Anthelmintic heterocyclic compounds

Abstract

The present invention provides compounds, compositions, and methods for use in treating, controlling, or preventing parasitic invasion or infection in animals. [Solution] The variable element is a compound of the following formula, or a salt thereof, a composition containing these compounds, and a method for treating, controlling, or preventing parasitic invasion or infection in animals by administering an effective amount of these compounds to an animal in need. JPEG2026090328000305.jpg5683

Description

[Technical Field]

[0001] This patent application relates to a novel antiparasitic compound, a composition containing the compound, a method for preparing the same, and a method for using the compound to control parasites that harm animals and humans. Cross-reference of related applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 031,656 filed May 29, 2020, which is incorporated herein by whole reference. [Background technology]

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

[0003] One type of endoparasite that seriously harms mammals is Dirofilaria immitis, also known as heartworm. Other filariatic endoparasites include Dirofilaria repens and Dirofilaria honkongensis, which can also infect humans. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected. Dirofilaria immitis goes through several life stages before becoming an adult worm that infects the pulmonary arteries of the host mammal. These worms require mosquitoes as intermediate hosts to complete their life cycle. The period between the initial infection, when a dog is bitten by a mosquito, and the maturation of the worm into an adult that resides in the heart and pulmonary arteries is 6-7 months in dogs and is known as the "promanent stage." L3 larvae migrate to the tip of the mosquito's mouthparts (lower lip) while the mosquito is feeding, leave the mosquito, deposit on the dog's skin, and then migrate into the host through the bite. Most L3 larvae molt into fourth-stage larvae (L4) in the dog's subcutaneous tissue within 1-3 days after infection. These larvae then migrate to the muscles of the thorax and abdomen, and molt into fifth-stage larvae (L5, immature adult) 45-60 days after infection. Then, between 75 and 120 days after infection, these immature canine heartworms enter the bloodstream, are carried through the heart, and reside in the pulmonary artery. Approximately 7 months after infection, adult Dirofilaria imitis mature and reproduce sexually in the pulmonary artery and right ventricle. Adult males are approximately 15 cm long, and females are approximately 25 cm long, and their normal lifespan as adults is calculated to be about 5 years.

[0004] Heartworm infection is a serious, life-threatening disease. Heartworm infection in dogs is preventable, and preventive treatment is prioritized in areas where heartworm is endemic. Treatment of mature heartworm infection with adulticidal agents (e.g., melarsomine dihydrochloride) is expensive and can cause serious side effects, so prophylaxis with monthly administration of drugs that inhibit larval development is widely used. The purpose of commercially available heartworm prophylactic therapies is to prevent the parasite from developing into adult heartworms by disrupting the life cycle of Dirofilaria imitis after infection. Macrocyclic lactones (MLs, e.g., ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemopreventive agents, administered monthly or every six months. These drugs were effective against third-stage (L3) and mature fourth-stage (L4) larvae of Dirofilaria imitis deposited by mosquitoes. When administered monthly, MLs kill L3 and L4 larvae infected within the previous 30 days, thus preventing disease caused by adult helminths. MLs can also be used monthly in infected dogs to suppress adult helminth reproduction, eliminate microfilariae, thereby reducing transmission and gradually decreasing the adult helminth population (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206).

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

[0006] International Publication No. 2017 / 178416 provides pyrazolopyrimidine derivatives for the control, treatment and / or prevention of helminths. International Publication No. 2018 / 197401 provides bicyclic pyrazole derivatives for the control, treatment and / or prevention of helminths. International Publication No. 2018 / 087036 provides quinolone-3-carboxamide derivatives for the control, treatment and / or prevention of helminths. International Publication No. 2019 / 025341 provides quinoline compounds for the treatment, control and / or prevention of helminth infections, and International Publication No. 2019 / 002132 provides azaquinone derivatives for the control, treatment and / or prevention of helminths. All of these publications are by Bayer Animal Health GmbH and are incorporated herein by reference in their entirety. More recently, International Publication No. 2020 / 014068 (incorporated herein by reference) describes an anthelmintic heterocyclic compound found to be active against Dirofilaria imitis. It is expressly noted that the citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. All documents cited in the application and all documents cited or referred to in the application citation documents ( "application citation documents") and all documents cited or referred to in the application citation documents, and all documents cited or referred to in this specification ( "documents cited in this specification"), and all documents cited or referred to in the documents cited in this specification, are incorporated herein by reference in conjunction with the manufacturer's instructions, descriptions, product specifications and product sheets for any product mentioned in any document mentioned in this specification or any document incorporated herein by reference, and can be used in the implementation of the present invention.

Summary of the Invention

[0007] This application provides novel anthelmintic and antiparasitic heterocyclic compounds having improved activity against endoparasites and ectoparasites. This application also relates to compositions, methods and uses of compounds for eradicating, controlling and / or preventing parasite infestation and / or infection in animals including humans. The compounds can be administered to animals, particularly mammals, fish and birds, to prevent and / or treat parasite infections. One aspect of the present invention is a compound of formula (I):

Chemical Formula

Chemical Formula

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

[0009] In some embodiments, compounds of formula (I) and compositions comprising said compounds are substantially effective against filarial worms (e.g., Dirofilaria imitis) of the digestive tract of animals and humans, and against endoparasites such as hookworms, whipworms, and roundworms. In certain embodiments, compounds of formula (I) and compositions comprising said compounds are effective against Dirofilaria imitis (Dirofilaria imitis) isolates that are less susceptible to treatment with macrocyclic lactones. In other embodiments, the compounds and compositions of the present invention are effective in treating and / or preventing animal infections by nematodes that are less susceptible to treatment with commercially available or known activators. In one embodiment, the present invention includes a combination of a compound of formula (I) and at least a second activator that can broaden the range of protection provided to an animal against endoparasites and / or ectoparasites.

[0010] Another embodiment includes a method for treating and / or preventing parasitic infections and / or invasiveness in animals, comprising the step of administering a compound of formula (I) to an animal. Another embodiment includes the use of a compound of formula (I) for treating and / or preventing parasitic infections and / or invasiveness in animals, and the use of a compound of formula (I) in the preparation of a pharmaceutical for treating and / or preventing parasitic infections in animals. Therefore, the present invention includes the following non-limiting embodiments: (a) A compound of formula (I) that is an active endoparasite killer and, in some cases, also active against ectoparasites, or a pharmaceutically or veterinarily acceptable salt thereof; (b) A veterinary composition comprising a pharmaceutically or veterinarily acceptable amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, in combination with a pharmaceutically or veterinarily acceptable carrier or diluent; (c) A veterinary composition comprising an effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, in combination with one or more additional activators (i.e., active ingredients not included in formula (I)) and a pharmaceutically or veterinarily acceptable carrier or diluent; (d) A method for treating parasitic infection and / or invasiveness in or on an animal, comprising administering to the animal in need an effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, together with one or more additional activators (i.e., active ingredients not included in formula (I)); (e) A method for preventing parasitic infection and / or invasion in an animal, comprising administering to an animal in need an effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, together with one or more additional activators (i.e., active ingredients not included in formula (I)); (f) Use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, and optionally one or more additional activators (i.e., active ingredients not included in formula (I)) for the treatment and / or prevention of parasitic infections and, if applicable, parasitic invasions in animals; (g) Use of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, and optionally one or more additional activators (i.e., active ingredients not included in formula (I)) for the manufacture of a veterinary medicine for treating and / or preventing parasitic infections and / or invasiveness in animals; (h) A method for preparing the compound of formula (I). These and other embodiments are disclosed by the following detailed description or are obvious from the following detailed description and are included therein.

[0011] Definition: In this disclosure, particularly in the claims and / or paragraphs, terms such as “comprises,” “comprised,” and “comprising” may be interpreted as “includes,” “included,” and “including”; and terms such as “consisting essentially of” and “consists essentially of” may be interpreted as allowing elements not explicitly enumerated, but excluding elements found in the prior art as well as elements that affect the fundamental or novel features of the present invention.

[0012] Terms used herein have their conventional meanings in the art unless otherwise specified. The organic moiety referred to in the definition of a compound, for example, the variable element of a compound of formula (I), is like the term halogen—that is, a collective term for the individual enumerations of halogens: fluoro, chloro, bromo, and iodine. The prefix C n -C m This represents the number of carbon atoms in the group from an integer n to another integer m in each case. In this specification and in the claims, the phrase "including but not limited to" is equivalent to "included".

[0013] The term “compound of formula (I)” includes any stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof. The term "optionally substituded" means a group that may be substituted by one or more of the following parts: halogen, hydroxyl, alkyl, haloalkyl, carboxyl, acyl, acyloxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, amino, alkyl- or dialkylamino, amide, arylamino, alkoxy, haloalkoxy, aryloxy, nitro, cyano, azide, thiol, Thiamides, iminos, amidines, guanidines, carbonates, silyls, silyl ethers, SF5, sulfonic acids, sulfates, sulfonyls, alkoxysulfonyls, sulfanyls, sulfinyls, sulfamoyls, sulfoximines, sulfinimines, sulfonimidoamides, sulfondiimines, esters, phosphonils, phosphinils, phosphoryls, phosphines, phosphoamides, phosphine amides, phosphine oxides, thioesters, thioethers, acid halides, anhydrides, oximes, hydrazines, carbamates, phosphonic acids, phosphates, phosphonates, aryls, and heteroaryls.

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

[0015] In other embodiments, the term "optionally substituded" means that the core group is a halogen (chloro, fluoro, bromo, iodo), C1-C3-alkyl, C1-C3-haloalkyl, 3- to 8-membered cycloalkyl, amino, C1-C3-alkylamino, C1-C3-dialkylamino, C1-C3-alkoxy, C1-C3-haloalkoxy, cyano, nitro, SF5, acetyl, C1-C3-alkoxycarbonyl, C1-C3-haloalkoxycarbonyl, C1-C3-alkylcarbonyl, C1-C3-haloalkylcarbonyl This includes substitution with aminocarbonyl, C1-C3-alkylaminocarbonyl, C1-C3-dialkylaminocarbonyl, C1-C3-haloalkylaminocarbonyl, C1-C3-dihaloalkylaminocarbonyl, C1-C3-alkylthio, C1-C3-alkylsulfinyl, C1-C3-alkylsulfonyl, C1-C3-haloalkylthio, C1-C3-haloalkylsulfinyl, C1-C3-haloalkylsulfonyl, phenyl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl.

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

[0017] Unless otherwise specified, "alkyl" means saturated linear, branched, primary, secondary, or tertiary hydrocarbons having 1 to 12 atoms, either alone or in combination with heteroatoms, such as alkoxy, thioalkyl, and alkylamino. In some embodiments, the alkyl group is C1-C 10 , containing C1-C8, C1-C6, C1-C4 or C1-C3 alkyl groups. C1-C 10Examples of alkyl groups, though not limited to these, include 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, as well as their isomers. C1-C4-alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

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

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

[0020] "Alkynyl" refers to both straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1 to 3; in another embodiment of alkynyl, the number of triple bonds is 1. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In other embodiments, the alkynyl group is C2-C 10 This may include C2-C8, C2-C6, or C2-C4 alkynyl groups. Other ranges of carbon-carbon triple bonds and carbon number are also intended depending on the position of the alkynyl moiety on the molecule. For example, the "C2-C" used herein. 10 The term "-alkynyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, propa-1-in-1-yl, propa-2-in-1-yl, n-buta-1-in-1-yl, n-buta-1-in-3-yl, n-buta-1-in-4-yl, n-buta-2-in-1-yl, n-penta-1-in-1-yl, n-penta-1-in-3-yl, n-penta-1-in-4-yl, n-penta-1-in-5-yl, n-penta-2-in-1-yl, n-penta-2-in-4-yl, n-penta-2-in-5-yl, 3-methylbuta-1-in-3-yl, 3-methylbuta-1-in-4-yl, n-hexa -1-in-1-il, n-hexa-1-in-3-il, n-hexa-1-in-4-il, n-hexa-1-in-5-il, n-hexa-1-in-6-il, n-hexa-2-in-1-il, n-hexa-2-in-4-il, n-hexa-2-in-5-il, n-hexa-2-in-6-il, n-hexa-3-in-1-il, This refers to n-hexa-3-in-2-yl, 3-methylpenta-1-in-1-yl, 3-methylpenta-1-in-3-yl, 3-methylpenta-1-in-4-yl, 3-methylpenta-1-in-5-yl, 4-methylpenta-1-in-1-yl, 4-methylpenta-2-in-4-yl, or 4-methylpenta-2-in-5-yl, etc.

[0021] The term "haloalkyl" refers to an alkyl group as defined herein, which is substituted with one or more halogen atoms. For example, C1-C4-haloalkyls include, but are 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 others. As used herein, the term "fluoroalkyl" refers to alkyl groups in which one or more hydrogen atoms are replaced by fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. The term "haloalkenyl" refers to an alkenyl group as defined herein that is substituted with one or more halogen atoms. The term "haloalkynyl" refers to an alkynyl group as defined herein, which is substituted with one or more halogen atoms.

[0022] The term "alkoxy" refers to alkyl-O- (wherein alkyl is as defined above). Similarly, the terms "alkenyloxy," "alkynyloxy," "haloalkoxy," "haloalkenyloxy," "haloalkynyloxy," "cycloalkoxy," "cycloalkenyloxy," "halocycloalkoxy," and "halocycloalkenyloxy" refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O- (wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above). Examples of C1-C6 alkoxys 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, and 1-methylpentoxy. Examples include toxic, 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, and 1-ethyl-2-methylpropoxy.

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

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

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

[0026] Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolidinyl, benzofuryl, chromonyl, coumalinyl, benzopyranyl, sinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, flupyridinyl (flu[2,3-c]pyridinyl, flu[3,2-b]pyridinyl, or flu[2,3-b]pyridinyl, etc.), dihydroisoindolyl, dihydroquinazolinyl (3,4-dihydro-4-oxo-quinazolinyl, etc.), tetrahydroquinolinyl, etc.

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

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

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

[0030] The term "alkylsulfonyl" refers to the group alkyl-S(=O)2- (wherein the formula, the term "alkyl" is as defined above). In some embodiments, the alkyl component of the alkylsulfonyl group is C1-C 12 , C1-C 10 , containing C1-C8, C1-C6 or C1-C4 alkyl groups. Examples, but not limited to these, include -SO2-CH3, -SO2-C2H5, n-propylsulfonyl, -SO2-CH(CH3)2, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO2-C(CH3)3, n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, Examples include 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl, or 1-ethyl-2-methylpropylsulfonyl.

[0031] The terms "alkenylsulfonyl," "alkynylsulfonyl," "haloalkylsulfonyl," "haloalkenylsulfonyl," and "haloalkynylsulfonyl" refer to the groups alkenyl-S(=O)2-, alkynyl-S(=O)2-, haloalkyl-S(=O)2-, haloalkenyl-S(=O)2-, and haloalkynyl-S(=O)2- (wherein the formulas, the terms "alkenyl," "alkynyl," "haloalkyl," "haloalkenyl," and "haloalkynyl" are as defined above). The terms "alkylamino," "dialkylamino," "alkenylamino," "alkynylamino," "di(alkenyl)amino," and "di(alkynyl)amino" refer to the groups -NH(alkyl), -N(alkyl)2, -NH(alkenyl), -NH(alkynyl), -N(alkenyl)2, and N(alkynyl)2 (wherein the terms "alkyl," "alkenyl," and "alkynyl" are as defined above). In some embodiments, the alkyl component of the alkylamino or dialkylamino group is C1-C 12 , C1-C 10 It contains C1-C8, C1-C6, or C1-C4 alkyl groups.

[0032] The terms "alkylcarbonyl," "alkoxycarbonyl," "alkylaminocarbonyl," and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)-, and dialkylamino-C(O)- (wherein alkyl, alkoxy, alkylamino, and dialkylamino are as defined above). Similarly, the terms "haloalkylcarbonyl," "haloalkoxycarbonyl," "haloalkylaminocarbonyl," and "dihaloalkylaminocarbonyl" refer to haloalkyl-C(O)- group, haloalkoxy-C(O)- group, haloalkylamino-C(O)- group, and dihaloalkylamino-C(O)- group (wherein haloalkyl, haloalkoxy, haloalkylamino, and dihaloalkylamino are as defined above). [Modes for carrying out the invention]

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

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

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

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

[0037] R 4 and R 4’ Independently in each appearance, 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 (which may be substituted alkyl or haloalkyl); or R 4 is R 4’Together with these, they form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and together with the carbon atoms to which they are bonded, they form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d is independently H or an optionally substituted alkyl; or R c and R d These, together with the nitrogen to which they are bonded, may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group;

[0038] R 8 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl; R 9 and R 9’ is independently hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy; or R 9 is R 9’ Together with these, they form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and together with the carbon atoms to which they are bonded, they form a carbocyclic or heterocyclic ring, and the carbon or nitrogen atoms in the chain may be substituted; Q is CR 8 or N; X is O, S, or N-R'; Y 1 and Y 6 These are N, C, or -CR, each independently. 4 -and; Y 2 , Y 3 , Y 4 and Y 5 These are N and NR, respectively, independently. ’ S, O, -CR 4 - or CR4 R 4’ is; W is CR 5 R 6 、O、 SO p 、 or N-R 7 and; Z is CR 5 R 6 、 O、 SO p 、 or N-R 7 and; wherein; R 5 and R 6 are each independently, hydrogen, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or cycloalkoxy, or R 5 is R 6 together with may contain one or two heteroatoms selected from the group consisting of N, O, Si and S to form a 2- to 6-membered chain, which together with the carbon atom to which they are attached forms a carbocyclic or heterocyclic ring, and the carbon or nitrogen in the carbocyclic or heterocyclic ring may be substituted;

[0039] R 7 is hydrogen or C1-C4-alkyl; Y 1 、 Y 2 、 Y 3 、 Y 4 、 Y 5 and Y 6 at most three of are heteroatoms; a is 0 or 1; q is 0 or 1; p is each independently, 0, 1 or 2; dashed bond

Chemical formula

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

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

[0042] R 3C1-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 substituted or alternatively substituted 3-7 membered heterocyclils containing 1-3 heteroatoms selected from the group consisting of (C1-C6-alkyl or C1-C6-haloalkyl), N, O, and S; optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, 5-11 membered spirocyclic heterocyclyl-carbocyclyl group, 5-11 membered spirocyclic heterocyclyl-heterocyclyl group, 5-11 membered spirocyclic carbocyclyl-carbocyclyl group, 5-11 membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b is independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b These, together with the nitrogen to which they are bonded, may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group;

[0043] R 4 and R 4’Each appearance independently includes hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cyclo Lukyloxy, 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 (C1-C6-alkyl or C1-C6-haloalkyl which may be substituted); or R 4 is R 4’ Together with these, they form a 2-6 membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and together with the carbon atoms to which they are bonded, they form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d is independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R c and R d These, together with the nitrogen to which they are bonded, may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group;

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

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

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

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

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

[0049] In another embodiment, R 1 These are methyl, ethyl, propyl, butyl, pentyl, isopropyl (i-Pr), tert-butyl (t-butyl), propa-1-en-2-yl, 2-fluoropropa-2-yl, 1,1-difluoroethyl, or 2-hydroxypropa-2-yl. In another embodiment, R 1 is a C1-C3-alkoxy or C1-C3-haloalkoxy. In another embodiment, R 1 This is either OCH3 or OCH2CH3. In another embodiment, R 1 This is either OCF3 or SCF3. In another embodiment, R 1 These are CF3, -CH2CF3, -CHFCF3, or CF2CF3. In some embodiments, R 1 These are C2-C4-alkenyls or C2-C4-haloalkenyls. In some embodiments, R 1 The compound is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

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

[0051] In some embodiments, R 1 Tetrahydrofuryl, dihydrofuryl, morpholino, pyranil, dihydropyranil, piperidinil, dihydropiperidinil, dihydrothiophene, or tetrahydrothiophene may be substituted. In some embodiments, R 1 This is a phenyl that may be substituted. In some embodiments, R 1is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl.

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

[0053] In another embodiment, R 2 These are C1-C4-alkenyls or C1-C4-haloalkenyls. In some embodiments, R 2 The compound is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, R 2 It is a saturated or unsaturated six-membered heterocyclyl group, which may be substituted. In some embodiments, R 2 Tetrahydrofuryl, dihydrofuryl, morpholino, pyranil, dihydropyranil, piperidinil, dihydropiperidinil, dihydrothiophene, or tetrahydrothiophene may be substituted. In some embodiments, R 2 It is a phenyl that may be substituted.

[0054] In other embodiments, R 2However, the phenyl is independently substituted with one, two, or three substituents which are halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In another embodiment, R 2 However, it is a 5-membered or 6-membered heteroaryl having one or two substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In one embodiment, R 2 is halo, cyano, nitro, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy or (C1-C3-alkyl or C1-C3-haloalkyl)S(O) p It is a pyridinyl that may be substituted with [another compound].

[0055] In some embodiments, R 2Azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, pi These are perazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, or triazinyl. In some embodiments, R 2 However, all of these are azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, which may be substituted with one or more halogens. In some embodiments, R 3 It is a 6- to 10-membered aryl compound which may be substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, R 3 These are C1-C4-alkyl and C1-C4-haloalkyl groups. In some embodiments, R 3 The active ingredients are methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl, sec-butyl, or isobutyl.

[0056] In other embodiments, R 3 These are CF3, -CH2CF3, -CHFCF3, or CF2CF3. In some embodiments, R 3 It is a C3-C8 cycloalkyl group which may be substituted. In yet another embodiment, R 3 It is a C3-C6 cycloalkyl group which may be substituted. In yet another embodiment, R 3A C3-C8-cycloalkenyl or C3-C6-cycloalkenyl which may be substituted. In some embodiments, R 3 It is a cyclopentyl or cyclohexyl which may be substituted. In other embodiments, R 3 It is a cyclopropyl or cyclobutyl which may be substituted. In one embodiment, R 3 R is a cyclohexyl which may be substituted with one or more halo, C1-C3-alkyl or C1-C3-haloalkyl groups. In another embodiment, R 3 It is a cyclohexyl molecule substituted with one or two fluoro, chloro, or CF3 groups.

[0057] In some embodiments, R 3 The piperidinyl, morpholinyl, tetrahydrofuranil, or dihydrofuranil may be substituted. In some embodiments, R 3 However, it is piperidinyl, morpholinyl, tetrahydrofuranil, or dihydrofuranil substituted with one or more halo, C1-C6-alkyl, or C1-C6-haloalkyl. In another embodiment, R 3 The particles are piperidinyl, morpholinyl, tetrahydrofuranyl, or dihydrofuranyl, which are substituted with one or more methyl, chloro, or fluoro groups. In some embodiments, R 3 The 5-10 member heteroaryl is a 5-10 member heteroaryl which may be substituted with 1, 2, 3, 4, or 5 substituents. In one embodiment, the 5-10 member heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidyl, or pyrrolopyrimidyl.

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

[0059] In some embodiments, R 3 R is a phenyl compound substituted with 1 to 4 substituents. In another embodiment, R 3 R is a phenyl compound substituted with 1 to 3 substituents. In yet another embodiment, R 3 R is a phenyl molecule substituted with one or two substituents. In some embodiments, R 3However, the phenyl is independently substituted with 1, 2, 3 or 4 substituents which are halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy. In some embodiments, R 3 This is a para-substituted phenyl. In some embodiments, R 3 This is a metasubstituted phenyl. In some embodiments, R 3 This is an ortho-substituted phenyl compound. In some embodiments, R 3 is a halophenyl. In some embodiments, R 3 These are haloalkylphenyls. In some embodiments, R 3 This is a haloalkoxyphenyl.

[0060] In some embodiments, R 3 However, the phenyl is substituted with two substituents that are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 This is a 2,3-disubstituted phenyl compound. In some embodiments, R 3 This is a 2,4-disubstituted phenyl compound. In some embodiments, R 3 This is a 2,5-disubstituted phenyl compound. In some embodiments, R 3 This is a 2,6-disubstituted phenyl compound. In some embodiments, R3 is a 3,5-disubstituted phenyl. In other embodiments, R 3 This is a 3,4-disubstituted phenyl compound. In other embodiments, R 3 This is a 3,6-disubstituted phenyl compound. In some embodiments, R 3 These are dihalophenyls, such as dichloro; difluoro; or chloro,fluoro.

[0061] In some embodiments, R 3 This is 2,3-dihalophenyl. In some embodiments, R 3 is chlorophenyl. In another embodiment, R 3 is fluorophenyl. In another embodiment, R 3 is dichlorophenyl. In another embodiment, R 3 In yet another embodiment, R 3 In another embodiment, R 3 In another embodiment, R 3 In another embodiment, R 3 This is 2,6-difluorophenyl. In some embodiments, R 3 These are phenyls substituted with halo and haloalkyl groups. In some embodiments, R 3 This is phenyl substituted with halo and haloalkoxy. In some embodiments, R 3 This is a phenyl substituted with a haloalkyl or haloalkoxy.

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

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

[0064] In some embodiments, R 3 However, 3-pyridyl may be independently substituted with one or two substituents which are halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy. In some embodiments, R 3 However, 4-pyridyl may be independently substituted with one or two substituents which are halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0065] In another embodiment, R 3However, it is 4-pyridyl that is unsubstituted or substituted with one or two chloro or fluoro groups. In yet another embodiment, R 3 However, it is an unsubstituted 3-pyridyl, or one or two chloro or fluoro-substituted 3-pyridyls. In other embodiments, R 3 It is a 3- to 7-membered complex ring in which R may be substituted. In some embodiments, R 3 Azilidinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, pi These are perazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, triazolyl, or triazinyl.

[0066] In another embodiment, R 3 It may be a heterocyclic or bridging bicyclic group, which may be substituted. In some embodiments, R 4 and / or R 4’ That is hydrogen. Several embodiments, each R 4 and / or R 4’ These are independently hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, amino, C1-C4-alkylamino, or di-(C1-C4 alkyl)amino. Several embodiments, each R 4 and / or R 4’These are independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In another embodiment, R 4 and / or R 4’ These are independently hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3. In some embodiments, R 4 and / or R 4’ These are independently hydrogen or halogen. In another embodiment, R 4 and / or R 4’ These are independently hydrogen, fluoro, or chloro. In another embodiment, R 4 and / or R 4’ These independently consist of hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or S(O) p (C1-C4-alkyl or C1-C4-haloalkyl) (wherein p is 0, 1, or 2).

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

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

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

[0070] In one embodiment, R 8 In another embodiment, R 8 The compound is C1-C3-alkyl or C1-C3-haloalkyl. In some embodiments, R 9 and / or R 9’ Each of these is hydrogen. In another embodiment, R 9 and / or R 9’ These combine to form 2-6 membered chains, which together with the carbon atoms to which they are bonded form spirocyclic ring substituents. In another embodiment, R 9 and / or R 9’ These combine to form 2-5 membered chains, which together with the carbon atoms to which they are bonded form spirocyclic substituents. In another embodiment, R 9 and / or R 9’These combine to form 2-4 membered chains, which together with the carbon atoms to which they are bonded form spirocyclic substituents. In another embodiment, R 9 and / or R 9’ These combine to form a 2 or 3-membered chain, which together with the carbon atoms to which they are bonded to form a spirocyclic substituent. In another embodiment, R 9 and / or R 9’ These combine to form a two-membered chain, which, together with the carbon atom to which they are bonded, forms a spirocyclic substituent. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, Q is N.

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

[0072] In some embodiments, the compound of formula (I) is the compound of formula (I-1): [ka] (I-1) (In the formula, variable elements 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 defined for equation (I)) That is the case.

[0073] In one embodiment of formula (I-1), W is CH2 and Z is O. In another embodiment, Q is N. In yet another embodiment, Q is CR 8 In another embodiment of equation (I-1), W is CH2 and Z is CH2. In another embodiment of equation (I-1), W is CR 5 R 6 (In the formula, R 5 and R 6 (where is C1-C3-alkyl or C1-C3-haloalkyl, and Z is O). In another embodiment of formula (I-1), W is CR 5 R 6 And Z is CR 5 R 6 (In the formula, each R 5 and R 6 (is independently C1-C3-alkyl or C1-C3-haloalkyl). In another embodiment of formula (I-1), W is CR 5 R 6 (In the formula, R 5 and R 6 In another embodiment, a is 0 and Z is O. In yet another embodiment, a is 0, Z is O and W is CH2. In one embodiment of formula (I-1), Y 3 S is. In one embodiment of equation (I-1), Y 5In another embodiment, Y 3 In another embodiment, Y 5 This is N. In another embodiment of equation (I-1), Y 5 N is Y 3 In yet another embodiment of equation (I-1), Y 5 S is Y 3 This is N. In another embodiment of equation (I-1), Y 6 and Y 3 These are N, respectively. In another embodiment of equation (I-1), Y 6 N is Y 3 In another embodiment, Y 1 N is Y 5 This is N.

[0074] In some embodiments, the compound of formula (I) is the compound of formula (I-2): [ka] (I-2) (In the formula, the variable element 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 defined for equation (I)) That is the case.

[0075] In other embodiments, the compound of formula (I) is the following compound of formula (I-3): [ka] (I-3) (In the formula, the variable element R 1 , R 2 , R 3 , R ’ , R 8 , R 9 , R 9’ , Y 2 , Y3 , Y 4 , Y 5 (X, W, Z, and a are defined for equation (I)) That is the case.

[0076] In other embodiments, the compound of formula (I) is the compound of formula (I-4): [ka] (I-4) (In the formula, the variable element 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 defined for equation (I)) That is the case.

[0077] In another embodiment, the compound of formula (I) is the compound of formula (I-5): [ka] (I-5) (In the formula, the variable element 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 defined for equation (I)) That is the case.

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

[0079] In some embodiments, the compound of formula (I) is the compound of formula (Ib): [ka] (Ib) (In the formula, the variable element 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 defined for equation (I)) That is the case.

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

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

[0082] In other embodiments, the compound of formula (I) is the compound of formula (Ie): [ka] (Ie) (In the formula, the variable element 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 equation (I); m is 0, 1, 2, 3 or 4; each R 10cyano, halo, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C3-C8-hydroxy substituted 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of cycloalkyl, optionally substituted C3-C8-cycloalkyloxy, N, O, Si, and S; 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 c R d (In the formula, R a and R b is independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b These, together with the nitrogen to which they are bonded, may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group.

[0083] In one embodiment of formula (Ie), R 10 This is a halo. In another embodiment, R 10 In yet another embodiment, R 10 is fluoro. In another embodiment, R 10In yet another embodiment, R 10 In another embodiment, R 10 In another embodiment, R 10 In another embodiment, R 10 is fluoro or chloro, m is 2, and the fluoro or chloro is substituted at the 2nd and 6th positions of the phenyl ring.

[0084] In other embodiments, the compound of formula (I) is the compound of formula (If): [ka] (If) (In the formula, the variable element 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 defined for equation (I); R 10 and m are as defined for equation (Ie); b is 0 or 1; dashed connection [ka] indicates a single or double bond; D is N, SiR 11 (In the formula, R 11 (is C1-C6 alkyl or C1-C6 haloalkyl), C or CR 4 And; D 1 are N, O, SiR 11 R 12 (In the formula, R 11 and R 12 (These are independently C1-C6 alkyl or C1-C6 haloalkyl), -CR 4 R 4’ , S(O) p(wherein the formula p is 0, 1 or 2) or D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ These atoms combine to form a 2- to 5-membered chain, which may be replaced by one heteroatom in the chain, and form a spirocyclic group.

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

[0086] In some embodiments, the present invention is D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ The present invention provides a compound of formula (If), in which (together, together with an arbitrary heteroatom in the chain, form a 2-5 membered chain to form a spirocyclic group). In some embodiments, the present invention is D 1 The present invention provides a compound of formula (If) in which is CH2, and independently C-(halo)2, CH(C1-C3-alkyl), or CH(C1-C3-haloalkyl). In some embodiments, the present invention is D 1 The present invention provides a compound of formula (If) in which is CH2, and independently CF2, CH(CH3), or CH(CF3). In some embodiments, the present invention is D 1 The present invention provides a compound of formula (If) in which is O, S, S(O), or S(O)2.

[0087] In some embodiments, the present invention is that D is CH or C-halo; D 1This provides a compound of formula (If) in which is CH2. In some embodiments, the present invention is D is N; D 1 The present invention provides a compound of formula (If) in which is CH2, O, or S. In some embodiments, the present invention is that D is N, and D 1 SiR 11 R 12 The present invention provides a compound of formula (If), wherein D is CH2, and D 1 SiR 11 R 12 In yet another embodiment, D is N, and D 1 This is Si(CH3)2.

[0088] In some embodiments, the present invention is such that the dashed bond is a double bond; D is C; D 1 The present invention provides a compound of formula (If) in which is CH2, CF2, O, or S. In some embodiments, the present invention is D is N; D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ The present invention provides a compound of formula (If), in which (these two atoms combine to form a 2-4 membered chain with any one oxygen atom in the chain, forming a spirocyclic group). In some embodiments, the present invention is that D is CH; D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ The present invention provides a compound of formula (If), in which (these two atoms combine to form a 2-4 membered chain with any one oxygen atom in the chain, forming a spirocyclic group). In some embodiments, the present invention is such that D is C and the dashed line indicates a double bond; D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ The present invention provides a compound of formula (If), in which (these two atoms combine to form a 2-4 membered chain with any one oxygen atom in the chain, forming a spirocyclic group). Variable element R 4 It has been shown that (R) exists as a substituent on the aromatic ring (for example, (R 4 ) o The group (wherein o is 0, 1, 2, 3, or 4) In the above formulas (Ic) and (Id), in the embodiment where o is 0, R4 is absent, so it will be recognized by those skilled in the art that these represent non-hydrogen substituents. The same principle applies to the variable element R in the compounds of formulas (Ie) and (If). 10 Applies to this.

[0089] In other embodiments, the present invention relates to a compound of formula (Ia) (wherein the formula, variable element R 1 , R 2 , R 3 , R', R 4 , R 9 , R 9’ W, Z, R 8 And a are defined for equation (I) above, and Y 2 , Y 3 , Y 4 and Y 5 The following are provided (as shown in Table 1): [ka] (Ia)

[0090] [Table 1]

[0091] In other embodiments, the present invention relates to a compound of formula (Ib) (wherein the formula is a variable element R 1 , R 2 , R 3 , R 4 , R', R 9 , R 9’ W, Z, R 8 And a are defined for equation (I) above, and Y 2 , Y 3 , Y 4 and Y 5 The following are provided (as shown in Table 2): [ka] (Ib)

[0092] [Table 2]

[0093] In some embodiments, the present invention relates to each R 2 These are independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy (haloaloxy) or S(O) p The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), which are (C1-C4-alkyl or C1-C4-haloalkyl). In some embodiments, the present invention relates to each R 2 The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein H is independently, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0094] In some embodiments, the present invention relates to each R 2 The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3 are independently present. In some embodiments, the present invention relates to each R 2 The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein H is independently methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention relates to each R 2The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein H, -OCF3, or -SCF3 are independently present. In some embodiments, the present invention relates to each R 4 and / or R 4’ These are independently H, halo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy (haloaloxy) or S(O) p The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), which are (C1-C4-alkyl or C1-C4-haloalkyl).

[0095] In some embodiments, the present invention relates to each R 4 and / or R 4’ The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein H is independently, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, the present invention relates to each R 4 and / or R 4’ The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3 are independently present. In some embodiments, the present invention relates to each R 4 and / or R 4’ The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein H is independently methoxy, ethoxy, propoxy, or butoxy. In some embodiments, the present invention relates to each R 4 and / or R 4’The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein H, -OCF3, or -SCF3 are independently present.

[0096] In other embodiments, the present invention is R ’ and R 8 The present invention provides compounds of formula (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein each of the elements is independently H or C1-C3-alkyl. In other embodiments, the present invention provides compounds of formulas (Ia) to (If) where a is 1, W is CH2, and Z is O. In other embodiments, the present invention is R 1 is C1-C6-alkyl, C1-C6-haloalkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, optionally substituted C3-C8-cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, or -NR a R b (In the formula, R a and R b is independently H or an optionally substituted C1-C6 alkyl; or R a and R b The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), which may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, together with the nitrogen to which they are bonded, and which may form a substituted 3-membered, 4-membered, 5-membered, or 6-membered heterocyclyl group.

[0097] In other embodiments, the present invention is R 3NR is a substituted 3-7 member heterocycline containing 1-3 heteroatoms selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, optionally substituted C3-C8-cycloalkyl, N, O, and S; optionally substituted phenyl, optionally substituted 5-10 member heteroaryl, 5-11 member spirocyclic heterocyclyl-carbocyclyl group, 5-11 member spirocyclic heterocyclyl-heterocyclyl group, 5-11 member spirocyclic carbocyclyl-carbocyclyl group, or NR a R b (In the formula, R a and R b is independently H, C1-C6-alkyl or C1-C6-haloalkyl; or R a and R b The present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), which may contain 1 to 3 additional heteroatoms selected from the group consisting of N, O, and S, together with the nitrogen to which they are bonded, and which may form a substituted 3-membered, 4-membered, 5-membered, or 6-membered heterocyclyl group.

[0098] In other embodiments, the present invention is R 3 The present invention provides compounds of the above formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), which are phenyl which may be substituted. In another embodiment, R 3 Compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R is a phenyl substituted with one or more halogens. In yet another embodiment, R 3 Compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, where R is a phenyl substituted with one halogen. In another embodiment, R 3Compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, where R is a phenyl substituted with two halogens. In yet another embodiment, R 3 Compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein one of the compounds is a phenyl substituted with three or four halogens.

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

[0100] In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y5 Each of these is a CH. In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y 5 Each of these independently undergoes CH or CR 4 (In the formula, R 4 ( is a non-hydrogen substituent.) In other embodiments of formulas (I-1), (I-4), and (I-5), Y 3 , Y 4 and Y 5 Each of these is a CH. In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib), and (Ie), Y 2 , Y 3 , Y 4 , Y 5 Each of these is independently either CH or C-halogen. In any of the embodiments of the above formulas (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.

[0101] In any of the embodiments of the above formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 1 The compound is C1-C4-alkyl, and is a C1-C4 alkenyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl. In any of the embodiments of the above formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If), R 4 But other R 4Independently from these, phenyl may be substituted once or twice with a halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, or halo or C1-C4-alkyl. In some embodiments, the present invention includes compounds of formula (I), the group being as follows.

[0102] In other embodiments, the present invention is L, R 1 , R 2 and R 3 As defined in Table 3 below, X is O, R' is hydrogen, and the base [ka] However, it provides a compound of formula (I) shown in Table 3 below, which is one of the following ring systems: [ka] Ring system A;

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

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

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

[0106]

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[0107]

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[0108]

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[0109]

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[0110]

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[0111]

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[0112]

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[0113]

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[0114]

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[0115]

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[0116]

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[0117]

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[0118]

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[0119]

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[0120]

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[0121]

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[0122]

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[0123]

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[0124]

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[0125]

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[0126]

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[0127]

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[0128]

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[0129]

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[0130]

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

[0132] 2-F-prop-2-il is based on [ka] It represents; 1,1-difluoroethyl is a group [ka] It represents.

[0133] [ka] Equation (I)

[0134] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] To avoid any ambiguity, each of the compounds presented in Table 3 was prepared.

[0135] Stereoisomers and polymorphs It is recognized by those skilled in the art that compounds can exist and be isolated in optically active and racemic forms. Compounds having one or more chiral centers, including one located on a sulfur atom, can exist as 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 a racemic mixture. Furthermore, the compounds of the present invention contain one or more chiral centers and can result in a theoretical number of optically active isomers. In this case, the compound of formula (I) is such that Q is CR 8 When this is the case, the variable element R 8 The carbon atom having at least one chiral center. If the compound herein contains n chiral centers, the compound may have up to 2 n It may contain multiple optical isomers. Therefore, the compounds of the present invention contain at least two enantiomers encompassed by the present invention. The present invention encompasses specific enantiomers or diastereomers of each compound having the useful properties described herein, as well as mixtures of various enantiomers and / or diastereomers of the compounds. The optically active form can be prepared, for example, by selective crystallization techniques for racemic form resolution, synthesis from optically active precursors, chiral synthesis, chromatographic separation using a chiral stationary phase, or enzymatic resolution. Compounds can also exist in various solid forms, such as various crystalline forms, or in amorphous solid forms. This invention includes various crystalline and amorphous forms of compounds. Furthermore, the compounds may exist as hydrates or solvates in which a certain stoichiometric amount of water or solvent is associated with molecules in crystalline form. Hydrates and solvates of compounds are also the subject of this invention.

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

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

[0138] Method for preparing compounds Compounds of formula (I) or pharmaceutically or veterinarily acceptable salts thereof can be prepared by employing the procedures of schemes 1 and 2 and the examples below: Scheme 1 [ka]

[0139] Scheme 2 [ka] In scheme 2, the variable element R 1 , R 2 and R 3 R represents the group defined in formula (I) above, which can be introduced by a metal-catalyzed cross-coupling reaction. Examples include the Heck reaction, the Negishi coupling reaction, the Still cross-coupling reaction, the Suzuki reaction, and other reactions well known in the art. Variable element R 5 represents a linker L bonded at this position on the bicyclic core to one of the bicyclic rings shown in formula (I). Adapting these schemes to synthesize the specific compounds of the present invention is well within the skill level of those skilled in the art. Furthermore, the starting materials are readily available or can be prepared through known procedures.

[0140] Veterinary composition Compounds and compositions containing the compounds are useful for the prevention and / or treatment of parasitic invasion / infection in animals. The compositions of the present invention contain an effective amount of the compound or a veterinarily acceptable salt thereof in combination with a veterinarily acceptable carrier or diluent and optionally an inactive excipient. The compositions may be in various solid and liquid forms suitable for various forms of administration or administration to animals. For example, veterinary compositions containing the compounds may be compositions suitable for oral administration, injection administration including subcutaneous and parenteral administration, and topical administration (e.g., spot-on and pore-on), skin or subcutaneous administration. The compositions are intended for administration to animals, including mammals, birds and fish, but are not limited to these. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other domesticated or farmed mammals. Examples of birds include turkeys, chickens, ostriches and other domesticated or farmed birds. The use of the compounds is particularly useful for protecting companion animals such as dogs and cats from endoparasites.

[0141] As discussed above, the compositions of the present invention may be in forms suitable for oral use (e.g., see U.S. Patent No. 4,564,631, which is thus entirely incorporated by reference), dietary supplements, lozenges, chewable tablets, tablets, hard or soft capsules, boluses, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral aqueous drug compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric-coated compositions or pastes. Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more sweeteners, bittering agents, flavoring agents, coloring agents and preservatives to provide pharmaceutically fine and tasty preparations. Tablets may contain the active ingredient in a mixture with non-toxic and pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents; granulators and disintegrants; binders; and lubricants. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period. Tablets may also be coated by techniques described in U.S. Patents 4,256,108; 4,166,452; and 4,265,874 (all incorporated herein by reference in their entirety) to form osmotic therapeutic tablets for controlled release.

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

[0143] The compounds may also contain other inert components, such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the field of composition. Antioxidants may be added to the compositions of the present invention to inhibit the degradation of the activators. The compositions of the present invention may also comprise one or more lubricants and / or machining aids. In some cases, the lubricants / machining aids may also act as solvents, and therefore some of the components of the compositions of the present invention may have dual functions. Many flavoring agents can be used in the compositions of the present invention to improve the palatability of the oral veterinary composition. Preferred flavoring agents are those not derived from animal sources. In various embodiments, flavorings derived from fruits, meat (including, but not limited to, pork, beef, chicken, fish, and poultry), vegetables, cheese, bacon, cheese-bacon, and / or artificial flavorings may be used. Flavorings are typically selected based on considerations relating to the organisms that will ingest the soft chew. For example, horses may prefer apple flavorings, while dogs may prefer meat flavorings. While flavorings derived from non-animal sources are preferred, in some embodiments, natural flavorings containing beef or liver extracts such as boiled beef flavorings, artificial powdered beef flavorings, roast beef flavorings, and corned beef flavorings may be used.

[0144] In another embodiment of the present invention, the active composition may be administered via an aqueous solution, which may be administered topically or orally. The aqueous solution is such that the liquid-containing composition of the present invention is administered into the mouth or throat of an animal, or poured onto the skin or fur of an animal. The compositions of the present invention may also be in the form of oil-in-water or water-in-oil emulsions that may contain emulsifiers known in the art. The emulsions may also contain sweeteners, bittering agents, flavoring agents and / or preservatives. In one embodiment, the composition of the present invention may be in the form of a microemulsion. Microemulsions are well suitable as liquid carrier vehicles. A microemulsion is a four-component system comprising an aqueous phase, an oil phase, a surfactant, and a co-surfactant. These are translucent, isotropic liquids. Microemulsions consist of a stable dispersion of minute droplets of an aqueous phase in an oil phase, or conversely, a stable dispersion of minute droplets of an oil phase in an aqueous phase.

[0145] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil. Oily suspensions may contain thickeners. Sweeteners, bittering agents, and flavoring agents can be added to obtain palatable oral preparations. These compositions can be preserved by adding antioxidants or other known preservatives. The aqueous suspension may contain the active material as a mixture with excipients suitable for the preparation of the aqueous suspension. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavorings, and one or more sweeteners and / or bitterings. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water may provide the active ingredient in mixtures with a dispersant or wetting agent, a suspending agent and one or more preservatives. Additional excipients, such as sweeteners, bittering agents, flavoring agents and coloring agents, may also be present. Syrups and elixirs may be formulated using sweeteners. Such compositions may also contain lubricants, preservatives, flavorings, and / or colorings. In another embodiment of the present invention, the composition may be in paste form. Examples of embodiments in paste form include, but are not limited to, those described in U.S. Patents 6,787,342 and 7,001,889 (each incorporated herein by reference). In addition to the compounds of the present invention, the paste may further contain fumed silica; viscosity modifiers; carriers; optionally, absorbents; and optionally, colorants, stabilizers, surfactants, or preservatives.

[0146] In some embodiments, the composition may be in the form of an aqueous or oily suspension for sterile injection. This suspension may be formulated according to the prior art using suitable dispersants or wetting agents and suspending agents as mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent. Furthermore, sterile non-volatile oils may conventionally be used as solvents or suspension media. Topical skin and subcutaneous compositions may include, in non-limiting examples, emulsions, creams, ointments, gels, pastes, powders, shampoos, pore-on compositions, ready-to-use compositions, spot-on solutions and suspensions, dips, and sprays. Topical application of the compounds of the present invention or compositions in the form of spot-on, spray-on, or pore-on compositions, which contain at least one of the compounds of the present invention among several active agents, may enable the compositions of the present invention to be absorbed through the skin to achieve systemic levels, or distributed through the sebaceous glands or onto the surface of the skin to achieve levels through the fur. Spot-on compositions are typically applied to localized areas that refer to areas other than the entire animal. In one embodiment, the location may be between the shoulders. In another embodiment, the topical composition may be administered as stripes on the surface of the animal, for example, stripes from the animal's head to its tail.

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

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

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

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

[0151] The use of compounds of formula (I) in the preparation of pharmaceuticals for treating and / or preventing ectoparasitic infections in animals is also provided. The present invention also provides compounds of formula (I) for use in treating and / or preventing ectoparasitic infections in animals. In another embodiment, the present invention provides a method for treating and / or preventing endoparasitic infections and extrinsic parasitic invasions in or on an animal, comprising administering to the animal a composition comprising an effective amount of a compound of formula (I) in combination with an effective amount of at least a second activator or a veterinarily acceptable salt thereof. Compounds of formula (I) used in combination with at least a second activator for use in treating and / or preventing endoparasitic infections and extrinsic parasitic infections are also provided herein. Furthermore, compounds of formula (I) used in combination with at least a second activator are provided in the preparation of pharmaceuticals for the preparation of pharmaceuticals for treating and / or preventing endoparasitic infections and extrinsic parasitic infections.

[0152] In yet another embodiment of the present invention, a method is provided for treating and / or preventing a parasitic infestation of a site, comprising administering or applying a parasitic effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof to the site. With respect to animal health applications, “site” is intended to mean a habitat, breeding ground, region, material or environment in which a parasite is growing or can grow, except in and on an animal. In another embodiment, the present invention provides methods and compounds for controlling plant and crop pests or for protecting wood-containing structures. In some embodiments, the animals that can be treated are mammals, 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 invention, the mammal being treated is a human, a cat, or a dog. In one embodiment of this specification, the compound of formula (I) was found to have excellent efficacy against endoparasites, particularly against endoparasites resistant to macrocyclic lactone class activators. In one embodiment, the compounds and compositions of the present invention are effective in controlling Haemonchus contortus, Ostertagia circumcincta, and Trichostrongylus colubriformis in mammals or birds.

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

[0154] In one embodiment, the compounds and compositions of the present invention may be used to treat and / or prevent endoparasitic infections of the following parasites: Anaplocephala (Anoplocephala), Hookworm, American Hookworm, Roundworm, Brugia, Bunostomum, Capillary Nematodes, Chabertia, Cooperia, Cyatostomum, Silicocyclus (C) ylicocyclus), Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Gyō Genus *Chu*, *Fasciola*, *Filaroides*, *Habronema*, *Haemonchus*, *Metastrongylus*, *Moniezia*, *Hookworm*, *Nematodirus*, *Nippostrongylus*, *Oesophagostomum*, *Onchocerca*, *Ostertagia* ertagia), genera Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Stronyloides, Toxascaris, Trichinella, Whipworms, Trichostrongylus, Triodontophorus, Uncinaria, Wuchereria, and combinations thereof.

[0155] In a particularly preferred embodiment of the present invention, the compounds and compositions of the present invention are used to treat and / or prevent infection by Dirophila imitis. The compounds have been found to be highly effective against D. imitis microfilariae and L4 larvae. Therefore, by using the compounds, animals can be prevented from developing canine heartworm disease by killing the immature stage of D. imitis before it can develop into an adult. In one embodiment, the development of canine heartworm disease can be prevented by using the compounds and compositions containing the compounds to kill the immature stage of D. imitis resistant to macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are used to treat and / or prevent infection by Dirophila repens or Dirophila hongkongensis. In another embodiment of the present invention, the parasite is torsion gastritis, Ostertasia sarcumcinct, Trichostrongylus axei, Trichostrongylus colbriformis, Cooperia curticei, Nematodirus battus, or a combination thereof.

[0156] In another embodiment of treatment for both endoparasites and ectoparasites when combined with an exocaridant agent, the ectoparasites include species of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, and Sarcoptes. ), one or more insects or arachnids, including those belonging to the genera Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.

[0157] In another embodiment of treatment for ectoparasites, the ectoparasites are of the genera *Ixodes*, *Ixodes*, *Ixodes*, *Ixodes*, and / or *Ixodes*. The ectoparasites treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides). Examples include fleas (such as *Felis*), ticks (such as *Ixodes*, *Ixodes*, *Amblyoma*, and *Amblyoma rhodopolium*), mites (such as *Demodex*, *Sarcoptes*, and *Otodectes*), lice (such as *Lysimachia*, *Cheyletiella*, and *Lysimachia*), mosquitoes (such as *Aedes*, *Culex*, and *Anopheles*), and flies (such as *Haematobia*, *Musca*, *Stomoxys*, *Dermatobia*, and *Cochliomyia*). In yet another embodiment of treatment for ectoparasites, the ectoparasite is a flea and / or tick.

[0158] Additional examples of ectoparasites include, but are not limited to, ticks, particularly the Ixodes species Ixodes microplus, Ixodes decoloratus, and Ixodes annulatus; fly larvae, e.g., Dermatobia hominis (known as Bern in Brazil) and Cochliomyia hominivorax (blowfly); sheep fly larvae, e.g., Lucilia sericata and Lucilia cuprina (known as black fly myiasis in Australia, New Zealand, and South Africa). Examples of endemic flies include adults that are parasitic, such as the stable fly (Haematobia irritans); lice, such as the cow louse (Linognathus vitulorum); and mites, such as the scabies mite (Sarcoptes scabiei) and the sheep mite (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.

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

[0160] Furthermore, with or without the addition of other biological agents to the composition, the present invention may also be used to treat other pests, including, but not limited to, the following pests: (1) Species of the order Isopoda, such as Oniscus asellus, Armadillidium vulgare, and Porcellio scaber; (2) Species of the order Diplopoda, such as Blaniulus guttulatus; (3) Species of the order Chilopoda, such as Geophilus carpophagus and species of the genus Scutigera; (4) Those belonging to the order Symphyla, for example, Scutigerella immaculata; (5) Those with the thysanura pattern, such as the silverfish (Lepisma saccharina);

[0161] (6) Those of the order Collembola, for example, Onychiurus armatus; (7) Species of the order Blattaria, such as the oriental cockroach (Blatta orientalis), the American cockroach (Periplaneta americana), the Madera cockroach (Leucophaea maderae), and the German cockroach; (8) Species of the order Hymenoptera, such as species of the genera Diprion, Hoplocampa, Lasius, Monomorium pharaonis, and Vespa; (9) Fleas of the order Siphonaptera, such as the mouse flea Xenopsylla cheopis and species of the genus Ceratophyllus; (10) Species of the suborder Anoplura (or Phthiraptera), such as species of the genus Damarina, species of the genus Pediculus, species of the genus Pediculus, and species of the genus Pediculus;

[0162] (11) Species of the class Arachnida, such as Acarus siro, Aceria sheldoni, species of the genera Aculops, Aculus, Ixodes, Argas, Ixodes, Brevipalpus, Bryobia praetiosa, Dermanyssus gallinae, Eotetranychus, and Epitrimerus piri Pyrri), species of Eutetranychus, Eriophyes, Hemitarsonemus, species of Ixodes, species of Ixodes, black widow spider (Latrodectus mactans), species of Metatetranychus, species of Oligonychus, species of Ornithodoros, species of Panonychus, citrus rust mite (Phyllocoptruta oleivora), broad mite (Polyphagotarsonemus latus), species of Sarcoptes scabiei, species of Ixodes, species of Rhizoglyphus, species of Sarcoptes, Scorpio maurus), species of the genus Stenotarsonemus, species of Tarsonemus, species of Tetranychus, Vasates lycopersici; (12) Species of the class Bivalva, such as the genus Dreissena;

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

[0164] (14) Diptera species, such as Aedes mosquitoes, Anopheles mosquitoes, Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia species, Cochlomyia species, Cordylobia anthropophaga, Culex species, Cuterebra species, and olive fruit flies (Dacus) oleae), human botfly, species of Drosophila, species of Fannia, species of Gastrophilus, species of Hylemyia, species of Hyppobosca, species of Hypoderma, species of Liriomyza, species of Lucilia, species of Musca, species of Nezara, species of Oestrus, Oscinella frit, Pegomyia hyoscyami, species of Phorbia, species of Stomoxis, species of Tabanus, species of Tannia, Tipula pardosa paludosa), a species of the genus Wohlfahrtia; (15) Species of the Gastropoda class, such as species of the genera Arion, Biomphalaria, Bulinus, Deroceras, Galba, Lymnaea, Oncomelania, and Succinea;

[0165] (16) Heterinarians, such as Ancylostoma duodenale, Ancylostoma ceylanicum, Ancylostoma braziliensis, species of the genus Ancylostoma, Ascaris lubricoides, species of Ascaris, Brugia malayi, Brugia timori, species of the genus Bunostomum, species of Cabertia, species of the genus Clonorchis, species of the genus Cuperia, species of the genus Dicrocoelium, Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, and Echinococcus granulosus), Echinococcus multilocularis, pinworm (Enterobius vermicularis), species of Faciola, species of Heterakis, species of Hymenolepis nana, species of Hyostrongulus, Loa, species of Nematodilus, species of Opisthorchis, Onchocerca volvulus, species of Ostertagia, species of Paragonimus, species of Schistosoma, Strongyloides fuelleborni, Strongyloides stercoralis, species of Strongyloides, Taenia saginata saginata), Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsilaris (Trichinella(pseudopsiralis), species of the genus Trichostrongulus, whipworm (Trichuris trichuria), Wuchereria bancrofti;

[0166] (17) Species of the Heteroptera, such as Anasa tristis, species of the genera Antestiopsis, Blissus, Calocoris, Campylomma livida, species of Cavelerius, species of Cimex, Creontiades dilutus, Dasynus piperis, Dichelops furcatus, and Diconocoris hewech Hewetti), species of the genera Dysdercus, Euschistus, Eurygaster, Heliopeltis, Horchias nobiellus, Leptocorisa, Leptoglossus phyllopus, Lygus, Macropes excavatus, Miridae, species of Nezara, species of Oebalus, Pentatomidae, Piesma quadrata, Piezodorus, Psallus *Seriatus*, *Pseudacysta persea*, species of the genus *Rhodonius*, *Sahlbergella singularis*, species of the genus *Scotinophora*, *Stephanitis nashi*, species of the genus *Tibraca*, species of the genus *Triatoma*;

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

[0168] (19) Species of the order Isoptera, such as species of the genera Reticulitermes and Odontotermes;

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

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

[0171] Mixture with other activators In another embodiment, a composition comprising the compound of formula (I) may also include other veterinary therapeutic agents. Veterinary formulations that may be included in the composition of the present invention are well known in the art (e.g., Plumb's Veterinary Drug Handbook, 5 th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 th(See Edition, January 2005), but not limited to these, acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide bisulfate, aminophylline / theophylline, Amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate, amphotericin B lipid preparations, ampicillin, amprolium antacid (oral), antibenin, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracliu besylate Mu, atropine sulfate, auranofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturate, benazepril, betamethasone, betanethol chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin, calcitrol, cal Cium salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxyl, cefazolin sodium, cefixime, chlorthrol, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, cefthioflu sodium, cefthioflu, ceftriaxone sodium, cephalexin, cephalosporin, cefapillin, charcoal (active), chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - cridinium bromide, chlorothiazide,Chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, cloprostenol sodium, dipotassium clorazepate, chlorthrone, cloxacillin, codeine phosphate, colchicine, corticotropin ( ACTH, Cosyntropin, Cyclophosphamide, Cyclosporine, Cyproheptadine, Cytarabine, Dacarbazine, Dactinomycin / Actinomycin D, Dalteparin sodium, Danazol, Dantrolen sodium, Dapsone, Decoquinate, Deferoxamine mesylate, Delacoxib, Deslorerin acetate, Desmopressin acetate, Desoxycorticosterone pivalate, Detomidine, Dexamethasone, Dexpanthenol, Dexrazoxane, Dextran, Diazepam, Diazoxide (oral), Diclofenamide, Diclofenac Sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachisterol (DHT), diltiazem, dimenhydrinate, dimercaprol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, doxate / DSS, drasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, calcium disodium edetate. Calcium EDTA, edrophonium chloride, enalapril / enalaprilate, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin, epsiplantel, erythromycin, esmolol, estradiol cypionate, ethacrine / sodium ethacrine, ethanol (alcohol), sodium etidronate, etodolac, etomidate, euthanasia agent w / pentobarbital, famotidine, fatty acids (essential / ω), ferbamate, fentanyl, ferrous sulfate,Filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumetasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / chondroitin sulfate, glutamine, glybrid, glycerin Phosphorus (oral), glycopyrrolate, gonadrelin, griseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin, hetastarch, sodium hyaluronate, hydrazalin, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, dipropionimidocarb, imipenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon α-2 a (human recombinant), iodide (sodium / potassium), Tocon (syrup), Ipodart sodium, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxuprine, itraconazole, ivermectin, kaolin / pectin, ketamine, ketoconazole, ketoprofen, ketrolactromethamine, lactulose, leuprolide, levamisol, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, Magnesium, mannitol, marbofloxacin, mechloretamine, meclizine, meclofenamic acid, medetomidine, medium-chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, metazolamide, mandelic acid / methenamine hippurate, methimazole, methionine, methocarbamol, sodium methhexital, methotrexate, methoxyflurane, methylene blue,Methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidazole, mexiletine, mibolerlone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate Decanoate), naproxen, narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, orsalazine sodium, omeprazole, ondansetron, opiate antidiarrheal agents, orbifloxacin, oxacillin sodium, oxazepam, oxybutynin hydrochloride, oxymorphone, oxytetracycline, oxytocin, disodium pamidronate, pancrelipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine, general information penicillin, penicillin G, penicillin Phosphorus V potassium, pentazocine, pentoparbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenoparbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones, parenteral phosphate, phytonadione / vitamin K-1, pimobendan, piperazine, pirurimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisolone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes Acne injections, propofol, propranolol, protamine sulfate, pseudoephedrine, circulating hydrophilic mucus, pyridostigmine bromide, pyriramine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosylmethionine (SAMe), saline / saline laxatives, selamectin, selegiline / l-deprenyl, sertraline, sevelamer,Sevoflurane, Silymarin / Milk Thistle, Sodium Bicarbonate, Sodium Polystyrene Sulfonate, Sodium Stivogluconate, Sodium Sulfate, Sodium Thiosulfate, Somatropin, Sotalol, Spectinomycin, Spironolactone, Stanozolol, Streptokinase, Streptozocin, Succimer, Succinylcholine Chloride, Sucralfate, Sufentanyl Citrate, Sulfachlorpyridazine Sodium, Sulfadiazine / Trimethoprim, Sulfamethoxazole / Trimethoprim, Sulfadi Menthoxin, sulfadimethoxine / olmetoprim, sulfasalazine, taurine, tepoxaline, terbinafrine, terbutaline sulfate, testosterone, tetracycline, thiaacetalsamide sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, thiamlin, ticarcillin disodium salt, tyletamine / zolazepam, tilmocsin, thiopronin, tobramycin sulfate, tokainide, trazoline, tolfenamic acid This product contains, among other things, topiramate, tramadol, triamcinolone acetonide, trientine, trilostane, trimepraxin tartrate w / prednisolone, triperenamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E / selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate / zinc sulfate, zonisamide, and mixtures thereof.

[0172] In one embodiment of the present invention, an arylpyrazole compound such as phenylpyrazole may be included in the veterinary composition of the present invention. Arylpyrazoles are known in the art and may be suitable for combination with the compound of formula (I) in the compositions of this specification. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patents No. 6,001,384; No. 6,010,710; No. 6,083,519; No. 6,096,329; No. 6,174,540; No. 6,685,954; No. 6,998,131; and No. 7,759,381 (all of which are incorporated herein by reference). A particularly preferred arylpyrazole activator is fipronil.

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

[0174] Macrocyclic lactone compounds are known in the art and can be readily obtained commercially or through known synthetic techniques. Widely available technical and commercial literature is referenced. For avermectin, ivermectin, and abamectin, see, for example, the work “Ivermectin and Abamectin”, 1989, by MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag. or Albers-Schonberg et al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc., 103, 4216-4221. For dramectin, see “Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15. For milbemycin, see, in particular, Davies HG et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent No. 4,134,973, and European Patent No. 0677054, both of which are incorporated herein by reference.

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

[0176] In one embodiment, the veterinary composition of the present invention comprises an effective amount of at least one of abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxidectin, or nemadectin, or a combination thereof. In another embodiment, the present invention provides a veterinary composition comprising an effective amount of at least one of abamectin, emamectin, eprinomectin, ivermectin, doramectin, or selamectin, or a combination thereof. In yet another embodiment, the veterinary composition of the present invention comprises an effective amount of at least one of ivermectin, milbemectin, milbemycin oxime, or moxidectin, or a combination thereof. In another embodiment of the present invention, a composition is provided comprising a compound of formula (I) in combination with a miticide or insecticide of a class known as an insect growth regulator (IGR). Compounds belonging to this group are well known to those skilled in the art and constitute a wide range of different chemical classes. All of these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Patents No. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, European Patent No. 0179022 or British Patent No. 2140010 and U.S. Patents No. 6,096,329 and 6,685,954 (all incorporated herein by reference).

[0177] In one embodiment, the composition of the present invention may include an IGR compound that mimics or modulates the level of juvenile hormone in insects. Examples of juvenile hormone mimics include azadirachtin, diophenolane, phenoxycarb, hydroprene, quinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one. In another embodiment, the composition of the present invention may include a compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. In another embodiment, the composition of the present invention comprises an IGR compound that is a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorofluazurone, cyromazine, diflubenzuron, fluazurone, flucycloxurone, flufenoxurone, hexaflumorone, lufenuron, tebufenozide, teflubenzuron, triflumorone, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea, and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

[0178] In some embodiments, the compositions of the present invention may include, but are not limited to, one or more antinematode agents comprising benzimidazole, imidazothiazole, tetrahydropyrimidine, and organophosphorus class compounds as activators. In some embodiments, but are not limited to, the compositions may include benzimidazole comprising thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, and its o,o-dimethyl analogs. In other embodiments, the compositions of the present invention may include, but are not limited to, imidazothiazole compounds including tetramisole, levamizole, and butamizole. Furthermore, in other embodiments, the compositions of the present invention may include, but are not limited to, tetrahydropyrimidine activators comprising pyrantel, oxantel, and morantel. Suitable organophosphorus surfactants include, but are not limited to, coumaphos, trichlorfon, haloxone, naphthalophos and dichlorvos, heptenophos, mevinphos, monoclotophos, TEPP and tetrachlorvinphos.

[0179] In other embodiments, the composition may include, as neutral compounds and in various salt forms, antinematode compounds such as phenothiazine, piperazine, diethylcarbamazine, phenols such as disophenol, arsenic agents such as arcenamide, ethanolamines such as befenium, thenium crosilate, and methylidine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate, and dithiazanine iodide; isothiocyanates including vitoscanate, suramin sodium, and phthalofine, and various natural products including, but not limited to, hygromycin B, α-santonin, and kainic acid. In other embodiments, the composition of the present invention may include an antitrematode. Suitable antitrematodes include, but are not limited to, miracil, e.g., miracil D and mirasan; various bisphenol compounds known in the art, including praziquantel, clonazepam and its 3-methyl derivatives, ortipraz, rucanton, hicanton, oxamnichine, amoscanate, niridazole, nitroxynyl, hexachlorophene, bithionol, bithionol sulfoxide and meniclophorane; various salicylanilide compounds, including tribromusaran, oxyclozanide, crioxanide, rafoxanide, nitroxynyl, brothianide, bromoxanide and closantel; and triclabendazole, diamphenetide, chlorthrone, hetrin and emetine.

[0180] Anti-taeniorhynchite compounds, including, but not limited to, arecoline, bunamidine, niclosamide, nitroscanates, paromomycin, paromomycin II, praziquantel, and epsiplantel in various salt forms, can also be advantageously used in the compositions of the present invention. In further embodiments, the composition of the present invention may contain other activators effective against arthropod parasites. Suitable activators include, but are not limited to, bromocyclene, chlordan, DDT, endosulfan, lindan, methoxychlor, toxafen, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, clotoxyphos, cythioate, diazinon, dichlorenthion, dimethoate, dioxathion, ethion, fanfar, fenitrothion, fenthion, hospilate, iodophenphos, malathion, nared, hosalon, hosmet, phoxim, propethamphos, ronnel, stirophos, allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucitrinate, permethrin, phenothrin, and pi This includes rethrin, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, methoprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[0181] In another embodiment, antiparasitic agents that may be included in a veterinary composition containing the compound of formula (I) may be bioactive peptides or proteins containing depsipeptides other than the compound, but are not limited to these. These include PF1022A or its analogues and emodepside. Other cyclic depsipeptide compounds that may be included in a composition containing the compound of formula (I) are described in International Publication Nos. 2016 / 187534 and International Publication Nos. 2017 / 116702, both incorporated herein by reference. These compounds act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family, resulting in paralysis and death of parasites. In one embodiment of the depsipeptide, the depsipeptide is emodepside (see Wilson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86).

[0182] In another embodiment, the composition of the present invention may include an activator of a neonicotinoid class parasiticide. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, imidacloprid is a neonicotinoid insecticide that can be combined with the compound of formula (I) in the composition of the present invention. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or European Patent No. 0892060 (both incorporated herein by reference). In another embodiment, the composition of the present invention may include nitenpyram, another activator of a neonicotinoid class pesticide. The use of nitenpyram for flea control is described in U.S. Patent No. 5,750,548, which is incorporated herein by reference in whole. In certain other embodiments of the present invention, the compound of formula (I) can be combined with a semicarbazone such as metaflumizone.

[0183] In another embodiment, the composition of the present invention may advantageously include one or more isoxazoline compounds known in the art. Isoxazoline activators are highly effective against a variety of ectoparasites, and combinations with compounds of formula (I) will extend the range of effectiveness against these parasites. Particularly useful isoxazoline activators that can be combined with compounds include afoxolaner (containing substantially pure active enantiomer, esafoxolaner), sarolaner, fluralaner (containing substantially pure active enantiomer), lotilaner, and tigolaner. All of these activators are incorporated herein by reference in whole by U.S. Patent No. 7,964,204, U.S. Patent Publication No. 2010 / 0254960, U.S. Patent Publication No. 2011 / 0159107, U.S. Patent Publication No. 2012 / 0309620, U.S. Patent Publication No. 2012 / 0030841, U.S. Patent Publication No. 2010 / 0069247, International Publication No. 2007 / 125984, International Publication No. 2012 / 086462, U.S. Patent No. 8318757, U.S. Patent No. 8466115, U.S. Patent U.S. Patent No. 8618126, U.S. Patent No. 8822466, U.S. Patent No. 8383659, U.S. Patent No. 8853186, U.S. Patent No. 9221835, U.S. Patent Application Publication No. 2011 / 0144349, U.S. Patent No. 8,053,452; U.S. Patent Application Publication No. 2010 / 0137612, U.S. Patent No. 8410153, U.S. Patent Application Publication No. 2011 / 152081, International Publication No. 2012 / 089623, International Publication No. 2012 / 089622, U.S. Patent No. 8,119,671; U.S. Patent No. 7,947,715;International Publication No. 2102 / 120135, International Publication No. 2012 / 107533, International Publication No. 2011 / 157748, U.S. Patent Application Publication No. 2011 / 0245274, U.S. Patent Application Publication No. 2011 / 0245239, U.S. Patent Application Publication No. 2012 / 0232026, U.S. Patent Application Publication No. 2012 / 0077765, U.S. Patent Application Publication No. 2012 / 0035122, U.S. Patent Application Publication No. 2011 / 0251247, International Publication No. 2011 / 154433, International Publication No. 2011 / 15 U.S. Patent No. 4434, U.S. Patent Application Publication No. 2012 / 0238517, U.S. Patent Application Publication No. 2011 / 0166193, International Publication No. 2011 / 104088, International Publication No. 2011 / 104087, International Publication No. 2011 / 104089, U.S. Patent Application Publication No. 2012 / 015946, U.S. Patent Application Publication No. 2009 / 0143410, International Publication No. 2007 / 123855, U.S. Patent Application Publication No. 2011 / 0118212, U.S. Patent No. 7951828 and U.S. Patent No. 7662972, U.S. National Patent Application Publication No. 2010 / 0137372, U.S. Patent Application Publication No. 2010 / 0179194, U.S. Patent Application Publication No. 2011 / 0086886, U.S. Patent Application Publication No. 2011 / 0059988, U.S. Patent Application Publication No. 2010 / 0179195, U.S. Patent Application Publication No. 2015 / 0126523, International Publication No. 2010 / 003923, International Publication No. 2010 / 003877, International Publication No. 2010 / 072602, International Publication No. 2014 / 134236, International Publication No. 2017 / 147 This information is described in publications 352, U.S. No. 7897630, U.S. No. 7951828, International Publication No. 2020 / 007704, International Publication No. 2021 / 028479, International Publication No. 2014 / 122083, International Publication No. 2016 / 177619, International Publication No. 2014 / 012975, International Publication No. 2015 / 078846, International Publication No. 2015 / 078847, International Publication No. 2015 / 150302, International Publication No. 2015 / 181139, and International Publication No. 2016 / 026789.

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

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

[0186] The compositions of the present invention may also include paraherbicamide compounds, including Delcantel, and derivatives of these compounds (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherbicamide family of compounds is a known class of compounds containing a spirodioxepinoindole core that has activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380 and J. Antibiotics 1991, 44, 492). Furthermore, structurally related compounds of the marcfortin family, such as marcfortin A-C, are also known and can be combined with the compositions of the present invention (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to paraherbicamide derivatives can be found, for example, in International Publications 91 / 09961, 92 / 22555, 97 / 03988, 01 / 076370, 09 / 004432, and U.S. Patent Publications 2010 / 0197624, 5,703,078 and 5,750,695, all of which are incorporated by reference.

[0187] In another embodiment of the present invention, the composition may comprise a spinosyn activator produced by the soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado VL and Sparks TC, “The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance,” in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosoid activator. Spinosyns are typically referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or combinations thereof may be used in the composition of the present invention. Spinosine compounds can be 5,6,5-tricyclic systems formed by the condensation of a 12-membered macrocyclic lactone, a neutral sugar (rhamnose), and an amino sugar (pholosamine). These and other natural spinosine compounds, including 21-butenylspinosine produced by Saccharopolyspora pagona, which can be used in the compositions of the present invention, can be produced by fermentation according to the prior art known. Other spinosine compounds that may be used in the compositions of the present invention are all disclosed in U.S. Patents 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861; 5,670,486; 5,631,155 and 6,001,981, all of which are incorporated herein by reference in their entirety. Spinosine compounds may include, but are not limited to, spinosine A, spinosine D, spinosad, spinetoram, or combinations thereof. Spinosad is a combination of spinosine A and spinosine D, and spinetoram is a combination of 3'-ethoxy-5,6-dihydrospinosine J and 3'-ethoxyspinosine L.

[0188] Generally, additional activators (other than the compounds of formula (I) above) are included in the dosage unit of the present invention in amounts between about 0.1 μg and about 1000 mg. Typically, the activator may be included in amounts of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. More typically, the additional activator is present in the composition of the present invention in amounts between about 5 mg and about 50 mg. The concentration of additional activators in the compositions of the present invention is typically about 0.01% to about 30% (w / w), depending on the potency of the activator. In certain embodiments of extremely potent activators, including macrocyclic lactone activators, the concentration of the activator is typically about 0.01% to about 10% (w / w), about 0.01% to about 1% (w / w), about 0.01% to about 0.5% (w / w), about 0.1% to about 0.5% (w / w), or about 0.01% to about 0.1% (w / w). In other embodiments, the concentration of the activator is typically about 0.1% to about 2% (w / w) or about 0.1% to about 1% (w / w).

[0189] In other embodiments, additional activators are present, typically at higher concentrations, to achieve the desired efficacy. In some embodiments, the activator is present at concentrations of about 1% to about 30% (w / w), about 1% to about 20% (w / w), or about 1% to about 15% (w / w). Furthermore, in other embodiments, the activator is present in the composition at concentrations of about 5% to about 20% (w / w) or about 5% to about 15% (w / w). In various embodiments of the present invention, the composition may include additional activators that deliver doses of about 0.001 mg / kg to about 50 mg / kg or about 0.5 mg / kg to about 50 mg / kg per animal body weight. In other embodiments, the activator is present in an amount sufficient to deliver doses of typically about 0.05 mg / kg to about 30 mg / kg or about 0.1 mg / kg to about 20 mg / kg. In other embodiments, the activator is present in an amount sufficient to deliver doses of about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 1 mg / kg or about 0.5 mg / kg to about 50 mg / kg per animal body weight.

[0190] In certain embodiments of the present invention, the additional activator is an extremely potent compound such as a macrocyclic lactone or other potent compound, and the activator is present in a concentration that provides doses 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 activator 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 per animal body weight. In other embodiments, the additional activator may be present in an amount that delivers a dose of about 1 μg / kg to about 200 μg / kg or about 0.1 mg / kg to about 1 mg / kg per animal body weight. In addition to the other activators mentioned above, combinations of two or more activators can be used in compositions together with the compounds of the present invention to treat a desired range of pests and parasites. Determining which individual compounds can be used in the compositions of the present invention to treat specific insect infections will be well within the skill level of those skilled in the art. The present invention will be further described here by the following non-limiting embodiments. [Examples]

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

[0192] The terms “ambient temperature” and “room temperature” are used interchangeably and refer to a temperature of approximately 20°C. The following subject matter is described in some detail as examples and illustrations for clarity of understanding, but those skilled in the art will understand that certain changes and modifications may be made within the scope of the examples. List of abbreviations: ACN Acetonitrile AIBN Azobisisobutyronitrile BINAP (2,2'-bis(diphenylphosphin)-1,1'-binaphthyl) BSA (Bovine Serum Albumin) BOC tert-butoxycarbonyl BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinate chloride DAST Diethylaminosulfur Trifluoride DCC N,N'-Dicyclohexylcarbodiimide Solution DCM Dichloromethane DEAD Diethylazodicarboxylate DIEA (Diisopropylethylamine) DMF (N,N-dimethylformamide) DMAP 4-(dimethylamino)pyridine DMSO (Dimethyl Sulfoxide) EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ES Electrospray HCl or EA (ethyl acetate) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt or HOBT 1-hydroxybenzotriazole KHMDS potassium hexamethyldisilazide, more precisely potassium bis(trimethylsilyl)amide MeOH methanol m-CPBA m-chloroperbenzoic acid NMO N-methylmorpholine-N-oxide o / n overnight PE (Petroleum Ether) Pd(dtbpf)Cl2 Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II), complex with dichloromethane TBAF tert-butylammonium fluoride TfO triflate THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography)

[0193] Several examples of formula (I) were derived after separation of the racemic mixture and obtained as enantiomerically pure products. The stereochemistry was specified as appropriate, and the individual compounds were characterized by analytical methods as described below. [Table 4]

[0194] [Table 5]

[0195] [Table 6]

[0196] [Table 7]

[0197] [Table 8]

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

[0199] Scheme 3 [ka]

[0200] Scheme 4 [ka]

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

[0202] In a 3000 mL three-necked round-bottom flask, 2000 mL of DMF and ethyl 1H-imidazole-2-carboxylate (3-1, 50.0 g, 356.7 mmol, 1.0 equivalent) were added. Subsequently, NaH (21.0 g, 875.0 mmol, 2.4 equivalents) was added in small amounts at room temperature. Then, aminodiphenyl phosphinate (119.0 g, 510.2 mmol, 1.4 equivalents) was added in small amounts at 0°C. The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). As a result, 40 g (72.2%) of ethyl 1-aminoimidazole-2-carboxylate (3-2) was obtained as a white solid.

[0203] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) [ka] In a 500 mL round-bottom flask, 200.0 mL of DMF, ethyl 1-aminoimidazole-2-carboxylate (3-2, 35.0 g, 225.5 mmol, 1.0 equivalent), Boc2O (63.9 g, 293.2 mmol, 1.3 equivalents), and DMAP (13.7 g, 112.7 mmol, 0.5 equivalents) were added. The resulting solution was stirred at 80°C for 2 hours. Next, the reaction was quenched by adding 500 mL of water. The resulting solution was extracted three times with 200 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, 28 g (48.6%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) was obtained as a white solid.

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

[0205] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5) [ka] In a 1000 mL three-necked round-bottom flask, THF (400.0 mL) and ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4, 12.0 g, 35.9 mmol, 1.0 equivalent) were added. Subsequently, t-BuOK (60.0 g, 534.7 mmol, 14.9 equivalents) was added in small amounts over 30 minutes at 0°C. Ethyl acetate (32.0 g, 363.2 mmol, 10.1 equivalents) was added dropwise at 0°C while stirring. The resulting solution was stirred at room temperature for 2 hours. Next, the reaction was quenched by adding HCl (1 M). The resulting solution was extracted three times with 50 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 6.5 g (48.1%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5) was obtained as a yellow oil.

[0206] 5. Synthesis of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] In a 100 mL round-bottom flask, 30.00 mL of DCM, ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5, 6.50 g, 17.278 mmol, 1.00 equivalent), and 5.00 mL of DMF-DMA (37.3 mmol, 2.2 equivalents) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=90:10 to H2O:ACN=50:50 within 15 minutes; detector, 254 nm. As a result, 3.3 g (66.7%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) was obtained as a white solid.

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

[0208] 7. Synthesis of ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1) [ka] In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 20.0 mL of DCM, ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7, 200.0 mg, 0.9 mmol, 1.0 equivalent), and TEA (457.0 mg, 4.5 mmol, 5.0 equivalents) were added. Subsequently, Tf2O (765.6 mg, 2.7 mmol, 3.0 equivalents) was added dropwise while stirring at -78°C. The resulting solution was stirred at -50°C for 1 hour. Next, the reaction was quenched by adding water / ice. The resulting solution was extracted three times with 20 mL of dichloromethane, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 200 mg (62.6%) of ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1) was obtained as a brown oil.

[0209] 8. Synthesis of ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) [ka] In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, the following were added: THF (10.0 mL), H2O (2.0 mL), ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyridazine-7-carboxylate (4-1, 200.0 mmol, 0.6 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (179.0 mg, 1.0 mmol, 1.9 equivalents), Pd(dtbpf)Cl2 (37.2 mg, 0.06 mmol, 0.10 equivalents), and K2CO3 (234.0 mg, 1.7 mmol, 3.0 equivalents). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:4). As a result, 90 mg (64.8%) of ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) was obtained as a white solid.

[0210] 9. Synthesis of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate [ka] In a 50 mL round-bottom flask, EA (5.00 mL, 0.057 mmol, 0.03 equivalents), ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2, 90.0 mg, 0.4 mmol, 1.0 equivalent), PtO2 (30.00 mg, 0.1 mmol, 0.4 equivalents), and an atmosphere of H2 (g) via a balloon were added. The resulting solution was stirred at 50°C for 1 hour. The solid was filtered off. The resulting mixture was concentrated under vacuum. As a result, 90 mg (99.2%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate was obtained as a white solid.

[0211] 10. Synthesis of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate [ka] In a 50 mL round-bottom flask, CHCl3 (10.0 mL), ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3, 90.0 mg, 0.4 mmol, 1.0 equivalent), and NBS (90.0 mg, 0.5 mmol, 1.4 equivalents) were added. The resulting solution was stirred at 80°C for 1 hour. Next, the reaction was quenched by adding 10 mL of water. The resulting solution was extracted three times with 10 mL of dichloromethane, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 100 mg (crude raw material) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) was obtained as a white solid.

[0212] 11. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) [ka] In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, add dioxane (10.0 mL), H2O (3.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 90.0 mg, 0.3 mmol, 1.0 equivalent), and 3,5-difluorophenylboronic acid. (87.5 mg, 0.5 mmol, 2.0 equivalents), Pd(dtbpf)Cl2 (18.0 mg, 0.03 mmol, 0.1 equivalent), and K2CO3 (114.6 mg, 0.829 mmol, 3.0 equivalents) were added. The resulting solution was stirred at 100°C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) was obtained as a yellow solid.

[0213] 12. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) [ka] In a 50 mL round-bottom flask, H2O (1.0 mL), i-PrOH (5.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5, 80 mg, 0.2 mmol, 1.0 equivalent), and LiOH.H2O (28.0 mg, 0.7 mmol, 3.0 equivalents) were added. The resulting solution was stirred at 50°C for 2 hours. The pH of the solution was adjusted to 4 with HCl (2 M). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 60 mg (90%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) was obtained as a white solid.

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

[0215] Preparation Example 2: Compound 271 can be prepared using the steps shown in Scheme 5 to 7 below, similar to the steps described in Preparation Example 1. Scheme 5 [ka]

[0216] Scheme 6 [ka]

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

[0218] 1. Synthesis of ethyl 1-aminoimidazole-2-carboxylate (3-2) [ka] In a 5 L round-bottom flask, DMF (4000.00 mL, 51687.010 mmol, 144.87 equivalents) and ethyl 1H-imidazole-2-carboxylate (50.00 g, 356.781 mmol, 1.00 equivalent) were added. Subsequently, NaH (21.00 g, 875.083 mmol, 2.45 equivalents) was added in small amounts at room temperature over 30 minutes. Aminodiphenyl phosphinate (120.00 g, 514.564 mmol, 1.44 equivalents) was added in small amounts at room temperature. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was dried with nitrogen (while blowing nitrogen into it). The residue was dissolved in 2000 mL of EA. The solids were filtered off. The filtrate was concentrated under vacuum. As a result, 42 g (75.87%) of ethyl 1-aminoimidazole-2 carboxylate (3-2) was obtained as a white solid.

[0219] 2. Synthesis of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) [ka] In a 1000 mL round-bottom flask, DMF (500.00 mL, 6460.876 mmol, 28.64 equivalents), ethyl 1-aminoimidazole-2-carboxylate (35.00 g, 225.578 mmol, 1.00 equivalent), Boc2O (73.30 g, 335.858 mmol, 1.49 equivalents), and DMAP (13.78 g, 112.796 mmol, 0.50 equivalents) were added. The resulting solution was stirred at 80°C for 2 hours. Next, the reaction was quenched by adding water / ice. The resulting solution was extracted three times with 500 mL of ethyl acetate, and the organic layers were combined and washed twice with 500 mL of H2O and once with 500 mL of brine. The organic layers were dried on anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). As a result, 30 g (52.10%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-3) was obtained as a white solid.

[0220] 3. Synthesis of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) [ka] In a 1000 mL round-bottom flask, DMF (400.00 mL, 5168.701 mmol, 26.39 equivalents), ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (50.00 g, 195.868 mmol, 1.00 equivalent), and NBS (40.00 g, 0.225 mmol) were added. The resulting solution was stirred overnight at room temperature. Next, the reaction was quenched by adding water / ice. The resulting solution was extracted three times with 100 mL of ethyl acetate, and the organic layers were combined and washed twice with 500 mL of H2O and once with 500 mL of brine. The organic layers were dried on anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). As a result, 30 g (45.83%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3-4) was obtained as a yellow oil.

[0221] 4. Synthesis of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5) [ka] In a 1000 mL three-necked round-bottom flask, THF (500.00 mL, 6171.495 mmol, 58.92 equivalents), ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (35.00 g, 104.737 mmol, 1.00 equivalent), and EA (93.50 g, 1061.233 mmol, 10.13 equivalents) were added. Subsequently, t-BuOK (170.00 g, 1514.989 mmol, 14.46 equivalents) was added in small amounts at 0°C. The resulting solution was stirred at room temperature for 1 hour. Next, the reaction was quenched by adding NH4Cl (aqueous solution). The resulting solution was extracted three times with 300 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was dissolved in 500 mL of hexane. The solid matter was recovered by filtration. As a result, 22 g (55.83%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5) was obtained as a yellow oil.

[0222] 5. Synthesis of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] In a 100 mL round-bottom flask, DCM (30.00 mL, 471.901 mmol, 27.31 equivalents), ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (6.50 g, 17.278 mmol, 1.00 equivalent), and DMF-DMA (5.00 mL, 37.344 mmol, 2.16 equivalents) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing from H2O(0.1% TFA):ACN=90:10 to H2O(0.1% TFA):ACN=50:50 within 15 minutes; detector, 254 nm. As a result, 3.3 g (66.76%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) was obtained as a white solid.

[0223] 6. Synthesis of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) [ka] Dioxane (100.0 mL, 1180.408 mmol, 67.54 equivalents), ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (5.00 g, 17.477 mmol, 1.00 equivalent), trimethyl-1,3,5,2,4,6-trioxatriborinane (6.60 g, 52.577 mmol, 3.01 equivalents), Pd(PPh3)4 (2.00 g, 1.731 mmol, 0.10 equivalents), and K3PO4 (7.20 g, 52.096 mmol, 2.98 equivalents) were added to a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, increasing from H2O(0.1% NH3.H2O):ACN=100:0 to H2O(0.1% NH3.H2O):ACN=50:50 within 10 minutes; detector, 254 nm. As a result, 0.75 g (25.6%) of ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7) was obtained as a yellow solid.

[0224] 7. Synthesis of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) [ka] In a 100 mL round-bottom flask, CHCl3 (20.00 mL, 247.952 mmol, 18.28 equivalents), ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3.00 g, 13.561 mmol, 1.00 equivalent), oxalyl chloride (6.00 g, 47.274 mmol, 3.49 equivalents), and DMF (0.10 mL) were added. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated under vacuum. As a result, 3.6 g (crude raw material) of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) was obtained as a yellow solid.

[0225] 8. Synthesis of ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) [ka] In a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, add THF (30.00 mL, 370.290 mmol, 88.74 equivalents), H2O (5.00 mL, 277.542 mmol, 66.52 equivalents), and ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (1.00 g, 4.173 mmol, 1 0.00 equivalents) of 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (2.11 g, 12.557 mmol, 3.01 equivalents), Pd(dtbpf)Cl2 (410.00 mg, 0.629 mmol, 0.15 equivalents), and K3PO4 (2.66 g, 12.531 mmol, 3.00 equivalents) were added. The resulting solution was stirred at 70°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:2). As a result, 500 mg (48.85%) of ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) was obtained as a yellow oil.

[0226] 9. Synthesis of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3) [ka] In a 50 mL round-bottom flask, EA (5.00 mL, 0.057 mmol, 0.03 equivalents), ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (500.00 mg, 2.038 mmol, 1.00 equivalent), and PtO2 (100.00 mg, 0.440 mmol, 0.22 equivalents) were introduced into the above H2 (g). The resulting solution was stirred at 50°C for 2 hours. The solid was filtered off. The filtrate was concentrated under vacuum. As a result, 350 mg (69.43%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-3) was obtained as a yellow oil.

[0227] 10. Synthesis of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) [ka] In a 50 mL round-bottom flask, CHCl3 (5.00 mL, 61.988 mmol, 47.90 equivalents), ethyl 8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (320.00 mg, 1.294 mmol, 1.00 equivalent), and NBS (253.70 mg, 1.425 mmol, 1.10 equivalents) were added. The resulting solution was stirred at 80°C for 1 hour. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). As a result, 350 mg (82.92%) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4) was obtained as a yellow oil.

[0228] 11. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-2) [ka] In an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, the following were added: THF (1.00 mL, 12.343 mmol, 44.74 equivalents), H2O (0.20 mL, 11.102 mmol, 40.24 equivalents), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (90.00 mg, 0.276 mmol, 1.00 equivalent), 3,5-dichlorophenylboronic acid (53.17 mg, 0.279 mmol, 1.01 equivalent), Pd(dtbpf)Cl2 (17.98 mg, 0.028 mmol, 0.10 equivalents), and K2CO3 (75.88 mg, 0.549 mmol, 1.99 equivalents). The resulting solution was stirred at 50°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:4). As a result, 70 mg (64.67%) of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-2) was obtained as a colorless oil.

[0229] 12. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (271-3) [ka] In a 50 mL round-bottom flask, H2O (0.50 mL, 27.754 mmol, 155.53 equivalents), EtOH (2.00 mL, 0.043 mmol, 0.24 equivalents), ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (70.00 mg, 0.178 mmol, 1.00 equivalent), and LiOH·H2O (22.50 mg, 0.536 mmol, 3.00 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 5 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 50 mg (76.93%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (271-3) was obtained as a yellow oil.

[0230] Synthesis of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (compound 271) [ka] In a 50 mL round-bottom flask, DMA (1.00 mL, 10.755 mmol, 87.05 equivalents), 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (45.00 mg, 0.124 mmol, 1.00 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (29.30 mg, 0.196 mmol, 1.59 equivalents), HATU (93.90 mg, 0.247 mmol, 2.00 equivalents), and di-EA (47.80 mg, 0.370 mmol, 2.99 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The crude mixture was purified by Flash HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased within 20 minutes from H2O(0.1% NH3.H2O):ACN=50:50 to H2O(0.1% NH3.H2O):ACN=10:90; detector, 254 nm. As a result, 42.2 mg (68.95%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (271) was obtained as a white solid. 1 H NMR (300 MHz, CDCl3, ppm) δ 8.29 (s, 1H), 7.59 (d, J = 1.9 Hz, 2H), 7.43 (t, J = 1.9 Hz, 1H), 7.34-7.18 (m, 2H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.38 (q, J = 5.6 Hz, 1H), 4.40-4.36 (m, 1H), 4.28-4.14 (m, 1H), 3.78-3.73 (m, 1H), 2.64 (s, (ES, m / z): 495 [M+H] + .

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

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

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

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

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

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

[0237] 1. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (9-2) [ka] In a 500 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6, 2.0 g, 0.007 mmol, 1.0 equivalent), 3,5-dichlorophenylboronic acid (1.6 g, 0.008 mmol, 1.2 equivalents), K2CO3 (2.1 g, 0.015 mmol, 2.2 equivalents), dioxane (100.0 mL), H2O (20.0 mL), and Pd(dtbpf)Cl2 (0.27 g, 0.000 mmol, 0.06 equivalents) were added. The resulting solution was stirred in an oil bath at 100°C for 1 hour. Next, the reaction was quenched by adding 100 mL of water. The solid was recovered by filtration. As a result, 2.1 g (85.3%) of ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (9-2) was obtained as an off-white solid. (ES,m / z):352[M+H] + .

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

[0239] 3. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4) [ka] In a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (9-3, 1800.0 mg, 4.4 mmol, 1.0 equivalent), K3PO4 (2761.5 mg, 13.0 mmol, 3.0 equivalents), THF (20.0 mL), H2O (5.0 mL), Pd(dtbpf)Cl2 (282.6 mg, 0.4 mmol, 0.1 equivalent), and 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (801.6 mg, 4.8 mmol, 1.1 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. Next, the reaction was quenched by adding 20 mL of water. The resulting solution was extracted three times with 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). As a result, 0.55 g (33.7%) of ethyl 2-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4) was obtained as an off-white solid. (ES, m / z): 376 [M+H] + .

[0240] 4. Synthesis of ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-5) [ka] Ethyl 2-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (9-4, 500.0 mg, 1.3 mmol, 1.0 equivalent), EA (10.0 mL), and PtO2 (100.0 mg, 0.4 mmol, 0.3 equivalents) were added to a 50 mL round-bottom flask purged and maintained under an inert atmosphere of H2(g). The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The filtrate was concentrated. As a result, 450 mg (82.4%) of ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate was obtained as an off-white solid (9-5). (ES, m / z): 378 [M+H] + .

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

[0242] 6. Synthesis of 6-3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (9-7) [ka] In a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (9-6, 95.0 mg, 0.2 mmol, 1.0 equivalent), THF (5.0 mL), H2O (1.0 mL), and LiOH (27.6 mg, 1.2 mmol, 5.0 equivalents) were added. The resulting solution was stirred overnight at room temperature. The pH of the solution was adjusted to 3-4 with HCl (1 mol / L). The resulting solution was extracted three times with 10 mL of ethyl acetate, and the organic layers were combined. The organic phase was dried in an oven under reduced pressure and concentrated. As a result, 78 mg (88.1%) of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (9-7) was obtained as an off-white solid. (ES,m / z):384[M+H] + .

[0243] 7. Synthesis of 7.3-chloro-2-(3,5-dichlorophenyl)-N-[(4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (compound 304-0). [ka] (4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-aminedihydrochloride (51.0 mg, 0.2 mmol, 1.2 equivalents), 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 equivalent), DMF (5.0 mL), zidi EA (45.7 mg, 0.35 mmol, 2.5 equivalents), and HATU (100.8 mg, 0.3 mmol, 1.5 equivalents) were added to a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): Column: C18 silica gel; Mobile phase: Increased within 7 seconds from ACN:H2O=72 to ACN:H2O=95; Detector: 254. As a result, 67.7 mg (71.7%) of 3-chloro-2-(3,5-dichlorophenyl)-N-[(4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (304-0) was obtained as an off-white solid. (300 MHz, CDCl3, ppm) δ 8.36 (s, 1H), 7.83 (d, J = 1.8 Hz, 2H), 7.45 (t, J = 1.8 Hz, 1H), 7.02-6.93 (m, 2H), 6.87-6.83 (m, 1H), 6.06 (d, J = 7.8 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.38-4.32 (m, 1H), 4.24-4.16 (m, 1H), 3.73 (t, J = 6.9 Hz, 1H), 2.45-2.40 (m, 1H), 2.24-2.18 (m, 1H), 1.68-1.64 (m, 6H). Compound 321: (300 MHz, chloroform-d, ppm): δ 8.27 (s, 1H), 7.76-7.60 (m, 2H), 7.35-7.30 (m, 1H), 7.28-7.20 (m, 1H), 7.20-7.03 (m, 4H), 7.03-6.80 (m, 3H), 6.20-5.90 (m, 1H), 5.50-5.25 (m, 1H), 4.45-4.30 (m,1H), 4.30-4.10 (m, 1H), 3.80-3.65 (m, 1H), 2.55-2.35 (m, 1H), 2.33-2.15 (m, 1H), 1.72 (t, J = 6.3 Hz, 6H)

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

[0245] 1. Synthesis of N-(5-chloropyridazine-3-yl)-1,1-diphenylmethaneimine (10-2) [ka] In a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 3,5-dichloropyridazine (10⁻¹, 500.0 mg, 3.4 mmol, 1.0 equivalent), diphenylmethanymine (675.2 mg, 3.7 mmol, 1.1 equivalent), xanthophos (69.9 mg, 0.12 mmol, 0.04 equivalent), Pd₂(dba)₃ (34.7 mg, 0.06 mmol, 0.02 equivalent), Cs₂CO₃ (2187.1 mg, 6.7 mmol, 2.0 equivalent), and dioxane (5 mL) were added. The resulting solution was stirred in an oil bath at 90°C for 3 hours. The solids were filtered off. The resulting mixture was concentrated. As a result, 3 mL (30.4%) of N-(5-chloropyridazine-3-yl)-1,1-diphenylmethanimine (10-2) was obtained as a brown oil.

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

[0247] 3. Synthesis of 3,7-chloroimidazo[1,2-b]pyridazine (10-4) [ka] 5-Chloropyridazine-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H2O (17.5 mL), and i-PrOH (25 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred in an oil bath at 95°C for 5 hours. The resulting mixture was concentrated. The pH of the solution was adjusted to 9 with NaOH. The resulting solution was extracted three times with 50 mL of ethyl acetate, and the organic layer was washed three times with 50 mL of brine. The organic phase was collected, dried on anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2:3). As a result, 2.2 g (12.4%) of 7-chloroimidazo[1,2-b]pyridazine (10-4) was obtained as a yellow oil.

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

[0249] 5. Synthesis of 5,7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6) [ka] In a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, 7-chloro-3-iodoimidazo[1,2-b]pyridazine (10⁻⁵, 400.0 mg, 1.4 mmol, 1.0 equivalent), 2,6-difluorophenylboronic acid (452.0 mg, 2.9 mmol, 2.0 equivalent), Pd(dtbpf)Cl₂ (93.3 mg, 0.14 mmol, 0.1 equivalent), K₃PO₄ (911.4 mg, 4.3 mmol, 3.0 equivalent), THF (10 mL), and H₂O (2.5 mL) were added. The resulting solution was stirred overnight at room temperature for 1 hour. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, 150 mg (39.4%) of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10-6) was obtained as a white solid.

[0250] 6. Synthesis of methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10-7) [ka] In a 50 mL pressure tank reactor, 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine (10⁻⁶, 130.0 mg, 0.5 mmol, 1.0 equivalent), Pd(dppf)Cl₂ (35.8 mg, 0.05 mmol, 0.1 equivalent), TEA (148.6 mg, 1.5 mmol, 3.0 equivalent), CO (20 atm), and MeOH (10.00 mL) were added. The resulting solution was stirred in an oil bath at 110°C for 4 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, 95 mg (67.1%) of methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10⁻⁷) was obtained as a white solid.

[0251] 7. Synthesis of 7,3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10-8) [ka] In a 40 mL round-bottom flask, methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (10-7, 85.0 mg, 0.3 mmol, 1.0 equivalent), NaOH (58.7 mg, 1.5 mmol, 5.0 equivalents), MeOH (9 mL), and H2O (3 mL) were added. The resulting solution was stirred at room temperature for 3 hours. The resulting solution was diluted with 20 mL of water. The pH of the solution was adjusted to 3-4 with HCl (3 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic phase was collected, dried on anhydrous sodium sulfate, and concentrated. As a result, 65 mg (80.4%) of 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10-8) was obtained as a white solid.

[0252] 8. Synthesis of 8.3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]imidazo[1,2-b]pyridazine-7-carboxamide (compound 174) [ka] In a 40 mL round-bottom flask, 3-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (10⁻⁸, 60.0 mg, 0.2 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (48.8 mg, 0.3 mmol, 1.5 equivalents), HATU (165.79 mg, 0.436 mmol, 2 equivalents), di-EA (84.5 mg, 0.6 mmol, 3.0 equivalents), and DMF (3 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The crude product was purified by Prep-HPLC under the following conditions (Waters-2767): column, XBridge RP18, 5um, 19*100mm; mobile phase, 0.03% ammonia and CH3CN in water (30% to a maximum of 70% CH3CN in 15 mins); detector, UV 254nm. As a result, 19.4 mg (21.9%) of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]imidazo[1,2-b]pyridazine-7-carboxamide (174) was obtained as a white solid. (300 MHz, CDCl3, ppm) δ 8.95 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.55-7.45 (m, 1H), 7.25-7.24 (m, 1H), 7.17-7.08 (m, 4H), 6.91-6.81 (m, 2H), 5.43-5.39 (m, 1H), 4.35-4.25 (m, 2H), 2.41-2.31 (m, 1H), 2.28-2.21 (m, 1H).

[0253] Preparation Example 6: Example 277 was prepared according to the following scheme 11. Scheme 11 [ka]

[0254] 1. Synthesis of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) [ka] Ethyl 8-hydroxy-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (3-7, 2.8 g, 12.6 mmol, 1.0 equivalent), DMF (8.0 μL, 103.4 mmol, 8.2 equivalents), and CHCl3 (55.0 mL) were placed in a 100 mL round-bottom flask. Subsequently, (COCl)2 (8.0 g, 63.1 mmol, 5.0 equivalents) was added dropwise while stirring at room temperature. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated. The crude product was purified by Prep-Flash under the following conditions: column, C 18 Silica gel; mobile phase, 0.1% FA and CH3CN in water (CH3CN increased from 10% to 70% within 12 minutes). Detector, UV 254nm, 220nm. As a result, 537 mg (17.2%) of ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1) was obtained as a yellow solid.

[0255] 2. Synthesis of 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate ethyl (4-2) [ka] In a 50 mL three-necked round-bottom flask maintained under a nitrogen inert atmosphere, ethyl 8-chloro-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (271-1, 480.0 mg, 2.0 mmol, 1.0 equivalent), dioxane (19.0 mL), H2O (4.8 mL), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (673.1 mg, 4.0 mmol, 2.0 equivalent), Pd(dtbpf)Cl2 (130.5 mg, 0.20 mmol, 0.1 equivalent), and K2CO3 (553.6 mg, 4.0 mmol, 2.0 equivalent) were added. The resulting solution was stirred overnight at 80°C. The resulting solution was diluted with 10 mL of water. The obtained solution was extracted twice with 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed twice with 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-20%). As a result, 370 mg (73.0%) of ethyl 2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (4-2) was obtained as a white solid.

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

[0257] 4. Synthesis of ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5) [ka] In a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, ethyl 3-bromo-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-4, 490.0 mg, 1.5 mmol, 1.0 equivalent), dioxane (10.0 mL), H2O (2.5 mL), 3,5-difluorophenylboronic acid (477.4 mg, 3.0 mmol, 2.0 equivalent), K2CO3 (626.7 mg, 4.535 mmol, 3.0 equivalent), and Pd(dtbpf)Cl2 (98.5 mg, 0.15 mmol, 0.1 equivalent) were added. The resulting solution was stirred at 100°C for 30 minutes. The resulting solution was diluted with 10 mL of water. The obtained solution was extracted twice with 50 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (0-15%). As a result, 442 mg (80.2%) of ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5) was obtained as a yellow-green solid.

[0258] 5. Synthesis of 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6) [ka] In a 50 mL three-necked round-bottom flask, ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (11-5, 440.0 mg, 1.2 mmol, 1.0 equivalent), i-PrOH (15.0 mL), H2O (8.0 mL), and LiOH·H2O (155.0 mg, 3.7 mmol, 3.0 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The pH of the solution was adjusted to 3 with HCl (2 mol / L). The resulting solution was extracted twice with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated. As a result, 401 mg (89.0%) of 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6) was obtained as a yellow solid.

[0259] 6. Synthesis of 6.3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7) [ka] In a 50 mL three-necked round-bottom flask, 3-(3,5-difluorophenyl)-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (11-6, 400.0 mg, 1.2 mmol, 1.0 equivalent), DMF (12.0 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (362.4 mg, 2.4 mmol, 2.0 equivalent), di-EA (471.0 mg, 3.6 mmol, 3.0 equivalent), and HATU (692.8 mg, 1.8 mmol, 1.5 equivalent) were added. The resulting solution was stirred at room temperature for 2 hours. The crude product was purified by Prep-Flash under the following conditions: column, C18 silica gel; mobile phase, 0.1% FNH4HCO3 and CH3CN in water (CH3CN increased from 30% to 80% within 3 minutes); detector, UV 254 nm, 220 nm. As a result, 520 mg (92.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7) was obtained as a green solid.

[0260] 7. Synthesis of 7.3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (11-8) [ka] In a 50 mL three-necked round-bottom flask, combine 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (11-7, 200.0 mg, 0.4 mmol, 1.0 equivalent), ethanol (8.0 mL), and toluene (8. 0 mL of ethyl acetate was added to a solution containing NaBH4 (32.9 mg, 0.9 mmol, 2.0 equivalents), Mn(OAc)3·2H2O (9.3 mg, 0.03 mmol, 0.08 equivalents), and 2-[(1E)-([3-[(E)-[(2-hydroxyphenyl)methylidene]amino]-2,2-dimethylpropyl]imino)methyl]phenol (10.8 mg, 0.03 mmol, 0.08 equivalents). O2 (g) was introduced into the above solution. 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 twice with 20 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed twice with 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. As a result, 250 mg (crude raw material) of 7,3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (11-8) was obtained as a yellow oil.

[0261] 8. Synthesis of 8.3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-fluoropropan-2-yl)-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (compound 277) [ka] In a 25 mL three-necked round-bottom flask, 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 equivalent) and DCM (10.0 mL) were added. Subsequently, DAST (134.7 mg, 0.8 mmol, 2.0 equivalents) was added dropwise while stirring at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The crude product was purified by Prep-Flash under the following conditions: column, C 18 Silica gel; mobile phase, 0.1% TFA and CH3CN in water (CH3CN increased from 50% to 100% within 10 minutes). Detector, UV 254nm, 220nm. As a result, 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) was obtained as a white solid. (300 MHz, CDCl3, ppm) δ 8.26 (s, 1H), 7.35-7.33 (m, 1H), 7.29-7.19 (m, 3H), 6.98-6.85 (m, 3H), 5.94 (d, J = 7.5 Hz, 1H), 5.32-5.29 (m, 1H), 4.38-4.33 (m, 1H), 4.23-4.18 (m, 1H), 2.62 (s, 3H), 2.40-2.24 (m, 2H), 2.15 (d, J = 6.3 Hz, 3H), 2.08 (d, J = 6.3 Hz, 3H).

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

[0263] Synthesis of 1,8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-2) [ka] To a stirred mixture of ethyl 8-bromo-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-1, 30.0 g, 105.6 mmol, 1.0 equivalent) in THF (750.00 mL), LiBr (6.9 g, 791.9 mmol, 7.5 equivalents) was added at 0°C under a nitrogen atmosphere. CuI (150.8 g, 791.9 mmol, 7.5 equivalents) was added to the mixture in small amounts over 30 minutes at 0°C. The resulting mixture was stirred for a further 30 minutes at 0°C. Tert-butyl(chloro)magnesium (310.5 mL, 527.9 mmol, 5.0 equivalents) was added dropwise over 1 hour at 0°C. The resulting mixture was stirred for a further 5 minutes at 0°C. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (400 mL) at 0°C. The resulting mixture was extracted with SiO2 (2 × 800 mL). The combined organic layer was washed with brine (2 × 50 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture, ethyl 8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-2, 33 g, crude raw material), was used directly in the next step without further purification.

[0264] 2. Synthesis of ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3) [ka] To a stirred solution of ethyl 8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-2, 28.0 g, 107.1 mmol, 1.0 equivalent) in CHCl3 (300.0 mL), NBS (19.0 g, 107.1 mmol, 1.0 equivalent) was added at room temperature. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / SiO2 (3:1) to obtain ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3, 29.5 g, 80.9%) as a yellow solid.

[0265] Synthesis of ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate(12-4) [ka] To a stirred mixture of ethyl 3-bromo-8-tert-butyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-3, 26.0 g, 76.4 mmol, 1.0 equivalent) and 3,5-dichlorophenylboronic acid (14.5 g, 76.4 mmol, 1.0 equivalent) in THF (240.0 mL) and H2O (60.0 mL), K2CO3 (31.7 g, 229.2 mmol, 3.0 equivalent) and Pd(dtbpf)Cl2 (4980.7 mg, 7.6 mmol, 0.1 equivalent) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The mixture was cooled 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 ELISA (2 × 800 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (8:1) to obtain ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-4, 19 g, 61.2%) as an off-white solid.

[0266] 3. Synthesis of 3,8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5) [ka] Ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (12-4,18.0 g, 44.3 mmol, 1.0 equivalent), MeOH (100.0 mL, 344.3 mmol, 28.0 equivalents), THF (100.0 mL), H2O (200.0 mL), and KOH (53.1 g, 1329.0 mmol, 30.0 equivalents) were placed in a 250 mL round-bottom flask. The resulting solution was stirred at 80°C for 48 hours. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of water. The pH of the solution was adjusted to 4 with HCl (2 mol / L). The solid was recovered by filtration. This solid was dried in an oven under reduced pressure. As a result, 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5, 18g, crude raw material) was obtained as an off-white solid.

[0267] 4. Synthesis of 4,8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (compound 306) [ka] To a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (12-5, 17.0 g, 44.9 mmol, 1.0 equivalent) and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (8046.4 mg, 53.9 mmol, 1.2 equivalents) in DMF (80.0 mL), diEA (17.4 g, 134.8 mmol, 3.0 equivalents) and HATU (20.5 g, 53.9 mmol, 1.2 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise to 300 mL of H2O. The precipitated solid was collected by filtration and washed with water (2 × 20 mL). The residue was dissolved in MeCN (200 mL). Next, 800 mL of H2O was added dropwise. The precipitated solid was collected by filtration. The obtained solid was dried under infrared light to obtain 8-tert-butyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (306, 17.2 g, 75.1%) as a pale green solid. (300 MHz, CDCl3, ppm) δ: 8.08 (s, 1H), 7.57 (d, J = 1.8 Hz, 2H), 7.41 (s, 1H), 7.32-7.18 (m, 2H), 6.99-6.95 (m, 1H), 6.88 (dd, J = 8.1, 1.2 Hz, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.32-5.29 (m, 1H), 4.41-4.34 (m, 1H), 4.24-4.16 (m, 1H), 2.61 (s, 3H), 2.41-2.34 (m, 1H), 2.27-2.21 (m, 1H), 1.78 (s, 9H)

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

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

[0270] 1. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) [ka] In a 40 mL round-bottom flask, THF (5.0 mL), H2O (1.0 mL, 0.06 mmol, 0.18 equivalents), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.0 equivalent), 3,5-difluorophenylboronic acid (145.0 mg, 0.9 mmol, 3.0 equivalents), Pd(dtbpf)Cl2 (20.0 mg, 0.03 mmol, 0.1 equivalent), and K2CO3 (85.0 mg, 0.6 mmol, 2.0 equivalents) were added. The resulting solution was stirred at 70°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:6). As a result, 90 mg (81.7%) of ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5) was obtained as a white solid.

[0271] 2. Synthesis of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) [ka] In a 40 mL round-bottom flask, H2O (1.0 mL), EtOH (5.0 mL), ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-5, 90.0 mg, 0.25 mmol, 1.0 equivalent), and LiOH (60.0 mg, 2.5 mmol, 10.0 equivalent) were added. The resulting solution was stirred at 50°C for 2 hours. The pH was adjusted to 4 using HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 70 mg (84.4%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6) was obtained as a white solid.

[0272] 3. Synthesis of tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1) [ka] In a 40 mL round-bottom flask, DMF (1.0 mL, 0.01 mmol, 0.06 equivalents), t-BuOH (1.0 mL, 0.01 mmol, 0.06 equivalents), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (4-6, 70.0 mg, 0.2 mmol, 1.0 equivalent), DPPA (70.0 mg, 0.25 mmol, 1.2 equivalents), and TEA (24.0 mg, 0.2 mmol, 1.1 equivalents) were added. The resulting solution was stirred at 50°C for 3 hours. This mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing from H2O:ACN=90:10 to H2O:ACN=20:80 within 15 minutes; detector, 254 nm. As a result, tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1) was obtained as a white solid.

[0273] 4. Synthesis of 4,3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-amine(13-2) [ka] In a 50 mL round-bottom flask, HCl (gas) in 1,4-dioxane (4 M, 5.00 mL) and tert-butyl N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]carbamate (13-1, 65.0 mg, 0.2 mmol, 1.0 equivalent) were added. The resulting solution was stirred at 40°C for 2 hours. The resulting mixture was concentrated under vacuum. As a result, 40 mg (81.9%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-amine (13-2) was obtained as a white solid.

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

[0275] In a 50 mL round-bottom flask, 2.0 mL of DCM, 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-amine (13-2, 25.0 mg, 0.08 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-carbonic chloride (50.0 mg, 0.2 mmol, 3.0 equivalents), and 0.5 mg of DIEA (0.004 mmol, 0.05 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=50:50 to H2O:ACN=10:90 within 20; detector, 254 nm. As a result, 9.3 mg (24.3%) of (4S)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide (320) was obtained as a white solid, and 11 mg (26.0%) of (4R)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyridazin-7-yl]-3,4-dihydro-2H-1-benzopyran-4-carboxamide (320-0) was obtained. 1 H NMR: (300 MHz Chloroform-d, ppm): δ 8.93 (s, 1H), 7.50-7.43 (m, 1H), 7.37-7.30 (m, 1H), 7.27-7.25 (m, 2H), 7.08-7.00 (m, 2H), 6.89-6.81 (m, 1H), 4.44-4.40 (m, 1H), 4.16-4.07 (m, 1H), 3.92 (brs, 1H), 3.70-3.66 (m, 1H), 2.70-2.63 (m, 1H), 2.61 (s, 3H), 2.34-2.28 (m, 1H), 1.20-1.14 (m, 6H); 320-0 1H NMR: (300 MHz Chloroform-d, ppm): δ 8.94 (s, 1H), 7.50-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.27-7.20 (m, 2H), 7.15-7.00 (m, 2H), 6.94-6.82 (m, 1H), 4.44-4.40 (m, 1H), 4.14-4.07 (m, 1H), 3.92 (brs, 1H), 3.70-3.60 (m, 1H), 2.70-2.50 (m, 4H), 2.37-2.24 (m, 1H), 1.19-1.14 (m, 6H).

[0276] [Table 12]

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

[0278] 1. Synthesis of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2a) and ethyl 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2b) [ka] In an 8 mL round-bottom flask, 3.0 mL of THF, 4-4 ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate, 4.0 mL of di-tert-butylzinc, 2.0 mmol, 6.5 equivalents, and 40.0 mg of Pd(PPh3)4, 0.03 mmol, 0.1 equivalents were added. The resulting solution was stirred overnight at 80°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:4). As a result, 20 mg (mixture) of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2a) and ethyl 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (14-2b) were obtained as white solids.

[0279] 2. Synthesis of 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3b) [ka] In a 50 mL round-bottom flask, H2O (1.0 mL), EtOH (5.0 mL), a mixture of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (a mixture of 14-2a and 14-2b, 20.0 mg, 0.06 mmol, 1.00 equivalent), and NaOH (40.0 mg, 1.00 mmol, 15.2 equivalents) were added. The resulting solution was stirred at 80°C for 2 hours. The pH was adjusted to 4 using HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 12 mg (mixture) of 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (14-3b) were obtained as white solids.

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

[0281] A mixture of DMF (1.0 mL, 12.9 mmol, 237.2 equivalents), 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 equivalent), (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) was placed in a 50 mL round-bottom flask. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 within 20; detector, 254 nm. The product was obtained. As a result, 2.2 mg (9.9%) of 3-tert-butyl-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (323) 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-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxamide (323-0) was obtained. 1 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), 3.90-0.70 (m, 1H), 2.68 (s, 3H), 2.50-2.30 (s, 1H), 2.30-2.15 (m, 1H), 1.75-1.70 (m, 6H), 1.55 (s, 9H); 323-01 H NMR: (300 MHz Chloroform-d, ppm): δ 8.24 (s, 1H), 7.40-7.31 (m, 1H), 7.27-7.21 (m, 1H), 6.99-6.90 (m, 1H), 6.88-6.85 (m, 1H), 6.10 (brs, 1H), 5.41-5.37 (m, 1H), 4.40-4.34 (m, 1H), 4.25-4.17 (m, 1H), 3.80 (brs, 1H), 2.85 (d, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.44-2.38 (m, 1H), 2.28-2.10 (m, 2H), 1.60 (t, J = 6.6 Hz, 6H), 0.95 (d, J = 6.6 Hz, 6H).

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

[0283] Synthesis of 1,8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate ethyl (15-1) [ka] In an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, toluene (2.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 70.0 mg, 0.2 mmol, 1.0 equivalent), piperidine (120.0 mg, 1.4 mmol, 6.6 equivalents), Pd2(dba)3 (35.0 mg, 0.04 mmol, 0.2 equivalents), BINAP (38.0 mg, 0.06 mmol, 0.3 equivalents), and Cs2CO3 (200.0 mg, 0.6 mmol, 2.9 equivalents) were added. The resulting solution was stirred at 120°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). As a result, 60 mg (84.6%) of ethyl 8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate (15-1) was obtained as a yellow solid.

[0284] 2. Synthesis of 2,8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2) [ka] In a 50 mL round-bottom flask, i-PrOH (1.0 mL, 0.02 mmol), THF (1.0 mL), H2O (1.0 mL), ethyl 8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylate (15-1, 70.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH·H2O (30.0 mg, 0.7 mmol, 3.4 equivalents) were added. The resulting solution was stirred at 50°C for 1 hour. The pH was adjusted to 4 using HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 60 mg (93.7%) of 8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2) was obtained as a yellow solid.

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

[0286] In a 50 mL round-bottom flask, DMA (3.0 mL), 8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (15-2, 60.0 mg, 0.2 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (44.0 mg, 0.3 mmol, 1.5 equivalents), HATU (113.0 mg, 0.3 mmol, 1.5 equivalents), and DIEA (51.0 mg, 0.4 mmol, 2.0 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 within 20; detector, 254 nm. As a result, 36.4 mg (42.3%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-(piperidine-1-yl)imidazo[1,2-b]pyridazine-7-carboxamide (324) was obtained as a yellow solid. (300 MHz, Chloroform-d, ppm): δ 8.19 (s, 1H), 7.33-7.30 (m, 1H), 7.25-7.20 (m, 1H),6.97-6.90 (m, 1H), 6.89-6.80 (m, 1H), 6.10-6.02 (m, 1H), 5.40-5.30 (m, 1H), 4.38-4.34 (m, 1H), 4.22-4.10 (m, 1H), 3.79-3.76 (m, 1H), 3.30-3.20 (m, 4H), 2.52 (s, 3H), 2.50-2.35 (m, 1H), 2.30-2.15 (m, 1H), 1.80-1.70 (m, 4H), 1.65-1.58 (m, 8H).

[0287] [Table 13]

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

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

[0290] A mixture of dioxane (2.0 mL), H2O (0.4 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.00 mg, 0.3 mmol, 1.0 equivalent), 4-(trifluoromethyl)cyclohexane-1-en-1-ylboronic acid (120.0 mg, 0.6 mmol, 2.0 equivalents), Pd(dtbpf)Cl2 (20.0 mg, 0.03 mmol, 0.1 equivalent), and K2CO3 (100.0 mg, 0.7 mmol, 2.4 equivalents) was placed in an 8 mL round-bottom flask. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). As a result, 110 mg (90.7%) of ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylate (16-1) was obtained as a yellow solid phase.

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

[0292] In a 50 mL round-bottom flask, i-PrOH (2.0 mL), THF (2.0 mL), H2O (1.0 mL), ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylate (16-1, 110.0 mg, 0.3 mmol, 1.0 equivalent), and LiOH (70.0 mg, 2.9 mmol, 10.5 equivalents) were added. The resulting solution was stirred at 50°C for 1 hour. The pH of the solution was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 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) was obtained as a white solid.

[0293] 3. Synthesis of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexa-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327) [ka] In a 40 mL round-bottom flask, DMF (5.0 mL), 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexa-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxylic acid (16-2, 130.0 mg, 0.3 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (79.2 mg, 0.5 mmol, 1.5 equivalent), HATU (200.5 mg, 0.5 mmol, 1.5 equivalent), and DIEA (137.2 mg, 1.0 mmol, 3.0 equivalent) were added. The resulting solution was stirred at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 within 20 minutes; detector, 254 nm. As a result, 130 mg (73.7%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327) was obtained as a white solid. (300 MHz, Chloroform-d, ppm): δ 8.20 (s, 1H), 7.35-7.30 (m, 1H), 7.25-7.17 (m, 1H), 7.10-6.84 (m, 2H), 6.15-5.90 (m, 2H), 5.45-5.30 (m, 1H), 4.44-4.31 (m, 1H), 4.23-4.19 (m, 1H), 3.83-3.72 (m, 1H), 2.75-2.55 (m, 3H), 2.53 (s, 3H), 2.50-2.35 (m, 3H), 2.29-2.13 (m, 3H), 1.63 (d, J = 6.6 Hz, 6H).

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

[0295] In a 50 mL round-bottom flask, EA (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohexane-1-yl]imidazo[1,2-b]pyridazine-7-carboxamide (327 mg, 50.0 mg, 0.10 mmol, 1.0 equivalent), and aqueous Pd / C (50.0 mg) were added. H2 (g) was introduced into the above at room temperature. The resulting solution was stirred at room temperature for 2 hours. Solid matter was filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=50:50 to H2O:ACN=10:90 within 20 minutes; detector, 254 nm. The racemic mixture was purified using a column: XA-YMC Cellulose-SC, 4.6*100 mm, 3 μm; mobile phase A / mobile phase B, hexane / EtOH = 70 / 30; flow rate, 1 mL / min; gradient, 30B to 30B over 10 minutes; 254 nm; injection volume, 1 mL. As a result, 19.3 mg (38.4%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-b]pyridazine-7-carboxamide and 8.0 mg (15.8%) of N-((S)-chroman-4-yl)-8-isopropyl-2-methyl-3-((1s,4R)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-b]pyridazine-7-carboxamide (326 and 326-0) were obtained. Stereochemical representation is expected. 326 1¹H NMR spectrum: (300 MHz chloroform-d, ppm): δ 8.23 ​​(s, 1H), 7.35-7.30 (m, 1H), 7.27-7.20 (m, 1H), 7.02-6.94 (m, 1H), 6.90-6.80 (m, 1H), 6.07 (brs, 1H), 5.44-5.34 (m, 1H), 4.44-4.31 (m, 1H), 4.28-4.14 (m, 1H), 3.90-3.80 (m, 1H), 3.45-3.25 (m, 1H), 2.58 (s, 3H), 2.55-2.40 (m, 2H), 2.45-2.15 (m, 4H), 1.85-1.65 (m, 5H), 1.62 (d, J = 6.6 Hz, 6H); 326-0 1 ¹H NMR spectrum: (300 MHz, chloroform-d, ppm): δ 8.17 (s, 1H), 7.30-7.28 (m, 1H), 7.25-7.15 (m, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.15-5.90 (m, 1H), 5.45-5.20 (m, 1H), 4.40-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.81-3.65 (m, 1H), 3.30-3.10 (m, 1H), 2.53 (s, 3H), 2.46-2.31 (m, 1H), 2.30-2.00 (m, 6H), 2.00-1.85 (m, 2H), 1.65-1.55 (m, 6H), 1.50-1.45 (m, 1H).

[0296] [Table 14]

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

[0298] 1. Synthesis of ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (17-2) [ka] In a 1000 mL round-bottom flask, THF (85.0 g, 1178.8 mmol, 26.3 equivalents), ethyl 5-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (17-1, 15.0 g, 44.9 mmol, 1.0 equivalent), and ethyl acetate (50.0 g, 567.5 mmol, 12.6 equivalents) were added. Subsequently, t-BuOK (500 mL) was added in small amounts at 0°C. The resulting solution was stirred at room temperature for 2 hours. Next, the reaction was quenched by adding NH4Cl (aqueous solution). The resulting solution was extracted three times with 200 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:4). As a result, 13 g (77.0%) of ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (17-2) was obtained as a colorless oil.

[0299] 2. Synthesis of ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3) [ka] In a 500 mL round-bottom flask, DCM (100.0 mL, 1573.0 mmol, 59.2 equivalents), ethyl 3-[5-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (17-2, 10.0 g, 26.6 mmol, 1.0 equivalent), and DMF-DMA (9.0 g, 75.5 mmol, 2.8 equivalents) were added. The resulting solution was stirred at 40°C for 2 hours. Next, the reaction was quenched by adding water / ice. The resulting solution was extracted twice with 100 mL of MTBE, and the aqueous layers were combined. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The solid was recovered by filtration. As a result, 5 g (65.7%) of ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3) was obtained as a white solid.

[0300] 3. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4) [ka] In a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, H2O (1.0 mL), NMP (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3, 400.0 mg, 1.398 mmol, 1.0 equivalent), 3,5-dichlorophenylboronic acid (320.1 mg, 1.7 mmol, 1.2 equivalents), Pd(dtbpf)Cl2 (70.0 mg, 0.1 mmol, 0.08 equivalents), and Cs2CO3 (1.2 g, 3.7 mmol, 2.6 equivalents) were added. The resulting solution was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, and 5 ml of H2O was added. The solid was recovered by filtration. As a result, 300 mg (crude raw material) of ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4) was obtained as a yellow solid.

[0301] 4. Synthesis of ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5) [ka] In a 40 mL round-bottom flask, CHCl3 (5.0 mL, 0.04 mmol, 0.07 equivalents), DMF (15.0 mg, 0.2 mmol, 0.4 equivalents), ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-4, 200.0 mg, 0.6 mmol, 1.0 equivalent), and (COCl)2 (400.0 mg, 3.1 mmol, 5.5 equivalents) were added. The resulting solution was stirred at 80°C for 22 hours. The resulting mixture was concentrated under vacuum. The resulting mixture was washed 10 times with 10 mL of ACN:H2O = 1:1. The solid was recovered by filtration. As a result, 110 mg (52.3%) of ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5) was obtained as a yellow solid.

[0302] 5. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6) [ka] In a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, H2O (1.00 mL, 55.5 mmol, 187.0 equivalents), THF (5.0 mL, 61.7 mmol, 207.9 equivalents), ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5, 110.0 mg, 0.3 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (72.0 mg, 0.43 mmol, 1.4 equivalents), Pd(dtbpf)Cl2 (40.0 mg, 0.06 mmol, 0.2 equivalents), and K2CO3 (160.0 mg, 1.2 mmol, 3.9 equivalents) were added. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, 80 mg (71.6%) of ethyl 3-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6) was obtained as a yellow solid.

[0303] 6. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7) [ka] In a 50 mL round-bottom flask, EA (5.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-(propa-1-en-2-yl)imidazo[1,2-b]pyridazine-7-carboxylate (17-6, 80.0 mg, 0.21 mmol, 1.0 equivalent), and PtO2 (40.0 mg, 0.2 mmol, 0.8 equivalents) were added. H2 (g) was introduced into the mixture using a balloon. The resulting solution was stirred at 50°C for 1 hour. The solid was collected by filtration. The resulting mixture was concentrated under vacuum. As a result, 60 mg of ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7) was obtained as a yellow solid.

[0304] 7. Synthesis of 7,3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8) [ka] In an 8 mL round-bottom flask, EtOH (2.0 mL), H2O (0.50 mL), ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (17-7, 60.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH (30.0 mg, 1.2 mmol, 7.9 equivalents) were added. The resulting solution was stirred at 50°C for 1 hour. Next, the reaction was quenched by adding water / ice. The pH of the solution was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 40 mg (72.0%) of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8) was obtained as a white solid.

[0305] 8. Synthesis of 8,3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (352) [ka] In an 8 mL round-bottom flask, DMF (4.0 mL), 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (17-8, 40.0 mg, 0.1 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (22.0 mg, 0.15 mmol, 1.3 equivalents), HATU (70.0 mg, 0.2 mmol, 1.6 equivalents), and DIEA (46.0 mg, 0.4 mmol, 3.1 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 within 20; detector, 254 nm. As a result, 15.9 mg (28.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine-7-carboxamide (352) was obtained as a white solid. (300 MHz, Chloroform-d, ppm): δ 8.41 (s, 1H), 8.11 (s, 1H), 7.99 (d, J = 1.8 Hz, 2H), 7.39 (s, 1H),7.32-7.28 (m, 1H), 7.28-7.22 (m, 1H), 6.99-6.96 (m, 1H), 6.90 (d, J = 8.4, 1H), 6.13 (d, J = 7.5 Hz, 1H), 5.50-5.30 (m, 1H), 4.46-4.33 (m, 1H), 4.29-4.15 (m, 1H), 3.79-3.70 (m, 1H), 2.50-2.36 (m, 1H), 2.33-2.20 (m, 1H), 1.69-1.65 (m, 6H).

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

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

[0308] In a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, DMAC (5.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.0 equivalent), dppf (59.3 mg, 0.1 mmol, 0.3 equivalent), Zn(CN)2 (100.1 mg, 0.8 mmol, 2.8 equivalents), Pd2(dba)3 (50.5 mg, 0.05 mmol, 0.2 equivalents), and Zn (100.1 mg, 1.5 mmol, 5.0 equivalents) were added. The resulting solution was stirred at 100°C for 2 hours. Next, the reaction was quenched by adding water. The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). As a result, 40 mg (47.9%) of ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (18-1) was obtained as a yellow oil.

[0309] 2. Synthesis of 2,3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid [ka] In an 8 mL round-bottom flask, EtOH (1.0 mL), H2O (0.5 mL), ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylate (18-1, 40.0 mg, 0.15 mmol, 1.0 equivalent), and LiOH (30.0 mg, 1.2 mmol, 8.5 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 25 mg (69.7%) of 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (18-2) was obtained as a yellow oil.

[0310] 3. Synthesis of 3-cyano-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (366) [ka] In an 8 mL round-bottom flask, DMF (2 mL), 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxylic acid (18-2, 25.0 mg, 0.1 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (16.9 mg, 0.1 mmol, 1.1 equivalent), HATU (47.0 mg, 0.1 mmol, 1.21 equivalents), and DIEA (28.0 mg, 0.2 mmol, 2.1 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=70:30 to H2O:ACN=10:90 within 20 minutes; detector, 254 nm. As a result, 16.5 mg (42.9%) of 3-cyano-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methylimidazo[1,2-b]pyridazine-7-carboxamide (366) was obtained as a white solid. (300 MHz, CDCl3, ppm): δ 8.35 (s, 1H), 7.25-7.20 (m, 2H), 6.97-6.92 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.20-6.10 (m, 1H), 5.39-5.33 (m, 1H), 4.41-4.32 (m, 1H), 4.27-4.14 (m, 1H), 3.69-3.59 (m, 1H), 2.62 (s, 3H), 2.45-2.35 (m, 1H), 2.29-2.18 (m, 1H), 1.65-1.55 (m, 6H).

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

[0312] 1. Synthesis of methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1) [ka] In a 40 mL round-bottom flask, DMF (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (17-3, 150.0 mg, 0.5 mmol, 1.0 equivalent), methyl iodide (200.0 mg, 1.3 mmol, 2.4 equivalents), and K2CO3 (210.0 mg, 1.5 mmol, 2.9 equivalents) were added. The resulting solution was stirred at 70°C for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=90:10 to H2O:ACN=40:60 within 15 minutes; detector, 254 nm. As a result, 80 mg (48.6%) of methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1) was obtained as a white solid.

[0313] 2. Synthesis of methyl 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2) [ka] In an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, THF (5.0 mL), H2O (1.0 mL), methyl 3-bromo-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-1, 80.0 mg, 0.25 mmol, 1.0 equivalent), 3,5-dichlorophenylboronic acid (56.0 mg, 0.3 mmol, 1.1 equivalent), Pd(dtbpf)Cl2 (30.0 mg, 0.05 mmol, 0.2 equivalent), and K2CO3 (100.0 mg, 0.7 mmol, 2.8 equivalents) were added. The resulting solution was stirred at 80°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). As a result, 20 mg (20.6%) of methyl 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2) was obtained as a white solid.

[0314] 3. Synthesis of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3) [ka] In a 40 mL round-bottom flask, EtOH (5.0 mL), H2O (2.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (19-2, 70.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH (40.0 mg, 1.7 mmol, 8.7 equivalents) were added. The resulting solution was stirred at 50°C for 1 hour. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 40 mg (61.9%) of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3) was obtained as a white solid.

[0315] 4. Synthesis of 4.3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-methoxyimidazo[1,2-b]pyridazine-7-carboxamide (394) [ka]

[0316] In an 8 mL round-bottom flask, DMF (3.0 mL), 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylic acid (19-3, 40.0 mg, 0.1 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (19.5 mg, 0.1 mmol, 1.1 equivalent), HATU (75.1 mg, 0.2 mmol, 1.7 equivalents), and DIEA (35.9 mg, 0.3 mmol, 2.3 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increasing H2O:ACN=70:30 to H2O:ACN=10:90 within 20 minutes; detector, 254 nm. As a result, 12 mg (21.6%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-methoxyimidazo[1,2-b]pyridazine-7-carboxamide (394) was obtained as a white solid. (300 MHz, CDCl3, ppm): δ 10.08 (d, J = 7.8 Hz, 1H), 9.10 (s, 1H), 7.92 (s, 2H), 7.51 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.41-7.33 (m, 1H), 7.21-7.15 (m, 1H), 6.94-6.84 (m, 2H), 5.48-5.46 (m, 1H), 4.46 (s, 3H), 4.37-4.29 (m, 2H), 2.39-2.30 (m, 1H), 2.25-2.17 (m, 1H).

[0317] [Table 15]

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

[0319] Scheme 21 [ka]

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

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

[0322] 3. Synthesis of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) [ka] In a 250 mL three-necked round-bottom flask, ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-yl]-3-oxopropanoate (3-5, 10.0 g, 26.6 mmol, 1.0 equivalent), DMF (100.0 mL), K2CO3 (3.7 g, 26.6 mmol, 1.0 equivalent), and DMF-DMA (7.9 g, 66.5 mmol, 2.5 equivalents) were added. The resulting solution was stirred at room temperature for 1 hour. Next, the reaction was quenched by adding 300 mL of water. The solid was recovered by filtration. The crude product was recrystallized from ACN at a ratio of 10 ov. As a result, 7.5 g (98.6%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6) was obtained as a white solid.

[0323] 4. Synthesis of ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1) [ka] Ethyl 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylate (3-6, 8.0 g, 28.0 mmol, 1.0 equivalent), DMF (80.0 mL), K2CO3 (7.7 g, 55.9 mmol, 2.0 equivalent), and CH3I (11.9 g, 83.891 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 60°C for 2 hours. The residue was applied to a C18 column using (25%~45% ACN in water for 8 minutes). As a result, 2.9 g (34.0%) of ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1) was obtained as a white solid.

[0324] 5. Synthesis of ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2) [ka] In a 40 mL vial maintained under a nitrogen inert atmosphere, ethyl 2-bromo-8-methoxyimidazo[1,2-b]pyridazine-7-carboxylate (20-1, 300.0 mmol, 1.0 equivalent), DMF (6.0 mL), methyl 2,2-difluoro-2-sulfoacetate (960.2 mg, 5.0 mmol, 5.0 equivalent), HMPA (895.7 mg, 5.0 mmol, 5.0 equivalent), and CuI (761.5 mg, 4.0 mmol, 4.0 equivalent) were added. The resulting solution was stirred at 100°C for 16 hours. The solids were filtered off. The residue was applied to a C18 column using (25%~45%, 8 min, ACN (0.1% TFA) in H2O). As a result, 170 mg (56.6%) of ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2) was obtained as a yellow solid.

[0325] 6. Synthesis of ethyl 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-3) [ka] Ethyl 8-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-2, 1.8 g, 6.2 mmol, 1.0 equivalent), LiCl (2.6 g, 62.2 mmol, 10.0 equivalent), and DMF (18.0 mL) were added to a 40 mL vial purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120°C for 2 hours. The residue was applied to a C18 column using (75%~83%, 8 min, ACN (0.1% TFA) in H2O). As a result, 900 mg (52.5%) of ethyl 8-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-3) was obtained as a yellow solid.

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

[0327] 8. Synthesis of ethyl 8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1) [ka] Ethyl 8-bromo-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (20-4, 150.0 mg, 0.4 mmol, 1.0 equivalent), DMF (1.5 mL), and morpholine (193.3 mg, 2.2 mmol, 5.0 equivalents) were added to an 8 mL vial. The resulting solution was stirred at 100 °C for 1 hour. The residue was applied to a C18 column using (80%~90%, 6 min, ACN (0.1% FA) in H2O). As a result, 110 mg (72.0%) of ethyl 8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1) was obtained as a white solid.

[0328] 9. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2) [ka] A mixture of ethyl 8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-1, 90.00 mg, 0.3 mmol, 1.0 equivalent), NMP (1.8 mL), 1,3-dichloro-5-iodobenzene (214.0 mg, 0.8 mmol, 3.0 equivalents), Cs2CO3 (170.3 mg, 0.5 mmol, 2.0 equivalents), Pd(AcO)2 (11.7 mg, 0.05 mmol, 0.2 equivalents), and Ad2(n-Bu)P (28.0 mg, 0.08 mmol, 0.3 equivalents) was added to an 8 mL vial purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 100°C. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:5). As a result, 110 mg (72.2%) of ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2) was obtained as a white solid.

[0329] 10. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3) [ka] Ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylate (21-2, 110.0 mg, 0.2 mmol, 1.0 equivalent), i-PrOH (2.1 mL), H2O (0.7 mL), and LiOH·H2O (75.4 mg, 1.8 mmol, 8.0 equivalents) were placed in an 8 mL vial. The resulting solution was stirred at 60°C for 5 hours. The residue was applied to a C18 column using (80%~90%, 6 min, ACN (0.1% FA) in H2O). As a result, 70 mg (65.3%) of 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3) was obtained as a white solid.

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

[0331] 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxylic acid (21-3, 66.0 mg, 0.1 mmol, 1.0 equivalent), DMF (2.0 mL), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (32.0 mg, 0.2 mmol, 1.5 equivalents), DIEA (55.5 mg, 0.4 mmol, 3.0 equivalents), and HATU (81.6 mg, 0.2 mmol, 1.5 equivalents) were added to an 8 mL vial. The resulting solution was stirred at room temperature for 1 hour. The residue was applied to a C18 column using (90%~98%, 6 min, ACN (0.1% FA) in H2O). As a result, 35.1 mg (41.4%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholine-4-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-7-carboxamide (450) was obtained as a white solid. (300 MHz, DMSO-d6, ppm): δ 9.08 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.83 (t, J = 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.32 (d, J = 7.8Hz, 1H), 7.21-7.15 (m, 1H), 6.94-6.89 (m, 1H), 6.82-6.79 (m, 1H), 5.23-5.16(m, 1H), 4.30-4.20 (m, 2H), 3.94-3.81 (m, 8H), 2.27-2.16 (m, 1H), 2.08-2.01 (m, 1H).

[0332] [Table 16]

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

[0334] 1. Synthesis of ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1) [ka] In a 40 mL round-bottom flask, 5.0 mL of NMP, ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (17-5, 100.0 mg, 0.2 mmol, 1.0 equivalent), and morpholine (0.5 mL, 5.7 mmol, 23.6 equivalents) were added. The resulting solution was stirred at 80°C for 1 hour. Next, the reaction was quenched by adding 10 mL of water. The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 65 mg (64.0%) of ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1) was obtained as a yellow solid.

[0335] 2. Synthesis of 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (22-2) [ka] In a 40 mL round-bottom flask, EtOH (2.0 mL), H2O (1.5 mL), ethyl 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylate (22-1, 65.0 mg, 0.1 mmol, 1.0 equivalent), and LiOH·H2O (50.0 mg, 1.2 mmol, 7.7 equivalents) were added. The resulting solution was stirred at 50°C for 3 hours. The pH was adjusted to 4 using HCl (6 mol / L). The resulting solution was extracted three times with 20 mL of ethyl acetate, the organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum. As a result, 40 mg (65.9%) of 3-(3,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (22-2) was obtained as a yellow solid.

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

[0337] In a 40 mL round-bottom flask, 5.0 mL of DMF, 22-2 mg of 3,5-dichlorophenyl (2,5-dichlorophenyl)-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid, 1.0 equivalent of (4S)-3,4-dihydro-2H-1-benzopyran-4-amine, 17.0 mg of 3,12 equivalents of (4S)-3,4-dihydro-2H-1-benzopyran-4-amine, 650.2 mmol of HATU, and 38.0 mg of DIEA, 0.3 mmol of (2.9 equivalents of (4S)-3,4-dihydro-2H-1-benzopyran-4-amine) were added. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 within 20; detector, 254 nm. The product was obtained. As a result, 37.8 mg (70.9%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(morpholine-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (511) was obtained as a white solid. (300 MHz, CDCl3, ppm) δ 9.03 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.21-7.15 (m, 1H), 6.95-6.90 (m, 1H), 6.80-6.80 (m, 1H), 5.23-5.20 (m, 1H), 4.27-4.24(m, 2H), 3.93-3.78 (m, 8H), 2.23-2.21 (m, 1H), 2.10-2.07 (m, 1H). 512 1H NMR spectrum: (300 MHz, CDCl3, ppm) δ 8.36 (s, 1H), 7.98 (d, J = 1.9 Hz, 2H), 7.90 (s, 1H), 7.37-7.35 (m, 1H), 7.32-7.22 (m, 2H), 7.03-6.86 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.42-5.34 (m, 1H), 4.43-4.31 (m, 1H), 4.29-4.16 (m, 1H), 3.46 (s, 6H), 2.43-2.36 (m, 1H), 2.27-2.14 (m, 1H)

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

[0339] Synthesis of 1,7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2) [ka] To a stirred mixture of ethyl 7-chloroimidazo[1,2-b]pyridazine-2-carboxylate (23-1, 1.0 g, 4.4 mmol, 1.0 equivalent) and 1,3-dichloro-5-iodobenzene (1.8 g, 6.6 mmol, 1.5 equivalents) in toluene (10 mL, 105.0 mmol, 23.7 equivalents), K2CO3 (1.2 g, 8.9 mmol, 2.0 equivalents), Pd(OAc)2 (0.1 g, 0.4 mmol, 0.1 equivalent), and PPh3 (0.2 g, 0.9 mmol, 0.2 equivalents) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain ethyl 7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2, 1.2 g, 73.0%) as a yellow oil.

[0340] 2. Synthesis of 2,7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (23-3) [ka] LiOH·H2O (1.13 g, 27.0 mmol, 10.0 equivalent) was added at room temperature to a stirred mixture of ethyl 7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (23-2, 1.0 g, 2.7 mmol, 1.0 equivalent) in EtOH (8 mL) and H2O (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (50 mL). The mixture was acidified to pH 4 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (2 × 10 mL). The resulting solid was dried under infrared light.

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

[0342] 4. Synthesis of 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]ethenone (23-5) [ka] A stirred mixture of 7-chloro-3-(3,5-dichlorophenyl)-N-methoxy-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (23-4, 80.0 mg, 0.2 mmol, 1.0 equivalent) in THF (2 mL, 24.7 mmol, 119.0 equivalent) was mixed with chloromethylmagnesium (77.6 mg, 1.0 mmol, 5.0 equivalent) at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at 50°C for 60 minutes under a nitrogen atmosphere. The reaction product was quenched at room temperature with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with RINKAN (2 × 20 mL). The combined organic layers were washed with brine (2 × 4 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA4:1) to obtain 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]etanone (23-5 mg, 40 mg, 56.6%) as a pale yellow solid.

[0343] 5. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6) [ka] To a solution of 1-[7-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]ethanone (23-5, 40.0 mg, 0.1 mmol, 1 equivalent) in 1 mL of MeOH and 2 mL of dioxane, KOAc (34.6 mg, 0.4 mmol, 3.0 equivalents) and Pd(dppf)Cl2CH2Cl2 (9.6 mg, 0.01 mmol, 0.1 equivalent) were added in a pressure tank. The mixture was purged with nitrogen for 2 minutes, then pressurized to 30 atmospheres with carbon monoxide and heated overnight at 130°C. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by Prep-TLC (PE / EA3:1) to obtain 20 mg of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6, 46.8%) as a yellow solid.

[0344] 6. Synthesis of methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7) [ka] t-BuOOH (28.6 mg, 0.3 mmol, 5.0 equivalents) was added to a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)imidazo[1,2-b]pyridazine-7-carboxylate (23-6 mg, 20.0 mg, 0.05 mmol, 1.0 equivalent) and 2-[(propane-2-sulfonyl)dinthiosulfonyl]propane (46.1 mg, 0.2 mmol, 3.0 equivalents) in DMSO (2 mL) at room temperature. The resulting mixture was stirred at 50°C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ELISA (2 × 10 mL). The combined organic layer was washed with brine (2 × 5 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to obtain methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7, 10 mg, 44.8%) as a yellow oil.

[0345] 7. Synthesis of 7.2-Acetyl-3-(3,5-dichlorophenyl)-8-(propan-2-yl)imidazo[1,2-b]pyridazine-7-carboxylic acid (23-8) [ka] To a stirred mixture of methyl 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylate (23-7, 10.0 mg, 0.02 mmol, 1.0 equivalent) in EtOH (1 mL) and H2O (0.5 mL), LiOH·H2O (10.3 mg, 0.25 mmol, 10.0 equivalent) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (5 mL). The mixture was acidified to pH 4 with HCl (aqueous solution). The resulting mixture was extracted with ELISA (2 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried on 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.

[0346] 8. Synthesis of 8.2-Acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine (558) [ka]

[0347] DIEA (9.9 mg, 0.07 mmol, 3.0 equivalents) and HATU (14.5 mg, 0.04 mmol, 1.5 equivalents) were added to a stirred mixture of 2-acetyl-3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyridazine-7-carboxylic acid (23-8, 10.0 mg, 0.02 mmol, 1.0 equivalent) and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (5.7 mg, 0.04 mmol, 1.5 equivalents) in DMF (1 mL, 12.9 mmol, 506.8 equivalents) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The crude product was purified by Prep-HPLC under the following conditions (no gradient) to obtain 11 mg of 2-acetyl-3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropylimidazo[1,2-b]pyridazine (558, 95.) as a solid. (400 MHz, chloroform-d, ppm) δ: 8.31 (s, 1H), 7.56 (s, 2H), 7.45 (s, 1H), 7.225-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.88-6.86 (m, 1H), 6.06-6.05 (m, 1H), 5.38-5.36 (m, J = 4.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.21-4.16 (m, 1H), 3.73-3.67 (m 1H), 2.75 (s, 3H), 2.43-2.38 (m, 1H), 2.23-2.20 (m, 1H), 1.68 (t, J = 7.4 Hz, 6H). 559 1¹H NMR spectrum: (400 MHz, chloroform-d, ppm) δ: 8.44 (s, 1H), 7.88 (s, 2H), 7.50 (s, 1H), 7.26-7.21 (m, 2H), 6.98-6.94 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.08-6.07 (m, 1H), 5.40-5.36 (m, 1H), 4.39-4.34 (m, 1H), 4.21-4.15 (m, 1H), 3.71-3.64 (m, 1H), 2.44-2.39 (m, 1H), 2.26-2.20 (m, 1H), 1.65-1.54 (m, 6H)

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

[0349] Synthesis of 1,4-nitroso-3,4-dihydro-2H-1,4-benzoxazine [ka] In a 500 mL three-necked round-bottom flask, methyl 3,4-dihydro-2H-1,4-benzoxazine (24-1, 3.0 g, 22.2 mmol, 1.0 equivalent) and 3 M / HCl (300 ml) were added. NaNO2 (1.8 g, 26.1 mmol, 1.2 equivalents) was added dropwise 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 and eluted with PE / EA (10:01) to obtain 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine (24-2, 2.7 g, 75.1%) as a yellow oil.

[0350] 2. Synthesis of 3,4-dihydro-2H-1,4-benzoxazine-4-amine [ka] In a 500 mL three-necked round-bottom flask, methyl 4-nitroso-2,3-dihydro-1,4-benzoxazine (24-2, 2.7 g, 19.2 mmol, 1.0 equivalent) and THF (300 mL) were added, and LAH (1.35 g, 1.9 mmol, 2.0 equivalents) was added dropwise / in small amounts 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 and eluted with PE / EA (10:01) to obtain 3,4-dihydro-2H-1,4-benzoxazine-4-amine (24-3, 2.2 g, 44.9%) as a yellow oily substance.

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

[0352] Biological examples The present disclosure is further illustrated by the following biological examples, but these examples should not be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. The examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure. It should be further understood that there may be various other embodiments, modifications and means thereof that can be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0353] Biological Example 1: A screening method for testing the activity of a compound against microfilariae of Dirofilaria immitis. 400–600 microfilariae of Dirofilaria imitis were added to wells of a microtiter plate containing the test compound formulated in RPMI medium and 100% DMSO. The plate was kept at 37°C and 5% CO2 for 3 days. The efficacy of the compound was determined based on the motility of the microfilariae compared to the average motility of a control well containing DMSO alone. EC 50 A dose-response assay was performed to determine the values. Compounds 298-0, 304, 295, 296, A412, A406, A405, A411, A400, A401, 325, A419, 513-0, 450, A435, A439, and A442 were measured in EC2 concentrations of 0.1 μM to 1 μM. 50 The values ​​were shown. Compounds 279, 273, 276, 294, 322, 323, 326-0, 323-0, 352, 364, 371, 373, 298, 419, A403, A413, A407, A414, A449, A448, A447, A441, 512, 511, 513, 418, A428, A427, 305, 451 and 558 had an EC of 0.01 μM to 0.1 μM. 50 The values ​​were shown. Compounds 308, 271, 274, 306, 297, A410, 277, 299-0, 293, 275, 175, 573, 614, 572, 528, 560, 420, A422, 523, and 527 had EC values ​​of 0.001 μM to 0.01 μM. 50 The values ​​shown are: Compounds 307, 324, 345, 524, 526, and A421 have an EC of less than 0.001 μM. 50 The value was shown.

[0354] Biological Example 2: A screening method for testing the activity of a compound against the torsional gastric worm (Haemonchus contortus). Twenty L1 torsion gastric worm larvae were added to wells of a microtiter plate containing nutrient medium and DMSO-containing test compounds. Analysis was performed over 4 days to determine the developmental stage of L1-L3 larvae. Larvae exposed to DMSO alone were used as a control. A dose-response assay was performed to determine the EC (Emission Control Factor). 50 The values ​​were determined. Compounds 174, 366, 320-0, 369, 365, 321, 394, 298-0, 323-0, 323, 325, 296, 304-0, 373, 398, A404, 370, 326, and 299 had EC values ​​of 1 μM to 10 μM. 50 The values ​​indicated activity. Compounds 304, A405, A414, A403, A401, 371, 364, 352, 308, 320, 298, 299-0, 327, 324, 279, and 275 were found to be active at 0.1 μM to 1 μM EC2. 50 The values ​​were shown. Compounds 175, 272, 273, 295, 326-0, 277, 294, 344, A408, A410, A412, A409, A413 and A400 had an EC of 0.01 μM to 0.1 μM. 50 The values ​​shown are: compounds 297, 306, 271, 345, and 274 have an EC of less than 0.01 μM. 50 The value was shown.

[0355] Biological Example 3: A screening method for testing the activity of a compound against L4 stage larvae of Dirofilaria immits. Four to six L4 stage heartworms were added to wells of a microtiter plate containing the test compound formulated in maintenance nutrient medium and 100% DMSO. After holding the plate at 37°C and 5% CO2 for 3 days, the larval motility was determined. The effectiveness of the compound was determined by comparing the motility of the treated L4 worms to the average motility of worms in a control well containing only DMSO. EC 50 To determine the values, a dose-response assay is performed. Compounds 366, 320-0, 365, 321, 304-0, and 329 are subjected to EC2 assays of 1 μM to 10 μM. 50 The values ​​shown are for compounds 325, 323, and 370, with an EC of 0.1 μM to 1 μM. 50It was found that compounds 276, 322, 320, 364, 326, 298-0, 299, 323-0, 296, 295, and 307 had an EC of 0.01 μM to 0.1 μM. 50 The values ​​were shown. Compounds 304, 175, 272, 294, 273, 344, 275, 327, 326-0, 299-0, 298, 277, 324, and 297 had EC values ​​of 0.001 μM to 0.01 μM. 50 The values ​​were shown. Compounds 308, 271, 293, 345, 371, and 306 had an EC of less than 0.001 μM. 50 This was shown.

[0356] While preferred embodiments of the present invention have been described in detail as described above, it should be understood that the present invention as defined in the above paragraphs is not limited to the specific details shown above, and many obvious modifications are possible without departing from the spirit or scope of the invention.

Claims

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

2. R 1 is hydrogen, cyano, halo, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyloxy, C 2 -C 6 -haloalkenyloxy, C 2 -C 6 -alkynyloxy, C 2 -C 6 -haloalkynyloxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 1 [[ID=RO]]-C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 - Haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 -Cycloalkenyl, optionally substituted C 3 -C 8 -Cycloalkyloxy, optionally substituted 3- to 7-membered heterocyclyl, -SF 5 , -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl), or -NR a R b (In the formula, R a and R b These are independently H or C which may be substituted. 1 -C 6 - Alkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 2 is hydrogen, cyano, halo, hydroxyl, C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 1 -C 6 - Alkoxy, C 1 -C 6 - Haloalkoxy, C 2 -C 6 - Alkenil, C 2 -C 6 - Haloalkenyl, C 2 -C 6 - Alkinyl, C 2 -C 6 - Haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkoxy-C 1 -C 6 - alkyl, optionally substituted phenyl; optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 -Cycloalkenyl, optionally substituted C 3 -C 8 - A substituted 3-7 membered heterocycline containing 1-3 heteroatoms selected from the group consisting of cycloalkyloxy, N, O, and S, C 1 -C 6 - Alkylcarbonyl, C 1 -C 6 - Haloalkylcarbonyl, C 1 -C 6 - Alkoxycarbonyl, C 1 -C 6 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, C 1 -C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -Haloalkylaminocarbonyl, -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl), SF 5 , or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 3 C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 2 -C 6 - Alkenil, C 2 -C 6 - Haloalkenyl, C 2 -C 6 - Alkinyl, C 2 -C 6 - Haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkoxy-C 1 -C 6 - alkyl, optionally substituted C 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 -Cycloalkenyl, C 1 -C 6 - Alkylcarbonyl, C 1 -C 6 - Haloalkylcarbonyl, C 1 -C 6 - Alkoxycarbonyl, C 1 -C 6 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, C 1 -C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -Haloalkylaminocarbonyl, -SF 5 , -S(O) p (C 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl), substituted or substituted 3-7 membered heterocyclils containing 1-3 heteroatoms selected from the group consisting of N, O and S, substituted or substituted phenyl, substituted or substituted 5-10 membered heteroaryl, 5-11 membered spirocyclic heterocyclyl-carbocyclyl group, 5-11 membered spirocyclic heterocyclyl-heterocyclyl group, 5-11 membered spirocyclic carbocyclyl-carbocyclyl group, 5-11 membered spirocyclic carbocyclyl-heterocyclyl group, or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 4 and R 4’ Each instance independently produces hydrogen, halogen, cyano, nitro, hydroxyl, and C. 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 2 -C 6 - Alkenil, C 2 -C 6 - Haloalkenyl, C 2 -C 6 - Alkinyl, C 2 -C 6 - Haloalkynyl, C 1 -C 6 - Alkoxy, C 1 -C 6 - Haloalkoxy, C 1 -C 6 -Alkoxy-C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkoxy-C 1 -C 6 - alkyl, optionally substituted C 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 -Cycloalkyloxy, optionally substituted C 1 -C 6 - Alkylcarbonyl, optionally substituted C 1 -C 6 -alkoxycarbonyl, optionally substituted aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, di(C) 1 -C 6 -Alkyl)aminocarbonyl, optionally substituted C 1 -C 6 - Alkylcarbonyloxy, C may be substituted. 1 -C 6 -alkylcarbonylamino, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF 5 , -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 - is a haloalkyl; or R 4 is R 4’ Together with these, they form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and together with the carbon atoms to which they are bonded, they form a carbocyclic or heterocyclic ring; or -NR c R d (In the formula, R c and R d H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R c and R d These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 8 Hydrogen, halogen, C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 3 -C 8 - Cycloalkyl, C 2 -C 6 - Alkenyl or C 2 -C 6 - It is alkinyl; R 9 and R 9’ These are independently hydrogen, halo, and C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy or C 3 -C 8 - It is a cycloalkoxy; or R 9 is R 9’ Together with these, they form a 2- to 6-membered chain which may contain one or two heteroatoms selected from the group consisting of N, O, Si, and S, and together with the carbon atoms to which they are bonded, they form a carbocyclic or heterocyclic ring; R' is hydrogen, C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, optionally substituted C 3 -C 8 - A cycloalkyl or optionally substituted phenyl, The compound of formula (I) as described in claim 1.

3. R 1 C may be substituted with hydrogen, cyano, or other hydrogen atoms. 1 -C 4 - alkyl, optionally substituted C 1 -C 4 -alkoxy, possibly substituted C 2 -C 4 - Alkenyl, C may be substituted. 2 -C 4 Alkynyl, C may be substituted. 3 -C 8 - Cycloalkyl, optionally substituted, saturated or unsaturated 5-membered, 6-membered or 7-membered heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C 1 -C 4 - Alkylcarbonyl, optionally substituted C 1 -C 4 -alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C 1 -C 4 - Alkylaminocarbonyl, optionally substituted C 1 -C 4 -Dialkylaminocarbonyl, optionally substituted alkyl-SO p -, haloalkyl-SO p -, amino, -NH- substituted C 1 -C 4 -alkyl, or -NR a R b (In the formula, R a and R b R is independently an optionally substituted alkyl group; or R a and R b These may, together with the nitrogen to which they are bonded, form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group. R' is hydrogen or C 1 -C 4 - Alkyl; R 2 C may be substituted with hydrogen, halogen, cyano, nitro, -OH. 1 -C 4 - alkyl, optionally substituted C 1 -C 4 -alkoxy, possibly substituted C 3 -C 8 -Cycloalkyl, amino, NH-substituted C 1 -C 4 -alkyl, -SF 5 , or -NR a R b (In the formula, R a and R b C may be substituted independently. 1 -C 4 - Alkyl; or R a and R b These may, together with the nitrogen to which they are bonded, form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group), -SO p (C may be replaced) 1 -C 4 - Alkyl or haloalkyl; R 3 C 1 -C 4 - Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3 -C 8 - A cycloalkyl, 5-11 membered spirocyclic heterocyclyl-carbocyrill group, 5-11 membered spirocyclic heterocyclyl-carbocyrill group, 5-11 membered spirocyclic carbocyrill-carbocyrill group, or 5-11 membered spirocyclic carbocyrill-carbocyrill group (each of which may be substituted with one, two, or three substituents); Each R 4 C may be independently substituted with halogen, cyano, nitro, -OH, or other elements. 1 -C 4 - alkyl, optionally substituted C 1 -C 4 -alkoxy, possibly substituted C 3 -C 8 -Cycloalkyl, amino, NH-substituted C 1 -C 4 -alkyl, -SF 5 , or -NR c R d (In the formula, R c and R d C may be substituted independently. 1 -C 4 Alkyl or R c and R d These may, together with the nitrogen to which they are bonded, form substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl groups), SO p (C may be replaced) 1 -C 4 - Alkyl or haloalkyl) A compound of formula (I) according to claim 1 or 2.

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

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

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

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

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

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

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

11. L is L1; R' is hydrogen or C 1 -C 4 - Alkyl; R 1 Hello, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, hydroxy-C 1 -C 4 -Alkyl, hydroxy-C 1 -C 4 -Haloalkyl, alkoxy-C 1 -C 4 -Alkyl, alkoxy-C 1 -C 4 - Haloalkyl, C 2 -C 4 - Alkenil, C 2 -C 4 - Haloalkenyl, C 2 -C 4 - Alkinyl, C 2 -C 4 - Haloalkynyl, C 1 -C 4 - Alkylcarbonyl, C 1 -C 4 - Haloalkylcarbonyl, C 1 -C 4 - Alkoxycarbonyl, C 1 -C 4 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - Alkylaminocarbonyl, C 1 -C 4 - Haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 6 - Haloalkylaminocarbonyl, optionally substituted 5 or 6-membered heteroaryl or optionally substituted 5 or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms, or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted three-membered, four-membered, five-membered, or six-membered heterocyclyl group; R 2 Hydrogen, Halo, -SF 5 , C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, C 2 -C 4 - Alkenil, C 2 -C 4 - Haloalkenyl, C 2 -C 4 - Alkinyl, C 2 -C 4 - Haloalkynyl, C may be substituted. 3 -C 6 - Cycloalkyl, C 1 -C 4 - Alkylcarbonyl, C 1 -C 4 - Haloalkylcarbonyl, C 1 -C 4 - Alkoxycarbonyl, C 1 -C 4 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - Alkylaminocarbonyl, C 1 -C 4 - Haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 4 -Haloalkylaminocarbonyl, -SO p (C may be replaced) 1 -C 4 - Alkyl or C 1 -C 4 Haloalkyl), or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R 3 C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, optionally substituted C 3 -C 8 - Cycloalkyl, C 1 -C 6 - Alkylcarbonyl, C 1 -C 6 - Haloalkylcarbonyl, C 1 -C 6 - Alkoxycarbonyl, C 1 -C 6 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, C 1 -C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -Haloalkylaminocarbonyl, -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl), -SF 5 , a substituted or substituted 3-7 membered heterocycline containing 1-3 heteroatoms selected from the group consisting of N, O, and S, a substituted or substituted phenyl, a substituted or substituted 5 or 6 membered heteroaryl, a 5-11 membered spirocyclic heterocyclyl-carbocyclyl group, a 5-11 membered spirocyclic heterocyclyl-heterocyclyl group, a 5-11 membered spirocyclic carbocyclyl-carbocyclyl group (wherein each ring of the spirocyclic group contains 3, 4, 5, or 6 ring atoms), or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 4 Each instance independently produces hydrogen, halogen, and -SF. 5 , C 1 -C 6 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, - SO p (C may be replaced) 1 -C 4 - Alkyl or C 1 -C 4 -Haloalkyl), or -NR c R d (In the formula, R c and R d H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R 8 Hydrogen, halogen, C 1 -C 4 - Alkyl or C 1 -C 4 - It is a haloalkyl; X is either O or S; Z is O; W is CR 5 R 6 That is, A compound of formula (I) according to any one of claims 1 to 10.

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

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

14. Equation (Ie): 【Chemistry 4】 (Ie) (In the formula, Each R 10 C may be independently substituted with halo, cyano, or hydroxyl atoms. 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 -Cycloalkyloxy, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 3 -C 8 - Halocycloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, C 2 -C 6 - Alkenil, C 2 -C 6 - Haloalkenyl, C 2 -C 6 - Alkinyl, C 2 -C 6 - Haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkoxy-C 1 -C 6 - Alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5 or 6-membered heteroaryl, optionally substituted 3 to 7-membered heterocycline containing 1 to 3 heteroatoms selected from the group consisting of N, O, Si and S, C 1 -C 6 - Alkylcarbonyl, C 1 -C 6 - Haloalkylcarbonyl, C 1 -C 6 - Alkoxycarbonyl, C 1 -C 6 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, C 1 -C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -Haloalkylaminocarbonyl, -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl) (wherein p is 0, 1, or 2), SF 5 , or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 1 Hello, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, hydroxy-C 1 -C 4 -Alkyl, alkoxy-C 1 -C 4 - Alkyl, C 2 -C 4 - Alkenil, C 2 -C 4 - Haloalkenyl, C 2 -C 4 - Alkinyl, C 2 -C 4 - Haloalkynyl, C 1 -C 4 - Alkylcarbonyl, C 1 -C 4 - Haloalkylcarbonyl, C 1 -C 4 - Alkoxycarbonyl, C 1 -C 4 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 - Alkylaminocarbonyl, C 1 -C 4 - Haloalkylaminocarbonyl, di-C 1 -C 4 -Alkylaminocarbonyl, di-C 1 -C 6 - Haloalkylaminocarbonyl, substituted or otherwise substituted 5 or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted three-membered, four-membered, five-membered, or six-membered heterocyclyl group; R 2 Hydrogen, halo, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, - SO p (C may be replaced) 1 -C 4 - Alkyl or C 1 -C 4 -Haloalkyl), -SF 5 , or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R 4 Hydrogen, halo, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, - SO p (C may be replaced) 1 -C 4 - Alkyl or C 1 -C 4 -Haloalkyl), -SF 5 , or -NR c R d (In the formula, R c and R d H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R 5 and R 6 These independently produce hydrogen, halogen, and C 1 -C 3 - Alkyl or C 1 -C 3 - It is a haloalkyl; R' is hydrogen or C 1 -C 3 - Alkyl; R 8 is hydrogen; R 9 and R 9’ These independently produce hydrogen, halogen, and C 1 -C 3 - Alkyl or C 1 -C 3 - It is a haloalkyl; Z is CR 5 R 6 or O; Y 2 , Y 3 , Y 4 , Y 5 CR 4 or N; a is either 0 or 1; (m is 0, 1, 2, or 3) A compound of formula (I) according to claim 11, represented by the compound.

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

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

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

18. Formula (If): 【Transformation 5】 (If) (In the formula, R 10 These independently produce cyano, halo, hydroxyl, and C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 1 -C 6 - Alkoxy, C 1 -C 6 - Haloalkoxy, C 2 -C 6 - Alkenil, C 2 -C 6 - Haloalkenyl, C 2 -C 6 - Alkinyl, C 2 -C 6 - Haloalkynyl, C 1 -C 6 -Alkoxy-C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkoxy-C 1 -C 6 -alkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 3 -C 8 -Cycloalkyl, optionally substituted C 3 -C 8 - A substituted 3-7 membered heterocycline containing 1-3 heteroatoms selected from the group consisting of cycloalkyloxy, N, O, Si, and S, C 1 -C 6 - Alkylcarbonyl, C 1 -C 6 - Haloalkylcarbonyl, C 1 -C 6 - Alkoxycarbonyl, C 1 -C 6 - Haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 - Alkylaminocarbonyl, C 1 -C 6 - Haloalkylaminocarbonyl, di-C 1 -C 6 -Alkylaminocarbonyl, di-C 1 -C 6 -Haloalkylaminocarbonyl, -SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl) (wherein p is 0, 1, or 2), SF 5 , or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 6 - Alkyl or C 1 -C 6 - Whether it is a haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S, and may form a substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclyl group; R 1 is halo, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, hydroxy-C 1 -C 4 -alkyl, alkoxy-C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 2 -C 4 -alkynyl, C 2 -C 4 -haloalkynyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -haloalkylaminocarbonyl, di-C 1 -C 4 -alkylaminocarbonyl, di-C 1 -C 6 -haloalkylaminocarbonyl, optionally substituted 5- or 6-membered heterocyclyl containing 1 to 3 N, S or O heteroatoms or -NR a R b (wherein R a and R b are independently H, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; or R a and R b These may, together with the nitrogen to which they are bonded, include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may form a substituted three-membered, four-membered, five-membered, or six-membered heterocyclyl group; R 2 Hydrogen, halo, C 1 -C 4 - Alkyl, C 1 -C 4 - Haloalkyl, C 1 -C 4 - Alkoxy, C 1 -C 4 - Haloalkoxy, - SO p (C may be replaced) 1 -C 4 - Alkyl or C 1 -C 4 -Haloalkyl), -SF 5 , or -NR a R b (In the formula, R a and R b H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R 4 and R 4’ Independent, Hello, C 1 -C 6 - Alkyl, C 1 -C 6 - Haloalkyl, C 1 -C 6 - Alkoxy, C 1 -C 6 - Haloalkoxy, - SO p (C may be replaced) 1 -C 6 - Alkyl or C 1 -C 6 -Haloalkyl), -SF 5 , or -NR c R d (In the formula, R c and R d H and C are independent of each other. 1 -C 4 - Alkyl or C 1 -C 4 -It is a haloalkyl; R' is hydrogen or C 1 -C 3 - Alkyl; R 8 is hydrogen; R 9 and R 9’ are each hydrogen; D is N, SiR 11 (In the formula, R 11 is C 1 -C 6 Alkyl or C 1 -C 6 (haloalkyl), C or C-R 4 And; D 1 N, O, SiR 11 R 12 (In the formula, R 11 and R 12 C 1 -C 6 Alkyl or C 1 -C 6 (It is a haloalkyl), -CR 4 R 4’ , S(O) p (wherein p is 0, 1, or 2) and; or D 1 CR 4 R 4’ (In the formula, R 4 and R 4’ These together form a 2- to 5-membered chain (which may be replaced by one heteroatom selected from N and O in the chain) to form a spirocyclic group; Y 2 , Y 3 , Y 4 , Y 5 CR 4 or N; m is 0, 1, 2, or 3; b is either 0 or 1. The compound according to claim 11, which is a compound of the above.

19. R 1 C 1 -C 4 - Alkyl, C 2 -C 4 - Alkenyl, amino, C 1 -C 4 - Alkylamino, di(C) 1 -C 4 - Alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 Hydrogen, halogen, cyano, C 1 -C 4 - Alkyl, C 1 -C 4 - It is a haloalkyl; R 4 Each instance independently produces hydrogen, halogen, and C. 1 -C 4 - Alkyl or C 1 -C 4 - It is a haloalkyl, The compound according to claim 14.

20. R 1 C 1 -C 4 - Alkyl, di(C) 1 -C 4 - Alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 Hydrogen, halogen, C 1 -C 3 - Alkyl or C 1 -C 3 - It is a haloalkyl; R 4 Each instance independently produces hydrogen, halogen, and C. 1 -C 3 - Alkyl or C 1 -C 3 - It is a haloalkyl; R 10 is chloro or fluoro; m is 2 or 3. The compound according to claim 19.

21. R 1 C 1 -C 4 - Alkyl, C 2 -C 4 - Alkenyl, amino, C 1 -C 4 - Alkylamino, di(C) 1 -C 4 - Alkyl)amino, morpholino, pyranyl, tetrahydropyranyl, or dihydropyranyl; R 2 Hydrogen, halogen, C 1 -C 4 - Alkyl or C 1 -C 4 - It is a haloalkyl; D is N or CH, D 1 O, Si(CH 3 ) 2 or CH 2 And; R 4 Each instance independently produces hydrogen, halogen, and C. 1 -C 4 - Alkyl or C 1 -C 4 - It is a haloalkyl, The compound according to claim 18.

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

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

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

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

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

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

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

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

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

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

32. Y 3 and Y 4 N is Y 2 and Y 5 CR 4 The compound according to any one of claims 1 to 21.

33. The compound has the structure shown in the following table, where X is oxygen and R' is hydrogen; basis 【Transformation 6】 The following is the basis: 【Transformation 7】 Ring system A; 【Transformation 8】 Ring system B; 【Chemistry 9】 Ring system C; 【Chemistry 10】 Ring system D; 【Chemistry 11】 Ring system E; 【Chemistry 12】 Ring system F; 【Chemistry 13】 Ring system G; 【Chemistry 14】 Ring system H; 【Chemistry 15】 Ring system I; 【Chemistry 16】 Ring system J; 【Chemistry 17】 Ring system K; [Chemistry 18] Ring system L; 【Chemistry 19】 Ring system M; 【Chemistry 20】 Ring system N; 【Chemistry 21】 Ring system O; 【Chemistry 22】 Ring system P; 【Chemistry 23】 Ring system Q; 【Chemistry 24】 Ring system R; 【Chemistry 25】 Ring system S; 【Chemistry 26】 Ring system T; 【Chemistry 27】 Ring system U; 【Chemistry 28】 Ring system V; 【Chemistry 29】 Ring system X; 【Transformation 30】 Ring system Y; 【Chemistry 31】 Ring system Z; 【Chemistry 32】 Ring system AA; 【Transformation 33】 Ring system AB; 【Transformation 34】 Ring system AC; 【Chemistry 35】 Ring system AD; 【Transformation 36】 Ring system AE; 【Chemistry 37】 Ring system AF; 【Transformation 38】 Ring system AG; 【Chemistry 39】 Ring system AH; 【Chemistry 40】 Ring system AJ; 【Chemistry 41】 Ring system AK; 【Chemistry 42】 Ring system AL; 【Chemistry 43】 ring system AM; 【Chemistry 44】 Ring system AN; 【Chemistry 45】 Ring system AO; 【Chemistry 46】 ring system AP; 【Chemistry 47】 Ring system AQ; 【Chemistry 48】 Ring system AR; 【Chemistry 49】 Ring system AS; [Transformation 50] cyclic AT; 【Chemistry 51】 ring system AU; 【Chemistry 52】 Ring system AV; 【Chemistry 53】 Ring system AW; 【Chemistry 54】 Ring system AX; 【Transformation 55】 Ring system AY; 【Transformation 56】 Ring system AZ; 【Chemistry 57】 Ring system AAA; Representing, The compound according to claim 1. 【Transformation 58】 Equation (I) Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6

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

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

36. A method for treating, controlling and / or preventing a parasitic infection or invasion in an animal requiring such treatment, comprising administering to the animal an effective amount of a compound according to any one of claims 1 to 33 or a pharmaceutically or veterinarily acceptable salt thereof.

37. Use of a compound according to any one of claims 1 to 33 in the preparation of a pharmaceutical product for treating, controlling and / or preventing parasitic infections or invasiveness in animals.

38. A compound of formula (I) according to any one of claims 1 to 33, for use in methods for treating, controlling and / or preventing parasitic infections or invasive conditions in animals.

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