Parasite repellent aza-benzothiophene and aza-benzofuran compounds

Abstract

The present invention provides for parasite repellent aza-benzothiophene and aza-benzofuran compounds. The present invention provides compounds of formula: # imgabs0 # wherein the variables are as defined herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, compositions comprising these compounds, and methods of treating, controlling, or preventing parasite attack or infection in an animal in need thereof by administering to the animal an effective amount of these compounds.

Description

[0001] This application is a divisional application of the parent case, Chinese invention patent application 202080033529.7. Field of the Invention

[0002] The present patent application relates to novel antiparasitic compounds, compositions containing the compounds, methods for preparing the compounds, and methods for controlling parasites that harm animals using the compounds.

[0003] Cross-reference to related applications

[0004] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 820,352, filed on March 19, 2019, which is incorporated herein by reference in its entirety. Background of the Invention

[0006] Animals such as mammals and birds are often susceptible to parasites. These parasites can be external parasites such as fleas and ticks. Animals and humans also suffer from endoparasitic infections including, for example, helminthiasis, which is most frequently caused by a class of parasites described as nematodes or worms. These parasites cause serious economic losses in pigs, sheep, horses and cattle and affect companion animals (such as cats and dogs) and poultry. Other parasites include those present in the gastrointestinal tract of animals and humans, such as Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius. Other parasites present in the blood or other tissues and organs include filarial worms and the extraintestinal stages of Strongyloides and Trichinella.

[0007] A class of endoparasites that seriously harm mammals is Dirofilaria immitis, also known as Dirofilaria immitis. Other filarial endoparasites 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. Dirofilaria immitis goes through several life stages, and then they become adults, infecting the pulmonary arteries of host mammals. The worms need mosquitoes as intermediate hosts to complete their life cycle. The time period between the initial infection of dogs bitten by mosquitoes and the maturation of worms into adults living in the heart and pulmonary arteries is 6 to 7 months in dogs, and is called "prepatent period". L3 larvae migrate to the mosquito mouthparts (lower lip) during mosquito blood feeding, leave the mosquito and settle on the dog skin, and then they migrate into the host by the bite wound here. Most L3 larvae molt into four instar larvae (L4) in the dog subcutaneous tissue in 1-3 days after infection. Then, they migrate to the chest and abdominal muscles, and molt into five instars (L5, immature adults) in 45 to 60 days after infection. After infection, 75 to 120 days, these immature heartworms then enter the bloodstream and are carried through the heart and reside in the pulmonary artery. About 7 months after infection, the adult heartworm (Dirofilaria immitis) reaches maturity and is sexually propagated in the pulmonary artery and right ventricle. Male adults are about 15cm long and females are about 25cm long, and their normal life span as adults is calculated to be about 5 years.

[0008] Heartworm infection is a serious and life-threatening disease. Heartworm infection is preventable and preventive treatment is a priority in areas where heartworm is prevalent. Treatment of adult heartworm infection with adulticides (e.g., melarsomine dihydrochloride) is costly and can cause serious adverse side effects, so prevention is widely used by interrupting larval development with monthly medication. The purpose of canine heartworm preventive therapy on the market is to prevent the parasite from developing into adult heartworms by interrupting the life cycle of heartworms (Dirofilaria immitis) after infection.

[0009] Macrolides (MLs such as ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemopreventive agents and are given at monthly or six-month intervals. These drugs have been effective against the infective third-stage larvae (L3) and maturing fourth-stage larvae (L4) of Dirofilaria immitis attached to mosquitoes. When given monthly, MLs kill L3 and L4 larvae obtained in the first 30 days, thereby preventing diseases caused by adult worms. MLs can also be used monthly in infected dogs to inhibit adult worm reproduction and remove microfilariae, thereby reducing transmission and gradually causing adult worm loss (Vet. Parasitol. 2005 Oct 24 133 (2-3) 197-206).

[0010] In recent years, an increasing number of cases of lack of efficacy (LOE) have been reported, in which dogs develop adult Dirofilaria infections despite receiving monthly preventive doses of macrolide drugs. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) recently reported an increasing number of cases in which dogs tested positive for Dirofilaria antigen despite receiving Dirofilaria preventives; this means that certain populations of Dirofilaria have developed selective resistance to Dirofilaria preventives (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5.). Thus, there is a continuing need to develop new anthelmintics with improved activity against Dirofilaria immitis and other endoparasites.

[0011] WO 2017 / 178416 A1 provides pyrazolopyrimidine derivatives for controlling, treating and / or preventing helminths. WO 2018 / 197401 A1 provides bicyclic pyrazole derivatives for controlling, treating and / or preventing helminths. WO 2018 / 087036 A1 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 A1 provides azaquinone derivatives for controlling, treating and / or preventing helminths. All of these disclosures belong to Bayer Animal Health GmbH and are incorporated herein by reference in their entirety.

[0012] More recently WO 2020 / 014068 A1 (incorporated herein by reference) describes anthelmintic heterocyclic compounds which were found to be active against Dirofilaria immitis.

[0013] It should be noted that the citation or identification of any document in this application is not an admission that the document is prior art to this specification. Any of the aforementioned applications and all documents cited therein or during the prosecution of the application thereof ("application cited documents") and all documents cited or referenced by the application cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced by the cited documents herein, and any manufacturer's guides, instructions, product instructions, and product information sheets for any products mentioned herein or in any document incorporated herein by reference, are hereby incorporated by reference and may be used in the practice of this specification. SUMMARY OF THE INVENTION

[0014] The present application provides novel anthelmintic and antiparasitic heterocyclic compounds having improved activity against endoparasites and ectoparasites. The present application also relates to compositions comprising 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.

[0015] One aspect of the present invention includes compounds of formula (I):

[0016]

[0017] Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, wherein the 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’ and q are as defined herein, and the dashed bond Indicates a single bond or a double bond.

[0018] The present invention also includes veterinary acceptable compositions comprising a compound of formula (I) and a veterinary acceptable carrier; and methods for controlling parasites including helminths, comprising administering a compound or a veterinary acceptable composition thereof to an animal in need. Embodiments of the present invention also include the use of a compound of formula (I) for eradicating, controlling and preventing parasitic invasion and / or infection in animals. The compounds of the present invention can be administered to animals, particularly mammals, fish and birds, to prevent or treat parasitic infections.

[0019] The compounds and compositions containing the compounds are highly effective in treating and preventing endoparasites in mammals, fish and birds and especially cats, dogs, horses, chickens, pigs, sheep and cattle with the goal of substantially eliminating endoparasites from these hosts.

[0020] In an embodiment, the compound of formula (I) and the composition comprising the compound are substantially effective against endoparasites, such as filarial worms (e.g., heartworms), hookworms, whipworms, and roundworms of the digestive tract of animals and humans. In certain embodiments, the compound of formula (I) and the composition comprising the compound are effective against heartworm isolates that are insensitive to treatment with macrolides. In another embodiment, the compounds and compositions of the present invention are effective in treating and preventing animals from infecting nematodes that are less sensitive to treatment with commercially available or known activating agents.

[0021] In an embodiment, the present description encompasses combinations of a compound of formula (I) with at least a second active agent, which can broaden the scope of protection provided to an animal against endoparasites and / or ectoparasites.

[0022] Another embodiment includes a method of treating and / or preventing parasitic infections and / or infestations in animals, comprising 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 parasitic infections and / or infestations in animals and the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing parasitic infections in animals.

[0023] Thus, the present invention includes the following non-limiting embodiments:

[0024] (a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, which is active against endoparasiticides and in some cases also against ectoparasites;

[0025] (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;

[0026] (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 covered by formula (I)) and a pharmaceutically or veterinarily acceptable carrier or diluent;

[0027] (d) a method for treating 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, and optionally one or more additional active agents (i.e., active ingredients not covered by formula (I));

[0028] (e) a method for preventing parasitic infestation / infection in animals, 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, and optionally one or more additional active agents (i.e., active ingredients not covered by formula (I));

[0029] (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 parasitic infestations in animals;

[0030] (g) use of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof for the preparation of a veterinary medicament for the treatment or prevention of parasitic infections in animals; and

[0031] (h) A process for preparing a compound of formula (I).

[0032] Therefore, the present invention is not intended to cover any previously known product, process for preparing a product, or method for using a product in the present invention, and the applicant reserves the right and discloses here the abandonment of any previously known product, process, or method. It should also be noted that the present invention does not tend to cover within the scope of the present invention any product, method, or preparation of a product or method for using a product that does not meet the written description and implementation requirements of the USPTO (35 U.SC § 112, first paragraph) or the EPO (EPC Article 83), so the applicant reserves the right and discloses here the abandonment of any of the above products, methods, or preparations of products or methods for using products. It may be advantageous to follow Art.53 (c) EPC and Rule 28 (b) and (c) EPC in the practice of the present invention. What is expressly reserved is the full right to explicitly exclude any implementation method, which is the subject of any third-party application filed in any of the granted patents in the present application series or in any other series or in any prior application by the applicant. The content of this article is not interpreted as a stipulation.

[0033] The term "compound of formula (I)" includes any stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

[0034] These and other embodiments are disclosed or illustrated by and are encompassed by the following detailed description.

[0035] definition:

[0036] It should be noted that in this disclosure and especially in the claims and / or each paragraph, terms such as "comprising", "including", "containing", etc. may have the meaning assigned to them by U.S. patent law; for example, they may mean "including", "containing", "including", etc.; and terms such as "essentially consisting of..." and "essentially composed of..." have the meaning assigned to them by U.S. patent law, for example, they allow the inclusion of elements not explicitly stated, but exclude elements existing in the prior art or affecting the basic or new features of the invention.

[0037] The terms used herein have their conventional meanings in the art unless otherwise specified. The organic moieties mentioned in the definitions of the variables of compounds such as the compounds of formula (I) are collective terms like the term halogen, i.e. for individual listings of the individual group members (fluorine, chlorine, bromine and iodine in the case of halogen). The prefix C n -C m The possible number of carbon atoms in the radical is indicated in each case from an integer n to another integer m.

[0038] In this description and claims the term "including but not limited to" is equivalent to "comprising".

[0039] The term "optionally substituted" means that the residue is optionally substituted with one or more of the following moieties: halogen, hydroxy, carboxyl, acyl, acyloxy, amino, alkylamino or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acyl halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, aryl and heteroaryl, or any other possible functional groups (unprotected or optionally protected) known to those skilled in the art that do not inhibit the biological activity of the compounds of the present description, for example the teachings of Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, which are incorporated herein by reference. For the avoidance of doubt, "optionally substituted alkyl" includes haloalkyl.

[0040] Unless otherwise indicated, "alkyl" alone or in combination with heteroatoms such as alkoxy, thioalkyl, alkylamino, etc., means a saturated straight chain, branched, primary, secondary or tertiary hydrocarbon, including those having 1 to 12 atoms. In certain embodiments, alkyl includes C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl. 10 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C1-C4-alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[0041] Cyclic alkyl groups may be referred to as "cycloalkyl" and include those having single or multiple fused rings having 3 to 10 carbon atoms. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0042] Carbocyclic groups are cyclic groups consisting only of carbon. Carbocyclic groups include aromatic rings such as phenyl and non-aromatic rings such as cycloalkyl rings, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and include those with 3 to 14 carbon atoms of single or multiple condensed rings.

[0043] The term "alkenyl" refers to straight and branched carbon chains having at least one carbon-carbon double bond. In certain embodiments, alkenyl may include C2-C 12 In other embodiments, alkenyl includes C2-C 10, C2-C8, C2-C6, C2-C4 or C3-C4 alkenyl. In one embodiment of alkenyl, the number of double bonds is 1-3; in another embodiment of alkenyl, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the position of the alkenyl moiety on the molecule. An "alkenyl" group can include 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-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.

[0044] "Alkynyl" refers to straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of the alkynyl group, the number of triple bonds is 1-3; in another embodiment of the alkynyl group, the number of triple bonds is 1. In certain embodiments, the alkynyl group includes 2 to 12 carbon atoms. In other embodiments, the alkynyl group may include C2-C 10 , C2-C8, C2-C6 or C2-C4 alkynyl. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated, depending on the position of the alkynyl moiety on the molecule. For example, the term "C2-C 10 “-Alkynyl” as used herein refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl, and the like.

[0045] The term "haloalkyl" refers to an alkyl group as defined herein, which is substituted with 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 group in which one or more hydrogen atoms are replaced with fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

[0046] The term "haloalkenyl" refers to an alkenyl group as defined herein, substituted with one or more halogen atoms.

[0047] The term "haloalkynyl" refers to an alkynyl group as defined herein, substituted by one or more halogen atoms.

[0048] The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkyloxy", "cycloalkenyloxy", "halocycloalkyloxy", 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, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6-alkoxy groups 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-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 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, etc.

[0049] The term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic or multiple condensed rings. Aryl includes, but is not limited to, phenyl, biphenyl and naphthyl. In certain embodiments, aryl includes tetrahydronaphthyl, phenylcyclopropyl and indanyl. Aryl can be unsubstituted or substituted with one or more moieties selected from the following: halogen, cyano, nitro, hydroxyl, sulfhydryl, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkyloxy, cycloalkenyloxy, halocycloalkyloxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cyclo Alkylthio, halocycloalkylthio, 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.

[0050] The term "aralkyl" refers to a group consisting of a divalent alkylene bridge (-CH2-) n An aryl group bonded to a parent compound, wherein n is 1-12 and wherein "aryl" is as defined above.

[0051] The term "heteroaryl" refers to a monovalent aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, having oxygen, nitrogen and sulfur heteroatoms in one or more rings, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. Nitrogen and sulfur heteroatoms may be optionally oxidized. Heteroaryl generally includes 5- or 6-membered aromatic rings. The heteroaryl can have a monocyclic ring (e.g., pyridyl or furyl) or multiple condensed rings, provided that the point of attachment is via a heteroaryl ring atom. Examples of heteroaryl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, furanyl, thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothienyl, imidazopyridinyl, imidazopyrimidinyl, or pyrrolopyrimidinyl. Heteroaryl rings can be unsubstituted or substituted with one or more moieties as described above for aryl.

[0052] The term "heterocyclyl", "heterocycle" or "heterocyclic ring" refers to a fully saturated or unsaturated cyclic group, such as a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 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 in the ring. The nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more of the moieties described above for aryl.

[0053] 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, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepine Base, Aza 4-piperidinone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, triazolyl, triazinyl, etc.

[0054] Exemplary bicyclic heterocyclyls include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothiophenyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl] or furano[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.

[0055] Bicyclic and tricyclic carbocyclic or heterocyclic systems include spirocyclic systems, wherein at least two of the system rings are connected by a single carbon atom. Spirocyclic ring systems include combinations of 3- to 8-membered carbocyclic and / or heterocyclic systems connected at a shared carbon atom. Thus, spirocyclic ring systems can include 3-membered rings bonded to another 3-membered ring (carbocyclic or heterocyclic) up to 8-membered rings bonded to another 8-membered ring and all combinations of different ring sizes therebetween. The heterocyclic ring components of the spirocyclic ring system include one or two heteroatoms selected from N, O or S.

[0056] The term "alkylthio" refers to alkyl-S-, wherein "alkyl" is as defined above. In certain embodiments, the alkyl portion of the alkylthio group comprises C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl. 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.

[0057] Similarly, the terms "haloalkylthio," "cycloalkylthio," and "halocycloalkylthio" refer to the groups -S-haloalkyl, -S-cycloalkyl, and -S-halocycloalkyl, respectively, wherein the terms "haloalkyl," "cycloalkyl," and "halocycloalkyl" are as defined above.

[0058] The term "alkylsulfinyl" refers to the group alkyl-S(=O)-, wherein "alkyl" is as defined above. In certain embodiments, the alkyl portion of the alkylsulfinyl group includes C1-C 12 , C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl. Examples include, but are not limited to, -SO-CH3, -SO-C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl , 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

[0059] Similarly, the terms "alkenylsulfinyl," "alkynylsulfinyl," "haloalkylsulfinyl," "haloalkenylsulfinyl," and "haloalkynylsulfinyl" refer to the groups alkenyl-S(═O)—, alkynyl-S(═O)—, and haloalkyl-S(═O)—, haloalkenyl-S(═O)— and haloalkynyl-S(═O)—, wherein the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are as defined above.

[0060] The term "alkylsulfonyl" refers to the group alkyl-S(=O)2-, wherein the term "alkyl" is as defined above. In certain embodiments, the alkyl portion of the alkylsulfonyl group includes C1-C 12 , C1-C 10 , C1-C8, C1-C6 or C1-C4 alkyl. 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. acyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl and the like.

[0061] 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-, wherein the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are as defined above.

[0062] 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) wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined above. In certain embodiments, the alkyl portion of the alkylamino or dialkylamino group includes C1-C 12 , C1-C 10 , C1-C8, C1-C6 or C1-C4 alkyl.

[0063] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, wherein alkyl, alkoxy, alkylamino and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl", and "dihaloalkylaminocarbonyl" refer to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)-, wherein haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above. DETAILED DESCRIPTION OF THE INVENTION

[0065] Embodiments of the present invention include compounds of formula (I):

[0066]

[0067] in:

[0068] L is L1 or L2:

[0069]

[0070] R 1 is hydrogen, cyano, halo, hydroxy, 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 Where R a and R b is independently H or optionally substituted alkyl; or Ra and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0071] R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;

[0072] R 2’ is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;

[0073] 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, spirocyclic heterocyclyl-heterocyclyl, spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl or -NR a R b Where R a and R b is independently H or optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0074] R 4 Each specific value of is independently hydrogen, cyano, hydrogen, halo, hydroxy, 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 Where R a and R b is independently H or optionally substituted alkyl; or R a and Rb may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted

[0075] R 5 and R 5’ Each specific value of is independently hydrogen, halogen, cyano, nitro, hydroxy, 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 Where R c and R d is independently H or optionally substituted alkyl; or R c and R d may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0076] R 10 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl;

[0077] X is O or S;

[0078] Q is O, S or NR 2’ ;

[0079] Y 1 , Y 2 and Y 3 Each independently is N or -CR 4 -;

[0080] Y 1’ and Y 6’ Each independently is N, C, or -CR 5 -;

[0081] Y 2’ , Y 3’ , Y 4’ and Y 5’ Each independently is N, NR 2 ,S,O,-CR 5 - or CR 5 R 5’ ;

[0082] W is CR 6 R 7 , O, S, or NR 8 ,

[0083] Z is CR 6 R 7 , O, S, or NR 8 ,

[0084] in

[0085] R 6 and R 7 Each specific value of is independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy;

[0086] R 8 is hydrogen or C1-C4-alkyl; and

[0087] where Y 1’ , Y 2’ , Y 3’ , Y 4’ , Y 5’ and Y 6’ At most 3 of them are heteroatoms;

[0088] a is 0 or 1;

[0089] q is 0 or 1;

[0090] Each specific value of p is independently 0, 1 or 2; and

[0091] Dotted key represents a single or double bond;

[0092] Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts.

[0093] In another embodiment, the present invention provides a compound of formula (I)

[0094] in:

[0095] R 1is hydrogen, cyano, halo, hydroxy, 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- C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF5, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), or -NR a R b Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0096] R 2 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted phenyl;

[0097] R 2’ is C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, or optionally substituted phenyl;

[0098] R 3is 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 N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0099] R 4 Each specific value of is independently hydrogen, cyano, halo, hydroxy, 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 substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from 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 Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0100] R 5 and R 5’ Each specific value of is independently hydrogen, halogen, cyano, nitro, hydroxy, 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 Where R c and R d are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R c and R d may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0101] R 10 is hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C2-C6-alkenyl or C2-C6-alkynyl; and

[0102] 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 dotted bonds As defined above for compounds of formula (I).

[0103] In one embodiment, L is L1. In another embodiment, L is L2. In certain embodiments:

[0104] 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 Where R a and R b is independently optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0105] R 2 is hydrogen or C1-C4-alkyl;

[0106] 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 optionally substituted with 1, 2 or 3 substituents;

[0107] Each R 4 is independently 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 Where R c and R d is independently optionally substituted C1-C4-alkyl; or R a and Rb can form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic radical which may be optionally substituted, SO p (optionally substituted C1-C4-alkyl or haloalkyl);

[0108] Each R 5 is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, -amino, NH-optionally substituted C1-C4-alkyl, -SF5, or -NR c R d Where R c and R d is independently optionally substituted C1-C4-alkyl; or R c and R d can form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic radical which may be optionally substituted, SO p (optionally substituted C1-C4-alkyl or haloalkyl);

[0109] In certain embodiments, R 1 It's hydrogen.

[0110] In certain embodiments, R 1 is C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4-alkyl)amino.

[0111] In another embodiment, R 1 It's a halogen.

[0112] In another embodiment, R 1 It is C1-C4-alkyl-SO p -, C1-C4-haloalkyl-SO p -or-SF5.

[0113] In other embodiments, R 1 It is hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkoxy-C1-C4-alkyl or C1-C4-haloalkoxy-C1-C4-haloalkyl.

[0114] In another embodiment, R 1 It is methyl, ethyl, propyl, butyl, pentyl, isopropyl (iso-Pr), tert-butyl (tert-butyl), prop-1-en-2-yl, 2-fluoroprop-2-yl or 2-hydroxyprop-2-yl.

[0115] In another embodiment, R1 It is CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0116] In certain embodiments, R 1 is C2-C4-alkenyl or C2-C4-haloalkenyl. In certain embodiments, R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0117] In certain embodiments, R 1 is an optionally substituted saturated or unsaturated 6-membered heterocyclic group.

[0118] In one embodiment, R 1 Yes - NR a R b Where R a and R b is independently hydrogen or C1-C6 alkyl. 1 Yes - NR a R b Where R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0119] In another embodiment, R 1 It 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.

[0120] In certain embodiments, R 1 is optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0121] In certain embodiments, R 1 is optionally substituted phenyl.

[0122] In certain embodiments, R 1is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepine Base, Aza 4-Hydroxy-1,4-dopoxy-1,4-dopoxy-2 ...2,4-dopoxy-1,4-dopoxy-2,4-dopoxy-2,4-dopoxy-1,4-dopoxy-2,4-dopoxy-2,4-dopoxy-2,4-dop

[0123] In certain embodiments, R 1 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens.

[0124] In certain embodiments, R 3 is a 6- or 10-membered aryl group, optionally substituted with 1, 2, 3, 4 or 5 substituents.

[0125] In certain embodiments, R 3 It is C1-C4-alkyl or C1-C4-haloalkyl.

[0126] In certain embodiments, R 3 is methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl, sec-butyl or isobutyl.

[0127] In other embodiments, R 3 It is CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0128] In certain embodiments, R 3 is an optionally substituted C3-C8-cycloalkyl. 3 is an optionally substituted C3-C6-cycloalkyl. 3 is an optionally substituted C3-C8-cycloalkenyl or C3-C6-cycloalkenyl. 3 is optionally substituted cyclopentyl or cyclohexyl.

[0129] In one embodiment, R 3is a cyclohexyl group optionally substituted with one or more halo, C1-C3-alkyl or C1-C3-haloalkyl. 3 It is a cyclohexyl group substituted by 1 or 2 fluorine, chlorine or CF3.

[0130] In certain embodiments, R 3 is an optionally substituted piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl. In certain embodiments, R 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more halo, C1-C6-alkyl or C1-C6-haloalkyl. In another embodiment, R 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more methyl, chlorine or fluorine.

[0131] In certain embodiments, R 3 is a 5- to 10-membered heteroaryl group optionally substituted with 1, 2, 3, 4 or 5 substituents. In one embodiment, the 5- to 10-membered heteroaryl group is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, furanyl, thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolylbenzofuranyl, benzothienyl, imidazopyridinyl, imidazopyrimidinyl or pyrrolopyrimidinyl.

[0132] In other embodiments, R 3 is an optionally substituted spirocyclic heterocyclyl-carbocyclyl, an optionally substituted spirocyclic heterocyclyl-heterocyclyl, an optionally substituted spirocyclic carbocyclyl-carbocyclyl or an optionally substituted spirocyclic carbocyclyl-heterocyclyl. In other embodiments, R 3 It is a 5- to 11-member optionally substituted spiro heterocyclic radical-carbocyclic radical, a 5- to 11-member optionally substituted spiro heterocyclic radical-heterocyclic radical, a 5- to 11-member optionally substituted spiro carbocyclic radical-carbocyclic radical or a 5- to 11-member optionally substituted spiro carbocyclic radical-heterocyclic radical. The non-limiting examples of spiro carbocyclic radical-carbocyclic radical, spiro carbocyclic radical-heterocyclic radical and spiro heterocyclic radical-heterocyclic radical are shown below for example.

[0133]

[0134] However, it is obvious to those skilled in the art that the second ring of the spirocyclic group can be connected at any feasible carbon of the first ring. It should also be understood that the first ring of the spirocyclic group can be bonded to the molecule at any feasible atom. Thus, the present invention includes 3-, 4-, 5-, 6- and 7-membered carbocyclic or heterocyclic rings as defined herein, which are connected to a second 3-, 4-, 5-, 6- and 7-membered carbocyclic or heterocyclic ring at any feasible carbon atom of the first ring.

[0135] In certain embodiments, R 3 is phenyl substituted with 1 to 4 substituents. In another embodiment, R 3 is phenyl substituted with 1 to 3 substituents. In another embodiment, R 3 is phenyl substituted with 1 or 2 substituents. 3 is phenyl substituted with 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.

[0136] In certain embodiments, R 3 It is a para-substituted phenyl group.

[0137] In certain embodiments, R 3 It is a meta-substituted phenyl group.

[0138] In certain embodiments, R 3 It is an ortho-substituted phenyl group.

[0139] In certain embodiments, R 3 is a halogenated phenyl group. 3 It is a halogenated alkylphenyl group.

[0140] In certain embodiments, R 3 It is a halogenated alkoxyphenyl group.

[0141] In certain embodiments, R 3 is phenyl substituted with 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.

[0142] In certain embodiments, R 3 It is a 2,3-disubstituted phenyl group.

[0143] In certain embodiments, R 3 It is a 2,4-disubstituted phenyl group.

[0144] In certain embodiments, R 3 It is a 2,5-disubstituted phenyl group.

[0145] In certain embodiments, R 3It is a 2-,6-disubstituted phenyl group.

[0146] In certain embodiments, R 3 It is a 3-,5-disubstituted phenyl group.

[0147] In other embodiments, R 3 It is a 3-, 4-disubstituted phenyl group.

[0148] In other embodiments, R 3 It is a 3-,6-disubstituted phenyl group.

[0149] In certain embodiments, R 3 is a dihalophenyl group, for example, dichlorophenyl; difluorophenyl; or chlorofluorophenyl.

[0150] In certain embodiments, R 3 It is a 2,3-dihalogenophenyl group.

[0151] In certain embodiments, R 3 In another embodiment, R 3 In another embodiment, R 3 In another embodiment, R 3 In another embodiment, R 3 In another embodiment, R 3 is 3,5-difluorophenyl. In another embodiment, R 3 is 2,6-dichlorophenyl. In another embodiment, R 3 It is 2,6-difluorophenyl.

[0152] In certain embodiments, R 3 It is phenyl substituted with halo and haloalkyl.

[0153] In certain embodiments, R 3 It is phenyl substituted with halo and haloalkoxy.

[0154] In certain embodiments, R 3 It is phenyl substituted with haloalkyl and haloalkoxy.

[0155] In certain embodiments, R 3 is phenyl substituted with 3 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.

[0156] In certain embodiments, R3 is a trihalophenyl group, for example, trichlorophenyl; trifluorophenyl; or chlorochlorofluorophenyl, or fluorofluorochlorophenyl.

[0157] In certain embodiments, R 3 It is phenyl substituted with 2 halo and haloalkyl.

[0158] In certain embodiments, R 3 It is phenyl substituted with 2 halo and haloalkoxy groups.

[0159] In certain embodiments, R 3 It is phenyl substituted with 1 haloalkyl, 1 halo and 1 haloalkoxy.

[0160] In certain embodiments, R 3 It is phenyl substituted with 1 halo and 2 haloalkyl groups.

[0161] In certain embodiments, R 3 is a 5-membered heteroaryl optionally substituted with 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.

[0162] In certain embodiments, R 3 is a 6-membered heteroaryl optionally substituted with 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.

[0163] In certain embodiments, R 3 is 2-pyridyl optionally substituted with 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.

[0164] In certain embodiments, R 3 is 3-pyridyl optionally substituted with 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.

[0165] In certain embodiments, R 3 is 4-pyridinyl optionally substituted with 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.

[0166] In another embodiment, R 3 is 4-pyridyl, which is unsubstituted or substituted with 1 or 2 chloro or fluoro groups. In another embodiment R 3 is 3-pyridyl which is unsubstituted or substituted with 1 or 2 chloro or fluoro groups.

[0167] In other embodiments, R 3 is an optionally substituted 3- to 7-membered heterocyclic ring. 3 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepine Base, Aza 4-piperidinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiosulfoxidemorpholinyl, thiosulfoxidemorpholinyl, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, triazolyl or triazinyl.

[0168] In another embodiment, R 3 It may be a heterocyclic, bridged bicyclic group, which may be optionally substituted.

[0169] In certain embodiments, each R 4 are independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4-alkyl)amino.

[0170] In another embodiment, each R 4 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0171] In another embodiment, each R 4is independently hydrogen, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0172] In certain embodiments, R 4 It's hydrogen.

[0173] In certain embodiments, R 4 It's a halogen.

[0174] In another embodiment, R 4 It is fluorine or chlorine.

[0175] 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.

[0176] In yet another embodiment, R4 is methoxy, ethoxy, propoxy or butoxy.

[0177] In yet another embodiment, R4 is methylthio, ethylthio, propylthio or butylthio.

[0178] In yet another embodiment, R4 is -OCF3 or -SCF3.

[0179] In certain embodiments, R 4 It is C1-C4-alkenyl or C1-C4-haloalkenyl.

[0180] In certain embodiments, R 4 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0181] In certain embodiments, R 4 is an optionally substituted saturated or unsaturated 6-membered heterocyclic group.

[0182] In certain embodiments, R 4 is optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0183] In certain embodiments, R 4 is optionally substituted phenyl.

[0184] In other embodiments, R 4is phenyl substituted with 1, 2 or 3 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

[0185] In other embodiments, R 4 is a 5-membered or 6-membered heteroaryl substituted with 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.

[0186] In certain embodiments, R 4 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepine Base, Aza 4-piperidinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiosulfoxidemorpholinyl, thiosulfoxidemorpholinyl, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, triazolyl or triazinyl.

[0187] In certain embodiments, R 4 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens.

[0188] In certain embodiments, R 5 It's hydrogen.

[0189] In certain embodiments, each R 5 are independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4-alkyl)amino.

[0190] In another embodiment, each R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0191] In another embodiment, R 5 It is CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0192] In certain embodiments, R 5 It's a halogen.

[0193] In another embodiment, R 5 It is fluorine or chlorine.

[0194] In another embodiment, R 5 is C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) wherein p is 0, 1 or 2.

[0195] In yet another embodiment, R5 is methoxy, ethoxy, propoxy or butoxy.

[0196] In yet another embodiment, R5 is methylthio, ethylthio, propylthio or butylthio.

[0197] In yet another embodiment, R5 is -OCF3 or -SCF3.

[0198] In certain embodiments, R 5 is C1-C4-alkenyl or C1-C4-haloalkenyl

[0199] In certain embodiments, R 5 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0200] In certain embodiments, R 5 is optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0201] In certain embodiments, R 5 is optionally substituted phenyl.

[0202] 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, cycloalkyloxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

[0203] In other embodiments, R 5is a 5-membered or 6-membered heteroaryl substituted with 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.

[0204] In certain embodiments, R 5 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepine Base, Aza 4-piperidinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiosulfoxidemorpholinyl, thiosulfoxidemorpholinyl, 1,3-dioxolane and tetrahydro-1,1-dioxothiphenyl, triazolyl or triazinyl.

[0205] In certain embodiments, R 5 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens.

[0206] In some embodiments, it is 0.

[0207] In some embodiments, it is 1.

[0208] In certain embodiments, X is O.

[0209] In certain embodiments, X is S.

[0210] In certain embodiments, Q is O.

[0211] In certain embodiments, Q is S.

[0212] In certain embodiments, Q is NR 2’ .

[0213] In certain embodiments, W is CH2

[0214] In certain embodiments, Z is CH2.

[0215] In certain embodiments, Z is O.

[0216] In certain embodiments, Z is S.

[0217] In certain embodiments, Z is NH.

[0218] In certain embodiments, the compound of formula (I) is a compound of formula (I-1):

[0219]

[0220] 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 are as defined for formula (I).

[0221] In certain embodiments, the compound of formula (I) is a compound of formula (I-2):

[0222]

[0223] The 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 are as defined for formula (I).

[0224] In other embodiments, the compound of formula (I) is a compound of formula (I-3):

[0225]

[0226] The 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 are as defined for formula (I).

[0227] In other embodiments, the compound of formula (I) is a compound of formula (I-4):

[0228]

[0229] The 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 are as defined for formula (I).

[0230] In another embodiment, the compound of formula (I) is a compound of formula (I-5):

[0231]

[0232] The 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 are as defined for formula (I).

[0233] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

[0234]

[0235] The 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 are as defined for formula (I).

[0236] In certain embodiments, the compound of formula (I) is a compound of formula (Ib):

[0237]

[0238] The variable Y 1 , Y 2 , Y 3 , R 1 , R 2 , R 3 , R 5 , W, Z, R 10 and a are as defined for formula (I), and o is 0, 1, 2, 3 or 4.

[0239] In certain embodiments, the compound of formula (I) is a compound of formula (Ic):

[0240]

[0241] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2, 3 or 4.

[0242] In other embodiments, the compound of formula (I) is a compound of formula (Id):

[0243]

[0244] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2, 3 or 4.

[0245] In certain embodiments, the compound of formula (I) is a compound of formula (Ie):

[0246]

[0247] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

[0248] In certain embodiments, the compound of formula (I) is a compound of formula (If):

[0249]

[0250] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

[0251] In certain embodiments, the compound of formula (I) is a compound of formula (Ig):

[0252]

[0253] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2, 3 or 4.

[0254] In other embodiments, the compound of formula (I) is a compound of formula (Ih):

[0255]

[0256] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

[0257] In certain embodiments, the compound of formula (I) is a compound of formula (Ii):

[0258]

[0259] The variable R 1 , R 2 , R 3 , R 4 , R 5 , W, Z, R 10 and a are as defined for formula (I); n is 0, 1, 2 or 3; and o is 0, 1, 2, 3 or 4.

[0260] Those skilled in the art will recognize that in any of Formulas (Ib) to (Ii), in the case of variable R 4 and R 5 Indicated as an aromatic ring substituent (e.g. as (R4 ) n and (R 5 ) o Where groups (where n is 0, 1, 2 or 3 and o is 0, 1, 2, 3 or 4) are present, they will represent non-hydrogen substituents, since in the embodiment where n and o are 0, R 4 and R 5 will not exist.

[0261] In other embodiments, the present invention includes compounds of formula (I) having the structures of formula (Ia) to (Ii) shown above, but wherein the sulfur atom corresponding to the variable X of 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'), which correspond to formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) and (Ii) but wherein the sulfur atom of formula (Ia) to (Ii) corresponding to the variable X of formula (I) is replaced with an oxygen.

[0262] In other embodiments, the present invention provides compounds of formula (IA), wherein the variable R 1 , R 2 , R 3 , R 4 , R 5 , X, W, Z, R 10 and a are as defined above for formula (I), and Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’ As shown in Table 1:

[0263]

[0264] Table 1

[0265]

[0266]

[0267] In certain embodiments, the present invention provides compounds of Formulae IA-1 to IA-56 wherein X is S.

[0268] In certain embodiments, the present invention provides compounds of Formulae IA-1 to IA-56 wherein X is O.

[0269] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 4are 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).

[0270] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 4 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0271] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 4 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0272] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0273] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 4 are independently H, -OCF3 or -SCF3.

[0274] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 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).

[0275] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 5 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0276] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 5 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0277] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 5 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0278] In certain embodiments, the present invention provides compounds of Formula IA-1 to IA-56 wherein each R 5 are independently H, -OCF3 or -SCF3.

[0279] In other embodiments, the present invention provides compounds of formula IA-1 to IA-56, wherein R 2 and R 10 is independently H or C1-C3-alkyl.

[0280] In other embodiments, the present invention provides compounds of Formulae IA-1 to IA-56 wherein a is 1, W is CH2 and Z is O.

[0281] In other embodiments, the present invention provides compounds of formula IA-1 to IA-56, wherein 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 Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0282] In other embodiments, the present invention provides compounds of formula IA-1 to IA-56, wherein 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 N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R bTogether with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0283] In other embodiments, the present invention provides compounds of formula IA-1 to IA-56, wherein X is S, R 2 and R 10 are independently H or C1-C3-alkyl; W is CH2, Z is O and a is 1.

[0284] In other embodiments, the present invention provides compounds of formula IA-1 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0285] In other embodiments, the present invention provides compounds of formula IA-1 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0286] In other embodiments, the present invention provides compounds of formula IA-9 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0287] In other embodiments, the present invention provides compounds of formula IA-9 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0288] In other embodiments, the present invention provides compounds of formula IA-17 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0289] In other embodiments, the present invention provides compounds of formula IA-17 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0290] In other embodiments, the present invention provides compounds of formula IA-25 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0291] In other embodiments, the present invention provides compounds of formula IA-25 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0292] In other embodiments, the present invention provides compounds of formula IA-49 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0293] In other embodiments, the present invention provides compounds of formula IA-49 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R 5 are independently H or halo; and R 2 is H or C1-C3-alkyl.

[0294] In other embodiments, the present invention provides compounds of formula (IB) as shown below, wherein the variable R 1 , R 2 , R 4 , R 5 , X, W, Z, R 10 and a is as defined above for formula (I);

[0295] Each R 9 is cyano, halo, hydroxy, 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 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 Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted;

[0296] m is 0, 1, 2, 3 or 4; and Y1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’ As shown in Table 2:

[0297]

[0298] Table 2

[0299]

[0300]

[0301] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein X is S.

[0302] In certain embodiments, the present invention provides compounds of Formula IB-1 to IB-56 wherein X is O.

[0303] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 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).

[0304] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 4 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0305] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 4 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0306] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0307] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 4 are independently H, -OCF3 or -SCF3.

[0308] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 5are 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).

[0309] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 5 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0310] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 5 is independently H, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0311] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 5 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0312] In certain embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein each R 5 are independently H, -OCF3 or -SCF3.

[0313] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56, wherein R 2 and R 10 is independently H or C1-C3-alkyl.

[0314] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56, wherein 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 Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0315] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56, wherein 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 N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0316] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein a is 1, W is CH2 and Z is O.

[0317] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein R 9 is 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.

[0318] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein R 9 is independently halo and m is 1, 2 or 3.

[0319] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein R 9 is independently fluoro or chloro and m is 1, 2 or 3.

[0320] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein X is S, R 9 are independently halo and m is 1, 2 or 3, R 2 and R 10 are independently H or C1-C3-alkyl; W is CH2, Z is O and a is 1.

[0321] In other embodiments, the present invention provides compounds of formula IB-1 to IB-56 wherein X is S, R 9 are independently chlorine or fluorine and m is 1, 2 or 3, R 2 and R 10 are independently H or C1-C3-alkyl; W is CH2, Z is O and a is 1.

[0322] In other embodiments, the present invention provides compounds of formula IB-1 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0323] In other embodiments, the present invention provides compounds of formula IB-1 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0324] In other embodiments, the present invention provides compounds of formula IB-9 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0325] In other embodiments, the present invention provides compounds of formula IB-9 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0326] In other embodiments, the present invention provides compounds of formula IB-17 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0327] In other embodiments, the present invention provides compounds of formula IB-17 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0328] In other embodiments, the present invention provides compounds of formula IB-25 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0329] In other embodiments, the present invention provides compounds of formula IB-25 above, wherein X is O; R1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0330] In other embodiments, the present invention provides compounds of formula IB-49 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0331] In other embodiments, the present invention provides a compound of formula (I) B-49 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0332] In other embodiments, the present invention provides compounds of formula (IC), wherein 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; and Y 1 , Y 2 and Y 3 As shown in Table 3:

[0333]

[0334] Table 3

[0335] Mode <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 3 ]]> IC-1 <![CDATA[CR 4 ]]> <![CDATA[CR 4 ]]> <![CDATA[CR 4 ]]> IC-2 N <![CDATA[CR 4 ]]> <![CDATA[CR 4 ]]> IC-3 <![CDATA[CR 4 ]]> N <![CDATA[CR 4 ]]> IC-4 <![CDATA[CR 4 ]]> <![CDATA[CR 4 ]]> N IC-5 N N <![CDATA[CR 4 ]]> IC-6 <![CDATA[CR 4 ]]> N N IC-7 N <![CDATA[CR 4 ]]> N

[0336] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein X is S.

[0337] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein X is O.

[0338] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 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).

[0339] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 4 and tert-butyl.

[0340] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 4 are independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3.

[0341] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 4 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0342] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 4 are independently H, -OCF3 or -SCF3.

[0343] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 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.

[0344] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 5 is independently chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; and o is 0, 1, 2 or 3.

[0345] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 5 are independently CF3, -CH2CF3, -CHFCF3 or -CF2CF3; and o is 0, 1, 2 or 3.

[0346] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 5 is independently methoxy, ethoxy, propoxy or butoxy; and o is 0, 1, 2 or 3.

[0347] In certain embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein each R 5 are independently -OCF3 or -SCF3; and o is 0, 1, 2 or 3.

[0348] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7, wherein R 2 is H or C1-C3-alkyl.

[0349] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein 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 Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0350] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein R 3is 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 N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0351] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein R 9 R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

[0352] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein R 9 is independently halo and m is 1, 2 or 3.

[0353] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein R 9 is independently fluoro or chloro and m is 1, 2 or 3.

[0354] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein X is S, R 9 are independently halo and m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl.

[0355] In other embodiments, the present invention provides compounds of formula IC-1 to IC-7 wherein X is S, R 9 are independently chloro or fluoro and m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl.

[0356] In other embodiments, the present invention provides compounds of formula IC-1 above, wherein R 9 R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0357] In other embodiments, the present invention provides compounds of formula IC-2 above, wherein R 9 R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0358] In other embodiments, the present invention provides compounds of formula IC-3 above, wherein R 9 R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0359] In other embodiments, the present invention provides compounds of formula IC-7 above, wherein R 9 R is independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or haloalkoxy, and m is 0, 1, 2 or 3.

[0360] In other embodiments, the present invention provides compounds of formula IC-1 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0361] In other embodiments, the present invention provides compounds of formula IC-1 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0362] In other embodiments, the present invention provides compounds of formula IC-2 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R5 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.

[0363] In other embodiments, the present invention provides compounds of formula IC-2 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; R 5 is halogenated 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.

[0364] In other embodiments, the present invention provides compounds of formula IC-3 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0365] In other embodiments, the present invention provides compounds of formula IC-3 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0366] In other embodiments, the present invention provides compounds of formula IC-7 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0367] In other embodiments, the present invention provides compounds of formula IC-7 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0368] In other embodiments, the present invention provides compounds of formula (ID) wherein 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 are as defined above for Formula IB; b is 0 or 1; the dotted bond is a single bond or a double bond; D is N, C or CR 4 ;D 1 N, O, -CR 4 R 5 ,S(O) p Where p is 0, 1, or 2, or D 1 Yes CR 4 R 5 Where R 4 and R 5 together form a 2- to 5-membered chain optionally with 1 catenary heteroatom to form a spirocyclic group; and Y 1 , Y 2 , Y 3 , Y 2’ , Y 3’ , Y 4’ and Y 5’ As shown in Table 4:

[0369]

[0370] Table 4

[0371]

[0372]

[0373] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein X is S.

[0374] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein X is O.

[0375] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein the dashed bond is a single bond.

[0376] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein the dashed bond is a double bond.

[0377] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is CH, C-halo or N.

[0378] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is C, CH, CF or N.

[0379] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56, wherein D 1 Yes CR 4 R 5 Where R 4 and R 5 Together they form a 2- to 5-membered chain optionally with 1 catenated heteroatom to form a spirocyclic group.

[0380] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D 1 is CH2, independently C-(halo)2, CH(C1-C3-alkyl) or CH(C1-C3-haloalkyl).

[0381] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D 1 is CH2, independently CF2, CH(CH3) or CH(CF3).

[0382] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D 1 is O, S, S(O) or S(O)2.

[0383] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is CH or C-halo; and D 1 It is CH2.

[0384] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is N; and D 1 is CH2, O or S.

[0385] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein the dashed line is a double bond; D is C; and D 1 is CH2, CF2, O or S.

[0386] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is N; and D 1 Yes CR 4 R 5 Where R 4 and R 5 Together they form a 2- to 4-membered chain optionally with 1 catenated oxygen to form a spirocyclic group.

[0387] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is CH; and D 1 Yes CR 4 R 5 Where R 4 and R 5 Together they form a 2- to 4-membered chain optionally with 1 catenated oxygen to form a spirocyclic group.

[0388] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein D is C and the dashed bond represents a double bond; and D 1 Yes CR 4 R 5 Where R 4 and R 5 Together they form a 2- to 4-membered chain optionally with 1 catenated oxygen to form a spirocyclic group.

[0389] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 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).

[0390] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 4and tert-butyl.

[0391] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 4 are independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3.

[0392] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 4 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0393] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 4 are independently H, -OCF3 or -SCF3.

[0394] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 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).

[0395] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 5 and tert-butyl.

[0396] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 5 are independently H, CF3, -CH2CF3, -CHFCF3, -CF2CF3.

[0397] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 5 is independently H, methoxy, ethoxy, propoxy or butoxy.

[0398] In certain embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 5 are independently H, -OCF3 or -SCF3.

[0399] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56, wherein R 2 is H or C1-C3-alkyl.

[0400] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein 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 Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b Together with the nitrogen to which they are attached they may form a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted.

[0401] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 9 are independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, m is 0, 1, 2, or 3, and b is 0 or 1.

[0402] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 9 is independently halo and m is 1, 2 or 3.

[0403] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein R 9 is independently fluoro or chloro and m is 1, 2 or 3.

[0404] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein X is S, R 9 are independently halo and m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl.

[0405] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein X is S, R 9 are independently chloro or fluoro and m is 1, 2 or 3, and R 2 is H or C1-C3-alkyl.

[0406] In other embodiments, the present invention provides compounds of formula ID-1 to ID-56 wherein X is S, R 9are 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.

[0407] In other embodiments, the present invention provides compounds of formula ID-1 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0408] In other embodiments, the present invention provides compounds of formula ID-1 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0409] In other embodiments, the present invention provides compounds of formula ID-9 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0410] In other embodiments, the present invention provides compounds of formula ID-9 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 4 are independently H or halo; each R5 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.

[0411] In other embodiments, the present invention provides compounds of formula ID-17 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0412] In other embodiments, the present invention provides compounds of formula ID-17 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0413] In other embodiments, the present invention provides compounds of formula ID-25 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0414] In other embodiments, the present invention provides compounds of formula ID-25 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R4 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.

[0415] In other embodiments, the present invention provides compounds of formula ID-49 above, wherein X is S; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0416] In other embodiments, the present invention provides compounds of formula ID-49 above, wherein X is O; R 1 is optionally substituted C1-C3-alkyl; R 3 is phenyl optionally substituted by 1 to 3 halo groups; each R 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.

[0417] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ , Y 5’ Each is CH.

[0418] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ One of them is CR 5 Where R 5 is a non-hydrogen substituent.

[0419] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’Two of them are CR 5 Among them, each R 5 are independently non-hydrogen substituents.

[0420] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Three of them are CR 5 Among them, each R 5 are independently non-hydrogen substituents.

[0421] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ All four of them are CR 5 Among them, each R 5 are independently non-hydrogen substituents.

[0422] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Each is CH.

[0423] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One of them is CR 4 Where R 4 is a non-hydrogen substituent.

[0424] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Two of them are CR 4 Among them, each R 4 are independently non-hydrogen substituents.

[0425] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Three of them are CR 4 Among them, each R 4 are independently non-hydrogen substituents.

[0426] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ One of them is C-halogen.

[0427] In any of the embodiments of Table 1, 2 or 4 above, Y2’ , Y 3’ , Y 4’ and Y 5’ Two of them are C-halogens.

[0428] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Three of them are C-halogens.

[0429] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One of them is C-halogen.

[0430] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Two of them are C-halogens.

[0431] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Three of them are C-halogens.

[0432] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ One is C-Cl or CF.

[0433] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Two of them are independently C—Cl or CF.

[0434] In any of the embodiments of Table 1, 2 or 4 above, Y 2’ , Y 3’ , Y 4’ and Y 5’ Three of them are independently C-Cl or CF.

[0435] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 One is C-Cl or CF.

[0436] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y3 Two of them are independently C—Cl or CF.

[0437] In any of the embodiments of Tables 1 to 4 above, Y 1 , Y 2 and Y 3 Three of them are independently C-Cl or CF.

[0438] In any of the embodiments of Tables 1, 2 or 4 above, a is 1, W is -CH2-, and Z is O.

[0439] In any of the embodiments of Tables 1 to 4 above, R 1 is C1-C4-alkyl, C1-C4-alkenyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl.

[0440] In any of the embodiments of Tables 1 to 4 above, 1, 2 or 3 R 4 It's hydrogen.

[0441] In any of the embodiments of Tables 1 to 4 above, an R 4 Independent of other R 4 The radicals are halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl which is optionally substituted one or two times by halogen or C1-C4-alkyl.

[0442] In any of the embodiments of Tables 1 to 4 above, an R 5 Independent of other R 5 The radicals are halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl which is optionally substituted one or two times by halogen or C1-C4-alkyl.

[0443] In other embodiments, the present invention includes compounds of formula (I) shown in Table 5 below, wherein Y1, Y2, Y3, L, X, R1 and R3 are as shown in the table; R 2 and R 2’ are all hydrogen; Q is oxygen; and the group:

[0444] In the tables the abbreviations "ring system" and represent the following radicals:

[0445]

[0446]

[0447] In Table 5, the expression "3,5-di-F-Ph" represents 3,5-difluorophenyl; "3,5-di-Cl-Ph" represents 3,5-dichlorophenyl; "2,3,5-tri-F-Ph" represents 2,3,5-trifluorophenyl; "3-F-Ph" represents 3-fluorophenyl; "2,6-di-F-Ph" represents 2,6-difluorophenyl; "2,3-di-Cl-Ph" represents 2,3 -dichlorophenyl; "2,3,6-tri-F-Ph" represents 2,3,6-trifluorophenyl; "4-F-2,6-di-Me-Ph" represents 4-fluoro-2,6-dimethylphenyl; "2-Cl-6-F-Ph" represents 2-chloro-6-fluorophenyl; "3-Cl-5-(3,5-di-Cl-Ph)-Ph represents 3-chloro-5-(3,5-dichlorophenyl)phenyl; etc.;

[0448] Prop-1-en-2-yl representative group

[0449] 2-OH-propan-2-yl representative group and

[0450] 2-F-propan-2-yl representative group

[0451]

[0452] Table 5

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461] For the avoidance of doubt, each compound shown in Table 5 has been prepared and tested.

[0462] Stereoisomers and polymorphic forms

[0463] Those skilled in the art will recognize that compounds can exist and separate in optically active and racemic forms. Compounds having one or more chiral centers (including at the sulfur atom) 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. In addition, the compounds of this specification may include one or more chiral centers, which give rise to a theoretical number of optically active isomers. In the present case, the compound of formula (I) includes at least one chiral center, i.e., carrying the variable R 10 Where a compound of the present specification includes n chiral centres, the compound may contain up to 2 n The compounds of the invention include at least two enantiomers as contemplated by the invention. This specification covers specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and / or diastereomers of the compounds having the useful properties described herein. Optically active forms can be prepared, for example, by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase, or by enzymatic resolution to resolve the racemic form.

[0464] The compounds may also exist in different solid forms such as different crystalline forms or amorphous solid forms. The present description includes different crystalline forms as well as amorphous forms of the compounds.

[0465] Furthermore, the compounds may exist as hydrates or solvates, in which a certain stoichiometric amount of water or solvent is associated with the molecule in the crystalline form. Hydrates and solvates of the compounds are also subject matter of the present description.

[0466] Salt

[0467] In addition to the neutral compounds, the salt forms of the compounds are also active against endoparasites. The term "veterinarily acceptable salt" is used throughout the specification to describe any salt of a compound that is acceptable for administration in veterinary applications and that provides an active compound upon administration.

[0468] In the case where the compound is sufficiently alkaline or acidic to form a stable non-toxic acid or base salt, the compound may be in the form of a veterinary or agriculturally acceptable salt. Veterinary acceptable salts include those derived from veterinary or agriculturally acceptable inorganic bases and acids 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. Also suitable are salts containing transition metals including but not limited to manganese, copper, zinc and iron. In addition, this specification covers salts containing ammonium cations (NH4 + ) and salts of substituted ammonium cations in which one or more of the hydrogen atoms are replaced with alkyl or aryl groups.

[0469] Particularly suitable are salts derived from inorganic acids including but not limited to halogenated hydrochloric acid (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, etc. Suitable inorganic salts also include, but are not limited to, bicarbonate and carbonate. In certain embodiments, the organic acid addition salts formed by the example of veterinary and agriculturally acceptable salts and organic acids include but are not limited to maleate, dimaleate, fumarate, toluenesulfonate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoic acid, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Of course, other acceptable organic acids can be used.

[0470] Alkali metal (eg, sodium, potassium or lithium) or alkaline earth metal (eg, calcium) salts of the compounds can also be prepared by reacting a sufficiently acidic residue on the compound with an alkali metal or alkaline earth metal hydroxide.

[0471] Veterinarily acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acidic functionality present in the compound, or by reacting a suitable acid with a suitable basic functionality on a compound of the invention.

[0472] Methods for preparing compounds

[0473] The compounds of formula (I) or their pharmaceutically or veterinarily acceptable salts can be prepared by using the procedures in one of Schemes 1 to 4 or Schemes 5 to 12 below and in the Examples:

[0474] Solution 1

[0475]

[0476] Solution 2

[0477]

[0478] Solution 3

[0479]

[0480] Solution 4

[0481]

[0482] Those of ordinary skill in the art are fully capable of adapting these schemes to synthesize specific compounds of the present invention. In addition, starting materials are readily available or can be prepared via known methods.

[0483] Veterinary composition

[0484] Compounds and compositions comprising the compounds can be used to prevent and treat parasite invasion / infection in animals. This specification composition comprises an effective amount of a compound or its veterinary acceptable salt, and a veterinary acceptable carrier or diluent and an optional inactive excipient in combination therewith. The composition can be in various solid and liquid forms, which are suitable for application or administration to various forms of animals. For example, the veterinary composition comprising the compound can be present in a formulation suitable for oral administration, injectable administration including subcutaneous and parenteral administration, and topical administration (such as smearing or pouring), skin or subcutaneous administration. The composition is expected to be administered to animals but is 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 livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or domestic birds. The use of compounds to protect companion animals such as dogs and cats from the effects of endoparasites is particularly useful.

[0485] As discussed above, the compositions of the present disclosure may be in a form suitable for oral use (see, e.g., U.S. Pat. No. 4,564,631, which is incorporated herein by reference in its entirety), feed supplements, lozenges, troches, chewables, tablets, hard or soft capsules, pills, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral pour-on compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric-coated compositions or pastes. Compositions intended for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions and the compositions may contain one or more sweeteners, bittering agents, flavoring agents, coloring agents and preservatives to provide pharmaceutically aesthetic and palatable preparations.

[0486] Tablets can contain active ingredients, which are mixed with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, for example, corn starch or alginic acid; binding agents, such as starch, gelatin or gum arabic, and lubricants, for example, magnesium stearate, stearic acid or talc. Tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in US Patent Nos. 4,256,108; 4,166,452; and 4,265,874 (all of which are incorporated herein by reference in their entirety) to form osmotic therapeutic tablets for controlled release.

[0487] 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. The capsules may also be soft gelatin capsules in which the active ingredient is mixed with water or a solvent miscible with water such as propylene glycol, various PEGs and ethanol, or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0488] In one embodiment, the compound can be administered in a chewable tablet composition or a soft chewable composition, such as those described in US 2013 / 0203692 A1, US 2010 / 0087492, US 2006 / 0222684, US 2004 / 0151759, US7955632, all of which are incorporated herein by reference. The veterinary composition can be in the form of a soft chewable composition ("soft chewable") that is palatable and acceptable to animals. In addition to the active ingredient, the soft chewable of the present specification may also include one or more of the following components: a solvent or a solvent mixture, 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 regulators, and one or more flavoring agents.

[0489] The solvents that can be used in the compositions of the present specification include, but are not limited to, various grades of liquid polyethylene glycol (PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylene carbonate; propylene glycol; triglycerides including, but not limited to, caprylic / capric triglyceride, caprylic / capric / linoleic triglyceride (e.g. and 812, caprylic / capric / succinic triglycerides, propylene glycol dicaprylate / dicaprate, etc.; water, sorbitol solution, glyceryl caprylate / caprate and polyglycolized glycerides (e.g. ), or a combination thereof.

[0490] Various fillers known in the art can be used in the soft chewable compositions of the present specification. Fillers include, but are not limited to, corn starch, pregelatinized corn starch, soy protein powder, corn cobs, and corn gluten meal, etc. In certain embodiments, a combination of two or more fillers can be used in the composition.

[0491] Binders that can be used in the compositions of the present specification include, but are not limited to, polyvinyl pyrrolidone (e.g., povidone), cross-linked polyvinyl pyrrolidone (crospovidone), various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000, PEG 8000, and even PEG 20,000, etc.; copolymers of vinyl pyrrolidone and vinyl acetate (e.g., copolyvidone) such as BASF under the trade name 64 marketed products, etc.; starches such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and various types of sugars; or a combination of two or more binders.

[0492] Humectants that can be used in the composition include, but are not limited to, glycerin (also referred to herein as glycerol), propylene glycol, cetyl alcohol, and glyceryl monostearate, etc. Various grades of polyethylene glycol can also be used as a humectant.

[0493] Surfactants may be present in the composition to improve their solubility and absorption after ingestion. Surfactants are generally present in a concentration of about 1 to 10% (w / w), more generally about 1 to about 5% (w / w). Examples of surfactants that may be used in the composition include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate 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 etc.), polyethylene glycol castor oil derivatives including polyethylene glycol 35 castor oil Macrogol 40 hydrogenated castor oil ( 40), Macrogol 60 hydrogenated castor oil Propylene glycol monolaurate Glycerides including Glyceryl Caprylate / Caprate Polyethylene glycol glycerides PEG 300 Caprylic / Capric Glycerides PEG400 Caprylic / Capric Glycerides PEG 300 Oleic Acid Glyceryl PEG300 Linoleic Acid Glyceryl The polyethylene glycol stearates and polyethylene glycol hydroxystearates include polyethylene glycol 8 stearate (PEG 400 monostearate), polyethylene glycol 40 stearate (PEG 1750 monostearate), and the like.

[0494] The composition may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the art of compositions. Antioxidants may be added to the present description composition to inhibit degradation of the active agent. Suitable antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) monothioglycerol, etc.

[0495] This specification sheet composition can also include one or more lubricants and / or processing aids. Lubricants / processing aids can also be shown as solvents in some cases, so some components of the present composition can 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.

[0496] Many flavoring agents can be used in the present specification compositions to improve the palatability of oral veterinary compositions. Preferred flavoring agents are those that are not derived from animal sources. In various embodiments, flavoring components derived from fruits, meats (including but not limited to pork, beef, chicken, fish, poultry, etc.), vegetables, cheese, bacon, cheese-bacon and / or artificial flavoring agents can be used. Flavoring components are generally selected based on considerations related to the organism that swallows the soft chewable. For example, horses may like apple flavoring components, while dogs may like meat flavoring components. Although flavoring components derived from non-animal sources are preferred, natural flavoring agents containing beef or liver extracts, such as stewed beef flavoring, artificially powdered beef flavoring, roast beef flavoring, and corned beef flavoring, etc., can be used in certain embodiments.

[0497] In another embodiment of the present specification, the active composition can be administered via pour-on, and can be administered topically or orally. Pour-on compositions are those in which the liquid-containing composition of the present specification is administered to the mouth or throat of an animal, or poured onto the skin or fur of an animal.

[0498] The present specification composition can also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase can be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or a mixture of these. Suitable emulsifiers include natural phospholipids, for example, soybean lecithin, and esters or partial esters derived from fatty acids and hexitol dehydrates, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners, bittering agents, flavoring agents, and / or preservatives.

[0499] In one embodiment, the present description composition can be in the form of a microemulsion. Microemulsions are well suited for use as liquid carrier vehicles. Microemulsions are quaternary systems comprising an aqueous phase, an oil phase, a surfactant, and a co-surfactant. They are translucent and isotropic liquids.

[0500] Microemulsions consist of a stable dispersion of droplets of an aqueous phase in an oily phase, or vice versa. The size of these droplets can be less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film can be composed of alternating surfactant (SA) and co-surfactant (Co-SA) molecules, which allow the spontaneous formation of microemulsions by reducing the interfacial tension.

[0501] In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from a mixture of said compounds. In one embodiment of the oil phase, the oil phase may contain triglycerides; in another embodiment of the oil phase, the triglycerides are medium chain triglycerides, such as C8-C 10 Caprylic / capric triglyceride. In yet another embodiment, the oil phase may comprise a % v / v range of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v / v of the microemulsion.

[0502] The aqueous phase may include, for example, water or a glycol derivative, such as propylene glycol, glycol ethers, polyethylene glycol or glycerol. In one embodiment, the glycol may be propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether or a mixture thereof. Typically, the aqueous phase will comprise about 1 to about 4% v / v in the microemulsion.

[0503] Surfactants used in microemulsions may include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyethylene glycol-modified C8-C 10 Glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, co-surfactants may also include short chain alcohols such as ethanol and propanol.

[0504] Certain compounds are common to the three components discussed above, i.e., the aqueous phase, the surfactant, and the co-surfactant. However, the skill level of practitioners is sufficient to use different compounds well for each component of the same composition. In one embodiment of the amount of surfactant / co-surfactant, the ratio of co-surfactant to surfactant is from about 1 / 7 to about 1 / 2. In another embodiment of the amount of co-surfactant, there is about 25 to about 75% v / v of surfactant and about 10 to about 55% v / v of co-surfactant in the microemulsion.

[0505] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions can contain thickeners, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as vitamin C or other known preservatives.

[0506] Aqueous suspensions may contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents include natural phosphatides, for example lecithin, or condensation products of olefin oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening and / or bittering agents, such as those described above.

[0507] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water may 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 such as those already mentioned above. Additional excipients may also be present, for example sweeteners, bittering agents, flavoring agents and coloring agents.

[0508] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. The compositions may also contain a demulcent, a preservative, a flavoring and / or a coloring agent.

[0509] In another embodiment of the present specification, the composition can be in the form of a paste. Examples of paste embodiments include, but are not limited to, those described in U.S. Pat. Nos. 6,787,342 and 7,001,889 (each of which is incorporated herein by reference). In addition to the present specification compound, the paste may further contain fumed silica; a viscosity modifier; a carrier; optionally, an absorbent; and optionally, a colorant, a stabilizer, a surfactant or a preservative.

[0510] In one embodiment of the composition, the composition may be a paste, which contains the compound of the present specification, fumed silica, a viscosity modifier, an absorbent, a colorant; and a hydrophilic carrier, which is triacetin, monoglyceride, diglyceride or triglyceride.

[0511] The paste may also include a viscosity modifier. Suitable viscosity modifiers include, but are not limited to, polyethylene glycols (PEGs) including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600; monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or Tween 80), or poloxamer (e.g., Pluronic L81); absorbents such as magnesium carbonate, calcium carbonate, starch, and cellulose and its derivatives; and colorants include, but are not limited to, titanium dioxide, iron oxides, or FD&C Blue #1 aluminum color.

[0512] In certain embodiments, the composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques with those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, water, Ringer's solution and isotonic sodium chloride solution are particularly mentioned. Cosolvents such as ethanol, propylene glycol, cyclopentyl glycerol ether or polyethylene glycol can also be used. Preservatives such as phenol or benzyl alcohol can be used.

[0513] 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 can be used to prepare injectables.

[0514] Topical, skin and subcutaneous compositions can include, as non-limiting examples, lotions, creams, ointments, gels, pastes, powders, shampoos, pour-on compositions, ready-to-use compositions, liniment solutions and suspensions, drops and sprays. The present invention compounds or compositions comprising at least one of the present invention compounds in an active agent are topically applied as liniment, spray or pour-on compositions, so that the present invention compositions can be absorbed through the skin to achieve systemic levels, distributed through the sebaceous glands or on the surface of the skin, and each level is achieved throughout the fur. In the case where the compounds are distributed through the sebaceous glands, they can serve as reservoirs, and at this time, long-term lasting effects (up to several months) can be achieved. The smear composition is generally applied to a local area, which refers to an area that is not the entire animal. In one embodiment, the position can be between the shoulders. In another embodiment, it can be a band, such as an application band from the head of the animal to the tail.

[0515] Pour-on compositions are described in US Patent No. 6,010,710, also incorporated herein by reference. Pour-on compositions may advantageously be oily and generally comprise a diluent or vehicle for the active ingredient and, if the active ingredient is not soluble in the diluent, a solvent (eg, an organic solvent).

[0516] The organic solvents useful in the present specification include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl adipate, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, ethanol, 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 polyethylene glycol, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, triacetin, C1-C1 carboxylic acids, 10 Esters such as butyl or octyl acetate, and diethyl phthalate, or a mixture of at least two of these solvents.

[0517] The solvent is used in proportion to the active compound and its solubility in the solvent. Efforts should be made to achieve the smallest possible volume. The difference is made up to 100% with vehicle.

[0518] The vehicle or diluent used in the composition may include dimethyl sulfoxide (DMSO), glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol or glycerol. As vehicles or diluents, vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc., mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc., aliphatic or cyclic hydrocarbons or alternatively such as medium chain (such as C8 to C12) triglycerides may also be mentioned.

[0519] In another embodiment of the present specification, a softener and / or a spreading agent and / or a film-forming agent may be added. In one embodiment, the softener and / or a spreading agent and / or a film-forming agent may be:

[0520] (a) polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oil, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils), for example those containing silanol functions, or 45V2 oil,

[0521] (b) anionic surfactants such as alkaline stearates, sodium stearate, potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium rosinate; salts of alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (e.g. those derived from coconut oil),

[0522] (c) Cationic surfactants include water-soluble + R'R"R"'R"",Y - Quaternary ammonium salts, wherein the residue R is an optionally hydroxylated hydrocarbon residue and Y - It is an anion of a strong acid such as a halide, sulfate and sulfonate anion; hexadecyltrimethylammonium bromide is a cationic surfactant that can be used.

[0523] (d) Formula N + HR'R"R'" amine salts, wherein the residue R is an optionally hydroxylated hydrocarbon residue; octadecylamine hydrochloride is among the cationic surfactants that can be used,

[0524] (e) nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrene ether; polyethylene glycol stearates, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,

[0525] (f) amphoteric surfactants such as substituted lauryl compounds of betaine; or

[0526] (g) A mixture of at least two of these agents.

[0527] In one embodiment of the amount of softener, the softener ratio used can be about 0.1 to 50% or 0.25 to 5% by volume. In another embodiment, the softener ratio used can be about 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%, or about 5% to about 20% by volume.

[0528] In another embodiment of the present specification, the composition can be in the form of a ready-to-use solution, which is described in U.S. Patent No. 6,395,765, which is incorporated herein by reference. In addition to the compounds of the present specification, the ready-to-use solution can also contain a crystallization inhibitor and an organic solvent or a mixture of organic solvents. In certain embodiments, water can include an organic solvent.

[0529] In various embodiments of the present specification, the composition may include a crystallization inhibitor in an amount of about 1 to about 50% (w / v) or about 5 to about 40% (w / v) by total weight of the composition. In other embodiments, the amount of the crystallization inhibitor in the composition of the present invention may be about 1% to about 30%, about 5% to about 20%, about 1% to about 15%, or about 1% to about 10% (w / w). The type of crystallization inhibitor used in the composition of the present invention is not limited, as long as it effectively inhibits the active agent or inactive agent from crystallizing in the composition. For example, in certain embodiments of the present specification, the solvent or cosolvent of the composition may also act as a crystallization inhibitor if it sufficiently inhibits crystal formation over time when the composition is administered.

[0530] Crystallization inhibitors that can be used in this specification include but are not limited to:

[0531] (a) polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, polyoxyethylene esters of sorbitol or sorbitan; lecithin or sodium carboxymethyl cellulose; or acrylic acid derivatives, such as acrylic acid or methacrylic acid or polymers or copolymers thereof, polyethylene glycol (PEG) or polymers containing polyethylene glycol, such as glycofurol, etc.;

[0532] (b) anionic surfactants, such as alkaline stearates (e.g., sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium rosinate; salts of alkyl sulfates, including but not limited to sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzene sulfonate or sodium dioctyl sulfosuccinate; or fatty acids (e.g., coconut oil);

[0533] (c) cationic surfactants, such as water-soluble + R'R"R'"R""Yˉquaternary ammonium salts, wherein the R residues are the same or different optionally hydroxylated hydrocarbon residues and Yˉ is an anion of a strong acid, such as a halide, sulfate and sulfonate anion; hexadecyltrimethylammonium bromide is one of the cationic surfactants that can be used;

[0534] (d) Formula N + HR'R"R'" amine salts, wherein the R residues are the same or different optionally hydroxylated hydrocarbon residues; octadecylamine hydrochloride is one of the cationic surfactants that can be used;

[0535] (e) nonionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, for example polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearates, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and propylene oxide;

[0536] (f) amphoteric surfactants, such as lauryl-substituted betaine compounds;

[0537] (g) a mixture of at least two of the compounds listed in (a) to (f) above; or

[0538] (h) an organic solvent or mixture of solvents that inhibits the formation of crystalline or amorphous solids after administration of the composition.

[0539] In one embodiment of the crystallization inhibitor, a crystallization inhibitor pair will be used. The above pair includes, for example, a combination of a polymeric film former and a surfactant. These agents will be selected from the compounds mentioned above as crystallization inhibitors.

[0540] In certain embodiments, the organic solvent may have a dielectric constant of about 10 to about 35 or about 20 to about 30. In other embodiments, the organic solvent may have a dielectric constant of about 10 to about 40 or about 20 to about 30. The amount of the organic solvent or solvent mixture in the total composition is not limited and will be present in an amount sufficient to dissolve the desired components to the desired concentration. As discussed above, the organic solvent may also act as a crystallization inhibitor in the composition.

[0541] In certain embodiments, one or more of the organic solvents may have a boiling point of less than about 100° C. or less than about 80° C. In other embodiments, the organic solvent may have a boiling point of less than about 300° C., less than about 250° C., less than about 230° C., less than about 210° C., or less than about 200° C.

[0542] In some embodiments where there is a solvent mixture, i.e., a solvent and a cosolvent, the solvent can be present in the composition with a weight / weight (W / W) ratio of about 1 / 50 to about 1 / 1. In general, the ratio of the solvent is about 1 / 30 to about 1 / 1, about 1 / 20 to about 1 / 1, or about 1 / 15 to about 1 / 1 weight. Preferably, two solvents are present with a weight / weight ratio of about 1 / 15 to about 1 / 2. In some embodiments, at least one of the solvents present can improve the solubility of the activating agent or serve as a drying accelerator. In a special embodiment, at least one of the solvents can be mixed with water.

[0543] The composition may also include an antioxidant, desirably 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%.

[0544] In one embodiment of the film-forming agent, the agent is a polymer type, which includes but is not limited to various grades of polyvinyl pyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinyl pyrrolidone.

[0545] In one embodiment of the surfactant, the agent includes but is not limited to those composed of non-ionic surfactants; in another embodiment of the surfactant, the agent is a polyoxyethylene ester of dehydrated sorbitan, and in another embodiment of the surfactant, the agent includes various grades of polysorbate, such as polysorbate 80.

[0546] In yet another embodiment of the present specification, the film former and the surfactant can be added in similar or identical amounts within the limits of the total amount of the crystallization inhibitor mentioned elsewhere.

[0547] Crystallization inhibitors inhibit the formation of crystals on the fur and improve the maintenance of the cosmetic appearance of the skin or hide; that is, there is no tendency to stick or a sticky appearance, despite the high concentration of the active substance. Substances not mentioned in the text can be used as crystallization inhibitors in the present specification. In one embodiment, the effectiveness of the crystallization inhibitor can be demonstrated by a test according to which 0.3 mL of a solution containing 10% (w / v) active agent and 10% (w / v) of a compound acting as a crystallization inhibitor in a suitable solvent as defined above is placed on a slide at 20° C. for 24 hours, after which less than 10 crystals, preferably less than 0 crystals, are observed with the naked eye on the slide.

[0548] In one embodiment of the antioxidant, the agent is conventional in the art and includes, but is not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate or a mixture of at least two compounds having antioxidant properties.

[0549] The composition adjuvants discussed above are well known to practitioners in the art and are commercially available or obtained by known techniques. These concentrated compositions are generally prepared by simply mixing the components as defined above; advantageously, the starting point is to mix the active substance into the main solvent and then add other ingredients or adjuvants.

[0550] The volume of the composition used will depend on the type of animal and the size of the animal as well as the strength of the composition and the effectiveness of the active agent. In one embodiment, the composition of an amount of about 0.1 to about 20 ml can be administered to the animal. In other embodiments of the volume, the volume can 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.

[0551] In another embodiment of the present specification, in the case of applying the solution to mammals or birds, applying the smear composition according to the present specification can also provide long-lasting and broad-spectrum efficacy. The smear composition supports the topical administration of concentrated solutions, suspensions, microemulsions or emulsions for intermittent application to sites on animals, generally between the shoulders (smear type solutions).

[0552] For the coating composition, the carrier can be a liquid carrier vehicle described in U.S. Patent No. 6,426,333 (incorporated herein by reference), which in one embodiment of the coating composition can include a solvent or a solvent mixture, 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, etc.; aromatic alcohols such as phenol, cresol, naphthol, benzyl alcohol, etc.; acetonitrile, butyl diglycol, organic amides such as dimethylacetamide, dimethylformamide , monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone, etc.; propylene carbonate or ethylene carbonate, dimethyl sulfoxide (DMSO), glycol polymers or their ethers, such as various grades of polyethylene glycol (PEG), various grades of polypropylene glycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters, such as diethyl adipate or diisobutyl adipate, or a mixture of at least two of these solvents.

[0553] The liquid carrier vehicle may optionally contain a crystallization inhibitor including, but not limited to, those described above in (a) to (h), or a compound that can act as both a solvent and a crystallization inhibitor (as defined above), or a mixture of such crystallization inhibitors.

[0554] The smear composition can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, the smear composition can be prepared by encapsulating the active ingredient so that residues of the therapeutic agent are left on the surface of the animal. Depending on the species of the host animal to be treated, the severity and type of infection and the weight of the host, these compositions will vary with the weight of the therapeutic agent in the combination.

[0555] Each dosage form can generally contain about 0.1 mg to about 5 g of active agent. In other embodiments, the dosage form can contain about 0.5 mg to about 5 g of active agent. In one embodiment of the dosage form, the dosage can contain about 1 mg to about 500 mg of active agent, generally 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.

[0556] In one embodiment of the specification, the compound of formula (I) may be present in the composition at a concentration of about 0.05 to about 50% weight / weight. In other embodiments, the compound of formula (I) may be present at a concentration of about 0.1 to about 30% (w / w). In other embodiments, 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 other embodiments, 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), about 10 to about 20% (w / w). In 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 specification, 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 description, 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 description, the active agent may be present in the composition at a concentration of about 1% w / w.

[0557] Treatment

[0558] 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 specification provides a method for treating or preventing endoparasitic infections in or on an animal (e.g., a mammal or bird), comprising administering to the animal an endoparasiticidal effective amount of a compound of formula (I), or a veterinarily acceptable salt thereof, or a composition of the present specification.

[0559] In certain embodiments, the compound of formula (I) can also effectively resist ectoparasites and can be used to treat and prevent ectoparasite invasion on animals. In another embodiment, the present specification provides a method for treating or preventing ectoparasite invasion in or on an animal (e.g., a mammal or a bird), comprising administering to the animal an ectoparasiticidal effective amount of a compound of formula (I), or a veterinary acceptable salt thereof, or a composition of the present specification.

[0560] In another embodiment, the present disclosure provides a method for treating or preventing endoparasitic infections and ectoparasitic infestations in and on an animal, comprising administering to the animal a composition comprising an effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof and an effective amount of at least a second active agent in combination therewith.

[0561] In another embodiment of the present specification, a method for treating or preventing parasitic infestation in a place is provided, which comprises administering or applying a parasiticidal effective amount of a compound of formula (I), or a veterinarily acceptable salt thereof, to the place. With regard to animal health applications, "place" is intended to mean a habitat, breeding ground, region, material or environment in which a parasite grows or can grow, excluding the body or surface of an animal.

[0562] In another embodiment, the present disclosure provides methods and uses of compounds for controlling pests and diseases in plants and crops or for protecting wood-containing structures.

[0563] Mammals that can be treated include, but are not limited to, humans, cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep and yaks. In one embodiment of the present specification, the mammals treated are humans, cats or dogs.

[0564] In one embodiment of the present specification, it is found that the compound of formula (I) has excellent efficacy against endoparasites, especially endoparasites resistant to macrolide active agents. In one embodiment, the compounds and compositions of the present specification are effective for controlling Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds.

[0565] In another embodiment, the present specification provides a method for treating parasitic invasion or infection in an animal, including administering an effective amount of the present specification anthelmintic compound and an effective amount of an invertebrate GABA receptor activator including avermectin or milbemycin in combination to an animal in need. Avermectins (avermectins) that can be used in combination with the present specification compound include but are not limited to avermectin, demadectin, doramectin, avermectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Milbemycins (milbemycins) compounds that can be used in combination with the present specification compound include but are not limited to milbemectin (milbemectin), milbemycin D (milbemycin D), moxidectin (moxidectin) and nemadectin (nemadectin). Also included are 5-oxo and 5-oxime derivatives of the avermectins and milbemycins.

[0566] In one embodiment, the compounds and compositions of the present disclosure can be used to treat or prevent endoparasitic infections of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, C. yathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fa sciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum, Onchocerca, Ostertagia, Oxyuris, Pachycera, racaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorous, Uncinaria, Wuchereria, and combinations thereof.

[0567] In a particularly preferred embodiment of the present specification sheets, the present specification sheets compound and composition are used to treat or prevent the infection caused by Dirofilaria immitis. The compound has been found to be highly effective against Dirofilaria immitis microfilariae and L4 larvae. Thus, the compound can be used to protect animals from the Dirofilaria immitis disease impact of development by eliminating the Dirofilaria immatura before it can develop into adult worms. In one embodiment, the compound and the composition comprising the compound can be used to prevent Dirofilaria immatura disease development by eliminating the Dirofilaria immatura resistant to macrolides. In another embodiment, the present specification sheets compound and composition are used to treat or prevent the infection caused by Dirofilaria repens or Dirofilaria hongkongensis.

[0568] In another embodiment of the present specification, the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus and combinations thereof.

[0569] In yet another embodiment of the combined treatment with an ectoparasiticide against endoparasites and ectoparasites, the ectoparasite is one or more insects or arachnids, including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.

[0570] In another embodiment of the treatment against ectoparasites, the ectoparasites are from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and / or Boophilus. The ectoparasites 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, Ctenocephalides spp., etc.), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., etc.), and mites (Demodex spp., Sarcoptes spp., Otodectes spp., etc.), lice (Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.), mosquitoes (Aedes spp., Culex spp., Anopheles spp., etc.). spp.), etc.) and flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.). In yet another embodiment of the treatment against ectoparasites, the ectoparasites are fleas and / or ticks.

[0571] Additional examples of ectoparasites include, but are not limited to, those of the genus Boophilus, particularly those of the species Boophilus microplus, Boophilus achromaticus, and Boophilus annularis; myiasis such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (green fly); sheep myiasis such as Lucilia sericata, Lucilia cuprina (known as green fly disease in Australia, New Zealand, and South Africa). Diptera, i.e., those whose adults are parasites, such as Haematobia irritans; lice such as Linognathus vitulorum, etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example, migratory Diptera larvae.

[0572] In another embodiment of the present specification, the compounds and compositions of the present specification are suitable for controlling pests and diseases such as insects selected from the following: German cockroach (Blatella germanica), tobacco budworm (Heliothis virescens), potato beetle (Leptinotarsa ​​decemlineata), pavement ant (Tetramorium caespitum) and combinations thereof.

[0573] 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, Rotylenchus spp., Trichodorus spp. spp.), Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenemenetrans, Xiphinema spp.

[0574] In addition, whether or not other pesticide agents are added to the composition, the present invention can also be used to treat other pests and diseases, including but not limited to the following pests and diseases:

[0575] (1) Isopoda, e.g., Oniscus asellus, Armadillidium vulgare and Porcellio scaber;

[0576] (2) Diplopoda, e.g. Blaniulus guttulatus;

[0577] (3) Chilopoda, e.g. Geophilus carpophagus and Scutigera spp.;

[0578] (4) Symphyla, such as the white pine borer (Scutigerella immaculata);

[0579] (5) Thysanura, e.g. Lepisma saccharina;

[0580] (6) Order Collembola, e.g. Onychiurus armatus;

[0581] (7) Order Blattaria, for example, Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica;

[0582] (8) Order of the Hymenoptera, for example, Diprion spp., Hoplocampas spp., Lasius spp., Monomorium pharaonis and Vespa spp.;

[0583] (9) Siphonaptera, for example, Xenopsylla cheopis and Ceratophyllus spp.;

[0584] (10) From the order of the Anoplura (Phthiraptera), for example, Damalinia spp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectes spp.;

[0585] (11) Class Arachnida, for example, Acarus siro, Aceriasheldoni, Aculops spp., Aculus spp., Amblyommas spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes spp. spp.), Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp.), Scorpiomaurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici;

[0586] (12) Bivalva, for example, Dreissena spp.;

[0587] (13) Order of the Coleoptera, for example, Acanthoscelides obtectus, Adoretus spp., Agelasta alni, Agriotes spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidius 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, Hylotrupes bajulus, Hypera postica, Hypothenemus spp.), Lachnosterna consanguinea, Leptinotarsa ​​decemlineata, Lissorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolontha, Migdolus spp., Monochamus spp.), Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedoncochleariae, 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.;

[0588] (14) From the order of the Diptera, for example, Aedes spp., Anopheles spp., Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanus spp., Tannia spp., Tipulapaludosa, Wohlfahrtia spp.;

[0589] (15) Class Gastropoda, for example, Arion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.;

[0590] (16) Helminthes, for example, Ancylostoma duodenale, Ancylostomaceylanicum, Acylostoma braziliensis, Ancylostoma spp., Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugiatimori, Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp., Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa, Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloides spp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp., Whipworm (Trichuris trichuria), Wuchereria bancrofti;.

[0591] (17) 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 hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergella singularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatoma spp.;

[0592] (18) Order of the Homoptera, for example, Acyrthosipon spp., Aeneolamia spp., Agonascena spp., Aleurodes spp., Aleurolobus barodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui, Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis, Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicoryne brassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacunalanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp.), Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp., Diaspis spp., Doralis spp., Drosichas spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp.), Erythroneura spp., Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus 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, Monelliacostalis, Monelliopsis pecanis, Myzus spp., Nasonoviaribisnigri, Nephotettix spp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp., Peregrinus maidis, Phenacoccus spp.), Phloeomyzus passerinii, Phorodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp., Psylla spp., Pteromalus spp., Pyrillaspp., Quadraspidiotus spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp.), greenhouse whitefly (Trialeurodes vaporariorum), individual psyllids (Trioza spp.), leafhoppers (Typhlocybas spp.), sharp shield scales (Unaspis spp.), grape phylloxera (Viteus vitifolii.);.

[0593] (19) Order of the Isoptera, for example, Reticulitermes spp., Odontotermes spp.;

[0594] (20) Lepidoptera, for example, Acronicta major, Aedialeucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp., Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Earias insulana, Ephestiakuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp., Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella, Laphygma spp., Lithocolletis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestrabrassicae, Mocis repanda, Mythimna separata, Oria spp., Oulemaoryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris spp.), Plutella xylostella, Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesiagemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia spp.;

[0595] (21) Order of the Orthoptera, for example, Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, Locusta spp., Melanoplus spp., Periplaneta americana, Schistocerca gregaria;

[0596] (22) Order of the Thysanoptera, for example, Baliothrips biformis, Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips cardamoni, Thrips spp.;

[0597] (23) Protozoa, for example, Eimeria spp.

[0598] In various aspects of the present specification, the compounds and compositions of the present specification can be applied against individual pests or insect pests or their combinations.

[0599] Mixtures with other active agents

[0600] In another embodiment, the composition comprising the compound of formula (I) may also include other veterinary therapeutic agents. Veterinary agents that may be included in the compositions of this specification are well known in the art (see, for example, Plumb's Veterinary Drug Handbook, 5 th Edition, ed.Donald C.Plumb, Blackwell Publishing, (2005) or TheMerck Veterinary Manual, 9 th Edition, (January 2005)) and include, but are not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxyamine, acetylcysteine, acitretin, acyclovir, albendazole, salbutamol sulfate, alfentanil, allopurinol, alprazolam, allylgestaltin, amantadine, amikacin sulfate, aminocaproic acid, aminovaleramide hydrosulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, clavulanate potassium, amphotericin B deoxycholate, lipid-based amphotericin B, ampicillin, ampronium, antacids (oral), antivenom, apramycin sulfate, vitamin C, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose Sugar, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine hydrochloride, buspirone hydrochloride, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitriol, calcium salt, captopril , carindacillin sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, ceftriaxone sodium, cefotetan disodium, cefoxime sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporin, cefapirin, charcoal (activated charcoal), chlorambucil, chloramphenicol, chlordiazepoxide Chlorpheniramine + / - Clindamycin bromide, chlorthiazide, chlorpheniramine maleate, chlorpromazine hydrochloride, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine hydrochloride, clonazepam, clonidine, cloprostenol sodium, chlordiazepoxide dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), teicosin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin D / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), diclofenac sodium, dicloxacillin, ethotripsy, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem , dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydroxylamine, disopyramide phosphate, dobutamine hydrochloride, docusate / DSS, dolasetron mesylate, domperidone, dopamine hydrochloride, doramectin, doxapram hydrochloride, doxepin hydrochloride, doxorubicin hydrochloride, doxycycline, calcium disodium edetate, calcium edetate, edrophonium chloride, enalapril / enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin, escitalol, erythromycin, esmolol hydrochloride, estradiol cypionate, ethacrynic acid / ethacrynic acid sodium, ethanol (ethanol), etidronate sodium, etodolac, etomidate, euthanasia agent w / valerate barbiturates, famotidine, fatty acids (essential / omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, 5-fluorouracil (5-FU), fluoxetine, fluticasone propylacetate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine / chondroitin sulfate, glutamine, glyburide, glycerol (oral), glycopyrrolate, gonadorelin, griseofulvin, guaifenesin, halothane, glucorene-200 Heparin, hydroxyethyl starch, sodium hyaluronate, hydralazine, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocaprozil dipropionate, imiprotegerin-cilastatin sodium, imipramine, amrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium / potassium), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxazolidinone, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, fenacic acid, levetiracetam, levothyroxine sodium, lidocaine lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, nitrogen mustard, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, mydil, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate / hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibutal ketone, midazolam, mibemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, moxidectin, naloxone, nandrolone decanoate, naproxen, narcotic agonist analgesics, neomycin sulfate, neostigmine, nicotinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, sodium neomycin, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxytetracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium, paromomycin sulfate , parozetine, penicillamine, penicillins including penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, sodium xylindole, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphate, vitamin K1 / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, propionibacterium acnes acnes) injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic gel, pyridostigmine bromide, mepyramine maleate, pyrimethamine, mepaline, quinidine, ranitidine, rifampicin, s-adenosyl-methionine (SAMe), saline / hyperosmotic laxatives,selamectin, selegiline / l-deprenin, sertraline, sevelamer, sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate, pituitary growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, choline chloride succinylchloride, sucralfate, sufentanil citrate, sulfachlorpyrifos sodium, sulfadimentoxine / trimethroprim, sulfamethoxazole / trimethoprim, sulfadimentoxine, sulfadimentoxine / ormeprim, sulfasalazine, taurine, tepoxalin, terbinafline, terbutaline sulfate, Testosterone, tetracycline, thiothiazide sodium, vitamin B1, thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin, ticarcillin disodium, tiletamine / zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid, topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, alimamazine tartrate w / prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / sulfate, zonisamide, and mixtures thereof. ,

[0601] In one embodiment of the present specification, aryl pyrazole compounds such as phenylpyrazole may be included in the veterinary composition of the present specification. Aryl pyrazoles are known in the art and may be suitable for combination with compounds of formula (I) in the compositions of the present specification. Examples of the aryl pyrazole compounds include, but are not limited to, those described in US 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 aryl pyrazole active agent is fipronil.

[0602] In another embodiment of the present specification, one or more macrolides or lactams acting as acaricides, anthelmintics and / or insecticides can be included in the present specification composition in combination with the compound. For the avoidance of doubt, the term "macrolide" as used herein includes natural and synthetic or semi-synthetic avermectins and milbemycin compounds.

[0603] Macrolides that can be used in the compositions of the present disclosure include, but are not limited to, naturally occurring avermectins (e.g., including components designated as A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b) and milbemycin compounds, semisynthetic avermectins and milbemycins, avermectin monosaccharide compounds, and avermectin glycoside compounds. Examples of macrolide compounds that can be used in the composition include, but are not limited to, avermectin, demadectin, doramectin, avermectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554 and milbemycins, including, but not limited to, milbemectin, milbemectin D, milbemectin A3, milbemectin A4, milbemectin oxime, moxidectin and nemadectin. Also included are 5-oxo and 5-oxime derivatives of the avermectins and milbemycins.

[0604] Macrolide compounds are known in the art and can be readily obtained commercially or by synthetic techniques known in the art. See the widely available technical and commercial literature. For the avermectins, ivermectin and abamectin, see, for example, "Ivermectin and Abamectin", 1989, by MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag. or et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramectin, see "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15. For milbemycins, see especially 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 EP 0 677 054, all of which are incorporated herein by reference.

[0605] The structures of avermectins and milbemycins are closely related, for example, both have complex 16-membered macrolide rings. Natural product avermectins are disclosed in US Patent No. 4,310,519 and 22,23-dihydroavermectin compounds are disclosed in US Patent No. 4,199,569. In particular, US Patent Nos. 4,468,390, 5,824,653, EP 0 007812A1, UK Patent Specification 1 390 336, EP 0 002 916, and New Zealand Patent No. 237086 are also mentioned. Natural milbemycins are described in US Patent No. 3,950,360 and "The Merck Index" 12 thed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996) and various references cited therein. Lactidectin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, Vol. 17, No. 4, pp. 263-286, (2003). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in US 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 EP 0 667 054, all of which are incorporated herein by reference.

[0606] In one embodiment, the veterinary composition of the present specification comprises an effective amount of avermectin, demadectin, doramectin, avermectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, mibemycin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin or nemadectin, or a combination thereof. In another embodiment, the present specification provides a veterinary composition comprising an effective amount of avermectin, avermectin, eprinomectin, ivermectin, doramectin or selamectin, or a combination thereof. In another embodiment, the veterinary composition of the present specification comprises an effective amount of ivermectin, mibemycin, milbemycin oxime or moxidectin, or a combination thereof.

[0607] In another embodiment of the present specification, a composition is provided, the composition comprising a class of acaricides or insecticides called insect growth regulators (IGRs) in combination with a compound of formula (I). Compounds belonging to this class are well known to practitioners and cover a wide range of different chemical classes. These compounds all work by interfering with the development or growth of insect pests. Insect growth regulators are described in, for example, US Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or UK2 140 010 and US Patent Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).

[0608] In one embodiment of the present description composition, an IGR compound that simulates juvenile hormone or regulates juvenile hormone levels in insects may be included. Examples of juvenile hormone mimetics include azadirachtin, benzylpenicillin, fenoxycarb, methoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin and 4-chloro-2 (2-chloro-2-methyl-propyl) -5- (6-iodo-3-pyridylmethoxy) pyridazine-3 (2H) -one. In another embodiment, the present description composition comprises a compound of formula (I) and methoprene or pyriproxyfen in combination therewith and a pharmaceutically acceptable carrier.

[0609] In another embodiment, the composition of the present disclosure includes an IGR compound that is a chitin synthesis inhibitor. Chitin synthesis inhibitors include cyromazine, cyromazine, diflubenzuron, fluazifop, flufenoxuron, flufenoxuron, hexaflumuron, lufenuron, fenthiocarb, flubendiamide, flufenoxuron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0610] In certain embodiments, the composition of the present specification may include one or more antinematode agents, including but not limited to active agents in the categories of benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphate compounds. In certain embodiments, the composition may include benzimidazoles, including but not limited to thiabendazole, thiabendazole, butylbenzamide, propoxybenzazole, mebendazole, flubendazole, thiobenzazole, thiobenzazole, propylthiocarbendazole, cyclobendazole, fenthiocarbamate, thiophanate and its o,o-dimethyl analogs.

[0611] In other embodiments, the compositions of the present disclosure may include imidazothiazole compounds, including, but not limited to, chloranil, thiabendazole, and thiabendazole.

[0612] In other embodiments, the compositions of the disclosure may include an ectohydropyrimidine active agent, including, but not limited to, pyrantel, mesopyrimidine, and thienylpyrimidine.

[0613] Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, chloranthate, naphthiophos and dichlorvos, heptylphos, mefenphos, monocrotophos, TEPP, and chlorpyrifos.

[0614] In other embodiments, the composition may include anti-nematode compounds, phenothiazines, piperazine as a neutral compound and its various salt forms, ethodicarb, phenols such as diiodonitrophenol, arsenic-containing preparations such as thioethionine, ethanolamines such as benzylphenidate, thiophenoxam chlorobenzenesulfonate, and methoxypyridinium; cyanine dyes include chloramphenicol chloride, chloramphenicol pamoate and iodide; isothiocyanates include p-bisisothiocyanatobenzene, suramin sodium, phthalide, and various natural products including, but not limited to, hygromycin B, α-artemisinin and kainic acid.

[0615] In other embodiments, the composition of the present specification may include an anti-trematode agent. Suitable anti-trematodes include, but are not limited to, milasic acid such as milasic acid D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives, oltipraz, amine methylthiothione, hydroxylamine thiothione, hydroxylamine quine, nitrosocyanamide, nitrosothiocyanamide, nitrosothiodazole, nitrosocyanamide, various bisphenol compounds known in the art include chloranil, thiochlorophenol, thiochlorophenol sulfoxide and dinitrochlorophenol; various anti-mold amine (salicylanilide) compounds include tribromosalanilide, hydroxychlorosalanilide, cloiodamide, rafoxanide, nitrosocyanamide, bromothiosamide, bromoflunic acid and closantel; triclobendazole, diacetamidophenoxyethyl ether, clorsulon, hytoline and emetine.

[0616]

[0013] Antitaeniasis compounds that may also be advantageously employed in the compositions of the present disclosure include, but are not limited to, arecoline in various salt forms, butyralidone, spiroxamine, nitrothiocyanate, paromomycin, paromomycin II, praziquantel, and ethacrylamide.

[0617] In other embodiments, the compositions of the present specification may include other active agents that are effective against arthropod parasites. Suitable active agents include, but are not limited to, bromoxynil, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromothion, ethyl bromothion, trithion, chlorpyrifos, chlorpyrifos, baclofos, oxazolidinone, diazinon, dimethoate, dimethoate, ethion, famoxathion, fenitrothion, fenthion, fospirate, iodine thion, malathion, dibromothion, phosalone, phosmet, phoxim, amine propiconazole, skin fly phosphorus, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin, cypermethrin, flucythrin, permethrin, phenothrin, pyrethrin, resmethrin, benzyl benzoate, carbon disulfide, clorox Miton, diflubenzuron, diphenylamine, disulfiram, isobornylthiocyanatoacetate, methoprene, sulfilam, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, chlorpyrifos, 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).

[0618] 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 the depsipeptide that is different from the compound. They include PF1022A or its analogs and emodepside. Other cyclic depsipeptide compounds that can be included in the composition comprising the compound of formula (I) are those described in WO 2016 / 187534 A1 and WO 2017 / 116702 A1, which are incorporated herein by reference. These compounds act on the neuromuscular junction by stimulating the presynaptic receptors belonging to the secretin receptor family, causing paralysis and death of parasites. In one embodiment of depsipeptide, the depsipeptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126 (Pt 1): 79-86).

[0619] In another embodiment, the present description composition may include an active agent from a neonicotinoid parasiticide. Neonicotinoids bind 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 present description composition is imidacloprid. Such agents are described in, for example, US Patent No. 4,742,060 or EP 0 892 060 (both of which are incorporated herein by reference). In another embodiment, the present description composition may include nitenpyram, i.e., another active agent of neonicotinoid pesticides. The use of nitenpyram for preventing and controlling fleas is described in US Patent No. 5,750,548, which is incorporated herein in its entirety by reference.

[0620] In certain other embodiments of the present specification, the compound of formula (I) that can be combined with the composition of the present specification is a semicarbazone, such as metaflumizone.

[0621] In another embodiment, the present description composition can advantageously include one or more pesticide isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against various ectoparasites and the combination with the compound of formula (I) will expand the scope of efficacy against these parasites. Particularly useful isoxazoline active agents that can be combined with the compound include afolan (including substantially pure active enantiomers), sarolana, flurellana (including substantially pure active enantiomers) and lotirana.These active agents are described in US 7,964,204, US 2010 / 0254960 A1, US 2011 / 0159107, US 2012 / 0309620, US 2012 / 0030841, US 2010 / 0069247, WO 2007 / 125984, WO 2012 / 086462, US 8318757, US 8466115, US 8618126, US 8822466, US 8383659, US 8853186, US 9221835, US 2011 / 0144349, US 8,053,452; US 2010 / 0137612, US 8410153, US 2011 / 152081, WO 2012 / 089623, WO 2012 / 089622, US 8,119,671; US ​​7,947,715; WO 2102 / 120135, WO 2012 / 107533, WO 2011 / 157748, US 2011 / 0245274, US 2011 / 0245239, US 2012 / 0232026, US2012 / 0077765, US 2012 / 0035122, US 2011 / 0251247, WO 2011 / 154433, WO 2011 / 154434, US2012 / 0238517, US 2011 / 0166193, WO 2011 / 104088, WO 2011 / 104087, WO 2011 / 104089, US2012 / 015946, US 2009 / 0143410, WO 2007 / 123855 A2, US 2011 / 0118212, US 7951828&US7662972, US 2010 / 0137372 A1, US 2010 / 0179194 A2, US 2011 / 0086886 A2, US 2011 / 0059988 A1, US 2010 / 0179195 A1, US 2015 / 0126523,WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236, WO 2017 / 147352, US 7897630, and US 7951828, all of which are incorporated herein by reference.

[0622] In another embodiment of the present specification, nodulisporic acid and its derivatives can be added to the present specification composition. These compounds are used to treat or prevent infections in humans and animals and are described in, for example, US Patent Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference. The composition can include one or more of nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the references cited above.

[0623] In another embodiment, an anthelmintic compound of aminoacetonitrile (AAD) compounds such as monepantel (ZOLVIX) can be added to the composition of the present specification. These compounds are described in, for example, US 7,084,280 of 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.

[0624] The compositions of the present specification may also include aryl and pyrrol-2-yl cyanoethylamino compounds such as those described in US Patent No. 8,088,801 to Soll et al., which is incorporated herein by reference; and thioamide derivatives of these compounds are described in US Patent No. 7,964,621 to Le Hir de Fallois, which is also incorporated herein by reference. Aryl and pyrrol-2-yl cyanoethylamino active agents that act systemically on endoparasites can be used in combination with compounds in the veterinary compositions of the present specification.

[0625] The compositions of the present disclosure may also include paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Paraherquamide compounds are a known class of compounds with activity against certain parasites, which include a spirodioxepindole core (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, structurally related marcfortines, such as marcfortines AC, are also known and can be combined with the compositions of the present invention (see J. Chem. Soc. -Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Other descriptions of para-plum-shaped penicillamide derivatives can be found in, for example, WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, WO 09 / 004432 and US 2010 / 0197624, U.S. Pat. No. 5,703,078 and U.S. Pat. No. 5,750,695, all of which are incorporated herein by reference.

[0626] In another embodiment of the present specification, the composition may include a spinosyn active agent produced by soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado V.L. and Sparks TC, "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance," Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semisynthetic spinosoid active agent. Spinosyns are generally 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 their combinations may be used in the present specification composition. Spinosad compounds can be fused to a 5,6,5-tricyclic ring system of a 12-membered macrolide, a neutral sugar (rhamnose), and an amino sugar (forosamine). These and other natural spinosad compounds, including 21-butenyl spinosad produced by Saccharopolyspora pagona, which can be used in the compositions of the present specification, can be produced by fermentation using conventional techniques known in the art. Other spinosad compounds that can be used in the compositions of the present specification are disclosed in US 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 entirety. The spinosyn compound may include, but is not limited to, spinosyn A, spinosyn D, spinosyn, ethyl spinosyn, or a combination thereof. Spinosyn is a combination of spinosyn A and spinosyn D, while ethyl spinosyn is a combination of 3'-ethoxy-5,6-dihydrospinosyn J and 3'-ethoxyspinosyn L.

[0627] Typically, the additional active agent (different from the above-mentioned formula (I) compound) is included in the dosage unit of the present specification in an amount of about 0.1 μg to about 1000 mg. Typically, the active agent can be included in an amount of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg or about 10 mg to about 100 mg. More typically, the additional active agent is present in the composition of the present invention in an amount of about 5 mg to about 50 mg.

[0628] Depending on the potency of the active agent, the concentration of the additional active agent in the present description composition is generally about 0.01% to about 30% (w / w). In certain embodiments of very effective active agents including but not limited to macrolide active agents, the concentration of the active agent is generally 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 is generally about 0.1% to about 2% (w / w) or about 0.1% to about 1% (w / w).

[0629] In other embodiments, the additional active agent is generally present in higher concentrations to achieve the desired efficacy. In certain 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 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).

[0630] In various embodiments of the present specification, additional active agents can be included in the composition to deliver a dosage 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 generally present in an amount sufficient to deliver a dosage of about 0.05 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg. In other embodiments, the active agent is present in an amount sufficient to deliver a dosage of about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 1 mg / kg or about 0.5 mg / kg to about 50 mg / kg per animal body weight.

[0631] In certain embodiments of the present specification, wherein the additional active agent is a very effective compound such as a macrolide or other effective compound, the active agent is present at a concentration providing a dosage 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 other embodiments, the active agent is present in an amount sufficient to deliver a dosage of about 0.01 mg / kg to about 2 mg / kg or about 0.1 mg / kg to about 1 mg / kg per animal body weight. In other embodiments, the additional active agent can be present in an amount delivering a dosage of about 1 μg / kg to about 200 μg / kg or about 0.1 mg / kg to about 1 mg / kg animal body weight.

[0632] In addition to the other active agents mentioned above, a combination of two or more active agents may be used in the composition with the compounds of the present disclosure to treat a desired range of pests and parasites. The practitioner's skill level will be sufficient to determine which individual compounds can be used in the compositions of the present invention to treat a particular insect infestation.

[0633] The present description will now be further described by way of example by the following non-limiting examples. Example

[0634] Preparation Example

[0635] The compounds of formula (I) or their pharmaceutically or veterinarily acceptable salts can be prepared by adopting one of the following reaction schemes. The raw materials for preparing them can be commercially available or can be prepared by methods known to those skilled in the art and described in the literature. It should be recognized that those skilled in the art can modify the following procedures to prepare additional compounds of the present invention. For example, those skilled in the art will understand that replacing certain raw materials or using different intermediates will make it possible to prepare different compounds of formula (I).

[0636] List of abbreviations:

[0637] ACN Acetonitrile

[0638] AIBN Azobisisobutyronitrile

[0639] BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

[0640] BSA bovine serum albumin

[0641] BOC tert-Butyloxycarbonyl

[0642] BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride

[0643] DAST Diethylaminosulfur trifluoride

[0644] DCC N,N′-Dicyclohexylcarbodiimide Solution

[0645] DCM Dichloromethane

[0646] DEAD Diethyl azodicarboxylate

[0647] DIEA Diisopropylethylamine

[0648] DMF N,N-Dimethylformamide

[0649] DMAP 4-(dimethylamino)pyridine

[0650] DMSO Dimethyl sulfoxide

[0651] EDAC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0652] ES Electrospray

[0653] EtOAc or EA Ethyl acetate

[0654] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate

[0655] HOBt or HOBT 1-Hydroxybenzotriazole

[0656] KHMDS Potassium hexamethyldisilazide, more precisely potassium bis(trimethylsilyl)amide

[0657] MeOH Methanol

[0658] m-CPBA m-Chloroperoxybenzoic acid

[0659] NMO N-Methylmorpholine-N-oxide

[0660] o / n Overnight

[0661] PE Petroleum Ether

[0662] Pd(dtbpf)Cl2 Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)

[0663] Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0)

[0664] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed with dichloromethane

[0665] TBAF tert-Butylammonium fluoride

[0666] TfO triflate

[0667] THF Tetrahydrofuran

[0668] TLC Thin layer chromatography

[0669] The method described in Scheme 5 can be used to prepare the following compounds:

[0670] 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.

[0671] In certain cases for certain compounds, the method of Scheme 5 can be modified according to methods known to those skilled in the art to introduce different functional groups into the core structure. For example, Intermediate 026-E can be used to introduce the corresponding variable R in the structure. 1 Similarly, intermediate 026-C can be used to generate different groups corresponding to the variable R 3 Different groups are introduced at the positions.

[0672] Solution 5

[0673]

[0674] 1. Synthesis of methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate

[0675]

[0676] 3-bromo-2-hydroxybenzoic acid methyl ester (5.0g, 21.6mmol, 1.0 equivalent), ethyl bromoacetate (3.6g, 21.6mmol, 1 equivalent), acetone (50mL), K2CO3 (8.97g, 64.9mmol, 3.0 equivalent) were added to a 100-mL round-bottom flask. The resulting solution was stirred overnight at 60°C. The reaction mixture was cooled. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 2). This obtained 7g (rough) of 3-bromo-2-(2-ethoxy-2-oxoethoxy) methyl benzoate, which was a light yellow solid.

[0677] 2. Synthesis of methyl 7-bromo-3-hydroxybenzofuran-2-carboxylate

[0678]

[0679] To a 50-mL round-bottom flask was added 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoic acid methyl ester (5.0 g, 15.7 mmol, 1.0 equiv), CH3OH (20.0 mL, 315.3 mmol), CH3ONa (1.7 g, 31.5 mmol, 2.0 equiv). The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This obtained 3.5 g (81.9%) of 7-bromo-3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester as a white solid.

[0680] 3. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-hydroxybenzofuran-2-carboxylate

[0681]

[0682] 7-bromo-3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester (1.50g, 5.53mmol, 1.00 equivalent), 3,5-dichlorophenyl substituted boronic acid (1.1g, 6.1mmol, 1.1 equivalent), Pd (dtbpf) Cl2 (180mg, 0.28mmol, 0.05 equivalent), H2O (2.0mL), THF (8.0mL), K3PO4 (2.3g, 11.0mmol, 2.0 equivalent) were added to a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere. The obtained solution was stirred at room temperature overnight. The obtained mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 3). This obtained 1g (53.6%) of 7- (3,5-dichlorophenyl) -3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester, which was a white solid.

[0683] 4. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethylsulfonyloxy)benzofuran-2-carboxylate

[0684]

[0685] 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester (0.9 g, 2.67 mmol, 1.0 equivalent), TEA (0.5 g, 5.3 mmol, 2.0 equivalent), DCM (10.0 mL) were added to a 50-mL 3-neck round-bottom flask flushed and maintained with an inert nitrogen atmosphere at 0 ° C, and Tf2O (0.9 g, 3.20 mmol, 1.2 equivalent) was subsequently added thereto. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 2x10 mL of dichloromethane and the organic layer was combined. The resulting mixture was washed with 1x10 mL of brine. The mixture was dried and concentrated over anhydrous sodium sulfate. This gave 1.1 g (87.8%) of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate as a yellow solid.

[0686] 5. Synthesis of 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)benzofuran-2-carboxylic acid methyl ester

[0687]

[0688] 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylic acid methyl ester (1.10 g, 2.34 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (0.5 g, 2.8 mmol, 1.2 equivalent), Pd(dtbpf)Cl2 (76.4 mg, 0.12 mmol, 0.05 equivalent), H2O (2.0 mL), THF (8.0 mL), K3PO4 (1.0 g, 4.7 mmol, 2.0 equivalent) were added to a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with 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.

[0689] 6. Synthesis of methyl 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylate

[0690]

[0691] To a 50-mL round-bottom flask was added 7-(3,5-dichlorophenyl)-3-(prop-1-ene-2-yl)-1-benzofuran-2-carboxylic acid methyl ester (390 mg, 1.1 mmol, 1.0 equiv), PtO2 (37 mg, 0.16 mmol, 0.15 equiv), EA (10 mL), and H2 gas (1 atm) was introduced into the above. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered off. The resulting mixture was concentrated. This obtained 370 mg (94.4%) of 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid methyl ester as a gray solid.

[0692] 7. Synthesis of 7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxylic acid

[0693]

[0694] To a 25-mL round-bottom flask was added 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid methyl ester (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), H2O (1.0 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The pH value of the solution was adjusted to 4 by adding HCl aqueous solution (1 mol / L). The solid was collected by filtration. This obtained 300 mg (89.2%) of 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid as a white solid.

[0695] 8. Synthesis of (S)-N-(chroman-4-yl)-7-(3,5-dichlorophenyl)-3-isopropylbenzofuran-2-carboxamide

[0696]

[0697] To a 25-mL round-bottom flask was added 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), DCM (5 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was further purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, 0.05% FA / water and CH3CN (40% CH3CN increased to 95% in 13 minutes); 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] + ; 1H-NMR (300MHz, CDCl3): δ=7.88 (dd, J=7.9, 1.2Hz, 1H), 7.66 (d, J=1.9Hz, 2H), 7.51 (dd, J=7.5, 1.2Hz, 1H), 7.45-7.32 (m, 3H), 7.27-7.18 (m, 1H), 6.96 (td, J=7.5, 1.2H z, 1H), 6.89 (dd, J=8.2, 1.2Hz, 1H), 6.80 (d, J=7.8Hz, 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, 2.1Hz, 6H) ppm.

[0698] The following reaction can be used to prepare methyl 7-(3,5-dichlorophenyl)-3-morpholinobenzofuran-2-carboxylate, which can be converted into the corresponding R according to Scheme 5. 3 An alternative compound having a morpholine group at the position of

[0699]

[0700] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylic acid methyl ester (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), 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 adding 20 mL of water. The resulting solution was extracted with 2x15 mL of ethyl acetate, and the organic layers were combined and dried and concentrated over anhydrous sodium sulfate. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 5). This gave 200 mg (46.2%) of methyl 7-(3,5-dichlorophenyl)-3-(morpholin-4-yl)-1-benzofuran-2-carboxylate as a white solid.

[0701] The following compounds can be synthesized by using Scheme 6 below and the following reaction scheme:

[0702] 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.

[0703] Solution 6:

[0704]

[0705] 1. Synthesis of 4-(3,5-difluorophenyl)-3-fluoropyridine

[0706]

[0707] 3-Fluoro-4-iodopyridine (30.0 g, 134.5 mmol, 1.0 equivalent), dioxane (20 mL), 3,5-difluorophenyl substituted boronic acid (25.5 g, 161.4 mmol, 1.2 equivalent), Pd (dppf) Cl2 (4.92 g, 6.7 mmol, 0.05 equivalent), K2CO3 (37.2 g, 269.0 mmol, 2.0 equivalent), H2O (4 mL) were added to a 1000-mL 3-neck round bottom flask flushed and maintained with an inert nitrogen atmosphere. The obtained solution was stirred at ℃ for 2 hours. The obtained solution was extracted with 3x500 mL of ethyl acetate and concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0% to 30%). This obtained 26 g (92.4%) of 4- (3,5-difluorophenyl) -3-fluoropyridine as a white solid.

[0708] 2. Synthesis of 4-(3,5-difluorophenyl)-3-fluoropyridine 1-oxide

[0709]

[0710] To a 1000-mL round-bottom flask was added 4-(3,5-difluorophenyl)-3-fluoropyridine (26.0 g, 124.3 mmol, 1.0 equiv), DCM (500 mL), 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 in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 100%) to EA / MeOH (1 / 2). This obtained 21 g (75.0%) of 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-olate as a white solid.

[0711] 3. Synthesis of 4-(3,5-difluorophenyl)-3-fluoropicolinecarbonitrile

[0712]

[0713] 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.), TEA (19.8 g, 195.8 mmol, 2.10 equiv.) were added to a 1000-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere. The resulting solution was stirred overnight at 80 ° C. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 30%). This obtained 10 g (45.8%) of 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile as an off-white solid.

[0714] 4. Synthesis of methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

[0715]

[0716] To a 250-mL round-bottom flask was added 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile (6.0 g, 25.6 mmol, 1.0 equiv), CH3CN (100 mL), methyl thioglycolate (8.2 g, 76.9 mmol, 3.0 equiv), K2CO3 (10.6 g, 76.86 mmol, 3 equiv). The resulting solution was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding 200 mL of water. The solid was collected by filtration and washed with water (3x20 mL). This obtained 6 g (73.1%) of 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester as a light yellow solid.

[0717] 5. Synthesis of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

[0718]

[0719] To a 250-mL 3-neck round-bottom flask flushed and maintained with an inert argon atmosphere was added HBr (25.0 mL), CuBr (705.4 mg, 4.9 mmol, 1.0 equiv), 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (1.5 g, 4.7 mmol, 1.0 equiv). Thereafter, a solution of NaNO2 (388 mg, 5.6 mmol, 1.2 equiv) in H2O (5 mL) was added dropwise at 0 ° C. The resulting solution was stirred at 20 ° C for 1 night. 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 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 1.5 g (83.4%) of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a light yellow solid.

[0720] 6. Synthesis of methyl 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylate

[0721]

[0722] To a 40-mL vial flushed and maintained with an inert nitrogen atmosphere was added 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (500 mg, 1.3 mmol, 1.0 equiv), THF (10 mL), potassium vinyl trifluoroborate (523 mg, 3.9 mmol, 3.0 equiv), H2O (2 mL), Pd(PPh3)2Cl2 (91.4 mg, 0.1 mmol, 0.1 equiv), Cs2CO3 (1.27 g, 3.9 mmol, 3.0 equiv). The resulting solution was stirred at 80°C overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 30%). This gave 350 mg (81.2%) of methyl 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylate as a yellow solid.

[0723] 7. Synthesis of methyl 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylate

[0724]

[0725] To a 100-mL round-bottom flask was added K2OsO4.2H2O (200.2 mg, 0.5 mmol, 0.6 eq), acetone (10 mL), H2O (10 mL), NMO (636.4 mg, 5.4 mmol, 6.0 eq), NaIO4 (1.2 g, 5.4 mmol, 6 eq), 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylic acid methyl ester (300 mg, 0.90 mmol, 1.00 eq). The resulting solution was stirred at room temperature overnight. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x20 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 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.

[0726] 8. Synthesis of methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

[0727]

[0728] 7-(3,5-difluorophenyl)-3-formylthieno[3,2-b]pyridine-2-carboxylic acid methyl ester (170mg, 0.5mmol, 1.0 equivalent), DCM (5mL), DAST (0.5mL, 0.001mmol, 0.04 equivalent) were added to a 50-mL round-bottom flask. The resulting solution was stirred at room temperature for 3 hours. The reaction was added dropwise to 30mL water / ice. The resulting solution was extracted with 3x10mL of dichloromethane and the organic layers were combined. The resulting mixture was washed with 3x20mL of brine. The resulting mixture was concentrated. The residue was applied to silica gel Pre-TLC with ethyl acetate / petroleum ether (1 / 3). This obtained 130mg (71.7%) of 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester as a white solid.

[0729] 9. Synthesis of 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid

[0730]

[0731] A 25-mL round-bottom flask was charged with 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (110 mg, 0.3 mmol, 1.0 equiv), iso-PrOH (2.0 mL, 0.1 mmol), NaOH (200 mg, 5.0 mmol, 16.1 equiv), H2O (2.0 mL, 0.3 mmol). The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was cooled to room temperature. The pH value of the solution was adjusted to 5 by adding HCl aqueous solution (2 mol / L). The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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.

[0732] 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

[0733]

[0734] To a 50-mL round bottom flask was added 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), HATU (133.7 mg, 0.3 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 1 hour. The residue was applied to a C18 column with 0.05% FA / H2O and CH3CN (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] + ; 1H-NMR (300MHz, CDCl3): δ=8.88 (d, J=4.8Hz, 1H), 7.63 (t, J=54.9Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 7.39-7.19 (m, 5H), 7.15 (d, J=8.0Hz, 1H), 7.09-6.86 (m, 3H), 5.40 (q, J=5.9Hz, 1H), 4.39-4.22 (m, 2H), 2.43-2.24 (m, 2H)ppm.

[0735] Compounds 199-0 and 311-1 can be prepared according to the method described in Scheme 7 below and the following procedures:

[0736] Solution 7

[0737]

[0738] Synthesis of ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate

[0739]

[0740] To a 40-mL vial flushed and maintained with an inert nitrogen atmosphere was added 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid ethyl ester (1.0 g, 2.5 mmol, 1.0 equiv), dioxane (20 mL), tributyl(1-ethoxyvinyl)stannane (2.7 g, 7.5 mmol, 3.0 equiv), 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 adding HCl aqueous solution (10 mL, 2 mol / L). The resulting solution was extracted with 3x20 mL of ethyl acetate and concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (10% to 30%). This gave 800 mg (88.2%) of ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate as a light yellow solid.

[0741] Synthesis of 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid

[0742]

[0743] To a 25-mL round-bottom flask was added ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (300 mg, 0.8 mmol, 1.0 equiv), iso-PrOH (10 mL, 0.2 mmol, 0.2 equiv), H2O (10 mL), NaOH (300 mg, 7.5 mmol, 9.0 equiv). The resulting solution was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature. The pH of the solution was adjusted to 5 by adding HCl aqueous solution (2 mol / L). The resulting solution was extracted with 3x20 mL of ethyl acetate. The resulting mixture was washed with 3x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This obtained 270 mg (97.6%) of 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid as a yellow oil.

[0744] 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

[0745]

[0746] To a 25-mL round bottom flask was added 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), HATU (462 mg, 1.2 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 2 hours. The residue was applied to a C18 column with 0.05% FA / H2O and CH3CN (40% CH3CN to 90% in 10 minutes). 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.

[0747] 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

[0748]

[0749] 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), DCM (10 mL) were added to a 40-mL vial flushed and maintained with an inert nitrogen atmosphere. AlMe3 (0.2 mL, 1.7 mmol, 5.0 equiv) was then added dropwise at 0 ° C. The resulting solution was stirred for 1 hour at 0-10 ° C. The reaction was added dropwise to 20 mL of ice water. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers were combined. The resulting mixture was washed with 3x20 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with 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 light yellow solid. (ES, m / z): 447 [M+H] + ; 1 H-NMR (300MHz, CDCl3): δ=8.79 (d, J=4.8Hz, 1H), 7.35-7.20 (m, 5H), 7.06-6.92 (m, 2H), 6.88 (dd, J=8.3, 1.2Hz, 1H), 6.60 (d, J=7. 4Hz, 1H), 6.16 (s, 1H), 5.33 (q, J = 5.5Hz, 1H), 4.38-4.32 (m, 1H), 4.25-4.17 (m, 1H), 2.46-2.16 (m, 2H), 1.89 (d, J = 4.2Hz, 6H) ppm.

[0750] 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

[0751]

[0752] 7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-hydroxypropyl-2-yl)thieno[3,2-b]pyridine-2-carboxamide (108 mg, 0.2 mmol, 1.0 equiv), DCM (3 mL) were added to an 8-mL vial. DAST (72.5 mg, 0.4 mmol, 2.0 equiv) was then added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by adding 3 mL of water. The resulting solution was extracted with 3x5 mL of dichloromethane and the organic layers were combined and concentrated. The crude product was purified by preparative-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 (300MHz, DMSO-d6): δ=9.08 (d, J=8.2Hz, 1H), 8.87 (d, J=4.8Hz, 1H), 7.66-7.46 (m, 4H), 7.28 (d, J=7.6Hz, 1H), 7.21-7.11 (m, 1H), 6.90 (td, J=7. 5, 1.3Hz, 1H), 6.78 (dd, J=8.2, 1.2Hz, 1H), 5.24-5.13 (m, 1H), 4.29-4.17 ( m, 2H), 2.24-2.03 (m, 2H), 1.98 (d, J=9.9Hz, 3H), 1.90 (d, J=9.8Hz, 3H) ppm.

[0753] Compound 030 can be prepared according to the method described in Scheme 8 below and the following procedure:

[0754] Solution 8

[0755]

[0756] 1. Synthesis of 7-methoxy-1-benzofuran-2-carbonitrile

[0757] O-vanillin (50.0 g, 328.6 mmol, 1.0 eq.), chloroacetonitrile (29.7 g, 394.3 mmol, 1.2 eq.), K2CO3 (49.9 g, 361.5 mmol, 1.1 eq.), DMF (530 mL) were added to a 500-mL round-bottom flask. The resulting solution was stirred in an oil bath at 150 ° C for 1 hour. Then, additional K2CO3 (49.9 g, 361.5 mmol, 1.1 eq.) was added and stirred for 20 minutes. The reaction was then quenched by adding 530 mL of water. The resulting solution was extracted with 3x500 mL of ethyl acetate, and the organic layer was dried and concentrated over anhydrous sodium sulfate. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This obtained 14 g (24.6%) of 7-methoxy-1-benzofuran-2-carbonitrile, which was a white solid.

[0758] 2. Synthesis of 4-acetyl-7-hydroxy-1-benzofuran-2-carbonitrile

[0759]

[0760] 7-methoxy-1-benzofuran-2-carbonitrile (14.0 g, 80.8 mmol, 1.00 equivalent), acetyl chloride (19.0 g, 242.5 mmol, 3.0 equivalent), DCM (300 mL) were added to a 100-mL round-bottom flask. Thereafter, AlCl (43.1 g, 323.3 mmol, 4.0 equivalent) was added in batches at 0 ° C. The resulting solution was stirred at room temperature for 1 night. The reaction was then quenched by adding 500 mL of water / ice. The resulting solution was extracted with 3x400 mL of ethyl acetate, and the organic layer was dried and concentrated over anhydrous sodium sulfate. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This obtained 9 g (51.7%) of 4-acetyl-7-methoxy-1-benzofuran-2-carbonitrile, which was a white solid.

[0761] 3. Synthesis of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile

[0762]

[0763] Methyl triphenylphosphonium bromide (7.9 g, 22.3 mmol, 1.2 equivalents) and THF (50 mL) were added to a 250-mL 3-neck round-bottom flask rinsed and maintained with an inert nitrogen atmosphere. Thereafter, n-BuLi / hexane (12.6 mL, 31.6 mmol, 1.7 equivalents) was added dropwise at 0 ° C. The resulting solution was stirred at 0 ° C for 30 minutes. 4-acetyl-7-methoxy-1-benzofuran-2-nitrile (4.0 g, 18.5 mmol, 1.0 equivalents) was added dropwise at -78 ° C. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate. The organic phase was washed with 2x50 mL of brine. The mixture was dried and concentrated over anhydrous sodium sulfate. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:20). This gave 1.6 g (40.3%) of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile as a white solid.

[0764] 4. Synthesis of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid

[0765]

[0766] To a 100-mL round-bottom flask was added 7-methoxy-4-(prop-1-ene-2-yl)-1-benzofuran-2-carbonitrile (1.6 g, 7.5 mmol, 1.0 equiv) and aqueous NaOH solution (10 M) (50.0 mL). The resulting solution was stirred at 100° C. in an oil bath for 1.5 hours. The pH of the solution was adjusted to 3-4 with aqueous HCl solution (6 M). The solid was collected by filtration. This obtained 1.4 g (80.3%) of 7-methoxy-4-(prop-1-ene-2-yl)-1-benzofuran-2-carboxylic acid as a white solid.

[0767] 5. Synthesis of 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid

[0768]

[0769] To a 250-mL round-bottom flask was added 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid (2.2 g, 9.4 mmol, 1.0 eq), EA (50.0 mL), PtO2 (0.4 g, 1.8 mmol, 0.2 eq), and H2 (g) was introduced into the above. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated. This gave 2.2 g (99.1%) of 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid as a yellow solid.

[0770] 6. Synthesis of 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid

[0771]

[0772] 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid (500.0mg, 2.1mmol, 1.0 equivalent), DCM (50mL) are added to a 250-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere. Afterwards, BBr (10.6mL, 10.6mmol, 5.0 equivalent) is added dropwise at -70°C. The resulting solution is stirred at 5°C for 4 hours. The reaction is then quenched by adding NH4Cl (aq.50mL). The resulting solution is concentrated by extraction with 3x50mL of DCM. This obtains 500mg (rough) of 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid, which is a colorless oil.

[0773] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-hydroxy-4-isopropyl-1-benzofuran-2-carboxamide

[0774]

[0775] 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid (500.00 mg, 2.270 mmol, 1.00 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (508.1 mg, 3.4 mmol, 1.5 equivalent), HATU (1726.5 mg, 4.5 mmol, 2.0 equivalent), DIEA (880.3 mg, 6.8 mmol, 3.0 equivalent), DCM (20.0 mL) were added to a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3x30 mL of DCM, and the organic layer was concentrated. The residue was applied to a silica gel column with 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.

[0776] 8. Synthesis of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-4-isopropyl-1-benzofuran-7-yl trifluoromethanesulfonate

[0777]

[0778] To a 50-mL 3-neck round bottom flask flushed and maintained with an inert nitrogen atmosphere was added 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), TEA (138.2 mg, 1.3 mmol, 2.0 equiv). Thereafter, Tf2O (231.2 mg, 0.8 mmol, 1.2 equiv) was added dropwise at -70°C with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of NH4Cl (aq.). The resulting solution was extracted with 3x20 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.

[0779] 9. Synthesis of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-4-isopropyl-1-benzofuran-2-carboxamide

[0780]

[0781] 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 equivalent), 3,5-dichlorophenyl substituted boronic acid (143.6 mg, 0.7 mmol, 1.3 equivalent), Pd(dtbpf)Cl2 (37.7 mg, 0.058 mmol, 0.1 equivalent), K3PO4 (245.8 mg, 1.1 mmol, 2.0 equivalent), THF (12.00 mL), and water (3.00 mL) were added to a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate, and the organic layer was dried and concentrated over anhydrous sodium sulfate. The crude product was purified by preparative-HPLC using the following conditions (Waters-2767): column, X-bridge RP18, 5um, 19*100mm; mobile phase, 0.03% ammonia / water and CH3CN (50% CH3CN to 80% in 13 minutes); detector, UV 254nm. This yielded 87mg (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 (300MHz, DMSO-d6): δ=9.08 (d, J=8.2Hz, 1H), 8.05-7.87 (m, 3H), 7.72 (d, J=7.8Hz, 1H), 7.67 (t, J=1.9Hz, 1H), 7.31 (d, J=7.9Hz, 1H), 7.28-7 .14(m, 2H), 6.96-6.87(m, 1H), 6.86-6.79(m, 1H), 5.28(q, J=6.7Hz, 1H), 4.30 (dt, J=6.7, 3.8Hz, 2H), 2.25-1.97 (m, 2H), 1.35 (d, J=6.9Hz, 6H) ppm.

[0782] Compounds 264 and 264-0A can be prepared according to Scheme 9 below and the procedures detailed below:

[0783] Solution 9

[0784]

[0785] Exemplary procedures for compounds 264 and 264-0A: 1. Synthesis of (3,5-dichlorophenyl)acetyl chloride

[0786]

[0787] To a 1-L round-bottom flask was added (3,5-dichlorophenyl)acetic acid (20.00 g, 97.547 mmol, 1.0 equiv), toluene (120.0 mL), 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. This gave 19 g (crude) of (3,5-dichlorophenyl)acetyl chloride as a yellow oil.

[0788] 2. Synthesis of 1-bromo-3-(3,5-dichlorophenyl)propan-2-one

[0789]

[0790] To a 2-L 3-neck round-bottom flask flushed and maintained with an inert nitrogen atmosphere, (3,5-dichlorophenyl)acetyl chloride (20 g, 89.4 mmol, 1.0 equivalent), ACN (400.0 mL) was added. TMSCHN2 (83 mL, 116.3 mmol, 2.0 equivalents, 2 M) was added dropwise at 0 ° C. The resulting solution was stirred for 1 hour at 0 ° C. HBr (40.0 mL, 547.7 mmol, 6.1 equivalents, 40%) was added dropwise at 0 ° C. The resulting solution was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 200 mL of ethyl acetate and the resulting mixture was washed with 3x200 mL of water. The mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The residue was applied to a silica gel column with 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] + .

[0791] 3. Synthesis of 4-(3,5-dichlorophenyl)-3-oxobutanenitrile

[0792]

[0793] To a 500-mL round-bottom flask was added 1-bromo-3-(3,5-dichlorophenyl)propan-2-one (22.0 g, 78.0 mmol, 1.0 equiv), MeOH (120.0 mL), 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 adding 200 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. This obtained 5 g (28.1%) of 4-(3,5-dichlorophenyl)-3-oxobutanenitrile as an off-white solid. MS (ESI, m / z): 228 [M+H] + .

[0794] 4. Synthesis of 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile

[0795]

[0796] To a 250-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 4-(3,5-dichlorophenyl)-3-oxobutanenitrile (2.0 g, 8.7 mmol, 1.0 equiv), (dimethoxymethyl)dimethylamine (5.2 g, 43.9 mmol, 5.0 equiv). The resulting solution was stirred at 122 ° C for 1 hour. Thereafter, CH3COONH4 (5.0 g, 64.9 mmol, 7.4 equiv) and AcOH (50.0 mL) were added. The resulting solution was stirred at 80 ° C for an additional 1 hour. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with MeOH / DCM (1:10). This obtained 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] + .

[0797] 5. Synthesis of 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile

[0798]

[0799] To a 250-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 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] + .

[0800] 6. Synthesis of 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

[0801]

[0802] To a 250-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile (1.6 g, 5.6 mmol, 1.0 equiv), ethyl mercaptoacetate (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 filtered to collect the solid. 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] + .

[0803] 7. Synthesis of ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

[0804]

[0805] 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (300.0 mg, 0.8 mmol, 1.0 equiv), acetonitrile (10.0 mL), and HBr (10.0 mL) were added to a 100-mL round-bottom flask. Thereafter, CuBr2 (365.6 mg, 1.6 mmol, 2.0 equiv) was added at 0°C. NaNO2 (85.0 mg, 1.2 mmol, 1.5 equiv) was added thereto at 0°C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding 100 mL of 1M HCl. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 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] + .

[0806] 8. Synthesis of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyvinyl)thieno[3,2-c]pyridine-2-carboxylate

[0807]

[0808] 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (550.0 mg, 1.2 mmol, 1.0 equiv), tributyl(1-ethoxyvinyl)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) were added to a 20-mL vial flushed and maintained with an inert nitrogen atmosphere. The resulting solution was stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:3). This obtained 540 mg (crude) of 7-(3,5-dichlorophenyl)-3-(1-ethoxyvinyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester as a yellow solid. MS (ESI, m / z): 422 [M+H] + .

[0809] 9. Synthesis of ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate

[0810]

[0811] To a 50-mL round-bottom flask was added ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyvinyl)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 2M NaHCO3 aqueous solution. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. This obtained 500 mg (crude) of ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate as a yellow solid. MS (ESI, m / z): 394 [M+H] + .

[0812] 10. Synthesis of 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid

[0813]

[0814] To a 40-mL vial was added 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. H2O (160.0 mg, 3.8 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 3 with aqueous HCl (1 M). The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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] + .

[0815] 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

[0816]

[0817] To a 50-mL round-bottom flask was added 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), 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-preparative-HPLC using the following conditions (IntelFlash-1): C 18 ; Mobile phase, CH3CN:H2O=20% increased to CH3CN:H2O=90% within 20 minutes. This gave 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] + .

[0818] 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

[0819]

[0820] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added AlMe3 (5 mL, 2 M in hexanes). Thereafter, 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 at 0°C. The resulting solution was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 2 with aqueous HCl (3 M). The resulting solution was extracted with 3x20 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C 18 Silica gel; mobile phase, CH3CN:H2O=20% increased to CH3CN:H2O=50% within 20 minutes. 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] + ; 1 H-NMR (300MHz, CDCl3): δ = 9.58 (s, 1H), 9.40 (d, J = 7.8Hz, 1H), 8.45 (s, 1H), 7.71 (s, 3H), 7.20-7.13 (m, 2H), 6.90-6.86 (m, 1 H), 6.76 (d, J=9.0Hz, 1H), 5.14-5.13 (d, J=1.8Hz, 1H), 4.18 (s, 2H), 2.11-2.10 (m, 1H), 2.00-1.95 (m, 1H), 1.68 (s, 6H)ppm.

[0821] 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

[0822]

[0823] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(2-hydroxypropyl-2-yl)thieno[3,2-c]pyridine-2-carboxamide (35.0 mg, 0.06 mmol, 1.0 equiv), DCM (5.0 mL), 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 adding 5 mL of water. The resulting solution was extracted with 3x5 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C 18 Silica gel; mobile phase, CH3CN:H2O=45% increased to CH3CN:H2O=65% within 20 minutes. This gave 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 (300MHz, CDCl3): δ=9.37 (s, 1H), 8.50 (s, 1H), 7.54-7.50 (m, 3H), 7.31 (s , 1H), 7.23 (d, J=7.4Hz, 1H), 6.99-6.90 (m, 1H), 6.89 (d, J=8.2Hz, 1H), 6.31 (d, 3H), 1.94 (d, J = 7.1 Hz, 3H) ppm. The following compounds can be prepared according to Scheme 10 below and the procedures detailed below: 121, 226-3, 215, 227, 224, 225, 228, 225-0A, 230, 226, 234.

[0824] Solution 10

[0825]

[0826] Exemplary procedure for compound 226-3:

[0827] 1. Synthesis of 3-chloro-4-methoxypyridine

[0828]

[0829] 3-Chloro-4-nitropyridine (30.00 g, 189.2 mmol, 1.0 equiv.), MeOH (400.0 mL), CH3ONa (56.7 mL, 5 mol / L, 1.50 equiv.) were added to a 1000-mL round-bottom flask. 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 3x500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This obtained 25 g (92.0%) of 3-chloro-4-methoxypyridine as a yellow oil.

[0830] 2. Synthesis of 3-chloro-4-methoxypyridin-1-ium-1-olate

[0831]

[0832] 3-Chloro-4-methoxypyridine (25.00 g, 174.131 mmol, 1.00 equiv), DCM (500.0 mL), m-CPBA (60.1 g, 348.2 mmol, 2.0 equiv) were added to a 1000-mL round-bottom flask. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 100%) to EA / MeOH (1 / 2). This obtained 30 g (crude) of 3-chloro-4-methoxypyridin-1-ium-1-olate as an off-white solid.

[0833] 3. Synthesis of 3-chloro-4-methoxypyridine-2-carbonitrile

[0834]

[0835] 3-Chloro-4-methoxypyridin-1-ium-1-olate (30.00 g, 188.0 mmol, 1.0 equiv), CH3CN (600.0 mL), TMSCN (46.6 g, 470.0 mmol, 2.5 equiv), TEA (39.95 g, 394.8 mmol, 2.1 equiv) were added to a 1000-mL round-bottom flask. The resulting solution was stirred at 80 ° C for 6 hours. The resulting mixture was concentrated under reduced pressure. This obtained 35 g (crude) of 3-chloro-4-methoxypyridine-2-carbonitrile as a brown solid.

[0836] 4. Synthesis of methyl 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate

[0837]

[0838] To a 500-mL round-bottom flask was added 3-chloro-4-methoxypyridine-2-carbonitrile (16.00 g, 94.9 mmol, 1.0 equiv), CH3CN (300.0 mL), methyl thioglycolate (40.30 g, 379.6 mmol, 4.0 equiv), K2CO3 (52.47 g, 379.6 mmol, 4.0 equiv). The resulting solution was stirred at 80 ° C. for 1 night. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 70%). This obtained 2.7 g (11.9%) of 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid methyl ester as a yellow solid.

[0839] 5. Synthesis of methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate

[0840]

[0841] 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid methyl ester (1.00 g, 4.1 mmol, 1.0 equiv), HOAc (40.0 mL), HCHO (1260.2 mg, 41.9 mmol, 10.0 equiv), NaBH3CN (2637.5 mg, 41.9 mmol, 10.0 equiv) were added to a 250-mL round-bottom flask. The resulting solution was stirred at 35 ° C for 3 hours. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x100 mL of NaHCO3 (aq.) and 3x100 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (EA 0% to 50%). This gave 1.1 g (98.4%) of methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate as a light yellow solid.

[0842] 6. Synthesis of 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid

[0843]

[0844] To a 100-mL round-bottom flask was added 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid methyl ester (130.0 mg, 0.4 mmol, 1.0 equiv), THF (3.0 mL), NaOH (130.00 mg, 3.2 mmol, 6.6 equiv), H2O (3.0 mL). The resulting solution was stirred at 55 ° C for 3 hours. The resulting mixture was concentrated under reduced pressure. This gave 150 mg (crude) of 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid as a yellow solid.

[0845] 7. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxamide

[0846]

[0847] To a 100-mL round-bottom flask was added 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), HATU (2034.60 mg, 5.3 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x20 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with 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 semisolid.

[0848] 8. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide

[0849]

[0850] 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), LiCl (300.1 mg, 7.0 mmol, 5.4 equiv). The resulting solution was stirred at 140 °C for 6 hours. The reaction mixture was cooled to room temperature. The residue was applied to a silica C18 column with 0.05% TFA / H2O and CH3CN (20% CH3CN to 60% in 12 minutes). 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 light yellow solid.

[0851] 9. Synthesis of 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate

[0852]

[0853] 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), Tf2O (687.3 mg, 2.4 mmol, 5.0 equiv) were added to a 50-mL 3-neck round-bottom flask flushed and maintained with an inert nitrogen atmosphere. The resulting solution was stirred at 10 ° C for 2 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x20 mL of brine. The resulting mixture was concentrated in vacuo. The residue was applied to silica gel Pre-TLC with 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.

[0854] 10. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(1-ethoxyvinyl)thieno[3,2-b]pyridine-2-carboxamide

[0855]

[0856] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added toluene (20.0 mL), 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-ethoxyvinyl)stannane (1 g, 2.7 mmol, 2.7 equiv), Pd(dppf)Cl2 (160.00 mg, 0.2 mmol, 0.2 equiv), K2CO3 (250.0 mg, 1.8 mmol, 1.8 equiv). The resulting solution was stirred at 100 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column with 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-ethoxyvinyl)thieno[3,2-b]pyridine-2-carboxamide as a brown solid.

[0857] 11. Synthesis of 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide

[0858]

[0859] 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-ethoxyvinyl)thieno[3,2-b]pyridine-2-carboxamide (350.0 mg, 0.8 mmol, 1.0 equiv), and HCl (6M) (5.0 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was added to a silica gel column with 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. 1H-NMR (300MHz, CD3OD): δ=8.96 (d, J=4.7Hz, 1H), 8.04 (d, J=4.8Hz, 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, 1.2Hz, 1H), 5.31 (t, J=5.6Hz, 1H), 4.39-4.32 (m, 1H), 4.27-4.22 (m, 1 H), 2.99 (s, 6H), 2.80 (s, 3H), 2.39-2.33 (m, 1H), 2.21-2.16 (m, 1H)ppm.

[0860] 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

[0861]

[0862] To a 50-mL 3-neck round-bottom flask was added THF (5.0 mL), 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). Thereafter, bromo(2-methylprop-1-ene-1-yl)magnesium (1.0 mL, 0.006 mmol, 0.01 equiv) was added dropwise at 0 ° C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding water / ice. The resulting solution was extracted with 3x20 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with 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.

[0863] 13. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpentane-2-yl)thieno[3,2-b]pyridine-2-carboxamide

[0864]

[0865] 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 into the above. The resulting solution was stirred at 50°C for 2 hours. The solid was filtered off. 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.

[0866] 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

[0867]

[0868] To a 50-mL round-bottom flask was added pyridine (3.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(dimethylamino)-7-(2-hydroxy-4-methylpentane-2-yl)thieno[3,2-b]pyridine-2-carboxamide (100.0 mg, 0.2 mmol, 1.0 equiv), SOCl2 (0.5 mL). The resulting solution was stirred at 0 ° C for 1 hour. The reaction was then quenched by adding water / ice. The resulting solution was extracted with 3x20 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.

[0869] 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

[0870]

[0871] 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), Pd / C (20.0 mg, 0.19 mmol, 1.2 equiv). H2(g) was introduced into the above. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O and CH3CN (20% CH3CN increased to 90% in 20 minutes); detector, 220 nm. This gave 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] + ; 1 H-NMR (300MHz, CDCl3): δ=8.65 (d, J=4.8Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 ( m, 1H), 6.97-6.94 (m, 1H), 6.86 (d, J=8.3Hz, 1H), 5.31 (t, J=5.6Hz, 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.

[0872]

[0873] To an 8-mL sealed tube was added NMP (5.0 mL), 2-[[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (200.0 mg, 0.4 mmol, 1.0 equiv), 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-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O and CH3CN (20% CH3CN increased to 90% in 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 light yellow solid. (ES, m / z): 473 [M+H] + ; 1 H-NMR (300MHz, CD3OD): δ=8.51 (d, J=5.4Hz, 1H), 7.38-7.28 (m, 1H), 7.28-7.16 (m, 1H), 7.00-6.91 (m, 2H), 6.86 (d, J=8.3H z, 1H), 5.30 (t, J=5.6Hz, 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.

[0874] The following compounds can be prepared according to Scheme 11 below:

[0875] 115, 116, 117, 118, 237, 115-INT-3, 239, 239-INT-1, 237A.

[0876] Solution 11

[0877]

[0878] Exemplary procedures for compounds 115 and 116:

[0879] Synthesis of 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine as a white solid

[0880]

[0881] To a 250-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 4-chlorothieno [3,2-d] pyrimidine (5.0 g, 29.3 mmol, 1.0 equiv), 3,5-difluorophenyl substituted boronic 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), H2O (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 with ethyl acetate / petroleum ether (1 / 10-1 / 4). This obtained 7.8 g (crude) of 4- (3,5-difluorophenyl) thieno [3,2-d] pyrimidine as a white solid. (ES, m / z): 249 [M+H] + .

[0882] 1. Synthesis of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine

[0883]

[0884] 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), AcOH (52.0 mL). The resulting solution was stirred at 70 ° C for 2 days. The reaction was then quenched by pouring 500 mL of NaHCO3 ice water solution. The resulting solution was extracted with 2x500 mL of ethyl acetate. The EA mixture was washed with 2x500 mL of aq.NaCHO3 and 1x500 mL of aq.NaS2SO3. The resulting EA mixture was washed with 1x500 mL of brine. The EA mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated. This obtained 4 g of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine as a light yellow solid.

[0885] 2. Synthesis of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid

[0886]

[0887] 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (1.3 g, 1.0 eq.), THF (130.0 mL) were added to a 250-mL 3-neck round-bottom flask flushed and maintained with an inert nitrogen atmosphere. LDA (4.0 mL, 1.5 eq.) was then added dropwise with stirring at -78 °C. The resulting solution was stirred at -78 °C for 30 minutes. CO2 was passed through it at -50 °C. The resulting solution was stirred at -50 °C for an additional 2 hours. The resulting solution was stirred at room temperature for an additional 2 hours. Then, 100 mL of water was added to quench the reaction. The solid was collected by filtration. This obtained 500 mg of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid as a light yellow solid.

[0888] 3. Synthesis of 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide

[0889]

[0890] To a 250-mL round-bottom flask was added 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid (1.6 g, 4.3 mmol, 1.0 eq), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (707.4 mg, 4.7 mmol, 1.1 eq), HATU (3278.2 mg, 8.6 mmol, 2 eq), DIEA (1392.8 mg, 10.7 mmol, 2.5 eq), DMF (50.0 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 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 (300MHz, DMSO-d6): δ=9.49 (s, 1H), 9.40 (d, J=8.1Hz, 1H), 7.82 (d, J=6.6Hz, 2H), 7.65 (t, J=9.0Hz, 1H), 7.35 (d, J=7.2Hz, 1H ), 7.20 (t, J=6.9Hz, 1H), 6.94 (t, J=7.2Hz, 1H), 6.82 (d, J=8.1Hz, 1H), 5.29 (d, J=6.6Hz, 1H), 4.29 (s, 2H), 42.25-2.13 (m, 2H)ppm.

[0891] 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

[0892]

[0893] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 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)-λ4-borane (38.0 mg, 0.3 mmol, 2.0 equiv), Pd(dppf)Cl2 (15.0 mg, 0.02 mmol, 0.2 equiv), K3PO4 (48.0 mg, 0.3 mmol, 2.0 equiv), dioxane (3.0 mL), H2O (0.3 mL). The resulting solution was stirred at 80°C overnight. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O=20 / 80 increasing to ACN / H2O=100 / 0 within 15 minutes; detector, 254 nm. This gave 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 (300MHz, CD3OD): δ=9.34 (s, 1H), 7.81-7.78 (m, 2H), 7.49 (d, J=7.2Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.02 (m, 1H), 6.97-6.87 (m, 2H) ), 5.60 (t, J = 1.5Hz, 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.

[0894] 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

[0895]

[0896] 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), PtO2 (90.0 mg, 1.0 equiv), EA (20.0 mL). The mixture was flushed with H2 6 times. The resulting solution was stirred at room temperature overnight. The solid was filtered off. The filtrate was concentrated. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O=30 / 70 increasing to ACN / H2O=80 / 20 in 15 minutes; 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 (300MHz, DMSO-d6): δ=9.40 (s, 1H), 9.34 (d, J=6.9Hz, 1H), 7.79 (d, J=6.0Hz , 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),

[0897] 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.

[0898] 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

[0899]

[0900] 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), dimethylamine (2M in THF, 50.0 mL) were added to a 50-mL sealed tube. The resulting solution was stirred at 110°C for 4 hours. The resulting mixture was concentrated. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O=20 / 80 increased to ACN / H2O=90 / 10 in 15 minutes; 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 (300MHz, CDCl3): δ=10.36 (d, J=8.1Hz, 1H), 9.28 (s, 1H), 7.76 (dd, J=8.1, 2.1Hz, 2H), 7.32 (d, J=7.8Hz, 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.

[0901] 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

[0902]

[0903] To a 50-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 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), Pd2(dba)3 (20.0 mg, 0.02 mmol, 0.1 equiv), Xantphos (23.0 mg, 0.04 mmol, 0.2 equiv), toluene (10.0 mL), Cs2CO3 (130.0 mg, 0.4 mmol, 2.0 equiv). The resulting solution was stirred at 110°C for 3 hours. The solid was filtered off. The filtrate was concentrated. The crude product was purified by flash-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN / H2O=10 / 90 increasing to ACN / H2O=90 / 10 within 15 minutes; detector, 254 nm. This gave 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 (300MHz, CDCl3): δ=10.64 (d, J=6.9Hz, 1H), 9.31 (s, 1H), 7.80 (dd, J=8.1, 2.1Hz, 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.

[0904] The following compounds can be prepared according to Scheme 12 below and the procedures detailed below:

[0905] 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.

[0906] Solution 12

[0907]

[0908] Exemplary procedure for compound 201:

[0909] 1. Synthesis of 3-bromo-7-chlorothieno[3,2-b]pyridine

[0910]

[0911] To a 3000-mL 3-neck round bottom flask was added 7-chlorothieno[3,2-b]pyridine (25.0 g, 147.3 mmol, 1.0 eq), CHCl3 (4166.6 mL, 34903.0 mmol, 350.5 eq), KHSO4 (30.1 g, 221.0 mmol, 1.5 eq), NaHCO3 (12.3 g, 147.4 mmol, 1.0 eq), MgSO4 (26.6 g, 221.0 mmol, 1.5 eq), Br2 (235.5 g, 1473.8 mmol, 10.0 eq). The resulting solution was stirred at 70 °C for 16 hours. The reaction was cooled to room temperature. The reaction was then quenched by adding 500 mL of Na2S2O3 (aq.). The resulting solution was extracted with 2x1 L of DCM. The organic layers were combined, dried and concentrated under reduced pressure. This gave 30 g (81.9%) of 3-bromo-7-chlorothieno[3,2-b]pyridine as a yellow solid.

[0912] 2. Synthesis of 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid

[0913]

[0914] To a 2000-mL flask was added 3-bromo-7-chlorothieno[3,2-b]pyridine (30.0 g, 1.0 eq.), THF (1000.0 mL), LDA (84.0 mL, 1.5 eq.). The resulting solution was stirred at -78 °C for 2 hours. CO2 was introduced to the above at -78 degrees Celsius for 2 hours. The reaction was then quenched by adding 500 mL of NH4Cl. The solid was collected by filtration. This gave 18 g (51.1%) of 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid as a yellow solid.

[0915] 3. Synthesis of 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]thieno[3,2-b]pyridine-2-carboxamide

[0916]

[0917] To a 500-mL round-bottom flask was added 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), (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 adding 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.

[0918] 4. Synthesis of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-(prop-1-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide

[0919]

[0920] To a 500-mL round-bottom flask flushed and maintained with an inert nitrogen atmosphere was added 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), trifluoro(prop-1-en-2-yl)-λ4-borane potassium (2.6 g, 17.7 mmol, 1.5 equiv), Pd(dppf)Cl2 (0.8 g, 1.2 mmol, 0.1 equiv), K3PO4 (5.0 g, 23.6 mmol, 2.0 equiv), dioxane (100 mL), H2O (10 mL). The resulting solution was stirred at 90 ° C for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This 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.

[0921] 5. Synthesis of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide

[0922]

[0923] To a 1000-mL round-bottom flask was added 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, a yellow solid (2.50 g, 6.5 mmol, 1.0 equiv), EA (500.0 mL), Pt2O (1.5 g). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen flushing. The mixture was stirred at 40 ° C under a hydrogen atmosphere (balloon) for 3 h. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated. This obtained 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, a yellow solid.

[0924] 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

[0925]

[0926] To a 20-mL microwave tube flushed and maintained with an inert nitrogen atmosphere was added 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)Cl2 (17.00 mg, 0.026 mmol, 0.1 equiv), K3PO4 (137.0 mg, 0.6 mmol, 2.5 equiv), H2O (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-preparative-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, CH3CN / 0.05% NH3.H2O=100%; detector, 254 & 220nm. This obtained 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 (300MHz, DMSO-d6): δ=9.03 (d, J=7.8Hz, 1H), 8.84 (d, J=3.6Hz, 1H), 7.30 (d, J=3.9Hz, 1H), 7.20-7.09 (m, 4 H), 6.91-6.77 (m, 2H), 5.24-5.22 (m, 1H), 4.23 (s, 2H), 3.93 (t, J=6.9Hz, 1H), 2.12-2.04 (m, 8H), 1.53 (s, 6H)ppm.

[0927] Exemplary procedure for compound 255:

[0928]

[0929] To a 100-mL round-bottom flask was added 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), 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 H2O2 (30%) (2.50 mL, 107.3 mmol, 928.3 equiv), NaHCO3 (5 mL) were added dropwise in the flask. The resulting solution was allowed to stir and react for an additional 30 minutes at room temperature. 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 reduced pressure. The crude product was purified by preparative-HPLC using the following conditions (2# SHIMADZU (HPLC-01)): column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water and ACN (16% B phase to 40% in 7 minutes); detector, UV 254nm. 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.

[0930]

[0931] 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), DCM (2.0 mL). DAST (0.1 mL) was then added dropwise with stirring at 0°C. The resulting solution was stirred at 25°C for 1 hour. The reaction was then quenched by adding MeOH (0.5 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative-HPLC using the following conditions (2# SHIMADZU (HPLC-01)): column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water and ACN (16% CH3CN to 40% in 7 minutes); detector, UV 254nm. This gave 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. 1 H-NMR (300MHz, 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=6.9Hz, 1H), 5.35 (d, J=5.7Hz, 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.

[0932]

[0933] The following additional compounds were prepared according to the preceding scheme:

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956] Biological Examples

[0957] The present disclosure is further illustrated by the following biological examples, which are not to 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 it is not intended to limit the scope of the present disclosure thereby. It should also be understood that various other embodiments, modifications and equivalents which are apparent to those skilled in the art may be performed without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0958] Example 1: Screening method to test compounds for activity against Dirofilaria immitis microfilariae.

[0959] 400 to 600 Dirofilariae are added to each well of a microtiter plate containing RPMI medium and the test compound formulated in 100% DMSO. The plates are kept at 37°C and 5% CO2 for 3 days. The efficacy of the compound depends on the motility of the microfilariae compared to the average motility in control wells containing only DMSO. Dose response tests are performed to determine the EC 50 Compounds 310, 228, 217, 301, 205 and 259-4 showed EC values ​​ranging from 100 nM to 10 μM.50 Compounds 259-5, 260, 258, 220, 222, 203, 213, 199, 229, 224, 221, 247 and 214 showed EC values ​​ranging from 10 nM to 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 showed an EC value of less than 10 nM. 50 value.

[0960] Example 2: Screening method to test compounds for activity against Haemonchus contortus.

[0961] Twenty L1 Haemonchus contortus larvae were added to the wells of a microtiter plate containing a nutrient culture and a DMSO solution of the test compound. Analysis was performed on day 4 to determine the extent of growth of L1 to L3 larvae. Larvae exposed to DMSO alone served as controls. Dose response tests were 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 were tested to have EC 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 showed EC values ​​of less than 100 nM. 50 value.

[0962] Example 3: In vivo efficacy against Dirofilaria immitis in immunodeficient NSG mice.

[0963] The following in vivo studies for evaluating the effectiveness of the compounds of the present invention in preventing heartworm infection in mammals were performed according to the procedures described in WO 2018 / 148392 A1 (incorporated herein by reference). For the following studies, heartworms were obtained from the University of Georgia Vet School's Filariasis Research Reagent Resource Center (hereinafter referred to as "FR3") and internal insect rooms. Typically, worms are obtained from mosquitoes and transported overnight in culture medium and antibiotics. The worms are washed and counted for use in mice. At day 0, 50 L3 heartworms (2005Missouri isolates or JYD-34) were injected subcutaneously or via intraperitoneal injection into immunodeficient NSG mice susceptible to heartworm infection. The compounds of the present invention at the dosage levels indicated in the study were orally administered to NSG mice at days 1, 15, and 30 after infection.

[0964] To recover parasites, mice were bled 6 weeks after infection to collect serum, skinned and scored for fascia, eviscerated, and scored for muscle fascia. All samples were soaked overnight at room temperature in RPMI medium supplemented with 10% FBS and Pen / strep antibiotics. The next morning, approximately 18 hours later, worms were counted and fixed in 95% ethanol / 5% glycerol. Worms were sealed in glycerol jelly and then measured with cellSens software.

[0965] Study #1

[0966] Four groups of 6 immunodeficient NSG mice were set up. One untreated group served as a control, and the other three groups were given dose levels of 25 mg / kg body weight, 50 mg / kg and 25 mg / kg of compounds 211, 204 and 212, respectively. The compounds were in Labrasol / M 1944CS (70:30) vehicle was formulated at a concentration of 2.5 mg / mL and orally administered to mice at the doses indicated in the table below. Compound efficacy was evaluated relative to a control group of untreated mice. Table 6 below shows the reduction in the percentage of live worms recovered from the treated groups compared to the control group.

[0967] Table 6

[0968] Compound# Dosage (mg / kg) Worm reduction % P-value 211 25 61 0.002 204 50 65 0.002 212 23 13 0.501

[0969] Study #2

[0970] The efficacy of compounds 119 and 120 was studied at two different dose levels using a protocol similar to Study #1. A control group of 6 NSG mice was assigned. Four groups of 5 NSG mice each were assigned for the study to be administered compounds 119 and 120 at dose levels of 25 mg / kg and 50 mg / kg body weight. The compounds were administered as in Study #1 in Labrasol / M1944 was formulated in CS (70:30) vehicle at a concentration of 2.5 mg / mL and orally administered to mice at the doses indicated in Table 7 below.

[0971] Table 7

[0972] Compound# Dose(mg / kg) Worm reduction % P-value 119 25 67 0.000 119 50 37 0.005 120 25 47 0.003 120 50 33 0.009

[0973] Study #3

[0974] The efficacy of compounds 210, 257, 207 and 102 was investigated using a protocol similar to that of Study #1. A control group of 7 NSG mice was assigned. Four additional test groups were assigned for administration of compounds 210, 257, 207 and 102. The group for compound 210 contained 7 NSG mice and the groups for compounds 257, 207 and 102 each contained 6 NSG mice. Compounds were administered as in Study #1 in Labrasol / M1944CS (70:30) was formulated in a vehicle at a concentration of 2.5 mg / mL and was orally administered to mice at a level of 25 mg / kg body weight. The results of the study are shown in Table 8 below.

[0975] Table 8

[0976] Compound# Worm reduction % P-value 210 55 0.008 257 45 0.028 207 55 0.010 102 50 0.018

[0977] Accordingly, compounds of the invention were tested in the NSG mouse model for activity against Dirofilaria immitis.

[0978] Example 4: In vivo efficacy against Haemonchus contortus and Trichostrongylus colubriformis in Mongolian gerbils (Meriones unguiculatus).

[0979] Several in vivo studies were conducted to test the efficacy of the compounds of the invention against Haemonchus contortus and Trichostrongylus hyaline in Mongolian gerbils. Groups of 5 animals were assigned to each treatment group, untreated control group, and positive control group. Gerbils in the untreated control group were given Labrasol / M 1944 CS (70:30) vehicle. Animals in the positive control group were treated with thiocarbamide (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 Mongolian gerbils were artificially infected with approximately 1,000 infective third instar larvae of the sheathed Haemonchus contortus. At least 4 hours later, the gerbils were also infected with approximately 1,000 third instar larvae of the sheathed Trichostrongylus nematode. Six days after infection, the gerbils were treated by oral gavage with the test compound dissolved in Labrasol / M 1944 CS (70:30) mixture. On day 9 (3 days after treatment), the gerbils were euthanized and autopsied to recover parasites from the stomach and small intestine. The efficacy was calculated as the average % reduction in the number of worms in each test group compared to the average number of worms in the control group. The efficacy of the tested compounds is shown in Tables 9 to 12 below.

[0980] Study 1:

[0981] Table 9

[0982]

[0983] Study 2:

[0984] Table 10

[0985]

[0986] Study 3:

[0987] Table 11

[0988]

[0989] Study 4:

[0990] Table 12

[0991]

[0992] Thus, the compounds of the present invention were tested in the Mongolian gerbil model to be highly effective against Haemonchus contortus and Trichostrongylus nematodes.

[0993] ***

[0994] Although the preferred embodiments of the present invention have been described above in detail, it should be understood that the invention defined in the preceding paragraphs is not limited to the specific details of the foregoing description, as many obvious variations are possible without departing from the spirit or scope of the present invention.

Claims

1. Compound of formula I: or a pharmaceutically acceptable salt thereof, in: L is L1 or L2: R 1 is hydrogen, cyano, halo, hydroxy, 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 Where R a and R b is independently H or optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; 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, spirocyclic heterocyclyl-heterocyclyl, spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b is independently H or optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 4 Each specific value of is independently hydrogen, cyano, halo, hydroxy, 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 Where R a and R b is independently H or optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 5 and R 5’ Each specific value of is independently hydrogen, halogen, cyano, nitro, hydroxy, 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 Where R c and R d is independently H or optionally substituted alkyl; or R c and R d may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 10 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl; X is O or S; Q is O, S or NR 2’ ; Y 1 , Y 2 and Y 3 Each independently is -N- or -CR 4 -; Y 1’ and Y 6’ Each independently is N, C, or -CR 5 -; Y 2’ , Y 3’ , Y 4’ , Y 5’ Each independently is N, NR 2 ,S,O,-CR 5 - or CR 5 R 5’ ; W is CR 6 R 7 , O, S, or N-R 8 , Z is CR 6 R 7 , O, S, or N-R 8 , in R 6 and R 7 Each specific value of is independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C3-C8-cycloalkoxy; R 8 is hydrogen or C1-C4-alkyl; and where Y 1’ , Y 2’ , Y 3’ , Y 4’ , Y 5’ and Y 6’ At most 3 of them are heteroatoms; a is 0 or 1; q is 0 or 1; Each specific value of p is independently 0, 1 or 2; and Dotted key represents a single bond or a double bond; Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts.

2. The compound of formula (I) according to claim 1, in: R 1 is hydrogen, cyano, halo, hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, hydroxy-C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-alkyl 6-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, 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, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), or -NR a R b Where R a and R b is independently H or optionally substituted C1-C6-alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; 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 N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 4 Each specific value of is independently hydrogen, cyano, halo, hydroxy, 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 substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from 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 Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 5 and R 5’ Each specific value of is independently hydrogen, halogen, cyano, nitro, hydroxy, 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 Where R c and R d are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R c and R d may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; and R 10 is hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C2-C6-alkenyl or C2-C6-alkynyl.

3. A compound of formula (I) according to claim 1 or 2, wherein R 1 is hydrogen, cyano, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C2-C4-alkenyl, optionally substituted C2-C4-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted saturated or unsaturated 5-, 6- or 7-membered heterocycle, 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 Where R a and R b is independently optionally substituted alkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic group which may be optionally substituted; R 2 is hydrogen or C1-C4-alkyl; R 3 is C1-C4-alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C3-C8-cycloalkyl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, or 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, each of which may be optionally substituted with 1, 2 or 3 substituents; R 4 is independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, amino, NH-optionally substituted C1-C4-alkyl, -SF5, or -NR a R b Where R a and R b is independently optionally substituted C1-C4-alkyl; or R a and R b can form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic radical, which may be optionally substituted, -SO p (optionally substituted C1-C4-alkyl or haloalkyl); and R 5 is independently 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 Where R c and R d is independently optionally substituted C1-C4-alkyl; or R c and R d can form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic radical which may be optionally substituted, SO p (optionally substituted C1-C4-alkyl or haloalkyl).

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

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

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

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

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

9. A compound of formula (I) according to any one of claims 1 to 8, wherein: L is L1; R 1 is halo, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-haloalkyl, alkoxy-C1-C4-alkyl, alkoxy-C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl , C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-haloalkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 2 is hydrogen or C1-C4-alkyl; R 3 is C1-C6-alkyl, C1-C6-haloalkyl, 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, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), -SF5, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, wherein each ring of the spirocyclic group contains 3, 4, 5 or 6 ring atoms; or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 4 Each specific value of is independently hydrogen, halo, -SF5, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, optionally substituted C3-C6-cycloalkyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-haloalkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, di-C1-C4-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 5 Each specific value of is independently hydrogen, halogen, -SF5, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), or -NR c R d Where R c and R d are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 10 is hydrogen, halogen, C1-C4-alkyl or C1-C4-haloalkyl; Q is O or S; Z is O; and W is CR 6 R 7 。 10. A compound of formula (I) according to claim 9, wherein a is 1 and q is 1.

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

12. The compound of formula (I) according to claim 9, which is represented by the following formula (IC): in R 9 is independently halo, cyano, nitro, C3-C8-cycloalkyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 1 is halo, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy-C1-C4-alkyl, alkoxy-C1-C4-alkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-haloalkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 4 Each specific value of is independently hydrogen, halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), -SF5, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 5 is halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), -SF5, or -NR c R d Where R c and R d are independently H, C1-C4-alkyl or C1-C4-haloalkyl; W is CR 6 R 7 ; R 2 is hydrogen or C1-C3-alkyl; R 10 It is hydrogen; o is 0, 1, or 2; and m is 0, 1, 2 or 3.

13. A compound of formula (I) according to claim 9, which is represented by the following structure: in: R 9 is independently halo, cyano, nitro, C3-C8-cycloalkyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 1 is halo, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy-C1-C4-alkyl, alkoxy-C1-C4-alkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-haloalkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 4 Each specific value of is independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), -SF5, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 5 and R 5’ Each specific value of is independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, -SO p (optionally substituted C1-C4-alkyl or C1-C4-haloalkyl), -SF5, or -NR c R d Where R c and R d are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 2 is hydrogen or C1-C3-alkyl; R 10 It is hydrogen; Z is CR 6 R 7 or O; Y 1’ and Y 6’ Each independently is C, N or CR 5 ; Y 3’ , Y 4’ , Y 5’ Independently CR 5 , CR 5 R 5’ ,N,NR 2 , O or S; Dotted key represents a single bond or a double bond; a is 0 or 1; and m is 0, 1, 2 or 3.

14. A compound according to claim 13, wherein Y 1’ and Y 6’ Each is C; Y 3’ and Y 4’ Independently CR 5 ;and Y 5’ It’s S.

15. A compound according to claim 13, wherein Y 3’ and Y 6’ is N; Y 1’ is C; and Y 4’ and Y 5’ Independently CR 5 .

16. A compound according to claim 13, wherein Y 1’ and Y 5’ is N; Y 6’ is C; and Y 3’ and Y 4’ Independently CR 5 .

17. A compound according to claim 9, which is represented by the following structure: in R 9 is independently halo, cyano, nitro, C3-C8-cycloalkyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or -NR a R b Where R a and R b are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 1 is halo, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy-C1-C4-alkyl, alkoxy-C1-C4-alkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C2-C4-alkynyl, C2-C4-haloalkynyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, aminocarbonyl, C1-C4-alkylaminocarbonyl, C1-C4-haloalkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b Where R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form with the nitrogen to which they are attached a 3-, 4-, 5- or 6-membered-heterocyclyl group which may include 1 to 3 additional heteroatoms selected from N, O and S and may be optionally substituted; R 5 is halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), -SF5, or -NR c R d Where R c and R d are independently H, C1-C4-alkyl or C1-C4-haloalkyl; R 2 is hydrogen or C1-C3-alkyl; R 10 It is hydrogen; D is -N- or -CH-, D 1 is -NH-, -O-, -CH2-; or D 1 bonded to a 2- to 5-membered chain optionally containing N, O or S heteroatoms to form a spirocyclic heterocyclyl-heterocyclyl, spirocyclic heterocyclyl-carbocyclyl, spirocyclic carbocyclyl-carbocyclyl or spirocyclic carbocyclyl-heterocyclyl; m is 0, 1, 2, or 3; and b is 0 or 1.

18. A compound according to claim 12, wherein 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; R 4 Each specific value of is independently hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl; and R 5 Each specific value of is independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl.

19. A compound according to claim 13, wherein 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; R 4 Each specific value of is independently hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl; and R 5 Each specific value of is independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl.

20. The compound according to claim 17, wherein 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; R 4 Each specific value of is independently hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl; and R 5 Each specific value of is independently halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, or phenyl which is optionally substituted 1 or 2 times by halogen or C1-C4-alkyl.

21. The compound of any one of claims 1 to 20, wherein Y 1 , Y 2 and Y 3 Each is -CR 4 .

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

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

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

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

26. The compound of claim 1, wherein the compound has the structure shown in the following table, wherein R 2 and R 2’ are all hydrogen; Q is oxygen; and Group In the tables, "ring systems" are abbreviated and represent the following radicals:

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

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

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

30. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for the treatment, control or prevention of parasitic infections or infestations in animals.

31. A compound of formula (I) as claimed in any one of claims 1 to 26 for use in the treatment, control or prevention of parasitic infections or infestations in animals.

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