), 2.22-2.19 (m, 4H) ppm.

[0293] 5. Synthesis of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-isopropylthieno[3,2-d]pyrimidine-6-carboxamide [ka] A 50 mL round-bottom flask was charged with 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 (90.0 mg, 0.2 mmol, 1.0 equiv.), PtO (90.0 mg, 1.0 equiv.), and EA (20.0 mL). The mixture was flushed with H six times. The resulting solution was stirred at room temperature overnight. The solids were filtered off. The filtrate was concentrated. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from ACN / HO = 30 / 70 to ACN / HO = 80 / 20 within 15 min; detector, 254 nm. This gave 27.7 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-isopropylthieno[3,2-d]pyrimidine-6-carboxamide as a white solid. (ES, m / z): 466 [M+H] + ; 1 H-NMR (300 MHz, DMSO-d6): δ = 9.40 (s, 1H), 9.34 (d, J = 6.9 Hz, 1H), 7.79 (d, J = 6.0 Hz, 2H), 7.64-7.61 (m, 1H), 7.27-7.16 (m, 2H), 6.96-6.93 (m, 1H), 6.82-6.79 (m, 1H), 5.30 (s, 1H), 4.26 (m, 2H), 3.85-3.81 (m, 1H), 2.30-1.98 (m, 2H), 1.51 (m, 6H) ppm.

[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 [ka] A 50 mL sealed tube was charged with 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide (80.0 mg, 0.16 mmol, 1.0 equiv.) and dimethylamine (2 M in THF, 50.0 mL). The resulting solution was stirred at 110 °C for 4 hours. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from ACN / HO = 20 / 80 to ACN / HO = 90 / 10 within 15 min; detector, 254 nm. This gave 5 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(dimethylamino)thieno[3,2-d]pyrimidine-6-carboxamide as a white solid. (ES, m / z): 467 [M+H] + ; 1 H-NMR (300 MHz, CDCl3): δ = 10.36 (d, J = 8.1 Hz, 1H), 9.28 (s, 1H), 7.76 (dd, J = 8.1, 2.1 Hz, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.26-7.20 (m, 1H), 7.08-7.01 (m, 1H), 6.96-6.88 (m, 2H), 5.42-5.38 (m, 1H), 4.39-4.33 (m, 1H), 4.28-4.20 (m, 1H), 2.99 (s, 6H), 2.44-2.38 (m, 1H), 2.23-2.16 (m, 1H) ppm.

[0295] 7. 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 [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide (100.0 mg, 0.2 mmol, 1.0 equiv.), morpholine (174.0 mg, 2.0 mmol, 10.0 equiv.), Pd(dba) (20.0 mg, 0.02 mmol, 0.1 equiv.), Xantphos (23.0 mg, 0.04 mmol, 0.2 equiv.), toluene (10.0 mL), and CsCO (130.0 mg, 0.4 mmol, 2.0 equiv.). The resulting solution was stirred at 110 °C for 3 h. The solid was filtered. The filtrate was concentrated. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from ACN / HO = 10 / 90 to ACN / HO = 90 / 10 within 15 min; detector, 254 nm. This afforded 47.4 mg 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 as a yellow solid. (ES, m / z): 509 [M+H] + ; 1 H-NMR (300 MHz, CDCl3): δ = 10.64 (d, J = 6.9 Hz, 1H), 9.31 (s, 1H), 7.80 (dd, J = 8.1, 2.1 Hz, 2H), 7.31-7.27 (m, 2H), 7.11-7.05 (m, 1H), 6.99-6.93 (m, 2H), 5.35-5.30 (m, 1H), 4.43-4.38 (m, 1H), 4.27-4.19 (m, 1H), 3.52-3.39 (m, 8H), 2.41-2.33 (m, 2H) ppm.

[0296] The following compounds can be prepared according to Scheme 12 below and the detailed procedures below: 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] [ka]

[0298] Exemplary Procedure for Compound 201: Synthesis of 1,3-bromo-7-chlorothieno[3,2-b]pyridine [ka] A 3000 mL three-necked round-bottom flask was charged with 7-chlorothieno[3,2-b]pyridine (25.0 g, 147.3 mmol, 1.0 equiv.), CHCl3 (4166.6 mL, 34903.0 mmol, 350.5 equiv.), KHSO4 (30.1 g, 221.0 mmol, 1.5 equiv.), NaHCO3 (12.3 g, 147.4 mmol, 1.0 equiv.), MgSO4 (26.6 g, 221.0 mmol, 1.5 equiv.), and Br2 (235.5 g, 1473.8 mmol, 10.0 equiv.). The resulting solution was stirred at 70 °C for 16 h. The reaction was cooled to room temperature. The reaction was then quenched by the addition of 500 mL of Na2SO3 (aq.). The resulting solution was extracted with 2 x 1 L of DCM. The organic layers were combined, dried, and concentrated in vacuo to give 30 g (81.9%) of 3-bromo-7-chlorothieno[3,2-b]pyridine as a yellow solid.

[0299] Synthesis of 2,3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid [ka] A 2000 mL flask was charged with 3-bromo-7-chlorothieno[3,2-b]pyridine (30.0 g, 1.0 equiv.), THF (1000.0 mL), and LDA (84.0 mL, 1.5 equiv.). The resulting solution was stirred at −78° C. for 2 hours. CO was introduced into the mixture at −78° C. for 2 hours. The reaction was then quenched by the addition of 500 mL of NH4Cl. The solid was collected by filtration. This afforded 18 g (51.1%) of 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid as a yellow solid.

[0300] Synthesis of 3.3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide [ka] A 500 mL round-bottom flask was charged with 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (25.0 g, 85.4 mmol, 1.0 equiv.), HATU (48.7 g, 128.2 mmol, 1.5 equiv.), DMF (300.0 mL), DIEA (33.1 g, 256.4 mmol, 3.0 equiv.), and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (19.1 g, 128.2 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 500 mL of water. The solid was collected by filtration. This gave 30 g (82.8%) of 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide as a yellow solid.

[0301] Synthesis of 4.7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(prop-1-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide [ka] A 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide (5.0 g, 11.8 mmol, 1.0 equiv.), potassium trifluoro(prop-1-en-2-yl)-lambda 4-borane (2.6 g, 17.7 mmol, 1.5 equiv.), Pd(dppf)Cl (0.8 g, 1.2 mmol, 0.1 equiv.), KPO (5.0 g, 23.6 mmol, 2.0 equiv.), dioxane (100 mL), and HO (10 mL). The resulting solution was stirred at 90 °C for 3 h. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:10), which gave 2.8 g (61.6%) 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 as a yellow solid.

[0302] 5. Synthesis of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide [ka] 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 (2.50 g, 6.5 mmol, 1.0 equiv.) as a yellow solid, EA (500 mL), and PtO (1.5 g). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon) at 40 °C for 3 h. The reaction mixture was cooled to room temperature. The solid was filtered. The filtrate was concentrated. This gave 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 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 [ka] A 20 mL microwave tube purged and maintained with an inert nitrogen atmosphere was charged with 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (100.0 mg, 0.2 mmol, 1.0 equiv), DME (3.00 mL), 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (162.0 mg, 0.6 mmol, 2.5 equiv), Pd(dtbpf)Cl (17.00 mg, 0.026 mmol, 0.1 equiv), KPO (137.0 mg, 0.6 mmol, 2.5 equiv), and HO (0.50 mL). The final reaction mixture was irradiated with microwave radiation at 100° C. for 0.5 hours. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, CH3CN / 0.05% NH3.H2O = 100%; detector, 254 nm &220 nm. This afforded 38.9 mg (31.7%) 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 as an off-white solid. (ES, m / z): 475 [M+H] + ; 1H-NMR (300 MHz, DMSO-d6): δ = 9.03 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.9 Hz, 1H), 7.20-7.09 (m, 4H), 6.91-6.77 (m, 2H), 5.24-5.22 (m, 1H), 4.23 (s, 2H), 3.93 (t, J = 6.9 Hz, 1H), 2.12-2.04 (m, 8H), 1.53 (s, 6H) ppm.

[0304] Exemplary Procedure for Compound 255: [ka] A 100 mL round-bottom flask was charged with 7-(cyclohex-1-en-1-yl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (50.0 mg, 0.1 mmol, 1.0 equiv.), THF (10.0 mL), and BH3-THF (1 M in THF) (2.5 mL, 26.1 mmol, 226.0 equiv.). The resulting solution was stirred at room temperature for 1 hour. Then, HO2 (30%) (2.50 mL, 107.3 mmol, 928.3 equiv.) and NaHCO3 (5 mL) were added dropwise to the flask. The resulting solution was allowed to react at room temperature with stirring for an additional 30 minutes. The resulting solution was diluted with 50 mL of DCM. The organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: Column, SunFire Prep C18 OBD column, 19 *150 mm, 5 μm, 10 nm; mobile phase, water and ACN (16% Phase B to 40% in 7 min); detector, UV 254 nm. This afforded 15 mg (28.8%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(1-hydroxycyclohexyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide as a white solid and 20 mg (38.4%) of N-((S)-chroman-4-yl)-7-(2-hydroxycyclohexyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide as a white solid.

[0305] [ka] A 50 mL round-bottom flask was charged with N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(1-hydroxycyclohexyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (15.0 mg, 0.03 mmol, 1.0 equiv.) and DCM (2.0 mL). This was followed by the dropwise addition of DAST (0.1 mL) while stirring at 0°C. The resulting solution was stirred at 25°C for 1 hour. The reaction was then quenched by the addition of MeOH (0.5 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC (2# SHIMADZU (HPLC-01)) under the following conditions: Column, SunFire Prep C18 OBD column, 19 * 150 mm, 5 μm, 10 nm; mobile phase, water and ACN (16% CH3CN to 40% in 7 min); detector, UV 254 nm. This afforded 2.0 mg (13.2%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-(1-fluorocyclohexyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide as a white solid. 1H-NMR (300 MHz, CDCl3): δ = 8.81 (s, 1H), 7.61 (s, 1H), 7.46-7.18 (m, 2H), 6.98-6.86 (m, 2H), 6.25 (d, J = 6.9 Hz, 1H), 5.35 (d, J = 5.7 Hz, 1H), 4.36-4.33 (m, 1H), 4.25-4.10 (m, 2H), 2.37-2.34 (m, 1H), 2.35-1.15 (m, 17H) ppm.

[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

[0308] Biological Examples The present disclosure is further illustrated by the following biological examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and that no limitation to the scope of the present disclosure is intended thereby. It should further be understood that there may be 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.

[0309] Example 1: Screening Method to Test the Activity of Compounds Against Microfilariae of Dirofilaria immitis 400-600 microfilariae of Dirofilaria immitis were added to wells of a microtiter plate containing RPMI medium and test compounds formulated in 100% DMSO. Plates were maintained at 37°C and 5% CO2 for 3 days. Compound efficacy was determined based on microfilarial motility compared to the average motility of control wells containing DMSO only. Dose-response assays were performed to determine EC 50 Compounds 310, 228, 217, 301, 205, and 259-4 had EC values ​​between 100 nM and 10 μM. 50Compounds 259-5, 260, 258, 220, 222, 203, 213, 199, 229, 224, 221, 247, and 214 had EC values ​​between 10 nM and 100 nM. 50 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 values ​​of less than 10 nM. 50 The values ​​were shown.

[0310] Example 2: Screening method to test the activity of compounds against Haemonchus contortus Twenty L1 Haemonchus larvae were added to wells of a microtiter plate containing nutrient medium and test compound in DMSO. Analysis was performed on day 4 to determine the extent of development of L1-L3 larvae. Larvae exposed to DMSO only served as controls. A dose-response assay was performed to determine the EC 50 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 had EC values ​​between 100 nM and 10 μM. 50 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 were found to be active at EC values ​​less than 100 nM. 50 The values ​​were shown.

[0311] Example 3: In vivo efficacy against Dirofilaria immitis in immunodeficient NSG mice The following in vivo studies to evaluate the efficacy of compounds of the present invention for preventing infection with Dirofilaria immitis in mammals were performed according to the procedures described in International Publication No. 2018 / 148392 (incorporated herein by reference). For the following studies, D. immitis were obtained from the Filariasis Research Reagent Resource Center (referred to herein as "FR3") and the internal insectary at the University of Georgia Vet School. Generally, worms were collected from mosquitoes and stored overnight in media and antibiotics. Worms were washed and counted for use in mice. Immunocompromised NSG mice susceptible to D. immitis infection were injected subcutaneously or intraperitoneally with 50 L3 D. immitis (2005 Missouri isolate or JYD-34) on day 0. NSG mice were orally administered compounds of the present invention at the dose levels indicated in the study on days 1, 15, and 30 post-infection. To collect parasites, mice were exsanguinated for serum collection 6 weeks post-infection, the skin was removed, the fascia was minced, the internal organs (viscera) were removed, and the fascia was minced. All pieces were left immersed overnight at room temperature in RPMI medium supplemented with 10% FBS and penicillin / streptomycin antibiotics. The following morning, approximately 18 hours later, worms were counted and fixed in 95% ethanol / 5% glycerol. Worms were mounted in glycerin jelly and then measured using cellSens software.

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

[0313] [Table 8]

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

[0315] [Table 9]

[0316] Test Number 3 The efficacy of compounds 210, 257, 207, and 102 was tested using a protocol similar to that of Study No. 1. A control group of seven NSG mice was assigned. Four additional test groups were assigned to administer compounds 210, 257, 207, and 102. The compound 210 group contained seven NSG mice, and the compound 257, 207, and 102 groups each contained six NSG mice. The compounds were formulated in Labrasol / Labrifil® M 1944 CS (70:30) vehicle at a concentration of 2.5 mg / mL as in Study No. 1 and orally administered to mice at a level of 25 mg / kg body weight. The results of the study are shown in Table 8 below.

[0317] [Table 10] Thus, the compounds of the present invention were found to be active against Dirofilaria immitis in the NSG mouse model.

[0318] Example 4: In vivo efficacy against Haemonchus contortus and Trichostrongylus colubriformis in Mongolian gerbils (Meriones unguiculatus) Several in vivo studies were conducted to test the efficacy of compounds of the present invention against Haemonchus contortus and Trichostrongylus colubriformis in gerbils. Groups of five animals each were assigned to each treatment group, untreated control group, and positive control group. Untreated gerbils were administered Labrasol / Labrifil® M 1944 CS (70:30) vehicle. Positive control animals were treated with levamisole (10 mg / kg in water vehicle) and / or ivermectin (0.1 mg / kg in DMSO / corn oil (50% / 50% v / v)). On day 0, immunosuppressed gerbils were artificially infected with approximately 1,000 infective, eclosed third-instar Haemonchus contortus larvae. After at least four hours, the gerbils were also infected with approximately 1,000 eclosed third-instar Trichostrongylus colubriformis larvae. Six days after infection, gerbils were treated by oral gavage with 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), gerbils were euthanized and necropsied to recover parasites from the stomach and small intestine. Efficacy was calculated as the mean % reduction in worm counts in each test group compared to the mean worm counts 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] Test 4:

[0322] [Table 14]

[0323] Thus, the compounds of the present invention were found to be highly effective against Haemonchus contortus and Trichostrongylus colubriformis in the gerbil model.

[0324] Having thus described in detail the preferred embodiments of the present invention, it should be understood that the invention as defined by the preceding paragraphs is not limited to the particular details set forth in the above description, and that many obvious variations thereof are possible without departing from the spirit or scope of the present invention.

Claims

1. Compounds of formula (I): 【Chemistry 1】 (I) or its salt (In the formula, L is L1 or L2: 【Chemistry 2】 R 1 is 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 (In the formula, R a and R b is independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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, a spirocyclic heterocyclyl-carbocyclyl group, a spirocyclic heterocyclyl-heterocyclyl group, a spirocyclic carbocyclyl-carbocyclyl group, a spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b is independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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 (In the formula, R a and R b is independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 5 is independently at each occurrence hydrogen or halogen; R 10 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; X is S; Q is O, S or NR 2’ and Y 1 is N; Y 2 and Y 3 Each independently represents -N- or -CR 4 - and Y 1’ and Y 6’ are C, respectively; Y 2’ , Y 3’ and Y 4’ Each independently represents -CR 5 - and Y 5’ Ha-CR 5 - or S; W is CR 6 R 7 and Z is CR 6 R 7 or O; R 6 and R 7 are each hydrogen; a is 0 or 1; q is 0 or 1; p is independently in each occurrence 0, 1 or 2; Dashed bond 【Chemistry 3】 indicates a single or double bond).

2. R 1 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 -haloalkylaminocarbonyl, 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, -SF 5 , -SO p (Optionally substituted C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl), or -NR a R b (In the formula, R a and R b are independently H or optionally substituted C 1 -C 6 -alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- 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’ C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted phenyl; R 3 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), optionally substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, a 5-11 membered spirocyclic heterocyclyl-carbocyclyl group, a 5-11 membered spirocyclic heterocyclyl-heterocyclyl group, a 5-11 membered spirocyclic carbocyclyl-carbocyclyl group, a 5-11 membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, 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 contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 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 (In the formula, 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 contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to 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, A compound of formula (I) according to claim 1.

3. R 1 is 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 heterocycle, 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, -SO p (optionally substituted alkyl), -SO p (optionally substituted haloalkyl), or -NR a R b (In the formula, R a and R b is independently an optionally substituted alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to 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 C 1 -C 4 -alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3 -C 8 -cycloalkyl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, or a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, each of which is optionally substituted by 1, 2 or 3 substituents; R 4 are independently hydrogen, halogen, cyano, hydroxyl, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 3 -C 8 -cycloalkyl, -SF 5 or -NR a R b (In the formula, R a and R b are independently hydrogen or optionally substituted C 1 -C 4 -alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to 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).

4. 4. A compound of formula (I) according to claim 3, wherein a is 1 and q is 1.

5. 4. A compound of formula (I) according to claim 3, wherein a is 0 and q is 0.

6. 4. A compound of formula (I) according to claim 3, wherein a is 1 and q is 0.

7. L is L1; R 1 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, optionally substituted 5- or 6-membered heteroaryl containing 1-3 N, S or O heteroatoms or optionally substituted 5- or 6-membered heterocyclyl, or -NR a R b (In the formula, 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, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 2 is hydrogen or C 1 -C 4 - alkyl; R 3 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 , an optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; an optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, each ring of said spirocyclic group containing 3, 4, 5 or 6 ring atoms; or -NR a R b (In the formula, 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 contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 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 (In the formula, R a and R b 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; A compound of formula (I) according to any one of claims 1 to 6.

8. 8. A compound of formula (I) according to claim 7, wherein a is 1 and q is 1.

9. 8. A compound of formula (I) according to claim 7, wherein a is 0 or 1 and q is 0.

10. The compound of formula (I) according to claim 7, represented by the following structure of formula (IC): 【Chemistry 4】 (I C) (In the formula, R 9 are 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 (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; R 1 is 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, an optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b (In the formula, 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, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 4 represents independently for 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 (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; R 5 is a halogen; 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).

11. The compound of formula (I) according to claim 7, represented by the following structure: 【Chemistry 5】 (In the formula, R 9 are 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 (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; R 1 is 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, an optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b (In the formula, 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 4 represents independently for 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 (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; R 5 is independently at each occurrence hydrogen or halogen; 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 C, respectively; Y 3’ and Y 4’ Independently, CR 5 and Y 5’ is CR 5 or S; Dashed bond 【Chemistry 6】 represents a single or double bond; a is 0 or 1; m is 0, 1, 2 or 3).

12. Y 5’ The compound of claim 11 , wherein is S.

13. Y 5’ is CR 5 12. The compound of claim 11, wherein

14. The compound of claim 7, represented by the following structure: 【Chemistry 7】 (In the formula, R 9 are 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 (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; R 1 is 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, an optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b (In the formula, 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 to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 5 is hydrogen or halogen; 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 attached to a 2-5 membered chain which may contain an N, O or S heteroatom to form a spirocyclic heterocyclyl-heterocyclyl group, a spirocyclic heterocyclyl-carbocyclyl group, a spirocyclic carbocyclyl-carbocyclyl group or a spirocyclic carbocyclyl-heterocyclyl group; m is 0, 1, 2 or 3; and b is 0 or 1.

15. R 1 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 independently for each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -cycloalkyl, or halo or C 1 -C 4 -phenyl optionally substituted once or twice by alkyl; R 5 is independently at each occurrence chloro or fluoro; The compound of claim 10.

16. R 1 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 independently for each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -cycloalkyl, or halo or C 1 -C 4 -phenyl optionally substituted once or twice by alkyl; R 5 is independently at each occurrence chloro or fluoro; The compound according to claim 11.

17. R 1 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 independently for each occurrence, hydrogen, halogen, cyano, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -cycloalkyl, or halo or C 1 -C 4 -phenyl optionally substituted once or twice by alkyl; R 5 is independently at each occurrence chloro or fluoro; 15. The compound of claim 14.

18. Y 2 and Y 3 Each of -C-R 4 The compound according to any one of claims 1 to 17,

19. Y 2 is N; Y 3 -CR 4 The compound according to any one of claims 1 to 17,

20. Y 1 and Y 3 is N; Y 2 -CR 4 The compound according to any one of claims 1 to 17,

21. Y 1 and Y 2 is N; Y 3 -CR 4 The compound according to any one of claims 1 to 17,

22. Compounds of formula (I): 【Chemistry 8】 (I) or its salt (In the formula, Y 1 , Y 2 , Y 3 , L, X, R 1 and R 3 are shown in the table below, L1 is 【Chemistry 9】 (wherein R 2 is hydrogen; Q is oxygen; L2 is 【Chemistry 10】 (In the formula, R 2 is hydrogen; Q is oxygen; basis 【Chemistry 11】 is abbreviated as "ring system" in the tables and represents the following ring systems: 【Chemistry 12】 Ring system A; 【Chemistry 13】 Ring system B; 【Chemistry 14】 Ring system C; 【Chemistry 15】 Ring system D; 【Chemistry 16】 Ring system E; 【Chemistry 17】 Ring system F; 【Chemistry 18】 Ring system G; 【Chemistry 19】 Ring system H; 【Chemistry 20】 Ring System I; and 【Chemistry 21】 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】

23. 23. A veterinary composition comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically or veterinarily acceptable salt thereof, and a veterinarily acceptable carrier.

24. 23. A veterinary composition comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically or veterinarily acceptable salt thereof, one or more additional active agents, and a veterinarily acceptable carrier.

25. 23. A method for treating, controlling or preventing a parasitic infestation or infection in a non-human animal in need thereof, comprising administering to said non-human animal an effective amount of a compound according to any one of claims 1 to 22, or a pharma- ceutical or veterinarily acceptable salt thereof.

26. 23. Use of a compound according to any one of claims 1 to 22 in the preparation of a medicament for treating, controlling or preventing a parasitic infection or infestation in a non-human animal.

27. Use of a compound of formula (I) as defined in any one of claims 1 to 22 for use in the treatment, control or prevention of a parasitic infection or infestation in a non-human animal.

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