Anthelmintic heterocyclic compounds

Abstract

The present invention provides compounds of formula (I), or salts thereof, in which the variables are defined herein, compositions comprising these compounds, and methods for treating, controlling, or preventing parasitic infestation or infection in animals by administering an effective amount of these compounds to an animal in need thereof. JPEG2023528822000306.jpg4482(I)

Description

[Technical Field]

[0001] This patent application relates to new antiparasitic compounds, compositions containing the compounds, methods for their preparation, and methods of using the compounds to control parasites that harm animals and humans. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 031,656, filed May 29, 2020, which is incorporated herein by reference in its entirety. [Background technology]

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

[0003] One type of internal parasite that seriously infects mammals is Dirofilaria immitis, also known as heartworm. Other filarial internal parasites include Dirofilaria repens and Dirofilaria honkongensis, which can also infect humans. The most common hosts are dogs and cats, but other mammals, such as ferrets and raccoons, can also be infected. Heartworms undergo several life stages before becoming adult worms that infect the pulmonary arteries of mammalian hosts. These worms require a mosquito as an intermediate host to complete their life cycle. The period between initial infection by a mosquito bite and maturation of the worms into adult worms that inhabit the heart and pulmonary arteries is 6 to 7 months in dogs, known as the "pre-occurring stage." During a blood meal, L3 larvae migrate to the tip of the mosquito's mouthparts (lower lip), exit the mosquito, and deposit themselves on the dog's skin, then migrate into the host through the bite wound. Most L3 larvae molt into fourth-stage nymphs (L4) in the dog's subcutaneous tissue within one to three days after infection. These larvae then migrate to the thoracic and abdominal muscles, where they molt into fifth-stage nymphs (L5, immature adults) 45 to 60 days after infection. Between 75 and 120 days after infection, these immature heartworms enter the bloodstream, are transported through the heart, and reside in the pulmonary artery. Approximately seven months after infection, Dirofilaria immitis adult worms mature and sexually reproduce in the pulmonary artery and right ventricle. Adult males are approximately 15 cm long, and females are approximately 25 cm long. Their normal adult lifespan is estimated to be approximately five years.

[0004] Heartworm infection is a serious, life-threatening disease. Heartworm infection in dogs is preventable, and preventive treatment is a priority in heartworm-endemic areas. Treatment of mature heartworm infection with adulticides (e.g., melarsomine dihydrochloride) is expensive and can cause serious side effects, so prevention with monthly administration of drugs that inhibit larval development is widely used. The goal of commercially available heartworm preventative therapy is to prevent the parasite from developing into adult heartworms by interrupting the Dirofilaria immitis life cycle after infection. Macrocyclic lactones (MLs, e.g., ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemoprophylactic agents and are administered monthly or at 6-month intervals. These drugs have been effective against mosquito-deposited Dirofilaria immitis infective third-stage (L3) and mature fourth-stage (L4) larvae. When administered monthly, MLs kill L3 and L4 larvae acquired within the previous 30 days, thereby preventing disease caused by adult worms. MLs can also be used monthly in infected dogs to suppress the reproduction of adult worms and eliminate microfilariae, thereby reducing transmission and gradually reducing the adult worm population (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206).

[0005] In recent years, an increasing number of cases of lack of efficacy (LOE) have been reported in dogs developing mature heartworm infections despite receiving monthly prophylactic doses of macrocyclic lactone drugs. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) recently reported an increase in the number of cases in dogs receiving heartworm preventative medication but testing positive for heartworm antigens, suggesting that some populations of Dirofilaria immitis are developing selective resistance to heartworm preventative medications (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5.). Therefore, there is a continuing need to develop new anthelmintics with improved activity against Dirofilaria immitis and other endoparasites.

[0006] WO 2017 / 178416 provides pyrazolopyrimidine derivatives for controlling, treating, and / or preventing helminths. WO 2018 / 197401 provides bicyclic pyrazole derivatives for controlling, treating, and / or preventing helminths. WO 2018 / 087036 provides quinolone-3-carboxamide derivatives for controlling, treating, and / or preventing helminths. WO 2019 / 025341 provides quinoline compounds for treating, controlling, and / or preventing helminth infections, and WO 2019 / 002132 provides azaquinone derivatives for controlling, treating, and / or preventing helminths. All of these publications are by Bayer Animal Health GmbH and are incorporated herein by reference in their entirety. More recently, WO 2020 / 014068 (incorporated herein by reference) describes anthelmintic heterocyclic compounds that were found to be active against Dirofilaria immitis. It is expressly noted that citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. The application and all documents cited therein or during its prosecution ("application cited documents") and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein ("documents cited herein"), and all documents cited or referenced in the documents cited herein, together with manufacturer's instructions, descriptions, product specifications and product sheets for any products referenced in this specification or any document incorporated by reference herein, are hereby incorporated by reference and may be used in the practice of this invention. Summary of the Invention

[0007] The present application provides novel antiparasitic and antiparasitic heterocyclic compounds with 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 / or preventing parasitic infestations and / or infections in animals, including humans. The compounds can be administered to animals, particularly mammals, fish and birds, to prevent and / or treat parasitic infections. One aspect of the present invention is a compound of formula (I): [ka] (I) its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, where variable R 1 , R 2 , R 3 , R 9 , R 9’ , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , L, Q, W, Z, a, and q are as defined herein; and the dashed bond [ka] indicates a single or double bond).

[0008] The present invention also includes veterinarily acceptable compositions comprising a compound of formula (I) and a veterinarily acceptable carrier, and methods for controlling parasites, including helminths, comprising administering the compound or a veterinarily acceptable composition thereof to an animal in need thereof. Some embodiments of the present invention also include the use of compounds of formula (I) to eradicate, control, and prevent parasitic infestations and / or infections in animals and humans. The compounds of the present invention can be administered to animals, particularly mammals, fish, and birds, to prevent or treat parasitic infections and / or infestations. The compounds and compositions containing the compounds are highly effective in treating and / or preventing endoparasites in mammals, fish and birds, particularly cats, dogs, horses, chickens, pigs, sheep and cattle, with the aim of substantially eliminating endoparasites from these hosts.

[0009] In one embodiment, compounds of Formula (I) and compositions comprising the compounds are substantially effective against filariasis (e.g., heartworms) of the gastrointestinal tract of animals and humans, and endoparasites such as hookworms, whipworms, and roundworms. In certain embodiments, compounds of Formula (I) and compositions comprising the compounds are effective against Dirofilaria immitis (heartworm) isolates that are less susceptible to treatment with macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are effective in treating and / or preventing infections in animals with nematodes that are less susceptible to treatment with commercially available or known active agents. In certain embodiments, the present invention comprises a combination of a compound of formula (I) and at least a second active agent that can broaden the scope of protection afforded to an animal against endoparasites and / or ectoparasites.

[0010] Another embodiment includes a method of treating and / or preventing a parasitic infection and / or infestation in an animal, the method comprising the step of administering to the animal a compound of formula (I). Another embodiment includes the use of a compound of formula (I) for treating and / or preventing a parasitic infection and / or infestation in an animal, and the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing a parasitic infection in an animal. Thus, the present invention includes the following non-limiting embodiments: (a) a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, which is an active endoparasiticidal agent and, optionally, is also active against ectoparasites; (b) a veterinary composition comprising a parasiticidally effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, in combination with a pharmaceutically or veterinarily acceptable carrier or diluent; (c) a veterinary composition comprising a parasiticidally effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, in combination with one or more additional active agents (i.e., active ingredients not encompassed by formula (I)) and a pharmaceutically or veterinarily acceptable carrier or diluent; (d) a method for treating parasitic infections and / or infestations in or on an animal, comprising administering to an animal in need thereof a parasiticidally effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, optionally together with one or more additional active agents (i.e., active ingredients not encompassed by formula (I)); (e) a method for preventing parasitic infection and / or infestation in an animal, comprising administering to an animal in need thereof a parasiticidally effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, optionally together with one or more additional active agents (i.e., active ingredients not encompassed by formula (I)); (f) the use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, optionally with one or more additional active agents (i.e., active ingredients not encompassed by formula (I)), for the treatment and / or prevention of parasitic infections and optionally parasitic infestations in animals; (g) The use 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 encompassed by formula (I)), for the manufacture of a veterinary medicine for the treatment and / or prevention of parasitic infections and / or infestations in animals; (h) A method for preparing a compound of formula (I). These and other embodiments are disclosed by or are obvious from and encompassed by the following detailed description.

[0011] Definition: It should be noted that in this disclosure, and particularly in the claims and / or paragraphs, terms such as "comprises," "comprised," "comprising," etc. may be interpreted as "includes," "included," "including," etc.; and terms such as "consisting essentially of" and "consists essentially of" may be interpreted to allow for elements not expressly recited, but to exclude elements found in the prior art or that affect a basic or novel characteristic of the invention.

[0012] Terms used herein have their conventional meaning in the art unless otherwise specified. The organic moieties referred to in the definitions of the variables of compounds, e.g., compounds of formula (I), are like the term halogen - i.e., members of the individual groups - generic to the individual enumerations of fluoro, chloro, bromo, and iodo for halogen. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group from an integer n to another integer m. In this specification and claims, the term "including but not limited to" is equivalent to "included."

[0013] The term "compounds of formula (I)" includes any stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof. The term "optionally substituted" means a group that is optionally substituted with one or more of the following moieties: halogen, hydroxyl, alkyl, haloalkyl, carboxyl, acyl, acyloxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, haloalkoxy, aryloxy, nitro, cyano, azido, thiol, Thioamide, imino, amidine, guanidine, carbonate, silyl, silyl ether, SF5, sulfonic acid, sulfate, sulfonyl, alkoxysulfonyl, sulfanyl, sulfinyl, sulfamoyl, sulfoximine, sulfinimine, sulfonimidamide, sulfondiimine, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, phosphonamidate, phosphineamidate, phosphinate, phosphine oxide, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, aryl and heteroaryl.

[0014] In some embodiments, the term "optionally substituted" refers to the substitution of the core group with halogen (chloro, fluoro, bromo, iodo), C-C 6-Alkyl, C1-C6-haloalkyl, 3- to 8-membered cycloalkyl, amino, C1-C6-alkylamino, C1-C6-dialkylamino, C1-C6-alkoxy, C1-C6-haloalkoxy, cyano, nitro, SF5, acetyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, aminocarbonyl, C1-C6-alkylamino C-C6-haloalkylaminocarbonyl, C-C6-dihaloalkylaminocarbonyl, C-C6-dihaloalkylaminocarbonyl, C-C6-alkylthio, C-C6-alkylsulfinyl, C-C6-alkylsulfonyl, C-C6-haloalkylthio, C-C6-haloalkylsulfinyl, C-C6-haloalkylsulfonyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl.

[0015] In another embodiment, the term "optionally substituted" refers to the core group being substituted with halogen (chloro, fluoro, bromo, iodo), C-C-alkyl, C-C-haloalkyl, 3- to 8-membered cycloalkyl, amino, C-C-alkylamino, C-C-dialkylamino, C-C-alkoxy, C-C-haloalkoxy, cyano, nitro, SF, acetyl, C-C-alkoxycarbonyl, C-C-haloalkoxycarbonyl, C-C-alkylcarbonyl, C-C-haloalkylcarbonyl, including substitution by aminocarbonyl, C1-C3-alkylaminocarbonyl, C1-C3-dialkylaminocarbonyl, C1-C3-haloalkylaminocarbonyl, C1-C3-dihaloalkylaminocarbonyl, C1-C3-alkylthio, C1-C3-alkylsulfinyl, C1-C3-alkylsulfonyl, C1-C3-haloalkylthio, C1-C3-haloalkylsulfinyl, C1-C3-haloalkylsulfonyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl.

[0016] In certain embodiments, the term "optionally substituted" includes substitution with halogen (chloro, fluoro, bromo, iodo), methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyl, thiol, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methoxy, ethoxy, propoxy, CF3, CF2CF3, -OCF3, -OCF2CF3, -SCH3, -SCF3, -S(O)CH3, -S(O)CF3, -S(O)2CH3, -S(O)2CF3, morpholino, piperidinyl, pyridyl, and phenyl. In some embodiments, the compounds may be substituted with any other variable functional group, unprotected or protected as needed, that does not interfere with the biological activity of the compounds of the invention, known to those skilled in the art, for example as taught in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, which is incorporated herein by reference. For the avoidance of doubt, "optionally substituted alkyl" includes haloalkyl and hydroxyalkyl.

[0017] Unless otherwise specified, "alkyl," alone or in combination with heteroatoms, refers to a saturated straight-chain, branched, primary, secondary, or tertiary hydrocarbon, including those having 1 to 12 atoms, such as alkoxy, thioalkyl, alkylamino, etc. In some embodiments, an alkyl group is C1-C 10 , C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. 10Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl, and decyl, and isomers thereof. C1-C4-Alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

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

[0019] The term "alkenyl" refers to both straight and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl group is a C2-C 12 In other embodiments, the alkenyl may be C2-C 10, C2-C8, C2-C6, C2-C4, or C3-C4 alkenyl groups. In one alkenyl embodiment, the number of double bonds is 1 to 3; in another alkenyl embodiment, the number of double bonds is 1. Other ranges of carbon-carbon double bonds and carbon numbers are contemplated depending on the position of the alkenyl moiety on the molecule. An "alkenyl" group can contain more than one double bond in the chain. Examples of alkenyl or specific ranges thereof include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl;1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl- 2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl 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;

[0020] "Alkynyl" refers to both straight and branched carbon chains containing at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1 to 3; in another embodiment of alkynyl, the number of triple bonds is 1. In some embodiments, alkynyl groups contain 2 to 12 carbon atoms. In other embodiments, alkynyl groups contain C2-C 10 , C2-C8, C2-C6, or C2-C4 alkynyl groups. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated, depending on the location of the alkynyl moiety on the molecule. For example, as used herein, "C2-C 10 The term "alkynyl" means a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex- -1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, This refers to n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl, etc.

[0021] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more halogen atoms. For example, C1-C4-haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, etc. The term "fluoroalkyl," as used herein, refers to an alkyl in which one or more of the hydrogen atoms have been replaced by a fluorine atom, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. The term "haloalkenyl" refers to an alkenyl group, as defined herein, that is substituted by one or more halogen atoms. The term "haloalkynyl" refers to an alkynyl group, as defined herein, that is substituted by one or more halogen atoms.

[0022] The term "alkoxy" refers to alkyl-O-, where alkyl is as defined above. Similarly, the terms "alkenyloxy," "alkynyloxy," "haloalkoxy," "haloalkenyloxy," "haloalkynyloxy," "cycloalkoxy," "cycloalkenyloxy," "halocycloalkoxy," and "halocycloalkenyloxy" refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, where alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, OCH2-C2H5, OCH(CH3)2, n-butoxy, OCH(CH3)-C2H5, OCH2-CH(CH3)2, OC(CH3)3, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpent ... butyloxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, and the like.

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

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

[0025] The terms "heterocyclyl," "heterocyclic," or "heterocyclo" refer to a fully saturated or partially unsaturated non-aromatic cyclic group having one or more oxygen, sulfur, silicon, or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, within the ring, such as a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more moieties as described above for aryl groups. Exemplary monocyclic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, pi Examples include peridinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

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

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

[0028] Similarly, the terms "haloalkylthio", "cycloalkylthio", and "halocycloalkylthio" refer to the groups -S-haloalkyl, -S-cycloalkyl, and -S-halocycloalkyl, respectively, where the terms "haloalkyl", "cycloalkyl", and "halocycloalkyl" are as defined above. The term "alkylsulfinyl" refers to the group alkyl-S(=O)-, where "alkyl" is defined above. In some embodiments, the alkyl component of the alkylsulfinyl group is C-C 12 , C1-C 10, C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. Examples include, but are not limited to, -SO-CH3, -SO-C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, Examples thereof include 1,1-dimethylbutylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl, and 1-ethyl-2-methylpropylsulfinyl.

[0029] Similarly, the terms "alkenylsulfinyl," "alkynylsulfinyl," "haloalkylsulfinyl," "haloalkenylsulfinyl," and "haloalkynylsulfinyl" refer to the groups alkenyl-S(=O)-, alkynyl-S(=O)-, and haloalkyl-S(=O)-, haloalkenyl-S(=O)-, and haloalkynyl-S(=O)-, where the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are defined above.

[0030] The term "alkylsulfonyl" refers to the group alkyl-S(=O)2-, where the term "alkyl" is defined above. In some embodiments, the alkyl component of the alkylsulfonyl group is C1-C 12 , C1-C 10 , C1-C8, C1-C6 or C1-C4 alkyl groups. Examples include, but are not limited to, -SO2-CH3, -SO2-C2H5, n-propylsulfonyl, -SO2-CH(CH3)2, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO2-C(CH3)3, n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, Examples thereof include 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, and 1-ethyl-2-methylpropylsulfonyl.

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

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

[0033] One embodiment of the present invention is a compound of formula (I): [ka] (I) (In the formula, L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14 or L15:

[0034] [ka] and; R' is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 1 is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted dialkylaminoalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF5, or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0035] R 2is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted dialkylaminoalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF5, or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0036] R 3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) p(optionally substituted alkyl), -SF5, optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbocyclyl group, spirocyclic heterocyclyl-heterocyclyl group, spirocyclic carbocyclyl-carbocyclyl group, spirocyclic carbocyclyl-heterocyclyl group or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0037] R 4 and R 4’ is independently in each occurrence hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted dialkylaminoalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted di(alkyl)aminocarbonyl, optionally substituted alkylcarbonyloxy, optionally substituted alkylcarbonylamino, optionally substituted aryl, optionally substituted heteroaryl, -SF5, -SO p (optionally substituted alkyl or haloalkyl); or R 4 is R 4’together with -NR - to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H or optionally substituted alkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0038] R 8 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; R 9 and R 9’ are independently hydrogen, halo, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy or cycloalkoxy; or R 9 is R 9’ together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring, and the carbon or nitrogen atom in the chain may be substituted; Q is CR 8 or N; X is O, S, or N-R'; Y 1 and Y 6 are each independently N, C, or -CR 4 - and; Y 2 , Y 3 , Y 4 and Y 5 are independently N, NR ’ ,S,O,-CR 4 - or CR4 R 4’ and; W is CR 5 R 6 , O, SO p , or NR 7 and Z is CR 5 R 6 , O, SO p , or NR 7 and During the ceremony, R 5 and R 6 is independently at each occurrence hydrogen, halo, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy or cycloalkoxy, or R 5 is R 6 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring, wherein the carbon or nitrogen in said carbocyclic or heterocyclic ring may be substituted;

[0039] R 7 is hydrogen or C1-C4-alkyl; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 up to three of which are heteroatoms; a is 0 or 1; q is 0 or 1; p is independently in each occurrence 0, 1, or 2; Dashed bond [ka] indicates a single or double bond); This includes stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof.

[0040] In another embodiment, the present invention provides R' is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl or optionally substituted phenyl; R 1 are hydrogen, cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, hydroxy-C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C2-C6-alkynyloxy, C2-C6-haloalkynyloxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylcarbonyl, C1 -C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF5, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), or -NR a R b (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0041] R 2 is 1 to 3 selected from the group consisting of hydrogen, cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted C3-C8-cycloalkyloxy, N, O and S. F Optionally substituted 3- to 7-membered heterocyclyl containing a hetero atom, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), SF5, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0042] R 3is C1-C6-alkyl, C1-C6-haloalkyl, 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 C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SF5, -S(O) p (C1-C6-alkyl or C1-C6-haloalkyl), optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0043] R 4 and R 4’represents independently for each occurrence hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, 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-cycloa alkyloxy, optionally substituted C1-C6-alkylcarbonyl, optionally substituted C1-C6-alkoxycarbonyl, optionally substituted aminocarbonyl, C1-C6-alkylaminocarbonyl, di(C1-C6-alkyl)aminocarbonyl, optionally substituted C1-C6-alkylcarbonyloxy, optionally substituted C1-C6-alkylcarbonylamino, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF5, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl); or R 4 is R 4’ together with -NR - to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H, C-C-alkyl or C-C-haloalkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0044] R 8is hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C2-C6-alkenyl or C2-C6-alkynyl; L, Q, X, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , W, Z, R 5 , R 6 , R 7 , R 9 , R 9’ , a, q, p and dashed bond [ka] is as defined above for compounds of formula (I), A compound of formula (I) is provided.

[0045] In one embodiment, L is L1. In another embodiment, L is L2. In another embodiment, L is L3. In another embodiment, L is L4. In another embodiment, L is L5. In another embodiment, L is L6. In another embodiment, L is L7. In another embodiment, L is L8. In another embodiment, L is L9. In another embodiment, L is L10. In another embodiment, L is L11. In another embodiment, L is L12. In another embodiment, L is L13. In another embodiment, L is L14. In another embodiment, L is L15.

[0046] In some embodiments, R 1is 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 C3-C8-cycloalkenyl, optionally substituted saturated or unsaturated 5-, 6- or 7-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C1-C4-alkylcarbonyl, optionally substituted C1-C4-alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C4-alkylaminocarbonyl, optionally substituted C1-C4-dialkylaminocarbonyl, optionally substituted alkyl-SO p -, haloalkyl-SO p -, amino, -NH- optionally substituted C1-C4-alkyl, or -NR a R b (In the formula, R a and R b are independently optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group;

[0047] R' is hydrogen or C1-C4-alkyl; R 2 is hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, -amino, NH-optionally substituted C1-C4-alkyl, -SF5, or -NR a R b (In the formula, R c and R dare independently optionally substituted C1-C4-alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group), SO p (optionally substituted C1-C4-alkyl or haloalkyl); R 3 is C1-C4-alkyl, C3-C6-cycloalkyl, optionally substituted C5-C7-cycloalkenyl, 4- to 6-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, each of which may be substituted by 1, 2 or 3 substituents; R 4 and R 4 ' are independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C3-C8-cycloalkyl, -amino, NH-optionally substituted C1-C4-alkyl, -SF5; or R 4 is R 4’ together with -NR' to form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si and S, or which may contain the group NR', which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; or -NR' c R d (In the formula, R c and R d are independently optionally substituted alkyl; or R c and R d may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group), SO p (optionally substituted C1-C4-alkyl or haloalkyl).

[0048] In some embodiments, R 1 is hydrogen. In some embodiments, R 1is C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino or di(C1-C4-alkyl)amino. In another embodiment, R 1 is a halogen. In another embodiment, R 1 C1-C4-Alkyl-SO p -, C1-C4-haloalkyl-SO p -or SF5. In other embodiments, R 1 is hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-haloalkoxy-C1-C4-alkyl or C1-C4-haloalkoxy-C1-C4-haloalkyl.

[0049] In another embodiment, R 1 is methyl, ethyl, propyl, butyl, pentyl, isopropyl (i-Pr), tert-butyl (t-butyl), prop-1-en-2-yl, 2-fluoroprop-2-yl, 1,1-difluoroethyl, or 2-hydroxyprop-2-yl. In another embodiment, R 1 is C1-C3-alkoxy or C1-C3-haloalkoxy. In another embodiment, R 1 is OCH3 or OCH2CH3. In another embodiment, R 1 is OCF3 or SCF3. In another embodiment, R 1 is CF3, -CH2CF3, -CHFCF3 or CF2CF3. In some embodiments, R 1 is C2-C4-alkenyl or C2-C4-haloalkenyl. In some embodiments, R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0050] In other embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is an optionally substituted saturated or unsaturated 6-membered heterocyclyl group. In one embodiment, R 1 Ga-NR a R b (In the formula, R a and R b are independently hydrogen or C1-C6 alkyl. In another embodiment, R 1 Ga-NR a R b (In the formula, R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group. In another embodiment, R 1 is C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl.

[0051] In some embodiments, R 1 is optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl nyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl.

[0052] In some embodiments, R 1 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be substituted by one or more halogens. In some embodiments, R 2 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino. In some embodiments, R 2 is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In another embodiment, R 2 is hydrogen, CF3, -CH2CF3, -CHFCF3 or -CF2CF3. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In another embodiment, R 2 is fluoro or chloro. In another embodiment, R 2 is hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) (wherein p is 0, 1 or 2). In another embodiment, R 2 is methoxy, ethoxy, propoxy or butoxy. In another embodiment, R 2 is methylthio, ethylthio, propylthio or butylthio. In another embodiment, R 2 is -OCF3 or -SCF3.

[0053] In another embodiment, R 2 is C1-C4-alkenyl or C1-C4-haloalkenyl. In some embodiments, R 2 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R 2 is an optionally substituted saturated or unsaturated 6-membered heterocyclyl group. In some embodiments, R 2 is optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene. In some embodiments, R 2 is optionally substituted phenyl.

[0054] In other embodiments, R 2is phenyl substituted with 1, 2, or 3 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In another embodiment, R 2 is a 5- or 6-membered heteroaryl having 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In one embodiment, R 2 is halo, cyano, nitro, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy or (C1-C3-alkyl or C1-C3-haloalkyl)S(O) p and pyridinyl optionally substituted by.

[0055] In some embodiments, R 2optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperidinyl, perazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl. In some embodiments, R 2 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be substituted by one or more halogens. In some embodiments, R 3 is a 6- to 10-membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, R 3 is C1-C4-alkyl, C1-C4-haloalkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, n-butyl, iso-propyl, tert-butyl, sec-butyl or iso-butyl.

[0056] In other embodiments, R 3 is CF3, -CH2CF3, -CHFCF3 or CF2CF3. In some embodiments, R 3 is optionally substituted C-C-cycloalkyl. In yet another embodiment, R 3 is optionally substituted C-C-cycloalkyl. In yet another embodiment, R 3is an optionally substituted C-C-cycloalkenyl or C-C-cycloalkenyl. In some embodiments, R 3 is optionally substituted cyclopentyl or cyclohexyl. In another embodiment, R 3 is optionally substituted cyclopropyl or cyclobutyl. In one embodiment, R 3 is cyclohexyl optionally substituted by one or more halo, C-C-alkyl or C-C-haloalkyl. 3 is cyclohexyl substituted by one or two fluoro, chloro or CF3.

[0057] In some embodiments, R 3 is optionally substituted piperidinyl, morpholinyl, tetrahydrofuranyl, or dihydrofuranyl. In some embodiments, R 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more halo, C-C-alkyl or C-C-haloalkyl. 3 is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more methyl, chloro or fluoro. In some embodiments, R 3 is a 5- to 10-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents. In one embodiment, the 5- to 10-membered heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidyl, or pyrrolopyrimidyl.

[0058] In other embodiments, R 3is an optionally substituted spirocyclic heterocyclyl-carbocyclyl group, an optionally substituted spirocyclic heterocyclyl-heterocyclyl group, an optionally substituted spirocyclic carbocyclyl-carbocyclyl group, or an optionally substituted spirocyclic carbocyclyl-heterocyclyl group. 3 is an optionally substituted 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, an optionally substituted 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, an optionally substituted 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, or an optionally substituted 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group. Non-limiting examples of spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl, and spirocyclic heterocyclyl-heterocyclyl groups are shown below for illustrative purposes. [ka] However, it will be apparent to those skilled in the art that the second ring of the spirocyclic group may be attached at any available carbon atom of the first ring. It will also be understood that the first ring of the spirocyclic group may be attached to the molecule at any available atom. Thus, the present invention includes 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic rings as defined herein that are attached to a second 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic ring at any available carbon atom of the first ring.

[0059] In some embodiments, R 3 is phenyl substituted with 1 to 4 substituents. In another embodiment, R 3 is phenyl substituted with 1 to 3 substituents. 3 is phenyl substituted with 1 or 2 substituents. In some embodiments, R 3is phenyl substituted by 1, 2, 3, or 4 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 is a para-substituted phenyl. In some embodiments, R 3 is a meta-substituted phenyl. In some embodiments, R 3 is an ortho-substituted phenyl. In some embodiments, R 3 is halophenyl. In some embodiments, R 3 is haloalkylphenyl. In some embodiments, R 3 is haloalkoxyphenyl.

[0060] In some embodiments, R 3 is phenyl substituted by two substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 is a 2,3-disubstituted phenyl. In some embodiments, R 3 is a 2,4-disubstituted phenyl. In some embodiments, R 3 is a 2,5-disubstituted phenyl. In some embodiments, R 3 is a 2,6-disubstituted phenyl. In some embodiments, R3 is a 3,5-disubstituted phenyl In other embodiments, R 3 is a 3,4-disubstituted phenyl. In other embodiments, R 3 is a 3,6-disubstituted phenyl. In some embodiments, R 3 is dihalophenyl, for example dichloro; difluoro; or chloro, fluoro.

[0061] In some embodiments, R 3 is 2,3-dihalophenyl. In some embodiments, R 3 is chlorophenyl. In another embodiment, R 3 is fluorophenyl. In another embodiment, R 3 is dichlorophenyl. In another embodiment, R 3 is difluorophenyl. In yet another embodiment, R 3 is 3,5-dichlorophenyl. In another embodiment, R 3 is 3,5-difluorophenyl. In another embodiment, R 3 is 2,6-dichlorophenyl. In another embodiment, R 3 is 2,6-difluorophenyl. In some embodiments, R 3 is phenyl substituted with halo and haloalkyl. In some embodiments, R 3 is phenyl substituted with halo and haloalkoxy. In some embodiments, R 3 is phenyl substituted with haloalkyl and haloalkoxy.

[0062] In some embodiments, R 3is phenyl substituted by three substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 is trihalophenyl, for example trichloro; trifluoro; or chloro, chloro, fluoro or fluoro, fluoro, chloro. In some embodiments, R 3 is phenyl substituted with two halo and haloalkyl. In some embodiments, R 3 is phenyl substituted with two halo and haloalkoxy. In some embodiments, R 3 is phenyl substituted with one haloalkyl, one halo, and one haloalkoxy. In some embodiments, R 3 is phenyl substituted with one halo and two haloalkyl.

[0063] In some embodiments, R 3 is a 5-membered heteroaryl optionally substituted by 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3is a 6-membered heteroaryl optionally substituted by 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 is 2-pyridyl optionally substituted by one or two substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0064] In some embodiments, R 3 is 3-pyridyl optionally substituted by 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 is 4-pyridyl optionally substituted by 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0065] In another embodiment, R 3is 4-pyridyl that is unsubstituted or substituted with one or two chloro or fluoro. 3 is 3-pyridyl which is unsubstituted or substituted by one or two chloro or fluoro. In other embodiments, R 3 is an optionally substituted 3- to 7-membered heterocycle. In some embodiments, R 3 optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperidinyl, perazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl.

[0066] In another embodiment, R 3 may be an optionally substituted heterocyclic, bridged bicyclic group. In some embodiments, R 4 and / or R 4’ is hydrogen. In some embodiments, each R 4 and / or R 4’ are independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino. In some embodiments, each R 4 and / or R 4’are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. In another embodiment, R 4 and / or R 4’ are independently hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, R 4 and / or R 4’ are independently hydrogen or halogen. In another embodiment, R 4 and / or R 4’ are independently hydrogen, fluoro or chloro. In another embodiment, R 4 and / or 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).

[0067] In another embodiment, R 4 and / or R 4’ are independently hydrogen, methoxy, ethoxy, propoxy, or butoxy. In another embodiment, R 4 and / or R 4’ are independently hydrogen, methylthio, ethylthio, propylthio, or butylthio. In another embodiment, R 4 and / or R 4’ are independently hydrogen, OCF3, or -SCF3. In some embodiments, R 4 and / or R 4’ are independently hydrogen, C1-C4-alkenyl or C1-C4-haloalkenyl. In some embodiments, R 4 and / or R 4’ are independently hydrogen, C1-C4-alkylcarbonyl or C1-C4-alkoxycarbonyl. In some embodiments, R 4 and / or R4’ are independently hydrogen, C1-C4-alkylcarbonylamino. In some embodiments, R 4 and / or R 4’ are independently hydrogen, optionally substituted cyclopentyl, or optionally substituted cyclohexyl.

[0068] In some embodiments, R 4 and / or R 4’ are independently hydrogen, optionally substituted tetrahydrofuryl, dihydrofuryl, morpholino, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene. In some embodiments, R 4 and / or R 4’ are independently hydrogen or optionally substituted phenyl. In other embodiments, R 4 and / or R 4’ are independently hydrogen, phenyl substituted by 1, 2 or 3 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

[0069] In other embodiments, R 4 and / or R 4’ are independently hydrogen, a 5- or 6-membered heteroaryl having 1 or 2 substituents which are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 4and / or R 4’ are independently hydrogen, optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl nyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, or triazinyl. In some embodiments, R 4 and / or R 4’ are independently hydrogen, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl or morpholinyl, all of which may be substituted with one or more halogens.

[0070] In one embodiment, R 8 is H. In another embodiment, R 8 is C1-C3-alkyl or C1-C3-haloalkyl. In some embodiments, R 9 and / or R 9’ are each hydrogen. In another embodiment, R 9 and / or R 9’ together form a 2-6 membered chain which, together with the carbon atom to which they are attached, forms a spirocyclic (spiroxyclic ring) substituent. 9 and / or R 9’ together form a 2-5 membered chain which, together with the carbon atom to which they are attached, forms a spirocyclic substituent. In another embodiment, R 9 and / or R 9’together form a 2-4 membered chain which, together with the carbon atom to which they are attached, forms a spirocyclic substituent. In another embodiment, R 9 and / or R 9’ together form a two or three membered chain which, together with the carbon atom to which they are attached, forms a spirocyclic substituent. 9 and / or R 9’ together form a two-membered chain which, together with the carbon atom to which they are attached, forms a spirocyclic substituent. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, Q is N.

[0071] In other embodiments, Q is CR 8 is. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR ’ is. In some embodiments, W is CH2. In other embodiments, W is C(C1-C3-alkyl)2 or C(C1-C3-haloalkyl)2; In other embodiments, W is C(CH3)2, C(C2H5)2, or C(CF3)2. In some embodiments, Z is CH2. In some embodiments, Z is O. In some embodiments, Z is SO p is. In some embodiments, Z is SO2. In some embodiments, Z is SO. In some embodiments, Z is NH. In other embodiments, Z is N(C1-C3-alkyl) or N(C1-C3-haloalkyl).

[0072] In some embodiments, the compound of formula (I) is a compound of formula (I-1): [ka] (I-1) (wherein the variables L, R 1 , R 2 , R 3 , R 9 , R 9’ , Y 1 , Y 3 , Y 4’ , Y 5’ , Y 6’ , Q, W, Z and a are as defined for formula (I). is.

[0073] In one embodiment of Formula (I-1), W is CH2 and Z is O. In one embodiment, Q is N. In another embodiment, Q is CR 8 In another embodiment of formula (I-1), W is CH2 and Z is CH2. In another embodiment of formula (I-1), W is CR 5 R 6 (wherein R 5 and R 6 is C1-C3-alkyl or C1-C3-haloalkyl and Z is O. In another embodiment of formula (I-1), W is CR 5 R 6 and Z is CR 5 R 6 (wherein each R 5 and R 6 is independently C1-C3-alkyl or C1-C3-haloalkyl). In another embodiment of formula (I-1), W is CR 5 R 6 (In the formula, R 5 and R 6 are taken together to form a 2-5 membered chain to form a ring) and Z is O. In another embodiment, a is 0 and Z is O. In another embodiment, a is 0, Z is O, and W is CH2. In one embodiment of formula (I-1), Y 3 is S. In one embodiment of formula (I-1), Y 5is S. In another embodiment, Y 3 is N. In another embodiment, Y 5 is N. In another embodiment of formula (I-1), Y 5 is N and Y 3 is S. In yet another embodiment of formula (I-1), Y 5 is S and Y 3 is N. In another embodiment of formula (I-1), Y 6 and Y 3 are each N. In another embodiment of formula (I-1), Y 6 is N and Y 3 is S. In another embodiment, Y 1 is N and Y 5 is N.

[0074] In some embodiments, the compound of formula (I) is a compound of formula (I-2): [ka] (I-2) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 2 , Y 3 , Y 4 , Y 5 , X, W, Z and a are as defined for formula (I). is.

[0075] In another embodiment, the compound of formula (I) is a compound of formula (I-3): [ka] (I-3) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 2 , Y3 , Y 4 , Y 5 , X, W, Z and a are as defined for formula (I). is.

[0076] In other embodiments, the compound of formula (I) is a compound of formula (I-4): [ka] (I-4) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , X, W, Z and a are as defined for formula (I). is.

[0077] In another embodiment, the compound of formula (I) is a compound of formula (I-5): [ka] (I-5) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , X, W, Z and a are as defined for formula (I). is.

[0078] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): [ka] (Ia) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , W, Z, Y 2 , Y 3 , Y 4 , Y 5 and a is as defined for formula (I). is.

[0079] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib): [ka] (Ib) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 2 , Y 3 , Y 4 , Y 5 , W, Z and a are as defined for formula (I). is.

[0080] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] (I C) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , R 4 , W, Z and a are as defined for formula (I); o is 0, 1, 2, 3 or 4. is.

[0081] In other embodiments, the compound of formula (I) is a compound of formula (Id): [ka] (Id) where variable R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , R 4 , W, Z and a are as defined for formula (I); o is 0, 1, 2, 3 or 4. is.

[0082] In other embodiments, the compound of formula (I) is a compound of formula (Ie): [ka] (Ie) where variable R 1 , R 2 , R', R 8 , R 9 , R 9’ , Y 2 , Y 3 , Y 4 , Y 5 , W, Z, and a are as defined for formula (I); m is 0, 1, 2, 3, or 4; and each R 10is cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cyclo C-C-haloalkyl, optionally substituted C3-C8-cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, Si and S; C-C6-haloalkylcarbonyl, C-C6-alkoxycarbonyl, C-C6-haloalkoxycarbonyl, aminocarbonyl, C-C6-alkylaminocarbonyl, C-C6-haloalkylaminocarbonyl, di-C-C6-alkylaminocarbonyl, di-C-C6-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl) (wherein p is 0, 1 or 2), SF5, or -NR c R d (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group.

[0083] In one embodiment of Formula (Ie), R 10 is halo. In another embodiment, R 10 is chloro. In yet another embodiment, R 10 is fluoro. In another embodiment, R 10is fluoro or chloro and m is 1, 2, or 3. In yet another embodiment, R 10 is fluoro and m is 2. In another embodiment, R 10 is chloro and m is 2. In another embodiment, R 10 is fluoro or chloro, m is 2, and the fluoro or chloro is substituted at the 3 and 5 positions of the phenyl ring. 10 is fluoro or chloro, m is 2, and the fluoro or chloro is substituted at the 2 and 6 positions of the phenyl ring.

[0084] In other embodiments, the compound of formula (I) is a compound of formula (If): [ka] (If) where variable R 1 , R 2 , R', R 8 , R 9 , R 9’ , R 4 , R 4’ , Y 2 , Y 3 , Y 4 , Y 5 , W, Z and a are as defined for formula (I); R 10 and m is as defined for formula (Ie); b is 0 or 1; and the dashed bond [ka] represents a single or double bond; D represents N, SiR 11 (In the formula, R 11 is C1-C6 alkyl or C1-C6 haloalkyl is) , C or CR 4 in Yes;D 1 are N, O, SiR 11 R 12 (In the formula, R 11 and R 12 are independently C1-C6 alkyl or C1-C6 haloalkyl is) , -CR 4 R4’ 、 S(O) p (wherein p is 0, 1 or 2) Is it , or D 1 is CR 4 R 4’ (In the formula, R 4 and R 4’ and together form a 2- to 5-membered chain which may be replaced by one heteroatom in the chain to form a spirocyclic group).

[0085] In some embodiments, the invention provides compounds of formula (If), wherein the dashed bond is a single bond. In some embodiments, the invention provides compounds of formula (If), wherein the dashed bond is a double bond. In some embodiments, the invention provides compounds of formula (If) where D is CH, C-halo, or N. In some embodiments, the invention provides compounds of formula (If) where D is C, CH, CF, or N.

[0086] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CR 4 R 4’ (In the formula, R 4 and R 4’ and together form a 2-5 membered chain, optionally with one heteroatom in the chain, to form a spirocyclic group, provide a compound of formula (If). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CH2 and independently C-(halo)2, CH(C1-C3-alkyl) or CH(C1-C3-haloalkyl). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is CH2 and independently CF2, CH(CH3) or CH(CF3). In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is O, S, S(O) or S(O)2.

[0087] In some embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: 1 is CH2. In some embodiments, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein D is N; D 1 is CH2, O or S. In some embodiments, the present invention provides a method for treating psoriasis in which D is N and D 1 SiR 11 R 12 In another embodiment of formula (If), D is CH2 and D 1 SiR 11 R 12 In yet another embodiment, D is N and D 1 is Si(CH3)2.

[0088] In some embodiments, the present invention provides a compound in which the dashed bond is a double bond; D is C; 1 is CH2, CF2, O or S. In some embodiments, the present invention provides a method for producing a medicament for the treatment of psoriasis, wherein D is N; D 1 is CR 4 R 4’ (In the formula, R 4 and R 4’ together form a 2-4 membered chain, optionally with one oxygen in the chain, to form a spirocyclic group), provides a compound of formula (If). In some embodiments, the present invention provides a method for treating cancer wherein D is CH; D 1 is CR 4 R 4’ (In the formula, R 4 and R 4’ together form a 2-4 membered chain, optionally with one oxygen in the chain, to form a spirocyclic group), provides a compound of formula (If). In some embodiments, the present invention provides a method for producing a compound according to the present invention, wherein D is C and the dashed bond represents a double bond; 1 is CR 4 R 4’ (In the formula, R 4 and R 4’together form a 2-4 membered chain, optionally with one oxygen in the chain, to form a spirocyclic group), provides a compound of formula (If). Variable Element R 4 It has been shown that (R 4 ) o It will be appreciated by those skilled in the art that in the above formulas (Ic) and (Id), in embodiments where o is 0, R4 is absent and therefore represents a non-hydrogen substituent. The same principle applies to the variable R in compounds of formulas (Ie) and (If). 10 applies to.

[0089] In another embodiment, the present invention provides a compound of formula (Ia), wherein variable R 1 , R 2 , R 3 , R', R 4 , R 9 , R 9’ , W, Z, R 8 and a is as defined for formula (I) above, and Y 2 , Y 3 , Y 4 and Y 5 are as shown in Table 1): [ka] (Ia)

[0090] [Table 1]

[0091] In another embodiment, the present invention provides a compound of formula (Ib), wherein variable R 1 , R 2 , R 3 , R 4 , R', R 9 , R 9’ , W, Z, R 8 and a is as defined for formula (I) above, and Y 2 , Y 3 , Y 4and Y 5 are as shown in Table 2): [ka] (Ib)

[0092] [Table 2]

[0093] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 2 are independently H, halo, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 2 is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl.

[0094] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 2 is independently H, CF, —CHCF, —CHFCF, or —CFCF. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 2 is independently H, methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 2 is independently H, —OCF3, or —SCF3. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 4 and / or R 4’ are independently H, halo, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl)

[0095] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 4 and / or R 4’ is independently H, chloro, fluoro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 4 and / or R 4’ is independently H, CF, —CHCF, —CHFCF, or —CFCF. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 4 and / or R 4’ is independently H, methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... a method for treating a cancer treatment, and a method for treating a cancer treatment, each R 4 and / or R 4’is independently H, —OCF3, or —SCF3.

[0096] In another embodiment, the present invention provides a compound comprising R ’ and R 8 is independently H or C1-C3-alkyl. In other embodiments, the present invention provides compounds of Formula (Ia)-(If), wherein a is 1, W is CH 2 , and Z is O. In another embodiment, the present invention provides a compound comprising R 1 is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (In the formula, R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b and together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0097] In another embodiment, the present invention provides a compound comprising 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 the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or NR a R b (In the formula, R a and R b are independently H, C-C-alkyl or C-C-haloalkyl; or R a and R b and together with the nitrogen to which they are attached may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S to form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group.

[0098] In another embodiment, the present invention provides a compound comprising R 3 In another embodiment, R is an optionally substituted phenyl. 3 In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with one or more halogens. 3 In another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with one halogen. 3In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with two halogens. 3 is phenyl substituted with 3 or 4 halogens.

[0099] In another embodiment, R 3 In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with one or more chloro or fluoro. 3 In another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with one chloro or fluoro. 3 In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) are provided, wherein R is phenyl substituted with two chloro or fluoro. 3 is phenyl substituted with 3 or 4 chloro or fluoro. In another embodiment, the present invention provides a compound comprising R ’ and R 8 is independently H or C1-C3-alkyl; W is CH2, Z is O and a is 1.

[0100] In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y5 Each of these is CH. In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y 5 each independently represents CH or CR 4 (In the formula, R 4 is a non-hydrogen substituent). In other embodiments of formulas (I-1), (I-4) and (I-5), Y 3 , Y 4 and Y 5 Each of these is CH. In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y 5 are independently CH or C-halogen. In any of the above embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), a is 1, W is —CH—, and Z is O.

[0101] In any of the above embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 1 is C1-C4-alkyl and is C1-C4-alkenyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl. In any of the above embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 4 Other R 4is independently halogen, cyano, C1-C4-alkyl, C1-C4 haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl optionally substituted once or twice by halo or C1-C4-alkyl. In some embodiments, the present invention includes compounds of formula (I) where the group is as follows:

[0102] In another embodiment, the present invention provides a method for producing a medicament comprising: 1 , R 2 and R 3 is as defined in Table 3 below, X is O, R' is hydrogen, and the group [ka] is one of the following ring systems: [ka] Ring system A;

[0103] [ka] Ring system B; [ka] Ring system C;

[0104] [ka] ring system D; [ka] Ring system E;

[0105] [ka] ring system F; [ka] Ring system G;

[0106]

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[0107]

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[0108]

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[0109]

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[0110]

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[0111]

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[0112]

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[0113]

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[0114]

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[0115]

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[0116]

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[0117]

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[0118]

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change

[0119]

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[0120]

change

change

[0121]

change

change

[0122]

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[0123]

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change

[0124]

change

change

[0125]

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change

[0126]

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[0127]

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change

[0128]

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[0129]

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change

[0130]

change

[0131] In Table 3, "Me" represents methyl, the expression "3,5-di-F-Ph" represents a 3,5-difluorophenyl group; "3,5-di-Cl-Ph" represents 3,5-dichlorophenyl; "2,3,5-tri-F-Ph" represents 2,3,5-trifluorophenyl; "3-F-Ph" represents 3-fluorophenyl; "2,6-di-F-Ph" represents 2,6-dichlorophenyl; "2 "2,6-di-Cl-Ph" represents 2,6-dichlorophenyl; "2,4-di-F-Ph" represents 2,4-difluorophenyl; "4-F-Ph" represents 4-fluorophenyl; "3-Cl-4-F-Ph" represents 3-chloro-4-fluorophenyl; "3-Cl-Ph" represents 3-chlorophenyl; "2,3-di-F-Ph" represents 2,3-difluorophenyl; and so forth; Prop-1-en-2-yl is a group [ka] represents;

[0132] 2-F-prop-2-yl is a group [ka] represents; 1,1-Difluoroethyl is a group [ka] Represents.

[0133] [ka] Formula (I)

[0134] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] For the avoidance of doubt, each of the compounds presented in Table 3 has been prepared.

[0135] Stereoisomers and polymorphic forms It is recognized by those skilled in the art that compounds can exist and be isolated in optically active and racemic forms. Compounds with one or more chiral centers, including those at sulfur atoms, can exist as single enantiomers or diastereomers, or as mixtures of enantiomers and / or diastereomers. For example, it is well known in the art that sulfoxide compounds can be optically active and can exist as single enantiomers or racemic mixtures. Furthermore, the compounds of the present invention can contain one or more chiral centers, resulting in a theoretical number of optically active isomers. In this case, compounds of formula (I) can be prepared by treating a compound in which Q is CR 8 When 8 When a compound herein contains n chiral centers, the compound contains at most 2 n The compounds of the present invention may contain two optical isomers. Thus, the compounds of the present invention include at least two enantiomers encompassed by the present invention. The present invention encompasses specific enantiomers or diastereomers of each compound having the useful properties described herein, as well as mixtures of various enantiomers and / or diastereomers of the compounds. Optically active forms can be prepared, for example, by resolution of racemic forms by selective crystallization techniques, synthesis from optically active precursors, chiral synthesis, chromatographic separation using chiral stationary phases, or enzymatic resolution. The compounds may also exist in various solid forms, such as various crystalline forms, or in amorphous solid form. The present invention includes various crystalline forms of the compounds as well as amorphous forms. Furthermore, the compounds may exist as hydrates or solvates in which a certain stoichiometric amount of water or solvent is associated with the molecule in crystalline form. Hydrates and solvates of the compounds are also the subject of the present invention.

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

[0137] Particularly suitable are salts derived from inorganic acids, including, but not limited to, hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable inorganic salts also include, but are not limited to, bicarbonates and carbonates. In some embodiments, examples of veterinarily and agriculturally acceptable salts include, but are not limited to, organic acid addition salts formed with organic acids, including, but not limited to, maleate, dimaleate, fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Of course, other acceptable organic acids may also be used. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of the compounds can also be prepared by reacting a sufficiently acidic residue on the compound with an alkali or alkaline earth metal hydroxide. Veterinarily acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with an appropriately acidic functional group present in the compound, or by reacting a suitable acid with an appropriately basic functional group on a compound of the invention.

[0138] Methods for preparing compounds Compounds of formula (I) or pharmaceutically or veterinarily acceptable salts thereof may be prepared by employing the procedures of Schemes 1 and 2 below and in the Examples: Scheme 1 [ka]

[0139] Scheme 2 [ka] In Scheme 2, the variable R 1 , R 2 and R 3 represents a group as defined in formula (I) above, and can be introduced by metal-catalyzed cross-coupling reactions. Examples include the Heck reaction, the Negishi coupling reaction, the Stille cross-coupling reaction, the Suzuki reaction, and other reactions well known in the art. The variable R 5 represents the linker L attached to one of the bicyclic rings shown in Formula (I) at this position of the bicyclic core. Adapting these schemes to synthesize specific compounds of the invention is well within the level of skill of one of ordinary skill in the art. Additionally, the starting materials are readily available or can be prepared via known procedures.

[0140] Veterinary Compositions The compounds and compositions containing the compounds are useful for preventing and / or treating parasitic infestations / infections in animals. The compositions of the present invention comprise an effective amount of the compound or a veterinarily acceptable salt thereof in combination with a veterinarily acceptable carrier or diluent and, optionally, inactive excipients. The compositions may be in various solid and liquid forms suitable for various modes of application or administration to animals. For example, veterinary compositions containing the compounds may be suitable for oral administration, injection administration, including subcutaneous and parenteral administration, and topical administration (e.g., spot-on and pour-on), dermal or subcutaneous administration. The compositions are intended for administration to animals, including, but not limited to, mammals, birds, and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other domestic or farmed mammals. Examples of birds include turkeys, chickens, ostriches, and other domestic or farmed birds. The use of the compounds to protect companion animals, such as dogs and cats, from internal parasites is particularly useful.

[0141] As discussed above, the compositions of the present invention may be in a form suitable for oral use (see, e.g., U.S. Pat. No. 4,564,631, hereby incorporated by reference in its entirety), dietary supplement, troche, lozenge, chewable, tablet, hard or soft capsule, bolus, emulsion, aqueous or oily suspension, aqueous or oily solution, oral drench composition, dispersible powder or granule, premix, syrup or elixir, enteric composition, or paste. Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more sweetening agents, bittering agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents; granulating and disintegrating agents; binders; and lubricants. Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. Tablets may also be coated by techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 (all of which are incorporated herein by reference in their entireties) to form osmotic therapeutic tablets for controlled release.

[0142] Oral compositions include hard gelatin capsules. The capsules may also be soft gelatin capsules in which the active ingredient is mixed with water, a water-miscible solvent, or an oil medium. In one embodiment, the compound may be administered in a chewable tablet composition or soft chewable composition, such as those described in U.S. Patent Application Publication Nos. 2013 / 0203692, 2010 / 0087492, 2006 / 0222684, 2004 / 0151759, and U.S. Patent No. 7,955,632, all of which are incorporated herein by reference. Veterinary compositions may be in the form of palatable, animal-acceptable soft chewable compositions ("soft chews"). In addition to the active ingredient, the soft chews of the present invention may contain one or more of the following ingredients known in the art for these dosage forms: a solvent or mixture of solvents, one or more fillers, one or more binders, one or more surfactants, one or more humectants, one or more lubricants, one or more disintegrants, one or more coloring agents, one or more antimicrobial agents, one or more antioxidants, one or more pH adjusting agents, and one or more flavoring agents.

[0143] The composition may also contain other inactive ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the field of composition. Antioxidants can be added to the compositions of the present invention to inhibit the decomposition of the active agent. The compositions of the present invention may also include one or more lubricants and / or processing aids. In some cases, the lubricants / processing aids may also act as solvents, and thus some of the components of the compositions of the present invention may have dual functions. Many flavoring agents can be used in the compositions of the present invention to improve the palatability of the oral veterinary composition. Preferred flavoring agents are those not derived from animal sources. In various embodiments, flavoring ingredients derived from fruit, meat (including, but not limited to, pork, beef, chicken, fish, poultry, etc.), vegetables, cheese, bacon, cheese bacon, and / or artificial flavors can be used. Flavoring ingredients are typically selected based on considerations related to the organism that will consume the soft chew. For example, horses may prefer apple flavoring ingredients, while dogs may prefer meat flavoring ingredients. While flavoring ingredients derived from non-animal sources are preferred, in some embodiments, natural flavorings can be used, including beef or liver extracts, such as braised beef flavor, artificial powdered beef flavor, roast beef flavor, and corned beef flavor.

[0144] In another embodiment of the present invention, the active composition may be administered via a drench, which may be administered topically or orally. A drench composition is one in which the liquid-containing composition of the present invention is administered into the animal's mouth or throat or poured onto the animal's skin or coat. The compositions of the invention may also be in the form of oil-in-water or water-in-oil emulsions which may contain emulsifying agents known in the art. The emulsions may also contain sweetening, bittering, flavoring and / or preservative agents. In one embodiment, the composition of the present invention may be in the form of a microemulsion. Microemulsions are well suited as liquid carrier vehicles. Microemulsions are four-component systems that include an aqueous phase, an oil phase, a surfactant, and a co-surfactant. They are translucent, isotropic liquids. A microemulsion consists of a stable dispersion of minute droplets of an aqueous phase in an oily phase, or conversely, a stable dispersion of minute droplets of an oily phase in an aqueous phase.

[0145] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil. Oily suspensions can contain thickening agents. Sweeteners, bittering agents, and flavoring agents can be added to obtain a palatable oral preparation. These compositions can be preserved by adding antioxidants or other known preservatives. Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening and / or bittering agents. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, for example sweetening, bittering, flavoring and coloring agents, may also be present. Syrups and elixirs may be formulated with sweetening agents. Such compositions may also contain a demulcent, a preservative, a flavoring and / or a coloring agent. In another embodiment of the present invention, composition can be paste form.Examples of paste form include but are not limited to those described in United States Patent No. 6,787,342 and United States Patent No. 7,001,889 (each of which is incorporated herein by reference).In addition to the compound of the present invention, paste can also contain fumed silica; viscosity modifier; carrier; optionally, absorbent; and optionally, colorant, stabilizer, surfactant or preservative.

[0146] In some embodiments, the composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the prior art using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils may conventionally be employed as a solvent or suspending medium. Topical skin and subcutaneous compositions may include, but are not limited to, emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on compositions, ready-to-use compositions, spot-on solutions and suspensions, dips, and sprays. Topical application of the compounds of the present invention or compositions containing at least one compound of the present invention, among other active agents, in the form of a spot-on, spray-on, or pour-on composition may allow the compositions of the present invention to be absorbed through the skin to achieve a systemic level and distributed through the sebaceous glands or on the surface of the skin to achieve a level through the hair. Spot-on compositions are typically applied to a localized area, which refers to an area that is not the entire animal. In one embodiment, the location may be between the shoulders. In another embodiment, the topical composition may be administered as a stripe on the surface of the animal, for example, from the head to the tail of the animal.

[0147] Pour-on compositions are described in U.S. Patent No. 6,010,710, also incorporated herein by reference. Pour-on compositions are advantageously oil-based and generally may also include a diluent or vehicle for the active ingredient, and a solvent (e.g., organic solvent) if the active ingredient is insoluble in the diluent. In other embodiments, the pour-on composition may include a water-miscible organic solvent. The solvent is used according to the concentration of the active agent compound and its solubility in this solvent. The solvent is made to have the lowest possible volume. The vehicle makes up the difference to 100%. In another embodiment of the present invention, emollients and / or spreading agents and / or film-forming agents may be added to the topical composition. In another embodiment of the present invention, the composition can be in the form of a ready-to-use solution, as described in U.S. Patent No. 6,395,765, which is incorporated herein by reference.In addition to the compound of the present invention, the ready-to-use solution can also contain a crystallization inhibitor and an organic solvent or a mixture of organic solvents.In some embodiments, water can be included together with the organic solvent. The composition may also contain an antioxidant intended to inhibit oxidation in air, which may be present in a proportion of about 0.005 to about 1% (w / v), about 0.01 to about 0.1%, or about 0.01 to about 0.05%.

[0148] The composition excipients discussed above are well known to those skilled in the art and can be obtained commercially or through known techniques. These compositions are generally prepared by simple mixing of the components defined above; advantageously, the starting point is to mix the active material in a primary solvent, followed by the addition of other ingredients or adjuvants. The volume of composition applied will depend on the species and size of the animal, as well as the concentration of the composition and the potency of the active agent. In one embodiment, an amount of about 0.1 to about 20 ml of composition may be applied to the animal. In other volume embodiments, the volume may be about 0.1 to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, or about 0.3 to about 3 ml. Spot-on compositions can be prepared by dissolving the active ingredients in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, spot-on compositions can be prepared by encapsulating the active ingredients to leave a residue of the therapeutic agent on the surface of the animal. These compositions vary in terms of the mass of the combined therapeutic agent, depending on the species of the host animal being treated, the severity and type of infection, and the body weight of the host. Dosage forms may typically contain from about 0.1 mg to about 5 g. In other embodiments, dosage forms may contain from about 0.5 mg to about 5 mg of active agent. In one embodiment of the dosage form, the dosage may contain from about 1 mg to about 500 mg of active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 mg.

[0149] In one embodiment of the present specification, the compound of formula (I) may be present in the composition at a concentration of about 0.05 to about 50% mass / mass. In another embodiment, the compound of formula (I) may be present at a concentration of about 0.1 to about 30% (w / w). In another embodiment, the compound of formula (I) may be present at a concentration of about 0.5 to about 30% (w / w), about 1 to about 20% (w / w), or about 0.05 to about 10% (w / w). In another embodiment, the compound of formula (I) may be present at a concentration of about 10 to about 50% (w / w), about 10 to about 30% (w / w), or about 10 to about 20% (w / w). In yet another embodiment, the compound of formula (I) may be present at a concentration of about 1 to 10% (w / w) or about 5 to about 15% (w / w). In another embodiment of the invention, the active agent may be present in the composition at a concentration of about 0.1 to about 2% w / w. In yet another embodiment of the invention, the active agent may be present in the composition at a concentration of about 0.25 to about 1.5% w / w. In yet another embodiment of the invention, the active agent may be present in the composition at a concentration of about 1% w / w.

[0150] Treatment method As discussed above, the compounds of formula (I) are effective against endoparasites and can be used to treat and / or prevent parasitic infections in animals. In one embodiment, the present invention provides a method for treating and / or preventing endoparasitic infections in or on an animal (e.g., a mammal or a bird), comprising administering to the animal an endoparasiticidally effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition of the invention. Also provided herein is the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing a parasitic infection in an animal. Also provided herein is a compound of formula (I) for use in treating and / or preventing a parasitic infection in an animal. In certain embodiments, the compounds of formula (I) may also be effective against ectoparasites and may be used to treat and / or prevent ectoparasite infestations on animals. In another embodiment, the present invention provides a method of treating and / or preventing ectoparasite infestations on an animal (e.g., a mammal or a bird), comprising administering to the animal an ectoparasiticidally effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition of the invention.

[0151] There is also provided the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing ectoparasitic infections in an animal. The present invention also provides a compound of formula (I) for use in treating and / or preventing ectoparasitic infections in an animal. In another embodiment, the present invention provides a method for treating and / or preventing endoparasitic infections and ectoparasitic infestations in or on an animal, comprising administering to the animal a composition comprising an effective amount of a compound of formula (I) in combination with an effective amount of at least a second active agent, or a veterinarily acceptable salt thereof. Also provided herein are compounds of formula (I) combined with at least a second active agent for use in treating and / or preventing endoparasitic and ectoparasitic infections. Further provided are compounds of formula (I) combined with at least a second active agent in the preparation of a medicament for treating and / or preventing endoparasitic and ectoparasitic infections.

[0152] In yet another embodiment of the present invention, there is provided a method of treating and / or preventing parasitic infestation of a locus, the method comprising administering or applying to the locus a parasiticidally effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof. For animal health applications, "locus" is intended to mean a habitat, breeding ground, area, material or environment in which a parasite is growing or may grow, excluding in and on an animal. In another embodiment, the present invention provides methods and uses of compounds for controlling plant and crop pests or protecting wood-containing structures. In some embodiments, animals that can be treated are mammals, including, but not limited to, humans, cats, dogs, cows, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep, and yaks. In one embodiment of the present invention, the mammal being treated is a human, cat, or dog. In one embodiment herein, the compounds of formula (I) have been found to have excellent efficacy against endoparasites, particularly against endoparasites resistant to the macrocyclic lactone class of active agents. In one embodiment, the compounds and compositions of the present invention are effective in controlling Haemonchus contortus, Ostertagia circumcincta, and Trichostrongylus colubriformis in mammals or birds.

[0153] In another embodiment, the present invention provides a method for treating or preventing a parasitic infestation or infection in an animal, comprising administering to an animal in need thereof an effective amount of an anthelmintic compound of the present invention in combination with an effective amount of an activator of an invertebrate GABA receptor, including an avermectin and a milbemycin. In another embodiment, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for treating or preventing a parasitic infestation or infection in an animal. In yet another embodiment, the present invention provides a compound of formula (I) for use in treating or preventing a parasitic infection or infestation in an animal. Avermectins that can be used in combination with the compounds of the present invention include, but are not limited to, abamectin, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Milbemycin compounds that can be used in combination with the compounds of the present invention include, but are not limited to, milbemectin, milbemycin D, moxidectin, and nemadectin. 5-oxo and 5-oxime derivatives of the avermectins and milbemycins are also included.

[0154] In one embodiment, the compounds and compositions of the present invention may be used to treat and / or prevent endoparasitic infections of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Ancylostoma, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Silicocyclus, ylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, The genera include: Bacillus, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia ertagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Tridonothorus, Uncinaria, Wuchereria, and combinations thereof.

[0155] In a particularly preferred embodiment of the present invention, the compounds and compositions of the present invention are used to treat and / or prevent infection by Dirofilaria immitis. The compounds have been found to be highly effective against D. immitis microfilariae and L4 larvae. Thus, the compounds can be used to prevent animals from developing heartworm disease by killing immature stages of D. immitis before they can mature into adults. In one embodiment, the compounds and compositions containing the compounds can be used to prevent the development of heartworm disease by killing immature stages of D. immitis that are resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are used to treat and / or prevent infection by Dirofilaria repens or Dirofilaria hongkonensis. In another embodiment of the present invention, the parasite is Haemonchus contortus, Ostertagia circumcinctus, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, and combinations thereof.

[0156] In another embodiment of the treatment for both endoparasites and ectoparasites when combined with an ectoparasiticide, the ectoparasites are selected from the group consisting of Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, and the like. ), Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalini, Linognathus, Haematopinus, Solenopotes, Trichodectes, and Felicola.

[0157] In another embodiment of the ectoparasite treatment, the ectoparasite is of the genus Rhipicephalus, Rhizopus, Dermacentor, Ixodes, and / or Rhipicephalus. Ectoparasites to be treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Dolichorax spp., etc.), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., etc.), and mites (Demodex spp., Sarcoptes spp., Otodectes spp., etc.), lice (Dermatobia spp., Cheyletiella spp., Otodectes spp., etc.), mosquitoes (Aedes spp., Culex spp., Anopheles spp., etc.), and flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.). In yet another embodiment of the treatment for ectoparasites, the ectoparasites are fleas and / or ticks.

[0158] Additional examples of ectoparasites include, but are not limited to, ticks, Boophilus genus, particularly the species Boophilus microplus (cattle tick), decoloratus and annulatus; myiasis, such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (blood fly); sheep myiasis, such as Lucilia sericata, Lucilia cuprina (known as blowfly myiasis in Australia, New Zealand and South Africa). Indigenous flies include those whose adult forms are parasitic flies, such as Haematobia irritans (horn flies); lice, such as Linognathus vitulorum; and mites, such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive, and other ectoparasites are known in the art to be harmful to animals and humans. These include, for example, migratory dipteran larvae.

[0159] In another embodiment of the present invention, the compounds and compositions of the present invention are suitable for controlling pests such as insects selected from the group consisting of the German cockroach (Blattella germanica), the tobacco budworm (Heliothis virescens), the Colorado potato beetle (Leptinotarsa ​​decemlineata), the brown ant (Tetramorium caespitum), and combinations thereof. Plant parasitic nematodes include, for example, Anguina spp., Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, and the like. similis, Rotylenchus species, Trichodorus species, Tylenchorhynchus species, Tylenchulus species, Tylenchulus semipenetrans, and Xiphinema species.

[0160] Additionally, the present invention may also be used to treat other pests, including but not limited to the following pests, with or without other pesticides added to the composition: (1) Isopoda, such as Oniscus asellus, Armadillidium vulgare, and Porcellio scaber; (2) Diplopoda, e.g., Blaniulus guttulatus; (3) Chilopoda, e.g., Geophilus carpophagus and Scutigera species; (4) Order Symphyla, e.g., Scutigerella immaculata; (5) Thysanura, e.g., Lepisma saccharina;

[0161] (6) Collembola, e.g., Onychiurus armatus; (7) Blattaria, such as the Asian cockroach (Blatta orientalis), the American cockroach (Periplaneta americana), the Madera cockroach (Leucophaea maderae) and the German cockroach; (8) Hymenoptera, such as Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis spp., and Vespa spp.; (9) Siphonaptera, for example, Xenopsylla cheopis and Ceratophyllus species; (10) From the suborder Anoplura (order Phthiraptera), for example, Damarinia spp., Piglice spp., Piglice spp., Pediculus spp., Piglice spp.;

[0162] (11) From the class of Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Rhipicephalus spp., Brevipalpus spp., Bryobia praetiosa, Dermanyssus spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pili pyri, Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhizoglyphus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus maurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici; (12) From the class of Bivalva, for example, Dreissena species;

[0163] (13) From the order Coleoptera, for example, Acanthoscelides obtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidius obtectus obtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp., Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosterna consanguinea, Colorado potato beetle, Lissorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligethes aeneusaeneus, Melolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodes chrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica, Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp., Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp., Xylotrechus spp., Zabrus spp.;

[0164] (14) From the order Diptera, for example, Aedes spp., Anopheles spp., Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus spp., oleae, human flies, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia spp., Hypobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxis spp., Tabanus spp., Tannia spp., Tipula paludosa paludosa), Wohlfahrtia species; (15) From the class of Gastropoda, for example, Arion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.;

[0165] (16) From the class of the Helminths, for example, Ancylostoma duodenale, Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma spp., Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Cavertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp., Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa, Nematogyrus spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosoma spp., Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloides spp., Taenia spp. saginata), Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsillarispseudopsiralis), Trichostrongulus species, Trichuris trichuria, Wuchereria bancrofti;

[0166] (17) From the order of the Heteroptera, for example, Anasa tristis, Antestiopsis spp., Blissus spp., Calocoris spp., Campylomma livida, Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris heweti hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horchias nobiellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp., Pentatomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus seriatus, Pseudacysta persea, Rhodonius species, Sahlbergella singularis, Scotinophora species, Stephanitis nashi, Tibraca species, Triatoma species;

[0167] (18) From the order of the Homoptera, for example, Acyrthosipon spp., Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobus barodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui, Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis apicalis, Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia spp., Brachycaudus helichrysi, Brachycolus spp., Brevicoryne brassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacuna lanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii, Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus species, Cryptomyzusribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp., Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis arundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphax striatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari, Metcalfiella spp., Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettix spp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, and Parabemisiamyricae, Paratrioza spp., Parlatoria spp., Pemphigus spp., Corn planthopper (Peregrinus maidis), Phenacoccus spp., Phloeomyzus passerinii, Phorodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Pear scale (Protopulvinaria pyriformis), Mulberry scale (Pseudaulacaspis pentagona, Pseudococcus spp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata spp., Sogatella furcifera furcifera, Sogatodes spp., Stictocephala festina, Tenalapha malayensis, Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis spp., Viteus vitifolii;

[0168] (19) Isoptera, such as Reticulitermes species and Odontotermes species;

[0169] (20) Lepidoptera, such as Acronicta major, Aedia leucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp., Choristoneura fumiferana, Grapevine moth (Clysia ambiguella), Cnaphalocerus spp., Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp., Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padera, padella, Laphygma species, Lithocolletis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria species, Malacosoma neustria, Mamestrabrassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesia gemmatalis gemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia species;

[0170] (21) Orthoptera, such as Acheta domesticus, the Asian cockroach, the German cockroach, Gryllotalpa species, the Madeira cockroach, Locusta species, Melanoplus species, the American cockroach, and the desert locust (Schistocerca gregaria); (22) Those of the order Thysanoptera, such as Baliothrips biformis, Enneothrips flavens, species of the genus Frankliniella, species of the genus Heliothrips, Hercinothrips femoralis, species of the genus Kakothrips, Rhipiphorothrips cruentatus, species of the genus Scirtothrips, Taeniothrips cardamoni, species of the genus Thrips; (23) Those of the class Protozoa, such as species of the genus Eimeria. In each aspect of the present invention, the compounds and compositions of the present invention can be applied to a single pest or a combination thereof.

[0171] Mixtures with other active agents In another embodiment, the composition comprising the compound of formula (I) may also contain other veterinary therapeutic agents. Veterinary formulations that can be included in the compositions of the present invention are well known in the art (e.g., Plumb's Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 thEdition, (January 2005)), including, but not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline / theophylline, Amiodarone, amitriptyline, amlodipine besilate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, amphotericin B lipid formulation, ampicillin, amprolium antacid (oral), antivenin, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besilate , atropine sulfate, auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin, calcitrol, calcitonin sodium salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiafur, ceftriaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal (active), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - clidinium bromide, chlorothiazideChlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin ( ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), diclofenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium. Calcium EDTA, edrophonium chloride, enalapril / enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid / sodium ethacrynate, ethanol (alcohol), sodium etidronate, etodolac, etomidate, euthanasia agents with pentobarbital, famotidine, fatty acids (essential / omega), felbamate, fentanyl, ferrous sulfate,Filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / chondroitin sulfate, glutamine, glyburide, glycerol Phosphate (oral), glycopyrrolate, gonadorelin, griseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin, hetastarch, sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, imipenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alpha-2 a (human recombinant), iodide (sodium / potassium), ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, Magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate / hippurate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue,Methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole, mexiletine, mibolerlone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate decanoate), naproxen, narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin hydrochloride, oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, penicillamine, general information penicillin, penicillin G, penicillin Phosphate V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisolone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes acnes) injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilage, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline / saline laxatives, selamectin, selegiline / l-deprenyl, sertraline, sevelamer,Sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, somatropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succinimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium, sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadiazine Menthoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxalin, terbinafrine, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, tiamulin, ticarcillin disodium salt, tiletamine / zolazepam, tilmicosin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid acid), topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, trimepraxin tartrate with prednisolone, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide, and mixtures thereof.

[0172] In one embodiment of the present invention, arylpyrazole compounds, such as phenylpyrazoles, can be included in the veterinary compositions of the present invention. Arylpyrazoles are known in the art and may be suitable for combination with the compounds of formula (I) in the compositions herein. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954; 6,998,131; and 7,759,381 (all of which are incorporated herein by reference). A particularly preferred arylpyrazole active agent is fipronil.

[0173] In another embodiment of the present invention, one or more macrocyclic lactones that act as acaricides, anthelmintics, and / or insecticides may be included in the compositions of the present invention in combination with compounds. For the avoidance of doubt, the term "macrocyclic lactone" as used herein includes both naturally occurring and synthetic or semi-synthetic avermectin and milbemycin compounds. Macrocyclic lactones that can be used in the compositions of the present invention include, but are not limited to, naturally occurring avermectins (e.g., containing components designated as A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b) and milbemycin compounds, semi-synthetic avermectins and milbemycins, avermectin monosaccharide compounds, and avermectin aglycone compounds. Examples of macrocyclic lactone compounds that can be used in the compositions include, but are not limited to, abamectin, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, ML-1,694,554, and milbemycins, including, but not limited to, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, and nemadectin. 5-oxo and 5-oxime derivatives of the avermectins and milbemycins are also included.

[0174] Macrocyclic lactone compounds are known in the art and can be easily obtained commercially or through synthetic techniques known in the art. Reference is made to widely available technical and commercial literature. For avermectins, ivermectin, and abamectin, reference can be made, for example, to the work "Ivermectin and Abamectin", 1989, by M. H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag, or to Albers-Schonberg et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramectin, reference can be made to "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15. For milbemycins, reference may be made in particular to Davies H. G. et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121; Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336; U.S. Pat. No. 4,134,973; and European Patent No. 0677054, all of which are incorporated herein by reference.

[0175] The structures of the avermectins and milbemycins are closely related, for example, by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519, and 22,23-dihydroavermectin compounds are disclosed in U.S. Pat. No. 4,199,569. See also, inter alia, U.S. Pat. Nos. 4,468,390, 5,824,653, European Patent No. 0007812, British Patent Specification No. 1390336, European Patent No. 0002916, and New Zealand Patent No. 237086. Naturally occurring milbemycins are disclosed in U.S. Pat. No. 3,950,360, as well as in "The Merck Index" 12. th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is listed in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148, and European Patent No. 0667054, all of which are incorporated herein by reference.

[0176] In one embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of abamectin, zimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, or nemadectin, or a combination thereof. In another embodiment, the present invention provides a veterinary composition comprising an effective amount of at least one of abamectin, emamectin, eprinomectin, ivermectin, doramectin, or selamectin, or a combination thereof. In yet another embodiment, the veterinary compositions of the present invention comprise an effective amount of at least one of ivermectin, milbemectin, milbemycin oxime, or moxidectin, or a combination thereof. Another embodiment of the present invention provides a composition comprising a compound of formula (I) in combination with a miticide or insecticide from the class known as insect growth regulators (IGRs). Compounds belonging to this group are well known to those skilled in the art and represent a wide variety of chemical classes. All of these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Pat. Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179022, or GB 2140010, and U.S. Pat. Nos. 6,096,329 and 6,685,954, all of which are incorporated herein by reference.

[0177] In one embodiment, the compositions of the present invention may contain an IGR compound that mimics juvenile hormone or regulates the level of juvenile hormone in insects. Examples of juvenile hormone mimetics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3(2H)-one. In another embodiment, the compositions of the present invention contain a compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. In another embodiment, the compositions of the present invention comprise an IGR compound that is a chitin synthesis inhibitor, including chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumorone, lufenuron, tebufenozide, teflubenzuron, triflumolone, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0178] In some embodiments, the compositions of the present invention may include one or more nematicides, including but not limited to active agents from the benzimidazole, imidazothiazole, tetrahydropyrimidine, and organophosphorus classes of compounds. In some embodiments, the compositions may include benzimidazoles, including but not limited to thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, and its o,o-dimethyl analogs. In other embodiments, the compositions of the present invention may include imidazothiazole compounds, including, but not limited to, tetramisole, levamisole, and butamisole. In yet other embodiments, the compositions of the present invention may include tetrahydropyrimidine active agents, including, but not limited to, pyrantel, oxantel, and morantel. Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naphthalophos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP and tetrachlorvinphos.

[0179] In other embodiments, the compositions may include the nematicidal compounds phenothiazine, piperazine, diethylcarbamazine, both as neutral compounds and in various salt forms, phenols such as disophenol, arsenicals such as arsenamide, ethanolamines such as bephenium, thenium closylate, and methylidine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate, and dithiazanine iodide; isothiocyanates including bitoscanate, sodium suramin, phthalophine, and various natural products including, but not limited to, hygromycin B, α-santonin, and kainic acid. In other embodiments, the compositions of the present invention may contain an anti-fluke agent. Suitable anti-fluke agents include, but are not limited to, miracil, such as miracil D and mirasan; various bisphenol compounds known in the art, including praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, hexachlorophene, bithionol, bithionol sulfoxide, and meniclofolan; various salicylanilide compounds, including tribromsalan, oxyclozanide, clioxanide, lafoxanide, nitroxynil, brothianide, bromoxanide, and closantel; triclabendazole, diamfenetide, clorsulon, hetrin, and emetine.

[0180] Anti-taenid compounds, including but not limited to arecoline, bunamidine, niclosamide, nitroscanate, paromomycin, paromomycin II, praziquantel, and epsiprantel in various salt forms, may also be advantageously used in the compositions of the present invention. In yet other embodiments, the compositions of the present invention may contain other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate, dioxathion, ethion, fenfen, fenitrothion, fenthion, phospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stylophos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, fenothrin, piriso ... Included are lethrin, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, methoprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and the compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[0181] 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, depsipeptides other than the present compound. These include PF1022A or analogs thereof and emodepside. Other cyclic depsipeptide compounds that can be included in the composition containing the compound of Formula (I) are those described in WO 2016 / 187534 and WO 2017 / 116702, both of which are incorporated herein by reference. These compounds act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of the parasite. In one depsipeptide embodiment, the depsipeptide is emodepside (see Wilson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

[0182] In another embodiment, the compositions of the present invention may contain an active agent from the neonicotinoid class of parasiticides. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be combined with the compound of formula (I) in the compositions of the present invention is imidacloprid. This class of agent is described, for example, in U.S. Pat. No. 4,742,060 or European Patent No. 0892060 (both of which are incorporated herein by reference). In another embodiment, the compositions of the present invention may contain nitenpyram, another active agent from the neonicotinoid class of pesticides. The use of nitenpyram to control fleas is described in U.S. Pat. No. 5,750,548, the entire contents of which are incorporated herein by reference. In certain other embodiments of the present invention, the compound of formula (I) may be combined with a semicarbazone, such as metaflumizone.

[0183] In another embodiment, the compositions of the present invention may advantageously contain one or more isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against a variety of ectoparasites, and combination with a compound of formula (I) may extend the spectrum of effectiveness against these parasites. Particularly useful isoxazoline active agents that can be combined with the compound include afoxolaner (including the substantially pure active enantiomer, esafoxolaner), sarolaner, fluralaner (including the substantially pure active enantiomer), lotilaner, and tigolaner. These active agents are disclosed in U.S. Pat. No. 7,964,204, U.S. Patent Application Publication No. 2010 / 0254960, U.S. Patent Application Publication No. 2011 / 0159107, U.S. Patent Application Publication No. 2012 / 0309620, U.S. Patent Application Publication No. 2012 / 0030841, U.S. Patent Application Publication No. 2010 / 0069247, WO 2007 / 125984, WO 2012 / 086462, U.S. Pat. No. 8,318,757, U.S. Pat. No. 8,466,115, U.S. Pat. No. No. 8618126, U.S. Patent No. 8822466, U.S. Patent No. 8383659, U.S. Patent No. 8853186, U.S. Patent No. 9221835, U.S. Patent Application Publication No. 2011 / 0144349, U.S. Patent No. 8,053,452; U.S. Patent Application Publication No. 2010 / 0137612, U.S. Patent No. 8410153, U.S. Patent Application Publication No. 2011 / 152081, WO 2012 / 089623, WO 2012 / 089622, U.S. Patent No. 8,119,671; U.S. Patent No. 7,947,715;WO 2102 / 120135, WO 2012 / 107533, WO 2011 / 157748, U.S. Patent Application Publication No. 2011 / 0245274, U.S. Patent Application Publication No. 2011 / 0245239, U.S. Patent Application Publication No. 2012 / 0232026, U.S. Patent Application Publication No. 2012 / 0077765, U.S. Patent Application Publication No. 2012 / 0035122, U.S. Patent Application Publication No. 2011 / 0251247, WO 2011 / 154433, WO 2011 / 15 No. 4434, U.S. Patent Application Publication No. 2012 / 0238517, U.S. Patent Application Publication No. 2011 / 0166193, WO 2011 / 104088, WO 2011 / 104087, WO 2011 / 104089, U.S. Patent Application Publication No. 2012 / 015946, U.S. Patent Application Publication No. 2009 / 0143410, WO 2007 / 123855, U.S. Patent Application Publication No. 2011 / 0118212, U.S. Patent No. 7,951,828 and U.S. Patent No. 7,662,972, U.S. US Patent Application Publication No. 2010 / 0137372, US Patent Application Publication No. 2010 / 0179194, US Patent Application Publication No. 2011 / 0086886, US Patent Application Publication No. 2011 / 0059988, US Patent Application Publication No. 2010 / 0179195, US Patent Application Publication No. 2015 / 0126523, International Publication No. 2010 / 003923, International Publication No. 2010 / 003877, International Publication No. 2010 / 072602, International Publication No. 2014 / 134236, International Publication No. 2017 / 147 352, U.S. Patent No. 7,897,630, U.S. Patent No. 7,951,828, WO 2020 / 007704, WO 2021 / 028479, WO 2014 / 122083, WO 2016 / 177619, WO 2014 / 012975, WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 150302, WO 2015 / 181139 and WO 2016 / 026789;

[0184] In another embodiment of the present invention, nodulisporic acid and its derivatives can be added to the compositions of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent Nos. 5,399,582, 5,962,499, 6,221,894, and 6,399,786, all of which are incorporated herein by reference in their entireties. The compositions may include one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above-cited documents.

[0185] In another embodiment, anthelmintic compounds of the aminoacetonitrile class (AAD) of compounds, such as monepantel (ZOLVIX), can be added to the compositions of the present invention.These compounds are described, for example, in U.S. Patent No. 7,084,280 to Ducray et al. (incorporated herein by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature, vol. 452, 13 March 2008, 176-181. The compositions of the present invention may also include aryloazol-2-ylcyanoethylamino compounds, such as those described in U.S. Patent No. 8,088,801 to Soll et al., which is incorporated herein by reference, and thioamide derivatives of these compounds described in U.S. Patent No. 7,964,621, which is also incorporated herein by reference. Aryloazol-2-ylcyanoethylamino active agents that are systemically active against endoparasites can be used in combination with compounds in the veterinary compositions of the present invention.

[0186] The compositions of the present invention may also contain paraherquamide compounds and derivatives of these compounds, including delquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds containing a spirodioxepinoindole core that have activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380; and J. Antibiotics 1991, 44, 492). Additionally, the structurally related marcfortine family of compounds, e.g., marcfortines A-C, are known and can be combined with the compositions of the invention (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to paraherquamide derivatives can be found, for example, in WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, WO 09 / 004432, and U.S. Patent Application Publication No. 2010 / 0197624, U.S. Patent No. 5,703,078, and U.S. Patent No. 5,750,695, all of which are hereby incorporated by reference in their entireties.

[0187] In another embodiment of the invention, the compositions may include spinosyn active agents produced by the soil actinomycete Saccharopolyspora spinosa (see, e.g., Salgado VL and Sparks TC, "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance," in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or semi-synthetic spinosoid active agents. Spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or combinations thereof may be used in the compositions of the invention. Spinosyn compounds can be a 12-membered macrocyclic lactone, a 5,6,5-tricyclic ring system fused with a neutral sugar (rhamnose) and an amino sugar (forosamine). These and other naturally occurring spinosyn compounds, including the 21-butenyl spinosyn produced by Saccharopolyspora pagona, which can be used in the compositions of the invention, can be produced via fermentation by conventional techniques known in the art. Other spinosyn compounds that may be used in the compositions of the present invention are disclosed in U.S. Patent Nos. 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861; 5,670,486; 5,631,155; and 6,001,981, all of which are incorporated herein by reference in their entireties. Spinosyn compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or combinations thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydrospinosyn J and 3'-ethoxyspinosyn L.

[0188] Generally, the additional active agent (other than the compound of Formula (I) above) is included in the dosage unit of the present invention in an amount of between about 0.1 μg and about 1000 mg. Typically, the active agent may be included in an amount of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. More typically, the additional active agent is present in the composition of the present invention in an amount of about 5 mg to about 50 mg. The concentration of additional active agents in the compositions of the present invention will typically be about 0.01% to about 30% (w / w), depending on the potency of the active agent. In certain embodiments of highly potent active agents, including but not limited to macrocyclic lactone active agents, the concentration of the active agent will typically be about 0.01% to about 10% (w / w), about 0.01 to about 1% (w / w), about 0.01% to about 0.5% (w / w), about 0.1% to about 0.5% (w / w), or about 0.01% to about 0.1% (w / w). In other embodiments, the concentration of the active agent will typically be about 0.1% to about 2% (w / w), or about 0.1% to about 1% (w / w).

[0189] In other embodiments, the additional active agent is present, typically at a higher concentration to achieve the desired efficacy. In some embodiments, the active agent is present in a concentration of about 1% to about 30% (w / w), about 1% to about 20% (w / w), or about 1% to about 15% (w / w). In yet other embodiments, the active agent is present in the composition at a concentration of about 5% to about 20% (w / w), or about 5% to about 15% (w / w). In various embodiments of the present invention, the composition may include an additional active agent to deliver a dose of about 0.001 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 50 mg / kg of animal body weight. In other embodiments, the active agent is present in an amount sufficient to deliver a dose of typically about 0.05 mg / kg to about 30 mg / kg, or about 0.1 mg / kg to about 20 mg / kg. In other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.5 mg / kg to about 50 mg / kg of animal body weight.

[0190] In certain embodiments of the invention where the additional active agent is a highly potent compound, such as a macrocyclic lactone or other potent compound, the active agent is present in a concentration that provides a dose of about 0.001 mg / kg to about 5 mg / kg, about 0.001 mg / kg to about 0.1 mg / kg, or about 0.001 mg / kg to about 0.01 mg / kg. In yet other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.01 mg / kg to about 2 mg / kg, or about 0.1 mg / kg to about 1 mg / kg of animal body weight. In yet other embodiments, the additional active agent may be present in an amount to deliver a dose of about 1 μg / kg to about 200 μg / kg, or about 0.1 mg / kg to about 1 mg / kg of animal body weight. In addition to the other active agents mentioned above, combinations of two or more active agents can be used in compositions with the compounds of the present invention to treat a desired range of pests and parasites. It will be well within the skill level of one of ordinary skill in the art to determine which individual compounds can be used in the compositions of the present invention to treat a particular insect infestation. The invention will now be further illustrated by the following non-limiting examples. [Example]

[0191] Preparation Examples The following examples are intended only to illustrate the present invention and are not intended to limit it. Compounds of formula (I) or pharmaceutically or veterinarily acceptable salts thereof can be prepared by employing one of the following reaction schemes. The starting materials for the preparation can be commercially available or can be prepared by methods known to those skilled in the art and as described in the literature, or can be intermediates in any other scheme described herein. It will be appreciated that the following procedures can be modified by those skilled in the art to prepare additional compounds according to the present invention. For example, those skilled in the art will understand that the substitution of certain starting materials or the use of different intermediates will allow the preparation of various compounds of formula (I).

[0192] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20° C. Although the following subject matter has been described in some detail by way of illustration and example for clarity of understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the examples. List of abbreviations: ACN Acetonitrile AIBN Azobisisobutyronitrile BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BSA Bovine serum albumin BOC tert-butoxycarbonyl BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride DAST Diethylaminosulfur trifluoride DCC N,N'-dicyclohexylcarbodiimide solution DCM dichloromethane DEAD Diethyl azodicarboxylate DIEA Diisopropylethylamine DMF N,N-dimethylformamide DMAP 4-(dimethylamino)pyridine DMSO dimethyl sulfoxide EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ES Electrospray EtOAc or EA ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt or HOBT 1-hydroxybenzotriazole KHMDS potassium hexamethyldisilazide, more precisely potassium bis(trimethylsilyl)amide MeOH Methanol m-CPBA m-chloroperbenzoic acid NMO N-methylmorpholine-N-oxide o / n overnight PE Petroleum Ether Pd(dtbpf)Cl2 Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane TBAF tert-butylammonium fluoride TfO Triflate THF tetrahydrofuran TLC thin layer chromatography

[0193] Some examples of formula (I) are derived after separation of the racemic mixture to obtain enantiomerically pure products, where appropriate the stereochemistry is indicated, and individual compounds have been characterized by analytical methods as described below. [Table 4]

[0194] [Table 5]

[0195] [Table 6]

[0196] [Table 7]

[0197] [Table 8]

[0198] Preparative Example 1: The following example compounds can be synthesized by one skilled in the art by employing the following Schemes 3 and 4 shown below for compound 175: 271, 272, 273, 274, 275, 276, 279, 293, 294, 295, 296, 304, 305, 307, 308, 322, 344, 345, 364, 527, 528, A402, A403, A404, A406, A407, A410, A411, A412, A413, A414, A415, A416, A417, A418, 419, A419, A420, A423, A424, A425, A426, A428, A429, A430, A431, A432, A433, A434, A435, A436, A437, A438, A439, A440, A441, A442, A443, A445, A446, A447, A448, A451, A452, A453, A454, A455, A456, A457, A458, A460, A472, 560.

[0199] Scheme 3 [ka]

[0200] Scheme 4 [ka]

[0201] 1. Synthesis of ethyl 1-aminoimidazole-2-carboxylate [ka]

[0202] A 3000 mL three-necked round-bottom flask was charged with DMF (2000 mL) and ethyl 1H-imidazole-2-carboxylate (3-1, 50.0 g, 356.7 mmol, 1.0 equiv). Subsequently, NaH (21.0 g, 875.0 mmol, 2.4 equiv) was added portionwise at room temperature. Aminodiphenylphosphinate (119.0 g, 510.2 mmol, 1.4 equiv) was added portionwise at 0 °C. The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This resulted in 40 g (72.2%) of ethyl 1-aminoimidazole-2-carboxylate (3-2) as a white solid.

[0203] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) [ka] A 500 mL round-bottom flask was charged with DMF (200 mL), ethyl 1-aminoimidazole-2-carboxylate (3-2, 35.0 g, 225.5 mmol, 1.0 equiv.), BocO (63.9 g, 293.2 mmol, 1.3 equiv.), and DMAP (13.7 g, 112.7 mmol, 0.5 equiv.). The resulting solution was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted three times with 200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 28 g (48.6%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) as a white solid.

[0204] 3. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) [ka] A 250 mL round-bottom flask was charged with DMF (100.0 mL), ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3, 15.0 g, 58.7 mmol, 1.0 equiv.), and NBS (10.4 g, 58.8 mmol, 1.0 equiv.). The resulting solution was stirred at room temperature for 1 day. The reaction was then quenched by the addition of 300 mL of water. The resulting solution was extracted three times with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 12 g (61.1%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) as a colorless oil.

[0205] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) [ka] A 1000 mL three-necked round-bottom flask was charged with THF (400 mL) and ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4, 12.0 g, 35.9 mmol, 1.0 equiv.). This was followed by the addition of t-BuOK (60.0 g, 534.7 mmol, 14.9 equiv.) in small portions over 30 min at 0 °C. Ethyl acetate (32.0 g, 363.2 mmol, 10.1 equiv.) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of HCl (1 M). The resulting solution was extracted three times with 50 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 6.5 g (48.1%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) as a yellow oil.

[0206] 5. Synthesis of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] A 100 mL round-bottom flask was charged with DCM (30.00 mL), ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5, 6.50 g, 17.278 mmol, 1.00 equiv.), and DMF-DMA (5.00 mL, 37.3 mmol, 2.2 equiv.). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 90:10 HO:ACN to 50:50 HO:ACN within 15 min; detector, 254 nm. This resulted in 3.3 g (66.7%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) as a white solid.

[0207] 6. Synthesis of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) [ka] A 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with dioxane (60.0 mL), ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6, 3.0 g, 10.5 mmol, 1.0 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (2.6 g, 20.9 mmol, 2.0 equiv.), Pd(PPh3)4 (1.2 g, 1.0 mmol, 0.1 equiv.), and K2CO3 (4.3 g, 31.3 mmol, 3.0 equiv.). The resulting solution was stirred at 100 °C for 4 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in 2 g (86.2%) of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) as a yellow solid.

[0208] 7. Synthesis of ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1) [ka] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with DCM (20 mL), ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7, 200 mg, 0.9 mmol, 1.0 equiv.), and TEA (457 mg, 4.5 mmol, 5.0 equiv.). Following this, TfO (765.6 mg, 2.7 mmol, 3.0 equiv.) was added dropwise with stirring at -78 °C. The resulting solution was stirred at -50 °C for 1 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted three times with 20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 200 mg (62.6%) of ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1) as a brown oil.

[0209] 8. Synthesis of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) [ka] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with THF (10.0 mL), HO (2.0 mL), ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1, 200.0 mmol, 0.6 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (179.0 mg, 1.0 mmol, 1.9 equiv.), Pd(dtbpf)Cl (37.2 mg, 0.06 mmol, 0.10 equiv.), and KCO (234.0 mg, 1.7 mmol, 3.0 equiv.). 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 (1:4), resulting in 90 mg (64.8%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) as a white solid.

[0210] 9. Synthesis of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate [ka] A 50 mL round-bottom flask was charged with EA (5.00 mL, 0.057 mmol, 0.03 equiv), ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2, 90.0 mg, 0.4 mmol, 1.0 equiv), PtO (30.00 mg, 0.1 mmol, 0.4 equiv), and a balloon atmosphere of H(g). The resulting solution was stirred at 50 °C for 1 h. The solids were filtered off. The resulting mixture was concentrated in vacuo. This resulted in 90 mg (99.2%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate as a white solid.

[0211] 10. Synthesis of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate [ka] A 50 mL round-bottom flask was charged with CHCl3 (10.0 mL), ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3, 90.0 mg, 0.4 mmol, 1.0 equiv.), and NBS (90.0 mg, 0.5 mmol, 1.4 equiv.). The resulting solution was stirred at 80 °C for 1 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted three times with 10 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 100 mg (crude) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) as a white solid.

[0212] 11. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) [ka] In a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, dioxane (10.0 mL), HO (3.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 90.0 mg, 0.3 mmol, 1.0 equiv.), 3,5-difluorophenylboronic acid (87.5 mg, 0.5 mmol, 2.0 equiv.), Pd(dtbpf)Cl2 (18.0 mg, 0.03 mmol, 0.1 equiv.), and K2CO3 (114.6 mg, 0.829 mmol, 3.0 equiv.) were added to the reaction mixture. The resulting solution was stirred at 100 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This afforded ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) as a yellow solid.

[0213] 12. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) [ka] A 50 mL round-bottom flask was charged with HO (1.0 mL), i-PrOH (5.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5, 80 mg, 0.2 mmol, 1.0 equiv.), and LiOH.HO (28.0 mg, 0.7 mmol, 3.0 equiv.). The resulting solution was stirred at 50 °C for 2 h. The pH of the solution was adjusted to 4 with 2 M HCl. The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 60 mg (90%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) as a white solid.

[0214] 13. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (Compound 175) [ka] A 50 mL round-bottom flask was charged with DMA (5.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6, 60.0 mg, 0.2 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (57.2 mg, 0.4 mmol, 2.1 equiv.), HATU (138.0 mg, 0.4 mmol, 2.0 equiv.), and diEA (70.0 mg, 0.5 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. This mixture was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from H2O:ACN=60:40 to H2O:ACN=10:90 within 25 min; detector, 220 nm. This resulted in 38.6 mg (46.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (175) as a white solid (300 MHz, CD3OD, ppm) δ 8.33 (s, 1H), 7.41-7.33 (m, 3H), 7.21-7.16 (m, 1H), 7.06-6.97 (m, 1H), 6.95-6.92 (m, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.32 (t, J = 5.1 Hz, 1H), 4.33-4.25. (m, 2H), 3.70-3.65 (m, 1H), 2.62 (s, 3H), 2.33-2.28 (m, 1H), 2.23-2.19 (m, 1H), 1.62 (t, J = 6.6 Hz, 6H).

[0215] Preparative Example 2: Similar to the steps described in Preparative Example 1, compound 271 can be prepared using the steps shown in Schemes 5-7 below. Scheme 5 [ka]

[0216] Scheme 6 [ka]

[0217] Scheme 7 [ka] The processes described above in Schemes 3-7 can be modified by methods known to those skilled in the art to incorporate various functional groups into the core structure. For example, intermediates 3-6 can be reacted with alternative coupling partners to provide different R 2 Similarly, intermediates 4-1, 271-1 and 4-4 can be reacted with alternative compounds to introduce different R 1 and R 3 Substituents can be introduced.

[0218] 1. Synthesis of ethyl 1-aminoimidazole-2-carboxylate (3-2) [ka] A 5 L round-bottom flask was charged with DMF (4000.00 mL, 51687.010 mmol, 144.87 equiv.) and ethyl 1H-imidazole-2-carboxylate (50.00 g, 356.781 mmol, 1.00 equiv.). Subsequently, NaH (21.00 g, 875.083 mmol, 2.45 equiv.) was added portionwise over 30 min at room temperature. To this was added aminodiphenylphosphinate (120.00 g, 514.564 mmol, 1.44 equiv.) portionwise at room temperature. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was dried with nitrogen (by blowing). The residue was dissolved in 2000 mL of EA. The solid was filtered off. The filtrate was concentrated in vacuo. This resulted in 42 g (75.87%) of ethyl 1-aminoimidazole-2-carboxylate (3-2) as a white solid.

[0219] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) [ka] A 1000 mL round-bottom flask was charged with DMF (500.00 mL, 6460.876 mmol, 28.64 equiv.), ethyl 1-aminoimidazole-2-carboxylate (35.00 g, 225.578 mmol, 1.00 equiv.), BocO (73.30 g, 335.858 mmol, 1.49 equiv.), and DMAP (13.78 g, 112.796 mmol, 0.50 equiv.). The resulting solution was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted three times with 500 mL of ethyl acetate, and the organic layers were combined and washed twice with 500 mL of HO and once with 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in 30 g (52.10%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) as a white solid.

[0220] 3. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) [ka] A 1000 mL round-bottom flask was charged with DMF (400.00 mL, 5168.701 mmol, 26.39 equiv.), ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (50.00 g, 195.868 mmol, 1.00 equiv.), and NBS (40.00 g, 0.225 mmol). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted three times with 100 mL of ethyl acetate, and the organic layers were combined and washed twice with 500 mL of HO and once with 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in 30 g (45.83%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) as a yellow oil.

[0221] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) [ka] A 1000 mL three-necked round-bottom flask was charged with THF (500.00 mL, 6171.495 mmol, 58.92 equiv.), ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (35.00 g, 104.737 mmol, 1.00 equiv.), and EA (93.50 g, 1061.233 mmol, 10.13 equiv.). Following this, t-BuOK (170.00 g, 1514.989 mmol, 14.46 equiv.) was added portionwise at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of NHCl (aq.). The resulting solution was extracted three times with 300 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was dissolved in 500 mL of hexane. The solid was collected by filtration, resulting in 22 g (55.83%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) as a yellow oil.

[0222] 5. Synthesis of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] A 100 mL round-bottom flask was charged with DCM (30.00 mL, 471.901 mmol, 27.31 equiv.), ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (6.50 g, 17.278 mmol, 1.00 equiv.), and DMF-DMA (5.00 mL, 37.344 mmol, 2.16 equiv.). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 90:10 HO (0.1% TFA):ACN to 50:50 HO (0.1% TFA):ACN within 15 min; detector, 254 nm. This resulted in 3.3 g (66.76%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) as a white solid.

[0223] 6. Synthesis of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) [ka] A 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with dioxane (100.0 mL, 1180.408 mmol, 67.54 equiv.), ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (5.00 g, 17.477 mmol, 1.00 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (6.60 g, 52.577 mmol, 3.01 equiv.), Pd(PPh3)4 (2.00 g, 1.731 mmol, 0.10 equiv.), and K3PO4 (7.20 g, 52.096 mmol, 2.98 equiv.). The resulting solution was stirred at room temperature for 4 h. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 100:0 HO (0.1% NH3.HO):ACN to 50:50 HO (0.1% NH3.HO):ACN within 10 min; detector, 254 nm. This resulted in 0.75 g (25.6%) of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) as a yellow solid.

[0224] 7. Synthesis of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) [ka] A 100 mL round-bottom flask was charged with CHCl3 (20.00 mL, 247.952 mmol, 18.28 equiv.), ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3.00 g, 13.561 mmol, 1.00 equiv.), oxalyl chloride (6.00 g, 47.274 mmol, 3.49 equiv.), and DMF (0.10 mL). The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. This resulted in 3.6 g (crude) of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) as a yellow solid.

[0225] 8. Synthesis of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) [ka] A 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with THF (30.00 mL, 370.290 mmol, 88.74 equiv.), HO (5.00 mL, 277.542 mmol, 66.52 equiv.), ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (1.00 g, 4.173 mmol, 1 The resulting mixture was stirred at 70 °C for 2 h. The mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in 500 mg (48.85%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) as a yellow oil.

[0226] 9. Synthesis of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3) [ka] A 50 mL round-bottom flask was charged with EA (5.00 mL, 0.057 mmol, 0.03 equiv.), ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (500.00 mg, 2.038 mmol, 1.00 equiv.), and PtO (100.00 mg, 0.440 mmol, 0.22 equiv.) in H (g). The resulting solution was stirred at 50 °C for 2 h. The solids were filtered off. The filtrate was concentrated under vacuum. This resulted in 350 mg (69.43%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3) as a yellow oil.

[0227] 10. Synthesis of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) [ka] A 50 mL round-bottom flask was charged with CHCl3 (5.00 mL, 61.988 mmol, 47.90 equiv.), ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (320.00 mg, 1.294 mmol, 1.00 equiv.), and NBS (253.70 mg, 1.425 mmol, 1.10 equiv.). The resulting solution was stirred at 80 °C for 1 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 350 mg (82.92%) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) as a yellow oil.

[0228] 11. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-2) [ka] In an 8 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, add THF (1.00 mL, 12.343 mmol, 44.74 equiv.), HO (0.20 mL, 11.102 mmol, 40.24 equiv.), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (90.00 mg, 0.276 mmol, 1.00 equiv.), 3,5-dichlorophenylboronic acid (53.17 mg, 0.279 mmol, 1.01 equiv.), Pd(dtbpf)Cl (17.98 mg, 0.028 mmol, 0.10 equiv.), and KCO (75.88 mg, 0.549 mmol, 1.99 equiv.). The resulting solution was stirred at 50 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). This gave 70 mg (64.67%) of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-2) as a colorless oil.

[0229] 12. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (271-3) [ka] A 50 mL round-bottom flask was charged with HO (0.50 mL, 27.754 mmol, 155.53 equiv.), EtOH (2.00 mL, 0.043 mmol, 0.24 equiv.), ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (70.00 mg, 0.178 mmol, 1.00 equiv.), and LiOH·HO (22.50 mg, 0.536 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature for 1 h. The pH of the solution was adjusted to 5 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 50 mg (76.93%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (271-3) as a yellow oil.

[0230] Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (Compound 271) [ka] A 50 mL round-bottom flask was charged with DMA (1.00 mL, 10.755 mmol, 87.05 equiv.), 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (45.00 mg, 0.124 mmol, 1.00 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (29.30 mg, 0.196 mmol, 1.59 equiv.), HATU (93.90 mg, 0.247 mmol, 2.00 equiv.), and diEA (47.80 mg, 0.370 mmol, 2.99 equiv.). The resulting solution was stirred at room temperature for 1 h. The crude mixture was purified by Flash-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO (0.1% NH3.HO):ACN to 10:90 HO (0.1% NH3.HO):ACN within 20 min; detector, 254 nm. This resulted in 42.2 mg (68.95%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (271) as a white solid. 1 H NMR (300 MHz, CDCl3, ppm) δ 8.29 (s, 1H), 7.59 (d, J = 1.9 Hz, 2H), 7.43 (t, J = 1.9 Hz, 1H), 7.34-7.18 (m, 2H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.38 (q, J = 5.6 Hz, 1H), 4.40-4.36 (m, 1H), 4.28-4.14 (m, 1H), 3.78-3.73 (m, 1H), 2.64 (s, (ES, m / z): 495 [M+H] + .

[0231] As described above, the following compounds can be prepared according to Schemes 3-7. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7]

[0232] Preparation Example 3: Example compounds A400, A401, A405 and A459 were prepared according to Scheme 8 using reactions adapted from known reactions in the literature. See, for example, Campbell, Alison N. et al. Organic Process Research & Development (2013), 17(2), 273-281 and Stanovnik, B. et al., Tetrahedron (1967), 23(6), 2739-46.

[0233] Scheme 8 [ka] Description of Key Steps: Synthesis of Methyl 3-(3,5-dichlorophenyl)-8-(4,4-difluorocyclohexyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (8-6)

[0234] [ka] A mixture of 90 mg (0.3 mmol) of methyl 3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (8-5) in 5 mL of DMSO was treated with 200 mg (1.0 mmol) of zinc sulfate, and the solution was cooled in an ice bath. 185 μL (1 mmol) of 2-methyl-prop-2-yl-hydroperoxide (TBHP) was added dropwise, and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with sodium carbonate solution and extracted with EE. The organic layer was collected, dried, filtered, and evaporated. The mixture was evaporated and purified by column chromatography (silica gel; CyH / EtOAc), and the solvent was removed in vacuo to give 900 mg (74%) of the product as a yellow oil. (400 MHz, DMSO-d6) δ ppm 9.11 (d, J=8.11 Hz, 1 H) 8.52 (s, 1 H) 7.76 (d, J=1.77 Hz, 2 H) 7.66 - 7.71 (m, 1 H) 7.39 (d, J=7.35 Hz, 1 H) 7.18 (t, J=7.73 Hz, 1 H) 6.89 - 6.95 (m, 1 H) 6.80 (d, J=8.11 Hz, 1 H) 5.23 - 5.30 (m, 1 H) 4.18 - 4.33 (m, 2 H) 2.61 - 2.80 (m, 3 H) 2.53 (s, 3 H) 2.30 - 2.39 (m, 1 H) 2.09 - 2.30 (m, 3 H) 1.73 - 1.94 (m, 4 H).

[0235] Conversion of compound 8-6 to the product can be achieved by hydrolysis of the methyl ester to the carboxylic acid, followed by coupling of the acid with the desired amine, as in Scheme 4. As mentioned above, compounds A400, A401 and A405 are prepared by employing the process described in Scheme 8. [Table 10]

[0236] Preparative Example 4: Example 304-0 was prepared according to the following Scheme 9. Similarly, compound 321 can be similarly prepared by one skilled in the art. Scheme 9 [ka]

[0237] 1. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (9-2) [ka] A 500 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6, 2.0 g, 0.007 mmol, 1.0 equiv.), 3,5-dichlorophenylboronic acid (1.6 g, 0.008 mmol, 1.2 equiv.), KCO (2.1 g, 0.015 mmol, 2.2 equiv.), dioxane (100 mL), HO (20 mL), and Pd(dtbpf)Cl (0.27 g, 0.000 mmol, 0.06 equiv.). The resulting solution was stirred in an oil bath at 100 °C for 1 h. The reaction was then quenched by the addition of 100 mL of water. The solid was collected by filtration. This resulted in 2.1 g (85.3%) of ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (9-2) as an off-white solid. (ES, m / z): 352 [M+H] + .

[0238] 2. Synthesis of ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (9-3) [ka] A 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (9-2, 2.0 g, 5.7 mmol, 1.0 equiv.), CHCl3 (25.0 mL), and POBr3 (8.14 g, 28.4 mmol, 5.0 equiv.). The resulting solution was stirred at 80 °C overnight. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with 50 mL of water. The pH of the solution was adjusted to 7–8 with Na2CO3 (saturated). The resulting solution was extracted three times with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This resulted in 810 mg (34.4%) of ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (9-3) as an off-white solid. (ES, m / z): 414 [M+H] + .

[0239] 3. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4) [ka] A 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (9-3, 1800.0 mg, 4.4 mmol, 1.0 equiv.), KPO (2761.5 mg, 13.0 mmol, 3.0 equiv.), THF (20.0 mL), HO (5.0 mL), Pd(dtbpf)Cl (282.6 mg, 0.4 mmol, 0.1 equiv.), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (801.6 mg, 4.8 mmol, 1.1 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted three times with 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This resulted in 0.55 g (33.7%) of ethyl 2-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4) as an off-white solid. (ES, m / z): 376 [M + H] + .

[0240] 4. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-5) [ka] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of H2(g) was charged with ethyl 2-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4, 500.0 mg, 1.3 mmol, 1.0 equiv.), EA (10.0 mL), and PtO2 (100.0 mg, 0.4 mmol, 0.3 equiv.). The resulting solution was stirred at room temperature for 1 h. The solids were filtered off. The filtrate was concentrated. This resulted in 450 mg (82.4%) of ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate as an off-white solid (9-5). (ES, m / z): 378 [M+H] + .

[0241] 5. Synthesis of ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-6) [ka] A 20 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-5, 100.0 mg, 0.3 mmol, 1.0 equiv.), CHCl3 (5.0 mL), and NCS (38.8 mg, 0.3 mmol, 1.1 equiv.). The resulting solution was stirred at 50 °C overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with EA / PE (1 / 20). This resulted in 106.6 mg (97.7%) of ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-6) as an off-white solid. (ES, m / z): 412 [M+H] + .

[0242] 6. Synthesis of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (9-7) [ka] A 20 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-6, 95.0 mg, 0.2 mmol, 1.0 equiv.), THF (5.0 mL), HO (1.0 mL), and LiOH (27.6 mg, 1.2 mmol, 5.0 equiv.). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 3-4 with HCl (1 mol / L). The resulting solution was extracted three times with 10 mL of ethyl acetate, and the organic layers were combined. The organic phase was dried and concentrated in an oven under reduced pressure. This resulted in 78 mg (88.1%) of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (9-7) as an off-white solid. (ES, m / z): 384 [M+H] + .

[0243] 7. Synthesis of 3-chloro-2-(3,5-dichlorophenyl)-N-[(4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (compound 304-0). [ka] A 20 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with (4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-amine dihydrochloride (51.0 mg, 0.2 mmol, 1.2 equiv.), 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (9-7, 68.0 mg, 0.2 mmol, 1.0 equiv.), DMF (5.0 mL), DiDiEA (45.7 mg, 0.35 mmol, 2.5 equiv.), and HATU (100.8 mg, 0.3 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature overnight. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column: C18 silica gel; mobile phase: ACN:HO = 72 increasing to ACN:HO = 95 within 7 days; detector: 254. This resulted in 67.7 mg (71.7%) of 3-chloro-2-(3,5-dichlorophenyl)-N-[(4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (304-0) as an off-white solid. (300 MHz, CDCl3, ppm) δ 8.36 (s, 1H), 7.83 (d, J = 1.8 Hz, 2H), 7.45 (t, J = 1.8 Hz, 1H), 7.02-6.93 (m, 2H), 6.87-6.83 (m, 1H), 6.06 (d, J = 7.8 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.38-4.32 (m, 1H), 4.24-4.16 (m, 1H), 3.73 (t, J = 6.9 Hz, 1H), 2.45-2.40 (m, 1H), 2.24-2.18 (m, 1H), 1.68-1.64 (m, 6H). Compound 321: (300 MHz, chloroform-d, ppm): δ 8.27 (s, 1H), 7.76-7.60 (m, 2H), 7.35-7.30 (m, 1H), 7.28-7.20 (m, 1H), 7.20-7.03 (m, 4H), 7.03-6.80 (m, 3H), 6.20-5.90 (m, 1H), 5.50-5.25 (m, 1H), 4.45-4.30 (m,1H), 4.30-4.10 (m, 1H), 3.80-3.65 (m, 1H), 2.55-2.35 (m, 1H), 2.33-2.15 (m, 1H), 1.72 (t, J = 6.3 Hz, 6H)

[0244] Preparative Example 5: Example 174 was prepared according to Scheme 10. Scheme 10 [ka]

[0245] 1. Synthesis of N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (10-2) [ka] A 40 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 3,5-dichloropyridazine (10-1, 500.0 mg, 3.4 mmol, 1.0 equiv.), diphenylmethanimine (675.2 mg, 3.7 mmol, 1.1 equiv.), Xantphos (69.9 mg, 0.12 mmol, 0.04 equiv.), Pd(dba) (34.7 mg, 0.06 mmol, 0.02 equiv.), CsCO (2187.1 mg, 6.7 mmol, 2.0 equiv.), and dioxane (5 mL). The resulting solution was stirred in an oil bath at 90 °C for 3 h. The solids were filtered off. The resulting mixture was concentrated. This resulted in 3 mL (30.4%) of N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (10-2) as a brown oil.

[0246] Synthesis of 2,5-chloropyridazin-3-amine [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (10-2, 10.0 mL) and HCl (3 M) (15.0 mL). The resulting solution was stirred at room temperature for 1 hour. The pH value of the solution was adjusted to 7 with NaHCO3. The resulting mixture was concentrated. This resulted in 15 mL of 5-chloropyridazin-3-amine (5-1) as a brown oil.

[0247] Synthesis of 3,7-chloroimidazo[1,2-b]pyridazine (10-4) [ka] A 250 mL round-bottom flask was charged with 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), HO (17.5 mL), and i-PrOH (25 mL). The resulting solution was stirred in an oil bath at 95 °C for 5 h. The resulting mixture was concentrated. The pH of the solution was adjusted to 9 with NaOH. The resulting solution was extracted three times with 50 mL of ethyl acetate, and the organic layer was washed three times with 50 mL of brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:3). This resulted in 2.2 g (12.4%) of 7-chloroimidazo[1,2-b]pyridazine (10-4) as a yellow oil.

[0248] 4. Synthesis of 7-chloro-3-iodoimidazo[1,2-b]pyridazine (10-5) [ka] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of H2(g) was charged with 7-chloroimidazo[1,2-b]pyridazine (1.0 g, 7.0 mmol, 1.0 equiv.), NIS (2.2 g, 10.0 mmol, 1.5 equiv.), and DMF (10 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted three times with 20 mL of concentrated ethyl acetate. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This resulted in 800 mg (43.9%) of 7-chloro-3-iodoimidazo[1,2-b]pyridazine as a yellow oil.

[0249] 5. Synthesis of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6) [ka] A 40 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 7-chloro-3-iodoimidazo[1,2-b]pyridazine (10-5, 400.0 mg, 1.4 mmol, 1.0 equiv.), 2,6-difluorophenylboronic acid (452.0 mg, 2.9 mmol, 2.0 equiv.), Pd(dtbpf)Cl2 (93.3 mg, 0.14 mmol, 0.1 equiv.), K3PO4 (911.4 mg, 4.3 mmol, 3.0 equiv.), THF (10 mL), and HO (2.5 mL). The resulting solution was stirred at room temperature for 1 h overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 150 mg (39.4%) of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6) as a white solid.

[0250] 6. Synthesis of methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10-7) [ka] A 50 mL pressure tank reactor was charged with 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6, 130.0 mg, 0.5 mmol, 1.0 equiv.), Pd(dppf)Cl (35.8 mg, 0.05 mmol, 0.1 equiv.), TEA (148.6 mg, 1.5 mmol, 3.0 equiv.), CO (20 atm), and MeOH (10.00 mL). The resulting solution was stirred in an oil bath at 110 °C for 4 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 95 mg (67.1%) of methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10-7) as a white solid.

[0251] 7. Synthesis of 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10-8) [ka] A 40 mL round-bottom flask was charged with methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10-7, 85.0 mg, 0.3 mmol, 1.0 equiv.), NaOH (58.7 mg, 1.5 mmol, 5.0 equiv.), MeOH (9 mL), and HO (3 mL). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 20 mL of water. The pH of the solution was adjusted to 3–4 with HCl (3 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated. This resulted in 65 mg (80.4%) of 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10-8) as a white solid.

[0252] 8. Synthesis of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]imidazo[1,2-b]pyridazine-7-carboxamide (Compound 174) [ka] A 40 mL round-bottom flask was charged with 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10-8, 60.0 mg, 0.2 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (48.8 mg, 0.3 mmol, 1.5 equiv.), HATU (165.79 mg, 0.436 mmol, 2 equiv.), diEA (84.5 mg, 0.6 mmol, 3.0 equiv.), and DMF (3 mL). The resulting solution was stirred at room temperature for 2 h. The crude product was purified by Prep-HPLC (Waters-2767) using the following conditions: column, XBridge RP18, 5 μm, 19*100 mm; mobile phase, 0.03% ammonia and CHCN in water (30% to 70% CHCN in 15 min); detector, UV 254 nm, to give 19.4 mg (21.9%) of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]imidazo[1,2-b]pyridazine-7-carboxamide (174) as a white solid. (300 MHz, CDCl3, ppm) δ 8.95 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.55-7.45 (m, 1H), 7.25-7.24 (m, 1H), 7.17-7.08 (m, 4H), 6.91-6.81 (m, 2H), 5.43-5.39 (m, 1H), 4.35-4.25 (m, 2H), 2.41-2.31 (m, 1H), 2.28-2.21 (m, 1H).

[0253] Preparative Example 6: Example 277 was prepared according to Scheme 11 below. Scheme 11 [ka]

[0254] 1. Synthesis of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) [ka] A 100 mL round-bottom flask was charged with ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7, 2.8 g, 12.6 mmol, 1.0 equiv.), DMF (8.0 μL, 103.4 mmol, 8.2 equiv.), and CHCl3 (55.0 mL). This was followed by the dropwise addition of (COCl)2 (8.0 g, 63.1 mmol, 5.0 equiv.) with stirring at room temperature. The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated. The crude product was purified by Prep-Flash using the following conditions: column, C 18 Silica gel; mobile phase, 0.1% FA and CHCN in water (increasing from 10% to 70% CHCN within 12 min); detector, UV 254 nm, 220 nm. This resulted in 537 mg (17.2%) of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) as a yellow solid.

[0255] 2. Synthesis of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) [ka] A 50 mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1, 480.0 mg, 2.0 mmol, 1.0 equiv.), dioxane (19.0 mL), HO (4.8 mL), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (673.1 mg, 4.0 mmol, 2.0 equiv.), Pd(dtbpf)Cl (130.5 mg, 0.20 mmol, 0.1 equiv.), and KCO (553.6 mg, 4.0 mmol, 2.0 equiv.). The resulting solution was stirred at 80 °C overnight. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted twice with 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed twice with 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-20%). This resulted in 370 mg (73.0%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) as a white solid.

[0256] 3. Synthesis of ethyl 3-bromo-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-4) [ka] A 40 mL round-bottom flask was charged with ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2, 370.0 mg, 1.5 mmol, 1.0 equiv.), CHCl3 (7.0 mL, 86.8 mmol), and NBS (295.3 mg, 1.7 mmol, 1.1 equiv.). The resulting solution was stirred at 65 °C for 30 min. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted twice with 20 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed twice with 20 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated. This resulted in 491 mg (95.4%) of ethyl 3-bromo-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-4) as a brown solid.

[0257] 4. Synthesis of ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5) [ka] A 50 mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 3-bromo-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-4, 490.0 mg, 1.5 mmol, 1.0 equiv.), dioxane (10.0 mL), HO (2.5 mL), 3,5-difluorophenylboronic acid (477.4 mg, 3.0 mmol, 2.0 equiv.), KCO (626.7 mg, 4.535 mmol, 3.0 equiv.), and Pd(dtbpf)Cl (98.5 mg, 0.15 mmol, 0.1 equiv.). The resulting solution was stirred at 100 °C for 30 min. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted twice with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-15%). This resulted in 442 mg (80.2%) of ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5) as a yellow-green solid.

[0258] 5. Synthesis of 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6) [ka] A 50 mL three-neck round-bottom flask was charged with ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5, 440.0 mg, 1.2 mmol, 1.0 equiv.), i-PrOH (15.0 mL), HO (8.0 mL), and LiOH·HO (155.0 mg, 3.7 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The pH of the solution was adjusted to 3 with HCl (2 mol / L). The resulting solution was extracted twice with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. This resulted in 401 mg (89.0%) of 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6) as a yellow solid.

[0259] 6. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7) [ka] A 50 mL three-necked round-bottom flask was charged with 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6, 400.0 mg, 1.2 mmol, 1.0 equiv.), DMF (12.0 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (362.4 mg, 2.4 mmol, 2.0 equiv.), diEA (471.0 mg, 3.6 mmol, 3.0 equiv.), and HATU (692.8 mg, 1.8 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 2 h. The crude product was purified by Prep-Flash under the following conditions: column, C18 silica gel; mobile phase, 0.1% FNHHCO and CHCN in water (increasing from 30% to 80% CHCN within 3 min); detector, UV 254 nm, 220 nm. This resulted in 520 mg (92.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7) as a green solid.

[0260] 7. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (11-8) [ka] In a 50 mL three-necked round-bottom flask was added 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7, 200.0 mg, 0.4 mmol, 1.0 equiv.), ethanol (8.0 mL), toluene (8.0 mL), and HCl (11-7). 0 mL), NaBH4 (32.9 mg, 0.9 mmol, 2.0 equiv), Mn(OAc)3·2H2O (9.3 mg, 0.03 mmol, 0.08 equiv), and 2-[(1E)-([3-[(E)-[(2-hydroxyphenyl)methylidene]amino]-2,2-dimethylpropyl]imino)methyl]phenol (10.8 mg, 0.03 mmol, 0.08 equiv). O2 (g) was introduced. The resulting solution was stirred at room temperature for 4 h. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted twice with 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed twice with 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 250 mg (crude) of 7,3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (11-8) as a yellow oil.

[0261] 8. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-fluoropropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (Compound 277) [ka] A 25 mL three-necked round-bottom flask was charged with 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (11-8, 200.0 mg, 0.4 mmol, 1.0 equiv.) and DCM (10.0 mL). This was followed by the dropwise addition of DAST (134.7 mg, 0.8 mmol, 2.0 equiv.) with stirring at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The crude product was purified by Prep-Flash using the following conditions: column, C 18 Silica gel; mobile phase, 0.1% TFA and CHCN in water (increasing from 50% to 100% CHCN within 10 min). Detector, UV 254 nm, 220 nm. This resulted in 9.5 mg (4.6%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-fluoropropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (277) as a white solid. (300 MHz, CDCl3, ppm) δ 8.26 (s, 1H), 7.35-7.33 (m, 1H), 7.29-7.19 (m, 3H), 6.98-6.85 (m, 3H), 5.94 (d, J = 7.5 Hz, 1H), 5.32-5.29 (m, 1H), 4.38-4.33 (m, 1H), 4.23-4.18 (m, 1H), 2.62 (s, 3H), 2.40-2.24 (m, 2H), 2.15 (d, J = 6.3 Hz, 3H), 2.08 (d, J = 6.3 Hz, 3H).

[0262] Preparative Example 7: Compounds 306, 297, 298, 298-0, 299, 299-0, 418, 420, 523, 524, 525, 526, 571, 572, 573, 574, A472 can be prepared by utilizing the process shown in Scheme 12 below. Scheme 12 [ka]

[0263] Synthesis of 1,8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-2) [ka] To a stirred mixture of ethyl 8-bromo-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-1, 30.0 g, 105.6 mmol, 1.0 equiv) in THF (750.00 mL) under a nitrogen atmosphere at 0 °C, LiBr (6.9 g, 791.9 mmol, 7.5 equiv) was added. To the mixture, CuI (150.8 g, 791.9 mmol, 7.5 equiv) was added portionwise over 30 min at 0 °C. The resulting mixture was stirred for an additional 30 min at 0 °C. To the mixture, tert-butyl(chloro)magnesium (310.5 mL, 527.9 mmol, 5.0 equiv) was added dropwise over 1 h at 0 °C. The resulting mixture was stirred for an additional 5 min at 0 °C. The reaction was quenched by adding saturated NH4Cl(aq) (400 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 × 800 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture, ethyl 8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-2, 33 g, crude), was used directly in the next step without further purification.

[0264] 2. Synthesis of ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3) [ka] To a stirred solution of ethyl 8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-2, 28.0 g, 107.1 mmol, 1.0 equiv.) in CHCl3 (300.0 mL) at room temperature was added NBS (19.0 g, 107.1 mmol, 1.0 equiv.). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3, 29.5 g, 80.9%) as a yellow solid.

[0265] Synthesis of ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-4) [ka] To a stirred mixture of ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3, 26.0 g, 76.4 mmol, 1.0 equiv.) and 3,5-dichlorophenylboronic acid (14.5 g, 76.4 mmol, 1.0 equiv.) in THF (240.0 mL) and HO (60.0 mL) was added KCO (31.7 g, 229.2 mmol, 3.0 equiv.) and Pd(dtbpf)Cl (4980.7 mg, 7.6 mmol, 0.1 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (800 mL). The resulting mixture was extracted with EtOAc (2 × 800 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-4, 19 g, 61.2%) as an off-white solid.

[0266] Synthesis of 3,8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5) [ka] A 250 mL round-bottom flask was charged with ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-4, 18.0 g, 44.3 mmol, 1.0 equiv.), MeOH (100.0 mL, 344.3 mmol, 28.0 equiv.), THF (100.0 mL), HO (200.0 mL), and KOH (53.1 g, 1329.0 mmol, 30.0 equiv.). The resulting solution was stirred at 80 °C for 48 h. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of water. The pH of the solution was adjusted to 4 with HCl (2 mol / L). The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5, 18 g, crude) as an off-white solid.

[0267] Synthesis of 4,8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (Compound 306) [ka] To a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5, 17.0 g, 44.9 mmol, 1.0 equiv.) and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (8046.4 mg, 53.9 mmol, 1.2 equiv.) in DMF (80.0 mL) was added diEA (17.4 g, 134.8 mmol, 3.0 equiv.) and HATU (20.5 g, 53.9 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise to 300 mL of HO. The precipitated solid was collected by filtration and washed with water (2 × 20 mL). The residue was dissolved in MeCN (200 mL). Next, 800 mL of HO was added dropwise. The precipitated solid was collected by filtration. The resulting solid was dried under infrared light to give 8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (306, 17.2 g, 75.1%) as a pale green solid. (300 MHz, CDCl3, ppm) δ: 8.08 (s, 1H), 7.57 (d, J = 1.8 Hz, 2H), 7.41 (s, 1H), 7.32-7.18 (m, 2H), 6.99-6.95 (m, 1H), 6.88 (dd, J = 8.1, 1.2 Hz, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.32-5.29 (m, 1H), 4.41-4.34 (m, 1H), 4.24-4.16 (m, 1H), 2.61 (s, 3H), 2.41-2.34 (m, 1H), 2.27-2.21 (m, 1H), 1.78 (s, 9H)

[0268] [Table 11-1] [Table 11-2]

[0269] Preparative Example 8: By employing the process shown in Scheme 13 below, the following compounds can be synthesized: 320, 320-0, 513, 513-0, 514, 514-0. Scheme 13 [ka]

[0270] 1. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) [ka] A 40 mL round-bottom flask was charged with THF (5.0 mL), HO (1.0 mL, 0.06 mmol, 0.18 equiv.), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.0 equiv.), 3,5-difluorophenylboronic acid (145.0 mg, 0.9 mmol, 3.0 equiv.), Pd(dtbpf)Cl (20.0 mg, 0.03 mmol, 0.1 equiv.), and KCO (85.0 mg, 0.6 mmol, 2.0 equiv.). The resulting solution was stirred at 70 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:6). This resulted in 90 mg (81.7%) of ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) as a white solid.

[0271] Synthesis of 2,3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) [ka] A 40 mL round-bottom flask was charged with HO (1.0 mL), EtOH (5.0 mL), ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5, 90.0 mg, 0.25 mmol, 1.0 equiv.), and LiOH (60.0 mg, 2.5 mmol, 10.0 equiv.). The resulting solution was stirred at 50 °C for 2 h. The pH was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 70 mg (84.4%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) as a white solid.

[0272] 3. Synthesis of tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1) [ka] A 40 mL round-bottom flask was charged with DMF (1.0 mL, 0.01 mmol, 0.06 equiv.), t-BuOH (1.0 mL, 0.01 mmol, 0.06 equiv.), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6, 70.0 mg, 0.2 mmol, 1.0 equiv.), DPPA (70.0 mg, 0.25 mmol, 1.2 equiv.), and TEA (24.0 mg, 0.2 mmol, 1.1 equiv.). The resulting solution was stirred at 50 °C for 3 h. This mixture was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 90:10 HO:ACN to 20:80 HO:ACN within 15 min; detector, 254 nm. This afforded tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1) as a white solid.

[0273] 4. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-amine (13-2) [ka] A 50 mL round-bottom flask was charged with HCl (gas) and tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1, 65.0 mg, 0.2 mmol, 1.0 equiv) in 1,4-dioxane (4 M, 5.00 mL). The resulting solution was stirred at 40 °C for 2 h. The resulting mixture was concentrated in vacuo. This resulted in 40 mg (81.9%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-amine (13-2) as a white solid.

[0274] 5. Synthesis of (4S)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide and (4R)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide (320 and 320-0) [ka]

[0275] A 50 mL round-bottom flask was charged with DCM (2.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-amine (13-2, 25.0 mg, 0.08 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-carbonic chloride (50.0 mg, 0.2 mmol, 3.0 equiv.), and DIEA (0.5 mg, 0.004 mmol, 0.05 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 9.3 mg (24.3%) of (4S)—N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide (320) as a white solid, and 11 mg (26.0%) of (4R)—N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide (320-0). 1 H NMR: (300 MHz Chloroform-d, ppm): δ 8.93 (s, 1H), 7.50-7.43 (m, 1H), 7.37-7.30 (m, 1H), 7.27-7.25 (m, 2H), 7.08-7.00 (m, 2H), 6.89-6.81 (m, 1H), 4.44-4.40 (m, 1H), 4.16-4.07 (m, 1H), 3.92 (brs, 1H), 3.70-3.66 (m, 1H), 2.70-2.63 (m, 1H), 2.61 (s, 3H), 2.34-2.28 (m, 1H), 1.20-1.14 (m, 6H); 320-0 1H NMR: (300 MHz Chloroform-d, ppm): δ 8.94 (s, 1H), 7.50-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.27-7.20 (m, 2H), 7.15-7.00 (m, 2H), 6.94-6.82 (m, 1H), 4.44-4.40 (m, 1H), 4.14-4.07 (m, 1H), 3.92 (brs, 1H), 3.70-3.60 (m, 1H), 2.70-2.50 (m, 4H), 2.37-2.24 (m, 1H), 1.19-1.14 (m, 6H).

[0276] [Table 12]

[0277] Preparative Example 9: Compounds 323 and 323-0 can be synthesized according to the process shown in Scheme 14 below. Scheme 14 [ka]

[0278] 1. Synthesis of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2a) and ethyl 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2b) [ka] An 8 mL round-bottom flask was charged with THF (3.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.00 equiv.), di-tert-butylzinc (4.0 mL, 2.0 mmol, 6.5 equiv.), and Pd(PPh3)4 (40.0 mg, 0.03 mmol, 0.1 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 (1:4). This resulted in 20 mg (mixture) of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2a) and ethyl 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2b) as a white solid.

[0279] Synthesis of 2,3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3b) [ka] A 50 mL round-bottom flask was charged with HO (1.0 mL), EtOH (5.0 mL), a mixture of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (a mixture of 14-2a and 14-2b, 20.0 mg, 0.06 mmol, 1.00 equiv.), and NaOH (40.0 mg, 1.00 mmol, 15.2 equiv.). The resulting solution was stirred at 80 °C for 2 h. The pH was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 12 mg (mixture) of 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3b) as a white solid.

[0280] Synthesis of 3,3-tert-butyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (323) and N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-3-(2-methylpropyl)-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (323-0) [ka]

[0281] A 50 mL round-bottom flask was charged with a mixture of DMF (1.0 mL, 12.9 mmol, 237.2 equiv.), 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (a mixture of 14-3a and 14-3b, 15.0 mg, 0.05 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (10.0 mg, 0.06 mmol, 1.2 equiv.), HATU (35.0 mg, 0.09 mmol, 1.7 equiv.), and DIEA (17.0 mg, 0.1 mmol, 2.4 equiv.). The resulting solution was stirred at room temperature for 1 h. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from HO:ACN=50:50 to HO:ACN=10:90 within 20 minutes; detector, 254 nm. The product was obtained. This resulted in 2.2 mg (9.9%) of 3-tert-butyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (323) as a white solid and 5 mg (21%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-3-(2-methylpropyl)-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (323-0). 1 H NMR: (300 MHz chloroform-d, ppm): δ 8.22 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.99-6.96 (m, 1H), 6.91-6.88 (m, 1H), 6.11-5.90 (m, 1H), 5.45-5.30 (m, 1H), 4.41-4.37 (m, 1H), 4.30-4.14 (m, 1H), 3.90-0.70 (m, 1H), 2.68 (s, 3H), 2.50-2.30 (s, 1H), 2.30-2.15 (m, 1H), 1.75-1.70 (m, 6H), 1.55 (s, 9H); 323-01 H NMR: (300 MHz Chloroform-d, ppm): δ 8.24 (s, 1H), 7.40-7.31 (m, 1H), 7.27-7.21 (m, 1H), 6.99-6.90 (m, 1H), 6.88-6.85 (m, 1H), 6.10 (brs, 1H), 5.41-5.37 (m, 1H), 4.40-4.34 (m, 1H), 4.25-4.17 (m, 1H), 3.80 (brs, 1H), 2.85 (d, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.44-2.38 (m, 1H), 2.28-2.10 (m, 2H), 1.60 (t, J = 6.6 Hz, 6H), 0.95 (d, J = 6.6 Hz, 6H).

[0282] Preparative Example 10: Compound 324 can be synthesized by the process shown in Scheme 15 below. Similarly, compounds 325, 369, 372-0, and 373 can be prepared by analogous methods by one skilled in the art. Scheme 15 [ka]

[0283] Synthesis of 1,8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate ethyl ester (15-1) [ka] An 8 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with toluene (2.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 70.0 mg, 0.2 mmol, 1.0 equiv.), piperidine (120.0 mg, 1.4 mmol, 6.6 equiv.), Pd(dba) (35.0 mg, 0.04 mmol, 0.2 equiv.), BINAP (38.0 mg, 0.06 mmol, 0.3 equiv.), and CsCO (200.0 mg, 0.6 mmol, 2.9 equiv.). The resulting solution was stirred at 120 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 60 mg (84.6%) of ethyl 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate (15-1) as a yellow solid.

[0284] Synthesis of 2,8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2) [ka] A 50 mL round-bottom flask was charged with i-PrOH (1.0 mL, 0.02 mmol), THF (1.0 mL), HO (1.0 mL), ethyl 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate (15-1, 70.0 mg, 0.2 mmol, 1.0 equiv.), and LiOH·HO (30.0 mg, 0.7 mmol, 3.4 equiv.). The resulting solution was stirred at 50 °C for 1 h. The pH was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 60 mg (93.7%) of 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2) as a yellow solid.

[0285] 3. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxamide (324) [ka]

[0286] A 50 mL round-bottom flask was charged with DMA (3.0 mL), 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2, 60.0 mg, 0.2 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (44.0 mg, 0.3 mmol, 1.5 equiv.), HATU (113.0 mg, 0.3 mmol, 1.5 equiv.), and DIEA (51.0 mg, 0.4 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The mixture was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 36.4 mg (42.3%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyridazine-7-carboxamide (324) as a yellow solid. (300 MHz, Chloroform-d, ppm): δ 8.19 (s, 1H), 7.33-7.30 (m, 1H), 7.25-7.20 (m, 1H),6.97-6.90 (m, 1H), 6.89-6.80 (m, 1H), 6.10-6.02 (m, 1H), 5.40-5.30 (m, 1H), 4.38-4.34 (m, 1H), 4.22-4.10 (m, 1H), 3.79-3.76 (m, 1H), 3.30-3.20 (m, 4H), 2.52 (s, 3H), 2.50-2.35 (m, 1H), 2.30-2.15 (m, 1H), 1.80-1.70 (m, 4H), 1.65-1.58 (m, 8H).

[0287] [Table 13]

[0288] Preparative Example 11: Compounds 327, 326, 326-0, 365, 370, and 371 can be prepared by the process shown in Scheme 16 below. Scheme 16 [ka]

[0289] 1. Synthesis of ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexan-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylate (16-1) [ka]

[0290] An 8 mL round-bottom flask was charged with a mixture of dioxane (2.0 mL), HO (0.4 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.00 mg, 0.3 mmol, 1.0 equiv.), 4-(trifluoromethyl)cyclohexan-1-en-1-ylboronic acid (120.0 mg, 0.6 mmol, 2.0 equiv.), Pd(dtbpf)Cl (20.0 mg, 0.03 mmol, 0.1 equiv.), and KCO (100.0 mg, 0.7 mmol, 2.4 equiv.). The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 110 mg (90.7%) of ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylate (16-1) as a yellow solid.

[0291] Synthesis of 2,8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexyl-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid (16-2) [ka]

[0292] A 50 mL round-bottom flask was charged with i-PrOH (2.0 mL), THF (2.0 mL), HO (1.0 mL), ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylate (16-1, 110.0 mg, 0.3 mmol, 1.0 equiv.), and LiOH (70.0 mg, 2.9 mmol, 10.5 equiv.). The resulting solution was stirred at 50 °C for 1 h. The pH of the solution was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 90 mg (88.0%) of 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid (16-2) as a white solid.

[0293] 3. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327) [ka] A 40 mL round-bottom flask was charged with DMF (5.0 mL), 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid (16-2, 130.0 mg, 0.3 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (79.2 mg, 0.5 mmol, 1.5 equiv.), HATU (200.5 mg, 0.5 mmol, 1.5 equiv.), and DIEA (137.2 mg, 1.0 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The mixture was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 130 mg (73.7%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327) as a white solid. (300 MHz, Chloroform-d, ppm): δ 8.20 (s, 1H), 7.35-7.30 (m, 1H), 7.25-7.17 (m, 1H), 7.10-6.84 (m, 2H), 6.15-5.90 (m, 2H), 5.45-5.30 (m, 1H), 4.44-4.31 (m, 1H), 4.23-4.19 (m, 1H), 3.83-3.72 (m, 1H), 2.75-2.55 (m, 3H), 2.53 (s, 3H), 2.50-2.35 (m, 3H), 2.29-2.13 (m, 3H), 1.63 (d, J = 6.6 Hz, 6H).

[0294] 4. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-b]pyridazine-7-carboxamide and N-((S)-chroman-4-yl)-8-isopropyl-2-methyl-3-((1s,4R)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-b]pyridazine-7-carboxamide (326 and 326-0) [ka]

[0295] A 50 mL round-bottom flask was charged with EA (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexan-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327, 50.0 mg, 0.10 mmol, 1.0 equiv.), and aqueous Pd / C (50.0 mg). H2(g) was introduced into the flask at room temperature. The resulting solution was stirred at room temperature for 2 hours. The solids were filtered off. The mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 minutes; detector, 254 nm. The racemate was purified using a column: XA-YMC Cellulose-SC, 4.6*100 mm, 3 μm; mobile phase A / mobile phase B, hexane / EtOH=70 / 30; flow rate, 1 mL / min; gradient, 30B to 30B in 10 min; 254 nm; injection volume, 1 mL. This resulted in 19.3 mg (38.4%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-b]pyridazine-7-carboxamide and 8.0 mg (15.8%) of N-((S)-chroman-4-yl)-8-isopropyl-2-methyl-3-((1s,4R)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-b]pyridazine-7-carboxamide (326 and 326-0). The stereochemical representation of 326 is assumed. 1H NMR spectrum: (300 MHz chloroform-d, ppm): δ 8.23 ​​(s, 1H), 7.35-7.30 (m, 1H), 7.27-7.20 (m, 1H), 7.02-6.94 (m, 1H), 6.90-6.80 (m, 1H), 6.07 (brs, 1H), 5.44-5.34 (m, 1H), 4.44-4.31 (m, 1H), 4.28-4.14 (m, 1H), 3.90-3.80 (m, 1H), 3.45-3.25 (m, 1H), 2.58 (s, 3H), 2.55-2.40 (m, 2H), 2.45-2.15 (m, 4H). 1.85-1.65 (m, 5H), 1.62 (d, J = 6.6 Hz, 6H); 326-0 1 H NMR spectrum: (300 MHz, chloroform-d, ppm): δ 8.17 (s, 1H), 7.30-7.28 (m, 1H), 7.25-7.15 (m, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.15-5.90 (m, 1H), 5.45-5.20 (m, 1H), 4.40-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.81-3.65 (m, 1H), 3.30-3.10 (m, 1H), 2.53 (s, 3H), 2.46-2.31 (m, 1H). 2.30-2.00 (m, 6H), 2.00-1.85 (m, 2H), 1.65-1.55 (m, 6H), 1.50-1.45 (m, 1H).

[0296] [Table 14]

[0297] Preparative Example 12: Compound 352 can be prepared by the process shown in Scheme 17 below. Scheme 17 [ka]

[0298] 1. Synthesis of ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (17-2) [ka] A 1000 mL round-bottom flask was charged with THF (85.0 g, 1178.8 mmol, 26.3 equiv.), ethyl 5-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (17-1, 15.0 g, 44.9 mmol, 1.0 equiv.), and ethyl acetate (50.0 g, 567.5 mmol, 12.6 equiv.). Following this, t-BuOK (500 mL) was added portionwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of NH4Cl (aq.). The resulting solution was extracted three times with 200 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 13 g (77.0%) of ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (17-2) as a colorless oil.

[0299] 2. Synthesis of ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3) [ka] A 500 mL round-bottom flask was charged with DCM (100.0 mL, 1573.0 mmol, 59.2 equiv.), ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (17-2, 10.0 g, 26.6 mmol, 1.0 equiv.), and DMF-DMA (9.0 g, 75.5 mmol, 2.8 equiv.). The resulting solution was stirred at 40 °C for 2 h. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted twice with 100 mL of MTBE, and the aqueous layers were combined. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The solid was collected by filtration. This resulted in 5 g (65.7%) of ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3) as a white solid.

[0300] 3. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4) [ka] A 40 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with HO (1.0 mL), NMP (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3, 400.0 mg, 1.398 mmol, 1.0 equiv.), 3,5-dichlorophenylboronic acid (320.1 mg, 1.7 mmol, 1.2 equiv.), Pd(dtbpf)Cl (70.0 mg, 0.1 mmol, 0.08 equiv.), and CsCO (1.2 g, 3.7 mmol, 2.6 equiv.). The resulting solution was stirred at 100 °C for 2 h. The mixture was cooled to room temperature, and 5 mL of HO was added. The solid was collected by filtration. This resulted in 300 mg (crude) of ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4) as a yellow solid.

[0301] 4. Synthesis of ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5) [ka] A 40 mL round-bottom flask was charged with CHCl3 (5.0 mL, 0.04 mmol, 0.07 equiv), DMF (15.0 mg, 0.2 mmol, 0.4 equiv), ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4, 200.0 mg, 0.6 mmol, 1.0 equiv), and (COCl)2 (400.0 mg, 3.1 mmol, 5.5 equiv). The resulting solution was stirred at 80 °C for 22 h. The resulting mixture was concentrated in vacuo. The resulting mixture was washed ten times with 10 mL of ACN:HO (1:1). The solid was collected by filtration. This resulted in 110 mg (52.3%) of ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5) as a yellow solid.

[0302] 5. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6) [ka] A 40 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with HO (1.00 mL, 55.5 mmol, 187.0 equiv.), THF (5.0 mL, 61.7 mmol, 207.9 equiv.), ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5, 110.0 mg, 0.3 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (72.0 mg, 0.43 mmol, 1.4 equiv.), Pd(dtbpf)Cl (40.0 mg, 0.06 mmol, 0.2 equiv.), and KCO (160.0 mg, 1.2 mmol, 3.9 equiv.). The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 80 mg (71.6%) of ethyl 3-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6) as a yellow solid.

[0303] 6. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7) [ka] A 50 mL round-bottom flask was charged with EA (5.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6, 80.0 mg, 0.21 mmol, 1.0 equiv.), and PtO (40.0 mg, 0.2 mmol, 0.8 equiv.). H (g) was introduced to the flask using a balloon. The resulting solution was stirred at 50 °C for 1 h. The solid was collected by filtration. The mixture was concentrated under vacuum. This resulted in 60 mg of ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7) as a yellow solid.

[0304] 7. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8) [ka] An 8 mL round-bottom flask was charged with EtOH (2.0 mL), HO (0.50 mL), ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7, 60.0 mg, 0.2 mmol, 1.0 equiv.), and LiOH (30.0 mg, 1.2 mmol, 7.9 equiv.). The resulting solution was stirred at 50 °C for 1 h. The reaction was then quenched by the addition of water / ice. The pH of the solution was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 40 mg (72.0%) of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8) as a white solid.

[0305] 8. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (352) [ka] An 8 mL round-bottom flask was charged with DMF (4.0 mL), 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8, 40.0 mg, 0.1 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (22.0 mg, 0.15 mmol, 1.3 equiv.), HATU (70.0 mg, 0.2 mmol, 1.6 equiv.), and DIEA (46.0 mg, 0.4 mmol, 3.1 equiv.). The resulting solution was stirred at room temperature for 1 h. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 15.9 mg (28.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (352) as a white solid. (300 MHz, Chloroform-d, ppm): δ 8.41 (s, 1H), 8.11 (s, 1H), 7.99 (d, J = 1.8 Hz, 2H), 7.39 (s, 1H),7.32-7.28 (m, 1H), 7.28-7.22 (m, 1H), 6.99-6.96 (m, 1H), 6.90 (d, J = 8.4, 1H), 6.13 (d, J = 7.5 Hz, 1H), 5.50-5.30 (m, 1H), 4.46-4.33 (m, 1H), 4.29-4.15 (m, 1H), 3.79-3.70 (m, 1H), 2.50-2.36 (m, 1H), 2.33-2.20 (m, 1H), 1.69-1.65 (m, 6H).

[0306] Preparative Example 13: Compound 366 was prepared according to Scheme 18 shown below. Scheme 18 [ka]

[0307] 1. Synthesis of ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate [ka]

[0308] A 20 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with DMAC (5.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.0 equiv.), dppf (59.3 mg, 0.1 mmol, 0.3 equiv.), Zn(CN) (100.1 mg, 0.8 mmol, 2.8 equiv.), Pd(dba) (50.5 mg, 0.05 mmol, 0.2 equiv.), and Zn (100.1 mg, 1.5 mmol, 5.0 equiv.). The resulting solution was stirred at 100 °C for 2 h. The reaction was then quenched by the addition of water. The resulting solution was extracted three times with 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:5), resulting in 40 mg (47.9%) of ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (18-1) as a yellow oil.

[0309] Synthesis of 2,3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid [ka] An 8 mL round-bottom flask was charged with EtOH (1.0 mL), HO (0.5 mL), ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (18-1, 40.0 mg, 0.15 mmol, 1.0 equiv.), and LiOH (30.0 mg, 1.2 mmol, 8.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 25 mg (69.7%) of 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (18-2) as a yellow oil.

[0310] 3. Synthesis of 3-cyano-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (366) [ka] An 8 mL round-bottom flask was charged with DMF (2 mL), 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (18-2, 25.0 mg, 0.1 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (16.9 mg, 0.1 mmol, 1.1 equiv.), HATU (47.0 mg, 0.1 mmol, 1.21 equiv.), and DIEA (28.0 mg, 0.2 mmol, 2.1 equiv.). The resulting solution was stirred at room temperature for 1 h. The mixture was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 70:30 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 16.5 mg (42.9%) of 3-cyano-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (366) as a white solid. (300 MHz, CDCl3, ppm): δ 8.35 (s, 1H), 7.25-7.20 (m, 2H), 6.97-6.92 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.20-6.10 (m, 1H), 5.39-5.33 (m, 1H), 4.41-4.32 (m, 1H), 4.27-4.14 (m, 1H), 3.69-3.59 (m, 1H), 2.62 (s, 3H), 2.45-2.35 (m, 1H), 2.29-2.18 (m, 1H), 1.65-1.55 (m, 6H).

[0311] Preparative Example 14: Compounds 394, 397-0, 395 and 398 can be synthesized according to Scheme 19 shown below. Scheme 19 [ka]

[0312] 1. Synthesis of methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1) [ka] A 40 mL round-bottom flask was charged with DMF (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3, 150.0 mg, 0.5 mmol, 1.0 equiv.), methyl iodide (200.0 mg, 1.3 mmol, 2.4 equiv.), and KCO (210.0 mg, 1.5 mmol, 2.9 equiv.). The resulting solution was stirred at 70 °C for 1 h. The mixture was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 90:10 HO:ACN to 40:60 HO:ACN within 15 min; detector, 254 nm. This resulted in 80 mg (48.6%) of methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1) as a white solid.

[0313] 2. Synthesis of methyl 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2) [ka] An 8 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with THF (5.0 mL), HO (1.0 mL), methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1, 80.0 mg, 0.25 mmol, 1.0 equiv.), 3,5-dichlorophenylboronic acid (56.0 mg, 0.3 mmol, 1.1 equiv.), Pd(dtbpf)Cl (30.0 mg, 0.05 mmol, 0.2 equiv.), and KCO (100.0 mg, 0.7 mmol, 2.8 equiv.). The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 20 mg (20.6%) of methyl 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2) as a white solid.

[0314] 3. Synthesis of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3) [ka] A 40 mL round-bottom flask was charged with EtOH (5.0 mL), HO (2.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2, 70.0 mg, 0.2 mmol, 1.0 equiv.), and LiOH (40.0 mg, 1.7 mmol, 8.7 equiv.). The resulting solution was stirred at 50 °C for 1 h. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 40 mg (61.9%) of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3) as a white solid.

[0315] 4. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-methoxyimidazo[1,2-b]pyridazine-7-carboxamide (394) [ka]

[0316] An 8 mL round-bottom flask was charged with DMF (3.0 mL), 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3, 40.0 mg, 0.1 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (19.5 mg, 0.1 mmol, 1.1 equiv.), HATU (75.1 mg, 0.2 mmol, 1.7 equiv.), and DIEA (35.9 mg, 0.3 mmol, 2.3 equiv.). The resulting solution was stirred at room temperature for 1 h. The mixture was purified by Flash-Prep-HPLC (IntelFlash-1) using the following conditions: column, C18 silica gel; mobile phase, increasing from 70:30 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. This resulted in 12 mg (21.6%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-methoxyimidazo[1,2-b]pyridazine-7-carboxamide (394) as a white solid. (300 MHz, CDCl3, ppm): δ 10.08 (d, J = 7.8 Hz, 1H), 9.10 (s, 1H), 7.92 (s, 2H), 7.51 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.41-7.33 (m, 1H), 7.21-7.15 (m, 1H), 6.94-6.84 (m, 2H), 5.48-5.46 (m, 1H), 4.46 (s, 3H), 4.37-4.29 (m, 2H), 2.39-2.30 (m, 1H), 2.25-2.17 (m, 1H).

[0317] [Table 15]

[0318] Preparative Example 15: Compounds 450, 451, A408, A409, A421, A422, A460, A461, A462, A463 and A464 can be prepared employing the processes of Schemes 20 and 21 shown below. Scheme 20 [ka]

[0319] Scheme 21 [ka]

[0320] 1. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) [ka] A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3, 20.0 g, 78.4 mmol, 1.0 equiv.) and DMF (200.0 mL). This was followed by the addition of NBS (15.3 g, 86.2 mmol, 1.1 equiv.) in several portions. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1 L of water. The resulting solution was extracted three times with 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed twice with 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:8). This resulted in 15 g (56.2%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) as a white solid.

[0321] 2. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) [ka] A 1 L three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4, 14 g, 41.9 mmol, 1.0 equiv.), THF (140.0 mL, 1728.0 mmol, 41.2 equiv.), and ethyl acetate (18.5 g, 209.5 mmol, 5.0 equiv.). This was followed by the dropwise addition of LiHMDS (209.5 mL, 209.5 mmol, 5.0 equiv.) with stirring at 0 °C. The resulting solution was stirred at 0 °C for 30 min. The reaction was then quenched by the addition of 200 mL of saturated NH4Cl. The resulting solution was extracted three times with 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed once with 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 11.5 g (65.7%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5) as a yellow solid.

[0322] 3. Synthesis of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] A 250 mL three-necked round-bottom flask was charged with ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoate (3-5, 10.0 g, 26.6 mmol, 1.0 equiv.), DMF (100.0 mL), KCO (3.7 g, 26.6 mmol, 1.0 equiv.), and DMF-DMA (7.9 g, 66.5 mmol, 2.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of 300 mL of water. The solid was collected by filtration. The crude product was recrystallized from ACN in a 10:1 ratio. This resulted in 7.5 g (98.6%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) as a white solid.

[0323] 4. Synthesis of ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1) [ka] A 250 mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6, 8.0 g, 28.0 mmol, 1.0 equiv.), DMF (80.0 mL), KCO (7.7 g, 55.9 mmol, 2.0 equiv.), and CHCl (11.9 g, 83.891 mmol, 3.0 equiv.). The resulting solution was stirred at 60 °C for 2 h. The residue was applied to a C18 column using a 25% to 45% ACN solution in water (8 min). This resulted in 2.9 g (34.0%) of ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1) as a white solid.

[0324] 5. Synthesis of ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2) [ka] A 40 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1, 300.0 mmol, 1.0 equiv.), DMF (6.0 mL), methyl 2,2-difluoro-2-sulfoacetate (960.2 mg, 5.0 mmol, 5.0 equiv.), HMPA (895.7 mg, 5.0 mmol, 5.0 equiv.), and CuI (761.5 mg, 4.0 mmol, 4.0 equiv.). The resulting solution was stirred at 100 °C for 16 h. The solids were filtered off. The residue was applied to a C18 column with 25% to 45% ACN (0.1% TFA) in HO (8 min). This resulted in 170 mg (56.6%) of ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2) as a yellow solid.

[0325] 6. Synthesis of ethyl 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-3) [ka] A 40 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2, 1.8 g, 6.2 mmol, 1.0 equiv.), LiCl (2.6 g, 62.2 mmol, 10.0 equiv.), and DMF (18.0 mL). The resulting solution was stirred at 120 °C for 2 h. The residue was applied to a C18 column (75%-83%, 8 min, ACN in HO (0.1% TFA)). This resulted in 900 mg (52.5%) of ethyl 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-3) as a yellow solid.

[0326] 7. Synthesis of ethyl 8-bromo-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-4) [ka] Ethyl 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-3, 400.0 mg, 1.4 mmol, 1.0 equiv.) and POBr3 (3333.7 mg, 11.6 mmol, 8.0 equiv.) were placed in a 40 mL vial purged and maintained under an inert atmosphere of nitrogen. The resulting solution was stirred at 120 °C for 30 min. The reaction was then quenched by the addition of 10 mL of water / ice. The pH of this solution was adjusted to 8 with Na2CO3. The resulting solution was extracted three times with 10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed once with 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 520 mg (97.3%) of ethyl 8-bromo-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-4) as a yellow solid.

[0327] 8. Synthesis of ethyl 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1) [ka] An 8 mL vial was charged with ethyl 8-bromo-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-4, 150.0 mg, 0.4 mmol, 1.0 equiv.), DMF (1.5 mL), and morpholine (193.3 mg, 2.2 mmol, 5.0 equiv.). The resulting solution was stirred at 100 °C for 1 h. The residue was applied to a C18 column (80%-90%, 6 min, ACN in HO (0.1% FA)). This resulted in 110 mg (72.0%) of ethyl 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1) as a white solid.

[0328] 9. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2) [ka] A mixture of ethyl 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1, 90.00 mg, 0.3 mmol, 1.0 equiv.), NMP (1.8 mL), 1,3-dichloro-5-iodobenzene (214.0 mg, 0.8 mmol, 3.0 equiv.), CsCO (170.3 mg, 0.5 mmol, 2.0 equiv.), Pd(AcO) (11.7 mg, 0.05 mmol, 0.2 equiv.), and Ad(n-Bu)P (28.0 mg, 0.08 mmol, 0.3 equiv.) was placed in an 8 mL vial purged and maintained under an inert atmosphere of nitrogen. The resulting solution was stirred at 100 °C overnight. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 110 mg (72.2%) of ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2) as a white solid.

[0329] 10. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3) [ka] An 8 mL vial was charged with ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2, 110.0 mg, 0.2 mmol, 1.0 equiv.), i-PrOH (2.1 mL), HO (0.7 mL), and LiOH·HO (75.4 mg, 1.8 mmol, 8.0 equiv.). The resulting solution was stirred at 60 °C for 5 h. The residue was applied to a C18 column (80%-90%, 6 min, ACN in HO (0.1% FA)). This resulted in 70 mg (65.3%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3) as a white solid.

[0330] 11. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxamide (450) [ka]

[0331] An 8 mL vial was charged with 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3, 66.0 mg, 0.1 mmol, 1.0 equiv.), DMF (2.0 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (32.0 mg, 0.2 mmol, 1.5 equiv.), DIEA (55.5 mg, 0.4 mmol, 3.0 equiv.), and HATU (81.6 mg, 0.2 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The residue was applied to a C18 column (90%-98%, 6 min, ACN in HO (0.1% FA)). This resulted in 35.1 mg (41.4%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxamide (450) as a white solid. (300 MHz, DMSO-d6, ppm): δ 9.08 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.83 (t, J = 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.32 (d, J = 7.8Hz, 1H), 7.21-7.15 (m, 1H), 6.94-6.89 (m, 1H), 6.82-6.79 (m, 1H), 5.23-5.16(m, 1H), 4.30-4.20 (m, 2H), 3.94-3.81 (m, 8H), 2.27-2.16 (m, 1H), 2.08-2.01 (m, 1H).

[0332] [Table 16]

[0333] Preparative Example 16: Compounds 511 and 512 can be prepared employing the process of Scheme 22 below. Scheme 22 [ka]

[0334] 1. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1) [ka] A 40 mL round-bottom flask was charged with NMP (5.0 mL), ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5, 100.0 mg, 0.2 mmol, 1.0 equiv.), and morpholine (0.5 mL, 5.7 mmol, 23.6 equiv.). The resulting solution was stirred at 80 °C for 1 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted three times with 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 65 mg (64.0%) of ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1) as a yellow solid.

[0335] 2. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (22-2) [ka] A 40 mL round-bottom flask was charged with EtOH (2.0 mL), HO (1.5 mL), ethyl 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1, 65.0 mg, 0.1 mmol, 1.0 equiv.), and LiOH·HO (50.0 mg, 1.2 mmol, 7.7 equiv.). The resulting solution was stirred at 50 °C for 3 h. The pH was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 40 mg (65.9%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (22-2) as a yellow solid.

[0336] 3. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (511) [ka]

[0337] A 40 mL round-bottom flask was charged with DMF (5.0 mL), 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (22-2, 40.0 mg, 0.1 mmol, 1.0 equiv.), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (17.0 mg, 0.1 mmol, 1.12 equiv.), HATU (650.2 mmol, 1.7 equiv.), and DIEA (38.0 mg, 0.3 mmol, 2.9 equiv.). The resulting solution was stirred at room temperature for 1 h. The crude product was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silica gel; mobile phase, increasing from 50:50 HO:ACN to 10:90 HO:ACN within 20 min; detector, 254 nm. The product was obtained as a white solid, 37.8 mg (70.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholin-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (511). (300 MHz, CDCl3, ppm) δ 9.03 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.21-7.15 (m, 1H), 6.95-6.90 (m, 1H), 6.80-6.80 (m, 1H), 5.23-5.20 (m, 1H), 4.27-4.24(m, 2H), 3.93-3.78 (m, 8H), 2.23-2.21 (m, 1H), 2.10-2.07 (m, 1H). 512 1H NMR spectrum: (300 MHz, CDCl3, ppm) δ 8.36 (s, 1H), 7.98 (d, J = 1.9 Hz, 2H), 7.90 (s, 1H), 7.37-7.35 (m, 1H), 7.32-7.22 (m, 2H), 7.03-6.86 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.42-5.34 (m, 1H), 4.43-4.31 (m, 1H), 4.29-4.16 (m, 1H), 3.46 (s, 6H), 2.43-2.36 (m, 1H), 2.27-2.14 (m, 1H)

[0338] Preparative Example 17: Compound 558 was prepared according to Scheme 23 shown below. Compound 559 can be prepared by those skilled in the art by adapting the process described in Scheme 23. Scheme 23 [ka]

[0339] Synthesis of 1,7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2) [ka] To a stirred mixture of ethyl 7-chloroimidazo[1,2-b]pyridazine-2-carboxylate (23-1, 1.0 g, 4.4 mmol, 1.0 equiv.) and 1,3-dichloro-5-iodobenzene (1.8 g, 6.6 mmol, 1.5 equiv.) in toluene (10 mL, 105.0 mmol, 23.7 equiv.), KCO (1.2 g, 8.9 mmol, 2.0 equiv.), Pd(OAc) (0.1 g, 0.4 mmol, 0.1 equiv.), and PPh (0.2 g, 0.9 mmol, 0.2 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give ethyl 7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2, 1.2 g, 73.0%) as a yellow oil.

[0340] Synthesis of 2,7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (23-3) [ka] To a stirred mixture of ethyl 7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2, 1.0 g, 2.7 mmol, 1.0 equiv.) in EtOH (8 mL) and HO (4 mL) was added LiOH·HO (1.13 g, 27.0 mmol, 10.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (50 mL). The mixture was acidified to pH 4 with HCl (aq.). The precipitated solid was collected by filtration and washed with water (2 × 10 mL). The resulting solid was dried under infrared light.

[0341] Synthesis of 3,7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (23-4) [ka] 7-Chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (23-3, 1.0 g, 3.0 mmol, 1.0 equiv.) and N,O-dimethylhydroxylamine (0.5 equiv.) were dissolved in DCM (10 mL, 157.3 mmol, 53.9 equiv.) and EDCI (0.6 g, 2.9 mmol, 1.0 equiv.), PyBOP (1.5 g, 2.9 mmol, 1.0 equiv.), and DIEA (1.1 g, 8.7 mmol, 3.0 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, gradient from 50% to 90% in 10 min; detector, UV 254 nm to obtain 400 mg of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (23-4, 35.5%) as a yellow oil.

[0342] 4. Synthesis of 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]ethenone (23-5) [ka] To a stirred mixture of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (23-4, 80.0 mg, 0.2 mmol, 1.0 equiv) in THF (2 mL, 24.7 mmol, 119.0 equiv) was added chloromethylmagnesium (77.6 mg, 1.0 mmol, 5.0 equiv) at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 60 minutes under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×4 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA 4:1) to give 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]ethanone (23-5, 40 mg, 56.6%) as a pale yellow solid.

[0343] 5. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6) [ka] To a solution of 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]ethanone (23-5, 40.0 mg, 0.1 mmol, 1 equiv.) in 1 mL of MeOH and dioxane (2 mL) was added KOAc (34.6 mg, 0.4 mmol, 3.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (9.6 mg, 0.01 mmol, 0.1 equiv.) in a pressure tank. The mixture was purged with nitrogen for 2 minutes, then pressurized with carbon monoxide to 30 atmospheres and heated at 130 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by prep-TLC (PE / EA 3:1) to give 20 mg of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6, 46.8%) as a yellow solid.

[0344] 6. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7) [ka] To a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6, 20.0 mg, 0.05 mmol, 1.0 equiv.) and 2-[(propane-2-sulfonyl)zinethiosulfonyl]propane (46.1 mg, 0.2 mmol, 3.0 equiv.) in DMSO (2 mL) was added t-BuOOH (28.6 mg, 0.3 mmol, 5.0 equiv.) at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA 2:1) to give methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7, 10 mg, 44.8%) as a yellow oil.

[0345] 7. Synthesis of 2-acetyl-3-(3,5-dichlorophenyl)-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (23-8) [ka] To a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7, 10.0 mg, 0.02 mmol, 1.0 equiv.) in EtOH (1 mL) and HO (0.5 mL) was added LiOH·HO (10.3 mg, 0.25 mmol, 10.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (5 mL). The mixture was acidified to pH 4 with HCl (aq.). The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (23-8) was used directly in the next step without further purification.

[0346] 8. Synthesis of 2-acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine (558) [ka]

[0347] To a stirred mixture of 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (23-8, 10.0 mg, 0.02 mmol, 1.0 equiv.) and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (5.7 mg, 0.04 mmol, 1.5 equiv.) in DMF (1 mL, 12.9 mmol, 506.8 equiv.) was added DIEA (9.9 mg, 0.07 mmol, 3.0 equiv.) and HATU (14.5 mg, 0.04 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The crude product was purified by Prep-HPLC under the following conditions (gradient: isocratic) to give 11 mg of 2-acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine (558, 95.0) as a solid. (400 MHz, chloroform-d, ppm) δ: 8.31 (s, 1H), 7.56 (s, 2H), 7.45 (s, 1H), 7.225-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.88-6.86 (m, 1H), 6.06-6.05 (m, 1H), 5.38-5.36 (m, J = 4.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.21-4.16 (m, 1H), 3.73-3.67 (m 1H), 2.75 (s, 3H), 2.43-2.38 (m, 1H), 2.23-2.20 (m, 1H), 1.68 (t, J = 7.4 Hz, 6H). 559 1H NMR spectrum: (400 MHz, chloroform-d, ppm) δ: 8.44 (s, 1H), 7.88 (s, 2H), 7.50 (s, 1H), 7.26-7.21 (m, 2H), 6.98-6.94(m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.08-6.07 (m, 1H), 5.40-5.36 (m, 1H), 4.39-4.34 (m, 1H), 4.21-4.15 (m, 1H), 3.71-3.64 (m, 1H), 2.44-2.39 (m, 1H), 2.26-2.20 (m, 1H), 1.65-1.54 (m, 6H)

[0348] Preparative Example 18: Compound 614 can be prepared according to the process described in Scheme 24. Scheme 24 [ka]

[0349] Synthesis of 1,4-nitroso-3,4-dihydro-2H-1,4-benzoxazine [ka] To a 500 mL three-necked round-bottom flask were added methyl 3,4-dihydro-2H-1,4-benzoxazine (24-1, 3.0 g, 22.2 mmol, 1.0 equiv.) and 3 M HCl (300 mL), and NaNO (1.8 g, 26.1 mmol, 1.2 equiv.) was added dropwise / portionwise over 2 h at 0 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:01) to give 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine (24-2, 2.7 g, 75.1%) as a yellow oil.

[0350] 2. Synthesis of 3,4-dihydro-2H-1,4-benzoxazin-4-amine [ka] To a 500 mL three-necked round-bottom flask were added methyl 4-nitroso-2,3-dihydro-1,4-benzoxazine (24-2, 2.7 g, 19.2 mmol, 1.0 equiv.) and THF (300 mL), and LAH (1.35 g, 1.9 mmol, 2.0 equiv.) was added dropwise over 2 h at 0 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:01) to give 3,4-dihydro-2H-1,4-benzoxazin-4-amine (24-3, 2.2 g, 44.9%) as a yellow oil.

[0351] Synthesis of 3,8-tert-butyl-3-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (614) [ka] To a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5, 100.0 mg, 0.3 mmol, 1.0 equiv.) and 2,3-dihydro-1,4-benzoxazin-4-amine (119.1 mg, 0.8 mmol, 3.0 equiv.) in DMF (5 mL) was added DIEA (170.8 mg, 1.3 mmol, 5.0 equiv.) and HATU (301.6 mg, 0.8 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool to room temperature. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 40% to 95% in 10 min; detector, UV 254 nm. Obtained 8-tert-butyl-3-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (614, 43.8 mg, 32.5%) as an off-white solid. (300 MHz, DMSO-d6, ppm) δ 10.44 (s, 1H), 8.39 (s, 1H), 7.76 (d, J = 1.8 Hz, 2H), 7.61 (t, J = 2.1 Hz, 1H), 7.05-6.96 (m, 1H), 6.88-6.82 (m, 1H), 6.79-6.66 (m, 2H), 4.36-4.33 (m, 2H), 3.65-3.62 (m, 2H), 2.55 (s, 3H), 1.73 (s, 9H).

[0352] Biological Examples The present disclosure is further illustrated by the following biological examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and that no limitation to the scope of the disclosure is intended thereby. It should further be understood that various other embodiments, modifications, and equivalents thereof may be made that may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0353] Biological Example 1: Screening method for testing the activity of compounds against microfilariae of Dirofilaria immitis. 400-600 microfilariae of Dirofilaria immitis were added to wells of a microtiter plate containing RPMI medium and test compounds formulated in 100% DMSO. Plates were maintained at 37°C and 5% CO2 for 3 days. Compound efficacy was determined based on microfilarial motility compared to the average motility of control wells containing DMSO only. EC 50 Dose-response assays were performed to determine EC values. Compounds 298-0, 304, 295, 296, A412, A406, A405, A411, A400, A401, 325, A419, 513-0, 450, A435, A439, and A442 had EC values ​​between 0.1 μM and 1 μM. 50 Compounds 279, 273, 276, 294, 322, 323, 326-0, 323-0, 352, 364, 371, 373, 298, 419, A403, A413, A407, A414, A449, A448, A447, A441, 512, 511, 513, 418, A428, A427, 305, 451, and 558 had EC values ​​between 0.01 μM and 0.1 μM. 50 Compounds 308, 271, 274, 306, 297, A410, 277, 299-0, 293, 275, 175, 573, 614, 572, 528, 560, 420, A422, 523, and 527 had EC values ​​between 0.001 μM and 0.01 μM. 50 Compounds 307, 324, 345, 524, 526, and A421 had EC values ​​of less than 0.001 μM. 50 The values ​​were shown.

[0354] Biological Example 2: Screening method for testing the activity of compounds against Haemonchus contortus. Twenty L1 Haemonchus larvae were added to wells of a microtiter plate containing nutrient medium and test compound in DMSO. Analysis was performed on day 4 to determine the extent of development of L1-L3 larvae. Larvae exposed to DMSO only served as controls. A dose-response assay was performed to determine the EC 50 Compounds 174, 366, 320-0, 369, 365, 321, 394, 298-0, 323-0, 323, 325, 296, 304-0, 373, 398, A404, 370, 326, and 299 had EC values ​​of 1 μM to 10 μM. 50 Compounds 304, A405, A414, A403, A401, 371, 364, 352, 308, 320, 298, 299-0, 327, 324, 279, and 275 were found to be active at EC values ​​between 0.1 μM and 1 μM. 50 Compounds 175, 272, 273, 295, 326-0, 277, 294, 344, A408, A410, A412, A409, A413, and A400 had EC values ​​of 0.01 μM to 0.1 μM. 50 Compounds 297, 306, 271, 345, and 274 had EC values ​​of less than 0.01 μM. 50 The values ​​were shown.

[0355] Biological Example 3: Screening method to test the activity of compounds against L4 stage larvae of Dirofilaria immits. Four to six L4 stage heartworms are added to wells of a microtiter plate containing maintenance nutrient medium and test compound formulated in 100% DMSO. The plates are kept at 37°C and 5% CO2 for 3 days, after which larval motility is determined. Compound efficacy is determined by comparing treated L4 motility to the average motility of worms in control wells containing DMSO only. EC 50 A dose-response assay is performed to determine the EC values. Compounds 366, 320-0, 365, 321, 304-0, and 329 exhibited EC values ​​between 1 μM and 10 μM. 50 Compounds 325, 323, and 370 had EC values ​​of 0.1 μM to 1 μM. 50Compounds 276, 322, 320, 364, 326, 298-0, 299, 323-0, 296, 295, and 307 were found to have EC values ​​of 0.01 μM to 0.1 μM. 50 Compounds 304, 175, 272, 294, 273, 344, 275, 327, 326-0, 299-0, 298, 277, 324, and 297 had EC values ​​of 0.001 μM to 0.01 μM. 50 Compounds 308, 271, 293, 345, 371, and 306 had EC values ​​of less than 0.001 μM. 50 showed.

[0356] Having thus described in detail the preferred embodiments of the present invention, it should be understood that the invention as defined by the preceding paragraphs is not limited to the particular details set forth in the above description, and that many obvious variations thereof are possible without departing from the spirit or scope of the present invention. Preferred embodiments of the present invention are as follows. [1] A compound of formula (I): JPEG0007818759000241.jpg5092 (I) (In the formula, L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14 or L15: JPEG0007818759000242.jpg161160 and; R' is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 1 is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted dialkylaminoalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF 5 , or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 2 is hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF 5 , or -NRa R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 3 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) p (optionally substituted alkyl), -SF 5 , optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbocyclyl group, spirocyclic heterocyclyl-heterocyclyl group, spirocyclic carbocyclyl-carbocyclyl group, spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 and R 4’ is independently in each occurrence hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, alkylaminocarbonyl, or di(alkyl)aminocarbonyl, optionally substituted alkylcarbonyloxy, optionally substituted alkylcarbonylamino, optionally substituted aryl, optionally substituted heteroaryl, -SF 5 , -SO p (optionally substituted alkyl or haloalkyl); or R 4 is R 4’ together with -NR - to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H or optionally substituted alkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 8 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; R 9 and R 9’ are independently hydrogen, halo, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or cycloalkoxy; or R 9 is R9’ together with the carbon atom to which they are attached form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; Q is N or CR 8 and; X is O, S, or N-R'; Y 1 and Y 6 are each independently N, C, or -CR 4 - and; Y 2 、Y 3 、Y 4 and Y 5 are each independently N, NR', S, O, -CR 4 - or CR 4 R 4’ and; W is CR 5 R 6 , O, SO p , or NR 7 and Z is CR 5 R 6 , O, SO p , or NR 7 and During the ceremony, R 5 and R 6 independently for each occurrence: hydrogen, halo, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or cycloalkoxy; or R 5 is R 6 together with the carbon atom to which they are attached form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; R 7 is hydrogen or C 1-C 4 - is alkyl; Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 up to three of which are heteroatoms; a is 0 or 1; q is 0 or 1; p is independently in each occurrence 0, 1, or 2; Dashed bond TIFF0007818759000243.tif412 indicates a single or double bond); or a pharmaceutically acceptable salt thereof. 〔2〕R 1 is hydrogen, cyano, halo, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -Alkyl, Hydroxy-C 1 -C 6 -haloalkyl, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkoxy-C 1 -C 6 -Alkyl, Amino-C 1 -C 6 -Alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -Alkenyloxy, C 2 -C 6 -haloalkenyloxy, C 2 -C 6 -alkynyloxy, C 2 -C 6 -haloalkynyloxy, C 1 -C 6 -Haloalkoxy, C 2 -C 6 -Alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -Alkylcarbonyl, C1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -Alkylaminocarbonyl, C 1 -C 6 -Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF 5 , -SO p (Optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), or -NR a R b (In the formula, R a and R b are independently H or optionally substituted C 1 -C 6 -alkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 2 is hydrogen, cyano, halo, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -Haloalkoxy, C 2 -C 6 -Alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkoxy-C 1 -C 6 -alkyl, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, C 1 -C 6 -Alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -Alkylaminocarbonyl, C 1 -C 6 -Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (Optionally substituted C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl), SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 3 C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -Alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, C 1 -C 6 -Alkylcarbonyl, C 1 -C6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -Alkylaminocarbonyl, C 1 -C 6 -Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SF 5 , -S(O) p (C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl), optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 and R 4’ independently at each occurrence, hydrogen, halogen, cyano, nitro, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -Alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -Haloalkoxy, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted C 1 -C 6 -Alkylcarbonyl, optionally substituted C 1 -C6 -alkoxycarbonyl, optionally substituted aminocarbonyl, C 1 -C 6 -Alkylaminocarbonyl, di(C 1 -C 6 -alkyl)aminocarbonyl, optionally substituted C 1 -C 6 -Alkylcarbonyloxy, optionally substituted C 1 -C 6 -alkylcarbonylamino, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF 5 , -SO p (Optionally substituted C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl); or R 4 is R 4’ together with -NR - to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R c and R d may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, together with the nitrogen to which they are attached, to form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 8 are hydrogen, halogens, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; R 9 and R 9’ are independently hydrogen, halo, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 3 -C 8 -cycloalkoxy; or R 9 is R 9’ together with the carbon atom to which they are attached form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; R' is hydrogen, C 1 -C 6 -Alkyl, C1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted phenyl, The compound of formula (I) described in [1] above. 〔3〕R 1 is hydrogen, cyano, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 2 -C 4 -alkenyl, optionally substituted C 2 -C 4 Alkynyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted saturated or unsaturated 5-, 6- or 7-membered heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C 1 -C 4 -Alkylcarbonyl, optionally substituted C 1 -C 4 -alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C 1 -C 4 -Alkylaminocarbonyl, optionally substituted C 1 -C 4 -dialkylaminocarbonyl, optionally substituted alkyl-SO p -, haloalkyl-SO p -, amino, -NH- optionally substituted C 1 -C 4 -alkyl, or -NR a R b (In the formula, R a and R b are independently optionally substituted alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group; R' is hydrogen or C 1 -C 4 - is alkyl; R 2 is hydrogen, halogen, cyano, nitro, -OH, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 3 -C 8 -cycloalkyl, amino, NH- optionally substituted C 1 -C 4 -Alkyl, -SF 5 , or -NR a R b (In the formula, R a and R b are independently optionally substituted C 1 -C 4 -alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group), -SO p (Optionally substituted C 1 -C 4 -alkyl or haloalkyl); R 3 C 1 -C 4 -alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3 -C 8 -cycloalkyl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, or a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group (each of which is optionally substituted by 1, 2, or 3 substituents); Each R 4 are independently selected from halogen, cyano, nitro, -OH, and optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 3 -C 8 -cycloalkyl, amino, NH- optionally substituted C 1 -C 4 -Alkyl, -SF 5 , or -NR c R d (In the formula, R c and R d are independently optionally substituted C 1 -C 4 alkyl; or R c and R d may be taken together with the nitrogen to which they are attached to form an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group), SO p (Optionally substituted C 1 -C 4 -alkyl or haloalkyl), The compound of formula (I) described in [1] or [2] above. [4] The compound of formula (I) according to any one of the above [1] to [3], wherein Q is N. [5] Q is CR 8 The compound of formula (I) according to any one of the above [1] to [3], [6] The compound of formula (I) according to any one of the above [1] to [5], wherein X is O. [7] The compound of formula (I) according to any one of the above [1] to [5], wherein X is S. [8] The compound of formula (I) according to any one of the above [1] to [7], wherein a is 1 and q is 1. [9] The compound of formula (I) according to any one of the above [1] to [7], wherein a is 0 and q is 0.

[10] The compound of formula (I) according to any one of the above [1] to [7], wherein a is 1 and q is 0.

[11] L is L1; R' is hydrogen or C 1 -C 4 - is alkyl; R 1 Halo, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -Alkyl, Hydroxy-C 1 -C 4 -haloalkyl, alkoxy-C 1 -C 4 -Alkyl, alkoxy-C 1 -C 4 -haloalkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 ...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (I) (In the formula, L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14 or L15: 【Chemistry 2】 and R' is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R 1 is hydrogen, cyano, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted dialkylaminoalkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl), —SO p (optionally substituted haloalkyl), —SF 5 , or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 2 is hydrogen, cyano, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl; optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl), —SO p (optionally substituted haloalkyl), —SF 5 , or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 3 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) p (optionally substituted alkyl), —SF 5 , optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbocyclyl group, spirocyclic heterocyclyl-heterocyclyl group, spirocyclic carbocyclyl-carbocyclyl group, spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H or optionally substituted alkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 and R 4’ is independently in each occurrence hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, or optionally substituted di(alkyl)aminocarbonyl, optionally substituted alkylcarbonyloxy, optionally substituted alkylcarbonylamino, optionally substituted aryl, optionally substituted heteroaryl, -SF 5 , -SO p (optionally substituted alkyl), —SO p (optionally substituted haloalkyl); or R 4 is R 4’ together with -NR to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H or optionally substituted alkyl; or R c and R d may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 8 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; R 9 and R 9’ are independently hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or cycloalkoxy; or R 9 is R 9’ together with the carbon atom to form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si and S, which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; Q is N or C-R 8 and X is O, S, or N—R′; Y 1 and Y 6 are each independently N, C, or -CR 4 - and; Y 2 , Y 3 , Y 4 and Y 5 are each independently N, NR′, S, O, or —CR 4 - or CR 4 R 4’ and W is CR 5 R 6 , O, SO p , or N-R 7 and Z is CR 5 R 6 , O, SO p , or N-R 7 and During the ceremony, R 5 and R 6 independently in each occurrence, hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or cycloalkoxy; or R 5 is R 6 together with the carbon atom to form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si and S, which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; R 7 is hydrogen or C 1 -C 4 - alkyl; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 up to three of which are heteroatoms; a is 0 or 1; q is 0 or 1; p is independently in each occurrence 0, 1 or 2; Dashed bond 【Transformation 3】 represents a single or double bond); or a pharmaceutically acceptable salt thereof.

2. R 1 is hydrogen, cyano, halogen, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -Alkyl, hydroxy-C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -Alkyl, amino-C 1 -C 6 -Alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyloxy, C 2 -C 6 -haloalkenyloxy, C 2 -C 6 -alkynyloxy, C 2 -C 6 -haloalkynyloxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 - alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF 5 , -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl), or -NR a R b (In the formula, R a and R b are independently H or optionally substituted C 1 -C 6 - alkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 2 is hydrogen, cyano, halogen, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, C 1 -C 6 - alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl), SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 3 is C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkenyl, C 1 -C 6 - alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SF 5 , -SO p(C 1 -C 6 -alkyl), -SO p (C 1 -C 6 -haloalkyl), optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 and R 4’ independently at each occurrence, hydrogen, halogen, cyano, nitro, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted C 1 -C 6 -Alkylcarbonyl, optionally substituted C 1 -C 6 -alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C 1 -C 6 -alkylaminocarbonyl, optionally substituted di(C 1 -C 6 -alkyl)aminocarbonyl, optionally substituted C 1 -C 6 -alkylcarbonyloxy, optionally substituted C 1 -C 6 -alkylcarbonylamino, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF 5 , -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl); or R 4 is R 4’ together with -NR to form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, which together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R c and R d may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 8 is hydrogen, halogen, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; R 9 and R 9’ are independently hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 3 -C 8 -cycloalkoxy; or R 9 is R 9’ together with the carbon atom to form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si and S, which together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; R' is hydrogen, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted phenyl, A compound of formula (I) according to claim 1.

3. R 1 is hydrogen, cyano, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 2 -C 4 -alkenyl, optionally substituted C 2 -C 4 Alkynyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted saturated or unsaturated 5-, 6- or 7-membered heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C 1 -C 4 -Alkylcarbonyl, optionally substituted C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, optionally substituted C 1 -C 4 -alkylaminocarbonyl, optionally substituted C 1 -C 4 -dialkylaminocarbonyl, -SO p (optionally substituted alkyl), -SO p (optionally substituted haloalkyl), amino, -NH-optionally substituted C 1 -C 4 -alkyl, or -NR a R b (In the formula, R a and R b are independently optionally substituted alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group which may be substituted and which may contain one or two additional heteroatoms selected from the group consisting of N, O, and S; R' is hydrogen or C 1 -C 4 - alkyl; R 2 is hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 3 -C 8 -cycloalkyl, amino, NH-optionally substituted C 1 -C 4 -alkyl, -SF 5 , or -NR a R b (In the formula, R a and R b are independently optionally substituted C 1 -C 4 - alkyl; or R a and R b may be taken together with the nitrogen to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may be substituted and which may contain one or two additional heteroatoms selected from the group consisting of N, O, and S), —SO p (Optionally substituted C 1 -C 4 -alkyl) or -SO p (optionally substituted haloalkyl); R 3 is optionally substituted C 1 -C 4 -alkyl, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, or a 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl group; Each R 4 are independently halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, optionally substituted C 3 -C 8 -cycloalkyl, amino, NH-optionally substituted C 1 -C 4 -alkyl, -SF 5 , or -NR c R d (In the formula, R c and R d are independently optionally substituted C 1 -C 4 alkyl; or R c and R d may be taken together with the nitrogen to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl group, which may be substituted and which may contain one or two additional heteroatoms selected from the group consisting of N, O, and S), —SO p (Optionally substituted C 1 -C 4 -alkyl) or -SO p (optionally substituted haloalkyl); A compound of formula (I) according to claim 1 or 2.

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

5. Q is C-R 8 The compound of formula (I) according to any one of claims 1 to 3, wherein

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

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

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

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

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

11. L is L1; R' is hydrogen or C 1 -C 4 - alkyl; R 1 is halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -Alkyl, hydroxy-C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 - alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heteroaryl containing 1 to 3 N, S, or O heteroatoms or optionally substituted 5- or 6-membered heterocyclyl, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 2 is hydrogen, halogen, -SF 5 , C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, optionally substituted C 3 -C 6 -cycloalkyl, C 1 -C 4 - alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 4 -haloalkylaminocarbonyl, -SO p (Optionally substituted C 1 -C 4 -alkyl), -SO p (optionally substituted C 1 -C 4 haloalkyl), or —NR a R b (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R 3 is C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, optionally substituted C 3 -C 8 -cycloalkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 4 -haloalkylaminocarbonyl, -SO p (optionally substituted C 1 -C 4 -alkyl), —SO p (optionally substituted C 1 -C 4 -haloalkyl), —SF 5 , optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, a 5- to 11-membered spirocyclic heterocyclyl-carbocyclyl group, a 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl group, a 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl group, wherein each ring of the spirocyclic group contains 3, 4, 5 or 6 ring atoms, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 4 independently in each occurrence, hydrogen, halogen, -SF 5 , C 1 -C 6 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (Optionally substituted C 1 -C 4 -alkyl), -SO p (optionally substituted C 1 -C 4 -haloalkyl), or -NR c R d (In the formula, R c and R d are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R 8 is hydrogen, halogen, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; X is O or S; Z is O; W is CR 5 R 6 That is, A compound of formula (I) according to claim 1 or 2.

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

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

14. Formula (Ie): 【Chemistry 4】 (Ie) (In the formula, Each R 10 are independently halogen, cyano, hydroxyl, optionally substituted C 3 -C 8 -cycloalkyl, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, Si and S, C 1 -C 6 - alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl) (wherein p is 0, 1 or 2), SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl); R 1 is halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -Alkyl, alkoxy-C 1 -C 4 -Alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 - alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S, or O heteroatoms, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 2 is hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (Optionally substituted C 1 -C 4 -alkyl), -SO p (optionally substituted C 1 -C 4 -haloalkyl), -SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R 4 is hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (Optionally substituted C 1 -C 4 -alkyl), -SO p (optionally substituted C 1 -C 4 -haloalkyl), -SF 5 , or -NR c R d (In the formula, R c and R d are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R 5 and R 6 are independently hydrogen, halogen, C 1 -C 3 -Alkyl or C 1 -C 3 -haloalkyl; R' is hydrogen or C 1 -C 3 - alkyl; R 8 is hydrogen; R 9 and R 9’ are independently hydrogen, halogen, C 1 -C 3 -Alkyl or C 1 -C 3 -haloalkyl; Y 2 , Y 3 , Y 4 , Y 5 Independently, CR 4 or N; a is 0 or 1; m is 0, 1, 2, or 3 12. The compound of formula (I) according to claim 11, represented by the compound:

15. Each R 10 15. The compound of claim 14, wherein is independently halogen and m is 2 or 3.

16. Each R 10 15. The compound of claim 14, wherein is independently chloro or fluoro and m is 2 or 3.

17. Each R 10 are independently chloro or fluoro; m is 2 or 3; R 1 is C 1 -C 3 -alkyl or -NR a R b and R 2 is hydrogen, halogen, C 1 -C 3 -Alkyl or C 1 -C 3 -haloalkyl; W is CH 2 and Z is O; R 9 and R 9’ are hydrogen, 15. The compound of claim 14.

18. Formula (If): 【Transformation 5】 (If) (In the formula, R 10 are independently cyano, halogen, hydroxyl, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkoxy-C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of N, O, Si and S, C 1 -C 6 - alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - alkylaminocarbonyl, C 1 -C 6 -haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl) (wherein p is 0, 1 or 2), SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si and S, and may form an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group; R 1 is halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -Alkyl, alkoxy-C 1 -C 4 -Alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 - alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S, or O heteroatoms, or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 6 -Alkyl or C 1 -C 6 -haloalkyl; or R a and R b may, together with the nitrogen to which they are attached, contain 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and may form an optionally substituted 3-, 4-, 5- or 6-membered heterocyclyl group; R 2 is hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, -SO p (Optionally substituted C 1 -C 4 -alkyl), -SO p (optionally substituted C 1 -C 4 -haloalkyl), -SF 5 , or -NR a R b (In the formula, R a and R b are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R 4 and R 4’ are independently hydrogen, halo, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, -SO p (Optionally substituted C 1 -C 6 -alkyl), -SO p (optionally substituted C 1 -C 6 -haloalkyl), -SF 5 , or -NR c R d (In the formula, R c and R d are independently H, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl); R' is hydrogen or C 1 -C 3 - alkyl; R 8 is hydrogen; R 9 and R 9’ are each hydrogen; D is N, SiR 11 (In the formula, R 11 is C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl), C or C-R 4 and D 1 is N, O, SiR 11 R 12 (In the formula, R 11 and R 12 is independently C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl), -CR 4 R 4’ , S(O) p where p is 0, 1 or 2; or D 1 is CR 4 R 4’ (In the formula, R 4 and R 4’ are taken together to form a 2-5 membered chain optionally replaced in the chain by one heteroatom selected from N and O to form a spirocyclic group; Y 2 , Y 3 , Y 4 , Y 5 Independently, CR 4 or N; m is 0, 1, 2, or 3; b is 0 or 1) 12. The compound of claim 11,

19. R 1 is C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, amino, C 1 -C 4 -Alkylamino, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 is hydrogen, halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl; R 4 independently at each occurrence, hydrogen, halogen, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl, 15. The compound of claim 14.

20. R 1 is C 1 -C 4 -Alkyl, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 is hydrogen, halogen, C 1 -C 3 -Alkyl or C 1 -C 3 -haloalkyl; R 4 independently at each occurrence, hydrogen, halogen, C 1 -C 3 -Alkyl or C 1 -C 3 -haloalkyl; R 10 is chloro or fluoro; m is 2 or 3; 20. The compound of claim 19.

21. R 1 is C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, amino, C 1 -C 4 -Alkylamino, di(C 1 -C 4 -alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 is hydrogen, halogen, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl; D is N or CH; D 1 is O, Si(CH 3 ) 2 or CH 2 and R 4 independently at each occurrence, hydrogen, halogen, C 1 -C 4 -Alkyl or C 1 -C 4 -haloalkyl, 19. The compound of claim 18.

22. Y 2 , Y 3 , Y 4 and Y 5 are each independently -C-R 4 The compound according to any one of claims 1 to 21,

23. Y 2 is N; Y 3 , Y 4 and Y 5 Independently -C-R 4 The compound according to any one of claims 1 to 21,

24. Y 3 is N; Y 2 , Y 4 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21,

25. Y 4 is N; Y 2 , Y 3 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21,

26. Y 5 is N; Y 2 , Y 3 and Y 4 Independently -CR 4 The compound according to any one of claims 1 to 21,

27. Y 2 and Y 3 is N; Y 4 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21,

28. Y 3 and Y 4 is N; Y 2 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21,

29. Y 4 and Y 5 is N; Y 2 and Y 3 Independently -CR 4 The compound according to any one of claims 1 to 21,

30. Y 2 and Y 4 is N; Y 3 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21,

31. Y 3 and Y 5 is N; Y 2 and Y 4 Independently -CR 4 The compound according to any one of claims 1 to 21,

32. Y 3 and Y 4 is N; Y 2 and Y 5 Independently -CR 4 The compound according to any one of claims 1 to 21, 33. A compound of formula (I): 【Transformation 6】 (I) (In the formula, R 1 , R 2 , R 3 and L are as shown in the table below: L1 is 【Transformation 7】 where X is oxygen and R' is hydrogen; L2 is 【Transformation 8】 where X is oxygen and R' is hydrogen; "Me" is methyl, "i-Pr" is isopropyl; "t-Bu" is tert-butyl; Prop-1-en-2-yl 【Chemistry 9】 and 2-F-prop-2-yl is the following group: 【Chemistry 10】 represents 1,1-Difluoroethyl is the following group: 【Chemistry 11】 represents The following groups 【Chemistry 12】 is a ring system: 【Chemistry 13】 Ring system A; 【Chemistry 14】 Ring system B; 【Chemistry 15】 Ring system C; 【Chemistry 16】 Ring system D; 【Chemistry 17】 Ring system E; [Chemistry 18] Ring system F; 【Chemistry 19】 Ring system G; 【Chemistry 20】 Ring system H; 【Chemistry 21】 Ring system I; 【Chemistry 22】 Ring system J; 【Chemistry 23】 Ring system K; 【Chemistry 24】 Ring system L; 【Chemistry 25】 Ring system M; 【Chemistry 26】 Ring system N; 【Chemistry 27】 Ring system O; 【Chemistry 28】 Ring system P; 【Chemistry 29】 Ring system Q; 【Transformation 30】 Ring system R; 【Chemistry 31】 Ring system S; 【Chemistry 32】 Ring system T; 【Transformation 33】 Ring system U; 【Transformation 34】 Ring system V; 【Chemistry 35】 Ring system X; 【Transformation 36】 Ring system Y; 【Chemistry 37】 Ring system Z; 【Transformation 38】 Ring system AA; 【Chemistry 39】 Ring system AB; 【Chemistry 40】 Ring system AC; 【Chemistry 41】 Ring system AD; 【Chemistry 42】 Ring system AE; 【Chemistry 43】 Ring system AF; 【Chemistry 44】 Ring system AG; 【Chemistry 45】 Ring system AH; 【Chemistry 46】 Ring system AJ; 【Chemistry 47】 Ring system AK; 【Chemistry 48】 Ring system AL; 【Chemistry 49】 ring system AM; [Transformation 50] Ring system AN; 【Chemistry 51】 Ring system AO; 【Chemistry 52】 ring system AP; 【Chemistry 53】 Ring system AQ; 【Chemistry 54】 Ring system AR; 【Transformation 55】 Ring system AS; 【Transformation 56】 cyclic AT; 【Chemistry 57】 ring system AU; 【Transformation 58】 Ring system AV; 【Chemistry 59】 Ring system AW; 【Transformation 60】 Ring system AX; 【Chemistry 61】 Ring system AY; 【Transformation 62】 Ring system AZ; 【Transformation 63】 Ring system AAA; (represents one of the following): 【Chemistry 64】 Formula (I) Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6

34. 34. A veterinary composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically or veterinarily acceptable salt thereof, and a veterinarily acceptable carrier.

35. 34. A veterinary composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically or veterinarily acceptable salt thereof, one or more additional active agents, and a veterinarily acceptable carrier.

36. 34. A method for treating, controlling and / or preventing a parasitic infection or infestation in a non-human animal in need thereof, comprising administering to said non-human animal an effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically or veterinarily acceptable salt thereof.

37. Use of a compound according to any one of claims 1 to 33 in the preparation of a medicament for treating, controlling and / or preventing a parasitic infection or infestation in an animal.

38. 36. A veterinary composition according to claim 34 or 35 for use in a method for the treatment, control and / or prevention of a parasitic infection or infestation in an animal.

39. The following formula: 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical 77】 【Transformation 78】 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 or 【Chemistry 83】 or a pharmaceutically acceptable salt thereof.

40. The following formula: 【Chemical 84】 Compound.

41. The following formula: 【Chemical 85】 Compound.

42. The following formula: 【Chemical 86】 Compound.

43. The following formula: 【Chemistry 87】 Compounds of

44. The following formula: 【Chemical 88】 Compound.

45. The following formula: 【Chemical 89】 Compound.

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