Insect repellent heterocyclic compounds

Abstract

The present invention provides compounds of Formula (I) or salts thereof, compositions comprising these compounds, and methods of treating, controlling, or preventing a parasitic infestation or infection in an animal by administering to the animal in need an effective amount of these compounds, wherein the variables are as defined herein.

Description

TECHNICAL FIELD

[0001] The present patent application relates to new antiparasitic compounds, compositions comprising the compounds, methods for their preparation, and methods of using the compounds to control parasites that harm animals and humans.

[0002] Cross Reference to Related Applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 031,656, filed May 29, 2020, which is incorporated by reference in its entirety. BACKGROUND

[0005] Animals such as mammals and birds are generally susceptible to infection by parasites. These parasites can be ectoparasites, such as fleas and ticks. Animals and humans are also susceptible to infection by endoparasites, including, for example, helminthiases, which are most commonly caused by a class of parasites known as nematodes or roundworms. These parasites cause significant economic losses in swine, sheep, horses, and cattle, and affect companion animals (such as 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, as well as the extra-intestinal stages of Strongyloides and Trichinella.

[0006] One serious endoparasite of mammals is Dirofilaria immitis, also known as heartworm. Other filarial endoparasites include Dirofilaria repens and Dirofilaria honkongensis, which can also infect humans. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected. Heartworms go through several life stages before becoming adult worms in the pulmonary arteries of the infected host mammal. The helminth requires a mosquito as an intermediate host to complete its life cycle. For canines, the time period between the initial infection of the dog by a mosquito bite and the maturation of the helminth into an adult worm living in the heart and pulmonary arteries is 6 to 7 months, this time period is called the "prepatent period". L3 larvae migrate to the tip of the mosquito's mouthpart portion (labium) during mosquito blood feeding, exit the mosquito and are deposited on the dog's skin, from where they migrate into the host through a bite wound. Most L3 larvae molt to fourth stage larvae (L4) in the subcutaneous tissue of the dog within 1-3 days after infection. They then migrate to the pectoral and abdominal muscles and molt to fifth stage (L5, immature adult worms) 45 to 60 days after infection. These immature heartworms then enter the bloodstream and are carried through the heart, residing in the pulmonary arteries 75 to 120 days after infection. About 7 months after infection, Dirofilaria immitis adult worms reach maturity and sexually reproduce in the pulmonary arteries and right ventricle. Male adult worms are about 15 cm long and females are about 25 cm long, and their normal lifespan as adults is estimated to be about 5 years.

[0007] Heartworm infection is a serious and life-threatening disease. Heartworm infection in dogs is preventable and prophylactic treatment is a priority in heartworm endemic areas. Treatment of adult heartworm infection with adulticidal agents (e.g. melarsomine dihydrochloride) is costly and can result in serious adverse effects, therefore, prophylaxis by monthly administration of a drug that interrupts the development of larvae is widely used. The goal of marketed prophylactic therapies for heartworm in dogs is to prevent the development of the parasitic helminth into adult heartworm by interrupting the life cycle of Dirofilaria immitis after infection.

[0008] Macrolides (MLs, e.g. ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemical preventatives and are given at monthly or six-month intervals. These drugs have been effective against infective third stage larvae (L3) of Dirofilaria immitis deposited by mosquitoes as well as against maturing fourth stage larvae (L4). In the case of monthly administration, MLs kill L3 and L4 larvae acquired within the previous 30 days, thereby preventing disease caused by adult worms. MLs are also capable of being used monthly in infected dogs to inhibit adult worm reproduction and remove microfilariae, thereby reducing transmission and gradually leading to adult worm depletion (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206).

[0009] An increasing number of cases of lack of efficacy (LOE) have been reported in recent years, in which dogs develop adult heartworm infections despite receiving a prophylactic dose of a macrolide drug on a monthly basis. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) recently reported an increasing number of cases in which dogs tested positive for Dirofilaria immitis antigen despite receiving heartworm prophylaxis, which means that some populations of Dirofilaria immitis have developed selective resistance to heartworm preventatives (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5). Therefore, there is an ongoing need to develop new anthelmintics with improved activity against Dirofilaria immitis and other endoparasites.

[0010] WO 2017 / 178416 A1 provides pyrazolopyrimidine derivatives for controlling, treating and / or preventing helminths. WO 2018 / 197401 A1 provides bicyclic pyrazole derivatives for controlling, treating and / or preventing helminths. WO 2018 / 087036 A1 provides quinolone-3-carboxamide derivatives for controlling, treating and / or preventing helminths. WO 2019 / 025341 provides quinoline compounds for treating, controlling and / or preventing helminth infections, while WO 2019 / 002132 A1 provides naphthoquinone 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.

[0011] WO 2020 / 014068 Al (incorporated herein by reference) recently described anthelmintic heterocyclic compounds found to be active against Dirofilaria immitans.

[0012] It is expressly stated herein that any reference or identification of any document in this application is not an admission that such document is prior art to this specification. Any and all pre-characterising applications and all documents cited or referenced in any of the pre-characterising applications (‘application cited documents’) and all documents cited or referenced in the application cited documents (‘cited document cited documents’), and all documents cited or referenced in this specification (‘herein cited documents’), and all documents cited or referenced in the herein cited documents (‘cited document cited documents’), and all products mentioned in any of the documents mentioned in this section, are hereby incorporated herein by reference. The contents of all such cited and non-cited documents, product brochures, manufacturer’s instructions and product specifications are expressly incorporated herein by reference. SUMMARY

[0013] The present application provides novel anthelmintic and anti-parasitic heterocyclic compounds with improved activity against endo- and ecto-parasites. The present application also relates to compositions comprising said compounds, methods and uses of the compounds for eradicating, controlling and preventing parasitic infections and / or infestations in animals, including humans. The compounds can be administered to animals, in particular mammals, fish and birds, to prevent or treat parasitic infections.

[0014] One aspect of the present application comprises a compound of formula (I):

[0015]

[0016] a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, wherein the variables 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 bond ( ) with the dashed line represents a single or a double bond.

[0017] The present application also includes veterinarily acceptable compositions comprising a compound of Formula (I) and a veterinarily acceptable carrier; and methods of controlling parasites, including helminths, comprising administering to an animal in need thereof the compound or a veterinarily acceptable composition thereof. Embodiments of the present application also include the use of a compound of Formula (I) for eradicating, controlling and / or preventing parasitic infections and / or infestations in animals or humans. The compounds of the present application can be administered to animals, particularly mammals, fish and birds, to prevent and / or treat parasitic infections and / or infestations.

[0018] The compounds and compositions comprising the compounds are highly effective for treating and / or preventing internal parasites in mammals, fish and birds, especially cats, dogs, horses, chickens, pigs, sheep and cattle, with the objective of substantially removing the endoparasites from these hosts.

[0019] In embodiments, the compounds of Formula (I) and compositions comprising the compounds are substantially effective against endoparasites, such as filarial worms (e.g., Dirofilaria immitis), hookworms, whipworms and roundworms of the digestive tract of animals and humans. In certain embodiments, the compounds of Formula (I) and compositions comprising the compounds are effective against canine Dirofilaria immitis (heartworm) isolates that are not susceptible to treatment with a macrolide. In another embodiment, the compounds and compositions of the present application are effective to treat and / or prevent infections of animals with nematodes that are less susceptible to treatment with commercially available or known active agents.

[0020] In embodiments, the present specification includes combinations of a compound of Formula (I) with at least a second active agent, which can extend the range of protection provided to animals against endoparasites and / or ectoparasites.

[0021] Another embodiment includes a method of treating and / or preventing parasitic infections and / or infestations in animals comprising administering to the animal a compound of Formula (I). Another embodiment includes the use of a compound of Formula (I) for treating and / or preventing parasitic infections and / or infestations in animals and the use of a compound of Formula (I) in the manufacture of a medicament for treating and / or preventing parasitic infections in animals.

[0022] Thus, the present application includes the following non-limiting embodiments:

[0023] (a) a compound of Formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, which is an active endoparasiticide and in some cases also has activity against ectoparasites;

[0024] (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;

[0025] (c) a veterinary composition comprising a parasiticidally effective amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, in combination with one or more additional active agents (i.e. active ingredients not covered by formula (I)) and a pharmaceutically or veterinarily acceptable carrier or diluent;

[0026] (d) a method of treating a parasitic infection and / or infestation of an animal, comprising administering to an animal in need thereof a parasiticidally effective amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and optionally one or more additional active agents (i.e. active ingredients not covered by formula (I));

[0027] (e) a method of preventing a parasitic infection and / or infestation of an animal, comprising administering to an animal in need thereof a parasiticidally effective amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and optionally one or more additional active agents (i.e. active ingredients not covered by formula (I));

[0028] (f) 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 covered by formula (I)), for the treatment and / or prevention of a parasitic infection and possibly also infestation in an animal;

[0029] (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 covered by formula (I)), for the manufacture of a veterinary medicament for the treatment or prevention of a parasitic infection and / or infestation in an animal; and

[0030] (h) a method of manufacturing a compound of formula (I).

[0031] These and other embodiments are disclosed or exemplified by the following detailed description of the application.

[0032] Definitions:

[0033] It should be noted that in this disclosure and particularly in the claims and / or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can be interpreted to be equivalent to "includes", "included", "including" and the like; and terms such as "consisting essentially of and "consists essentially of are construed to permit the inclusion of unspecified elements of a genus so long as the essential or novel characteristics of the application are not affected by the inclusion of such unspecified elements.

[0034] The terms used herein have their ordinary meanings in the art, unless otherwise specified. Organic moieties mentioned in the definition of variables of a compound, e.g. of a compound of formula (I), are as the term halogen, i.e. a collective term for a separate list of members of a group (fluorine, chlorine, bromine and iodine in the case of halogen). The prefix C n -C m In each case the possible number of carbon atoms in the group is indicated as an integer n to another integer m.

[0035] The term "including but not limited to" and the like means "including" as in the term "including, but not limited to," in the claims and / or paragraphs below is used to mean the term "including" and does not exclude other unrecited elements.

[0036] The term "compound of formula (I)" includes any stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

[0037] The term "optionally substituted" means a group that is optionally substituted with one or more of the following: halo, hydroxy, alkyl, haloalkyl, carboxy, acyl, acyloxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, amino, alkyl- or dialkylamino, acylamino, arylamino, alkoxyl, haloalkoxyl, aryloxy, nitro, cyano, azido, thiol, thioamide, imine, amidine, guanidine, carbonate, silyl, silyl ether, SF5, sulfonic acid, sulfate, sulfonyl, alkoxysulfonyl, sulfanyl, sulfinyl, sulfamoyl, sulfimide, sulfonimidate, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, phosphonamidate, phosphoramidate, phosphinate, phosphine oxide, thioester, thioether, acyl halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, aryl and heteroaryl.

[0038] In some embodiments, the term "optionally substituted" includes the core group being substituted with a substituent selected from the group consisting of halogen (chlorine, fluorine, bromine, iodine), Ci-C6-alkyl, Ci-C6-haloalkyl, 3-8 membered cycloalkyl, amino, Ci-C6-alkylamino, Ci-C6-dialkylamino, Ci-C6-alkoxy, Ci-C6-haloalkoxy, cyano, nitro, SF5, acetyl, Ci-C6-alkoxycarbonyl, Ci-C6-haloalkoxycarbonyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, aminocarbonyl, Ci-C6-alkylaminocarbonyl, Ci-C6-dialkylaminocarbonyl, Ci-C6-haloalkylaminocarbonyl, Ci-C6-dihaloalkylaminocarbonyl, Ci-C6-alkylthio, Ci-C6-alkylsulfinyl, Ci-C6-alkylsulfonyl, Ci-C6-haloalkylthio, Ci-C6-haloalkylsulfinyl, Ci-C6-haloalkylsulfonyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl.

[0039] In other embodiments, the term "optionally substituted" includes the core group being substituted with a substituent selected from the group consisting of halogen (chlorine, fluorine, bromine, iodine), Ci-C3-alkyl, Ci-C3-haloalkyl, 3-8 membered cycloalkyl, amino, Ci-C3-alkylamino, Ci-C3-dialkylamino, Ci-C3-alkoxy, Ci-C3-haloalkoxy, cyano, nitro, SF5, acetyl, Ci-C3-alkoxycarbonyl, Ci-C3-haloalkoxycarbonyl, Ci-C3-alkylcarbonyl, Ci-C3-haloalkylcarbonyl, aminocarbonyl, Ci-C3-alkylaminocarbonyl, Ci-C3-dialkylaminocarbonyl, Ci-C3-haloalkylaminocarbonyl, Ci-C3-dihaloalkylaminocarbonyl, Ci-C3-alkylthio, Ci-C3-alkylsulfinyl, Ci-C3-alkylsulfonyl, Ci-C3-haloalkylthio, Ci-C3-haloalkylsulfinyl, Ci-C3-haloalkylsulfonyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl.

[0040] In certain embodiments, the term "optionally substituted" includes being substituted with a substituent selected from the group consisting of halogen (chlorine, fluorine, bromine, and iodine), methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, morpholinyl, piperidinyl, pyridinyl, and phenyl.

[0041] In some embodiments, the compounds can be substituted with possible functional groups that do not inhibit the biological activity of the compounds, either unprotected or protected as desired, as 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 (incorporated herein by reference). For the avoidance of doubt, "optionally substituted alkyl" includes haloalkyl and hydroxyalkyl.

[0042] Unless otherwise indicated, "alkyl" when used alone or in conjunction with heteroatoms (e.g., alkoxy, thioalkyl, alkylamino, etc.) refers to straight-chain or branched-chain primary, secondary, or tertiary hydrocarbons including those having from 1 to 12 atoms. In some embodiments, alkyl groups include C1-C 10 C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. C1-C4-alkyl groups refer to, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl. 10 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl, and decyl and isomers thereof. C1-C4-alkyl groups refer to, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

[0043] Cyclic alkyl groups can be referred to as "cycloalkyl" and include those having a single ring or multiple condensed rings having from 3 to 10 carbon atoms. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0044] "Carbocyclic" groups are cyclic groups composed of only carbon. Carbocyclic groups include aromatic rings such as phenyl, and non-aromatic rings such as cycloalkyl rings, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and include those having from 3 to 14 carbon atoms with a single or multiple condensed rings.

[0045] The term "alkenyl" refers to straight-chained and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, alkenyl groups can include C2-C 12 alkenyl groups. In other embodiments, alkenyl includes C2-C 10C2-C8, C2-C6, C2-C4, or C3-C4 alkenyl group. In one embodiment of alkenyl, the number of double bonds is 1-3; in another embodiment of alkenyl, the number of double bonds is one. Other ranges of carbon-carbon double bond numbers and carbons are contemplated depending on the location of the alkenyl moiety on the molecule. An "alkenyl" group can include more than one double bond in the chain. Examples of alkenyl or specific ranges thereof include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -methyl-ethenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1 -propenyl, 2-methyl- 1 -propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl; 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1 -butenyl, 2-methyl- 1 -butenyl, 3-methyl- 1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 -methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1, 1 -dimethyl-2-propenyl, 1,2-dimethyl- 1 -propenyl, 1,2-dimethyl-2-propenyl, 1 -ethyl- 1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1 -pentenyl, 2-methyl- 1 -pentenyl, 3-methyl- 1 -pentenyl, 4-methyl- 1 -pentenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1 -methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1 -methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1 -dimethyl-2-butenyl, 1, 1 -dimethyl-3-butenyl, 1,2-dimethyl- 1 -butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl- 1 -butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl- 1 -butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl- 1 -butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl- 1 -butenyl, 1 -ethyl-2-butenyl, 1 -ethyl-3-butenyl, 2-ethyl- 1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1,2-trimethyl-2-propenyl, 1 -ethyl- 1 -methyl-2-propenyl, 1 -ethyl-2-methyl- 1 -propenyl, and 1 -ethyl-2-methyl-2-propenyl.

[0046] "Alkynyl" refers to straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one. In some embodiments, alkynyl groups include 2 to 12 carbon atoms. In other embodiments, alkynyl groups can include C2-C8, C2-C6, or C2-C4alkynyl groups. Other ranges of carbon-carbon triple bonds and carbons are contemplated depending on the position of the alkynyl moiety on the molecule. For example, the term "C2-C6alkynyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group having from 2 to 6 carbon atoms and containing one triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, n-but-1-ynyl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-ynyl, n-pent-1-ynyl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-ynyl, 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-ynyl, 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-ynyl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-ynyl, n-hex-3-yn-2-yl, 3-methylpent-1-ynyl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-ynyl, 4-methylpent-2-yn-4-yl, or 4-methylpent-2-yn-5-yl, and the like. 10 10 The term "alkynyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group having from 2 to 10 carbon atoms and containing one triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, n-but-1-ynyl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-ynyl, n-pent-1-ynyl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-ynyl, 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-ynyl, 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-ynyl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-ynyl, n-hex-3-yn-2-yl, 3-methylpent-1-ynyl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-ynyl, 4-methylpent-2-yn-4-yl, or 4-methylpent-2-yn-5-yl, and the like.

[0047] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen atoms. For example, C1-C4-haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and the like. The term "fluoroalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms, for example, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl.

[0048] ​The term "haloalkynyl" means an alkynyl group as defined herein, substituted by one or more halogen atoms.

[0049] The term "haloalkynyl" means an alkynyl group as defined herein, substituted by one or more halogen atoms.

[0050] The term "alkoxy" means alkyl-O-, wherein alkyl is defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "halocycloalkoxy", and "halocycloalkenyloxy" mean the groups alkyl-O-, alkyl-O-, haloalkyl-O-, haloalkyl-O-, haloalkyl-O-, cycloalkyl-O-, cycloalkyl-O-, halo-cycloalkyl-O-, and halo-cycloalkyl-O-, respectively, wherein alkyl, alkyl, haloalkyl, haloalkyl, haloalkyl, cycloalkyl, cycloalkyl, halo-cycloalkyl, and halo-cycloalkyl 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-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, and the like.

[0051] The term "aryl" refers to a monovalent aromatic carbocyclic ring radical of six to fourteen 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. The aryl group can be unsubstituted or substituted with one or more moieties selected from halogen, cyano, nitro, hydroxyl, thiol, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkoxy, cycloalkenoxy, halocycloalkoxy, halocycloalkenoxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, -SF5, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.

[0052] The term "aralkyl" refers to an acyclic alkyl radical n The term "aryl" refers to a monovalent aromatic carbocyclic ring radical of six to fourteen 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. The aryl group can be unsubstituted or substituted with one or more moieties selected from halogen, cyano, nitro, hydroxyl, thiol, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkoxy, cycloalkenoxy, halocycloalkoxy, halocycloalkenoxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, -SF5, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.

[0053] The term "heteroaryl" refers to a monovalent aromatic radical of one to fifteen carbon atoms, preferably one to ten carbon atoms, having in the ring one or more oxygen, nitrogen, and sulfur heteroatoms, preferably one to four heteroatoms, or one to three heteroatoms. The nitrogen and sulfur heteroatoms can optionally be oxidized. Heteroaryl radicals typically include a five- or six-membered ring. Such heteroaryl radicals can have a single ring (e.g., pyridinyl or furanyl) or multiple condensed rings, provided the ring(s) is / are annulated via a ring atom of the heteroaryl radical. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothienyl, imidazopyridinyl, imidazopyrimidinyl, or pyrrolopyrimidinyl. The heteroaryl ring can be unsubstituted or substituted with one or more moieties described above for aryl.

[0054] The terms "heterocyclyl," "heterocyclic" or "heterocycle" refer to a fully saturated or partially unsaturated, but non-aromatic, ring-based group, e.g., a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, having one or more oxygen, sulfur, silicon, or nitrogen heteroatoms in the ring, preferably 1 to 4 or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. The heterocyclyl group can be attached at any heteroatom or carbon atom of the ring or ring system and can be unsubstituted or substituted with one or more moieties as described above for aryl groups.

[0055] Exemplary monocyclic heterocyclyl groups include, but are not limited to, azirdinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-l,l-dioxothienyl, triazolyl, triazinyl, and the like.

[0056] Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothiophenyl, quinuclidinyl, quinazolinyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl (e.g., furoplo[2,3-c]pyridinyl, furoplo[3,2-b]pyridinyl] or furoplo[2,3-b]pyridinyl), indolinyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.

[0057] Bicyclic and tricyclic carbocyclic or heterocyclic ring systems include spiro ring systems, wherein at least two rings in the system are connected by a single carbon atom. Spiro ring systems include combinations of 3-8 membered carbocyclic and / or heterocyclic ring systems connected at a common carbon atom. Thus, spiro ring systems can include a 3-membered ring bonded to another 3-membered ring (carbocyclic or heterocyclic) up to an 8-membered ring bonded to another 8-membered ring and all combinations of different ring sizes in between. The heterocyclic portion of a spiro ring system includes one or two heteroatoms selected from N, O, Si, or S.

[0058] The term "alkylthio" refers to an alkyl-S- group, wherein "alkyl" is as defined above. In some embodiments, the alkyl portion of an alkylthio group includes 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. 10 The term "alkylthio" refers to an alkyl-S- group, wherein "alkyl" is as defined above. In some embodiments, the alkyl portion of an alkylthio group includes 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.

[0059] Similarly, the terms "haloalkylthio," "cycloalkylthio," and "halocycloalkylthio" refer to the groups -S-haloalkyl, -S-cycloalkyl, and -S-halocycloalkyl, respectively, wherein the terms "haloalkyl," "cycloalkyl," and "halocycloalkyl" are as defined above.

[0060] The term "alkylsulfinyl" refers to the group alkyl-S(=0)-, wherein "alkyl" is as defined above. In some embodiments, the alkyl portion of an alkylsulfinyl group includes C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. For example, C1-C4-alkylsulfinyl includes, but is not limited to, -SO–CH3, -SO–C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl, or 1-ethyl-2-methylpropylsulfinyl. 12 The term "alkylsulfinyl" refers to the group alkyl-S(=0)-, wherein "alkyl" is as defined above. In some embodiments, the alkyl portion of an alkylsulfinyl group includes C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. For example, C1-C4-alkylsulfinyl includes, but is not limited to, -SO–CH3, -SO–C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl, or 1-ethyl-2-methylpropylsulfinyl. 10 The term "alkylsulfinyl" refers to the group alkyl-S(=0)-, wherein "alkyl" is as defined above. In some embodiments, the alkyl portion of an alkylsulfinyl group includes C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. For example, C1-C4-alkylsulfinyl includes, but is not limited to, -SO–CH3, -SO–C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl, or 1-ethyl-2-methylpropylsulfinyl.

[0061] Similarly, the terms "alkenylsulfinyl," "alkynylsulfinyl," "haloalkylsulfinyl," "haloalkenylsulfinyl," and "haloalkynylsulfinyl" refer to the groups alkenyl-S(=0)-, alkynyl-S(=0)-, and haloalkyl-S(=0)-, haloalkenyl-S(=0)-, and haloalkynyl-S(=0)-, where the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are as defined above.

[0062] The term "alkylsulfonyl" refers to the group alkyl-S(=0)2-, where the term "alkyl" is as defined above. In some embodiments, the alkyl portion of the alkylsulfonyl group includes C1-C 12 , C1-C 10 , C1-C8, C1-C6, or C1-C4 alkyl groups. Examples include, but are not limited to, -SO2-CH3, -SO2-C2H5, n-propylsulfonyl, -SO2-CH(CH3)2, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO2-C(CH3)3, n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl, or 1-ethyl-2-methylpropylsulfonyl, and the like.

[0063] The terms "alkenylsulfonyl," "alkynylsulfonyl," "haloalkylsulfonyl," "haloalkenylsulfonyl," and "haloalkynylsulfonyl" refer to the groups alkenyl-S(=0)2-, alkynyl-S(=0)2-, and haloalkyl-S(=0)2-, haloalkenyl-S(=0)2-, and haloalkynyl-S(=0)2-, where the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are as defined above.

[0064] The terms "alkylamino," "dialkylamino," "alkenylamino," "alkynylamino," "di(alkenyl)amino," and "di(alkynyl)amino" mean the groups -NH(alkyl), -N(alkyl)2, -NH(alkenyl), -NH(alkynyl), -N(alkenyl)2, and -N(alkynyl)2, respectively, where the terms "alkyl," "alkenyl," and "alkynyl" are as defined above. In some embodiments, the alkyl moieties in the alkylamino or dialkylamino groups include C1-C 12 , C1-C 10 , C1-C8, C1-C6, or C1-C4 alkyl groups.

[0065] The terms "alkylcarbonyl," "alkoxycarbonyl," "alkylaminocarbonyl," and "dialkylaminocarbonyl" mean alkyl-C(O)-, alkoxyl-C(O)-, alkylamino-C(O)-, and dialkylamino-C(O)-, respectively, where alkyl, alkoxyl, alkylamino, and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl," "haloalkoxycarbonyl," "haloalkylaminocarbonyl," and "dihaloalkylaminocarbonyl" mean the groups haloalkyl-C(O)-, haloalkoxyl-C(O)-, haloalkylamino-C(O)-, and dihaloalkylamino-C(O)-, respectively, where haloalkyl, haloalkoxyl, haloalkylamino, and dihaloalkylamino are as defined above. DETAILED DESCRIPTION

[0067] One embodiment of the present application includes a compound of Formula (I):

[0068]

[0069] wherein:

[0070] L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, or L15:

[0071]

[0072]

[0073] R ’ is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl;

[0074] R 1hydrogen, 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 or haloalkyl), -SF5, or -NR a R b wherein R a and R b are independently H or optionally substituted alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three additional heteroatoms selected from N, O, Si and S and which can optionally be substituted;

[0075] R 2 is hydrogen, cyano, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, 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, optionally substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO p (optionally substituted alkyl or haloalkyl), -SF5, or -NR a R b wherein R a and R b are independently H or optionally substituted alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three additional heteroatoms selected from N, O, Si and S and which can optionally be substituted;

[0076] R3 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)m- p (optionally substituted alkyl), -SF5, optionally substituted heterocyclyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclyl-carbocyclyl, spirocyclic heterocyclyl-heterocyclyl, spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl, or -NR a R b wherein R a and R b are independently H or optionally substituted alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can contain one to three additional heteroatoms selected from N, O, Si and S and which can optionally be substituted;

[0077] R 4 and R 4’ are independently, at 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 forms, together with R 4’ , a 2-6 membered chain optionally containing one or two heteroatoms selected from N, O, Si and S to form, together with the carbon atom to which they are attached, a carbocyclic ring or a heterocyclic ring; or is -NR c R d wherein R c and R d are independently H or optionally substituted alkyl; or R c and R dmay form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8- membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O, Si and S and which can be optionally substituted;

[0078] R 8 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl;

[0079] R 9 and R 9’ are independently hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy, or R 9 form, together with R 9’ , a 2-6 membered chain optionally containing one or two heteroatoms selected from N, O, Si and S to form, together with the carbon atom to which they are attached, a carbocyclic or heterocyclic ring, wherein the carbon or nitrogen atom in the chain can be optionally substituted;

[0080] Q is C-R 8 or N;

[0081] X is O, S or N-R ’ ;

[0082] Y 1 and Y 6 are each independently N, C, or -CR 4 -;

[0083] Y 2 , Y 3 , Y 4 and Y 5 are each independently N, NR ’ , S, O, -CR 4 - or CR 4 R 4’ ;

[0084] W is CR 5 R 6 , O, SO p , or N-R 7 ;

[0085] Z is CR 5 R 6 , O, SO p , or N-R 7 ;

[0086] wherein

[0087] R 5 and R 6independently at each occurrence is hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy, or R 5 together with R 6 form a 2-6 membered chain optionally containing one or two heteroatoms selected from N, O, Si and S to form, together with the carbon atoms to which they are attached, a carbocyclic ring or a heterocyclic ring, and wherein each carbon or nitrogen in said carbocyclic ring or heterocyclic ring can optionally be substituted;

[0088] R 7 is hydrogen or C1-C4-alkyl; and

[0089] wherein at most three of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are heteroatoms;

[0090] a is 0 or 1 ;

[0091] q is 0 or 1 ;

[0092] p is independently at each occurrence 0, 1, or 2; and

[0093] a dashed bond ( ) represents a single or double bond;

[0094] a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

[0095] In another embodiment, the present application provides a compound of formula (I)

[0096] wherein:

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

[0098] R 1hydroxy-Ci-C6-haloalkyl, Ci-C6-alkoxy-Ci-C6-alkyl, Ci-C6-haloalkoxy-Ci-C6-alkyl, amino-Ci-C6-alkyl, Ci-C6-alkoxy, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C2-C6-alkynyloxy, C2-C6-haloalkynyloxy, Ci-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, Ci-C6-alkoxycarbonyl, Ci-C6-haloalkoxycarbonyl, aminocarbonyl, Ci-C6-alkylaminocarbonyl, Ci-C6-haloalkylaminocarbonyl, di-Ci-C6- alkylaminocarbonyl, di-Ci-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-cycloalkoxy, optionally substituted 3- to 7-membered heterocyclyl, -SF5, -SO p (optionally substituted Ci-C6-alkyl or Ci-C6-haloalkyl), or -NR a R b wherein R a and R b are independently H or optionally substituted Ci-C6-alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three further heteroatoms selected from N, O, Si and S and can be optionally substituted;

[0099] R 2is hydrogen, cyano, halogen, 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 phenoxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted C3-C8-cycloalkoxy, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from N, O and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO p is hydrogen, cyano, halogen, 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 phenoxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted C3-C8-cycloalkoxy, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from N, O and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO a R b is hydrogen, cyano, halogen, 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 phenoxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted C3-C8-cycloalkoxy, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from N, O and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three further heteroatoms selected from N, O, Si and S and can be optionally substituted;

[0100] R 3 is 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 heterocyclic groups comprising one to three heteroatoms selected from N, O, and S, optionally substituted phenyl groups, optionally substituted 5- to 10-membered heteroaryl groups, 5- to 11-membered spirocyclic heterocyclic-carbocyclic groups, 5- to 11-membered spirocyclic heterocyclic-heterocyclic groups, 5- to 11-membered spirocyclic carbocyclic-carbocyclic groups, 5- to 11-membered spirocyclic carbocyclic-heterocyclic groups, or –NR a R b , where R a and R b Independently H, C1-C6-alkyl, or C1-C6-haloalkyl; or R a and R b They can form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups together with the nitrogen to which they are attached, which may contain one to three additional heteroatoms selected from N, O, Si, and S and may optionally be substituted.

[0101] R 4 and R 4’ Each time it appears independently of 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, or optionally substituted C3-C8-cycloalkyl. Optionally substituted C3-C8-cycloalkoxy, 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 (Optional substituted C1-C6-alkyl or C1-C6-haloalkyl); or R 4 With R 4’ Together they form 2-6 membered chains, optionally containing one or two heteroatoms selected from N, O, Si, and S, to form carbon rings or heterocycles together with the carbon atoms to which they are attached; or –NR c R d , where R c and R d Independently H, C1-C6-alkyl, or C1-C6-haloalkyl; or R c and R dmay form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8- membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O, Si and S and which can be optionally substituted;

[0102] R 8 is hydrogen, halogen, Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C8-cycloalkyl, C2-C6-alkenyl or C2-C6-alkynyl; and

[0103] 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 the bond drawn with a dashed line are as defined above for the compound of formula (I).

[0104] 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.

[0105] In some embodiments:

[0106] R 1 is hydrogen, cyano, optionally substituted Ci-C4-alkyl, optionally substituted Ci-C4-alkoxy, optionally substituted Ci-C4-alkenyl, optionally substituted Ci-C4-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted saturated or partially unsaturated 5-, 6- or 7-membered heterocyclyl group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted Ci-C4-alkylcarbonyl, optionally substituted Ci-C4-alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted Ci-C4-alkylaminocarbonyl, optionally substituted Ci-C4-dialkylaminocarbonyl, optionally substituted alkyl-SOp haloalkyl-SO p amino, -NH-optionally substituted C1-C4-alkyl, or -NR a R b wherein R a and R b are independently optionally substituted alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O and S and which can be optionally substituted;

[0107] R' is hydrogen or C1-C4-alkyl;

[0108] 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 wherein R c and R d are independently optionally substituted C1-C4-alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can be optionally substituted, SO p (optionally substituted C1-C4-alkyl or haloalkyl);

[0109] 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 can optionally be substituted by 1, 2 or 3 substituents;

[0110] 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 together with R 4’ form a 2- to 6-membered chain which optionally contains one or two heteroatoms selected from O, Si and S, or a group NR ’ together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; or -NRc R d , wherein R c and R d are independently optionally substituted C1-C4-alkyl; or R c and R d may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can be optionally substituted; or R p is hydrogen, optionally substituted C1-C4-alkyl or haloalkyl.

[0111] In some embodiments, R 1 is hydrogen.

[0112] In some embodiments, R 1 is C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4-alkyl)amino.

[0113] In another embodiment, R 1 is halogen.

[0114] In another embodiment, R 1 is C1-C4-alkyl-SO p -, C1-C4-haloalkyl-SO p - or -SF5.

[0115] 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.

[0116] 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.

[0117] In another embodiment, R 1 is C1-C3-alkoxy or C1-C3-haloalkoxy.

[0118] In another embodiment, R 1 is OCH3 or OCH2CH3.

[0119] In another embodiment, R 1 is OCF3 or SCF3.

[0120] In another embodiment, R 1is CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0121] In some embodiments, R 1 is C2-C4-alkenyl or C2-C4-haloalkenyl.

[0122] In some embodiments, R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0123] In other embodiments, R 1 is cyclopropyl or cyclobutyl.

[0124] In some embodiments, R 1 is an optionally substituted saturated or unsaturated 6-membered heterocyclyl group.

[0125] In one embodiment, R 1 is -NR a R b wherein R a and R b are independently hydrogen or C1-C6 alkyl. In another embodiment, R 1 is -NR a R b wherein R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three additional heteroatoms selected from N, O and S and can be optionally substituted.

[0126] 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.

[0127] In some embodiments, R 1 is optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholinyl, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0128] In some embodiments, R 1 is optionally substituted phenyl.

[0129] In some embodiments, R 1azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, azepanyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-l,l-dioxothienyl, triazolyl, or triazinyl.

[0130] In some embodiments, R 1 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino.

[0131] In some embodiments, R 2 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino.

[0132] In another embodiment, R 2 is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl.

[0133] In another embodiment, R 2 is hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0134] In some embodiments, R 2 is hydrogen.

[0135] In some embodiments, R 2 is halogen.

[0136] In another embodiment, R 2 is fluorine or chlorine.

[0137] 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. p (C1-C4-alkyl or C1-C4-haloalkyl), wherein p is 0, 1, or 2.

[0138] In another embodiment, R 2R is methoxy, ethoxy, propoxy or butoxy.

[0139] In another embodiment, R 2 R is methylthio, ethylthio, propylthio or butylthio.

[0140] In another embodiment, R 2 R is -OCF3 or -SCF3.

[0141] In some embodiments, R 2 R is C1-C4-alkenyl or C1-C4-haloalkenyl.

[0142] In some embodiments, R 2 R is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0143] In some embodiments, R 2 R is optionally substituted saturated or unsaturated 6-membered heterocyclyl group.

[0144] In some embodiments, R 2 R is optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholinyl, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0145] In some embodiments, R 2 R is optionally substituted phenyl.

[0146] In other embodiments, R 2 R is phenyl substituted with 1, 2, or 3 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0147] In another embodiment, R 2 R is 5- or 6-membered heteroaryl having 1 or 2 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0148] In one embodiment, R 2 R is pyridyl optionally substituted with halogen, 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 .

[0149] In some embodiments, R 2 is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, azepanyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-l,l-dioxothienyl, triazolyl, or triazinyl.

[0150] In some embodiments, R 2 is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogen.

[0151] In some embodiments, R 3 is a 6- to 10-membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0152] In some embodiments, R 3 is C1-C4-alkyl or C1-C4-haloalkyl.

[0153] In some embodiments, R 3 is methyl, ethyl, n-propyl, n-butyl, i-propyl, t-butyl, sec-butyl, or i-butyl.

[0154] In other embodiments, R 3 is CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0155] In some embodiments, R 3 is optionally substituted C3-C8-cycloalkyl. In other embodiments, R 3 is optionally substituted C3-C6-cycloalkyl. In other embodiments, R 3 is optionally substituted C3-C8-cycloalkenyl or C3-C6-cycloalkenyl. In some embodiments, R 3 is optionally substituted cyclopentyl or cyclohexyl. In other embodiments, R 3 is optionally substituted cyclopropyl or cyclobutyl.

[0156] In one embodiment, R3 cyclohexyl optionally substituted with one or more halogen, C1-C3-alkyl or C1-C3-haloalkyl. In another embodiment, R 3 cyclohexyl substituted with 1 or 2 fluorine, chlorine or CF3.

[0157] In some embodiments, R 3 optionally substituted piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl. In some embodiments, R 3 substituted with one or more halogen, C1-C6-alkyl or C1-C6-haloalkyl. In another embodiment, R 3 substituted with one or more methyl, chlorine or fluorine.

[0158] In some embodiments, R 3 optionally substituted with 1, 2, 3, 4 or 5 substituents. In one embodiment, the 5- to 10-membered heteroaryl is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridinyl, imidazopyrimidinyl or pyrrolopyrimidinyl.

[0159] In other embodiments, R 3 optionally substituted spirocyclic heterocyclyl-carbocyclyl group, optionally substituted spirocyclic heterocyclyl-heterocyclyl group, optionally substituted spirocyclic carbocyclyl-carbocyclyl group or optionally substituted spirocyclic carbocyclyl-heterocyclyl group. In other embodiments, R 3 5- to 11-membered optionally substituted spirocyclic heterocyclyl-carbocyclyl group, 5- to 11-membered optionally substituted spirocyclic heterocyclyl-heterocyclyl group, 5- to 11-membered optionally substituted spirocyclic carbocyclyl-carbocyclyl group or 5- to 11-membered optionally substituted spirocyclic carbocyclyl-heterocyclyl group. Non-limiting examples of spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl and spirocyclic heterocyclyl-heterocyclyl groups are shown below.

[0160]

[0161] However, it will be apparent to those skilled in the art that the second ring of the spirocyclic group can be attached at any available carbon of the first ring. It will also be appreciated that the first ring of the spirocyclic group can be bound to the molecule at any available atom. Thus, the present application includes 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic rings as defined herein bound to a second 3-, 4-, 5-, 6-, and 7-membered carbocyclic or heterocyclic ring at any available carbon atom of the first ring.

[0162] In some embodiments, R is phenyl substituted with 1 to 4 substituents. 3 In another embodiment, R is phenyl substituted with 1 to 3 substituents. 3 In yet another embodiment, R is phenyl substituted with 1 to 2 substituents. 3 In some embodiments, R is phenyl substituted with 1, 2, 3, or 4 substituents, which are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy. 3 In some embodiments, R is phenyl substituted with 1, 2, 3, or 4 substituents, which are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0163] In some embodiments, R is phenyl substituted with 1 to 4 substituents. 3 In some embodiments, R is para-substituted phenyl.

[0164] In some embodiments, R is phenyl substituted with 1 to 4 substituents. 3 In some embodiments, R is meta-substituted phenyl.

[0165] In some embodiments, R is phenyl substituted with 1 to 4 substituents. 3 In some embodiments, R is ortho-substituted phenyl.

[0166] In some embodiments, R is halo-substituted phenyl. 3 In some embodiments, R is halo-substituted phenyl.

[0167] In some embodiments, R is halo-substituted phenyl. 3 In some embodiments, R is halo-substituted phenyl.

[0168] In some embodiments, R is halo-substituted phenyl. 3 In some embodiments, R is halo-substituted phenyl.

[0169] In some embodiments, R is phenyl substituted with 1, 2, 3, or 4 substituents, which are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy. 3 In some embodiments, R is phenyl substituted with 1, 2, 3, or 4 substituents, which are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0170] In some embodiments, R is phenyl substituted with 1, 2, 3, or 4 substituents, which are independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy. 3is 2,3-disubstituted phenyl.

[0171] In some embodiments, R 3 is 2,4-disubstituted phenyl.

[0172] In some embodiments, R 3 is 2,5-disubstituted phenyl.

[0173] In some embodiments, R 3 is 2,6-disubstituted phenyl.

[0174] In some embodiments, R 3 is 3,5-disubstituted phenyl.

[0175] In other embodiments, R 3 is 3,4-disubstituted phenyl.

[0176] In other embodiments, R 3 is 3,6-disubstituted phenyl.

[0177] In some embodiments, R 3 is dihalophenyl, e.g., dichloro; difluoro; or chloro, fluoro.

[0178] In some embodiments, R 3 is 2,3-dihalophenyl.

[0179] 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.

[0180] In some embodiments, R 3 is phenyl substituted with halo and haloalkyl.

[0181] In some embodiments, R 3 is phenyl substituted with halo and haloalkoxy.

[0182] In some embodiments, R 3 is phenyl substituted with haloalkyl and haloalkoxy.

[0183] In some embodiments, R 3 is phenyl substituted with 3 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or halodialkenoxy.

[0184] In some embodiments, R 3 is trihalophenyl, for example, trichloro; trifluoro; or chloro, chloro, fluoro; or fluoro, fluoro, chloro.

[0185] In some embodiments, R 3 is phenyl substituted with 2 halogens and 1 haloalkyl.

[0186] In some embodiments, R 3 is phenyl substituted with 2 halogens and 1 haloalkyl.

[0187] In some embodiments, R 3 is phenyl substituted with 1 haloalkyl, 1 halogen, and 1 haloalkoxy.

[0188] In some embodiments, R 3 is phenyl substituted with 1 halogen and 2 haloalkyl.

[0189] In some embodiments, R 3 is 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or halodialkenoxy.

[0190] In some embodiments, R 3 is 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or halodialkenoxy.

[0191] In some embodiments, R 3is 2-pyridyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0192] In some embodiments, R 3 is 3-pyridyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0193] In some embodiments, R 3 is 4-pyridyl optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0194] In another embodiment, R 3 is 4-pyridyl which is unsubstituted or substituted with 1 or 2 chloro or fluoro. In yet another embodiment, R 3 is 3-pyridyl which is unsubstituted or substituted with 1 or 2 chloro or fluoro.

[0195] In other embodiments, R 3 is an optionally substituted 3- to 7-membered heterocycle. In some embodiments, R 3 is an optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, azepanyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-l,l-dioxothiophenyl, triazolyl, or triazinyl.

[0196] In another embodiment, R 3which can be optionally substituted.

[0197] In some embodiments, R 4 and / or R 4’ is hydrogen.

[0198] In some embodiments, each R 4 and / or R 4’ is independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino.

[0199] In another embodiment, each R 4 and / or R 4’ is independently hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl.

[0200] In another embodiment, R 4 and / or R 4’ is independently hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0201] In some embodiments, R 4 and / or R 4’ is independently hydrogen or halogen.

[0202] In another embodiment, R 4 and / or R 4’ is independently hydrogen, fluorine, or chlorine.

[0203] In another embodiment, R 4 and / or R 4’ is independently hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or S(O)p-(C1-C4-alkyl or C1-C4-haloalkyl), wherein p is 0, 1, or 2. p

[0204] In another embodiment, R 4 and / or R 4’ is independently hydrogen, methoxy, ethoxy, propoxy, or butoxy.

[0205] In another embodiment, R 4 and / or R 4’ is independently hydrogen, methylthio, ethylthio, propylthio, or butylthio.

[0206] In another embodiment, R 4 and / or R 4’ is independently hydrogen, -OCF3, or -SCF3. ​

[0207] In some embodiments, R 4 and / or R 4’ is independently hydrogen, C1-C4-alkenyl or C1-C4-haloalkenyl.

[0208] In some embodiments, R 4 and / or R 4’ is independently hydrogen, C1-C4-alkylcarbonyl or C1-C4-alkoxycarbonyl.

[0209] In other embodiments, R 4 and / or R 4’ is independently hydrogen, C1-C4-alkylcarbonylamino.

[0210] In some embodiments, R 4 and / or R 4’ is independently hydrogen, optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[0211] In some embodiments, R 4 and / or R 4’ is independently hydrogen, optionally substituted tetrahydrofuranyl, dihydrofuranyl, morpholinyl, pyranyl, dihydropyranyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0212] In some embodiments, R 4 and / or R 4’ is independently hydrogen, optionally substituted phenyl.

[0213] In other embodiments, R 4 and / or R 4’ is independently hydrogen, phenyl substituted with 1, 2, or 3 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0214] In other embodiments, R 4 and / or R 4’ is independently hydrogen, 5- or 6-membered heteroaryl having 1 or 2 substituents independently halogen, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy, alkynoxy, haloalkoxy, or haloalkenoxy.

[0215] In some embodiments, R 4 and / or R4’ independently hydrogen, optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepanyl, azepanyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-l,l-dioxothienyl, triazolyl, or triazinyl.

[0216] In some embodiments, R 4 and R 4’ are independently hydrogen, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogen.

[0217] In one embodiment, R 8 is H. In another embodiment, R 8 is C1-C3-alkyl or C1-C3-haloalkyl.

[0218] In one embodiment, R 9 and R 9’ are each hydrogen. In another embodiment, R 9 and R 9’ together form a 2- to 6-membered chain to form, together with the carbon atom to which they are attached, a spirocyclic substituent. In another embodiment, R 9 and R 9’ together form a 2- to 5-membered chain to form, together with the carbon atom to which they are attached, a spirocyclic substituent. In another embodiment, R 9 and R 9’ together form a 2- to 4-membered chain to form, together with the carbon atom to which they are attached, a spirocyclic substituent. In another embodiment, R 9 and R 9’ together form a 2- or 3-membered chain to form, together with the carbon atom to which they are attached, a spirocyclic substituent. In another embodiment, R 9 and R 9’ together form a 2-membered chain to form, together with the carbon atom to which they are attached, a spirocyclic substituent.

[0219] In some embodiments, a is 0.

[0220] In some embodiments, a is 1.

[0221] In some embodiments, Q is N.

[0222] In other embodiments, Q is C-R 8 .

[0223] In some embodiments, X is O.

[0224] In some embodiments, X is S.

[0225] In some embodiments, X is NR’.

[0226] In some embodiments, W is CH2.

[0227] In other embodiments, W is C(C1-C3-alkyl)2or C(C1-C3-haloalkyl)2;

[0228] In other embodiments, W is C(CH3)2, C(C2H5)2, or C(CF3)2.

[0229] In some embodiments, Z is CH2.

[0230] In some embodiments, Z is O.

[0231] In some embodiments, Z is SO p .

[0232] In some embodiments, Z is SO2.

[0233] In other embodiments, Z is SO.

[0234] In some embodiments, Z is NH.

[0235] In other embodiments, Z is N(C1-C3-alkyl) or N(C1-C3-haloalkyl).

[0236] In some embodiments, the compound of formula (I) is a compound of formula (I-1):

[0237]

[0238] 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).

[0239] In one embodiment of formula (I-1), W is CH2and Z is O. In one embodiment, Q is N. In another embodiment, Q is C-R 8 In another embodiment of formula (I-1), W is CH2and Z is CH2. In another embodiment of formula (I-1), W is CR 5 R 6 wherein R 5 and R 6 are each independently 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 wherein R 5 and R 6 are taken together to form a 2 to 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.

[0240] In one embodiment of formula (I-1), Y 3 is S. In another embodiment of formula (I-1), Y 5 is 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 N. In another embodiment, Y 1 is N and Y 5 is N.

[0241] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

[0242]

[0243] 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 with respect to equation (I).

[0244] In other embodiments, the compound of formula (I) is a compound of formula (I-3) as follows:

[0245]

[0246] 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 with respect to equation (I).

[0247] In other embodiments, the compound of formula (I) is the compound of formula (I-4):

[0248]

[0249] 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 with respect to equation (I).

[0250] In another embodiment, the compound of formula (I) is the compound of formula (I-5):

[0251]

[0252] Where variable R 1 R 2 R 3 、R'、R 8 R 9 R9’ , Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , X, W, Z and a are as defined for formula (I).

[0253] In some embodiments, the compound of formula (I) is a compound of formula (la):

[0254]

[0255] wherein the variables 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 are as defined for formula (I).

[0256] In some embodiments, the compound of formula (I) is a compound of formula (lb):

[0257]

[0258] wherein the variables 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).

[0259] In some embodiments, the compound of formula (I) is a compound of formula (lc):

[0260]

[0261] wherein the variables 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), and o is 0, 1, 2, 3 or 4.

[0262] In other embodiments, the compound of formula (I) is a compound of formula (Id):

[0263]

[0264] wherein the variables 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), and o is 0, 1, 2, 3 or 4.

[0265] In other embodiments, the compound of formula (I) is a compound of formula (Ie):

[0266]

[0267] wherein the variables 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 10 is cyano, halogen, 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 phenoxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkoxy, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from N, O, Si and S, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-haloalkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, di-C1-C6-haloalkylaminocarbonyl, -SO p (optionally substituted C1-C6-alkyl or C1-C6-haloalkyl), wherein p is 0, 1 or 2, SF5, or –NR a R b , wherein R a and R bindependently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O, Si and S and which can be optionally substituted.

[0268] In one embodiment of formula (Ie), R 10 is halogen. In another embodiment, R 10 is chlorine. In yet another embodiment, R 10 is fluorine. In another embodiment, R 10 is chlorine or fluorine and m is 1, 2 or 3. In yet another embodiment, R 10 is fluorine and m is 2. In another embodiment, R 10 is chlorine and m is 2. In another embodiment, R 10 is fluorine or chlorine, m is 2 and the fluorine or chlorine is substituted in the 3- and 5- position of the phenyl ring. In another embodiment, R 10 is fluorine or chlorine, m is 2 and the fluorine or chlorine is substituted in the 2- and 6- position.

[0269] In other embodiments, the compound of formula (I) is a compound of formula (If):

[0270]

[0271] wherein the variables 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 are as defined for formula (Ie); b is 0 or 1 ; the bond with the dotted line represents a single or double bond; D is N, SiR 11 (wherein R 11 is C1-C6 alkyl or C1-C6 haloalkyl), C or C-R 4 ; D 1 is N, O, SiR 11 R 12 (wherein R 11 and R 12 are independently C1-C6 alkyl or C1-C6 haloalkyl), -CR 4 R4’ , S(O) p (wherein p is 0, 1, or 2), or D 1 is CR 4 R 4’ (wherein R 4 and R 4’ together form a 2 to 5 membered chain optionally substituted in the chain with one heteroatom to form a spirocyclic group).

[0272] In some embodiments, the present application provides a compound of Formula (If), wherein the bond with the dotted line is a single bond.

[0273] In some embodiments, the present application provides a compound of Formula (If), wherein the bond with the dotted line is a double bond.

[0274] In some embodiments, the present application provides a compound of Formula (If), wherein D is CH, C-halogen, or N.

[0275] In some embodiments, the present application provides a compound of Formula (If), wherein D is C, CH, C-F, or N.

[0276] In some embodiments, the present application provides a compound of Formula (If), wherein D 1 is CR 4 R 4’ , wherein R 4 and R 4’ together form a 2 to 5 membered chain optionally substituted in the chain with one heteroatom to form a spirocyclic group.

[0277] In some embodiments, the present application provides a compound of Formula (If), wherein D 1 is CH2, independently C-(halogen)2, CH(C1-C3-alkyl), or CH(C1-C3-haloalkyl).

[0278] In some embodiments, the present application provides a compound of Formula (If), wherein D 1 is CH2, independently CF2, CH(CH3), or CH(CF3).

[0279] In some embodiments, the present application provides a compound of Formula (If), wherein D 1 is O, S, S(O), or S(O)2.

[0280] In some embodiments, the present application provides a compound of Formula (If), wherein D is CH or C-halogen; and D 1 is CH2.

[0281] In some embodiments, the present application provides a compound of Formula (If), wherein D is N; and D 1 is CH2, O, or S.

[0282] In another embodiment, the present application provides a compound of formula (If), wherein D is N and D 1 is SiR 11 R 12 In another embodiment of formula (If), D is CH2and D 1 is SiR 11 R 12 In yet another embodiment, D is N and D 1 is Si(CH3)2.

[0283] In some embodiments, the present application provides a compound of formula (If), wherein the dotted line is a double bond; D is C; and D 1 is CH2, CF2, O or S.

[0284] In some embodiments, the present application provides a compound of formula (If), wherein D is N; and D 1 is CR 4 R 4’ wherein R 4 and R 4’ together form a 2 to 4 membered chain optionally having one oxygen in the chain to form a spirocyclic group.

[0285] In some embodiments, the present application provides a compound of formula (If), wherein D is CH; and D 1 is CR 4 R 4’ wherein R 4 and R 4’ together form a 2 to 4 membered chain optionally having one oxygen in the chain to form a spirocyclic group.

[0286] In some embodiments, the present application provides a compound of formula (If), wherein D is C, the bond indicated with a dotted line represents a double bond; and D 1 is CR 4 R 4’ wherein R 4 and R 4’ together form a 2 to 4 membered chain optionally having one oxygen in the chain to form a spirocyclic group.

[0287] It will be understood by those skilled in the art that in the above formulae (Ic) and (Id), the variable R 4 represents a non-hydrogen substituent when present as a substituent on an aromatic ring (e.g., a (R 4 ) o group, wherein o is 0, 1, 2, 3 or 4), since in the embodiment wherein o is 0, R 4 is not present. The same principle applies to the variable R10 .

[0288] In other embodiments, the present application provides compounds of Formula (Ia), wherein the variables R 1 , R 2 , R 3 , R’, R 4 , R 9 , R 9’ , W, Z, R 8 and a are as defined for Formula (I), and Y 2 , Y 3 , Y 4 and Y 5 are as shown in Table 1:

[0289]

[0290] Table 1

[0291] Formula Y 2 ]]> Y 3 ]]> <![CDATA[Y 4 ]]> <![CDATA[Y 5 ]]> Ia-1 CR 4 ]]> CR 4 ]]> CR 4 ]]> CR 4 ]]> Ia-2 N CR 4 ]]> CR 4 ]]> CR 4 ]]> Ia-3 CR 4 ]]> N CR 4 ]]> CR 4 ]]> Ia-4 CR 4 ]]> CR 4 ]]> N CR 4 ]]> Ia-5 CR 4 ]]> CR 4 ]]> CR 4 ]]> N Ia-6 N N CR 4 ]]> CR 4 ]]> Ia-7 CR 4 ]]> N N CR 4 ]]> Ia-8 CR 4 ]]> CR 4 ]]> N N Ia-9 N CR 4 ]]> N CR 4 ]]> Ia-10 CR 4 ]]> N CR 4 ]]> N Ia-11 N CR 4 ]]> CR 4 ]]> N

[0292] In other embodiments, the present application provides compounds of Formula (Ib), wherein the variables R 1 , R 2 , R 3 , R 4 , R’, R 9 , R 9’ , W, Z, R 8 and a are as defined for Formula (I), and Y 2 , Y 3 , Y 4 and Y 5 are as shown in Table 2:

[0293]

[0294] Table 2

[0295]

[0296]

[0297] In some embodiments, the present application provides compounds of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each R 2 is independently H, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl).

[0298] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each R 2 independently H, chloro, fluoro, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl.

[0299] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each R 2 independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0300] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each R 2 independently H, methoxy, ethoxy, propoxy, or butoxy.

[0301] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each R 2 independently H, -OCF3, or -SCF3.

[0302] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R 4 and / or R 4’ independently H, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl).

[0303] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R 4 and / or R 4’ independently H, chloro, fluoro, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl.

[0304] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R 4 and / or R 4’ is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0305] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R 4 and / or R 4’ is independently H, methoxy, ethoxy, propoxy, or butoxy.

[0306] In some embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R 4 and / or R 4’ is independently H, -OCF3, or -SCF3.

[0307] In other embodiments, the present application provides a compound of Formula (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein R ’ and R 8 are independently H or C1-C3-alkyl.

[0308] In other embodiments, the present application provides a compound of Formula (Ia) to (If), wherein a is 1, W is CH2, and Z is O.

[0309] In other embodiments, the present application provides a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein R 1 is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b wherein R a and R bindependently H or optionally substituted C1-C6-alkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5- or 6- membered heterocyclyl group which can comprise one to three additional heteroatoms selected from N, O and S and which can be optionally substituted.

[0310] In other embodiments, the present application provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) wherein R 3 C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from N, O and S, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, 5- to 11- membered spirocyclic heterocyclyl-carbocyclyl, 5- to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5- to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5- to 11-membered spirocyclic carbocyclyl-heterocyclyl, or -NR a R b wherein R a and R b are independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b may form, together with the nitrogen to which they are attached, a 3-, 4-, 5- or 6- membered heterocyclyl group which can comprise one to three additional heteroatoms selected from N, O and S and which can be optionally substituted.

[0311] In other embodiments, the present application provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) as described above, wherein R 3 is optionally substituted phenyl. In another embodiment, there are provided compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) wherein R 3 is phenyl substituted by one or more halogen. In yet another embodiment, there are provided compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) wherein R 3 is phenyl substituted by 1 halogen. In another embodiment, there are provided compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic) or (Id) wherein R 3In another embodiment, the present application provides a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R 3 is phenyl substituted with three or four halogens.

[0312] In another embodiment, the present application provides a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R 3 is phenyl substituted with one or more chloro or fluoro. In another embodiment, the present application provides a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R 3 is phenyl substituted with one chloro or fluoro. In another embodiment, the present application provides a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R 3 is phenyl substituted with two chloro or fluoro. In another embodiment, the present application provides a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R 3 is phenyl substituted with three or four chloro or fluoro.

[0313] In other embodiments, the present application provides a compound of formula (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein R' and R 8 are each independently H or C1-C3-alkyl; W is CH2, Z is O and a is 1.

[0314] In other embodiments of formula (I), (I-2), (I-3), (Ia), (Ib), and (Ie), each Y 2 , Y 3 , Y 4 , Y 5 is each CH.

[0315] In other embodiments of formula (I), (I-2), (I-3), (Ia), (Ib), and (Ie), each Y 2 , Y 3 , Y 4 , Y 5 is each independently CH or CR 4 , wherein R 4 is a non-hydrogen substituent.

[0316] In other embodiments of formula (I-1), (I-4), and (I-5), Y 3 , Y 4 , and Y 5 are each CH.

[0317] In other embodiments of formula (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y 5 are each independently CH or C-halo.

[0318] In any of the above embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), a is 1, W is -CH2-, and Z is O.

[0319] In any of the above embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 1 is C1-C4-alkyl, C1-C4-alkenyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, morpholinyl, pyranyl, tetrahydropyranyl, or dihydropyranyl.

[0320] In any of the above embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 4 is independently of the other R 4 halo, cyano, C1-C4-alkyl, C1-C4haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or phenyl optionally substituted one or two times with halo or C1-C4-alkyl.

[0321] In other embodiments, the present application includes compounds of formula (I) wherein the group:

[0322] In other embodiments, the present application provides compounds of formula (I) as shown in Table 3 below, wherein L, R 1 , R 2 , and R 3 are defined in the table, X is O, R' is hydrogen, and wherein the group

[0323] is one of the following ring systems:

[0324] Ring system A;

[0325] Ring system B;

[0326] Ring system C;

[0327] Ring system D;

[0328] Ring system E;

[0329] Ring system F;

[0330] Ring system G;

[0331] Ring system H;

[0332] Ring system I;

[0333] Ring system J;

[0334] Ring system K;

[0335] Ring system L;

[0336] Ring system M;

[0337] Ring system N;

[0338] Ring system O;

[0339] Ring system P;

[0340] Ring system Q;

[0341] Ring system R;

[0342] Ring system S;

[0343] Ring system T;

[0344] Ring system U;

[0345] Ring system V;

[0346] Ring system W;

[0347] Ring system X;

[0348] Ring system Y;

[0349] Ring system Z;

[0350] Ring system AA;

[0351] Ring system AB;

[0352] Ring system AC;

[0353] Ring system AD;

[0354] Ring system AE;

[0355] Ring system AF;

[0356] Ring system AG;

[0357] Ring system AH;

[0358] Ring system AJ;

[0359] Ring system AK;

[0360] Ring system AL;

[0361] Ring system AM;

[0362] Ring system AN;

[0363] Ring system AO;

[0364] Ring system AP;

[0365] Ring system AQ;

[0366] Ring system AR;

[0367] Ring system AS;

[0368] Ring system AT;

[0369] Ring system AU;

[0370] Ring system AV;

[0371] Ring system AW;

[0372] Ring system AX;

[0373] Ring system AY;

[0374] Ring system AZ;

[0375] Ring system AAA;

[0376] In Table 3, "Me" represents methyl; the expression "3,5-di-F-Ph" represents 3,5-difluorophenyl; "3,5-di-Cl-Ph" represents 3,5-dichlorophenyl; "2,3,5-tri-F-Ph" represents 2,3,5-trifluorophenyl; "3-F-Ph" represents 3-fluorophenyl; "2,6-di-F-Ph" represents 2,6-difluorophenyl; "2,6-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 the like;

[0377] Prop-1 -en-2-yl represents the group

[0378] 2-F-prop-2-yl represents the group

[0379] 1,1 -Difluoroethyl represents the group

[0380]

[0381] Table 3

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] For the avoidance of doubt, each of the compounds shown in Table 3 has been prepared.

[0393] Stereoisomers and Polymorphs

[0394] Those skilled in the art will recognize that compounds can exist and be isolated in optically active and racemic forms. Compounds having one or more chiral centers (including at the sulfur atom) can exist as, or be resolved from, a single enantiomer or diastereomer, or as a mixture 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 a single enantiomer or as a racemic mixture. In addition, the compounds of the present description can include one or more chiral centers, resulting in a theoretical number of optically active isomers. In the present case, when Q is C-R 8 , the compounds of Formula (I) include at least one chiral center at the carbon atom bearing the variable R 8 . In the case where the compounds of the present description include n chiral centers, the compound can contain up to 2 n optical isomers. Accordingly, the compounds of the present invention include at least 2 enantiomers encompassed by the present invention. The present description encompasses particular enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and / or diastereomers of compounds, which have useful properties described herein. The optically active forms can be prepared, for example, by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by resolution of the racemic form by chromatography using a chiral stationary phase or by enzymatic resolution.

[0395] The compounds can also exist in different solid forms, such as different crystalline forms or amorphous solids. The present description includes different crystalline forms of the compounds as well as the amorphous form.

[0396] In addition, the compounds can exist as hydrates or solvates, in which a certain stoichiometric amount of water or solvent is bound to the molecule in the crystalline form. Hydrates and solvates of the compounds are also subject of the present description.

[0397] Salts

[0398] In addition to neutral compounds, salts of the compounds are active against endoparasites. The term "veterinarily acceptable salt" describes throughout the specification any salt of the compounds which is acceptable for veterinary administration and which provides the active compound at the time of administration.

[0399] In cases where the compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, the compounds can be veterinary or agriculturally acceptable salt forms. Veterinary acceptable salts include those derived from the following inorganic and organic acids and bases. Suitable salts include those derived from alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, magnesium and barium. Also suitable are salts derived from transition metals, including but not limited to manganese, copper, zinc and iron. In addition, the present specification encompasses salts derived from ammonium cations (NH4 + ), as well as substituted ammonium cations in which one or more hydrogen atoms are replaced by alkyl or aryl groups.

[0400] Particularly suitable are salts derived from inorganic acids that include, but are not limited to, hydrohalic acids (HC1, 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 veterinary and agriculturally acceptable salts are organic acid addition salts formed with organic acids including, but not limited to, maleate, difumarate, fumarate, tosylate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Of course, other acceptable organic acids can be used.

[0401] 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 metal or alkaline earth metal hydroxide.

[0402] 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 appropriate acid functional group present on the compounds, or by reacting an appropriate acid with an amine functional group present on the compounds of the present specification.

[0403] Methods of Making Compounds

[0404] The compounds of Formula (I) or a pharmaceutically or veterinarily acceptable salt thereof can be prepared by employing the procedures outlined in Schemes 1 and 2 below, as well as the Examples:

[0405] Scheme 1

[0406]

[0407] Scheme 2

[0408]

[0409] In Scheme 2, the variables R 1 , R 2 and R 3 represent groups defined above in Formula (I) and can be introduced by metal-catalyzed cross-coupling reactions. Examples include Heck reactions, Negishi coupling reactions, Stille cross-coupling reactions, Suzuki reactions, and others known in the art. The variable R 5 represents a linker L bound to one of the bicyclic rings shown in Formula (I) at this position of the bicyclic core. One of ordinary skill in the art is fully capable of adapting these schemes as appropriate to synthesize specific compounds of the invention. Furthermore, starting materials are readily available or can be prepared via known methods.

[0410] Veterinary Compositions

[0411] The compounds and compositions comprising the compounds can be used to prevent and / or treat parasitic infections or infestations in animals. Compositions of the present description comprise an effective amount of a compound or a veterinarily acceptable salt thereof, and in combination therewith a veterinarily acceptable carrier or diluent and optionally inactive excipients. The compositions can be in various solid and liquid forms, which are suitable for administration or dosing to animals in various forms. For example, the veterinary compositions comprising the compounds can be compositions suitable for oral dosing, injectable dosing (including subcutaneous and parenteral dosing), and topical dosing (e.g., painting or drenching), dermal or subcutaneous dosing. It is contemplated that the compositions will be dosed 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, swine, horses, donkeys, dogs, cats, and other livestock or domesticated mammals. Examples of birds include turkeys, chickens, ostriches, and other livestock or domesticated birds. The use of the compounds to protect companion animals such as dogs and cats from internal parasitism is particularly useful.

[0412] As discussed above, the compositions of the present description can be in a form suitable for oral use (see, e.g., U.S. Patent No. 4,564,631, incorporated herein by reference in its entirety), a bait supplement, a troche, a lozenge, a chewable, a tablet, a hard or soft capsule, a pill, an emulsion, an aqueous or oily suspension, a water or oil solution, an oral drench composition, a dispersible powder or granule, a premix, a syrup or elixir, an enteral composition or paste. Compositions intended to be used for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more sweetening agents, bittering agents, flavoring agents, coloring agents and preservatives in order to provide a pharmaceutically elegant and palatable preparation.

[0413] The tablets can contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period. They can also be coated to form osmotic therapeutic tablets for use in controlled release as described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 (all incorporated herein by reference in their entireties).

[0414] Oral compositions include hard gelatin capsules. The capsules can also be soft gelatin capsules in which the active ingredient is mixed with water or a water-miscible solvent or an oil medium.

[0415] In one embodiment, the compounds can be administered in a chewable tablet composition or a soft chewable composition, such as those described in US 2013 / 0203692 Al, US 2010 / 0087492, US 2006 / 0222684, US 2004 / 0151759, US 7,955,632, incorporated by reference in their entireties. The veterinary compositions can be in the form of a soft chewable composition ("soft chew") which is palatable and acceptable to an animal. In addition to the active ingredient, the soft chews described herein can also include one or more of the following components known in the art for use in such dosage forms: a solvent or solvent mixture, one or more fillers, one or more binders, one or more surfactants, one or more humectants, one or more lubricants, one or more disintegrants, one or more colorants, one or more antimicrobials, one or more antioxidants, one or more pH adjusters, and one or more flavoring agents.

[0416] The compositions can also include other inert ingredients such as antioxidants, preservatives, or pH stabilizers. Such compounds are well known in the art of compositions. Antioxidants can be added to the compositions of the present disclosure to inhibit the degradation of the active agent.

[0417] The compositions of the present disclosure can also include one or more lubricants and / or processing aids. In some cases, the lubricant / processing aid can also function as a solvent, and thus certain components of the compositions of the present disclosure can have a dual function.

[0418] A variety of flavoring agents can be used in the compositions of the present description to improve the palatability of the orally administered veterinary compositions. Preferred flavoring agents are those that are not derived from animal sources. In various embodiments, flavoring components derived from fruits, meats (including, but not limited to, pork, beef, chicken, fish, poultry, etc.), vegetables, cheeses, cured meats, cheese-cured meats, and / or artificial flavoring agents can be used. The flavoring components are generally selected based on considerations relating to the organism consuming the soft chew. For example, horses can prefer an apple flavoring component, while dogs can prefer a meat flavoring component. Although flavoring components derived from non-animal sources are preferred, in some embodiments natural flavoring agents containing beef or liver extracts, such as browned beef flavoring, artificial powdered beef flavoring, roast beef flavoring, and cured beef flavoring, among others, can be used.

[0419] In another embodiment of the present description, the active compositions can be administered via drenching, and can be administered topically or orally. Drenching compositions are those in which a liquid-containing composition of the present description is administered to the mouth or throat of an animal, or poured onto the skin or coat of an animal.

[0420] The compositions of the present description can also be in the form of an oil-in-water or water-in-oil emulsion, which can include emulsifiers known in the art. The emulsions can also contain sweetening agents, bittering agents, flavoring agents, and / or preservatives.

[0421] In one embodiment, the compositions of the present description can be in the form of a microemulsion. Microemulsions are well suited for use as liquid carrier vehicles. Microemulsions are four-component systems comprising an aqueous phase, an oil phase, a surfactant, and a co-surfactant. They are translucent and isotropic liquids.

[0422] Microemulsions are constituted as follows: a stable dispersion of droplets of the aqueous phase in the oil phase, or conversely, a stable dispersion of droplets of the oil phase in the aqueous phase.

[0423] Oil suspensions can be formulated by suspending an active ingredient in a vegetable oil. The oil suspensions can contain a thickening agent. Sweetening, bittering, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant or other known preservatives.

[0424] Aqueous suspensions can contain the active material in admixture with excipients suitable for the manufacture of an aqueous suspension. The aqueous suspension can also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweetening and / or bittering agents.

[0425] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Additional excipients, such as sweetening, bittering, flavoring, and coloring agents, can also be present.

[0426] Sugar and liquid suspensions can be prepared using a sweetening agent. The compositions can also contain a flavoring agent, a preservative, a coloring agent and / or a flavoring agent.

[0427] In another embodiment of the present description, the composition can be in the form of a paste. Examples of paste-form embodiments include, but are not limited to, those described in U.S. Patent Nos. 6,787,342 and 7,001,889, each of which is incorporated herein by reference. In addition to the compounds of the present description, the paste can further contain fumed silica; a viscosity modifier; a carrier; optionally an absorbent; and optionally a coloring agent, a stabilizer, a surfactant, or a preservative.

[0428] In some embodiments, the composition can be in the form of a sterile injectable aqueous or oleaginous suspensions. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.

[0429] In addition, sterile, fixed oils can conventionally be employed as a solvent or suspending medium.

[0430] Topical, dermal, and subcutaneous compositions can include, by way of non-limiting example, lotions, creams, ointments, gels, pastes, powders, shampoos, pour-on compositions, ready-to-use compositions, spot-on solutions and suspensions, drops, and sprays. Topical application of a compound of the present description or a composition including at least one compound of the present description in an active agent can result in transdermal absorption of the composition of the present description to achieve systemic levels, distribution through sebaceous glands, or distribution on the surface of the skin, to achieve various levels throughout the coat. Spot-on compositions are generally applied to a localized area, which refers to an area other than the entire animal. In one embodiment, the location can be between the shoulders. In another embodiment, the topical composition can be applied to the animal surface as a band, such as a band from the head to the tail of the animal.

[0431] Pour-on compositions are described in U.S. Patent No. 6,010,710, also incorporated herein by reference. Pour-on compositions can advantageously be oily, and generally comprise a diluent or vehicle, and, where the active ingredient is not soluble in the diluent, a solvent (e.g., an organic solvent) for the active ingredient. In other embodiments, the pour-on composition can include an organic solvent that is miscible with water.

[0432] The concentration of solvent to active agent compound is used in proportion to its solubility in that solvent. Efforts are made to achieve the smallest volume possible. The difference is made up to 100% with a vehicle.

[0433] In another embodiment of the present specification, a softening agent and / or spreading and / or film forming agent can be added to the topical composition.

[0434] In another embodiment of the present specification, the composition can be in the form of a ready-to-use solution, as described in U.S. Patent No. 6,395,765, incorporated herein by reference. In addition to the compounds of the present specification, the ready-to-use solution can also include a crystallization inhibitor and an organic solvent or mixture of organic solvents. In certain embodiments, water can be included with the organic solvent.

[0435] The composition can also include an antioxidant to desirably inhibit oxidation in air, which agent can be present in a proportion of about 0.005 to about 1% (w / v), about 0.01 to about 0.1%, or about 0.01 to about 0.05%.

[0436] The composition excipients discussed above are well known to those skilled in the art and are either commercially available or are obtained by known techniques. These compositions are generally prepared by simply mixing the components as defined previously; advantageously, the starting point is to mix the active substance into the main solvent, and then the other ingredients or auxiliaries are added.

[0437] The volume of the composition administered will depend on the type of animal and the size of the animal as well as the strength of the composition and the potency of the active agent. In one embodiment, about 0.1 to about 20 ml of the composition can be administered to the animal in an amount. In other embodiments of the volume, the volume can be about 0.1 to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, or about 0.3 to about 3 ml.

[0438] The application compositions can be prepared by dissolving the active ingredients in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, the application compositions can be prepared by encapsulating the active ingredients so that a residue of the therapeutic agent is left on the surface of the animal. These compositions will vary with the weight of the therapeutic agent in the combination, depending on the species of host animal to be treated, the severity and type of infection, and the body weight of the host.

[0439] Each dosage unit can typically contain from about 0.1 mg to about 5 g. In other embodiments, the dosage unit can contain from about 0.5 mg to about 5 g of the active agent. In one embodiment of the dosage unit, the dosage can contain from about 1 mg to about 500 mg of the active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 mg.

[0440] In one embodiment of the specification, the compound of formula (I) can be present in the composition at a concentration of about 0.05 to about 50% weight / weight. In other embodiments, the compound of formula (I) can be present at a concentration of about 0.1 to about 30% (w / w). In other embodiments, the compound of formula (I) can be present at a concentration of about 0.5 to about 30% (w / w), about 1 to about 20% (w / w), or about 0.05 to about 10% (w / w). In other embodiments, the compound of formula (I) can be present at a concentration of about 10 to about 50% (w / w), about 10 to about 30% (w / w), about 10 to about 20% (w / w). In yet another embodiment, the compound of formula (I) can be present at a concentration of about 1 to 10% (w / w) or about 5 to about 15% (w / w). In another embodiment of the specification, the active agent can be present in the composition at a concentration of about 0.1 to about 2% w / w. In yet another embodiment of the specification, the active agent can be present in the composition at a concentration of about 0.25 to about 1.5% w / w. In yet another embodiment of the specification, the active agent can be present in the composition at a concentration of about 1% w / w.

[0441] Methods of Treatment

[0442] As discussed above, the compound of formula (I) is effective against endoparasites and can be used to treat and / or prevent parasitic infections in animals. In one embodiment, the present specification provides a method of treating and / or preventing an endoparasitic infection in or on an animal, such as a mammal or a bird, comprising administering to the animal an endoparasiticidally effective amount of a compound of formula (I), or a veterinarily acceptable salt thereof, or a composition of the present specification.

[0443] The present specification also provides the use of a compound of formula (I) in the manufacture of a medicament for treating and / or preventing a parasitic infection in an animal. The present specification also provides a compound of formula (I) for use in treating and / or preventing a parasitic infection in an animal.

[0444] In certain embodiments, the compound of formula (I) can also be effective against ectoparasites and can be used to treat and / or prevent ectoparasitic infestations on animals. In another embodiment, the present specification provides a method of treating and / or preventing an ectoparasitic infestation on the body surface of an animal, such as 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 present specification.

[0445] The present specification also provides the use of a compound of formula (I) in the manufacture of a medicament for treating and / or preventing a parasitic infection in an animal. The present specification also provides a compound of formula (I) for use in treating and / or preventing a parasitic infection in an animal.

[0446] In another embodiment, the present specification provides a method for treating and / or preventing endoparasite infection and ectoparasite infestation in an animal comprising administering to said animal a composition comprising an effective amount of a compound of Formula (I), or a veterinarily acceptable salt thereof, in combination with an effective amount of at least a second active agent.

[0447] Also provided herein are compounds of Formula (I) in combination with at least a second active agent for use in the treatment and / or prevention of endoparasite infection and ectoparasite infestation. In addition, the use of a compound of Formula (I) in combination with at least a second active agent for the manufacture of a medicament for the treatment and / or prevention of endoparasite infection and ectoparasite infestation is provided.

[0448] In yet another embodiment of the present specification, a method of treating and / or preventing parasitic infestation in a locus is provided comprising administering or applying to said locus a parasiticidally effective amount of a compound of Formula (I), or a veterinarily acceptable salt thereof. With respect to animal health administration, "locus" means a habitat, breeding ground, area, substance, or environment in which parasites grow or can grow, excluding the interior or exterior of an animal.

[0449] In another embodiment, the present specification provides methods and uses of the compounds for controlling pests in plants and crops or for protecting wood-containing structures.

[0450] In some embodiments, the animal that can be treated is a mammal, including but not limited to humans, cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep, and yaks. In one embodiment of the present specification, the mammal treated is a human, cat, or dog.

[0451] In one embodiment of the present specification, the compounds of Formula (I) are found to have superior efficacy against endoparasites, especially against endoparasites resistant to macrolide active agents. In one embodiment, the compounds and compositions of the present specification are effective for controlling Haemonchus contortus, Ostertagia circumcincta, and Trichostrongylus colubriformis in mammals or birds.

[0452] In another embodiment, the present description 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 a parasiticidal compound of the present description in combination with an effective amount of an invertebrate GABA receptor activator including an avermectin or a milbemycin.

[0453] In another embodiment, the present description 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 description provides a compound of Formula (I) for use in treating or preventing a parasitic infestation or infection in an animal.

[0454] Avermectin compounds that can be used in combination with the compounds of the present description include, but are not limited to, avermectin, doramectin, moxidectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Milbemycin compounds that can be used in combination with the compounds of the present description include, but are not limited to, milbemectin, milbemycin D, moxidectin, and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of the avermectins and milbemycins.

[0455] In one embodiment, the compounds and compositions of the present specification are useful in the treatment and / or prevention of in vivo parasitic infections by Anaplocephala (Anoplocephala), Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum, Onchocerca, Ostertagia, Oxyuris, Paracaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorous, Uncinaria, Wuchereria, and combinations thereof.

[0456] In a particularly preferred embodiment of the present specification, the compounds and compositions of the present specification are used to treat and / or prevent infections caused by Dirofilaria immitis. The compounds have been found to be highly effective against Dirofilaria immitis microfilariae and L4 larvae. Thus, the compounds can be used to protect animals from developing heartworm disease by killing Dirofilaria immitis in the immature stages before they are able to develop into adult worms. In one embodiment, the compounds and compositions comprising the compounds can be used to prevent the development of heartworm disease by killing immature Dirofilaria immitis that are resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present specification are used to treat and / or prevent infections caused by Dirofilaria repens or Dirofilaria hongkongensis.

[0457] In another embodiment of the present specification, the parasitic worm is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, and combinations thereof.

[0458] In another embodiment of the treatment of antibody endoparasites and ectoparasites in combination with ectoparasiticidal agents, the ectoparasite is one or more insects or arachnids, including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.

[0459] In another embodiment of the treatment of ectoparasites, the ectoparasite is from the genus Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, and / or Boophilus. Ectoparasites treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, botflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalides spp., etc.), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., etc.), and mites (Demodex spp., Sarcoptes spp., Otodectes spp., etc.), lice (Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.), mosquitoes (Aedes spp., Culex spp., Anopheles spp., etc.), and flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., etc.). In yet another embodiment of the treatment of ectoparasites, the ectoparasite is a flea and / or a tick.

[0460] Additional examples of ectoparasites include, but are not limited to, Boophilus, particularly those of the species microplus, decoloratus, and annulatus; myiasis such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (green bottle fly); sheep myiasis such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand, and South Africa). Dipteran flies, i.e., those whose adult stage is parasitic, such as Haematobia irritans; lice such as Linognathus vitulorum and the like; and mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example, migratory dipteran larvae.

[0461] In another embodiment of the present specification, the compounds and compositions of the present specification are suitable for controlling pests, for example, insects selected from the group consisting of Blatella germanica, Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitum, and combinations thereof.

[0462] Plant parasitic nematodes include, for example, Anguina spp., Aphelenchoides spp., Belonolaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.

[0463] In addition, the present specification can also be used to treat other pests, including but not limited to the following pests, with or without the addition of other pesticide agents to the composition:

[0464] (1) Isopoda, for example Oniscus asellus, Armadillidium vulgare and Porcellio scaber;

[0465] (2) Diplopoda, for example Blaniulus guttulatus;

[0466] (3) Chilopoda, for example Geophilus carpophagus and Scutigera spp.;

[0467] (4) Symphyla, for example Scutigerella immaculata;

[0468] (5) Thysanura, for example Lepisma saccharina;

[0469] (6) Collembola, for example Onychiurus armatus;

[0470] (7) Blattaria, for example Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica;

[0471] (8) Hymenoptera, for example Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis and Vespa spp.;

[0472] (9) Siphonaptera, for example Xenopsylla cheopis and Ceratophyllus spp.;

[0473] (10) Anoplura (Phthiraptera), for example Damalinia spp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectes spp.;

[0474] (11) Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici;

[0475] (12) Bivalva, for example, Dreissena spp.;

[0476] (13) 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, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp., Fustinus cubae, Gibbium sylloides, Heteronychus arator, Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosterna consanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolontha, Migdolus spp., Monochamus spp., Orthomolus spp., Ortygia postvittata, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Phaedon cochleariae, Phyllobius spp., Phyllophaga spp., Phyllophaga helleri, Phyllopertha horticola, Popillia japonica, Ptinus spp., Rhizoglyphus spp., Rhynchophorus spp., Sitophilus spp., Sphenophorus spp., Tribolium spp., Trogoderma spp., Tychius spp., Xylotrechus speciosus, and Xylotrupes sibiricus;), 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.;.

[0477] (14) Diptera (flies), e.g., Aedes spp., Anopheles spp., Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fannia spp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanus spp., Tannia spp., Tipula paludosa, Wohlfahrtia spp.;

[0478] (15) Gastropoda (snails), e.g., Arion spp., Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.;

[0479] (16) Class of Helminths, for example, Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, Ancylostoma spp., Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa, Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloides spp.), Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp., Trichuris trichuria, Wuchereria bancrofti;.

[0480] (17) Heteroptera, for example, Anasa tristis, Antestiopsis spp., Blissus spp., Calocoris spp., Campylomma livida, Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergella singularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatoma spp.;

[0481] (18) 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, Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia spp., Brachycaudus helichrysii, 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 spp., Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp., Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp., Erythrioneura spp., Ferrisia spp., Gossyparia spp., Greenidea spp., Hemiberorta spp., Homalodisca coagulata, Hyalopterus spp., Hyperomyzus lactucae, Icerya spp., Laodelphax spp., Lecanium spp., Lepidosapholes spp., Lecanium spp., Lepidosapholes spp., Lecanium spp., Lepidosapholes spp., Lecanium spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lepidosapholes spp., Lep), Eriosoma spp., Erythroneura spp., euscelis bilobatus, Geococcus coffeae, Homalodiscus coagulata, Hyalopterus arundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphax striatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari, Metcalfiella spp., Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettix spp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp., Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp., Psylla spp.), Pteromalus spp., Pyrilla spp., Quadraspidiotus spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus, Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis spp., Viteus vitifolii.

[0482] (19) Isoptera, for example, Reticulitermes spp., Odontotermes spp.;

[0483] (20) Lepidoptera, for example, 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, 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 padella, Laphygma spp., Lithocolletis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestra brassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesia gemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana, Trichoplusia spp.

[0484] (21) Orthoptera, for example, Acheta domesticus, Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae, Locusta spp., Melanoplus spp., Periplaneta americana, Schistocerca gregaria;

[0485] (22) Thysanoptera, for example, Baliothrips biformis, Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothrips spp., Taeniothrips cardamoni, Thrips spp.

[0486] (23) protozoa, for example, Eimeria spp.

[0487] In aspects of the present description, the compounds and compositions of the present description can be applied against individual pests or combinations thereof.

[0488] Mixtures with Other Active Agents

[0489] In another embodiment, the compositions comprising a compound of Formula (I) can further comprise other veterinary therapeutic agents. Veterinary agents that can be included in the compositions of the present description are well known in the art (see, for example, Plumb's Veterinary Drug Handbook, 5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th Edition, (January 2005)) and include, but are not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminoglycine hydrochloride, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, lipid-based amphotericin B, ampicillin, amprolium, antacids (oral), antivenin, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, bethanechol, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine hydrochloride, buspirone hydrochloride, busulfan, butorphanol tartrate, cabergoline, calcitonin salmon, calcitriol, calcium salts, captopril, carindacillin sodium, carbmazepine, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporins, charcoal (activated), chlorambucil, chloramphenicol, chloraziepate , chloraziepate + / - clidinium bromide, chlorothiazide, chlorpheniramine maleate, chloφromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine hydrochloride, clonazepam, clonidine, cloprostenol sodium, chlordiazepoxide + / - clidinium bromide, chlorothiazide, chlorpheniramine maleate, chloφromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine hydrochloride, clonazepam, clonidine, cloprostenol sodium, chlordiazepoxide + / - clidinium bromide, chlorothiazide, chlorpheniramine maleate, chloφromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine hydrochloride, clonazepam, clonidine, cloprostenol sodium, chlordiazepoxide heparin, hetastarch, hyaluronate sodium, hydralazine, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, imipenem-cilastatin sodium, imipramine, insulins, interferon alfa-2a (human recombinant), iodide (sodium / potassium), ipecac (syrup), iopanoic acid 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, meclofenamate sodium, meperidine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine hippurate / malonate, methimazole, methionine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerone, midazolam, mibefradil, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, nandrolone decanoate, naproxen, narcotic agonist analgesic, neomycin sulfate, neostigmine, nicotinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, nystatin, octreotide acetate, oxaprozin sodium, omeprazole, ondansetron, opiate antidiarrheal, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin chloride, oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancrelipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine, penicillins, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenytoin sodium, pheromones, parenteral phosphates, phytonadione / vitamin K-1, pimobenz, piperazine, pirlimycin, piroxicam, polysulfated glycosaminoglycans, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, procyclidine, propantheline bromide, propionibacterium acnes,acnes) injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic gum, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl-methionine (SAMe), saline / high-osmolar laxative, selamectin, selegiline / l-deprenyl, sertraline, sevelamer, sevoflurane, silymarin / milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium stibgluconate, sodium sulfate, sodium thiosulfate, somatropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachloropyrolidate, sulfadiazine / trimethroprim, sulfamethoxazole / trimethoprim, sulfadimentoxine, sulfadimentoxine / ormetoprim, sulfasalazine, taurine, teprenone, terbinafine, terbutaline sulfate, testosterone, tetracycline, thiacetarsamide sodium, vitamin B1, thioguanine, thiopental sodium, thiotepa, thyrotropin, tiuxval, ticarcillin disodium, tilsitin / zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tocainide, tolazoline, tolfenamic acid, topiramate, triamcinolone acetonide, trientine, trilostane, trimeprazine tartrate w / 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.

[0490] In one embodiment of the present specification, arylpyrazole compounds such as phenylpyrazoles can be included in the present specification veterinary compositions. Arylpyrazoles are known in the art and can be suitable for combination with the compounds of Formula (I) in the present specification compositions. 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 (incorporated by reference in their entireties herein). A particularly preferred arylpyrazole active agent is fipronil.

[0491] In another embodiment of this specification, the composition may include one or more macrolides or lactams that act as acaricides, worm repellents, and / or insecticides in combination with the compounds described herein. For the avoidance of ambiguity, the term "macrolide" as used herein includes natural and synthetic or semi-synthetic compounds such as avermectin and milkemycin.

[0492] Macrolides that may be used in the compositions described herein include, but are not limited to, naturally occurring avermectins (including, for example, 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 glycosyl compounds. Examples of macrolide compounds that may be used in the composition include, but are not limited to, avermectin, dimethoprim, dolactin, emamectin, 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. Also included are 5-oxo and 5-oxime derivatives of the aforementioned avermectins and milbemycins.

[0493] Macrocyclic lactones are known in the art and are readily available commercially or synthesized using techniques known in the art. See the widely available technical and commercial literature. For avermectins, ivermectin, and abamectin, see, for example, "Ivermectin and Abamectin" published by Springer Verlag, 1989, MH Fischer and H. Mrozik, William C. Campbell, or Albers- For the avermectins, see, e.g., Albers-Schonberg et al. (1983), "Avermectins, a new class of anthelmintic agent: morphology of production organisms and their biological properties", Proc. Natl. Acad. Sci. USA, 80, 175-179; and Albers-Schonberg et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc, 103, 4216-4221. For doramectin, see "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15. For the milbemycins, see, inter alia, Davies H.G. et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121; Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336; U.S. Patent No. 4,134,973 and EP 0 677054, both of which are incorporated herein by reference.

[0494] The structures of the avermectins and milbemycins are closely related, e.g., both have complex 16-membered macrocyclic lactone rings. The natural products, the avermectins, are disclosed in U.S. Patent No. 4,310,519, and the 22,23-dihydroavermectin compounds are disclosed in U.S. Patent No. 4,199,569. U.S. Patent Nos. 4,468,390; 5,824,653; EP 0 007812 Al; U.K. Patent Specification 1 390 336; EP 0 002 916; and New Zealand Patent No. 237086 are also specifically mentioned. The natural milbemycins are described in U.S. Patent No. 3,950,360 and "The Merck Index", 12thEdition, 1996, Merck & Co., Inc., Rahway, New Jersey, USA, p. 1017. thed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996) cited in the various references. Latidectin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, Vol. 17, No. 4, pages 263-286, (2003). Semisynthetic derivatives of these classes of compounds are well known in the art and are described in, for example, U.S. Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148, and EP 0 667 054, all incorporated herein by reference.

[0495] In one embodiment, the veterinary compositions of the present description comprise an effective amount of at least one of abamectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemycin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, or nemadectin, or combinations thereof. In another embodiment, the present description provides veterinary compositions comprising an effective amount of at least one of abamectin, eprinomectin, ivermectin, doramectin, or selamectin, or combinations thereof. In yet another embodiment, the veterinary compositions of the present description comprise an effective amount of at least one of ivermectin, milbemycin, milbemycin oxime, or moxidectin, or combinations thereof.

[0496] In another embodiment of the present specification, compositions are provided comprising a compound of Formula (I) in combination with a class of miticides or insecticides known as insect growth regulators (IGRs). Compounds belonging to this class are well known to practitioners and encompass a wide range of different chemical classes. These compounds all act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Patent Nos. 3,748,356; 3,818,047; 4,225,598; 4,798,837; 4,751,225; EP 0 179 022; or UK 2 140 010; and U.S. Patent Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).

[0497] In one embodiment of the present specification compositions, an IGR compound that mimics or regulates the level of juvenile hormone in insects can be included. Examples of juvenile hormone mimics include azadirachtin, benzoylpyrene, fenoxycarb, hydroprene, methoprene, methoxyfenozide, tebufenozide, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridinylmethoxy)pyridazine-3(2H)-one. In another embodiment, the present specification compositions comprise a compound of Formula (I) in combination with methoxyfenozide or pyriproxyfen and a pharmaceutically acceptable carrier.

[0498] In another embodiment, the present specification compositions include IGR compounds that are chitin synthesis inhibitors. Chitin synthesis inhibitors include tralkoxydim, chlorbenzuron, diflubenzuron, flucycloxuron, flufenoxuron, flufenprox, hexaflumuron, hydroprene, methoxyfenozide, novaluron, tebufenozide, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0499] In some embodiments, the present specification compositions can include one or more antinematodal agents, including but not limited to benzimidazoles, imidazothiazoles, tetrahydropyrimidines, active agents in the class of organophosphate compounds. In some embodiments, benzimidazoles, including but not limited to thiabendazole, thiabendizole, fenbuconazole, propineb, tolylfluanid, flutianil, thiabendizole, thiabendizole, prothiocarb, cyclobendazole, thiuram, thiophanate, and o,o-dimethyl analogs thereof can be included in the compositions.

[0500] In other embodiments, the present specification compositions can include imidazothiazole compounds, including but not limited to, tetramisole, levamisole, and dibamisole.

[0501] In other embodiments, the compositions described herein may include tetrahydropyrimidine activators, including but not limited to pyrimidine, resorcinol pyrimidine, and thiamethoxam.

[0502] Suitable organophosphate surfactants include, but are not limited to, phosmet, trichlorfon, chlorpyrifos, naphthylphosphatide, dichlorvos, heptamethrin, phosmet, chlorpyrifos, TEPP, and chlorpyrifos.

[0503] In other embodiments, the composition may include the antinematode compound phenothiazine; piperazine as a neutral compound and its various salt forms; diethylamine; phenols, such as diiodonitrophenol; arsenic-containing preparations, such as thioaceridine; ethanolamines, such as benzylphenol, thiamethoxamium chlorobenzenesulfonate, and methoxypyridine; cyanine dyes, including chlorpyrifos, chlorpyrifos dihydroxynaphthyl phenol, and iododithiazine; isothiocyanates, including p-diisothiocyanophenyl; sodium suramin; phthalylhexynyl esters; and various natural products, including but not limited to hygromycin B, α-artemisinin, and erythrine.

[0504] In other embodiments, the compositions described herein may include an anti-trematode. Suitable anti-trematodes include, but are not limited to, mirezids such as mirezid D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives, pyrithione, aminothione, hydroxythione, hydroxyquinoline, nitrothiocyanate, nitrothiazide, nitrohydroxyiodobenzyl nitrile; various bisphenol compounds known in the art, including thiochlorophenol, thiochlorophenol sulfoxide, and binitrochlorophenol; various salicylanilide compounds, including tribromosalinomyline, hydroxychlorosalinomyline, chloriodamide, rafoxanide, nitrohydroxyiodobenzyl nitrile, bromothione, bromofluoronitrosalinomyline, and chlorsenoyl; trichlorobenzyl, diacetaminophenoxyethyl ether, clostridium, hyaluronate, and ipecacine.

[0505] Tapeworm anthelmintics, including but not limited to, arecoline in various salt forms, bufenamidin, molluscamine, diphenyl nitrosocyanate, paromomycin, paromomycin II, praziquantel, and estatel, may also be used advantageously in the compositions described herein.

[0506] In other embodiments, the compositions of this specification may include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromoxynil, chlordane, DDT, endosulfan, lindane, methoxydendron, toxaphene, bromothion, ethyl bromoxynil, trithion, chlorpyrifos, phosmet, phosmet, diazinon, dimethoate, dimethoate, dimethoate, ethion, phosmet, fenitrothion, fospirate, phosmet, malathion, dibromophos, phosmet ... The compounds include diflubenzuron, diphenylamine, disulfiram, isoborneol cyanothioacetate, tebufenozide, sulfamethrin, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, IR3535, and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofuranaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-bridged methylene-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridine dicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[0507] In another embodiment, the antiparasitic agent that may be included in a veterinary composition containing a compound of formula (I) may be a biologically active peptide or protein, including but not limited to peptides different from said compound. These include PF1022A or analogues thereof and emodepside. Other cyclic peptide compounds that may be included in a composition containing a compound of formula (I) are those described in WO 2016 / 187534A1 and WO 2017 / 116702A1, both of which are incorporated herein by reference. These compounds cause paralysis and death of parasites by stimulating presynaptic receptors belonging to the secretin receptor family at the neuromuscular junction. In one embodiment of the peptide, said peptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

[0508] In another embodiment, the compositions of the present description can include an active agent from the class of neonicotinoid 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 description is imidacloprid. This class of agents is described, for example, in U.S. Patent No. 4,742,060 or EP 0 892 060, both of which are incorporated herein by reference. In another embodiment, the compositions of the present description can include nitenpyram, which is another active agent from the class of neonicotinoid parasiticides. The use of nitenpyram to control fleas is described in U.S. Patent No. 5,750,548, incorporated herein by reference in its entirety.

[0509] In certain other embodiments of the present description, the compound of Formula (I) that can be combined with the compositions of the present description is a sulfoximine, such as sulfoxaflor.

[0510] In another embodiment, the compositions of the present specification can advantageously include one or more isoxazoline compounds known in the art. Isoxazoline active agents are highly effective against a variety of ectoparasites in vitro and the combination with the compounds of Formula (I) will extend the range of efficacy against these parasites. Particularly useful isoxazoline active agents that can be combined with the compounds include afolana (including the substantially pure active enantiomer, esafoxolaner), sarolaner, fluralaner (including the substantially pure active enantiomer), lotilaner, and tigolaner. These active agents are described in US 7,964,204, US 2010 / 0254960 Al, US 2011 / 0159107, US 2012 / 0309620, US 2012 / 0030841, US 2010 / 0069247, WO 2007 / 125984, WO 2012 / 086462, US 8318757, US 8466115, US 8618126, US 8822466, US 8383659, US 8853186, US 9221835, US 2011 / 0144349, US 8,053,452, S 2010 / 0137612, US 8410153, US 2011 / 152081, WO 2012 / 089623, WO 2012 / 089622, US 8,119,671; US 7,947,715;WO 2102 / 120135, WO 2012 / 107533, WO 2011 / 157748, US 2011 / 0245274, US 2011 / 0245239, US 2012 / 0232026, US 2012 / 0077765, US 2012 / 0035122, US 2011 / 0251247, WO 2011 / 154433, WO 2011 / 154434, US 2012 / 0238517, US 2011 / 0166193, WO 2011 / 104088, WO 2011 / 104087, WO 2011 / 104089, US 2012 / 015946, US 2009 / 0143410, WO 2007 / 123855A2, US 2011 / 0118212, US 7951828 & US 7662972, US 2010 / 0137372 Al, US 2010 / 0179194A2, US 2011 / 0086886 A2, US 2011 / 0059988 Al, US 2010 / 0179195 Al, US 2015 / 0126523, WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236, WO 2017 / 147352, US7897630, US7951828, WO 2020 / 007704 Al, WO 2021 / 028479 Al, WO 2014 / 122083 Al, WO 2016 / 177619 Al, WO 2014 / 012975 Al, WO 2015 / 078846 Al, WO 2015 / 078847 Al, WO 2015 / 150302 Al, WO 2015 / 181139 Al, and WO 2016 / 026789 Al, all of which are incorporated herein by reference in their entirety.

[0511] In another embodiment of the present specification, Nodulisporic acid and its derivatives can be added to the compositions of the present specification. These compounds are useful in the treatment or prevention of 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, incorporated herein by reference in their entirety. The compositions can include one or more of the nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above cited references.

[0512] In another embodiment, anthelmintic compounds such as monepantel (ZOLVIX) and the like can be added to the compositions of the present description. These compounds are described in, for example, US 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.

[0513] The compositions of the present description can also include arylazol-2-yl cyanoethylamino compounds, such as those described in US Patent No. 8,088,801 to Soll et al., incorporated herein by reference; while thioamide derivatives of these compounds are described in US Patent No. 7,964,621, also incorporated herein by reference. Arylazol-2-yl cyanoethylamino active agents that act systemically against endoparasites can be combined with compounds for use in the veterinary compositions of the present description.

[0514] The compositions of the present description can also include paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Paraherquamide compounds are a known class of compounds with activity against certain parasites, which include a spirodioxepinoindole core (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380 and J. Antibiotics 1991, 44, 492). In addition, structurally related macfurin compounds, such as macfurins A-C, are also known and can be combined with the compositions of the present description (see J. Chem. Soc.-Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Additional descriptions of paraherquamide derivatives can be found in, for example, WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, WO 09 / 004432, and US 2010 / 0197624, US Patent 5,703,078, and US Patent 5,750,695, incorporated herein by reference in their entireties.

[0515] In another embodiment of the present specification, the composition can include a spinosyn active agent produced by Saccharopolyspora spinosa (see, e.g., Salgado V.L. and Sparks T.C., "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance", Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosoid active agent. Spinosyns are generally referred to as Factor or Component A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or combinations thereof can be used in the compositions of the present specification. Spinosyn compounds can be a 5,6,5-tricyclic ring system fused to a 12-membered macrocyclic lactone, a neutral sugar (rhamnose), and an amino sugar (forosamine). These and other natural spinosyn compounds that can be used in the compositions of the present specification, including 21 -butenyl spinosyn produced by Saccharopolyspora pagona, can be produced by fermentation through conventional techniques known in the art. Other spinosyn compounds that can be used in the compositions of the present specification 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 incorporated herein by reference in their entirety. Spinosyn compounds can include, but are not limited to, spinosyn A, spinosyn D, spinosyn, spinetoram, or combinations thereof. Spinosyn 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.

[0516] Typically, the additional active agent (other than the compound of Formula (I) described above) is included in the dosage unit of the present specification in an amount of from about 0.1 μg to about 1000 mg. Typically, the active agent can be included in an amount of from about 10 μg to about 500 mg, from about 10 μg to about 400 mg, from about 1 mg to about 300 mg, from about 10 mg to about 200 mg, or from about 10 mg to about 100 mg. More typically, the additional active agent is present in the composition of the present specification in an amount of from about 5 mg to about 50 mg.

[0517] The concentration of additional active agents in the compositions of the present description is generally about 0.01% to about 30% (w / w), depending on the potency of the active agent. In certain embodiments for very potent active agents, including but not limited to macrolide active agents, the concentration of active agent is generally about 0.01% to about 10% (w / w), about 0.01 to about 1% (w / w), about 0.01% to about 0.5% (w / w), about 0.1% to about 0.5% (w / w), or about 0.01% to about 0.1% (w / w). In other embodiments, the concentration of active agent is generally about 0.1% to about 2% (w / w) or about 0.1% to about 1% (w / w).

[0518] In other embodiments, additional active agents are generally present in higher concentrations to achieve the desired potency. 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 other embodiments, the active agent is present in a concentration of about 5% to about 20% (w / w) or about 5% to about 15% (w / w) in the composition.

[0519] In various embodiments of the present description, additional active agents can be included in the composition 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 generally present in an amount sufficient to deliver a dose of about 0.05 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg. In other embodiments, the active 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.

[0520] In certain embodiments of the present description where the additional active agent is a very potent compound, such as a macrolide 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 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 other embodiments, the additional active agent can be present in an amount that delivers a dose of about 1 μg / kg to about 200 μg / kg or about 0.1 mg / kg to about 1 mg / kg of animal body weight.

[0521] In addition to the other active agents mentioned above, combinations of two or more active agents can be used in the compositions along with the compounds of the present specification to treat the desired range of pests and parasites. It is well within the skill of the practitioner to determine which individual compounds can be used in the compositions of the present application to treat a particular insect infestation.

[0522] The present application will now be further described, by way of example, with reference to the following non-limiting examples. Examples

[0523] Preparation Examples

[0524] The following examples are intended to be illustrative and not limiting of the present application. The compounds of Formula (I), or pharmaceutically or veterinarily acceptable salts thereof, can be prepared by employing one of the reaction schemes described below. The starting materials used to prepare them can be commercially available or can be prepared by methods known to those skilled in the art and described in the literature, or can be intermediates of any of the other schemes described herein. It will be appreciated that one skilled in the art can modify the procedures described below to generate additional compounds of the present application. For example, one skilled in the art will appreciate that substitution of certain starting materials or use of different intermediates will enable preparation of different compounds of Formula (I).

[0525] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20 °C. Although the following matters are described in considerable detail to provide thorough understanding of the embodiments, one skilled in the art will appreciate that certain changes and modifications can be made within the scope of the embodiments.

[0526] List of Abbreviations:

[0527] ACN acetonitrile

[0528] AIBN azobisisobutyronitrile

[0529] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0530] BSA bovine serum albumin

[0531] BOC tert-butoxycarbonyl

[0532] BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphonic chloride

[0533] DAST diethylaminosulfur trifluoride

[0534] DCC N,N'-dicyclohexylcarbodiimide solution

[0535] DCM dichloromethane

[0536] DEAD diethyl azodicarboxylate

[0537] DIEA diisopropylethylamine

[0538] DMF N,N-dimethylformamide

[0539] DMAP 4-(dimethylamino)pyridine

[0540] DMSO dimethyl sulfoxide

[0541] EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0542] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0543] ES electrospray

[0544] EtOAc or EA ethyl acetate

[0545] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate

[0546] HOBt or HOBT 1-hydroxybenzotriazole

[0547] KHMDS potassium hexamethyldisilyl diazide, more precisely potassium bis(trimethylsilyl)amide

[0548] MeOH methanol

[0549] m-CPBA meta-chloroperoxybenzoic acid

[0550] NMO N-methylmorpholine-N-oxide

[0551] o / n over night

[0552] PE petroleum ether

[0553] Pd(dtbpf)Cl2 dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)

[0554] Pd2dba3 tris(dibenzylideneacetone)dipalladium(0)

[0555] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

[0556] TBAF tert-butyl ammonium fluoride

[0557] TfO triflate

[0558] THF tetrahydrofuran

[0559] TLC thin layer chromatography

[0560] Some examples of formula (I) were derived after separation of racemic mixtures and obtained as enantiomerically pure products. The stereochemistry is arbitrarily assigned in some cases and the corresponding compounds were characterized by analytical methods as described below:

[0561] Method A

[0562]

[0563] CHIRAL Cellulose SJ_3x100mm_3μm(Agilent)

[0564] Method B

[0565]

[0566] CHIRAL Cellulose SJ_3x100mm_3μm(Agilent)

[0567] Method C

[0568]

[0569] CHIRAL Cellulose SJ_3x100mm_3μm(Agilent)

[0570] Method D

[0571]

[0572] CHIRAL Cellulose SB_4.6x250mm_5μm(Agilent)

[0573] Method E

[0574]

[0575] CHIRAL Cellulose SB_4.6x250mm_5μm(Agilent)

[0576] Preparation Example 1 : The following example compounds can be synthesized by those skilled in the art using the following schemes 3 and 4 shown 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.

[0577] Scheme 3

[0578]

[0579] Scheme 4

[0580]

[0581] 1. Synthesis of ethyl 1-aminoimidazole-2-carboxylate

[0582]

[0583] Into a 3000-mL 3-necked round bottom flask was placed DMF (2000 mL), ethyl 1H-imidazole-2-carboxylate (3-1, 50.0 g, 356.7 mmol, 1.0 equiv). NaH (21.0 g, 875.0 mmol, 2.4 equiv) was then added portionwise at room temperature. Aminodiphenylphosphinic acid (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 hours. The resulting mixture was concentrated in vacuo. The solid was filtered off. The resulting mixture was concentrated in vacuo. 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.

[0584] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3)

[0585]

[0586] Into a 500-mL round bottom flask was added DMF (200.0 mL), ethyl 1- aminoimidazole-2-carboxylate (3-2, 35.0 g, 225.5 mmol, 1.0 equiv), Boc20 (63.9 g, 293.2 mmol, 1.3 equiv), 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 with 3 x 200 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. 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.

[0587] 3. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2- carboxylate (3-4)

[0588]

[0589] Into a 250-mL round bottom flask was added DMF (100.0 mL), ethyl 1- [(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3, 15.0 g, 58.7 mmol, 1.0 equiv), 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 with 3 x 100 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 12 g (61.1%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) as a colorless oil.

[0590] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropionate (3-5)

[0591]

[0592] Into a 1000-mL 3-necked round bottom flask was placed THF (400.0 mL), 4-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (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 portions over 30 min at 0 °C. To this was added dropwise ethyl acetate (32.0 g, 363.2 mmol, 10.1 equiv) at 0 °C with stirring. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of HC1 (1 M). The resulting solution was extracted with 3 x 50 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 6.5 g (48.1%) of 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropionic acid ethyl ester (3-5) as a yellow oil.

[0593] 5. Synthesis of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6)

[0594]

[0595] Into a 100-mL round bottom flask was placed DCM (30.0 mL), 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropionic acid ethyl ester (3-5, 6.5 g, 17.2 mmol, 1.0 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H20:ACN = 90:10 increasing to H20:ACN = 50:50 over 15 min; detector, 254 nm. This resulted in 3.3 g (66.7%) of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6) as a white solid.

[0596] 6. Synthesis of 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-7)

[0597]

[0598] A 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was charged with dioxane (60.0 mL), 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6, 3.0 g, 10.5 mmol, 1.0 equiv), trimethyl-l,3,5,2,4,6-trioxaborinan (2.6 g, 20.9 mmol, 2.0 equiv), Pd(PPh3)4(1.2 g, 1.0 mmol, 0.1 equiv), 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 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-7) as a yellow solid.

[0599] 7. Synthesis of 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[l,2-b]pyridazine-7- carboxylic acid ethyl ester (4-1)

[0600]

[0601] A 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was charged with DCM (20.0 mL), 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-7, 200.0 mg, 0.9 mmol, 1.0 equiv), TEA (457.0 mg, 4.5 mmol, 5.0 equiv). Tf20 (765.6 mg, 2.7 mmol, 3.0 equiv) was then added dropwise at -78 °C with stirring. 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 with 3 x 20 mL of dichloromethane, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 200 mg (62.6%) of 2-methyl-8- (trifluoromethanesulfonyloxy)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-1) as a brown oil.

[0602] 8. Synthesis of 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2)

[0603]

[0604] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (10.0 mL), H20 (2.0 mL), 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-1, 200.0 mg, 0.6 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (179.0 mg, 1.0 mmol, 1.9 equiv), Pd(dtbpf)Cl2 (37.2 mg, 0.06 mmol, 0.10 equiv), K2CO3 (234.0 mg, 1.7 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at room temperature. 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 90 mg (64.8%) of 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2) as a white solid.

[0605] 9. Synthesis of 8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester

[0606]

[0607] Into a 50-mL round-bottom flask, was placed EA (5.0 mL), 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2, 90.0 mg, 0.4 mmol, 1.0 equiv), Pt02 (30.00 mg, 0.1 mmol, 0.4 equiv), and an atmosphere of H2(g) was applied via balloon. The resulting solution was stirred for 1 h at 50 °C. The solids were filtered off. The resulting mixture was concentrated in vacuo. This resulted in 90 mg (99.2%) of 8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-3) as a white solid.

[0608] 10. Synthesis of 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester

[0609]

[0610] To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added dioxane (10.0 mL), H20 (3.0 mL), 3-bromo-8-isopropyl-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid ethyl ester (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), K2CO3(114.6 mg, 0.829 mmol, 3.0 equiv). 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 resulted in 80 mg (80.7%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-5) as a yellow solid.

[0611] 11. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7- carboxylic acid ethyl ester (4-5)

[0612]

[0613] To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added dioxane (10.0 mL), H20 (3.0 mL), 3-bromo-8-isopropyl-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid ethyl ester (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), K2CO3(114.6 mg, 0.829 mmol, 3.0 equiv). 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 resulted in 80 mg (80.7%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-5) as a yellow solid.

[0614] 12. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7- carboxylic acid (4-6)

[0615]

[0616] To a 50-mL round bottom flask was added H20 (1.0 mL), i-PrOH (5.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-5, 80 mg, 0.2 mmol, 1.0 equiv), LiOH.H20 (28.0 mg, 0.7 mmol, 3.0 equiv). The resulting solution was stirred at 50 °C for 2 hours. The solution was pH adjusted to 4 with HC1 (2M). The resulting solution was extracted with 3x20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 60 mg (90%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (4-6) as a white solid.

[0617] 13. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (Compound 175)

[0618]

[0619] To a 50-mL round-bottom flask was added DMA (5.0 mL), 3-(3,5-difluorophenyl)-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (4-6, 60.0 mg, 0.2 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (57.2 mg, 0.4 mmol, 2.1 equiv), HATU (138.0 mg, 0.4 mmol, 2.0 equiv), DIEA (70.0 mg, 0.5 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 1 h. The mixture was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 60:40, increased to H2O:ACN = 10:90 over 25 min; detector, 220 nm. This resulted in 38.6 mg (46.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropyl-2-methylimidazo[l,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).

[0620] Preparation Example 2: The following methods shown in Scheme 5-7 can be used to prepare compound 271 in a manner similar to the methods described in Preparation Example 1:

[0621] Scheme 5

[0622]

[0623] Scheme 6

[0624]

[0625] Scheme 7

[0626]

[0627] The methods of Schemes 3-7 above can be altered according to methods known to those skilled in the art to introduce different functional groups in the core structure. For example, intermediate 3-6 can be reacted with alternative coupling partners to introduce different R 2 substituents. Similarly, intermediates 4-1, 271-1, and 4-4 can be reacted with alternative compounds to introduce different R 1 and R 3 substituents.

[0628] 1. Synthesis of ethyl 1-aminoimidazole-2-carboxylate (3-2)

[0629]

[0630] Into a 5-L round bottom flask was placed DMF (4000.00 mL, 51687.010 mmol, 144.87 eq), ethyl 1H-imidazole-2-carboxylate (50.00 g, 356.781 mmol, 1.00 eq). NaH (21.00 g, 875.083 mmol, 2.45 eq) was then added portionwise over 30 minutes at room temperature. Aminodiphenylphosphinic acid (120.00 g, 514.564 mmol, 1.44 eq) was added portionwise to it at room temperature. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was dried with nitrogen (nitrogen blow dry). The residue was dissolved in 2000 mL of EA. The solids were filtered off. The filtrate was concentrated under vacuum. This resulted in 42 g (75.87%) of ethyl 1-aminoimidazole-2-carboxylate (3-2) as a white solid.

[0631] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3)

[0632]

[0633] Into a 1000-mL round bottom flask was placed DMF (500.00 mL, 6460.876 mmol, 28.64 eq), ethyl 1-aminoimidazole-2-carboxylate (35.00 g, 225.578 mmol, 1.00 eq), Boc20 (73.30 g, 335.858 mmol, 1.49 eq), DMAP (13.78 g, 112.796 mmol, 0.50 eq). 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 with 3 x 500 mL of ethyl acetate, the organic layers were combined and washed with 2 x 500 mL of H20, 1 x 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied onto 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.

[0634] 3. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2- carboxylate (3-4)

[0635]

[0636] Into a 1000-mL round bottom flask was placed DMF (400.00 mL, 5168.701 mmol, 26.39 eq), ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (50.00 g, 195.868 mmol, 1.00 eq), NBS (40.00 g, 0.225 mmol). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of water / ice. The resulting solution was extracted with 3 x 100 mL of ethyl acetate and the organic layers were combined and washed with 2 x 500 mL of H20, 1 x 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied onto 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.

[0637] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropionate (3-5)

[0638]

[0639] Into a 1000-mL 3-necked round-bottom flask, was placed THF (500.00 mL, 6171.495 mmol, 58.92 eq), 4-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2- carboxylate (35.00 g, 104.737 mmol, 1.00 eq), EA (93.50 g, 1061.233 mmol, 10.13 eq). Then t-BuOK (170.00 g, 1514.989 mmol, 14.46 eq) 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 NH4CI (aq). The resulting solution was extracted with 3 x 300 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 500 mL of hexane. The solid was collected by filtration. This resulted in 22 g (55.83%) of 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropanoate (3-5) as a white solid.

[0640] 5. Synthesis of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6)

[0641]

[0642] Into a 100-mL round-bottom flask, was placed DCM (30.00 mL, 471.901 mmol, 27.31 eq), 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoic acid ethyl ester (6.50 g, 17.278 mmol, 1.00 eq), DMF-DMA (5.00 mL, 37.344 mmol, 2.16 eq). 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O (0.1% TFA):ACN = 90:10 increasing to H2O (0.1% TFA):ACN = 50:50 over 15 min; detector, 254 nm. This resulted in 3.3 g (66.76%) of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6) as a white solid.

[0643] 6. Synthesis of 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-7)

[0644]

[0645] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed CHCb (20.00 mL, 247.952 mmol, 18.28 eq), 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3.00 g, 13.561 mmol, 1.00 eq), oxalyl chloride (6.00 g, 47.274 mmol, 3.49 eq), 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 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1) as a yellow solid.

[0646] 7. Synthesis of 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1)

[0647]

[0648] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed CHCb (20.00 mL, 247.952 mmol, 18.28 eq), 8-hydroxy-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3.00 g, 13.561 mmol, 1.00 eq), oxalyl chloride (6.00 g, 47.274 mmol, 3.49 eq), 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 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1) as a yellow solid.

[0649] 8. Synthesis of 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2)

[0650]

[0651] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (30.00 mL, 370.290 mmol, 88.74 equiv), H2O (5.00 mL, 277.542 mmol, 66.52 equiv), ethyl 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylate (1.00 g, 4.173 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (2.11 g, 12.557 mmol, 3.01 equiv), Pd(dtbpf)Cl2 (410.00 mg, 0.629 mmol, 0.15 equiv), K3PO4 (2.66 g, 12.531 mmol, 3.00 equiv). The resulting solution was stirred at 70 °C for 2 h. The resulting mixture was concentrated in vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in 500 mg (48.85%) of ethyl 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylate (4-2) as a yellow oil.

[0652] 9. Synthesis of ethyl 8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylate (4-3)

[0653]

[0654] Into a 50-mL round-bottom flask, was placed EA (5.00 mL, 0.057 mmol, 0.03 equiv), ethyl 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylate (500.00 mg, 2.038 mmol, 1.00 equiv), PtO2 (100.00 mg, 0.440 mmol, 0.22 equiv), to which H2(g) was introduced. The resulting solution was stirred at 50 °C for 2 h. The solids were filtered off. The filtrate was concentrated in vacuum. This resulted in 350 mg (69.43%) of ethyl 8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylate (4-3) as a yellow oil.

[0655] 10. Synthesis of ethyl 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylate (4-4)

[0656]

[0657] Into a 50-mL round-bottom flask, was placed CHCb (5.00 mL, 61.988 mmol, 47.90 equiv), 8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (320.00 mg, 1.294 mmol, 1.00 equiv), 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 onto a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 350 mg (82.92%) of 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-4) as a yellow oil.

[0658] 11. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-2)

[0659]

[0660] Into an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (1.00 mL, 12.343 mmol, 44.74 equiv), H20 (0.20 mL, 11.102 mmol, 40.24 equiv), 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (90.00 mg, 0.276 mmol, 1.00 equiv), 3,5-dichlorophenylboronic acid (53.17 mg, 0.279 mmol, 1.01 equiv), Pd(dtbpf)Cl2(17.98 mg, 0.028 mmol, 0.10 equiv), K2CO3(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 in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 70 mg (64.67%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-2) as a colorless oil.

[0661] 12. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (271-3)

[0662]

[0663] To a 50-mL round-bottom flask, was added H20 (0.50 mL, 27.754 mmol, 155.53 equiv), EtOH (2.00 mL, 0.043 mmol, 0.24 equiv), 3-(3,5-dichlorophenyl)-8-isopropyl-2- methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (70.00 mg, 0.178 mmol, 1.00 equiv), LiOH.H20 (22.50 mg, 0.536 mmol, 3.00 equiv). The resulting solution was stirred at room temperature for 1 hour. The solution was pH adjusted to 5 with HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 50 mg (76.93%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (271-3) as a yellow oil.

[0664] Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (Compound 271)

[0665]

[0666] To a 50-mL round-bottom flask, was added DMA (1.00 mL, 10.755 mmol, 87.05 equiv), 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (45.00 mg, 0.124 mmol, 1.00 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (29.30 mg, 0.196 mmol, 1.59 equiv), HATU (93.90 mg, 0.247 mmol, 2.00 equiv), DIEA (47.80 mg, 0.370 mmol, 2.99 equiv). The resulting solution was stirred at room temperature for 1 hour. The crude mixture was purified by Flash-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H20 (0.1% NH3.H20):ACN = 50:50, increasing to H20 (0.1% NH3.H20):ACN = 10:90 over 20 minutes; detector, 254 nm. This resulted in 42.2 mg (68.95%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2- methylimidazo[l,2-b]pyridazine-7-carboxamide (271) as a white solid.

[0667] 1 H NMR (300 MHz, CDC13, 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, 3H), 2.44-2.41 (m, 1H), 2.26-2.22 (m, 1H), 1.65 (t, J = 6.7 Hz, 6H); (ES, m / z): 495 [M+H] + .

[0668] As described above, the following compounds can be prepared according to Schemes 3 to 7:

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677] Preparation Example 3: Example compounds A400, A401, A405, and A459 were prepared according to Scheme 8, with reactions adapted from known reactions sourced 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.

[0678] Scheme 8

[0679]

[0680] Description of key steps: synthesis of 3-(3,5-dichlorophenyl)-8-(4,4- difluorocyclohexyl)-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (8-6)

[0681]

[0682] A mixture of 90 mg (0.3 mmol) of 3-(3,5-dichlorophenyl)-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid methyl ester (8-5) in 5 mL of DMSO was treated with 200 mg (1.0 mmol) of zinc sulfite and the solution was cooled with an ice bath. 185 μL (1 mmol) of 2-methyl-propan-2-yl-hydroperoxide (TBHP) was added dropwise and the reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with a sodium carbonate solution and extracted with EE. The organic layer was collected, dried, filtered and evaporated. The mixture was evaporated, purified by column chromatography (silica gel; CyH / EtOAc), and the solvent was removed under vacuum 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, 1H) 8.52 (s, 1H) 7.76 (d, J = 1.77 Hz, 2H) 7.66 - 7.71 (m, 1H) 7.39 (d, J = 7.35 Hz, 1H) 7.18 (t, J = 7.73 Hz, 1H) 6.89 - 6.95 (m, 1H) 6.80 (d, J = 8.11 Hz, 1H) 5.23 - 5.30 (m, 1H) 4.18 - 4.33 (m, 2H) 2.61 - 2.80 (m, 3H) 2.53 (s, 3H) 2.30 - 2.39 (m, 1H) 2.09 - 2.30 (m, 3H) 1.73 - 1.94 (m, 4H).

[0683] The conversion of compound 8-6 to the product can be achieved as shown in Scheme 4 by hydrolysis of the methyl ester to the carboxylic acid and subsequent coupling of the acid with the desired amine.

[0684] As described above, compounds A400, A401 and A405 were prepared by employing the methods described in Scheme 8.

[0685]

[0686]

[0687] Preparation of Example 4: Example 304-0 was prepared according to the following Scheme 9. Similarly, compound 321 can be prepared by the same means by one skilled in the art.

[0688] Scheme 9

[0689]

[0690] 1. Synthesis of 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-2)

[0691]

[0692] To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-2, 2.0 g, 5.7 mmol, 1.0 equiv), CHCI3(25.0 mL), POBr3(8.14 g, 28.4 mmol, 5.0 equiv). The resulting solution was stirred at 80 °C for 1 night. 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 with 3 x 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 :10). This resulted in 810 mg (34.4%) of 8-bromo-2-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-3) as an off-white solid. (ES, m / z): 414 [M+H] + .

[0693] 2. Synthesis of 8-bromo-2-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-3)

[0694]

[0695] To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-2, 2.0 g, 5.7 mmol, 1.0 equiv), CHCI3(25.0 mL), POBr3(8.14 g, 28.4 mmol, 5.0 equiv). The resulting solution was stirred at 80 °C for 1 night. 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 with 3 x 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 :10). This resulted in 810 mg (34.4%) of 8-bromo-2-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-3) as an off-white solid. (ES, m / z): 414 [M+H] + .

[0696] 3. Synthesis of 2-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-4)

[0697]

[0698] To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of N2, was added 8-bromo-2-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-3, 1800.0 mg, 4.4 mmol, 1.0 equiv), K3PO4 (2761.5 mg, 13.0 mmol, 3.0 equiv), THF (20.0 mL), H2O (5.0 mL), Pd(dtbpf)Cl2 (282.6 mg, 0.4 mmol, 0.1 equiv), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,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 with 3 x 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 2-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-4) as an off-white solid. (ES, m / z): 376 [M+H] + .

[0699] 4. Synthesis of 2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-5)

[0700]

[0701] To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of H2(g), was added 2-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-4, 500.0 mg, 1.3 mmol, 1.0 equiv), EA (10.0 mL), 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 2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester as an off-white solid (9-5). (ES, m / z): 378 [M+H] + .

[0702] 5. Synthesis of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-6)

[0703]

[0704] Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-6, 95.0 mg, 0.2 mmol, 1.0 equiv), THF (5.0 mL), H2O (1.0 mL), LiOH (27.6 mg, 1.2 mmol, 5.0 equiv). The resulting solution was stirred at room temperature for 1 night. The solution was adjusted to pH 3-4 with HC1 (1 mol / L). The resulting solution was extracted with 3 x 10 mL of ethyl acetate and the organic layers combined. The organic phase was dried over the oven under reduced pressure and concentrated. This resulted in 78 mg (88.1%) of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (9-7) as an off-white solid. (ES, m / z): 384 [M+H] + .

[0705] 6. Synthesis of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (9-7)

[0706]

[0707] Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (9-6, 95.0 mg, 0.2 mmol, 1.0 equiv), THF (5.0 mL), H2O (1.0 mL), LiOH (27.6 mg, 1.2 mmol, 5.0 equiv). The resulting solution was stirred at room temperature for 1 night. The solution was adjusted to pH 3-4 with HC1 (1 mol / L). The resulting solution was extracted with 3 x 10 mL of ethyl acetate and the organic layers combined. The organic phase was dried over the oven under reduced pressure and concentrated. This resulted in 78 mg (88.1%) of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (9-7) as an off-white solid. (ES, m / z): 384 [M+H] + .

[0708] 7. Synthesis of 3-chloro-2-(3,5-dichlorophenyl)-N-[(4S)-6-fluoro-3,4-dihydro-2H-1- chromen-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (Compound 304-0)

[0709]

[0710] To a 20-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was added (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), DIEA (45.7 mg, 0.35 mmol, 2.0 equiv), HATU (100.8 mg, 0.3 mmol, 1.5 equiv). The resulting solution was stirred for 1 night at room temperature. The crude product was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): Column, C18 silica gel; Mobile Phase, ACN:H2O = 72 increasing to ACN:H2O = 95 in 7 min; 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- chromen-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (304-0) as an off-white solid. (300 MHz, CDC13, 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).

[0711] Compound 321 : (300 MHz, chloroform-d, ppm): δ 8.27 (s, 1 H), 7.76-7.60 (m, 2H), 7.35-7.30 (m, 1 H), 7.28-7.20 (m, 1 H), 7.20-7.03 (m, 4H), 7.03-6.80 (m, 3H), 6.20-5.90 (m, 1 H), 5.50-5.25 (m, 1 H), 4.45-4.30 (m, 1 H), 4.30-4.10 (m, 1 H), 3.80-3.65 (m, 1 H), 2.55-2.35 (m, 1 H), 2.33-2.15 (m, 1 H), 1.72 (t, J = 6.3 Hz, 6H)

[0712] Preparation Example 5: Example 174 was prepared according to Scheme 10:

[0713] Scheme 10

[0714]

[0715] 1. Synthesis of N-(5-chloropyridazin-3-yl)-1,1 -diphenylmethanamine (10-2)

[0716]

[0717] Into an inert atmosphere 40-mL round-bottom flask purged and maintained with nitrogen, was placed 3,5-dichloropyridazine (10-1, 500.0 mg, 3.4 mmol, 1.0 equiv), diphenylmethanamine (675.2 mg, 3.7 mmol, 1.1 equiv), XantPhos (69.9 mg, 0.12 mmol, 0.04 equiv), Pd2(dba)3(34.7 mg, 0.06 mmol, 0.02 equiv), Cs2CO3(2187.1 mg, 6.7 mmol, 2.0 equiv), dioxane (5 ml). The resulting solution was stirred at 90 °C in an oil bath 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 -diphenylmethanamine (10-2) as a brown oil.

[0718] 2. Synthesis of 5-chloropyridazin-3-amine

[0719]

[0720] Into a 50-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanamine (10-2, 10.0 mL), HC1 (3 M) (15.0 mL). The resulting solution was stirred at room temperature for 1 hour. The solution was pH adjusted to 7 with NaHC03. The resulting mixture was concentrated. This resulted in 15 mL of 5-chloropyridazin-3-amine (5-1) as a brown oil.

[0721] 3. Synthesis of 7-chloroimidazo[1,2-b]pyridazine (10-4)

[0722]

[0723] Into a 250-mL round bottom flask was placed 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H20 (17.5 mL), i-PrOH (25 mL). The resulting solution was stirred at 95 °C in an oil bath for 5 hours. The resulting mixture was concentrated. The solution was pH adjusted to 9 with NaOH. The resulting solution was extracted with 3 x 50 mL of ethyl acetate, the organic layer was washed with 3 x 50 mL of brine. The organic phase was collected and 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.

[0724] 4. Synthesis of 7-chloro-3-iodoimidazo[1,2-b]pyridazine (10-5)

[0725]

[0726] Into a 50-mL round bottom flask was placed 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), DMF (10 mL). The resulting solution was stirred at room temperature for 1 night. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 x 20 mL of ethyl acetate and concentrated. 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.

[0727] 5. Synthesis of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6)

[0728]

[0729] Into a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 7-chloro-3-iodoimidazo[l,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), H2O (2.5 mL). The resulting solution was stirred at room temperature for 1 hour overnight. The resulting mixture was concentrated. The residue was applied onto 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[l,2-b]pyridazine (10-6) as a white solid.

[0730] 6. Synthesis of methyl 3-(2,6-difluorophenyl)imidazo[l,2-b]pyridazine-7-carboxylate (10-7)

[0731]

[0732] Into a 50-mL pressure tank reactor, was placed 7-chloro-3-(2,6-difluorophenyl)imidazo[l,2-b]pyridazine (10-6) 130.0 mg, 0.5 mmol, 1.0 equiv), Pd(dppf)Cl2(35.8 mg, 0.05 mmol, 0.1 equiv), TEA (148.6 mg, 1.5 mmol, 3.0 equiv), CO (20 atm), MeOH (10.00 mL). The resulting solution was stirred at 110 °C in an oil bath for 4 hours. The resulting mixture was concentrated. The residue was applied onto 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[l,2-b]pyridazine-7-carboxylate (10-7) as a white solid.

[0733] 7. Synthesis of 3-(2,6-difluorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid (10-8)

[0734]

[0735] Into a 40-mL round-bottom flask, was placed methyl 3-(2,6-difluorophenyl)- imidazo[l,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), H20 (3 mL). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 20 mL of water. The solution was adjusted to pH 3-4 with HC1 (3 mol / L). The resulting solution was extracted with 3x20 mL of ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate and concentrated. This resulted in 65 mg (80.4%) of 3-(2,6-difluorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid (10-8) as a white solid.

[0736] 8. Synthesis of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]imidazo[l,2- b]pyridazine-7-carboxamide (Compound 174)

[0737]

[0738] To a 40-mL round-bottom flask was added 3-(2,6-difluorophenyl)imidazo[l,2- b]pyridazine-7-carboxylic acid (10-8, 60.0 mg, 0.2 mmol, 1.0 equiv), (4S)-3,4- dihydro-2H-l-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), DMF (3 mL). The resulting solution was stirred at room temperature for 2 hours. The crude product was purified by Prep-HPLC using the following conditions (Waters-2767): Column, X-bridge RP18, 5um, 19*100mm; Mobile phase, 0.03% ammonia and CH3CN (30% CH3CN up to 70% in 15 min); Detector, UV 254 nm. This resulted in 19.4 mg (21.9%) of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]imidazo[l,2- b]pyridazine-7-carboxamide (174) as a white solid. (300 MHz, CDC13, 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).

[0739] Preparation Example 6: Example 277 was prepared according to the following Scheme 11:

[0740] Scheme 11

[0741]

[0742] 1. Synthesis of 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1)

[0743]

[0744] Into a 100-mL round-bottom flask, was placed 8-hydroxy-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid ethyl ester (3-7, 2.8 g, 12.6 mmol, 1.0 equiv), DMF (8.0 uL, 103.4 mmol, 8.2 equiv), CHCl3(55.0 mL). Subsequently, (COCl)2(8.0 g, 63.1 mmol, 5.0 equiv) was added dropwise at room temperature under stirring. 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% aqueous FA and CH3CN (10% CH3CN increased to 70% over 12 min). Detector, UV 254 nm, 220 nm. This resulted in 537 mg (17.2%) of 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1) as a yellow solid.

[0745] 2. Synthesis of 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2)

[0746]

[0747] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 8-chloro-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (271-1, 480.0 mg, 2.0 mmol, 1.0 equiv), dioxane (19.0 mL), H2O (4.8 mL), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (673.1 mg, 4.0 mmol, 2.0 equiv), Pd(dtbpf)Cl2(130.5 mg, 0.20 mmol, 0.1 equiv), K2CO3(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 with 2 x 20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 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 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2) as a brown solid.

[0748] 3. Synthesis of 3-bromo-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (11-4)

[0749]

[0750] To a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2, 370.0 mg, 1.5 mmol, 1.0 equiv), CHCI3(7.0 mL, 86.8 mmol), 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 with 2x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2x20 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated. This resulted in 491 mg (95.4%) of 3-bromo-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (11-4) as a brown solid.

[0751] 4. Synthesis of 3-(3,5-difluorophenyl)-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (11-5)

[0752]

[0753] To a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added 2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-2, 370.0 mg, 1.5 mmol, 1.0 equiv), CHCI3(7.0 mL, 86.8 mmol), 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 with 2x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2x20 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated. This resulted in 491 mg (95.4%) of 3-bromo-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (11-4) as a brown solid.

[0754] 5. Synthesis of 3-(3,5-difluorophenyl)-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (11-6)

[0755]

[0756] To a 50-mL 3-necked round-bottom flask, was added 3-(3,5-difluorophenyl)-2- methyl-8-(prop-1-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (11-5, 440.0 mg, 1.2 mmol, 1.0 equiv), i-PrOH (15.0 mL), H2O (8.0 mL), LiOH.H2O (155.0 mg, 3.7 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The solution was adjusted to pH 3 with HC1 (2 mol / L). The resulting solution was extracted with 2 x 20 mL of ethyl acetate, the organic layers were combined and 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[l,2-b]pyridazine-7- carboxylic acid (11-6) as a yellow solid.

[0757] 6. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-2- methyl-8-(prop-1-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxamide (11-7)

[0758]

[0759] To a 50-mL 3-necked round-bottom flask, was added 3-(3,5-difluorophenyl)-2- methyl-8-(prop-1-en-2-yl)imidazo[l,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-l-benzopyran-4-amine (362.4 mg, 2.4 mmol, 2.0 equiv), DIEA (471.0 mg, 3.6 mmol, 3.0 equiv), HATU (692.8 mg, 1.8 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 2 hours. The crude product was purified by Prep-Flash using the following conditions: column, C18 silica gel; mobile phase, 0.1% NH4HCO3 in water and CH3CN (30% CH3CN increasing to 80% over 10 minutes). Detector, UV 254 nm, 220 nm. This resulted in 520 mg (92.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-2- methyl-8-(prop-1-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxamide (11-7) as a green solid.

[0760] 7. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8- (2-hydroxypropan-2-yl)-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (11-8)

[0761]

[0762] Into a 50-mL 3-necked round-bottom flask, was placed 3-(3,5-difluorophenyl)-N-[(4S)- 3,4-dihydro-2H-l-benzopyran-4-yl]-2-methyl-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7- carboxamide (11-7, 200.0 mg, 0.4 mmol, 1.0 equiv), ethanol (8.0 mL), toluene (8.0 mL), NaBH4(32.9 mg, 0.9 mmol, 2.0 equiv), Mn(OAc)3.2H2O (9.3 mg, 0.03 mmol, 0.08 equiv), 2-[(lE)-([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 into it. The resulting solution was stirred at room temperature for 4 hours. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2x20 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 2x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 250 mg (crude) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-(2- hydroxypropan-2-yl)-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (11-8) as a yellow oil.

[0763] 8. Synthesis of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-(2- fluoroprop-2-yl)-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (Compound 277)

[0764]

[0765] Into a 25-mL 3-necked round-bottom flask, was placed 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), DCM (10.0 mL). Subsequently, DAST (134.7 mg, 0.8 mmol, 2.0 equiv) was added dropwise at room temperature with stirring. The resulting solution was stirred at room temperature for 1 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% aqueous TFA and CH3CN (50% CH3CN increasing to 100% over 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, CDC13, 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).

[0766] Preparation 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 method shown in Scheme 12 below.

[0767] Scheme 12

[0768]

[0769] 1. Synthesis of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-2)

[0770]

[0771] To a stirred mixture of 8-bromo-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-1, 30.0 g, 105.6 mmol, 1.0 eq) in THF (750.00 mL) was added LiBr (6.9 g, 791.9 mmol, 7.5 eq) at 0 °C under nitrogen atmosphere. To the above mixture was added CuI (150.8 g, 791.9 mmol, 7.5 eq) portion wise at 0 °C over a period of 30 min. The resulting mixture was stirred at 0 °C for another 30 min. To the above mixture was added tert-butyl(magnesium chloride) (310.5 mL, 527.9 mmol, 5.0 eq) drop wise at 0 °C over a period of 1 h. The resulting mixture was stirred at 0 °C for another 5 min. The reaction was quenched by the addition of saturated NH4C1 (aqueous) (400 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 800 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture 8-tert-butyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-2, 33 g, crude) was used as such for the next step without further purification.

[0772] 2. Synthesis of 3-bromo-8-tert-butyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-3)

[0773]

[0774] To a stirred solution of 8-tert-butyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-2, 28.0 g, 107.1 mmol, 1.0 eq) in CHCI3 (300.0 mL) was added NBS (19.0 g, 107.1 mmol, 1.0 eq) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3: 1) to afford 3-bromo-8-tert-butyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-3, 29.5 g, 80.9%) as a yellow solid.

[0775] 8-tert-Butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-4) synthesis

[0776]

[0777] To a stirred mixture of 3-bromo-8-tert-butyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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 H2O (60.0 mL) was added K2CO3 (31.7 g, 229.2 mmol, 3.0 equiv) and Pd(dtbpf)Cl2 (4980.7 mg, 7.6 mmol, 0.1 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (800 mL). The resulting mixture was extracted with EtOAc (2 x 800 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. 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 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (12-4, 19 g, 61.2%) as off-white solid.

[0778] 3. Synthesis of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (12-5)

[0779]

[0780] To a 250-mL round bottom flask was added 8-tert-butyl-3-(3,5-dichlorophenyl)-2- methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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), H2O (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 solution was adjusted to pH 4 with HC1 (2 mol / L). The solid was collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (12-5, 18 g, crude) as off-white solid.

[0781] 4. Synthesis of 8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1- chromen-4-yl]-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (Compound 306)

[0782]

[0783] To a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid (12-5, 17.0 g, 44.9 mmol, 1.0 equiv) and (4S)-3,4- dihydro-2H-l-chromen-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 h. The reaction mixture was added dropwise to 300 mL of H2O. The precipitated solid was collected by filtration and washed with water (2 x 20 mL). The residue was dissolved in MeCN (200 mL). Then 800 mL of H2O was added dropwise. The precipitated solid was collected by filtration. The resulting solid was dried under an infrared lamp to give 8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-chromen-4-yl]-2- methylimidazo[l,2-b]pyridazine-7-carboxamide (306, 17.2 g, 75.1%) as a light green solid. (300 MHz, CDC13, 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)

[0784]

[0785]

[0786]

[0787] Preparation Example 8: The following compounds can be synthesized by employing the method shown in Scheme 13 below: 320, 320-0, 513, 513-0, 514, 514-0.

[0788] Scheme 13

[0789]

[0790] 1. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7- carboxylic acid ethyl ester (4-5)

[0791]

[0792] To a 40-mL round-bottom flask was added THF (5.0 mL), H2O (1.0 mL, 0.06 mmol, 0.18 equiv), 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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)Cl2 (20.0 mg, 0.03 mmol, 0.1 equiv), K2CO3 (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 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-5) as a white solid.

[0793] 2. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7- carboxylic acid (4-6)

[0794]

[0795] Into a 40-mL round-bottom flask, was placed H2O (1.0 mL), EtOH (5.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-5, 90.0 mg, 0.25 mmol, 1.0 equiv), 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 using HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 70 mg (84.4%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (4-6) as a white solid.

[0796] 3. Synthesis of tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7- yl]carbamate (13-1)

[0797]

[0798] Into a 40-mL round-bottom flask, was placed 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[l,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), TEA (24.0 mg, 0.2 mmol, 1.1 equiv). The resulting solution was stirred at 50 °C for 3 h. The mixture was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 90:10 increasing to H2O:ACN = 20:80 over 15 min; detector, 254 nm. This resulted in 65 mg (76.4%) of tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7-yl]carbamate (13-1) as a white solid.

[0799] 4. Synthesis of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-amine (13-2)

[0800]

[0801] To a 50-mL round-bottom flask, was added 1,4-dioxane (4 M, 5.00 mL) with HC1 (gas), tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7- yl]carbamate (13-1, 65.0 mg, 0.2 mmol, 1.0 equiv). 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[l,2-b]pyridazin-7-amine (13-2) as a white solid.

[0802] 5. Synthesis of (4S)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7-yl]-3,4-dihydro-2H-l-benzopyran-4-carboxamide and (4R)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7-yl]-3,4-dihydro-2H-l-benzopyran-4-carboxamide (320 and 320-0)

[0803]

[0804] To a 50-mL round-bottom flask, was added DCM (2.0 mL), 3-(3,5-difluorophenyl)-8- isopropyl-2-methylimidazo[l,2-b]pyridazin-7-amine (13-2, 25.0 mg, 0.08 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-carboxylic acid chloride (50.0 mg, 0.2 mmol, 3.0 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50 increasing to H2O:ACN = 10:90 over 20 min; detector, 254 nm. This resulted in 9.3 mg (24.3%) of (4S)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7-yl]-3,4-dihydro-2H-l-benzopyran-4-carboxamide (320) as a white solid; and 11 mg (26.0%) of (4R)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[l,2-b]pyridazin-7-yl]-3,4-dihydro-2H-l-benzopyran-4-carboxamide (320-0). The purity of 320 was 99.0% by HPLC. 1HNMR: (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 (br s, 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 of 1 HNMR: (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 (br s, 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 of

[0805]

[0806] Preparation Example 9: Synthesis of compounds 323 and 323-0 was carried out according to the method shown in the following Scheme 14.

[0807] Scheme 14

[0808]

[0809] 1. Synthesis of 3-tert-butyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (14-2a) and 3-isobutyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (14-2b)

[0810]

[0811] To an 8-mL round-bottom flask, was added THF (3.0 mL), 3-bromo-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-4, 100.0 mg, 0.3 mmol, 1.00 equiv), di-tert-butylzinc (4.0 mL, 2.0 mmol, 6.5 equiv), Pd(PPh3)4 (40.0 mg, 0.03 mmol, 0.1 equiv). The resulting solution was stirred at 80 °C for 1 night. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 20 mg (mixture) of 3-tert-butyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (14-2a) and 3-isobutyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (14-2b) as white solids.

[0812] 2. Synthesis of 3-tert-butyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (14-3b)

[0813]

[0814] To a 50-mL round-bottom flask, was added H2O (1.0 mL), EtOH (5.0 mL), a mixture of 3-tert-butyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester and 3-isobutyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ester (a mixture of 14-2a and 14-2b, 20.0 mg, 0.06 mmol, 1.00 equiv), NaOH (40.0 mg, 1.00 mmol, 15.2 equiv). The resulting solution was stirred at 80 °C for 2 hours. The pH was adjusted to 4 using HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, concentrated in vacuo. This resulted in 12 mg (mixture) of 3-tert-butyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (14-3b) as white solids.

[0815] 3. Synthesis of 3-tert-butyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-carboxamide (323) and N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-3-(2-methylpropyl)-8-(propyl-2-yl)imidazo[1,2-b]pyridazin-7-carboxamide (323-0)

[0816]

[0817] Add DMF (1.0 mL, 12.9 mmol, 237.2 equivalents), a mixture of 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 equivalents), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (10.0 mg, 0.06 mmol, 1.2 equivalents), HATU (35.0 mg, 0.09 mmol, 1.7 equivalents), and DIEA (17.0 mg, 0.1 mmol, 2.4 equivalents) to a 50-mL round-bottom flask. Stir the resulting solution at room temperature for 1 hour. The crude product was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50, increased to H2O:ACN = 10:90 over 20 minutes; detector, 254 nm. The product was obtained. Thus, 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]pyridazin-7-carboxamide (323) was obtained 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-(propyl-2-yl)imidazo[1,2-b]pyridazin-7-carboxamide (323-0). 1H 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-.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); 323-0 of 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-.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); 323-0 of

[0818] Preparation Example 10: Compound 324 can be synthesized by the method shown in Scheme 15 below. Similarly, compounds 325, 369, 372-0, 373 are prepared by similar methods by those skilled in the art.

[0819] Scheme 15

[0820]

[0821] 1. Synthesis of ethyl 8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7- carboxylate (15-1)

[0822]

[0823] Into an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (4-4, 70.0 mg, 0.2 mmol, 1.0 equiv), piperidine (120.0 mg, 1.4 mmol, 6.6 equiv), Pd2(dba)3(35.0 mg, 0.04 mmol, 0.2 equiv), BINAP (38.0 mg, 0.06 mmol, 0.3 equiv), Cs2CO3(200.0 mg, 0.6 mmol, 2.9 equiv) in toluene (2.0 mL). The resulting solution was stirred at 120 °C for 2 h. The resulting mixture was concentrated in vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 60 mg (84.6%) of 8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (15-1) as a yellow solid.

[0824] 2. Synthesis of 8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (15-2)

[0825]

[0826] Into a 50-mL round-bottom flask was placed i-PrOH (1.0 mL, 0.02 mmol), THF (1.0 mL), H2O (1.0 mL), 8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (15-1, 70.0 mg, 0.2 mmol, 1.0 equiv), LiOH.H2O (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 using HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuum. This resulted in 60 mg (93.7%) of 8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (15-2) as a yellow solid.

[0827] 3. Synthesis of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3-(piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxamide (324)

[0828]

[0829] To a 50-mL round-bottom flask was added DMA (3.0 mL), 8-isopropyl-2-methyl-3- (piperidin-l-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (15-2, 60.0 mg, 0.2 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (44.0 mg, 0.3 mmol, 1.5 equiv), HATU (113.0 mg, 0.3 mmol, 1.5 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50 increasing to H2O:ACN = 10:90 over 20 min; detector, 254 nm. This resulted in 36.4 mg (42.3%) of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3- (piperidin-l-yl)imidazo[l,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).

[0830]

[0831]

[0832] Preparation Example 11: Compounds 327, 326, 326-0, 365, 370, 371 can be prepared by the method shown in Scheme 16 below:

[0833] Scheme 16

[0834]

[0835]

[0836] 1. Synthesis of 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1- yl]imidazo[1,2-b]pyridazine-7-carboxylic acid ethyl ester (16-1)

[0837]

[0838] To a 8-mL round-bottom flask was added dioxane (2.0 mL), H2O (0.4 mL), 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid ethyl ester (4-4, 100.00 mg, 0.3 mmol, 1.0 equiv), 4-(trifluoromethyl)cyclohex-1-en-1-yl boronic acid (120.0 mg, 0.6 mmol, 2.0 equiv), Pd(dtbpf)Cl2 (20.0 mg, 0.03 mmol, 0.1 equiv), K2CO3 (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 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid ethyl ester (16-1) as a yellow solid.

[0839] 2. Synthesis of 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1- yl]imidazo[1,2-b]pyridazine-7-carboxylic acid (16-2)

[0840]

[0841] To a 50-mL round-bottom flask was added i-PrOH (2.0 mL), THF (2.0 mL), H2O (1.0 mL), 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid ethyl ester (16-1, 110.0 mg, 0.3 mmol, 1.0 equiv), LiOH (70.0 mg, 2.9 mmol, 10.5 equiv). The resulting solution was stirred at 50 °C for 1 h. The solution was adjusted to pH 4 with HCl (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. 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.

[0842] 3. Synthesis of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4- (trifluoromethyl)cyclohex-l-en-l-yl]imidazo[l,2-b]pyridazine-7-carboxamide (327)

[0843]

[0844] To a 40-mL round bottom flask was added DMF (5.0 mL), 8-isopropyl-2-methyl-3-[4- (trifluoromethyl)cyclohex-l-en-l-yl]imidazo[l,2-b]pyridazine-7-carboxylic acid (16-2, 130.0 mg, 0.3 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (79.2 mg, 0.5 mmol, 1.5 equiv), HATU (200.5 mg, 0.5 mmol, 1.5 equiv), DIEA (137.2 mg, 1.0 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50 increasing to H2O:ACN = 10:90 over 20 minutes; detector, 254 nm. This resulted in 130 mg (73.7%) of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4- (trifluoromethyl)cyclohex-l-en-l-yl]imidazo[l,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).

[0845] 4. Synthesis of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[(lr,4r)-4- (trifluoromethyl)cyclohexyl]imidazo[l,2-b]pyridazine-7-carboxamide and N-((S)-chroman-4-yl)-8- isopropyl-2-methyl-3-((ls,4R)-4-(trifluoromethyl)cyclohexyl)imidazo[l,2-b]pyridazine-7- carboxamide (326 and 326-0)

[0846]

[0847] To a 50-mL round bottom flask was added EA (5.0 mL), N-[(4S)-3,4-dihydro-2H-l- benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-l-en-l-yl]imidazo[l,2- b]pyridazine-7-carboxamide (327, 50.0 mg, 0.10 mmol, 1.0 equiv), aqueous Pd / C (50.0 mg). To this was introduced H2(g) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The solids were filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H20:ACN = 50:50 increasing to H20:ACN = 10:90 over 20 minutes; detector, 254 nm. The racemic product was purified as follows, column: XA-YMC Cellulose-SC, 4.6*100 mm, 3 um; mobile phase A / mobile phase B: n-hexane / EtOH = 70 / 30; flow rate: 1 mL / min; gradient: 30B to 30B, 10 minutes; 254 nm; injection volume: 1 ml; thereby affording 19.3 mg (38.4%) of N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[(lr,4r)-4- (trifluoromethyl)cyclohexyl]imidazo[l,2-b]pyridazine-7-carboxamide as a white solid, and 8.0 mg (15.8%) of N-((S)-chroman-4-yl)-8-isopropyl-2-methyl-3-((ls,4R)-4- (trifluoromethyl)cyclohexyl)imidazo[l,2-b]pyridazine-7-carboxamide as a white solid (326 and 326-0). The stereochemistry is assumed. Description of the stereochemistry of 326 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 (br s, 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 of 1 H 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 (br s, 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 of

[0848]

[0849]

[0850] Preparation Example 12: Compound 352 was prepared according to the method shown in Scheme 17 below:

[0851] Scheme 17

[0852]

[0853] 1. Synthesis of 3-[5-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropanoic acid ethyl ester (17-2)

[0854]

[0855] To a 1000-mL round bottom flask was added THF (85.0 g, 1178.8 mmol, 26.3 eq), 5-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (17-1, 15.0 g, 44.9 mmol, 1.0 eq), ethyl acetate (50.0 g, 567.5 mmol, 12.6 eq). Then t-BuOK (500 mL) was added portionwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. Then the reaction was quenched by adding NH4Cl (aq). The resulting solution was extracted with 3 x 200 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). This resulted in 13 g (77.0%) of 3-[5-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropionic acid ethyl ester (17-2) as a colorless oil.

[0856] 2. Synthesis of 3-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-3)

[0857]

[0858] To a 500-mL round bottom flask was added DCM (100.0 mL, 1573.0 mmol, 59.2 eq), 3-[5-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropionic acid ethyl ester (17-2, 10.0 g, 26.6 mmol, 1.0 eq), DMF-DMA (9.0 g, 75.5 mmol, 2.8 eq). The resulting solution was stirred at 40 °C for 2 h. Then the reaction was quenched by adding water / ice. The resulting solution was extracted with 2 x 100 mL of MTBE and the aqueous layers were combined. The solution was adjusted to pH 4 with HC1 (4 mol / L). The solids were collected by filtration. This resulted in 5 g (65.7%) of 3-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-3) as a white solid.

[0859] 3. Synthesis of 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-4)

[0860]

[0861] Into a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed H20 (1.0 mL), NMP (5.0 mL), 3-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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)Cl2 (70.0 mg, 0.1 mmol, 0.08 equiv), Cs2CO3 (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, then 5 ml H2O was added. The solid was collected by filtration. This resulted in 300 mg (crude) of 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-4) as a yellow solid.

[0862] 4. Synthesis of 8-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-5)

[0863]

[0864] Into a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed CHCl3 (5.0 mL, 0.04 mmol, 0.07 equiv), DMF (15.0 mg, 0.2 mmol, 0.4 equiv), 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-4, 200.0 mg, 0.6 mmol, 1.0 equiv), (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 with 10 x 10 mL of ACN:H2O = 1 : 1. The solid was collected by filtration. This resulted in 110 mg (52.3%) of 8-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-5) as a yellow solid.

[0865] 5. Synthesis of 3-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-6)

[0866]

[0867] Into a 40-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed H20 (1.00 mL, 55.5 mmol, 187.0 equiv), THF (5.0 mL, 61.7 mmol, 207.9 equiv), 8-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-5, 110.0 mg, 0.3 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (72.0 mg, 0.43 mmol, 1.4 equiv), Pd(dtbpf)Cl2 (40.0 mg, 0.06 mmol, 0.2 equiv), K2CO3 (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 3-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-6) as a yellow solid.

[0868] 6. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-7)

[0869]

[0870] Into a 50-mL round-bottom flask was placed EA (5.0 mL), 3-(3,5-dichlorophenyl)-8-(prop-l-en-2-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-6, 80.0 mg, 0.21 mmol, 1.0 equiv), PtO2 (40.0 mg, 0.2 mmol, 0.8 equiv). H2(g) was introduced to it with a balloon. The resulting solution was stirred at 50 °C for 1 h. The solid was collected by filtration. The resulting mixture was concentrated in vacuo. This resulted in 60 mg of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-7) as a yellow solid.

[0871] 7. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (17-8)

[0872]

[0873] To an 8-mL round bottom flask was added EtOH (2.0 mL), H2O (0.50 mL), 3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-7, 60.0 mg, 0.2 mmol, 1.0 equiv), 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 solution was pH adjusted to 4 with HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 40 mg (72.0%) of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (17-8) as a white solid.

[0874] 8. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropylimidazo[l,2-b]pyridazine-7-carboxamide (352)

[0875]

[0876] To an 8-mL round bottom flask was added DMF (4.0 mL), 3-(3,5-dichlorophenyl)-8- isopropylimidazo[l,2-b]pyridazine-7-carboxylic acid (17-8, 40.0 mg, 0.1 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (22.0 mg, 0.15 mmol, 1.3 equiv), HATU (70.0 mg, 0.2 mmol, 1.6 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50 increasing to H2O:ACN = 10:90 over 20 min; detector, 254 nm. This resulted in 15.9 mg (28.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropylimidazo[l,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).

[0877] Preparation Example 13: Compound 366 was prepared according to Scheme 18 shown below:

[0878] Scheme 18

[0879]

[0880] 1. Synthesis of 3-cyano-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester

[0881]

[0882] Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DMAC (5.0 mL), 3-bromo-8-isopropyl-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid ethyl ester (4-4, 100.0 mg, 0.3 mmol, 1.0 equiv), dppf (59.3 mg, 0.1 mmol, 0.3 equiv), Zn(CN)2(100.1 mg, 0.8 mmol, 2.8 equiv), Pd2(dba)3(50.5 mg, 0.05 mmol, 0.2 equiv), 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 with 3 x 20 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 :5). This resulted in 40 mg (47.9%) of 3-cyano-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (18-1) as a yellow oil.

[0883] 2. Synthesis of 3-cyano-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (18-2)

[0884]

[0885] Into an 8-mL round-bottom flask was placed EtOH (1.0 mL), H2O (0.5 mL), 3-cyano-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (18-1, 40.0 mg, 0.15 mmol, 1.0 equiv), LiOH (30.0 mg, 1.2 mmol, 8.5 equiv). The resulting solution was stirred at room temperature for 1 h. The solution was pH adjusted to 4 with HC1 (4 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 25 mg (69.7%) of 3-cyano-8-isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (18-2) as a yellow oil.

[0886] 3. Synthesis of 3-cyano-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-isopropyl-2- methylimidazo[l,2-b]pyridazine-7-carboxamide (366)

[0887]

[0888] To an 8-mL round-bottom flask was added DMF (2 mL), 3-cyano-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxylic acid (18-2, 25.0 mg, 0.1 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (16.9 mg, 0.1 mmol, 1.1 equiv), HATU (47.0 mg, 0.1 mmol, 1.21 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 70:30 increasing to H2O:ACN = 10:90 over 20 min; detector, 254 nm. This resulted in 16.5 mg (42.9%) of 3-cyano-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- isopropyl-2-methylimidazo[l,2-b]pyridazine-7-carboxamide (366) as a white solid. (300 MHz, CDC13, 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).

[0889] Preparation Example 14: Compounds 394, 397-0, 395, and 398 can be synthesized according to the following Scheme 19:

[0890] Scheme 19

[0891]

[0892] 1. Synthesis of 3-bromo-8-ethoxyimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (19-1)

[0893]

[0894] Into a 40-mL round-bottom flask, was placed DMF (5.0 mL), 3-bromo-8- hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-3, 150.0 mg, 0.5 mmol, 1.0 equiv), iodomethane (200.0 mg, 1.3 mmol, 2.4 equiv), K2CO3(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 with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 90:10, increased to H2O:ACN = 40:60 over 15 min; detector, 254 nm. This resulted in 80 mg (48.6%) of 3-bromo-8-ethoxyimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (19-1) as a white solid.

[0895] 2. Synthesis of 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (19-2)

[0896]

[0897] Into an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed THF (5.0 mL), H2O (1.0 mL), 3-bromo-8-ethoxyimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (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)Cl2(30.0 mg, 0.05 mmol, 0.2 equiv), K2CO3(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 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[l,2-b]pyridazine-7-carboxylic acid methyl ester (19-2) as a white solid.

[0898] 3. Synthesis of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid (19-3)

[0899]

[0900] Into a 40-mL round-bottom flask, was placed EtOH (5.0 mL), H2O (2.0 mL), 3-(3,5-dichlorophenyl)-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (19-2, 70.0 mg, 0.2 mmol, 1.0 equiv), LiOH (40.0 mg, 1.7 mmol, 8.7 equiv). The resulting solution was stirred at 50 °C for 1 h. The solution was adjusted to pH 4 with HC1 (4 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 40 mg (61.9%) of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid (19-3) as a white solid.

[0901] 4. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- methoxyimidazo[l,2-b]pyridazine-7-carboxamide (394)

[0902]

[0903] To an 8-mL round-bottom flask was added DMF (3.0 mL), 3-(3,5-dichlorophenyl)- 8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid (19-3, 40.0 mg, 0.1 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (19.5 mg, 0.1 mmol, 1.1 equiv), HATU (75.1 mg, 0.2 mmol, 1.7 equiv), 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 with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 70:30, increased to H2O:ACN = 10:90 over 20 min; detector, 254 nm. This resulted in 12 mg (21.6%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- methoxyimidazo[l,2-b]pyridazine-7-carboxamide (394) as a white solid. (300 MHz, CDC13, 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).

[0904]

[0905]

[0906] Preparation Example 15: Compounds 450, 451, A408, A409, A421, A422, A460, A461, A462, A463, and A464 can be prepared using the methods shown in Schemes 20 and 21 below:

[0907] Scheme 20

[0908]

[0909] Scheme 21

[0910]

[0911] 1. Synthesis of 4-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (3-4)

[0912]

[0913] To a 500-mL 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was added l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (3-3, 20.0 g, 78.4 mmol, 1.0 equiv), 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 at room temperature for 1 night. The reaction was then quenched by the addition of 1 L of water. The resulting solution was extracted with 3 x 300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 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 4-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (3-4) as a white solid.

[0914] 2. Synthesis of 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropanoic acid ethyl ester (3-5)

[0915]

[0916] To a 1-L 3 -necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was added 4-bromo-l-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylic acid ethyl ester (3-4, 14 g, 41.9 mmol, 1.0 equiv), THF (140.0 mL, 1728.0 mmol, 41.2 equiv), 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) at 0 °C with stirring. The resulting solution was stirred at 0 °C for 30 minutes. The reaction was then quenched by the addition of 200 mL of saturated NH4CI. The resulting solution was extracted with 3 x 200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 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 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-oxopropanoic acid ethyl ester (3-5) as a yellow solid.

[0917] 3. Synthesis of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6)

[0918]

[0919] Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[4-bromo-l-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3- oxopropanoic acid ethyl ester (3-5, 10.0 g, 26.6 mmol, 1.0 equiv), DMF (100.0 mL), K2CO3 (3.7 g, 26.6 mmol, 1.0 equiv), 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 solids were collected by filtration. The crude product was recrystallized from ACN at a ratio of 10 v. This resulted in 7.5 g (98.6%) of 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6) as a white solid.

[0920] 4. Synthesis of 2-bromo-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-1)

[0921]

[0922] Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-8-hydroxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (3-6, 8.0 g, 28.0 mmol, 1.0 equiv), DMF (80.0 mL), K2CO3 (7.7 g, 55.9 mmol, 2.0 equiv), CH3I (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 with (8 min from 25% to 45% ACN in water). This resulted in 2.9 g (34.0%) of 2-bromo-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-1) as a white solid.

[0923] 5. Synthesis of 8-methoxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-2)

[0924]

[0925] To a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was added 2-bromo-8-methoxyimidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-1, 300.0 mg, 1.0 mmol, 1.0 equiv), DMF (6.0 mL), 2,2-difluoro-2-sulfonylethyl methyl ester (960.2 mg, 5.0 mmol, 5.0 equiv), HMPA (895.7 mg, 5.0 mmol, 5.0 equiv), 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 onto a C18 column with (8 min from 25% to 45% ACN in H2O (0.1% TFA) solution). This resulted in 170 mg (56.6%) of 8-methoxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-2) as a yellow solid.

[0926] 6. Synthesis of 8-hydroxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-3)

[0927]

[0928] To a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was added 8-methoxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-2, 1.8 g, 6.2 mmol, 1.0 equiv), LiCl (2.6 g, 62.2 mmol, 10.0 equiv), DMF (18.0 mL). The resulting solution was stirred at 120 °C for 2 h. The residue was applied onto a C18 column with (8 min from 75% to 83% ACN in H2O (0.1% TFA) solution). This resulted in 900 mg (52.5%) of 8-hydroxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-3) as a yellow solid.

[0929] 7. Synthesis of 8-bromo-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-4)

[0930]

[0931] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 8-hydroxy-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-3, 400.0 mg, 1.4 mmol, 1.0 equiv), POBr3 (3333.7 mg, 11.6 mmol, 8.0 equiv). 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 solution was pH adjusted to 8 with Na2CO3. The resulting solution was extracted with 3 x 10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 520 mg (97.3%) of 8-bromo-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-4) as a yellow solid.

[0932] 8. Synthesis of 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (21-1)

[0933]

[0934] Into an 8-mL vial was placed 8-bromo-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (20-4, 150.0 mg, 0.4 mmol, 1.0 equiv), DMF (1.5 mL), 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 with (6 min from 80% to 90% ACN in H2O (0.1% FA)). This resulted in 110 mg (72.0%) of 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (21-1) as a white solid.

[0935] 9. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (21-2)

[0936]

[0937] An 8-mL vial purged and maintained with an inert atmosphere of nitrogen was charged with 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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), Cs2CO3(170.3 mg, 0.5 mmol, 2.0 equiv), Pd(AcO)2(11.7 mg, 0.05 mmol, 0.2 equiv), Ad2(n-Bu)P (28.0 mg, 0.08 mmol, 0.3 equiv). The resulting solution was stirred at 100 °C overnight. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 110 mg (72.2%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (21-2) as a white solid.

[0938] 10. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid (21-3)

[0939]

[0940] An 8-mL vial purged and maintained with an inert atmosphere of nitrogen was charged with 8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (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), Cs2CO3(170.3 mg, 0.5 mmol, 2.0 equiv), Pd(AcO)2(11.7 mg, 0.05 mmol, 0.2 equiv), Ad2(n-Bu)P (28.0 mg, 0.08 mmol, 0.3 equiv). The resulting solution was stirred at 100 °C overnight. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:5). This resulted in 110 mg (72.2%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (21-2) as a white solid.

[0941] 11. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,2-b]pyridazine-7-carboxamide (450)

[0942]

[0943] To an 8-mL vial was added 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)-2- (trifluoromethyl)imidazo[l,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-l-benzopyran-4-amine (32.0 mg, 0.2 mmol, 1.5 equiv), DIEA (55.5 mg, 0.4 mmol, 3.0 equiv), 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 with (6 min from 90% to 98% ACN in H2O (0.1% FA) solution). This resulted in 35.1 mg (41.4%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8-(morpholin-4-yl)-2-(trifluoromethyl)imidazo[l,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 = 7.8 Hz, 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).

[0944]

[0945]

[0946]

[0947] Preparation Example 16: Compounds 511 and 512 can be prepared using the method outlined in Scheme 22 below:

[0948] Scheme 22

[0949]

[0950] 1. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7- carboxylic acid ethyl ester (22-1)

[0951]

[0952] To a 40-mL round-bottom flask, was added NMP (5.0 mL), 8-chloro-3-(3,5- dichlorophenyl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (17-5, 100.0 mg, 0.2 mmol, 1.0 equiv), 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 with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 65 mg (64.0%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (22-1) as a yellow solid.

[0953] 2. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7- carboxylic acid (22-2)

[0954]

[0955] To a 40-mL round-bottom flask, was added EtOH (2.0 mL), H2O (1.5 mL), 3-(3,5- dichlorophenyl)-8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid ethyl ester (22-1, 65.0 mg, 0.1 mmol, 1.0 equiv), LiOH.H2O (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 using HC1 (6 mol / L). The resulting solution was extracted with 3 x 20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 40 mg (65.9%) of 3-(3,5-dichlorophenyl)-8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (22-2) as a yellow solid.

[0956] 3. Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- (morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxamide (511)

[0957]

[0958] To a 40-mL round-bottom flask was added DMF (5.0 mL), 3-(3,5-dichlorophenyl)- 8-(morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxylic acid (22-2, 40.0 mg, 0.1 mmol, 1.0 equiv), (4S)-3,4-dihydro-2H-l-benzopyran-4-amine (17.0 mg, 0.1 mmol, 1.12 equiv), HATU (65.0 mg, 0.2 mmol, 1.7 equiv), 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 using the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H2O:ACN = 50:50 increasing to H2O:ACN = 10:90 over 20 min; detector, 254 nm. The product was obtained. This resulted in 37.8 mg (70.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4-yl]-8- (morpholin-4-yl)imidazo[l,2-b]pyridazine-7-carboxamide (511) as a white solid.1H NMR Spectrum: (300 MHz, CDC13, 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).

[0959] 512 of 1 H NMR Spectrum: (300 MHz, CDC13, 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)

[0960] Preparation Example 17: Compound 558 was prepared according to the scheme 23 shown below. Compound 559 can be prepared by the method described in the scheme 23 by one skilled in the art.

[0961] Scheme 23

[0962]

[0963] 1. Synthesis of 7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-2-carboxylic acid ethyl ester (23-2)

[0964]

[0965] To a stirred mixture of 7-chloroimidazo[l,2-b]pyridazine-2-carboxylic acid ethyl ester (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) was added K2CO3(1.2 g, 8.9 mmol, 2.0 equiv) and Pd(OAc)2(0.1 g, 0.4 mmol, 0.1 equiv) and PPh3(0.2 g, 0.9 mmol, 0.2 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C overnight under 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 7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-2-carboxylic acid ethyl ester (23-2, 1.2 g, 73.0%) as a yellow oil.

[0966] 2. Synthesis of 7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-2-carboxylic acid (23-3)

[0967]

[0968] To a stirred mixture of 7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-2-carboxylic acid ethyl ester (23-2, 1.0 g, 2.7 mmol, 1.0 equiv) in EtOH (8 mL) and H2O (4 mL) was added LiOH.H2O (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 HC1 (aq). The precipitated solid was collected by filtration and washed with water (2 x 10 mL). The resulting solid was dried under an infrared lamp.

[0969] 3. Synthesis of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[l,2- b]pyridazine-2-carboxamide (23-4)

[0970]

[0971] To a stirred mixture of 7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-2- carboxylic acid (23-3, 1.0 g, 3.0 mmol, 1.0 eq) and N, O-dimethylhydroxylamine (0.3 g, 4.4 mmol, 1.5 eq) in DCM (10 mL, 157.3 mmol, 53.9 eq) was added EDCI (0.6 g, 2.9 mmol, 1.0 eq) and PyBOP (1.5 g, 2.9 mmol, 1.0 eq) and DIEA (1.1 g, 8.7 mmol, 3.0 eq) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, gradient from 50% to 90% in 10 min; detector, UV 254 nm to give 400 mg of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N- methylimidazo[l,2-b]pyridazine-2-carboxamide (23-4, 35.5%) as a yellow oil.

[0972] 4. Synthesis of l-[7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazin-2-yl]ethanone (23-5)

[0973]

[0974] To a stirred mixture of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[l,2- b]pyridazine-2-carboxamide (23-4, 80.0 mg, 0.2 mmol, 1.0 eq) in THF (2 mL, 24.7 mmol, 119.0 eq) was added methylmagnesium chloride (77.6 mg, 1.0 mmol, 5.0 eq) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 60 min under nitrogen atmosphere. The reaction was quenched with saturated NH4C1 (aq) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 4 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 4: 1) to give l-[7-chloro-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazin-2-yl]ethanone (23-5, 40 mg, 56.6%) as a light yellow solid.

[0975] 5. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[l,2-b]pyridazine-7- carboxylate (23-6)

[0976]

[0977] To a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[l,2- b]pyridazine-7-carboxylate (23-6, 20.0 mg, 0.05 mmol, 1.0 equiv) and 2- [(propan-2-sulfonyl)zinc sulfonyl]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 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na2S04. 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[l,2-b]pyridazine-7- carboxylate (23-7, 10 mg, 44.8%) as a yellow oil.

[0978] 6. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2- b]pyridazine-7-carboxylate (23-7)

[0979]

[0980] To a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[l,2- b]pyridazine-7-carboxylate (23-6, 20.0 mg, 0.05 mmol, 1.0 equiv) and 2- [(propan-2-sulfonyl)zinc sulfonyl]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 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na2S04. 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[l,2-b]pyridazine-7- carboxylate (23-7, 10 mg, 44.8%) as a yellow oil.

[0981] 7. Synthesis of 2-acetyl-3-(3,5-dichlorophenyl)-8-(propan-2-yl)imidazo[l,2- b]pyridazine-7-carboxylic acid (23-8)

[0982]

[0983] To a stirred mixture of 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2- b]pyridazine-7-carboxylic acid methyl ester (23-7, 10.0 mg, 0.02 mmol, 1.0 equiv) in EtOH (1 mL) and H2O (0.5 mL) was added LiOH.H2O (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 with HC1 (aq) to pH 4. The resulting mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (1 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (23-8) was used directly in the next step without further purification.

[0984] 8. Synthesis of 2-acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l-benzopyran-4- yl]-8-isopropylimidazo[l,2-b]pyridazine (558)

[0985]

[0986] To a stirred mixture of 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[l,2- b]pyridazine-7-carboxylic acid (23-8, 10.0 mg, 0.02 mmol, 1.0 equiv) and (4S)-3,4- dihydro-2H-l-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 using the following conditions (gradient: isocratic) to give 11 mg of 2-acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-l- benzopyran-4-yl]-8-isopropylimidazo[l,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).

[0987] 559 of 1 H 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)

[0988] Preparation Example 18: Compound 614 can be prepared according to the method described in Scheme 24.

[0989] Scheme 24

[0990]

[0991] 1. Synthesis of 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine

[0992]

[0993] Into a 500 mL round-bottom flask was added methyl 3,4-dihydro-2H-1,4- benzoxazine (24-1, 3.0 g, 22.2 mmol, 1.0 equiv) and 3M / HCl (300 ml) and NaNO2(1.8 g, 26.1 mmol, 1.2 equiv) was added dropwise / batchwise over 2 hours 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 afford 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine (24-2, 2.7 g, 75.1%) as a yellow oil.

[0994] 2. Synthesis of 3,4-dihydro-2H-1,4-benzoxazin-4-amine

[0995]

[0996] Into a 500 mL round-bottom flask was 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 / batchwise over 2 hours 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 afford 3,4-dihydro-2H-1,4-benzoxazin-4-amine (24-3, 2.2 g, 44.9%) as a yellow oil.

[0997] 3. Synthesis of 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)

[0998]

[0999] To a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[l,2- b]pyridazine-7-carboxylic acid (12-5, 100.0 mg, 0.3 mmol, 1.0 equiv) and 2,3- dihydro-l,4-benzoxazin-4-amine (119.1 mg, 0.8 mmol, 3.0 equiv) in DMF (5 mL) at room temperature was added DIEA (170.8 mg, 1.3 mmol, 5.0 equiv) and HATU (301.6 mg, 0.8 mmol, 3.0 equiv). The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool to room temperature. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient from 40% to 95% in 10 minutes; detector, UV 254 nm to give 8-tert-butyl-3-(3,5-dichlorophenyl)-N-(2,3-dihydro-l,4- benzoxazin-4-yl)-2-methylimidazo[l,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).

[1000] Biological Examples

[1001] The present disclosure is further illustrated by the following biological examples, which are not to be construed as limiting the scope or spirit of the disclosure to the particular procedures described herein. It is to be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the disclosure. It is also to be understood that various other embodiments, modifications, and equivalents thereof, which, given the benefit of this disclosure, can occur to one skilled in the art, are intended to be within the scope of the present disclosure.

[1002] Biological Example 1: Screening method for testing the activity of a compound on Dirofilaria immitis microfilariae.

[1003] Four hundred to six hundred Dirofilaria immitis microfilariae are added to each well of a microtiter plate containing RPMI medium and test compound formulated in 100% DMSO. The plates are maintained at 37 °C and 5% CO2for 3 days. The potency of the compound is determined by comparing the motility of the microfilariae to the average motility in control wells containing DMSO only. A dose response test is performed to determine the EC50 values. Compounds 298-0, 304, 295, 296, A412, A406, A405, A411, A400, A401, 325, A419, 513-0, 450, A435, A439, and A442 exhibited EC 50 values between 0.01 μΜ and 0.1 μΜ. 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 exhibited EC 50 values between 0.001 μΜ and 0.01 μΜ. Compounds 308, 271, 274, 306, 297, A410, 277, 299-0, 293, 275, 175, 573, 614, 572, 528, 560, 420, A422, 523, and 527 exhibited EC 50 values; and compounds 307, 324, 345, 524, 526, and A421 exhibited EC 50 values.

[1004] Biological Example 2: Screening method to test the activity of compounds against Haemonchus contortus.

[1005] Twenty L1 Haemonchus contortus larvae were added to a well of a microtiter plate containing nutrient medium and a DMSO solution of the test compound. Analysis was performed on day 4 to determine the extent of development of the larvae from L1 to L3. Larvae exposed to DMSO alone served as a control. Dose response testing was performed to determine the EC 50 values between 1 μΜ and 10 μΜ. 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 exhibited EC 50 values between 0.1 μΜ and 1 μΜ. Compounds 304, A405, A414, A403, A401, 371, 364, 352, 308, 320, 298, 299-0, 327, 324, 279, and 275 exhibited EC 50values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values.

[1006] Biological Example 3: Biological Example 4: Biological Example 5: Biological Example 6: Biological Example 7: Biological Example 8: Biological Example 9: Biological Example 10: Biological Example 11: Biological Example 12: Biological Example 13: Biological Example 14: Biological Example 15: Biological Example 16: Biological Example 17: Biological Example 18: Biological Example 19: Biological Example 20: Biological Example 21: Biological Example 22: Biological Example 23: Biological Example 24: Biological Example 25: Biological Example 26: Biological Example 27: Biological Example 28: Bi Screening method to test the activity of compounds against L4 stage larvae of Dirofilaria immitis.

[1007] Four to six L4 stage Dirofilaria immitis helminths were added to each well of a microtiter plate containing maintenance nutrient medium and test compound formulated in 100% DMSO. The plates were maintained at 37°C and 5% CO2 for 3 days, then evaluated to determine the motility of the larvae. The potency of the compounds was determined by comparing the motility of the treated L4s to the average motility of the helminths in DMSO only control wells. Dose response testing was performed to determine the EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 values; and compounds 297, 306, 271, 345, and 274 exhibited EC 50 .

[1008] ***

[1009] Having described in detail preferred embodiments of the present application, it is understood that the application defined by the above paragraphs is not limited to particular details of the embodiments set forth above, as various modifications can be made therein without departing from the spirit or scope of the present application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: L is L1or L2: X is O; wherein a is 0 or 1; q is 0 or 1; p is independently, at each occurrence, 0, 1, or 2; and wherein the optional substituents are independently selected, at each occurrence, from halogen, hydroxyl, alkyl, and haloalkyl.

2. The compound of Formula (I) according to claim 1, wherein:

3. The compound of Formula (I) according to claim 1, wherein R ’ is hydrogen or optionally substituted C1-C6-alkyl; R 1 is optionally substituted C1-C6-alkyl, optionally substituted C2-C6-alkenyl, optionally substituted C1-C6-alkoxy, optionally substituted C2-C6-alkenyloxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkenyl, or -NR a R b wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b may form, together with the nitrogen atom to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can comprise one to three further heteroatoms selected from N, O, Si and S and which can be optionally substituted; R 2 is hydrogen, cyano, halogen, optionally substituted C1-C6-alkyl, optionally substituted aryl; or optionally substituted C1-C6-alkylcarbonyl; R 3 is optionally substituted C1-C6-alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered cycloalkenyl, optionally substituted 3- to 7-membered heterocyclyl containing 1-3 oxygen, sulfur, silicon or nitrogen heteroatoms, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl containing 1-3 oxygen, nitrogen or sulfur heteroatoms, or -NR a R b , wherein R a and R b are independently H or optionally substituted C1-C6-alkyl; or R a and R b may form together with the nitrogen atom to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O, Si and S and which can optionally be substituted; R 4 is hydrogen, halogen, cyano, optionally substituted Ci-C6-alkoxy or optionally substituted Ci-C6-alkylcarbonylamino; R 8 is hydrogen; R 9 and R 9’ are independently hydrogen, C1-C4-alkyl, or R 9 and R 9’ form together a 2-6 membered chain to form together with the carbon atom to which they are attached a carbocyclic ring; Q is C-R 8 ; 4. The compound of Formula (I) according to claim 1, wherein a is 1 and q is 1. Y 1 and Y 6 each independently N or C; Y 2 , Y 3 , Y 4 and Y 5 are each independently N, S or -CR 4 -; W is CR 5 R 6 ; Z is CR 5 R 6 , O, SO p , or N-R 7 , 5. The compound of Formula (I) according to claim 1, wherein a is 0 and q is 0. R 5 and R 6 independently at each occurrence is hydrogen or C1-C4-alkyl; R 7 is hydrogen or CrC4-alkyl; and wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from the group consisting of hydrogen, halogen, -ORa, -SRa, -N(Ra)2, -C(O)Ra, -C(O)2Ra, -C(O)N(Ra)2, -NRaC(O)Ra, -NRaC(O) 6. The compound of Formula (I) according to claim 1, wherein a is 1 and q is 0.

7. The compound of Formula (I) according to claim 1, wherein: L is L1; Z is O; and 8. The compound of Formula (I) according to claim 7, wherein a is 1 and q is 1. a dashed bond represents a single or double bond; 9. The compound of Formula (I) according to claim 7, wherein a is 0 or 1 and q is 0.

10. A compound of Formula (Ie) or a pharmaceutically acceptable salt thereof: wherein: a is 0 or 1; and m is 0, 1, 2, or 3; wherein the optional substituents are independently selected, at each occurrence, from halogen, hydroxyl, alkyl, and haloalkyl.

11. The compound according to claim 10, wherein m is 2 or 3. R 1 is Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C2-C6-alkenyloxy, Ci-C6-haloalkoxy, C2-C6-alkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, or -NR a R b wherein R a and R b are independently H or optionally substituted Ci-C6-alkyl; or R a and R b may form together with the nitrogen atom to which they are attached a 4-, 5-, 6- or 7-membered heterocyclyl group which can contain one to three further heteroatoms selected from N, O and S and can be optionally substituted; R 2 is hydrogen, cyano, halogen, Ci-C6-alkyl, Ci-C6-haloalkyl, optionally substituted phenyl, or Ci-C6-alkylcarbonyl; R 3 is CrC6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl, optionally substituted 3- to 7-membered heterocyclyl comprising one to three heteroatoms selected from the group consisting of N, O and S; optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl comprising one or two N, O or S heteroatoms, or -NR a R b wherein R a and R b may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclyl group which can comprise one further heteroatom selected from the group consisting of N, O and Si and can be optionally substituted; R 4 independently at each occurrence is hydrogen, halogen, cyano, C1-C6-alkoxy or C1-C6- alkylcarbonyl; R 8 is hydrogen; R 9 and R 9’ are hydrogen, or R 9 and R 9’ together form a 2-6 membered chain to form, together with the carbon atom to which they are attached, a carbocyclic or heterocyclic ring; and R ’ is hydrogen.

13. The compound according to claim 10, wherein: m is 2 or 3; W is CH2; Z is O; and R 1 is optionally substituted C1-C4-alkyl, optionally substituted C1-C4-alkoxy, optionally substituted C2-C4-alkenyl, optionally substituted C2-C6-alkenyloxy, optionally substituted C5-C6-cycloalkyl, or -NR a R b wherein R a and R b are independently optionally substituted C1-C4-alkyl; or R a and R b together with the nitrogen atom to which they are attached can form a 5- or 6-membered heterocyclyl group which can be optionally substituted and which contains one additional heteroatom selected from the group consisting of N, O and S; R ’ is hydrogen; R 2 is hydrogen, halogen, cyano, optionally substituted C1-C4-alkyl; R 3 is optionally substituted C1-C4-alkyl, optionally substituted phenyl, optionally substituted 6-membered heteroaryl containing one or two N heteroatoms, optionally substituted C5-C6-cycloalkyl, or -NR a R b wherein R a and R b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl group which can contain one further heteroatom selected from N, O and Si and which can be optionally substituted; and Each R 4 It can be hydrogen, halogen, or cyano group independently.

14. A compound of Formula (If) or a pharmaceutically acceptable salt thereof: wherein a is 0 or 1; and b is 0 or 1; wherein the optional substituents are independently selected, at each occurrence, from halogen, hydroxyl, alkyl, and haloalkyl.

15. The compound according to claim 10, wherein 16. The compound according to claim 15, wherein m is 2 or 3.

17. The compound according to claim 14, wherein D is N or CH; E is N or CH; and 28. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: R ’ is hydrogen; R 1 is C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, or -NR a R b wherein R a and R b are independently H or C1-C4-alkyl; or R a and R b may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclyl group which can contain one further heteroatom selected from N, O and S and which can be optionally substituted; R 2 is hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl; R 3 is C1-C4-alkyl, optionally substituted C3-C6-cycloalkyl, optionally substituted 5 or 6 membered heterocyclyl comprising one or two heteroatoms selected from N, O and S; optionally substituted phenyl, optionally substituted 6 membered heteroaryl comprising one or two nitrogen heteroatoms; or -NR a R b wherein R a and R b together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl group which can comprise one further heteroatom selected from N, O and S and can be optionally substituted; R 4 independently at each occurrence, is hydrogen, halogen, or cyano; R 8 is hydrogen; 29. A veterinary composition comprising a parasiticidally effective amount of a compound of any one of claims 1 to 28, or a pharmaceutically or veterinarily acceptable salt thereof, and a veterinarily acceptable carrier. W is CR 5 R 6 .

30. A veterinary composition comprising a compound of any one of claims 1 to 28, or a pharmaceutically or veterinarily acceptable salt thereof, one or more additional active agents, and a veterinarily acceptable carrier. ​ ​ ​ Each R 10 Halogens are independent of each other; R 1 is C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C1-C4-alkoxy, C2-C4-alkenyloxy, or -NR a R b wherein R a and R b are independently H or C1-C6-alkyl; or R a and R b may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclyl group which can contain one further heteroatom selected from N, O and S and which can be optionally substituted; R 2 is hydrogen, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl; R 4 is hydrogen or halogen; R 5 and R 6 independently are hydrogen or C1-C3-alkyl; R ’ is hydrogen; R 8 is hydrogen; R 9 and R 9’ are independently hydrogen or C1-C3-alkyl; W is CR 5 R 6 ; Z is CR 5 R 6 or O; Y 2 , Y 3 , Y 4 , Y 5 independently CR 4 or N; ​ ​ ​ ​ 12. The compound of claim 10, wherein each R 10 is independently chlorine or fluorine and m is 2 or 3. ​ Each R 10 It can be chlorine or fluorine independently; ​ R 1 is Ci-C4-alkyl or -NR a R b ; R 2 halogen, C1-C3-alkyl or C1-C3-haloalkyl; ​ ​ R 9 and R 9’ each is hydrogen. ​ ​ R 1 is C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C1-C4-alkoxy, C2-C4-alkenyloxy, or -NR a R b wherein R a and R b are independently H or C1-C6-alkyl; or R a and R b may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclyl group which can contain one further heteroatom selected from N, O and S and which can be optionally substituted; R 2 is hydrogen, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl; R 4 and R 4’ independently are hydrogen, halogen or Ci-C6-alkyl; R ’ is hydrogen; R 8 is hydrogen; R 9 and R 9’ each is hydrogen; D is N; C; or C-R 4 ; D 1 is O; SiR 11 R 12 wherein R 11 and R 12 are independently C1-C6 alkyl; or D 1 is -CR 4 R 4’ ; Y 2 , Y 3 , Y 4 , Y 5 independently CR 4 or N; ​ ​ ​ ​ R 1 is C1-C4-alkyl, di(C1-C4-alkyl)amino or morpholinyl; R 2 is halogen, C1-C4-alkyl or C1-C4-haloalkyl; and R 4 is hydrogen. ​ R 1 is isopropyl, tert-butyl, dimethylamino or morpholinyl; R 2 is chloro, methyl or trifluoromethyl; and R 10 is chloro or fluoro; and ​ ​ R 1 is C1-C4-alkyl; R 2 is C1-C4-alkyl; ​ D 1 is O, Si(CH3)2or CH2; and R 4 is hydrogen.

18. The compound according to any one of claims 1 to 17, wherein Y 2 , Y 3 , Y 4 , and Y 5 are each independently -C-R 4 .

19. The compound according to any one of claims 1 to 17, wherein Y 2 is N; and Y 3 , Y 4 , and Y 5 are independently -C-R 4 .

20. The compound according to any one of claims 1 to 17, wherein Y 3 is N; and Y 2 , Y 4 , and Y 5 are independently -CR 4 .

21. The compound according to any one of claims 1 to 17, wherein Y 4 is N, and Y 2 , Y 3 , and Y 5 are independently -CR 4 .

22. The compound according to any one of claims 1 to 17, wherein Y 5 is N, and Y 2 , Y 3 , and Y 4 are independently -CR 4 .

23. The compound according to any one of claims 1 to 17, wherein Y 2 and Y 3 is N; and Y 4 and Y 5 are independently -CR 4 .

24. The compound according to any one of claims 1 to 17, wherein Y 3 and Y 4 is N; and Y 2 and Y 5 are independently -CR 4 .

25. The compound according to any one of claims 1 to 17, wherein Y 4 and Y 5 is N; and Y 2 and Y 3 are independently -CR 4 .

26. The compound according to any one of claims 1 to 17, wherein Y 2 and Y 4 is N; and Y 3 and Y 5 are independently -CR 4 .

27. The compound according to any one of claims 1 to 17, wherein Y 3 and Y 5 is N; and Y 2 and Y 4 are independently -CR 4 . ​ wherein R 1 , R 2 , R 3 and L are shown in the table below, wherein "Me" is methyl; "i-Pr" is isopropyl; "t-Bu" is tert-butyl; prop-1 -en-2-yl is 2-F-prop-2-yl represents the group 1,1-difluoroethyl represents a group L1is: wherein X is oxygen and R' is hydrogen; L2 is: wherein X is oxygen and R' is hydrogen; and the group represents one of the following ring systems: Ring system A; Ring system B; Ring system C; Ring system D; Ring system E; Ring system F; Ring system G; Ring system H; Ring system I; Ring system J; Ring system K; Ring system L; Ring system M; Ring system N; Ring system O; Ring system P; Ring system Q; Ring system R; Ring system S; Ring system T; Ring system U; Ring system V; Ring system X; Ring system Y; Ring system Z; Ring system AA; Ring system AB; Ring system AC; A / D system; AE (Area of ​​Rings) system; Ring system AF; Ring System AG; Ring system AH; Ring system AJ; Ring system AK; Ring system AL; Ring system AM; Ring system AN; Ring system AO; Ring system AP; AQ ring system; AR (Augmented Ring) System; Ring system AS; Ring system AT; Ring system AU; Ring system AV; Ring system AW; Ring system AX; Ring system AY; Ring system AZ; Ring system AAA; or is hydrogen; ​ ​

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