Anthelmintic heterocyclic compounds

Abstract

The present invention provides compounds of the following formula: wherein the variable is defined herein, or a salt thereof; compositions comprising such compounds; and methods for treating, controlling or preventing parasitic infestation or infection of an animal by administering an effective amount of such compounds to an animal in need.

Description

Technical Field

[0001] This patent application relates to novel antiparasitic compounds, compositions comprising such compounds, their preparation process, and methods of using such compounds to control parasites that harm animals and humans. Prior Technology

[0002] Animals such as mammals and birds are commonly susceptible to parasites. These parasites can be ectoparasites, such as fleas and ticks. Animals and humans also suffer from endoparasitic infections, including helminthiasis, most commonly caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause significant economic losses in pigs, sheep, horses, and cattle, and affect companion animals (such as cats and dogs) and poultry. Other parasites include those found in the gastrointestinal tract of animals and humans, such as *Ancylostoma*, *Necator*, *Ascaris*, *Strongyloides*, *Trichinella*, *Capillaria*, *Toxocara*, *Toxascaris*, *Trichuris*, and *Enterobius*. Other parasites present in the blood or other tissues and organs include filarial worms and extraintestinal nematodes such as strong nematodes and hairy nematodes.

[0003] One serious internal parasite affecting mammals is *Dirofilaria immitis*, also known as the heartworm. Other filarial internal parasites include *Dirofilaria repens* and *Dirofilaria honkongensis*, which can also infect humans. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected. The heartworm undergoes several life stages before becoming an adult worm that infects the pulmonary arteries of its host mammal. The worm requires a mosquito as an intermediate host to complete its life cycle. The period between the initial infection in a dog from a mosquito bite and the worm's maturation into an adult worm surviving in the heart and pulmonary arteries is six to seven months in dogs and is called the "incubation period." L3 larvae migrate to the tip of the mosquito's oral cavity (lip) during the mosquito's blood-feeding process, leave the mosquito, and deposit on the dog's skin. These larvae then migrate to the host through the bite wound. Most L3 larvae molt into fourth-stage larvae (L4) in the subcutaneous tissue of dogs within 1 to 3 days after infection. These fourth-stage larvae then migrate to the thoracic and abdominal muscles and molt into the fifth stage (L5, immature adult) 45 to 60 days after infection. Between 75 and 120 days after infection, these immature heartworms then enter the bloodstream and are carried through the heart to reside in the pulmonary artery. Approximately seven months after infection, the adult *Filaria canis* reaches maturity and reproduces sexually in the pulmonary artery and right ventricle. Male adults are approximately 15 cm long, and females are approximately 25 cm long, with a typical adult lifespan of approximately 5 years.

[0004] Heartworm infection is a serious and life-threatening disease. Canine heartworm infection is preventable, and preventative treatment is prioritized in heartworm-endemic areas. Treatment of mature heartworm infections with adult worm-killing agents (such as melarsomine dihydrochloride) is expensive and can cause serious adverse side effects; therefore, prevention is widely used by administering medication monthly to interrupt larval development. Commercially available canine heartworm prophylaxis aims to prevent the parasite from developing into adult heartworms by interrupting the canine heartworm life cycle after infection.

[0005] Macrocyclic lactones (MLs, such as ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemopreventive agents, administered monthly or every six months. These drugs are effective against the infective L3 larvae (L3) and mature L4 larvae (L4) of *Filaria canis*, which are carried by mosquitoes. When administered monthly, MLs kill L3 and L4 larvae acquired within the previous 30 days, thus preventing disease caused by adult worms. MLs can also be used monthly in infected dogs to suppress adult worm reproduction and remove microfilariae, thereby reducing transmission and gradually depleting adult worms (Vet. Parasitol. 2005 Oct 24 133(2-3) 197-206).

[0006] In recent years, there has been an increasing number of reported cases of lack of efficacy (LOE), in which dogs still develop mature heartworm infection despite receiving monthly prophylactic doses of macrocyclic lactone drugs. For example, Atkins et al. (Vet. Parasitol. 206 (2014) 106-113) recently reported an increase in the number of dogs testing positive for heartworm antigens while receiving prophylactic heartworm treatment, indicating that some populations of *Filaria canis* have developed selective resistance to prophylactic heartworm agents (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, Vol. 37. Bulletin of the American Heartworm Society, p. 5.). Therefore, there is an ongoing need to develop novel anthelmintics with improved activity against *Filaria canis* and other endoparasites.

[0007] WO 2017 / 178416 A1 provides pyrazolopyrimidine derivatives for the control, treatment and / or prevention of worms. WO 2018 / 197401 A1 provides bicyclic pyrazole derivatives for the control, treatment and / or prevention of worms. WO 2018 / 087036 A1 provides quinolinone-3-methamide derivatives for the control, treatment and / or prevention of worms. WO 2019 / 025341 provides quinoline compounds for the treatment, control and / or prevention of worm infections, and WO 2019 / 002132 A1 provides azaquinone derivatives for the control, treatment and / or prevention of worm infections. All of these disclosures are from Bayer Animal Health GmbH and are incorporated herein by reference in their entirety.

[0008] Recently, WO 2020 / 014068 A1 (which is incorporated herein by reference) describes a worm-repelling heterocyclic compound found to be active against canine filarial worms.

[0009] It is explicitly noted that any reference or identification of any document in this application does not constitute an admission that such document is prior art to this specification. All documents cited in or during the examination of any of the foregoing applications (“References in Applications”) and all documents cited or referenced in the References in Applications, and all documents cited or referenced herein (“References in This Document”), and all manufacturer’s descriptions, specifications, product descriptions, and product introductions of any product mentioned herein or in any document incorporated herein by reference, are hereby incorporated herein by reference and may be used in the practice of this specification. Summary of the Invention

[0010] This application provides novel anthelmintic and antiparasitic heterocyclic compounds with improved activity against both internal and external parasites. This application also relates to compositions comprising such compounds, and methods and uses of such compounds in animals (including humans) for eradicating, controlling, and / or preventing parasitic infestations and / or infections. The compounds can be administered to animals, particularly mammals, fish, and birds, to prevent and / or treat parasitic infections.

[0011] One embodiment of the present invention includes a compound of formula (I): Its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, wherein the variables R1, R2, R3, R9, R9', Y1, Y2, Y3, Y4, Y5, Y6, L, Q, W, Z, a, and q are as defined herein, and the dashed bond ( ) indicates a single bond or a double bond.

[0012] This invention also includes veterinary acceptable compositions comprising a compound of formula (I) and a veterinary acceptable carrier, and a method for controlling parasites including worms, the method comprising administering the compound or a veterinary acceptable composition thereof to an animal in need. One embodiment of the invention also includes the use of a compound of formula (I) for the eradication, control, and / or prevention of parasitic infections and / or infestations in animals or humans. The compounds of the present invention can be administered to animals, particularly mammals, fish, and birds, for the prevention and / or treatment of parasitic infections and / or infestations.

[0013] The compound and compositions containing the compound are effective in treating and / or preventing internal parasites in mammals, fish and birds, and especially cats, dogs, horses, chickens, pigs, sheep and cattle, with the aim of substantially eliminating these hosts from internal parasites.

[0014] In one embodiment, the compounds of formula (I) and compositions comprising such compounds are substantially effective against endoparasites, such as filarial worms (e.g., heartworms) and hookworms, whipworms, and roundworms of the animal and human digestive tract. In some embodiments, the compounds of formula (I) and compositions comprising such compounds are effective against *Heartworm* isolates that are less responsive to treatment with macrocyclic lactones. In another embodiment, the compounds and compositions of the present invention are effective in treating and / or preventing nematode infections in animals that are less responsive to treatment with commercially available or known active agents.

[0015] In one embodiment, this specification includes a composition of a compound of formula (I) and at least a second active agent, which can broaden the scope of protection provided to animals against internal and / or external parasites.

[0016] Another embodiment includes a method for treating and / or preventing parasitic infections and / or infestations in animals, comprising administering a compound of formula (I) to the animal. Another embodiment includes the use of a compound of formula (I) for treating and / or preventing parasitic infections and / or infestations in animals, and the use of a compound of formula (I) in the preparation of a medicament for treating and / or preventing parasitic infections in animals.

[0017] Therefore, the present invention includes the following non-limiting embodiments: (a) A compound of formula (I) or a pharmaceutically or veterinary acceptable salt thereof, which is an active endoparasitic agent and, in some cases, also active against ectoparasites; (b) A veterinary composition comprising a combination of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof with a pharmaceutically or veterinarily acceptable carrier or diluent, effective in killing parasites; (c) A veterinary composition comprising a combination of a parasitic effective amount of a compound of formula (I) or a pharmaceutically or veterinary acceptable salt thereof, and one or more additional active agents (i.e., active ingredients not covered by formula (I)) and a pharmaceutically or veterinary acceptable carrier or diluent; (d) A method for treating parasitic infection and / or infestation in or outside 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, where appropriate, one or more additional active agents (i.e., active ingredients not covered by formula (I)); (e) A method for preventing parasitic infection and / or infestation in animals, 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, where appropriate, one or more additional active agents (i.e., active ingredients not covered by formula (I)); (f) The use of a compound of formula (I) or a pharmaceutically or veterinary acceptable salt thereof, in combination with one or more additional active agents (i.e., active ingredients not covered by formula (I)) for the treatment and / or prevention of parasitic infections and possible parasitic infestations in animals; (g) The use of a compound of formula (I) or a pharmaceutically or veterinary acceptable salt thereof, as appropriate, in conjunction with one or more additional active agents (i.e., active ingredients not covered by formula (I)) in the manufacture of veterinary agents for the treatment and / or prevention of parasitic infections and / or infestations in animals; and (h) is used in the preparation process of compounds of formula (I).

[0018] These and other embodiments are disclosed in the following embodiments or are obvious from the following embodiments and are covered in the following embodiments. [ ]

[0019] [ ] [definition:] [ ] It should be noted that, in this invention and specifically in the claims and / or paragraphs, terms such as “comprises,” “comprised,” “comprising,” and the like may be interpreted as “includes,” “included,” “including,” and the like; and terms such as “consisting essentially of” and “consists essentially of” should be interpreted as allowing elements not expressly listed, but excluding elements found in the prior art that affect the essential or novel features of this invention.

[0020] Unless otherwise specified, the terminology used herein shall have the meanings conventionally used in this art. The organic part referred to in the definition of a variable of a compound (e.g., compound of formula (I)) is analogous to the term halogen, i.e., a collective term for individual lists of members of individual groups, fluorine, chlorine, bromine, and iodine in contrast to halogens. In each case, the prefixes Cn-Cm indicate that the possible number of carbon atoms in the group is an integer from n to another integer m.

[0021] In this specification and the scope of the patent application, the term "including but not limited to" is equivalent to "including".

[0022] The term "compound of formula (I)" includes any stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

[0023] The term "substituted as appropriate" means, depending on the case, a group partially substituted with one or more of the following: halogen, hydroxyl, alkyl, haloalkyl, carboxyl, acetyl, aceoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminecarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminecarbonyl, dihaloalkylaminecarbonyl, amino, alkyl or dialkylamino, acetyl, aromatic amino, alkoxy, haloalkoxy, aryloxy, nitro, cyano, azide, thiol, thioacetylamine, imino, amidine. Guanidine, carbonate, silyl, silyl ether, SF5, sulfonic acid, sulfate ester, sulfonyl, alkoxysulfonyl, thio, sulfene, aminesulfonyl, sulfenimine, sulfinimine, sulfadiazine, sulfonamide, ester, phosphonyl, oxyphosphonyl, phosphine, aminophosphate, aminophosphonite, phosphonite, phosphine oxide, thioester, thioether, acid halide, acid anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphate ester, phosphonate, aryl and heteroaryl.

[0024] In some embodiments, the term "substituted as appropriate" includes replacing the core group with one of the following: halogen (chlorine, fluorine, bromine, iodine), C1-C6 alkyl, C1-C6 haloalkyl, 3- to 8-membered cycloalkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, nitro, SF5, acetyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 alkylcarbonyl C1-C6 haloalkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, C1-C6 haloalkylaminocarbonyl, C1-C6 dihaloalkylaminocarbonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylthio, C1-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfinyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group.

[0025] In other embodiments, the term "substituted as appropriate" includes replacing the core group with one of the following: halogen (chlorine, fluorine, bromine, iodine), 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 haloalkyl carbonyl, amino carbonyl, C1-C3 alkylamino carbonyl, C1-C3 dialkylamino carbonyl, C1-C3 haloalkylamino carbonyl, C1-C3 dihaloalkylamino carbonyl, C1-C3 alkyl thio, C1-C3 alkyl sulfinyl, C1-C3 alkyl sulfinyl, C1-C3 haloalkyl thio, C1-C3 haloalkyl sulfinyl, C1-C3 haloalkyl sulfinyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group.

[0026] In some embodiments, the term "substituted as appropriate" includes substitution with the following: halogen (chlorine, fluorine, bromine, and iodine), methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, thiol, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methoxy, ethoxy, propoxy, CF3, CF2CF3, -OCF3, -OCF2CF3, -SCH3, -SCF3, -S(O)CH3, -S(O)CF3, -S(O)2CH3, -S(O)2CF3, N-hydroxylinyl, piperidinyl, pyridinyl, and phenyl.

[0027] In some embodiments, the compound may be substituted with a functional group that is unprotected or protected as desired and does not inhibit the biological activity of the compound described herein, as known to those skilled in the art, for example as taught in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 3rd edition, 1999, which is incorporated herein by reference. For the avoidance of doubt, "substituted alkyl group as desired" includes haloalkyl and hydroxyalkyl groups.

[0028] Unless otherwise stated, "alkyl" alone or in combination with heteroatoms (e.g., alkoxy, thioalkyl, alkylamino, and the like) means a saturated straight-chain, branched, primary, secondary, or tertiary hydrocarbon, including hydrocarbons having 1 to 12 atoms. In some embodiments, alkyl will include C1-C10, C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. Examples of C1-C10 alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methyl pentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl, and their isomers. C1-C4 alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

[0029] Cycloalkyl groups may be referred to as "cycloalkyl groups" and include those having 3 to 10 carbon atoms and having one or more fused rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and similar groups.

[0030] A "carbocyclic" group is a cyclic group consisting only of carbon atoms. Carbocyclic groups include both aromatic rings (such as phenyl) and non-aromatic rings (such as cycloalkyl rings, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and similar groups), and include carbocyclic groups having 3 to 14 carbon atoms and having one or more fused rings.

[0031] The term "alkenyl" refers to both straight-chain and branched carbon chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl group may include a C2-C12 alkenyl group. In other embodiments, an alkenyl group includes C2-C10, C2-C8, C2-C6, C2-C4, or C3-C4 alkenyl groups. In one embodiment of an alkenyl group, the number of double bonds is 1-3; in another embodiment, the number of double bonds is one. Depending on the position of the alkenyl moiety on the molecule, other ranges of carbon-carbon double bonds and the number of carbons are also covered. An "alkenyl" group may include more than one double bond in the chain.Examples of alkenyl groups or specific ranges thereof include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-methyl-vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl. 2-Methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1- Methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl- 3-Butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.

[0032] "Alynyl group" refers to both straight-chain and branched carbon chains having at least one carbon-carbon linkage. In one embodiment of the alkynyl group, the number of linkages is 1-3; in another embodiment, the number of linkages is one. In some embodiments, the alkynyl group comprises 2 to 12 carbon atoms. In other embodiments, the alkynyl group may include C2-C10, C2-C8, C2-C6, or C2-C4 alkynyl groups. Depending on the position of the alkynyl moiety on the molecule, other ranges of carbon-carbon linkages and the number of carbon atoms are also covered. For example, as used herein, the term "C2-C10 ynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pentan-1-yn-1-yl, n-pentan-1-yn-3-yl, n-pentan-1-yn-4-yl, n-pentan-1-yn-5-yl, n-pentan-2-yn-1-yl, n-pentan-2-yn-4-yl, n-pentan-2-yn-5-yl, 3-methylbutan-1-yn-3-yl, 3-methylbutan-1-yn-3-yl, 3-methylbutan-1-yn- 4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpentan-1-yn-1-yl, 3-methylpentan-1-yn-3-yl, 3-methylpentan-1-yn-4-yl, 3-methylpentan-1-yn-5-yl, 4-methylpentan-1-yn-1-yl, 4-methylpentan-2-yn-4-yl or 4-methylpentan-2-yn-5-yl and similar groups.

[0033] The term "haloalkyl" refers to an alkyl group as defined herein that has been substituted with one or more halogen atoms. For example, C1-C4 haloalkyl groups 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 similar groups. As used herein, the term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms have been substituted with fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl.

[0034] The term "haloalkenyl" refers to an alkenyl group as defined herein that has been substituted with one or more halogen atoms.

[0035] The term "haloynyl" refers to an ynyl group as defined herein that has been substituted with one or more halogen atoms.

[0036] The term "alkoxy" refers to alkyl-O-, where alkyl is as defined above. Similarly, the terms "alkenoxy," "alkynoxy," "haloalkoxy," "haloalkenoxy," "haloalkynoxy," "cycloalkoxy," "cycloalkenoxy," "halocycloalkoxy," and "halocycloalkenoxy" refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, where alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, OCH2-C2H5, OCH(CH3)2, n-butoxy, OCH(CH3)-C2H5, OCH2-CH(CH3)2, OC(CH3)3, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy, 1-methyl Pentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and similar groups.

[0037] The term "aryl" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms and having a single ring or multiple fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In some embodiments, aryl groups include tetrahydronaphthyl, phenylcyclopropyl, and dihydroindenyl. Aryl groups may be unsubstituted or partially substituted with one or more of the following: halogen, cyano, nitro, hydroxyl, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynoxy, haloalkoxy, haloalkenyloxy, haloalkynoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio , halogenated cycloalkyl thioyl, alkyl sulfinyl, alkenyl sulfinyl, alkynyl sulfinyl, haloalkyl sulfinyl, haloalkenyl sulfinyl, haloalkynyl sulfinyl, alkyl sulfinyl, alkenyl sulfinyl, alkynyl sulfinyl, haloalkyl sulfinyl, haloalkenyl sulfinyl, haloalkynyl sulfinyl, -SF5, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)amino, di(alkynyl)amino or trialkylsilyl.

[0038] The term "aryl group" refers to an aryl group of a parent compound that is bonded to the parent compound via a diradical alkyl bridge (-CH2-)n, where n is 1 to 12, and "aryl group" is as defined above.

[0039] The term "heteroaryl" refers to a monovalent aromatic group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and having one or more oxygen, nitrogen, and sulfur heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, within a ring. The nitrogen and sulfur heteroatoms may be oxidized, depending on the situation. Heteroaryls will typically comprise a 5- or 6-membered aromatic ring. Such heteroaryls may have a single ring (e.g., pyridyl or furanyl) or multiple fused rings, the limitation being that the linkages are connected via heteroaryl ring atoms. Examples of heteroaryl groups include pyridyl, pyridyl, pyrimidinyl, pyridyl, tripyridyl, pyrroloyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolinyl, furanyl, thiophenyl, furanyl, pyrroloyl, imidazolyl, succinyl, isosuccinyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidinyl, or pyrrolopyrimidinyl. The heteroaryl ring may be unsubstituted or partially substituted with one or more of the substituted groups as described above for aryl groups.

[0040] The terms "heterocyclyl," "heterocyclic," or "heterocyclo" refer to a fully saturated or partially unsaturated but non-aromatic cyclic group, such as a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, having one or more oxygen, sulfur, silicon, or nitrogen heteroatoms in the ring, preferably one to four or one to three heteroatoms. The nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen heteroatom may be quaternized, depending on the situation. The heterocyclic group may be attached to any heteroatom or carbon atom in the ring or ring system, and may be unsubstituted or partially substituted as described above for aryl groups.

[0041] Exemplary monocyclic heterocyclic groups include, but are not limited to, aziridinyl, aziridine, oxacyclobutane, pyrrolidinyl, pyrrolyl, pyrazolyl, oxacyclobutane, pyrazolinyl, imidazolyl, imidazolinyl, imidazodinyl, aziridine, isozolinyl, isozolinyl, thiazolyl, thiadiazolyl, thiazodinyl, isothiazolyl, isothiazolidine, furanyl, tetrahydrofuranyl, thiophenyl, azidiazolyl, and piperidine. The group includes: yl, piperyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, 2-side-oxynitropyridine, nitropyridine, 4-piperidinone, pyridyl, pyridine, pyrimidinyl, pyridyl, tetrahydropiperanyl, thiaolinyl, thiaolinyl phenoxide, thiaolinyl phenoxide, 1,3-dioxacyclopentane and tetrahydro-1,1-diside-oxythiophene, triazolyl, triazolyl and similar groups.

[0042] Exemplary bicyclic heterocyclic groups include, but are not limited to, indole, benzothiazolyl, benzothiazolyl, benzo-m-dioxacyclopentenyl, benzothiophene, quininecycloyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopiperanyl, indoleyl, benzofuranyl, chromonyl, coumarinyl, benzopiperanyl, quinolinyl, indazole, pyrrolopyridyl, furanopyridyl (such as furano[2,3-c]pyridyl, furano[3,2-b]pyridyl or furano[2,3-b]pyridyl), dihydroisoindole, dihydroquinazolinyl (such as 3,4-dihydro-4-sideoxy-quinazolinyl), tetrahydroquinolinyl and similar groups.

[0043] Bicyclic and tricyclic carbocyclic or heterocyclic systems include spirocyclic systems in which at least two of the rings in the system are linked by a single carbon atom. Spirocyclic systems will include combinations of 3- to 8-membered carbocyclic and / or heterocyclic systems linked at a common carbon atom. Therefore, a spirocyclic system can include all combinations of 3-membered rings bonded to another 3-membered ring (carbocyclic or heterocyclic) to another 8-membered ring, and intermediate rings of different sizes. The heterocyclic component of a spirocyclic system will include one or two heteroatoms selected from N, O, Si, or S.

[0044] The term "alkathio" refers to an alkyl-S- group, where "alkyl" is as defined above. In some embodiments, the alkyl component of the alkathio group will include C1-C10, C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. For example, C1-C4 alkathio groups include, but are not limited to, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, or 1,1-dimethylethylthio.

[0045] Similarly, the terms "haloalkylthio", "cycloalkylthio", and "halocycloalkylthio" refer to the groups -S-haloalkyl, -S-cycloalkyl, and -S-halocycloalkyl, respectively, as defined above.

[0046] The term "alkylsulfinyl" refers to the alkyl-S(=O)- group, where "alkyl" is as defined above. In some embodiments, the alkyl component in the alkylsulfinyl group will include C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C3 alkyl groups. Examples include, but are not limited to, -SO-CH3, -SO-C2H5, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 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.

[0047] Similarly, the terms "alkenylsulfinyl", "alkynylsulfinyl", "haloalkylsulfinyl", "haloalkenylsulfinyl" and "haloalkynylsulfinyl" refer to the groups alkenyl-S(=O)-, alkynyl-S(=O)-, haloalkyl-S(=O)-, haloalkenyl-S(=O)-, and haloalkynyl-S(=O)-, wherein the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" are as defined above.

[0048] The term "alkylsulfonyl" refers to the alkyl-S(=O)2- group, wherein the term "alkyl" is as defined above. In some embodiments, the alkyl component in the alkylsulfonyl group will include C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4 alkyl groups. Examples include, but are not limited to, -SO2-CH3, -SO2-C2H5, n-propylsulfonyl, -SO2-CH(CH3)2, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO2-C(CH3)3, n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, 2 -Methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl and similar groups.

[0049] 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 terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" are as defined above.

[0050] 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 in an alkylamino or dialkylamino group will include C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4 alkyl groups.

[0051] 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)-, haloalkoxy-C(O)-, haloalkylamino-C(O)-, and dihaloalkylamino-C(O)-, wherein haloalkyl, haloalkoxy, haloalkylamino, and dihaloalkylamino are as defined above. Implementation

[0052] [ ] [Cross-reference to related applications] [ ] This application claims priority to U.S. Provisional Application No. 63 / 031,656, filed May 29, 2020, which is incorporated herein by reference in its entirety.

[0053] One embodiment of the present invention includes a compound of formula (I): in: L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, or L15: , R' is hydrogen, a substituted alkyl group, a substituted cycloalkyl group, or a substituted aryl group; R1 is hydrogen, cyano, halogroup, hydroxyl, alkyl (subject to substitution), alkenyl (subject to substitution), alkynyl (subject to substitution), alkenylyl (subject to substitution), alkoxyalkyl (subject to substitution), aminoalkyl (subject to substitution), alkylaminoalkyl (subject to substitution), dialkylaminoalkyl (subject to substitution), alkenyl (subject to substitution), alkynyl (subject to substitution), aryl (subject to substitution), aryloxy (subject to substitution), heteroaryl (subject to substitution), cycloalkyl (subject to substitution), cycloalkenyl (subject to substitution), or, as appropriate, cycloalkyl. The alternatives include cycloalkoxy, heterocyclic groups as appropriate, alkylcarbonyl groups as appropriate, alkoxycarbonyl groups as appropriate, aminocarbonyl, alkylaminocarbonyl groups as appropriate, dialkylaminocarbonyl groups as appropriate, -SOp (alkyl or haloalkyl groups as appropriate), -SF5, or -NRaRb, wherein Ra and Rb are independently H or alkyl groups as appropriate; or Ra and Rb may form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups together with the nitrogen to which they are attached, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S and may be substituted as appropriate; R2 is hydrogen, cyano, halogroup, hydroxyl, alkyl (subject to substitution), alkoxy (subject to substitution), alkoxyalkyl (subject to substitution), aminoalkyl (subject to substitution), alkylaminoalkyl (subject to substitution), dialkylaminoalkyl (subject to substitution), alkenyl (subject to substitution), alkynyl (subject to substitution), aryl (subject to substitution), aryloxy (subject to substitution), heteroaryl (subject to substitution), cycloalkyl (subject to substitution), cycloalkenyl (subject to substitution), cycloalkoxy (subject to substitution), heterocyclic (subject to substitution), etc. Alkyl carbonyl, substituted alkoxy carbonyl, substituted amino carbonyl, substituted alkylamino carbonyl, substituted dialkylamino carbonyl, -SOp (substituted alkyl or haloalkyl), -SF5 or -NRaRb, wherein Ra and Rb are independently H or substituted alkyl; or Ra and Rb may together with the nitrogen to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S and may be substituted as appropriate; R3 is hydrogen, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, substituted alkanecarbonyl, substituted alkoxycarbonyl, aminocarbonyl, substituted alkylaminocarbonyl, substituted dialkylaminocarbonyl, -S(O)p (substituted alkyl), -SF5, substituted heterocyclic, substituted 6- to 10-membered aryl, etc. Furthermore, the substituted 5- to 10-membered heteroaryl, spirocyclic heterocyclic-carbamocyclic, spirocyclic heterocyclic-heterocyclic, spirocyclic carbamocyclic-carbamocyclic, spirocyclic carbamocyclic-heterocyclic, or -NRaRb, wherein Ra and Rb are independently H or, as appropriate, substituted alkyl groups; or Ra and Rb may, together with the nitrogen to which they are attached, form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups, which may include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S and may be substituted as appropriate; R4 and R4' are, in each instance, independently hydrogen, halogen, cyano, nitro, hydroxyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted alkoxyalkyl, substituted aminoalkyl, substituted alkylaminoalkyl, substituted dialkylaminoalkyl, substituted cycloalkyl, substituted cycloalkoxy, substituted alkoxycarbonyl, substituted alkoxycarbonyl, substituted aminocarbonyl, substituted alkylaminocarbonyl, substituted di(alkyl)aminocarbonyl, substituted alkylcarbonyloxy, substituted alkylcarbonylamino, substituted aryl, substituted heteroaryl, -SF5, -SOp (substituted alkyl or haloalkyl); or R4 and R4' Together they form a 2-6 member chain containing one or two heteroatoms selected from the groups N, O, Si, and S, to form a carbocyclic or heterocyclic ring with the carbon atom to which they are attached; or -NRcRd, wherein Rc and Rd are independently H or, as appropriate, substituted alkyl groups; or Rc and Rd may form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic group with the nitrogen atom to which they are attached, the heterocyclic group may include one to three additional heteroatoms selected from the groups N, O, Si, and S and may be substituted as appropriate; R8 can be hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; R9 and R9' are independently hydrogen, halogroup, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or cycloalkoxy, or R9 and R9' together form a 2-6 member chain containing one or two heteroatoms selected from the groups of N, O, Si, and S, to form a carbocyclic or heterocyclic chain with the carbon atom to which it is attached, wherein the carbon or nitrogen atom in the chain may be substituted, as appropriate; Q is either C-R8 or N; X is O, S, or N-R'; Y1 and Y6 are each independently N, C, or -CR4-; Y2, Y3, Y4, and Y5 are each independently N, NR', S, O, -CR4-, or CR4R4'; W is CR5R6, O, SOp, or N-R7. Z is CR5R6, O, SOp, or N-R7. in R5 and R6, each time they appear, are independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or cycloalkoxy, or R5 and R6 together form a 2-6 member chain containing one or two heteroatoms selected from the groups of N, O, Si, and S, to form a carbocyclic or heterocyclic ring with the carbon atom to which it is attached, wherein each carbon or nitrogen atom in the carbocyclic or heterocyclic ring may be substituted, as appropriate; R7 is hydrogen or a C1-C4 alkyl group; and Of these, at most three of Y1, Y2, Y3, Y4, Y5, and Y6 are heteroatoms; a is 0 or 1; q is 0 or 1; p is independently 0, 1, or 2 each time it appears; and dashed key ( () indicates a single or double bond; Or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts. In another embodiment, the present invention provides a compound of formula (I). in: R' is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted as appropriate, or phenyl substituted as appropriate; R1 can be hydrogen, cyano, halogen, 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 alkenoxy, C2-C6 haloalkenoxy, or C2-C6 alkyl. Acryloxy, C2-C6 haloalkynoxy, 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 alkylamine carbonyl, di-C1-C6 haloalkylamine carbonyl, aryl (substituted as appropriate), aryloxy (substituted as appropriate), heteroaryl (substituted as appropriate), C3-C8 cycloalkyl (substituted as appropriate), C3-C8 cycloalkenyl (substituted as appropriate), C3-C8 cycloalkyloxy (substituted as appropriate), 3- to 7-membered heterocyclic group (substituted as appropriate), -SF5, -SOp (C1-C6 alkyl or C1-C6 haloalkyl (substituted as appropriate)) or -NRaRb, wherein Ra and Rb are independently H or C1-C6 alkyl (substituted as appropriate); or Ra and Rb may, together with the nitrogen to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, Si, and S and may be substituted as appropriate; R2 is hydrogen, cyano, halogroup, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 haloalkoxy-C1-C6 alkyl, substituted phenyl as appropriate; substituted phenoxy as appropriate; substituted 5- or 6-membered heteroaryl as appropriate; substituted C3-C8 cycloalkyl as appropriate; substituted C3-C8 cycloalkenyl as appropriate; substituted C3-C8 cycloalkyloxy as appropriate; substituted 3- to 7-membered heterocyclic groups containing one to three heteroatoms selected from the groups of N, O, and S as appropriate; 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, -SOp (substituted C1-C6 alkyl or C1-C6 haloalkyl), SF5 or -NRaRb, wherein Ra and Rb are independently H, C1-C6 alkyl or C1-C6 haloalkyl; or Ra and Rb may, together with the nitrogen to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, Si and S and may be substituted as appropriate; R3 can be C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 haloalkoxy-C1-C6 alkyl, C3-C8 cycloalkyl (subject to substitution), C3-C8 cycloalkenyl (subject to substitution), C1-C6 alkylcarbonyl, C1-C6 haloalkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 haloalkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, di-C1-C6 haloalkylaminocarbonyl, -SF5, -S(O)p (C1-C6 alkyl or C1-C6 haloalkyl) The following are optionally substituted 3- to 7-membered heterocyclic groups containing one to three heteroatoms selected from the groups N, O, and S; optionally substituted phenyl groups; optionally substituted 5- to 10-membered heteroaryl groups; optionally substituted spirocyclic heterocyclic-carbocyclic groups; optionally substituted spirocyclic heterocyclic-heterocyclic groups; optionally substituted spirocyclic carbocyclic-carbocyclic groups; optionally substituted spirocyclic carbocyclic-heterocyclic groups; or -NRaRb, wherein Ra and Rb are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; or Ra and Rb may together with the nitrogen to which they are attached form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups, which may include one to three additional heteroatoms selected from the groups N, O, Si, and S and may be substituted as appropriate; R4 and R4' are, in each instance, independently hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 haloalkoxy-C1-C6 alkyl, substituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkyloxy, or substituted C3-C8 cycloalkyloxy. Substituted with C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, amino carbonyl, C1-C6 alkylamino carbonyl, di(C1-C6 alkyl)amino carbonyl, C1-C6 alkyl carbonyloxy, C1-C6 alkyl carbonylamino, phenyl, 5- or 6-membered heteroaryl, -SF5, -SOp (C1-C6 alkyl or C1-C6 haloalkyl, depending on the substitution); or R4 and R4 Together they form a 2-6 member chain containing one or two heteroatoms selected from the groups N, O, Si, and S, to form a carbocyclic or heterocyclic ring with the carbon atom to which they are attached; or -NRcRd, wherein Rc and Rd are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; or Rc and Rd may form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic group with the nitrogen atom to which they are attached, the heterocyclic group may include one to three additional heteroatoms selected from the groups N, O, Si, and S and may be substituted, as appropriate; R8 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 ynyl; and L, Q, X, Y1, Y2, Y3, Y4, Y5, Y6, W, Z, R5, R6, R7, R9, R9', a, q, p and dashed keys ( As defined above for compound (I).

[0054] 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.

[0055] In some embodiments: R1 is hydrogen, cyano, C1-C4 alkyl (subject to substitution), C1-C4 alkoxy (subject to substitution), C1-C4 alkenyl (subject to substitution), C1-C4 alkynyl (subject to substitution), C3-C8 cycloalkyl (subject to substitution), C3-C8 cycloalkenyl (subject to substitution), saturated or partially unsaturated 5, 6, or 7-membered heterocyclic group (subject to substitution), aryl (subject to substitution), heteroaryl (subject to substitution), aryloxy (subject to substitution), C1-C4 alkylcarbonyl (subject to substitution), C1-C4 alkoxycarbonyl (subject to substitution), or, as appropriate... The substituted amino carbonyl group, the substituted C1-C4 alkylamino carbonyl group, the substituted C1-C4 dialkylamino carbonyl group, the substituted alkyl-SOp-, haloalkyl-SOp-, amino group, -NH-, the substituted C1-C4 alkyl group, or -NRaRb, wherein Ra and Rb are independently substituted alkyl groups; or Ra and Rb may form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups together with the nitrogen to which they are attached, the heterocyclic group may include one to three additional heteroatoms selected from the groups of N, O, and S and may be substituted as appropriate; R' is hydrogen or a C1-C4 alkyl group; R2 is hydrogen, halogen, cyano, nitro, -OH, substituted C1-C4 alkyl, substituted C1-C4 alkoxy, substituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkenyl, -amino, NH-substituted C1-C4 alkyl, -SF5, or -NRaRb, wherein Rc and Rd are independently substituted C1-C4 alkyl; or Ra and Rb may, together with the nitrogen to which they are attached, form substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups, SOp (substituted C1-C4 alkyl or haloalkyl); R3 is a C1-C4 alkyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl (substituted as appropriate), 4-6 heterocyclic, 6-10 aryl, or 5-10 heteroaryl, each of which may be substituted with 1, 2, or 3 substituents as appropriate; R4 and R4' are independently hydrogen, halogen, cyano, nitro, -OH, substituted C1-C4 alkyl, substituted C1-C4 alkoxy, substituted C3-C8 cycloalkyl, -amino, NH-substituted C1-C4 alkyl, -SF5; or R4 and R4' together form a 2-6 member chain containing one or two heteroatoms selected from the group consisting of N, O, Si and S, or containing a group NR' to form a carbocyclic or heterocyclic ring with the carbon atom to which it is attached; or -NRcRd, wherein Rc and Rd are independently substituted C1-C4 alkyl; or Rc and Rd may form substituted 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups with the nitrogen to which they are attached, SOp (substituted C1-C4 alkyl or haloalkyl).

[0056] In some embodiments, R1 is hydrogen.

[0057] In some embodiments, R1 is a C1-C4 alkyl, C1-C4 haloalkyl, amino, C1-C4 alkylamino, or di-(C1-C4 alkyl)amino.

[0058] In another embodiment, R1 is a halogen.

[0059] In another embodiment, R1 is a C1-C4 alkyl-SOp-, a C1-C4 haloalkyl-SOp-, or -SF5.

[0060] In other embodiments, R1 is hydroxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy-C1-C4 alkyl, or C1-C4 haloalkoxy-C1-C4 haloalkyl.

[0061] In another embodiment, R1 is methyl, ethyl, propyl, butyl, pentyl, isopropyl (i-Pr), tert-butyl / t-butyl, prop-1-en-2-yl, 2-fluoroprop-2-yl, 1,1-difluoroethyl, or 2-hydroxyprop-2-yl.

[0062] In another embodiment, R1 is a C1-C3 alkoxy or a C1-C3 haloalkoxy.

[0063] In another embodiment, R1 is OCH3 or OCH2CH3.

[0064] In another embodiment, R1 is OCF3 or SCF3.

[0065] In another embodiment, R1 is CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0066] In some embodiments, R1 is a C2-C4 alkenyl or a C2-C4 haloalkenyl.

[0067] In some embodiments, R1 is a substituted cyclopentyl or a substituted cyclohexyl, depending on the situation.

[0068] In other embodiments, R1 is cyclopropyl or cyclobutyl.

[0069] In some embodiments, R1 is a substituted saturated or unsaturated 6-membered heterocyclic group, depending on the situation.

[0070] In one embodiment, R1 is -NRaRb, wherein Ra and Rb are independently hydrogen or C1-C6 alkyl. In another embodiment, R1 is -NRaRb, wherein Ra and Rb may form 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups together with the nitrogen to which they are attached, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S and may be substituted as appropriate.

[0071] In another embodiment, R1 is C1-C6 alkyl carbonyl, C1-C6 haloalkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 haloalkoxy carbonyl, amino carbonyl, C1-C6 alkylamino carbonyl, C1-C6 haloalkylamino carbonyl, di-C1-C6 alkylamino carbonyl, di-C1-C6 haloalkylamino carbonyl.

[0072] In some embodiments, R1 is, as appropriate, a substituted tetrahydrofuranyl, dihydrofuranyl, N-hydroxylyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0073] In some embodiments, R1 is a substituted phenyl group, as appropriate.

[0074] In some embodiments, R1 is aziridinyl, aziridine, oxacyclobutane, pyrrolidinyl, pyrrolyl, pyrazolyl, oxacyclobutane, pyrazolinyl, imidazolyl, imidazolinyl, imidazodinyl, aziridine, isozolinyl, isozolinyl, thiazolyl, thiazolyl, thiazodiazolyl, thiazodinyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, azidiazolyl, piperidinyl, piperidine, 2-sideoxypiperidine , 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, 2-side-oxynitropyridine, nitropyridine, 4-piperidinoneyl, pyridyl, pyrimidinyl, pyridyl, pyridyl, piperanyl, dihydropiperanyl, tetrahydropiperanyl, thiopiperanyl, dihydrothiopiperanyl, tetrahydrothiopiperanyl, piperinyl, thiaperinyl, thiaperinyl phosphate, thiaperinyl phosphate, 1,3-dioxacyclopentane and tetrahydro-1,1-diside-oxythiopheneyl, triazolyl or tripyridine.

[0075] In some embodiments, R1 is aziridinyl, aziridine, oxadiazine, pyrrolidyl, or α-linyl, all of which may be substituted with one or more halogens as appropriate.

[0076] In some embodiments, R2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, C1-C4 alkylamino, or di-(C1-C4 alkyl)amino.

[0077] In another embodiment, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, or tertiary butyl.

[0078] In another embodiment, R2 is hydrogen, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0079] In some embodiments, R2 is hydrogen.

[0080] In some embodiments, R2 is a halogen.

[0081] In another embodiment, R2 is fluorine or chlorine.

[0082] In another embodiment, R2 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.

[0083] In another embodiment, R2 is methoxy, ethoxy, propoxy, or butoxy.

[0084] In another embodiment, R2 is methylthio, ethylthio, propylthio, or butylthio.

[0085] In another embodiment, R2 is -OCF3 or -SCF3.

[0086] In some embodiments, R2 is a C1-C4 alkenyl or a C1-C4 haloalkenyl.

[0087] In some embodiments, R2 is a substituted cyclopentyl or a substituted cyclohexyl, depending on the situation.

[0088] In some embodiments, R2 is a substituted saturated or unsaturated 6-membered heterocyclic group, depending on the situation.

[0089] In some embodiments, R2 is, as appropriate, a substituted tetrahydrofuranyl, dihydrofuranyl, N-phospholinyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0090] In some embodiments, R2 is a substituted phenyl group, as appropriate.

[0091] In other embodiments, R2 is a phenyl group substituted with one, two, or three substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0092] In another embodiment, R2 is a 5- or 6-membered heteroaryl group having one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0093] In one embodiment, R2 is a pyridyl group substituted as follows: halogen, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or (C1-C3 alkyl or C1-C3 haloalkyl)S(O)p.

[0094] In some embodiments, R2 is, as appropriate, a substituted aziridinyl, aziridine, oxetidine, pyrrolidyl, pyrrolyl, pyrazolyl, oxetidine, pyrazolinyl, imidazolyl, imidazolinyl, imidazodinyl, aziridine, isozolinyl, isozolinyl, thiazolyl, thiazolyl, thiazodinyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, aziridine Azolyl, piperidinyl, piperidinyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, 2-side-oxynitropyrrolidinyl, nitropyrrolidinyl, 4-piperidinoneyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyridinyl, tetrahydropiperanyl, thiaolinyl, thiaolinyl phenoxide, thiaolinyl phenoxide, 1,3-dioxacyclopentane and tetrahydro-1,1-diside-oxythiopheneyl, triazolyl or triazolyl.

[0095] In some embodiments, R2 is aziridinyl, aziridine, oxadiazine, pyrrolidyl, or α-linyl, each of which may be substituted with one or more halogens as appropriate.

[0096] In some embodiments, R3 is a 6- to 10-member aryl group substituted with 1, 2, 3, 4, or 5 substituents, as appropriate.

[0097] In some embodiments, R3 is a C1-C4 alkyl or a C1-C4 haloalkyl.

[0098] In some embodiments, R3 is methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl, dibutyl, or isobutyl.

[0099] In other embodiments, R3 is CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0100] In some embodiments, R3 is a substituted C3-C8 cycloalkyl group, as appropriate. In still other embodiments, R3 is a substituted C3-C6 cycloalkyl group, as appropriate. In still other embodiments, R3 is a substituted C3-C8 or C3-C6 cycloalkenyl group, as appropriate. In some embodiments, R3 is a substituted cyclopentyl or cyclohexyl group, as appropriate. In other embodiments, R3 is a substituted cyclopropyl or cyclobutyl group, as appropriate.

[0101] In one embodiment, R3 is a cyclohexyl group substituted with one or more halogen groups, C1-C3 alkyl groups, or C1-C3 haloalkyl groups, as appropriate. In another embodiment, R3 is a cyclohexyl group substituted with one or two fluorine, chlorine, or CF3 groups.

[0102] In some embodiments, R3 is, as appropriate, a substituted piperidinyl, arginyl, tetrahydrofuranyl, or dihydrofuranyl. In some embodiments, R3 is a piperidinyl, arginyl, tetrahydrofuranyl, or dihydrofuranyl substituted with one or more halogen groups, C1-C6 alkyl groups, or C1-C6 haloalkyl groups. In another embodiment, R3 is a piperidinyl, arginyl, tetrahydrofuranyl, or dihydrofuranyl substituted with one or more methyl, chlorine, or fluorine groups.

[0103] In some embodiments, R3 is a 5- to 10-membered heteroaryl group substituted with 1, 2, 3, 4, or 5 substituents, as appropriate. In one embodiment, the 5- to 10-membered heteroaryl group is pyridyl, pyridyl, pyrimidinyl, pyridyl, tripyridyl, pyrroloyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolinyl, furanyl, thiophenyl, furanyl, pyrroloyl, imidazolyl, acezolyl, isoacezolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidinyl, or pyrrolopyrimidinyl.

[0104] In other embodiments, R3 is, as appropriate, a substituted spirocyclic heterocyclic-carbocyclic group, a substituted spirocyclic heterocyclic-heterocyclic group, a substituted spirocyclic carbocyclic-carbocyclic group, or a substituted spirocyclic carbocyclic-heterocyclic group. In other embodiments, R3 is 5 to 11 members of, as appropriate, a substituted spirocyclic heterocyclic-carbocyclic group, a substituted spirocyclic heterocyclic-heterocyclic group, a substituted spirocyclic carbocyclic-carbocyclic group, or a substituted spirocyclic carbocyclic-heterocyclic group. Non-limiting examples of spirocyclic carbocyclic-carbocyclic groups, spirocyclic carbocyclic-heterocyclic groups, and spirocyclic heterocyclic-heterocyclic groups are shown below for illustrative purposes.

[0105] However, those skilled in the art will readily recognize that the second ring of a spirocyclic group can be attached to any available carbon atom of the first ring. It will also be understood that the first ring of a spirocyclic group can be bonded to the molecule at any available atom. Therefore, the present invention includes 3-, 4-, 5-, 6-, and 7-membered carbon rings or heterocycles as defined herein, which are attached to a second 3-, 4-, 5-, 6-, and 7-membered carbon ring or heterocycle at any available carbon atom of the first ring.

[0106] In some embodiments, R3 is a phenyl substituted with 1 to 4 substituents. In another embodiment, R3 is a phenyl substituted with 1 to 3 substituents. In yet another embodiment, R3 is a phenyl substituted with 1 or 2 substituents. In some embodiments, R3 is a phenyl substituted with 1, 2, 3, or 4 substituents, wherein the substituents are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, or haloalkenyloxy.

[0107] In some embodiments, R3 is a p-substituted phenyl group.

[0108] In some embodiments, R3 is a meta-substituted phenyl group.

[0109] In some embodiments, R3 is an ortho-substituted phenyl group.

[0110] In some embodiments, R3 is a halophenyl group.

[0111] In some embodiments, R3 is a haloalkylphenyl.

[0112] In some embodiments, R3 is a haloalkoxyphenyl.

[0113] In some embodiments, R3 is a phenyl group substituted with two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0114] In some embodiments, R3 is a 2,3-disubstituted phenyl group.

[0115] In some embodiments, R3 is a 2,4-disubstituted phenyl group.

[0116] In some embodiments, R3 is a 2,5-disubstituted phenyl group.

[0117] In some embodiments, R3 is a 2,6-disubstituted phenyl group.

[0118] In some embodiments, R3 is a 3,5-disubstituted phenyl group.

[0119] In other embodiments, R3 is a 3,4-disubstituted phenyl group.

[0120] In other embodiments, R3 is a 3,6-disubstituted phenyl group.

[0121] In some embodiments, R3 is a dihalophenyl, such as dichloro; difluorine; or chlorine or fluorine.

[0122] In some embodiments, R3 is 2,3-dihalophenyl.

[0123] In some embodiments, R3 is chlorophenyl. In another embodiment, R3 is fluorophenyl. In another embodiment, R3 is dichlorophenyl. In another embodiment, R3 is difluorophenyl. In yet another embodiment, R3 is 3,5-dichlorophenyl. In another embodiment, R3 is 3,5-difluorophenyl. In another embodiment, R3 is 2,6-dichlorophenyl. In another embodiment, R3 is 2,6-difluorophenyl.

[0124] In some embodiments, R3 is a phenyl group substituted with a halogen group and a haloalkyl group.

[0125] In some embodiments, R3 is a phenyl group substituted with a halogen group and a haloalkoxy group.

[0126] In some embodiments, R3 is a phenyl group substituted with a haloalkyl group and a haloalkoxy group.

[0127] In some embodiments, R3 is a phenyl group substituted with three substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0128] In some embodiments, R3 is a trihalophenyl, such as trichloro; trifluoro; or chlorine, chlorine, fluorine; or fluorine, fluorine, chlorine.

[0129] In some embodiments, R3 is a phenyl group substituted with two halogen groups and a haloalkyl group.

[0130] In some embodiments, R3 is a phenyl group substituted with two halogen groups and a haloalkoxy group.

[0131] In some embodiments, R3 is a phenyl group substituted with one haloalkyl group, one halogroup, and one haloalkoxy group.

[0132] In some embodiments, R3 is a phenyl group substituted with one halogen group and two haloalkyl groups.

[0133] In some embodiments, R3 is a 5-membered heteroaryl group substituted with one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0134] In some embodiments, R3 is a 6-membered heteroaryl group substituted with one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0135] In some embodiments, R3 is a 2-pyridyl group substituted with one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, ynyloxy, haloalkoxy, or haloalkenyloxy.

[0136] In some embodiments, R3 is a 3-pyridyl group substituted with one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, ynyloxy, haloalkoxy, or haloalkenyloxy.

[0137] In some embodiments, R3 is a 4-pyridyl group substituted with one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0138] In another embodiment, R3 is an unsubstituted or substituted 4-pyridyl group with one or two chlorine or fluorine substituted groups. In yet another embodiment, R3 is an unsubstituted or substituted 3-pyridyl group with one or two chlorine or fluorine substituted groups.

[0139] In other embodiments, R3 is a substituted 3- to 7-membered heterocycle, depending on the specific embodiment. In some embodiments, R3 is substituted, depending on the specific embodiment, such as aziridinyl, aziridine, oxacyclobutane, pyrrolidinyl, pyrrolyl, pyrazolyl, oxacyclobutane, pyrazolinyl, imidazolyl, imidazolinyl, imidazodinyl, aziridine, isozolinyl, isozolinyl, thiazolyl, thiazolyl, thiazodinyl, isothiazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, aziridine, etc. Azolyl, piperidinyl, piperidinyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, 2-side-oxynitropyrrolidinyl, nitropyrrolidinyl, 4-piperidinoneyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyridinyl, tetrahydropiperanyl, thiaolinyl, thiaolinyl phenoxide, thiaolinyl phenoxide, 1,3-dioxacyclopentane and tetrahydro-1,1-diside-oxythiopheneyl, triazolyl or triazolyl.

[0140] In another embodiment, R3 may be a heterocyclic bridging bicyclic group that may be substituted, as appropriate.

[0141] In some embodiments, R4 and / or R4' are hydrogen.

[0142] In some embodiments, each R4 and / or R4' is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, amino, C1-C4 alkylamino or di-(C1-C4 alkyl)amino.

[0143] In another embodiment, each R4 and / or R4' is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, or tertiary butyl.

[0144] In another embodiment, R4 and / or R4' are independently hydrogen, CF3, -CH2CF3, -CHFCF3 or -CF2CF3.

[0145] In some embodiments, R4 and / or R4' are independently hydrogen or halogen.

[0146] In another embodiment, R4 and / or R4' are independently hydrogen, fluorine, or chlorine.

[0147] In another embodiment, R4 and / or R4' are independently hydrogen, C1-C4 alkoxy, C1-C4 haloalkoxy, or S(O)p (C1-C4 alkyl or C1-C4 haloalkyl), wherein p is 0, 1, or 2.

[0148] In another embodiment, R4 and / or R4' are independently hydrogen, methoxy, ethoxy, propoxy, or butoxy.

[0149] In another embodiment, R4 and / or R4' are independently hydrogen, methyl thio, ethyl thio, propyl thio, or butyl thio.

[0150] In another embodiment, R4 and / or R4' are independently hydrogen, -OCF3, or -SCF3.

[0151] In some embodiments, R4 and / or R4' are independently hydrogen, C1-C4 alkenyl, or C1-C4 haloalkenyl.

[0152] In some embodiments, R4 and / or R4' are independently hydrogen, C1-C4 alkane carbonyl, or C1-C4 alkoxy carbonyl.

[0153] In other embodiments, R4 and / or R4' are independently hydrogen, C1-C4 alkylcarbonylamine.

[0154] In some embodiments, R4 and / or R4' are independently hydrogen, a substituted cyclopentyl group, or a substituted cyclohexyl group.

[0155] In some embodiments, R4 and / or R4' is independently hydrogen, and optionally substituted tetrahydrofuranyl, dihydrofuranyl, N-hydroxylyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydrothiophene, or tetrahydrothiophene.

[0156] In some embodiments, R4 and / or R4' are independently hydrogen, or, where appropriate, substituted phenyl groups.

[0157] In other embodiments, R4 and / or R4' are independently hydrogen, phenyl substituted with 1, 2 or 3 substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

[0158] In other embodiments, R4 and / or R4' are independently hydrogen, a 5- or 6-membered heteroaryl group having one or two substituents, which are independently halogenated, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, or haloalkenyloxy.

[0159] In some embodiments, R4 and / or R4' is independently hydrogen, and optionally substituted with aziridinyl, aziridine, oxetane, pyrrolidyl, pyrrolyl, pyrazolyl, oxetane, pyrazolinyl, imidazolyl, imidazolinyl, imidazodinyl, azirazole, azirazole, isozolinyl, isozolinyl, thiazolyl, thiazolyl, thiazodinyl, isothiazolyl, furanyl, tetrahydrofuranyl, thiophenyl, or azirazoleyl. Piperidinyl, piperidinyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, 2-side-oxynitropyrrolidinyl, nitropyrrolidinyl, 4-piperidinoneyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyridinyl, tetrahydropiperanyl, thiaolinyl, thiaolinyl phenoxide, thiaolinyl phenoxide, 1,3-dioxacyclopentane and tetrahydro-1,1-diside-oxythiopheneyl, triazolyl or triazolyl.

[0160] In some embodiments, R4 and R4' are independently hydrogen, aziridinyl, aziridine, oxadiazine, pyrrolidyl, or α-linyl, each of which may be substituted with one or more halogens as appropriate.

[0161] In one embodiment, R8 is H. In another embodiment, R8 is a C1-C3 alkyl or a C1-C3 haloalkyl.

[0162] In one embodiment, R9 and R9' are each hydrogen. In another embodiment, R9 and R9' together form a 2- to 6-membered chain to form a spirocyclic substituent with the carbon atom to which they are attached. In another embodiment, R9 and R9' together form a 2- to 5-membered chain to form a spirocyclic substituent with the carbon atom to which they are attached. In another embodiment, R9 and R9' together form a 2- to 4-membered chain to form a spirocyclic substituent with the carbon atom to which they are attached. In another embodiment, R9 and R9' together form a 2- or 3-membered chain to form a spirocyclic substituent with the carbon atom to which they are attached. In another embodiment, R9 and R9' together form a 2-membered chain to form a spirocyclic substituent with the carbon atom to which they are attached.

[0163] In some embodiments, a is 0.

[0164] In some embodiments, a is 1.

[0165] In some embodiments, Q is N.

[0166] In other embodiments, Q is C-R8.

[0167] In some embodiments, X is 0.

[0168] In some embodiments, X is S.

[0169] In some embodiments, X is NR'.

[0170] In some embodiments, W is CH2.

[0171] In other embodiments, W is C(C1-C3 alkyl)2 or C(C1-C3 haloalkyl)2;

[0172] In other embodiments, W is C(CH3)2, C(C2H5)2, or C(CF3)2

[0173] In some embodiments, Z is CH2.

[0174] In some embodiments, Z is O.

[0175] In some embodiments, Z is SOp.

[0176] In some embodiments, Z is SO2.

[0177] In other embodiments, Z is SO.

[0178] In some embodiments, Z is NH.

[0179] In other embodiments, Z is N (C1-C3 alkyl) or N (C1-C3 haloalkyl).

[0180] In some embodiments, the compound of formula (I) is the compound of formula (I-1): The variables L, R1, R2, R3, R9, R9', Y1, Y3, Y4, Y5, Y6, Q, W, Z and a are as defined for equation (I).

[0181] In one embodiment of formula (I-1), W is CH2 and Z is O. In one embodiment, Q is N. In another embodiment, Q is C-R8. In another embodiment of formula (I-1), W is CH2 and Z is CH2. In another embodiment of formula (I-1), W is CR5R6, wherein R5 and R6 are C1-C3 alkyl or C1-C3 haloalkyl and Z is O. In another embodiment of formula (I-1), W is CR5R6 and Z is CR5R6, wherein each R5 and R6 is independently a C1-C3 alkyl or C1-C3 haloalkyl. In another embodiment of formula (I-1), W is CR5R6, wherein R5 and R6 together form a 2- to 5-membered chain to form a ring, and Z is O. In another embodiment, a is O and Z is O. In another embodiment, a is O, Z is O and W is CH2.

[0182] In one embodiment of equation (I-1), Y3 is S. In another embodiment of equation (I-1), Y5 is S. In another embodiment, Y3 is N. In another embodiment, Y5 is N. In another embodiment of equation (I-1), Y5 is N and Y3 is S. In yet another embodiment of equation (I-1), Y5 is S and Y3 is N. In another embodiment of equation (I-1), Y6 and Y3 are each N. In another embodiment of equation (I-1), Y6 is N and Y3 is N. In another embodiment, Y1 is N and Y5 is N.

[0183] In some embodiments, the compound of formula (I) is the compound of formula (I-2): The variables R1, R2, R3, R', R8, R9, R9', Y2, Y3, Y4, Y5, X, W, Z and a are as defined for equation (I).

[0184] In other embodiments, the compound of formula (I) is a compound of formula (I-3): The variables R1, R2, R3, R', R8, R9, R9', Y2, Y3, Y4, Y5, X, W, Z and a are as defined for equation (I).

[0185] In other embodiments, the compound of formula (I) is the compound of formula (I-4): The variables R1, R2, R3, R', R8, R9, R9', Y1, Y3, Y4, Y5, Y6, X, W, Z and a are as defined for equation (I).

[0186] In another embodiment, the compound of formula (I) is the compound of formula (I-5): The variables R1, R2, R3, R', R8, R9, R9', Y1, Y3, Y4, Y5, Y6, X, W, Z and a are as defined for equation (I).

[0187] In some embodiments, the compound of formula (I) is a compound of formula (Ia): The variables R1, R2, R3, R', R8, R9, R9', W, Z, Y2, Y3, Y4, Y5 and a are as defined for equation (I).

[0188] In some embodiments, the compound of formula (I) is a compound of formula (Ib): The variables R1, R2, R3, R', R8, R9, R9', Y2, Y3, Y4, Y5, W, Z and a are as defined for equation (I).

[0189] In some embodiments, the compound of formula (I) is a compound of formula (Ic): The variables R1, R2, R3, R', R8, R9, R9', R4, W, Z and a are as defined for equation (I); and o is 0, 1, 2, 3 or 4.

[0190] In other embodiments, the compound of formula (I) is the compound of formula (Id): The variables R1, R2, R3, R', R8, R9, R9', R4, W, Z and a are as defined for equation (I); and o is 0, 1, 2, 3 or 4.

[0191] In other embodiments, the compound of formula (I) is the compound of formula (Ie): Among them, the variables are R1, R2, R', R8, R9, and R9. Y1, Y2, Y3, Y4, Y5, W, Z and a are as defined with respect to formula (I); m is 0, 1, 2, 3 or 4; and each R10 is cyano, halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 haloalkoxy-C1-C6 alkyl, substituted phenyl, substituted phenoxy, substituted 5- or 6-membered heteroaryl, substituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkyloxy, substituted 3-membered heteroatom containing one to three heteroatoms selected from the groups N, O, Si and S, substituted 3-membered heteroatom. The heterocyclic group can be 7-membered, 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, -SOp (wherein substituted C1-C6 alkyl or C1-C6 haloalkyl), wherein p is 0, 1 or 2, SF5 or -NRaRb, wherein Ra and Rb are independently H, C1-C6 alkyl or C1-C6 haloalkyl; or Ra and Rb may together with the nitrogen to which they are attached form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, Si and S and may be substituted where appropriate.

[0192] In one embodiment of formula (Ie), R10 is a halogen group. In another embodiment, R10 is chlorine. In another embodiment, R10 is fluorine. In another embodiment, R10 is chlorine or fluorine and m is 1, 2, or 3. In another embodiment, R10 is fluorine and m is 2. In another embodiment, R10 is chlorine and m is 2. In another embodiment, R10 is fluorine or chlorine, m is 2, and the fluorine or chlorine is substituted at the 3- and 5-positions of the benzene ring. In yet another embodiment, R10 is fluorine or chlorine, m is 2, and the fluorine or chlorine is substituted at the 2- and 6-positions.

[0193] In other embodiments, the compound of formula (I) is the compound of formula (If): The variables R1, R2, R', R8, R9, R9', R4, R4', Y2, Y3, Y4, Y5, W, Z, and a are as defined for equation (I); R10 and m are as defined for equation (Ie); b is 0 or 1; the dashed key ( ) indicates a single or double bond; D is N, SiR11, where R11 is a C1-C6 alkyl or C1-C6 haloalkyl, C or C-R4; D1 is N, O, SiR11R12 (where R11 and R12 are independently C1-C6 alkyl or C1-C6 haloalkyl, -CR4R4'), S(O)p, where p is 0, 1 or 2; or D1 is CR4R4', where R4 and R4' together form a 2- to 5-membered chain, which may be substituted by one heteroatom in the chain to form a spirocyclic group.

[0194] In some embodiments, the present invention provides a compound of formula (If), wherein the dashed bond is a single bond.

[0195] In some embodiments, the present invention provides a compound of formula (If), wherein the dashed bond is a double bond.

[0196] In some embodiments, the present invention provides compounds of formula (If), wherein D is CH, C-halogen, or N.

[0197] In some embodiments, the present invention provides compounds of formula (If), wherein D is C, CH, CF, or N.

[0198] In some embodiments, the present invention provides a compound of formula (If), wherein D1 is CR4R4', wherein R4 and R4' together form a 2- to 5-membered chain with one heteroatom in the chain to form a spirocyclic group, as appropriate.

[0199] In some embodiments, the present invention provides a compound of formula (If), wherein D1 is CH2, independently of C-(halo)2, CH(C1-C3 alkyl) or CH(C1-C3 haloalkyl).

[0200] In some embodiments, the present invention provides compounds of formula (If), wherein D1 is CH2, independently of CF2, CH(CH3) or CH(CF3).

[0201] In some embodiments, the present invention provides a compound of formula (If), wherein D1 is O, S, S(O) or S(O)2.

[0202] In some embodiments, the present invention provides a compound of formula (If), wherein D is CH or C-halogen; and D1 is CH2.

[0203] In some embodiments, the present invention provides a compound of formula (If), wherein D is N; and D1 is CH2, O, or S.

[0204] In another embodiment, the present invention provides a compound of formula (If), wherein D is N and D1 is SiR11R12. In another embodiment of formula (If), D is CH2 and D1 is SiR11R12. In another embodiment, D is N and D1 is Si(CH3)2.

[0205] In some embodiments, the present invention provides a compound of formula (If), wherein the dashed line represents a double bond; D is C; and D1 is CH2, CF2, O, or S.

[0206] In some embodiments, the present invention provides a compound of formula (If), wherein D is N; and D1 is CR4R4', wherein R4 and R4' together form a 2- to 4-membered chain with one of the oxygens in the chain to form a spirocyclic group, as appropriate.

[0207] In some embodiments, the present invention provides a compound of formula (If), wherein D1 is CR4R4', wherein R4 and R4' together form a 2- to 4-membered chain with one of the oxygens in the chain to form a spirocyclic group, as appropriate.

[0208] In some embodiments, the present invention provides a compound of formula (If), wherein D is C and the dashed bond represents a double bond; and D1 is CR4R4', wherein R4 and R4' together form a 2- to 4-membered chain with one oxygen in the chain to form a spirocyclic group, as appropriate.

[0209] Those skilled in the art will understand that in formulas (Ic) and (Id) above, where the variable R4 is indicated to exist on the aromatic ring as a substituent (e.g., (R4)o group, where o is 0, 1, 2, 3, or 4), it will represent a non-hydrogen substituent, since R4 will not be present in the embodiment where o is 0. The same principle applies to the variable R10 in compounds of formulas (Ie) and (If).

[0210] In other embodiments, the present invention provides a compound of formula (Ia), wherein the variables R1, R2, R3, R', R4, R9, R9', W, Z, R8 and a are as defined above for formula (I), and Y2, Y3, Y4 and Y5 are shown in Table 1: Table 1 [Mode] [Y, 2 , ] [Y, 3 , ] [Y, 4 , ] [Y, 5 , ] Ia-1 CR4 CR4 CR4 CR4 Ia-2 N CR4 CR4 CR4 Ia-3 CR4 N CR4 CR4 Ia-4 CR4 CR4 N CR4 Ia-5 CR4 CR4 CR4 N Ia-6 N N CR4 CR4 Ia-7 CR4 N N CR4 Ia-8 CR4 CR4 N N Ia-9 N CR4 N CR4 Ia-10 CR4 N CR4 N Ia-11 N CR4 CR4 N

[0211] In other embodiments, the present invention provides a compound of formula (Ib), wherein the variables R1, R2, R3, R4, R', R9, R9', W, Z, R8 and a are as defined above for formula (I), and Y2, Y3, Y4 and Y5 are shown in Table 2: Table 2 [Mode] [Y, 2 , ] [Y, 3 , ] [Y, 4 , ] [Y,5 , ] Ib-1 CR4 CR4 CR4 CR4 Ib-2 N CR4 CR4 CR4 Ib-3 CR4 N CR4 CR4 Ib-4 CR4 CR4 N CR4 Ib-5 CR4 CR4 CR4 N Ib-6 N N CR4 CR4 Ib-7 CR4 N N CR4 Ib-8 CR4 CR4 N N Ib-9 N CR4 N CR4 Ib-10 CR4 N CR4 N Ib-11 N CR4 CR4 N

[0212] In some embodiments, 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 each R2 is independently H, a halogen, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 alkoxy, a C1-C4 haloalkoxy, or S(O)p (C1-C4 alkyl or C1-C4 haloalkyl).

[0213] In some embodiments, 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 each R2 is independently H, chlorine, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, or tertiary butyl.

[0214] In some embodiments, 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 each R2 is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0215] In some embodiments, 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 each R2 is independently H, methoxy, ethoxy, propoxy, or butoxy.

[0216] In some embodiments, 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 each R2 is independently H, -OCF3, or -SCF3.

[0217] In some embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R4 and / or R4' is independently H, a halogen, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 alkoxy, a C1-C4 haloalkoxy, or S(O)p (C1-C4 alkyl or C1-C4 haloalkyl).

[0218] In some embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R4 and / or R4' is independently H, chlorine, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, or tertiary butyl.

[0219] In some embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R4 and / or R4' is independently H, CF3, -CH2CF3, -CHFCF3, or -CF2CF3.

[0220] In some embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R4 and / or R4' is independently H, methoxy, ethoxy, propoxy, or butoxy.

[0221] In some embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ie), or (If), wherein each R4 and / or R4' is independently H, -OCF3, or -SCF3.

[0222] In other embodiments, the present invention provides compounds of formula (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein R' and R8 are independently H or C1-C3 alkyl groups.

[0223] In other embodiments, the present invention provides compounds of formulas (Ia) to (If), wherein a is 1, W is CH2 and Z is O.

[0224] In other embodiments, 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 R1 is a 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, or C1-C6 alkoxy. C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C3-C8 cycloalkyl substituted as appropriate, 3- to 7-membered heterocyclic substituted as appropriate, or -NRaRb, wherein Ra and Rb are independently H or C1-C6 alkyl substituted as appropriate; or Ra and Rb may together with the nitrogen to which they are attached form a 3-, 4-, 5-, or 6-membered heterocyclic alkyl group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S and may be substituted as appropriate.

[0225] In other embodiments, the present invention provides compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or, where appropriate, a substituted C3-C8 Cycloalkyl, 3- to 7-membered heterocyclic groups containing one to three heteroatoms selected from the groups of N, O, and S, which may be substituted as appropriate; phenyl, 5- to 10-membered heteroaryl, 5- to 11-membered spirocyclic heterocyclic-carbocyclic, 5- to 11-membered spirocyclic heterocyclic-heterocyclic, 5- to 11-membered spirocyclic carbocyclic-carbocyclic, 5- to 11-membered spirocyclic carbocyclic-heterocyclic, or -NRaRb, wherein Ra and Rb are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; or Ra and Rb may together with the nitrogen to which they are attached form 3-, 4-, 5-, or 6-membered heterocyclic groups, which may include one to three additional heteroatoms selected from the groups of N, O, and S and may be substituted as appropriate.

[0226] In other embodiments, the present invention provides compounds of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), wherein R3 is a substituted phenyl group, as appropriate. In another embodiment of a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id), R3 is a phenyl group substituted with one or more halogens. In yet another embodiment, compounds of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl group substituted with one halogen. In another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl group substituted with two halogens. In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl group substituted with three or four halogens.

[0227] In another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl substituted with one or more chlorine or fluorine atoms. In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl substituted with one chlorine or fluorine atom. In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl substituted with two chlorine or fluorine atoms. In yet another embodiment, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), or (Id) are provided, wherein R3 is a phenyl group substituted with three or four chlorine or fluorine compounds.

[0228] In other embodiments, the present invention provides compounds of formula (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), or (If), wherein R' and R8 are independently H or C1-C3 alkyl; W is CH2, Z is O, and a is 1.

[0229] In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib) and (Ie), each of Y2, Y3, Y4, and Y5 is CH.

[0230] In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib) and (Ie), Y2, Y3, Y4, and Y5 are each independently CH or CR4, wherein R4 is a non-hydrogen substituent.

[0231] In other embodiments of formulas (I-1), (I-4) and (I-5), each of Y3, Y4 and Y5 is CH.

[0232] In other embodiments of formulas (I), (I-2), (I-3), (Ia), (Ib) and (Ie), Y2, Y3, Y4, and Y5 are each independently CH or C-halogen.

[0233] 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 0.

[0234] In any of the embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If) above, R1 is C1-C4 alkyl, C1-C4 alkenyl, C1-C4 cycloalkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, N-pyrinyl, piperanyl, tetrahydropiperanyl, or dihydropiperanyl.

[0235] In any of the embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), and (If) above, R4 is independently of the others a halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, or, as appropriate, a phenyl group substituted with a halogen or C1-C4 alkyl group once or twice.

[0236] In other embodiments, the present invention provides compounds of formula (I) shown in Table 3 below, wherein L, R1, R2 and R3 are defined in the table, X is O, R' is hydrogen, and wherein the groups are... It is one of the following ring systems: Ring system A; Ring system B; Ring system C; Ring system D; Ring system E; Ring system F; Ring system G; Ring system H; Ring System I; Ring system J; Ring system K; Ring system L; Ring system M; Ring system N; Ring system O; Ring system P; Ring system Q; Ring system R; Ring system S; Ring system T; Ring system U; Ring system V; Ring system W; Ring system X; Ring system Y; Ring system Z; Ring system AA; Ring system AB; Ring system AC; Ring system AD; Ring system AE; Ring system AF; AG ring system AH ring system; Ring system AJ; Ring system AK; Ring system AL; Ring system AM; AN ring system; AO ring system; Ring system AP; Ring system AQ; Ring system AR; Ring system AS; Ring system AT; AU (Ring System) AV ring system; AW (Aperture System) Ring system AX; Ring system AY; Ring system AZ; Ring system AAA; In Table 3, the expressions "3,5-di-F-Ph" represent 3,5-difluorophenyl; "3,5-di-Cl-Ph" represents 3,5-dichlorophenyl; "2,3,5-tri-F-Ph" represents 2,3,5-trifluorophenyl; "3-F-Ph" represents 3-fluorophenyl; "2,6-di-F-Ph" represents 2,6-difluorophenyl; "2,6-di-Cl-Ph" represents 2,6-dichlorophenyl; "2,4-di-F-Ph" represents 2,4-difluorophenyl; "4-F-Ph" represents 4-fluorophenyl; "3-Cl-4-F-Ph" represents 3-chloro-4-fluorophenyl; "3-Cl-Ph" represents 3-chlorophenyl; "2,3-di-F-Ph" represents 2,3-difluorophenyl; and so on. Propylene-1-en-2-yl group ; 2-F-propyl-2-yl represents a group 1,1-Difluoroethyl represents a group . Formula (I) Table 3 [Compound Number] [L] [R, 1 , ] [R, 2 , ] [R, 3 , ] [Ring System] [ESI-MS] 271 L1 i-Pr Me 3,5-Di-Cl-Ph A 596 [M+H]+ 326 L1 i-Pr Me A 502 [M+H]+ 327 L1 i-Pr Me A 500 [M+H]+ 326-0 L1 i-Pr Me A 502 [M+H]+ 324 L1 i-Pr Me A 435 [M+H]+ 325 L1 i-Pr Me A 437 [M+H]+ 323 L1 i-Pr Me t-Bu A 408 [M+H]+ 175 L1 i-Pr Me 3,5-di-F-Ph A 463 [M+H]+ A407 L1 i-Pr Me 2,6-di-F-Ph A 463 [M+H]+ A406 L1 i-Pr Me 2,6-di-Cl-Ph A 495 [M+H]+ A413 L1 i-Pr Me 2,4-di-F-Ph A 463 [M+H]+ A408 L1 Me 3,5-di-Cl-Ph A 538 [M+H]+ A412 L1 i-Pr Me 4-F-Ph A 445 [M+H]+ A410 L1 i-Pr Me 3-Cl-4-F-Ph A 479 [M+H]+ A411 L1 i-Pr Me 3,5-di-Cl-Ph C 511 [M+H]+ A409 L1 -N(CH3)2 Me 3,5-di-Cl-Ph A 496 [M+H]+ A414 L1 i-Pr Me 3,5-di-Cl-Ph D 529 [M+H]+ 306 L1 t-Bu Me 3,5-di-Cl-Ph A 510 [M+H]+ 297 L1 t-Bu Me 3,5-di-Cl-Ph B 528 [M+H]+ 365 L1 i-Pr Me Cyclopropyl A 391 [M+H]+ 371 L1 i-Pr Me A 470 [M+H]+ 370 L1 i-Pr Me A 436 [M+H]+ 366 L1 i-Pr Me CN A 376 [M+H]+ 369 L1 i-Pr Me A 447 [M+H]+ 308 L1 prop-1-en-2-yl Me 3,5-di-Cl-Ph B 512 [M+H]+ 364 L1 i-Pr Me 3,5-di-Cl-Ph E 470 [M+H]+ 352 L1 i-Pr H 3,5-di-Cl-Ph A 481 [M+H]+ 320-321 L1 i-Pr Me 3,5-di-F-Ph F 463 [M+H]+ 345 L1 i-Pr Me 2,3,5-tri-F-Ph A 481 [M+H]+ 344 L1 i-Pr Me 2,3,5-tri-F-Ph B 499 [M+H]+ 294 L1 i-Pr Me 3,5-di-Cl-Ph B 514 [M+H]+ 320 L2 i-Pr Me 3,5-di-F-Ph A 463 [M+H]+ 277 L1 2-F-propan-2-yl Me 3,5-di-F-Ph A 481 [M+H]+ 323-0 L1 i-Pr Me -CH2CH(CH3)2 A 407 [M+H]+ 298-0 L1 t-Bu CF3 3-Cl-Ph B 548 [M+H]+ 299-0 L1 t-Bu CF3 3-Cl-Ph A 530 [M+H]+ 299 L1 t-Bu CF3 3,5-di-Cl-Ph B 582 [M+H]+ 298 L1 t-Bu CF3 3,5-di-Cl-Ph A 564 [M+H]+ 304-0 L1 i-Pr 3,5-di-Cl-Ph Cl B 535 [M+H]+ 321 L1 i-Pr 4-F-Ph 3,5-di-F-Ph A 544 [M+H]+ 322 L1 i-Pr Me A 463 [M+H]+ 304 L1 i-Pr Cl 3,5-di-Cl-Ph B 535 [M+H]+ 307 L1 prop-1-en-2-yl Me 3,5-di-F-Ph B 478 [M+H]+ 296 L1 i-Pr CF3 3,5-di-Cl-Ph B 568 [M+H]+ 295 L1 i-Pr CF3 3,5-di-Cl-Ph A 550 [M+H]+ 293 L1 i-Pr Me 2,3-di-Cl-Ph B 514 [M+H]+ 276 L1 i-Pr CF3 3,5-di-F-Ph A 517 [M+H]+ 274 L1 i-Pr Me 2,3-Di-Cl-Ph A 496 [M+H]+ 273 L1 i-Pr Me 3-F-Ph A 446 [M+H]+ 272 L1 i-Pr Me 3-Cl-5-F-Ph A 480 [M+H]+ 275 L1 i-Pr Me 3,5-di-F-Ph B 481 [M+H]+ 279 L1 propyl-1-en-2-yl Me 3,5-di-F-Ph A 461 [M+H]+ 174 L1 H H 2,6-di-F-Ph A 407 [M+H]+ A400 L1 1,1-Difluoroethyl Me 3,5-Di-Cl-Ph A 517 [M+H]+ A401 L1 CF3 Me 3,5-di-Cl-Ph A 521 [M+H]+ 373 L1 i-Pr Me A 479 [M+H]+ 372-0 L1 i-Pr Me A 421 [M+H]+ A402 L1 i-Pr Me 3,5-di-Cl-Ph G 599 [M+H]+ A403 L1 i-Pr -CH2OH 3,5-di-Cl-Ph A 511 [M+H]+ A404 L1 i-Pr -CF2CF3 3,5-di-Cl-Ph A 599 [M+H]+ 394 L1 -OCH3 H 3,5-di-Cl-Ph A 470 [M+H]+ 398 L1 -OCH2CH3 H 3,5-di-Cl-Ph A 484 [M+H]+ A405 L1 -CHF2 Me 3,5-di-Cl-Ph A 503 [M+H]+ 573 L1 t-Bu Cl 2,3,5-tri-F-Ph A 515 [M+H]+ 559 L1 i-Pr -CN 3,5-di-Cl-Ph A 504 [M+H]+ 614 L1 t-Bu Me 3,5-di-Cl-Ph AAA 510 [M+H]+ 451 L1 -N(CH3)2 CF3 3,5-di-Cl-Ph A 550 [M+H]+ 572 L1 t-Bu Cl 2,5-di-Cl-4-F-Ph A 547 [M+H]+ 528 L1 i-Pr Me 2,5-di-Cl-4-F-Ph A 513 [M+H]+ 571 L1 t-Bu Cl 2,4,5-tri-F-Ph A 515 [M+H]+ 574 L1 t-Bu Cl 2,3-di-Cl-5-F-Ph A 547 [M+H]+ A415 L1 i-Pr Me 3,5-di-Cl-Ph H 543 [M+H]+ A416 L1 i-Pr Me 3,5-di-Cl-Ph I 543 [M+H]+ A417 L1 i-Pr Me 3,5-di-Cl-Ph J 578 [M+H]+ A418 L1 i-Pr Me 3,5-di-Cl-Ph K 578 [M+H]+ A419 L1 i-Pr Me 3,5-di-Cl-Ph L 500 [M+H]+ A420 L1 i-Pr Me 3,5-di-Cl-Ph M 500 [M+H]+ 560 L1 i-Pr -CHF2 3,5-di-Cl-Ph A 530 [M+H]+ 305 L1 i-Pr -CHF2 3,5-di-Cl-Ph B 548 [M+H]+ A421 L1 Me 2,6-di-Cl-4-F A 556 [M+H]+ A422 L1 Me 2,3,5-tri-F-Ph A 524 [M+H]+ 420 L1 t-Bu Cl 3,5-di-Cl-Ph A 572 [M+H+ CH3CN] + A423 L1 i-Pr Me 3,5-di-Cl-Ph N 557 [M+H]+ A424 L1 i-Pr Me 3,5-di-Cl-Ph O 557 [M+H]+ 523 L1 t-Bu Me 2,6-di-Cl-4-F-Ph A 527 [M+H]+ A425 L1 i-Pr Me 3,5-di-Cl-Ph P 483 [M+H]+ A426 L1 i-Pr Me 3,5-di-Cl-Ph Q 483 [M+H]+ 526 L1 t-Bu Me 2,3-di-Cl-5-F-Ph A 527 [M+H]+ 527 L1 i-Pr Me 2,4,6-tri-F-Ph A 481 [M+H]+ 524 L1 t-Bu Me 2,4,6-tri-F-Ph A 495 [M+H]+ 525 L1 t-Bu Me 2,3,5-tri-F-Ph A 495 [M+H]+ 414-0 L2 i-Pr Me 3,5-di-Cl-Ph R 496 [M+H]+ 514 L2 i-Pr Me 3,5-di-Cl-Ph E 496 [M+H]+ A427 L1 i-Pr Me 3,5-di-Cl-Ph S 487 [M+H]+ A428 L1 i-Pr Me 3,5-di-Cl-Ph T 522 [M+H]+ A429 L1 i-Pr Me 3,5-di-Cl-Ph U 487 [M+H]+ A430 L1 i-Pr Me 3,5-di-Cl-Ph V 522 [M+H]+ 418 L1 t-Bu H 3,5-di-Cl-Ph A 495 [M+H]+ 513 L2 i-Pr Me 3,5-di-Cl-Ph A 495 [M+H]+ 513-0 L2 i-Pr Me 3,5-di-Cl-Ph F 496 [M+H]+ 511 L1 H 3,5-di-Cl-Ph A 524 [M+H]+ 512 L1 -N(CH3)2 H 3,5-di-Cl-Ph A 482 [M+H]+ A431 L1 i-Pr Me 3,5-di-Cl-Ph W 513 [M+H]+ 450 L1 CF3 3,5-di-Cl-Ph A 592 [M+H]+ A432 L1 i-Pr Me 3,5-di-Cl-Ph X 520 [M+H]+ A473 L1 i-Pr Me 3,5-di-Cl-Ph Y 520 [M+H]+ A433 L1 i-Pr Me 3,5-di-Cl-Ph Z 554 [M+H]+ A434 L1 i-Pr Me 3,5-di-Cl-Ph AA 554 [M+H]+ A435 L1 i-Pr Me 3,5-di-Cl-Ph AB 499 [M+H]+ A436 L1 L1 i-Pr Me N / A (H) 363 [M+H]+ A437 L1 i-Pr Me 3,5-di-Cl-Ph AC 499 [M+H]+ A438 L1 i-Pr Me 3,5-di-Cl-Ph AD 482 [M+H]+ A439 L1 i-Pr Me 3,5-di-Cl-Ph AF 494 [M+H]+ A440 L1 i-Pr Me 3,5-di-Cl-Ph AG 494 [M+H]+ A441 L1 i-Pr Me 3,5-di-Cl-Ph AH 499 [M+H]+ A442 L1 i-Pr Me 3,5-di-Cl-Ph AE 482 [M+H]+ A443 L1 i-Pr Me 3,5-di-Cl-Ph AJ 499 [M+H]+ A445 L1 i-Pr Me 3,5-di-Cl-Ph AK 511 [M+H]+ A446 L1 i-Pr Me 3,5-di-Cl-Ph AL 511 [M+H]+ A447 L1 i-Pr Me 3,5-di-Cl-Ph AM 482 [M+H]+ A448 L1 i-Pr Me 3,5-di-Cl-Ph AO 502 [M+H]+ A449 L1 i-Pr Me 3,5-di-Cl-Ph AQ 502 [M+H]+ A450 L1 i-Pr Me 3,5-di-Cl-Ph AR 502 [M+H]+ A451 L1 i-Pr Me 3,5-di-Cl-Ph AP 502 [M+H]+ A452 L1 i-Pr Me 3,5-di-Cl-Ph AS 523 [M+H]+ A472 L1 i-Pr Me 3,5-di-Cl-Ph AT 523 [M+H]+ A453 L1 i-Pr Me 3,5-di-Cl-Ph AN 482 [M+H]+ A454 L1 i-Pr Me 3,5-di-Cl-Ph AU 520 [M+H]+ 419 L1 i-Pr Cl 3,5-di-Cl-Ph A 558 [M+CH3CN]+ 397-0 L1 OCH2CH=CH2 Me 3,5-di-Cl-Ph A 495 [M+H]+ A455 L1 i-Pr Me 3,5-di-Cl-Ph AW 482 [M+H]+ A456 L1 i-Pr Me 3,5-di-Cl-Ph AX 482 [M+H]+ A457 L1 i-Pr Me 3,5-di-Cl-Ph AY 515 [M+H]+ A458 L1 i-Pr Me 3,5-di-Cl-Ph AZ 515 [M+H]+ 395 L1 -OCHF2 Me 3,5-di-Cl-Ph A 568 [M+CH3CN+Na]+ A459 L1 Me 3,5-di-Cl-Ph A 570 [M+H]+ A464 L1 -N(CH3)2 Me 2,6-di-Cl-4-F-Ph A 514 [M+H]+ A462 L1 -N(CH3)2 Me 2,4,6-tri-F-Ph A 481 [M+H]+ A463 L1 -N(CH3)2 Me 2,3-Di-Cl-5-F-Ph A 514 [M+H]+ A460 L1 -N(CH3)2 Me 2,3,5-Tri-F-Ph A 481 [M+H]+ A461 L1 -N(CH3)2 Me 2,3,5-Tri-Cl-Ph A 531 [M+H]+ 558 L1 i-Pr -C(O)CH3 3,5-Di-Cl-Ph A 523 [M+H]+

[0237] To avoid any doubt, each of the compounds presented in Table 3 has been prepared.

[0238] [ ] [Stereoisomers and polymorphic forms] [ ] Those skilled in the art will understand that compounds can exist and be separated in optically active and racemic forms. Compounds having one or more enantiomers (including enantiomers at sulfur atoms) 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 sulfene compounds can be optically active and can exist as a single enantiomer or a racemic mixture. Furthermore, compounds of this specification may include one or more enantiomers, which produce a theoretical number of optically active isomers. In the case of this invention, when Q is C-R8, the compound of formula (I) includes at least one enantiomer at a carbon atom having a variable R8. When the compound of this specification includes n enantiomers, the compound may contain up to 2n optical isomers. Therefore, the compounds of this invention include at least two enantiomers covered by this invention. This specification covers specific enantiomers or diastereomers of the compounds having the applicable properties described herein, as well as mixtures of different enantiomers and / or diastereomers of the compounds. The optically active form can be prepared, for example, by selective crystallization to resolve the racemic form, by synthesis from an optically active precursor, by palmar synthesis, by chromatographic separation using a palmar stationary phase, or by enzymatic resolution.

[0239] Compounds may also exist in different solid forms (such as different crystalline forms) or in amorphous solid forms. This specification includes different crystalline and amorphous forms of compounds.

[0240] Furthermore, compounds can exist as hydrates or solvates, where a certain stoichiometry of water or solvent is related to the crystalline form of the molecule. The hydrates and solvates of compounds are also the subject of this specification.

[0241] [ ] [Salt] [ ] In addition to neutral compounds, the salt form of the compound also has activity against endoparasites. The term "veterinary acceptable salt" is used throughout the specification to describe any salt of a compound that is acceptable for administration in veterinary applications and provides the active compound after administration.

[0242] The compound may be in the form of a veterinary or agriculturally acceptable salt, provided that it possesses sufficient basicity or acidity to form a stable, non-toxic acid salt or base salt. Veterinary-acceptable salts include salts 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 but not limited to manganese, copper, zinc, and iron) are also suitable. Furthermore, this specification covers salts containing ammonium cations (NH₄⁺) and substituted ammonium cations (where one or more hydrogen atoms are replaced by an alkyl or aryl group).

[0243] Salts derived from inorganic acids are particularly suitable, including but not limited to hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable inorganic salts also include, but are not limited to, bicarbonates and carbonates. In some embodiments, examples of veterinary and agriculturally acceptable salts are organic acid addition salts formed from organic acids, including but not limited to maleate, dimaleate, fumarate, toluenesulfonate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Of course, other acceptable organic acids may be used.

[0244] Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of compounds can also be prepared by reacting sufficiently acidic residues on the compound with hydroxides of alkali metals or alkaline earth metals.

[0245] Veterinary acceptable salts can be obtained using standard procedures well known in this technique, such as by reacting a sufficiently basic compound (such as an amine) with a suitable acidic functional group present in the compound, or by reacting a suitable acid with a suitable basic functional group on the compound described herein.

[0246] [ ] [Processes used to prepare compounds] [ ] Compounds of formula (I) or their pharmaceutically or veterinarily acceptable salts can be prepared by means of the following procedures 1 and 2 and the procedures in the examples: [ ] [process] [1]

[0247] [ ] [process] [2] [ ] In process 2, variables R1, R2, and R3 represent groups defined in formula (I) above and can be introduced by metal-catalyzed cross-coupling reactions. Examples include the Heck reaction, Negishi coupling reaction, Stille cross-coupling reaction, Suzuki reaction, and other reactions well known in this art. Variable R5 represents the linker L bonded at the core of this bicyclic ring to one of the bicyclic rings shown in formula (I). Those skilled in the art are fully capable of adapting these processes to synthesize the specific compounds of this invention. Furthermore, the starting materials are readily available or can be prepared using known procedures. [ ]

[0248] [ ] [Veterinary Composition] [ ] This compound and compositions comprising this compound are intended for the prevention and / or treatment of parasitic infections or infestations in animals. The compositions described herein comprise an effective amount of the compound or a veterinary-acceptable salt thereof, a veterinary-acceptable carrier or diluent, and, where applicable, an inactive excipient. The compositions are available in a variety of solid and liquid forms suitable for administration or delivery to animals in various forms. For example, veterinary compositions comprising the compound are available in forms suitable for oral, injectable (including subcutaneous and non-enteral) and topical (e.g., spot or pour), transdermal, or subdermal delivery. The compositions are intended for delivery to animals, including but not limited to mammals, birds, and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other livestock or domesticated mammals. Examples of birds include turkeys, chickens, ostriches, and other livestock or domesticated birds. The use of the compound to protect companion animals (such as dogs and cats) from internal parasites is particularly useful.

[0249] As discussed above, the compositions described herein may be in forms suitable for oral use (see, for example, U.S. Patent No. 4,564,631, which is hereby incorporated herein by reference in its entirety), dietary supplements, sugar-coated tablets, lozenges, chewable tablets, tablets, hard or soft capsules, pills, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral medication compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric-coated compositions, or pastes. Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more sweeteners, bittering agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation.

[0250] The tablets may contain an active ingredient mixed with pharmaceutically acceptable, non-toxic excipients suitable for manufacturing tablets. These excipients may be, for example, inert diluents, granulating and disintegrants, binders, and lubricants. The tablets may be uncoated, or may be co-coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. They may also be co-coated using the 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.

[0251] Oral compositions include hard gelatin capsules. The capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or a water-miscible solvent or oil medium.

[0252] In one embodiment, the compound may be administered in the form of a chewable tablet composition or a soft chewable composition, such as those described in US 2013 / 0203692 A1, US 2010 / 0087492, US 2006 / 0222684, US 2004 / 0151759, and US 7,955,632, all of which are incorporated herein by reference. The veterinary composition may be in the form of a soft chewable composition (“soft chewable tablet”) that is palatable and acceptable to animals. In addition to the active ingredient, the soft chewable tablets described herein may include one or more of the following components known in such dosage form technologies: solvent or solvent mixture, one or more fillers, one or more binders, one or more surfactants, one or more humectants, one or more lubricants, one or more disintegrants, one or more colorants, one or more antimicrobial agents, one or more antioxidants, one or more pH adjusters, and one or more flavoring agents.

[0253] The composition may also contain other inert components, such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the art of composition. Antioxidants may be added to the compositions described herein to inhibit the degradation of the active agents.

[0254] The compositions described herein may also include one or more lubricants and / or processing aids. In some cases, the lubricant / processing aid may also act as a solvent, and therefore, some components in the compositions of this invention may have dual functions.

[0255] Many flavoring agents can be used in the compositions described herein to improve the palatability of oral veterinary compositions. Preferred flavoring agents are those not derived from animal sources. In various embodiments, flavoring components derived from fruits, meats (including but not limited to pork, beef, chicken, fish, poultry, and the like), plants, cheeses, bacon, cheese-bacon, and / or artificial flavorings may be used. Flavoring components are typically selected based on considerations relevant to the organism that will ingest the soft chewable tablet. For example, a horse may prefer an apple flavoring component, while a dog may prefer a meat flavoring component. Although flavoring components derived from non-animal sources are preferred, in some embodiments, natural flavorings containing beef or liver extracts, such as stew beef flavorings, artificial beef powder flavorings, roast beef flavorings, and corned beef flavorings, and other flavorings, may be used.

[0256] In another embodiment of this specification, the active composition may be administered via oral infusion, and may be administered topically or orally. An oral infusion composition is a composition containing a liquid composition as described in this specification, administered or poured onto the skin or fur of an animal.

[0257] The compositions described herein may also be in the form of oil-in-water or water-in-oil emulsions, which may include emulsifiers known in the art. The emulsions may also contain sweeteners, bittering agents, flavoring agents, and / or preservatives.

[0258] In one embodiment, the composition of this specification may be in the form of a microemulsion. Microemulsions are ideally suited as liquid carriers. A microemulsion is a quaternary system comprising an aqueous phase, an oil phase, a surfactant, and an auxiliary surfactant. It is a translucent and isotropic liquid.

[0259] Microemulsions consist of a stable dispersion of aqueous microparticles in an oil phase or, conversely, a stable dispersion of oil microparticles in an aqueous phase.

[0260] Oily suspensions can be formulated by suspending the active ingredients in vegetable oil. Oily suspensions may contain thickeners. Sweeteners, bittering agents, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by adding antioxidants or other known preservatives.

[0261] Aqueous suspensions may contain active materials mixed with excipients suitable for manufacturing aqueous suspensions. Aqueous suspensions may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners and / or bittering agents.

[0262] Dispersible agents and granules suitable for preparing aqueous suspensions by adding water can provide mixtures of active ingredients with dispersants or wetting agents, suspending agents, and one or more preservatives. Additional excipients, such as sweeteners, bittering agents, flavoring agents, and coloring agents, may also be present.

[0263] Syrups and elixirs can be formulated with sweeteners. Such compositions may also contain modifiers, preservatives, flavoring agents, and / or coloring agents.

[0264] In another embodiment of this specification, the composition may be in the form of a paste. Examples of embodiments in the form of a paste include, but are not limited to, those described in U.S. Patent Nos. 6,787,342 and 7,001,889 (each of which is incorporated herein by reference). In addition to the compounds of this specification, the paste may further contain fumed silica; a viscosity modifier; a carrier; an absorbent, if applicable; and, if applicable, a colorant, stabilizer, surfactant, or preservative.

[0265] In some embodiments, the composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic injectable diluent or solvent.

[0266] In addition, sterile, non-volatile oils are conventionally used as solvents or suspension media.

[0267] By way of non-limiting examples, topical, transdermal, and subcutaneous compositions may include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-over compositions, ready-to-use compositions, spot solutions and suspensions, infusions, and sprays. Topical application of the compounds of the present invention, or compositions comprising at least one of the compounds of the present invention as active agents (in the form of spot, spray, or pour-over compositions), allows the compositions of the present invention to achieve systemic content through skin absorption, distribution via sebaceous glands, or distribution on the skin surface, thereby achieving content throughout the fur. Spot compositions are typically applied to a localized area, which refers to an area other than the whole animal. In one embodiment, this location may be between the shoulders. In another embodiment, the topical composition may be applied in the form of stripes on the animal's surface, such as stripes from the animal's head to its tail.

[0268] The pouring composition is described in U.S. Patent No. 6,010,710, which is incorporated herein by reference. Advantageously, the pouring composition may be oil-based and generally contains a diluent or mordant, and also contains a solvent (e.g., an organic solvent) for the active ingredient when the active ingredient is insoluble in the diluent. In other embodiments, the pouring composition may contain a water-miscible organic solvent.

[0269] The solvent will be used in proportion to the concentration of the surfactant compound and its solubility in the solvent. The goal is to achieve the minimum possible volume. The difference between the mediator composition and 100%.

[0270] In another embodiment of this specification, a softener and / or a dispersant and / or a film-forming agent may be added to the topical composition.

[0271] In another embodiment of this specification, 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 described herein, 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.

[0272] The composition may also contain an antioxidant intended to inhibit oxidation in the air, which may be present in proportions of about 0.005% to about 1% (w / v), about 0.01% to about 0.1% or about 0.01% to about 0.05%.

[0273] The excipients used in the compositions discussed above are well known to physicians in this field and are commercially available or obtained through known techniques. These compositions are generally prepared by simply mixing the ingredients as defined above; advantageously, the starting point is to mix the active material in a main solvent and then add other ingredients or adjuvants.

[0274] The volume of the composition applied will depend on the animal type and size, as well as the strength of the composition and the potency of the active agent. In one embodiment, the composition may be applied to an animal in an amount of about 0.1 to about 20 ml. 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.

[0275] Spotting compositions can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable medium. Alternatively, spotting compositions can be prepared by encapsulating the active ingredient to leave a therapeutic residue on the surface of the animal. Depending on the species of the host animal to be treated, the severity and type of infection, and the host's weight, the composition will vary with the weight of the therapeutic agent in the composition.

[0276] The dosage form may typically contain about 0.1 mg to about 5 g. In other embodiments, the dosage form may contain about 0.5 mg to about 5 g of active agent. In one embodiment of the dosage form, the dose may contain about 1 mg to about 500 mg of active agent, typically about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000 mg.

[0277] 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 weight. In other embodiments, the compound of formula (I) may be present at a concentration of about 0.1% to about 30% (w / w). In other embodiments, the compound of formula (I) may be present at a concentration of about 0.5% to about 30% (w / w), about 1% to about 20% (w / w), or about 0.05% to about 10% (w / w). In other embodiments, the compound of formula (I) may be present at a concentration of about 10% to about 50% (w / w), about 10% to about 30% (w / w), 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 this specification, the active agent may be present in the composition at a concentration of about 0.1% to about 2% w / w. In another embodiment of this specification, the surfactant may be present in the composition at a concentration of about 0.25% to about 1.5% w / w. In yet another embodiment of this specification, the surfactant may be present in the composition at a concentration of about 1% w / w.

[0278] [Treatment methods] As discussed above, compounds of formula (I) are effective against endoparasites and can be used to treat and / or prevent parasitic infections in animals. In one embodiment, this specification provides a method for treating and / or preventing endoparasitic infections in animals (e.g., mammals or birds), comprising administering to the animal an effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a composition thereof.

[0279] This specification also provides for the use of compounds of formula (I) in the preparation of pharmaceutical agents for the treatment and / or prevention of parasitic infections in animals. This specification also provides for compounds of formula (I) for the treatment and / or prevention of parasitic infections in animals.

[0280] In some embodiments, the compound of formula (I) is also effective against ectoparasites and can be used to treat and / or prevent ectoparasite infestations in animals. In another embodiment, this specification provides a method for treating and / or preventing ectoparasite infestations in 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 thereof.

[0281] The invention also provides the use of the compound of formula (I) in the preparation of a medicament for the treatment and / or prevention of ectoparasite infestation in animals. The invention also describes a compound of formula (I) for the treatment and / or prevention of ectoparasite infestation in animals.

[0282] In another embodiment, this specification provides a method for treating and / or preventing internal parasite infections and external parasite infestations in animals, comprising administering to the animal a composition comprising an effective amount of a compound of formula (I) and an effective amount of at least a second active agent or a veterinary acceptable salt thereof.

[0283] This document also provides a compound of formula (I) in combination with at least one second active agent for the treatment and / or prevention of endoparasitic infections and ectoparasitic infestations. Additionally, the use of a compound of formula (I) in combination with at least one second active agent in the preparation of a medicament for the treatment and / or prevention of endoparasitic infections and ectoparasitic infestations is provided.

[0284] In another embodiment of this specification, a method for treating and / or preventing parasitic infestation in a location is provided, comprising administering or applying to the location a parasitic-effective amount of a compound of formula (I) or a veterinarily acceptable salt thereof. Regarding animal health applications, "location" is intended to mean the habitat, feeding area, region, material, or environment in which parasites grow or may grow, excluding those inside or outside the animal.

[0285] In another embodiment, this specification provides methods and uses for using compounds to control pests in plants and crops or to protect wood-containing structures.

[0286] In some embodiments, the treatable animal is a mammal, including but not limited to humans, cats, dogs, cattle, chickens, cattle, bison, deer, goats, horses, llamas, camels, pigs, sheep, and yaks. In one embodiment of this specification, the mammal being treated is a human, cat, or dog.

[0287] In one embodiment of this specification, compounds of formula (I) have been found to have superior efficacy against in vivo parasites that are resistant to macrolide-like active agents. In one embodiment, the compounds and compositions of this specification effectively control Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in a mammal or bird.

[0288] In another embodiment, the specification provides a method of treating or preventing parasitic infestation or infection in an animal comprising administering to an animal in need an effective amount of an anthelmintic compound of this specification and an effective amount of an activator of the invertebrate GABA receptor (including avermectin or milbemycin).

[0289] In another embodiment, the invention provides the use of compounds of formula (I) in the manufacture of agents for the treatment or prevention of parasitic infestation or infection in animals. In yet another embodiment, the invention provides a compound of formula (I) which is used to treat or prevent parasitic infection or infestation of an animal.

[0290] Avermectins that may be used in combination with the compounds of this specification include, but are not limited to, abamectin, dimadectin, doracectin, emamectin, epectin, ivermectin, latidectin, lepimectin and ectin. Milbemycins that may be used in combination with the compounds of this specification include, but are not limited to, milbemectin, milbemectin D, moxictin, and nemectin. The 5-sideoxy and 5-oxime derivatives of those avermectin and milbemycin are also included.

[0291] In one embodiment, the compounds and compositions of this specification may be used to treat and / or prevent endoparasitic infections with the following parasites: Anaplocephala, hookworms, nematodes, roundworms, Brugia, Bunostomum, capillary nematodes, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, and intestinal nematodes. Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Ascaris, Trichodina, Whipworm, Triodontophorus, Uncinaria, Wuchereria and their combinations.

[0292] In one particularly preferable embodiment of this specification, the compounds and compositions of this specification are used for the treatment and / or prevention of infection by canine falciparum. The compounds have been found to be highly effective against canine malignant silkworm microfilariae and L4 larvae. Therefore, these compounds can be used to protect animals from the development of heartworm disease, which proceeds by killing the immature stage of Canine M. canis before it can develop into adults. In one embodiment, the compounds and compositions comprising such compounds may be used to prevent the development of heartworm disease, which is performed by killing filarial worms in immature stages that are resistant to macrolides. In another embodiment, the compounds and compositions of this specification are used to treat and / or prevent infection by creeping F. larvae or H. cerevisiae.

[0293] In another embodiment of this specification, the parasites are Trichostrongylus axei, Trichostrongylus axei, Trichostrongylus axei, Cooperia curticei, Nematodirus battus, and combinations thereof.

[0294] In another embodiment for use against in vivo parasites and for treatment against in vitro parasites when combined with an in vitro parasitic agent, the in vitro parasites are one or more insects or spiders, including those insects or spiders of the following genera: Ctenocephalides, fanhead Rhipicephalus, Dermacentor, Ixodes, Boophilus, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Hypoderma. Damalinia), Linognathus, Haematopinus, Solenoptes, Trichodectes and Felicola.

[0295] In another embodiment for treating ectoparasites, the ectoparasites are from the genera *Ctenopharynx*, *Ixodes*, *Ixodes*, *Ixodes*, and / or *Ixodes*. The ectoparasites being treated include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, bluebottle flies, and combinations thereof. Examples include, but are not limited to, fleas (Ctenopharynx catenella, Ctenopharynx genus and analogues), ticks (Ixodes genus, Ixodes genus, Ixodes genus, Ixodes genus and analogues) and mites (Demodex spp., Sarcoptes genus, Otosclerosis genus and analogues), lice (Cheyletiella spp., Cheyletiella genus and analogues), mosquitoes (Aedes spp., Culex spp., Anopheles spp. and analogues), and flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp. and analogues). In yet another embodiment for treating ectoparasites, the ectoparasites are fleas and / or ticks.

[0296] Additional examples of ectoparasites include, but are not limited to, ticks of the genus *Ix*, particularly species *Ixodes microtyle* (cattle tick), *Ixodes leucocephala*, and *Ixodes annularis*; myiasis, such as human blowflies (known as Berne in Brazil) and *Cochliomyia hominivorax* (blower flies); sheep myiasis, such as *Lucilia sericata* and *Lucilia cuprina* (known as bluebottle fly impact in Australia, New Zealand, and South Africa). Appropriate flies, i.e., flies whose adults constitute parasites, such as *Haematobia irritans* (hornflies); lice, such as the cattle long-mouthed louse; and mites, such as *Sarcoptes scabiei* and *Psoroptes ovis*. The above list is not exhaustive, and other ectoparasites known in this art to be harmful to animals and humans include, for example, migrating biwing larvae.

[0297] In another embodiment of this specification, the compounds and compositions of this specification are suitable for controlling pests, such as insects selected from the group consisting of: German cockroach (Blatella germanica), American tobacco leaf moth (Heliothis virescens), potato beetle (Leptinotarsa ​​decemlineata), pavement ant (Tetramorium caespitum), and combinations thereof.

[0298] Plant-parasitic nematodes include, for example, genera such as *Anguina* spp., *Aphelenchoides* spp., *Belonoaimus* spp., *Bursaphelenchus* spp., *Ditylenchus dipsaci*, *Globodera* spp., *Heliocotylenchus* spp., *Heterodera* spp., *Longidorus* spp., *Meloidogyne* spp., *Pratylenchus* spp., *Radiopholus similis*, *Rotylenchus* spp., *Trichodorus* spp., and *Tylenchorhynchus*. The genera *Tylenchulus* spp., *Tylenchulus semipenetrans*, and *Xiphinema* spp. are mentioned.

[0299] In addition, this specification may also be used to treat other pests, including but not limited to the following, in the presence or absence of other insecticides added to the composition: (1) From the order Isopoda, such as the comb beetle (Oniscus asellus), the leaf beetle (Armadillidium vulgare), and the woodlice (Porcellio scaber); (2) From the class Diplopoda, for example, Blaniulus guttulatus; (3) From the class Chilopoda, such as the centipede *Geophilus carpophagus* and the centipede genus *Scutigera* spp.; (4) From the class Symphyla, for example, the white pine worm (Scutigerella immaculata); (5) From the order Thysanura, such as silverfish (Lepisma saccharina); (6) From the order Collembola, such as Onychiurus armatus; (7) From the order Blattaria, such as the Oriental cockroach (Blatta orientalis), the American cockroach (Periplaneta americana), the Madeira cockroach (Leucophaea maderae), and the German cockroach; (8) From the order Hymenoptera, such as the genera *Diprion*, *Hoplocampa*, *Lasius*, *Monomorium pharaonis*, and *Vespa*. (9) From the order Siphonaptera, such as the rat flea (Xenopsylla cheopis) and the genus Ceratophyllus spp.; (10) From the order Anoplura (Phthiraptera), such as the genera *Damalinia* spp., *Haematopinus* spp., *Linognathus* spp., *Pediculus* spp., and *Trichodectes* spp.; (11) From the class Arachnida, such as the rough-legged white mite (Acarus siro), citrus leaf tick (Aceria sheldoni), *Aculops* spp., *Aculus* spp., *Achilliformis*, *Argas* spp., *Cattle tick*, *Brevipalpus* spp., *Bryobia praetiosa*, *Dermanyssus gallinae*, *Eotetranychus* spp., *Epitrimerus pyri*, *Eutetranychus* spp., *Eriophyes* spp., *Hemitarsonemus* spp., *Hypertricis*, *Hypertricis*, and *Latrodectus*. *Mactans*, *Metatetranychus* spp., *Oligonychus* spp., *Ornithodoros* spp., *Panonychus* spp., *Phyllocoptruta oleivora*, *Polyphagotarsonemus latus*, *Oligonychus*, *Rhizoglyphus* spp., *Scabies*, *Scorpio maurus*, *Stenotarsonemus* spp., *Tarsonemus* spp., *Tetranychus* spp., *Vasates lycopersici*; (12) From the class Bivalva, for example, the genus *Dreissena*; (13) From the order Coleoptera, such as the bean weevil (Acanthoscelides obtectus), the genus *Adoretus*, the alder leaf beetle (Agelastica alni), the genus *Agriotes*, the potato horned beetle (Amphimallon solstitialis), the fine-spotted cricket beetle (Anobium punctatum), the genus *Anoplophora*, the genus *Anthonomus*, the genus *Anthrenus*, the genus *Apogonia*, the genus *Atomaria*, the genus *Attagenus*, the genus *Bruchidius obtectus*, the genus *Bruchus*, the genus *Ceuthorhynchus*, and the swan beetle (Cleonus). The genera *Mendicus*, *Conoderus* spp., *Cosmopolites* spp., *Costelytra zealandica*, *Curculio* spp., *Cryptorhynchus lapathi*, *Dermestes* spp., *Diabrotica* spp., *Epilachna* spp., *Faustinus cubae*, *Gibbium psylloides*, *Heteronychus arator*, *Hylamorpha elegans*, *Hylotrupes bajulus*, *Hypera postica*, *Hypothenemus* spp., and *Lachnosterna* are mentioned. The following are genera of beetles: *Consanguinea*, *Leptinotarsa ​​decemlineata*, *Lissorhoptrus oryzophilus*, *Lixus spp.*, *Lyctus spp.*, *Meligethes aeneus*, *Melolontha*, *Migdolus spp.*, and *Monochamus spp.*.The following are listed: Yellow-striped white-edged beetle (Naupactus xanthographus), yellow spider beetle (Niptus hololeucus), coconut beetle (Oryctes rhinoceros), saw-toothed grain beetle (Oryzaephilus surinamensis), black grape ear weevil (Otiorrhynchus sulcatus), small blue-flowered beetle (Oxycetonia jucunda), horseradish leaf beetle (Phaedon cochleariae), leaf-eating gill beetle (Phyllophaga spp.), Japanese golden beetle (Popillia japonica), weevil (Premnotrypes pp.), rapeseed golden-headed flea beetle (Psylliodes chrysocephala), spider beetle (Ptinus spp.), dark ladybug (Rhizobius ventralis), grain beetle (Rhizopertha dominica), grain weevil (Sitophilus). spp.), *Sphenophorus* spp., *Sternechus* spp., *Symphyletes* spp., *Tenebrio molitor*, *Tribolium* spp., *Trogoderma* spp., *Tychius* spp., *Xylotrechus* spp., *Zabrus* spp.; . (14) From the order Diptera, such as the genera *Aedes*, *Anopheles*, *Bibio hortulanus*, *Calliphora erythrocephala*, *Ceratitis capitata*, *Chrysomyia* spp., *Cochliomyia* spp., *Cordylobia anthropophaga*, *Culex*, *Cuterebra* spp., *Dacus oleae*, *Dermatobia hominis*, *Drosophila* spp., *Fannia* spp., *Gastrophilus* spp., *Hylemyia* spp., *Hyppobosca* spp., *Hypoderma* spp., and *Liriomyza*. spp.), *Lucilia* spp., *Musca* spp., *Nezara* spp., *Oestrus* spp., *Oscinella frit*, *Pegomyia hyoscyami*, *Phorbia* spp., *Stomoxys* spp., *Tabanus* spp., *Tannia* spp., *Tipula paludosa*, *Wohlfahrtia* spp.; (15) From the class Gastropoda, such as the genera *Arion*, *Biomphalaria*, *Bulinus*, *Deroceras*, *Galba*, *Lymnaea*, *Oncomelania*, and *Succinea*. (16) From the class Helminthia, such as *Ancylostoma duodenale*, *Ancylostoma ceylanicum*, *Ancylostoma braziliensis*, *Ancylostoma* spp., *Ascaris lubricoides*, *Ascaris* spp., *Brugia malayi*, *Brugia timori*, *Bunostomum* spp., *Chabertia* spp., *Clonorchis* spp., *Cooperia* spp., *Dicrocoelium* spp., *Dictyocaulus filaria*, and *Diphyllobothrium*. *Echinococcus granulosus*, *Echinococcus multilocularis*, *Enterobius vermicularis*, *Faciola* spp., *Haemonchus* spp., *Heterakis* spp., *Hymenolepis nana*, *Hyostrongulus* spp., *Loa*, *Nematodirus* spp., *Oesophagostomum* spp., *Opisthorchis* spp., *Onchocerca volvulus*, *Ostertagia* The genera *Paragonimus* spp., *Schistosomen* spp., *Strongyloides fuelleborni*, *Strongyloides stercoralis*, and *Strongyloides spp.*), Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), Trichinella spiralis (trichinella spiralis), Trichinella nativa (native trichinella), Trichinella britovi (bristly trichinella), Trichinella nelsoni (southern trichinella), Trichinella pseudopsiralis (false trichinella), Trichostrongulus spp. (trichostrongulus spp.), Trichuris trichuria (trichuris trichuria), Wuchereria bancrofti (Wuchereria bancrofti); . (17) From the order Heteroptera, such as the pumpkin-footed bug (Anasa tristis), the genera *Antestiopsis*, *Blissus*, *Calocoris*, *Campylomma livida*, *Cavelerius*, *Cimex*, *Creontiades dilutus*, the pepper-footed bug (Dasynus piperis), the fork-tailed bug (Dichelops furcatus), the thick-necked lace bug (Diconocoris hewetti), the red cotton bug (Dysdercus), the American bug (Euschistus), and the flat-skinned bug (Eurygaster). spp.), Heliopeltis spp., Horcias nobilellus, Leptocorisa spp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae, Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp., Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergella *Singularis*, *Scotinophora* spp., *Stephanitis nashi*, *Tibraca* spp., and *Triatoma* spp.; (18) From the order Homoptera, such as the genera *Acyrthosipon*, *Aeneolamia*, *Agonoscena*, *Aleurodes*, *Aleurolobus barodensis*, *Aleurothrixus*, *Amrasca*, *Anuraphis cardui*, *Aonidiella*, *Aphanostigma piri*, *Aphis*, *Arboridia apicalis*, *Aspidiella*, *Aspidiotus*, and *Atanus*. spp.), Potato aphid (Aulacorthum solani), Whitefly (Bemisia spp.), Plum short-tailed aphid (Brachycaudus helichrysii), Microtubule aphid (Brachycolus spp.), Cabbage aphid (Brevicoryne brassicae), Brown rice flyhopper (Calligypona marginata), Red-headed leafhopper (Carneocephala fulgida), Sugarcane white horned aphid (Ceratovacuna lanigera), Cercopidae, Wax scale (Ceroplastes spp.), Strawberry nail aphid (Chaetosiphon fragaefolii), Sugarcane yellow snow shield scale (Chionaspis tegalensis), Tea green leafhopper (Chlorita onukii), Walnut black-spotted aphid (Chromaphis juglandicola), Black brown round shield scale (Chrysomphalus ficus), Corn leafhopper (Cicadulina) *Coccomytilus halli*, *Coccus* spp., *Cryptomyzus ribis*, *Dalbulus* spp., *Dialeurodes* spp., *Diaphorina* spp., *Diaspis* spp., *Doralis*, *Drosicha* spp., *Dysaphis* spp., and *Dysmicoccus* spp.The genera *Empoasca* spp., *Eriosoma* spp., *Erythroneura* spp., *Euscelis bilobatus*, *Geococcus coffeae*, *Homalodisca coagulata*, *Hyalopterus arundinis*, *Icerya* spp., *Idiocerus* spp., *Idioscopus* spp., *Laodelphax striatellus*, *Lecanium* spp., *Lepidosaphes* spp., *Lipaphis erysimi*, *Macrosiphum* spp., and *Mahanarva* are mentioned. The following aphids are listed: *Fimbriolata*, *Melanaphis sacchari*, *Metcalfiella*, *Metopolophium dirhodum*, *Monellia costalis*, *Monelliopsis pecanis*, *Myzus* spp., *Nasonovia ribisnigri*, *Nephotettix* spp., *Nilaparvata lugens*, *Oncometopia*, *Orthezia praelonga*, *Parabemisia myricae*, *Paratrioza* spp., *Parlatoria* spp., *Pemphigus* spp., *Peregrinus maidis*, and *Phenacoccus*. spp.), Phloeomyzus passerinii, Phrodon humuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp., Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp.The genera *Psylla*, *Pteromalus*, *Pyrilla*, *Quadraspidiotus*, *Quesada gigas*, *Rastrococcus*, *Rhopalosiphum*, *Saissetia*, *Scaphoides titanus*, *Schizaphis graminum*, *Selenaspidus articulatus*, *Sogata*, *Sogatella furcifera*, *Sogatodes*, *Stictocephala festina*, *Tenalaphara malayensis*, and *Tinocallis* are mentioned. The genera *Caryaefoliae*, *Tomaspis* spp., *Toxoptera* spp., *Trialeurodes vaporariorum*, *Trioza* spp., *Typhlocyba* spp., *Unaspis* spp., and *Viteus vitifolii* are mentioned. (19) From the order Isoptera, such as the genera *Reticulitermes* and *Odontotermes*; (20) From Lepidoptera, such as Acronicta major, Aedia leucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp., Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., and Earias The following are listed: * *Ephestia kuehniella*, *Euproctis chrysorrhoea*, *Euxoa* spp., *Feltia* spp., *Galleria mellonella*, *Helicoverpa* spp., *Heliothis* sspp., *Hofmannophila pseudospretella*, *Homona magnanima*, *Hyponomeuta padella*, *Laphygma* spp., *Lithocolletis blancardella*, *Lithophane antennata*, *Loxagrotis albicosta*, *Lymantria* spp., *Malacosoma neustria*, and *Mamestra*. (Brassicae), Rice hairy tibiae moth (Mocis repanda), Armyworm (Mythimna separata), and Oria spp.Rice leaf beetle (Oulema oryzae), small-eyed armyworm (Panolis flammea), red bollworm (Pectinophora gossypiella), citrus leafminer (Phyllocnistis citrella), cabbage white butterfly (Pieris spp.), diamondback moth (Plutella xylostella), beet armyworm (Prodenia spp.), armyworm (Pseudaletia spp.), soybean armyworm (Pseudoplusia includens), corn borer (Pyrausta nubilalis), gray-winged armyworm (Spodoptera spp.), bean armyworm (Thermesia gemmatalis), bagworm (Tinea pellionella), awnworm (Tineola bisselliella), oak green leafroller (Tortrix viridana), and white armyworm (Trichoplusia spp.). (21) From the order Orthoptera, such as the domestic cricket (Acheta domesticus), the Oriental cockroach, the German cockroach, the mole cricket (Gryllotalpa spp.), the Madeira cockroach, the migratory locust (Locusta spp.), the black locust (Melanoplus spp.), the American cockroach, and the desert locust (Schistocerca gregaria.); (22) From the order Thysanoptera, such as rice thrips (Baliothrips biformis), yellow thrips (Enneothrips flavens), flower thrips (Frankliniella spp.), netted thrips (Heliothrips spp.), greenhouse hedge thrips (Hercinothrips femoralis), carded thrips (Kakothrips spp.), grape thrips (Rhipiphorothrips cruentatus), hard thrips (Scirtothrips spp.), banded thrips (Taeniothrips cardamoni), and thrips (Thrips spp.); (23) From the class Protozoa, such as the genus Eimeria spp.

[0300] In each of the embodiments described herein, the compounds and compositions described herein may be applied to a single pest or a combination thereof.

[0301] [ ] [Mixture with other surfactants] [ ] In another embodiment, the composition comprising the compound of formula (I) may also include other veterinary therapeutic agents. Veterinary pharmaceutical agents that may be included in the compositions described herein are well known in the art (see, for example, Plumb's Veterinary Drug Handbook, 5th edition, edited by Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9th edition, (January 2005)), and include, but are not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, and albendazole sulfate. sulfate), alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline / theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, clavulanate potassium, amphotericin B desoxycholate, amphotericin B lipid-based, ampicillin, amprolium, antacids (oral).(oral), antivenin, apomorphine, apramycin sulfate, ascorbic acid, asparaginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbituates, benazepril, betamethasone, ammonium chloride, bisacodyl, bismuth subsalicylate, bleomycin sulfate sulfate), boldenone undecylenate, bromide, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium sodium), cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodiumsodium, ceftiofur, ceftriaxone sodium, cephalexin, cephalosporins, cephalexin, activated carbon, chloramphenicol, chlordiazepoxide, chlordiazepoxide + / - clidinium bromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine, chlorpropamide, tetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate. fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium, dipotassium clozapine, clorsulon, cloxacillin, codeine phosphate, colchicine, ACTH, cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, actinomycin D / actinomycin E, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, desoxycorticosteronepivalate, detomidine, dexamethasone, dexpantol, dexraazoxane, polydextrose, diazepam, diazepam (oral), sulfadiazine, sodium diclofenac, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimethylpropanol / BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylolamine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doxapram, doxepin, doxorubicin, doxycycline, sodium calcium EDTA, edrophonium chloride, enalapril / enalaprilat, enoxaparin Sodium, enrofloxacin, ephedrine sulfate, adrenaline, epoetin / erythropoietin, irimonin, epsiprantel, erythromycin, esmolol, estradiol cyclopentadiene, ethacrynic acid / sodium ethacrynic acid, ethanol, sodium etidronateSodium, etodolac, etomidate, pentobarbital-containing euthanasia agents, famotidine, fatty acids (essential fatty acids / ω-fatty acids), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, 5-FU, fluoxetine, fluticasone propionate, fluvoxamine maleate), mepiazole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoids, glucosamine / chondroitin sulfate, glutamic acid, glyburide, glycerol (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, polyglutaraldehyde hemoglobin-200 (OXYGLOBIN®), Heparin, Hydroxyethyl Starch, Sodium Hyaluronate, Hydrazine, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydromorphone, Hydroxyurea, Hydroxyzine, Ifosfamide, Imidacloprid, Imidocaloate, Impenetramide-Cilastatin Sodium, Imidacloprid, Inamrinone Lactate, Insulin, Interferon Alpha-2a(Human Recombinant), Iodides (Sodium Iodide / Potassium Iodide), Ipecain (Syrup), Sodium Iopoise, Iron Dextran, Isoflurane, Isoproterenol, Isotretinoin, Isoxsuprine, Itraconazole, Ivermectin, Kaolin / Pectin, Ketamine, Ketoconazole, Ketoprofen, Ketoprofen, Lactulose, Leuprolide, Levamisole, Levetiracetam, Levothyroxine Sodium, Lidocaine, Lincomycin, Liothyronine Sodium, Lisinopril, Lomustine (CCNU), Lufenuron, Lysine, Magnesium, Mannitol, Marbofloxacin, Mechlorethamine, Meclizine, Meclofenamic Acid, Medetomidine, Medium-Chain Triglycerides, Medroxyprogesterone Acetate, Medroxyprogesterone Acetate, Melasmamine, Melatonin, Meloxican, Melphalan, Meperidine, Mercaptopurine, Meropenem, Metformin, Methadone, Methazolamide, Methenamine Mandelate / Hippurate, Methimazole, Methionine, Methocarbamol, Methohexyl Sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam milbemycin oximeoxime), mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic (opium) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine, novobiocin sodium, nystatin, octreotide. Acetate), olsalazine sodium, omeprazole, ondansetron, opioid antidiarrheal drugs, orbifloxacin, oxacillin sodium, oxazepam, oxxibutynin chloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillin, general information penicillin, penicillin G, penicillin V potassium, pentazocin, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate mesylate, phenobarbital, phenoxybenzamine, pheylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodiumSodium, pheromones, non-enterogonal phosphates, phytonabinone / vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysaccharide sulfate, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, Propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic gel Hydrophilic mucilloid, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, S-adenosylmethionine (SAMe), saline / hyperosmolar laxatives, selamectin, selegiline / l-deprenyl hydrochloride, sertraline, sevelamer, sevoflurane, silymarin / milk thistle Thistle), sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate, growth promoter (somatotropin), sotalol, spectinomycin, spironolactone, stanozolol, streptococcal kinase, streptozocin, succimer, succinylcholine chloride, sucralfate, sufentanil citrate.citrate, sodium sulfadiazine, trimethoprim, trimethoprim, sulfadimentoxine, ormetoprim, sulfasalazine, taurine, tepoxaline, terbinafine, terbutaline sulfate, testosterone, tetracycline, sodium thioacetamide, thiamine, thioguanine, thiopental sodium, thiotepa, thyroid-stimulating hormone, tiamulin, ticarcilin disodium Disodium, Tiletamine / Zolazepam, Tilmocsin, Tiopronin, Tobramycin Sulfate, Tocainide, Tolazoline, Telfenamic Acid, Topiramate, Tramadol, Trimcinolone Acetonide, Trientine, Trilostane, Trimepraxine Tartrate (containing nylon), Tripelennamine, Tylosin, Urdosiol, Valproic Acid, 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.

[0302] In one embodiment of this specification, an arylpyrazole compound, such as phenylpyrazole, may be included in the veterinary compositions of this specification. Arylpyrazoles are known in the art and are suitable for combination with compounds 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. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954; 6,998,131 and 7,759,381 (all of which are incorporated herein by reference). A preferred arylpyrazole active agent is fipronil.

[0303] In another embodiment of this specification, one or more macrocyclic lactones, insect repellents, and / or insecticides acting as acaricides may be included in the compositions described herein in combination with the compounds. For the avoidance of doubt, the term "macrocyclic lactone" as used herein includes naturally occurring and synthetic or semi-synthetic compounds such as avermectin and milbemycin.

[0304] Macrocyclic lactones that can be used in the compositions described herein include, but are not limited to, naturally occurring avermectins (e.g., components named A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b) and milbemycin compounds, semi-synthetic avermectins and milbemycin, avermectin monosaccharide compounds, and avermectin glycoside compounds. Examples of macrocyclic lactone compounds that can be used in the compositions include, but are not limited to, abamectin, dimethoprim, doratocin, irimethin, ivermectin, latimectin, linpimethin, silatocin, ML-1,694,554, and milbemycins including, but not limited to, milbemycin, milbemycin D, milbemycin A3, milbemycin A4, milbemycin oxime, moxifloxacin, and nimoxetine. Also included are the 5-side oxygen and 5-oxime derivatives of these avermectins and milbemycins.

[0305] Macrocyclic lactones are known in this art and can be readily obtained commercially or through synthetic techniques known in this art. Refer to widely available technical and commercial literature. For avermectin, ivermectin, and abamectin, see, for example, works such as "Ivermectin and Abamectin," 1989, MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag, or Albers-Schönberg et al. (1981), "Avermectins Structure Determination," J. Am. Chem. Soc., 103, 4216-4221. For doraxetine, consult "Veterinary Parasitology," Vol. 49, No. 1, July 1993, 5-15. For information on milbemycins, see in particular Davies HG et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121; Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336; U.S. Patent Nos. 4,134,973 and EP 0 677 054, all of which are incorporated herein by reference.

[0306] Avermectin and milbemycin have closely related structures, for example, by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectin is disclosed in U.S. Patent No. 4,310,519, and the 22,23-dihydroavermectin compound is disclosed in U.S. Patent No. 4,199,569. References are also made in particular to U.S. Patent Nos. 4,468,390, 5,824,653, EP 0007 812 A1, British Patent Specification 1,390,336, EP 0002 916, and New Zealand Patent No. 237,086. Naturally occurring milbemycin is described in U.S. Patent No. 3,950,360 and in various references cited in The Merck Index, 12th edition, ed. S. Budavari, Merck & Co., Inc., Whitehouse Station, New Jersey (1996). Latimycin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, Vol. 17, No. 4, pp. 263-286, (2003). Semi-synthetic derivatives of these types of compounds are well known in the art and described, for example, in U.S. Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148 and EP 0 667 054, all of which are incorporated herein by reference.

[0307] In one embodiment, the veterinary composition of this specification comprises an effective amount of at least one of, or a combination thereof, abamectin, dimethoprim, dralakine, inmethoprim, irimonin, ivermectin, latimexin, linpimethoprim, slakine, mirbemycin D, mirbemycin A3, mirbemycin A4, mirbemycin oxime, moxifloxacin, or nimoxetine. In another embodiment, this specification provides a veterinary composition comprising an effective amount of at least one of, or a combination thereof, abamectin, irimonin, ivermectin, dralakine, or slakine. In yet another embodiment, the veterinary composition of this specification comprises an effective amount of at least one of, or a combination thereof, ivermectin, mirbemycin oxime, or moxifloxacin.

[0308] In another embodiment of this specification, a composition is provided comprising a compound of formula (I) and a combination of an acaricide or insecticide known as an insect growth regulator (IGR). Compounds belonging to this group are well known to physicians and represent a wide range of different chemical classes. These compounds all work by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022, or UK 2 140 010, and U.S. Patent Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).

[0309] In one embodiment, the compositions of this specification may include mimicking juvenile hormones in insects or IGR compounds that regulate juvenile hormone levels. Examples of juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2-(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridinylmethoxy)pyridyl-3(2H)-one. In another embodiment, the compositions of this specification comprise a combination of a compound of formula (I) with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier.

[0310] In another embodiment, the composition of this specification includes an IGR compound as a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumuron, 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.

[0311] In some embodiments, the compositions described herein may include one or more nematicides, including but not limited to benzimidazole, imidazothiazole, tetrahydropyrimidine, and active agents in organophosphate compounds. In some embodiments, the following benzimidazoles may be included in the composition: thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, doxycycline, and their o,o-dimethyl analogues.

[0312] In other embodiments, the compositions described herein may include imidazothiazole compounds, including but not limited to tetraimidazole, levamisole, and butamisole.

[0313] In other embodiments, the compositions described herein may include tetrahydropyrimidine activators, including but not limited to pyrantel, oxantel, and morantel.

[0314] Suitable organophosphate surfactants include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos, dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

[0315] In other embodiments, the composition may include the nematode-resistant compound phenanthrene; phenanthrene in neutral form and in various salt forms; diethylcarbamate; phenol, such as diiodonitrophenol; arsenic agents, such as arsenopyridine; ethanolamines, such as acetylphenol, chanyl chlorobenzenesulfonate, and methyridine; anthocyanin dyes, including pyrvinium chloride, pyrvinium bis(hydroxynaphthyl)-methyl, and dithiazanine iodide; isothiocyanates, including bitoscanate, suramin sodium, and phthalofyne; and various natural products, including but not limited to hygromycin B, santonin, and kainic acid.

[0316] In other embodiments, the compositions of this specification may include an anticor. Suitable anticoric agents include, but are not limited to, miracil, such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives; oltipraz, thioanthrone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil; and various bisphenol compounds known in the art, including hexachlorophenol and thiobis(dichlorophenoxy)pyridine. Phenols, thiobis(dichlorophenol) sulfoxide and binitrochlorophenol; various salicylaniline compounds, including tribromsalan, oxyclozanide, clioxanide, rafoxanide, nitrohydroxyiodobenzyl nitrile, brotianide, bromoxanide and closantel; trichlorobenzyl sulfadiazine, diamfenetide, clorsulon, hetolin and emetine.

[0317] Anti-tachycephalosporin compounds may also be advantageously used in the compositions described herein, including but not limited to various salt forms of arecoline, bunamidine, niclosamide, nitroscanate, paromomycin, paromomycin II, praziquantel, and epsiprantel.

[0318] In other embodiments, the compositions of this specification may include other active agents effective against arthropod parasites. Suitable surfactants include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxydichlorodiphenyltrichloroethane, toxaphene, bromothion, bromothion-ethyl, trithion, chlorpyrifos, chlorpyrifos, cythioate, diazinon, dichlorenthion, diemthoate, ethion, famur, fenitrothion, fenthion, fospirate, iodofenphos, malathion, dibromophos, phosalone, phosmet, phoxim, pyrethrum, ronnel, stirofos, pyrethrin, and cyprodinil. halothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin, pyrethrin, resmethrin, benzoyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isoborneol thiocyanate, mesopran, monosulfiram, p-ethylhexyl benzoate Pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate, and compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofuran carbaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methylbridged-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326), and 2-(octylthio)ethanol (MGK-874).

[0319] In another embodiment, the antiparasitic agent that may be included in the veterinary composition containing the compound of formula (I) may be a biologically active peptide or protein, including but not limited to ester peptides other than the compound. Such antiparasitic agents include PF1022A or analogues thereof and emodepside. Other cyclic ester peptide compounds that may be included in the composition containing the compound of formula (I) are those described in WO 2016 / 187534 A1 and WO 2017 / 116702 A1, both of which are incorporated herein by reference. These compounds act at the neuromuscular joint by stimulating presynaptic receptors belonging to the enterotrione receptor family, leading to paralysis and death of the parasite. In one embodiment of the ester peptide, the ester peptide is emodepside (see Wilson et al., Parasitology, January 2003, 126(Part 1):79-86).

[0320] In another embodiment, the compositions of this specification may comprise an active agent derived from a neonicotinoid insecticide. Neonicotinoid analogs bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, a neonicotinoid insecticide that can be combined with the compound of formula (I) in the compositions of this specification is imidacloprid. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or EP 0 892 060 (both incorporated herein by reference). In another embodiment, the compositions of this specification may comprise nitenpyram, another active agent of a neonicotinoid insecticide. The use of nitenpyram for the control of fleas is described in U.S. Patent No. 5,750,548, which is incorporated herein by reference in its entirety.

[0321] In some other embodiments of this specification, compounds of formula (I) that can be combined with the compositions of this specification are semicarbazones, such as metaflumizone.

[0322] In another embodiment, the compositions of this specification may advantageously include one or more isofazoline compounds known in the art. Isofazoline active agents are highly effective against a variety of ectoparasites, and combination with compounds of formula (I) will extend the scope of efficacy against such parasites. Particularly suitable isofazoline active agents that can be combined with the compounds include afoxolaner (including the substantially pure active enantiomer esafoxolaner), sarolaner, fluralaner (including the substantially pure active enantiomer), lotilaner, and tigolaner. These active agents are described in the following documents: US 7,964,204, US 2010 / 0254960 A1, US2011 / 0159107, US2012 / 0309620, US2012 / 0030841, US2010 / 0069247, WO 2007 / 125984, WO 2012 / 086462, US 8318757, US 8466115, US 8618126, US 8822466, US 8383659, US 8853186, US 9221835, US 2011 / 0144349, US 8,053,452; US 2010 / 0137612, US 8410153, US 2011 / 152081, WO 2012 / 089623, WO 2012 / 089622, US 8,119,671; US ​​7,947,715;WO 2102 / 120135, WO 2012 / 107533, WO 2011 / 157748, US 2011 / 0245274, US 2011 / 0245239, US 2012 / 0232026, US 2012 / 0077765, US 2012 / 0035122, US 2011 / 0251247, WO 2011 / 154433, WO 2011 / 154434, US 2012 / 0238517, US 2011 / 0166193, WO 2011 / 104088, WO 2011 / 104087, WO 2011 / 104089、US 2012 / 015946, US 2009 / 0143410, WO 2007 / 123855 A2, US 2011 / 0118212, US 7951828 & US 7662972, US 2010 / 0137372 A1, US 2010 / 0179194 A2, US 2011 / 0086886 A2, US 2011 / 0059988 A1, US 2010 / 0179195 A1, US 2015 / 0126523, WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236、WO The following patents are incorporated herein by reference in their entirety: 2017 / 147352, US 7897630, US 7951828, WO 2020 / 007704 A1, WO 2021 / 028479 A1, WO 2014 / 122083 A1, WO 2016 / 177619 A1, WO 2014 / 012975 A1, WO 2015 / 078846 A1, WO 2015 / 078847 A1, WO 2015 / 150302 A1, WO 2015 / 181139 A1, and WO 2016 / 026789 A1.

[0323] In another embodiment of this specification, nodoricklic acid and its derivatives may be added to the composition of this specification. These compounds are used to treat or prevent infections in humans and animals and are described in, for example, U.S. Patents 5,399,582, 5,962,499, 6,221,894, and 6,399,786, all of which are incorporated herein by reference in their entirety. The composition may include one or more nodoricklic acid derivatives known in the art, including all stereoisomers such as those described in the cited documents.

[0324] In another embodiment, an aminoacetonitrile anthelmintic (AAD) compound, such as monepantel (ZOLVIX) and its analogues, may be added to the composition of this specification. Such compounds are described, for example, in Ducrey et al., US 7,084,280 (incorporated herein by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature Vol. 452, March 13, 2008, 176-181.

[0325] The compositions described herein may also include arylazole-2-ylcyanoethylamine compounds, such as those described in U.S. Patent No. 8,088,801 to Soll et al. (which is incorporated herein by reference) and their thioamide derivatives (as described in U.S. Patent No. 7,964,621, which is also incorporated herein by reference). Arylazole-2-ylcyanoethylamine active agents acting systemically on endoparasites may be used in combination with the compounds in the veterinary compositions described herein.

[0326] The compositions described herein may also include paraherquamide compounds and derivatives thereof, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Paraherquamide family compounds are a known class of compounds, including spirodioxanindole cores with activity against certain parasites (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380 and J. Antibiotics 1991, 44, 492). Additionally, structurally related compounds of the marcfortine family (such as marcfortine AC) are known and can be combined with the compositions described herein (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to paramid derivatives can be found, for example, WO 91 / 09961, WO 92 / 22555, WO 97 / 03988, WO 01 / 076370, WO 09 / 004432 and US 2010 / 0197624, U.S. Patent 5,703,078 and U.S. Patent 5,750,695, all of which are incorporated herein by reference in their entirety.

[0327] In another embodiment of this specification, the composition may include a spinosynthetic agent produced by the soil actinomycete *Saccharopolyspora spinosa* (see, for example, Salgado VL and Sparks TC, "The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance", Comprehensive Molecular Insect Science, Vol. 6, pp. 137-173, 2005) or a semi-synthetic spinosynthetic agent. Spinosynthetic agents are commonly 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 one or a combination of these components may be used in the compositions of this specification. Spinosad compounds can be 5,6,5-tricyclic systems, fused with 12-membered macrocyclic lactones, neutral sugars (rhamnose), and amino sugars (forosamine). These and other natural spinosad compounds (including 21-butenyl spinosad produced by *Saccharopolyspora pagona*) that can be used in the compositions described herein can be produced by fermentation using conventional techniques known in this art. Other spinosad compounds that can be used in the compositions described herein are disclosed in U.S. Patent Nos. 5,496,931, 5,670,364, 5,591,606, 5,571,901, 5,202,242, 5,767,253, 5,840,861, 5,670,486, 5,631,155, and 6,001,981, all of which are incorporated herein by reference in their entirety. Spinosad compounds may include, but are not limited to, spinosad A, spinosad D, spinosad, spintoram, or combinations thereof. Spinosad is a combination of spinosad A and spinosad D, and Spintolan is a combination of 3'-ethoxy-5,6-dihydro spinosad J and 3'-ethoxy spinosad L.

[0328] Generally, other active agents (besides the compounds of formula (I) described above) are included in the dosage units of this specification in amounts between about 0.1 μg and about 1000 mg. Typically, the active agent may be included in amounts between about 10 μg and about 500 mg, about 10 μg and about 400 mg, about 1 mg and about 300 mg, about 10 mg and about 200 mg, or about 10 mg and about 100 mg. More typically, additional active agents will be present in the compositions of this specification in amounts between about 5 mg and about 50 mg.

[0329] Depending on the potency of the surfactant, the concentration of other surfactants in the compositions described herein will typically be from about 0.01% to about 30% (w / w). In some embodiments with extremely potent surfactants, including but not limited to macrocyclic lactone surfactants, the concentration of the surfactant will typically be from about 0.01% to about 10% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.5% (w / w), from about 0.1% to about 0.5% (w / w), or from about 0.01% to about 0.1% (w / w). In other embodiments, the concentration of the surfactant will typically be from about 0.1% to about 2% (w / w) or from about 0.1% to about 1% (w / w).

[0330] In other embodiments, the additional active agent will typically be present at a higher concentration to achieve the desired efficacy. In some embodiments, the active agent will be present at a concentration of about 1% to about 30% (w / w), about 1% to about 20% (w / w), or about 1% to about 15% (w / w). In still other embodiments, the active agent will be present in the composition at a concentration of about 5% to about 20% (w / w) or about 5% to about 15% (w / w).

[0331] In various embodiments of this specification, another active agent may be included in the composition to deliver a dose of about 0.001 mg to about 50 mg per kilogram of animal body weight, or about 0.5 mg to about 50 mg per kilogram of animal body weight. In other embodiments, the active agent will generally be present in an amount sufficient to deliver a dose of about 0.05 mg / kg to about 30 mg / kg, or about 0.1 mg / kg to about 20 mg / kg. In other embodiments, the active agent will be present in an amount sufficient to deliver a dose of about 0.1 mg to about 10 mg per kilogram of animal body weight, or about 0.1 mg to about 1 mg per kilogram of animal body weight, or about 0.5 mg to about 50 mg per kilogram of animal body weight.

[0332] In some embodiments of this specification, where the other active agent is a very potent compound such as a macrocyclic lactone or other potent compound, the active agent will be present at a concentration providing a dose of about 0.001 mg / kg to about 5 mg / kg, about 0.001 mg / kg to about 0.1 mg / kg, or about 0.001 mg / kg to about 0.01 mg / kg. In still other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.01 mg to about 2 mg or about 0.1 mg to about 1 mg per kilogram of animal body weight. In still other embodiments, the other active agent may be present in an amount delivering a dose of about 1 μg to about 200 μg or about 0.1 mg to about 1 mg per kilogram of animal body weight.

[0333] In addition to the other active agents mentioned above, combinations of two or more active agents may be used together with the compounds described herein in compositions for treating a desired spectrum of pests and parasites. Determining which individual compounds can be used in the compositions of this invention to treat specific insect infections will be entirely within the skill level of a physician.

[0334] The invention will now be further described with the aid of the following non-limiting examples.

[0335] [ ] [Example] [ ] [Preparation Example] [ ] The following examples are intended to illustrate the invention only and not to limit it. Compounds of formula (I) or their pharmaceutically or veterinarily acceptable salts can be prepared by employing one of the following reaction procedures. The starting materials for their preparation can be commercially available or prepared by methods known to those skilled in the art and described in the literature, or can be intermediates in any other process described herein. It will be understood that the following procedures can be modified by those skilled in the art to prepare other compounds according to the invention. For example, those skilled in the art will understand that substituting certain starting materials or using different intermediates will make it possible to prepare compounds of different formula (I).

[0336] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of approximately 20°C. Although the following objects are described in considerable detail for clarity by way of illustration and examples, those skilled in the art will understand that certain changes and modifications may be made within the scope of the examples.

[0337] [ ] [List of Abbreviations] [:] [ ] ACN Acetonitrile AIBN (Azobisisobutyronitrile) BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BSA (Bovine Serum Albumin) Boc tert-butoxycarbonyl BOP-Cl bis(2-sideoxy-3-azolidinyl)phosphine chloride DAST Diethylaminosulfonium Trifluoride DCC N,N'-dicyclohexylcarbodiimide solution DCM dichloromethane DEAD Diethyl azodicarbonate DIEA (Diisopropylethylamine) DMF N,N-dimethylformamide DMAP 4-(dimethylamino)pyridine DMSO (dimethylamine) EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ES Electrospray EtOAc or EA (ethyl acetate) HATU hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide HOBt or HOBT 1-hydroxybenzotriazole KHMDS, potassium hexamethyldisilamide, more precisely, potassium bis(trimethylsilyl)aminodioxide. MeOH (methanol) m-CPBA m-chloroperbenzoic acid NMO N-methylphospholine-N-oxide o / n overnight PE petroleum ether Pd(dtbpf)Cl2 dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) Pd2dba3 (diphenylmethyleneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex TBAF Tertiary Butylammonium Fluoride TfO trifluoromethanesulfonate THF Tetrahydrofuran TLC (Thin Layer Chromatography)

[0338] Some examples of formula (I) are derived after the separation of racemic mixtures and obtained as enantiomeric pure products. In some cases, the stereochemistry is arbitrarily specified and the individual compounds are characterized by the analytical methods described below: [, , ] [ ] [method] [A] Gradient / solvent time [min] Solvent % [scCO2] Solvent % [MeOH 20mM NH3] Flow rate [ml / min] Temperature [°C] Back pressure [PSI] 0.0 75.0 25.0 2.0 40.0 2175.0 4.0 75.0 25.0 2.0 40.0 2175.0 CHIRAL ART® Cellulose SJ_3 x 100 mm_3 µm (Agilent) [method] [B] Gradient / solvent time [min] Solvent % [scCO2] Solvent % [MeOH 20mM NH3] Flow rate [ml / min] Temperature [°C] Back pressure [PSI] 0.0 85.0 15.0 2.0 40.0 2175.0 4.0 85.0 15.0 2.0 40.0 2175.0 CHIRAL ART® Cellulose SJ_3 x 100 mm_3 µm (Agilent) [method] [C] Gradient / solvent time [min] Solvent % [scCO2] Solvent % [MeOH 20mM NH3] Flow rate [ml / min] Temperature [°C] Back pressure [PSI] 0.0 80.0 20.0 2.0 40.0 2175.0 4.0 80.0 20.0 2.0 40.0 2175.0 CHIRAL ART® Cellulose SJ_3 x 100 mm_3 µm (Agilent) [method] [D] Gradient / solvent time [min] Solvent % [scCO2] IPA solvent % 20mM NH3] Flow rate [ml / min] Temperature [°C] Back pressure [PSI] 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 70.0 30.0 4.0 40.0 2175.0 CHIRAL ART® Cellulose SB_4.6 x 250 mm_5 µm (Agilent) [, , ] [ ] [method] [E] Gradient / solvent time [min] Solvent % [scCO2] IPA solvent % [MeOH 20mM NH3] Flow rate [ml / min] Temperature [°C] Back pressure [PSI] 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 70.0 30.0 4.0 40.0 2175.0 CHIRAL ART® Cellulose SB_4.6 x 250 mm_5 µm (Agilent)

[0339] [Preparation Example] [1] The following example compounds can be synthesized by a person skilled in this art using the subsequent procedures 3 and 4 shown for compound 175: 271, 272, 273, 274, 275, 276, 279, 293, 294, 295, 296, 304, 305, 307, 308, 322, 344, 345, 364, 527, 528, A402, A403, A404, A406, A407, A410, A411, A412, A413, A414, A415, A416, A41 7. A418, 419, A419, A420, A423, A424, A425, A426, A428, A429, A430, A431, A432, A433, A434, A435, A436, A437, A438, A 439, A440, A441, A442, A443, A445, A446, A447, A448, A451, A452, A453, A454, A455, A456, A457, A458, A460, A472, 560.

[0340] [ ] [process] [3]

[0341] [ ] [process] [4]

[0342] [ ] [1] [.] [synthesis] [1] [-] [Aminoimidazole] [-] [2] [-] [Ethyl formate] [ester] [ ] DMF (2000 mL) and ethyl 1H-imidazolium-2-carboxylate (3-1, 50.0 g, 356.7 mmol, 1.0 equivalent) were placed in a 3000 mL three-necked round-bottom flask. NaH (21.0 g, 875.0 mmol, 2.4 equivalent) was then added fractionally at room temperature. Aminodiphenylphosphonite (119.0 g, 510.2 mmol, 1.4 equivalent) was added fractionally at 0 °C. The resulting solution was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum. The solid was filtered off. The mixture was concentrated under vacuum. The residue was applied to a silicone column with dichloromethane / methanol (10:1). This yielded 40 g (72.2%) of ethyl 1-aminoimidazolium-2-carboxylate as a white solid (3-2).

[0343] [2.] [synthesis] [1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] Ethyl formate [(3-3)] DMF (200.0 mL), ethyl 1-aminoimidazolium-2-carboxylate (3-2, 35.0 g, 225.5 mmol, 1.0 equivalent), Boc₂O (63.9 g, 293.2 mmol, 1.3 equivalent), and DMAP (13.7 g, 112.7 mmol, 0.5 equivalent) were placed in a 500 mL round-bottom flask. The resulting solution was stirred at 80 °C for 2 hours. The reaction mixture was then quenched by adding 500 mL of water. The resulting solution was extracted with 3 × 200 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silicone column containing ethyl acetate / petroleum ether (1:3). This yielded 28 g (48.6%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazolium-2-carboxylate (3-3) as a white solid.

[0344] [3.] [synthesis] [4-] [bromine] [-1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] Ethyl formate [(3-4)] DMF (100.0 mL), ethyl 1-[(tributoxycarbonyl)amino]imidazolium-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 placed in a 250 mL round-bottom flask. The resulting solution was stirred at room temperature for 1 day. The reaction mixture was then quenched by adding 300 mL of water. The resulting solution was extracted with 3 × 100 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was fed onto a silicone column with ethyl acetate / petroleum ether (1:4). This produced 12 g (61.1%) of ethyl 4-bromo-1-[(tributoxycarbonyl)amino]imidazolium-2-carboxylate (3-4) as a colorless oil.

[0345] [4.] [synthesis] [3-[4-] [bromine] [-1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] [base] []-3-] [Ethyl propionate] [(3-5)] THF (400.0 mL) and ethyl 4-bromo-1-[(tributoxycarbonyl)amino]imidazolium-2-carboxylate (3-4, 12.0 g, 35.9 mmol, 1.0 equivalent) were placed in a 1000 mL three-necked round-bottom flask. Then, t-BuOK (60.0 g, 534.7 mmol, 14.9 equivalent) was added fractionally over 30 minutes at 0 °C. Ethyl acetate (32.0 g, 363.2 mmol, 10.1 equivalent) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then quenched by adding HCl (1 M). The resulting solution was extracted with 3 × 50 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yields 6.5 g (48.1%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-sideoxypropionate (3-5), which is a yellow oil.

[0346] [ ] [5.] [synthesis] [2-] [bromine] [-8-] [Hydroxyimidazole] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(3-6)] Place DCM (30.0 mL), ethyl 3-[4-bromo-1-[(tributoxycarbonyl)amino]imidazol-2-yl]-3-sideoxypropionate (3-5 g, 6.5 g, 17.2 mmol, 1.0 equivalent), and DMF-DMA (5.00 mL, 37.3 mmol, 2.2 equivalent) into a 100 mL round-bottom flask. Stir the resulting solution at room temperature for 2 hours. Concentrate the mixture under vacuum. Purify the crude product by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN = 90:10 to H2O:ACN = 50:50 over 15 minutes; detector, 254 nm. This produces 3.3 g (66.7%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]tadalafil-7-carboxylate (3-6) as a white solid.

[0347] [ ] [6.] [synthesis] [8-] [Honki] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(3-7)] Place dimethyl ether (60.0 mL), ethyl 2-bromo-8-hydroxyimidazo[1,2-b]-dimethyl-7-carboxylate (3-6, 3.0 g, 10.5 mmol, 1.0 equivalent), trimethyl-1,3,5,2,4,6-trioxaborane-cyclohexane (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) into a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 100 °C for 4 hours. Concentrate the resulting mixture under vacuum. The residue was applied to a silicone column together with ethyl acetate / petroleum ether (1:2). This produced 2 g (86.2%) of ethyl 8-hydroxy-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (3-7) as a yellow solid.

[0348] [ ] [7.] [synthesis] [2-] [methyl] [-8-(] [Trifluoromethanesulfonyloxy] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-1)] DCM (20.0 mL), ethyl 8-hydroxy-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (3-7, 200.0 mg, 0.9 mmol, 1.0 equivalent), and TEA (457.0 mg, 4.5 mmol, 5.0 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Tf₂O (765.6 mg, 2.7 mmol, 3.0 equivalent) was then added dropwise at -78 °C with stirring. The resulting solution was stirred at -50 °C for 1 hour. The reaction mixture was then quenched by adding water / ice. The resulting solution was extracted with 3 × 20 mL dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This produces 200 mg (62.6%) of ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]tadalafil-7-carboxylate (4-1), which is a brown oil.

[0349] [ ] [8.] [synthesis] [2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4)] Place the following ingredients into a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere: THF (10.0 mL), H₂O (2.0 mL), ethyl 2-methyl-8-(trifluoromethanesulfonyloxy)imidazo[1,2-b]pyroxyl-7-carboxylate (4-1,200.0 mg, 0.6 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoboron (179.0 mg, 1.0 mmol, 1.9 equivalent), Pd(dtbpf)Cl₂ (37.2 mg, 0.06 mmol, 0.10 equivalent), and K₂CO₃ (234.0 mg, 1.7 mmol, 3.0 equivalent). Stir the resulting solution at room temperature for 2 hours. Concentrate the resulting mixture under vacuum. The residue was applied to a silicone column together with ethyl acetate / petroleum ether (1:4). This produced 90 mg (64.8%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate as a white solid (4-2).

[0350] [ ] [9.] [synthesis] [8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [ ] EA (5.0 mL), ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate (4-2, 90.0 mg, 0.4 mmol, 1.0 equivalent), PtO2 (30.00 mg, 0.1 mmol, 0.4 equivalent), and H2 (g) atmosphere were placed in a 50 mL round-bottom flask. The resulting solution was stirred at 50 °C for 1 hour. The solid was filtered off. The mixture was concentrated under vacuum. This yielded 90 mg (99.2%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate as a white solid (4-3).

[0351] [ ] [10.] [synthesis] [3-] [bromine] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [ ] To a 50 mL round-bottom flask, place 10.0 mL of CHCl3, ethyl 8-isopropyl-2-methylimidazo[1,2-b]tert-7-carboxylate (4-3, 90.0 mg, 0.4 mmol, 1.0 equivalent), and NBS (90.0 mg, 0.5 mmol, 1.4 equivalent). Stir the resulting solution at 80 °C for 1 hour. Then, quench the reactants with 10 mL of water. Extract the resulting solution with 3 × 10 mL of dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, and concentrate under vacuum. This yields 100 mg (crude) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]tert-7-carboxylate (4-4) as a white solid.

[0352] [ ] [11.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-5)] Dimethyl ether (10.0 mL), H₂O (3.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyroxene-7-carboxylate (4-4, 90.0 mg, 0.3 mmol, 1.0 equivalent), 3,5-difluorophenylboronic acid (87.5 mg, 0.5 mmol, 2.0 equivalent), Pd(dtbpf)Cl₂ (18.0 mg, 0.03 mmol, 0.1 equivalent), and K₂CO₃ (114.6 mg, 0.829 mmol, 3.0 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 3 hours. The resulting mixture was concentrated under vacuum. The residue was applied to a silicone column containing ethyl acetate / petroleum ether (1:3). This produces 80 mg (80.7%) of ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (4-5) as a yellow solid.

[0353] [ ] [12.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(4-6)] Place 1.0 mL of H₂O, 5.0 mL of i-PrOH, ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (4-5 mg, 0.2 mmol, 1.0 equivalent), and 28.0 mg of LiOH·H₂O (28.0 mg, 0.7 mmol, 3.0 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at 50 °C for 2 hours. Adjust the pH of the solution to 4 with HCl (2 M). Extract the resulting solution with 3 × 20 mL of ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under vacuum. This yields 60 mg (90%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (4-6) as a white solid.

[0354] [ ] [13.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [175)] Place DMA (5.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyroxen-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 equivalent), HATU (138.0 mg, 0.4 mmol, 2.0 equivalent), and DIEA (70.0 mg, 0.5 mmol, 3.0 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution 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=60:40 to H2O:ACN=10:90 over 25 minutes; detector, 220 nm. This yielded 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]pyridine-7-methamide (175 mg / mL) 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).

[0355] [Preparation Example] [2] [:] Similar to the process described in Preparation Example 1, the process depicted in procedures 5-7 can be used to prepare compound 271: [process] [5]

[0356] [ ] [process] [6]

[0357] [ ] [process] [7]

[0358] The processes described in steps 3-7 above can be modified using methods known to those skilled in the art to incorporate different functional groups into the core structure. For example, intermediates 3-6 can be reacted with alternative coupling complexes to introduce different R2 substituents. Similarly, intermediates 4-1, 271-1, and 4-4 can be reacted with alternative compounds to introduce different R1 and R3 substituents.

[0359] [ ] [1.] [synthesis] [1-] [Aminoimidazole] [-2-] Ethyl formate [(3-2)] DMF (4000.00 mL, 51687.010 mmol, 144.87 equivalents) and ethyl 1H-imidazolium-2-carboxylate (50.00 g, 356.781 mmol, 1.00 equivalents) were placed in a 5 L round-bottom flask. Then, NaH (21.00 g, 875.083 mmol, 2.45 equivalents) was added fractionally over 30 min at room temperature. Aminodiphenylphosphonite (120.00 g, 514.564 mmol, 1.44 equivalents) was added fractionally to this solution at room temperature. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was dried under nitrogen (nitrogen purging). The residue was dissolved in 2000 mL of EA. The solid was filtered off. The filtrate was concentrated under vacuum. This yielded 42 g (75.87%) of ethyl 1-aminoimidazolium-2-carboxylate as a white solid (3-2).

[0360] [2.] [synthesis] [1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] Ethyl formate [(3-3)] DMF (500.00 mL, 6460.876 mmol, 28.64 equivalents), ethyl 1-aminoimidazolium-2-carboxylate (35.00 g, 225.578 mmol, 1.00 equivalents), Boc₂O (73.30 g, 335.858 mmol, 1.49 equivalents), and DMAP (13.78 g, 112.796 mmol, 0.50 equivalents) were placed in a 1000 mL round-bottom flask. The resulting solution was stirred at 80 °C for 2 hours. The reactants were then quenched by adding water / ice. The resulting solution was extracted with 3 × 500 mL of ethyl acetate, and the organic layers were combined and washed with 2 × 500 mL of H₂O and 1 × 500 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:2). This produces 30 g (52.10%) of ethyl 1-[(tert-butoxycarbonyl)amino]imidazolium-2-carboxylate as a white solid (3-3).

[0361] [ ] [3.] [synthesis] [4-] [bromine] [-1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] Ethyl formate [(3-4)] DMF (400.00 mL, 5168.701 mmol, 26.39 equivalents), ethyl 1-[(tributoxycarbonyl)amino]imidazolium-2-carboxylate (50.00 g, 195.868 mmol, 1.00 equivalents), and NBS (40.00 g, 0.225 mmol) were placed in a 1000 mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding water / ice. The solution was extracted with 3 × 100 mL ethyl acetate, and the organic layers were combined and washed with 2 × 500 mL H₂O and 1 × 500 mL brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:1). This produces 30 g (45.83%) of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazolium-2-carboxylate (3-4), which is a yellow oil.

[0362] [4.] [synthesis] [3-[4-] [bromine] [-1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] [base] []-3-] [Ethyl propionate] [(3-5)] To a 1000 mL three-necked round-bottom flask, add THF (500.00 mL, 6171.495 mmol, 58.92 equivalents), ethyl 4-bromo-1-[(tributoxycarbonyl)amino]imidazolium-2-carboxylate (35.00 g, 104.737 mmol, 1.00 equivalents), and EA (93.50 g, 1061.233 mmol, 10.13 equivalents). Then, add t-BuOK (170.00 g, 1514.989 mmol, 14.46 equivalents) fractionally at 0 °C. Stir the resulting solution at room temperature for 1 hour. The reaction mixture is then quenched by adding NH4Cl (aqueous solution). Extract the resulting solution with 3 × 300 mL of ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under vacuum. Dissolve the residue in 500 mL of hexane. Collect the solid by filtration. This yields 22 g (55.83%) of ethyl 3-[4-bromo-1-[(tert-butoxycarbonyl)amino]imidazol-2-yl]-3-sideoxypropionate (3-5) as a white solid.

[0363] [5.] [synthesis] [2-] [bromine] [-8-] [Hydroxyimidazole] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(3-6)] DCM (30.00 mL, 471.901 mmol, 27.31 equivalents), ethyl 3-[4-bromo-1-[(tributoxycarbonyl)amino]imidazol-2-yl]-3-sideoxypropionate (6.50 g, 17.278 mmol, 1.00 equivalents), and DMF-DMA (5.00 mL, 37.344 mmol, 2.16 equivalents) were placed in a 100 mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The 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, increased from H2O (0.1% TFA):ACN = 90:10 to H2O (0.1% TFA):ACN = 50:50 over 15 minutes; detector, 254 nm. This produces 3.3 g (66.76%) of ethyl 2-bromo-8-hydroxyimidazo[1,2-b]tadalafil-7-carboxylate (3-6) as a white solid.

[0364] [6.] [synthesis] [8-] [Hydroxy] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(3-7)] Dioxane (100.0 mL, 1180.408 mmol, 67.54 equivalents), ethyl 2-bromo-8-hydroxyimidazo[1,2-b]-dioxane-7-carboxylate (5.00 g, 17.477 mmol, 1.00 equivalents), trimethyl-1,3,5,2,4,6-trioxaborane (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 placed in 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 mixture was then concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O (0.1% NH3·H2O):ACN=100:0 to H2O (0.1% NH3·H2O):ACN=50:50 over 10 minutes; detector, 254 nm. This yielded 0.75 g (25.6%) of ethyl 8-hydroxy-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (3-7) as a yellow solid.

[0365] [7.] [synthesis] [8-] [chlorine] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(271-1)] To a 100 mL round-bottom flask, add CHCl3 (20.00 mL, 247.952 mmol, 18.28 equivalents), ethyl 8-hydroxy-2-methylimidazo[1,2-b]-ethyl 8-chloro-2-methylimidazo[1,2-b]-ethyl 8-carboxylate (3.00 g, 13.561 mmol, 1.00 equivalents), oxalic acid chloride (6.00 g, 47.274 mmol, 3.49 equivalents), and DMF (0.10 mL). Stir the resulting solution at 80 °C for 2 hours. Concentrate the mixture under vacuum. This yields 3.6 g (crude) of ethyl 8-chloro-2-methylimidazo[1,2-b]-ethyl 8-chloro-2-methylimidazo[1,2-b]-ethyl 8-carboxylate (271-1) as a yellow solid.

[0366] [8.] [synthesis] [2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-2)] Place the following substances into a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere: THF (30.00 mL, 370.290 mmol, 88.74 equivalents), H₂O (5.00 mL, 277.542 mmol, 66.52 equivalents), ethyl 8-chloro-2-methylimidazo[1,2-b]dioxane-7-carboxylate (1.00 g, 4.173 mmol, 1.00 equivalents), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoboron (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 mg ... (mmol, 3.00 equivalent). The resulting solution was stirred at 70°C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:2). This produced 500 mg (48.85%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate (4-2) as a yellow oil.

[0367] [9.] [synthesis] [8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-3)] Place EA (5.00 mL, 0.057 mmol, 0.03 equivalents), ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tert-7-carboxylate (500.00 mg, 2.038 mmol, 1.00 equivalents), and PtO2 (100.00 mg, 0.440 mmol, 0.22 equivalents) into a 50 mL round-bottom flask, and introduce H2 (g) into the mixture. Stir the resulting solution at 50 °C for 2 hours. Filter off the solid. Concentrate the filtrate under vacuum. This yields 350 mg (69.43%) of ethyl 8-isopropyl-2-methylimidazo[1,2-b]tert-7-carboxylate (4-3), which is a yellow oil.

[0368] [10.] [synthesis] [3-] [bromine] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-4)] Place CHCl3 (5.00 mL, 61.988 mmol, 47.90 equivalents), ethyl 8-isopropyl-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (320.00 mg, 1.294 mmol, 1.00 equivalents), and NBS (253.70 mg, 1.425 mmol, 1.10 equivalents) into a 50 mL round-bottom flask. Stir the resulting solution at 80 °C for 1 hour. Concentrate the resulting mixture under vacuum. Apply the residue, along with ethyl acetate / petroleum ether (1:5), onto a silicone column. This produces 350 mg (82.92%) of ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (4-4), which is a yellow oil.

[0369] [11.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(271-2)] Place 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]pyroxyl-7-carboxylate (90.00 mg, 0.276 mmol, 1.00 equivalents), and 3,5-dichlorophenyl into an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Acid (53.17 mg, 0.279 mmol, 1.01 equivalents), Pd(dtbpf)Cl2 (17.98 mg, 0.028 mmol, 0.10 equivalents), K2CO3 (75.88 mg, 0.549 mmol, 1.99 equivalents). The resulting solution was stirred at 50 °C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:4). This produced 70 mg (64.67%) of ethyl 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyroxyl-7-carboxylate (271-2) as a colorless oil.

[0370] [12.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(271-3)] Add the following to 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]-diethyl-7-carboxylate (70.00 mg, 0.178 mmol, 1.00 equivalents), and LiOH·H₂O (22.50 mg, 0.536 mmol, 3.00 equivalents). Stir the resulting solution at room temperature for 1 hour. Adjust the pH of the solution to 5 with HCl (6 mol / L). Extract the resulting solution with 3 × 20 mL of ethyl acetate, combine the organic layers, dry to anhydrous sodium sulfate, and concentrate under vacuum. This produces 50 mg (76.93%) of 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (271-3), which is a yellow oil.

[0371] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [271)] Place DMA (1.00 mL, 10.755 mmol, 87.05 equivalents), 3-(3,5-dichlorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyro-7-carboxylic acid (45.00 mg, 0.124 mmol, 1.00 equivalents), (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 DIEA (47.80 mg, 0.370 mmol, 2.99 equivalents) into a 50 mL round-bottom flask. Stir the resulting solution 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 from H2O (0.1% NH3·H2O):ACN=50:50 to H2O (0.1% NH3·H2O):ACN=10:90 over 20 minutes; detector, 254 nm. This yielded 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]pyridine-7-methamide (271) as a white solid. 1H 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, 3H), 2.44-2.41 (m, 1H), 2.26-2.22(m, 1H), 1.65 (t, J = 6.7 Hz, 6H); (ES, m / z): 495 [M+H]+. As noted above, the following compounds can be prepared according to procedures 3 to 7: [Compound] [,1 , ] [¹H NMR] [Spectrum] 272 (300 MHz, CDCl3, ppm) δ 8.30 (s, 1H), 7.49 (s, 1H), 7.37-7.30 (m, 2H), 7.29-7.21 (m, 1H), 7.20-7.15 (m, 1H), 6.99-6.94 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.19 (d, J = 7.5 Hz, 1H), 5.38 (q, J = 6.9 Hz, 1H), 4.37-4.35 (m, 1H), 4.25-4.14 (m, 1H), 3.79-3.74 (m, 1H), 2.64 (s, 3H), 2.43-2.40 (m, 1H), 2.26-2.21 (m, 1H), 1.64 (t, J = 6.6 Hz, 6H) 273 (300 MHz, CDCl3, ppm) δ 8.31 (s, 1H), 7.53-7.40 (m, 3H), 7.40-7.31 (m, 1H),7.29-7.17 (m, 2H), 6.99-6.93 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 7.2 Hz, 1H), 5.38 (q, J = 7.2 Hz, 1H), 4.39-4.33 (m, 1H), 4.25-4.20 (m, 1H), 3.78-3.73 (m, 1H), 2.63 (s, 3H), 2.44-2.37 (m, 1H), 2.26-2.23 (m, 1H), 1.63 (t, J = 6.9 Hz, 6H) 274 (300 MHz, CDCl3, ppm) δ 8.24 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.2, 2.1 Hz, 1H), 7.41-7.35 (m, 2H), 7.33-7.29 (m, 1H), 7.27-7.20 (m, 1H), 6.98-6.93 (m, 1H), 6.90-6.87 (m, 1H), 6.20 (d, J = 7.5 Hz, 1H), 5.38 (q, J = 7.2 Hz, 1H), 4.37-4.34 (m, 1H), 4.27-4.13 (m, 1H), 3.79-3.74 (m, 1H), 2.47 (s, 3H), 2.41-2.39 (m, 1H), 2.27-2.20 (m, 1H), 1.69-1.63 (m, 6H) 275 (300 MHz, DMSO-d6, ppm) δ 9.16 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 7.51-7.47 (m, 2H), 7.36-7.30 (m, 1H), 7.16 (dd, J = 9.3, 2.7 Hz, 1H), 7.08-7.01 (m, 1H), 6.83 (dd, J = 9.0, 4.8 Hz, 1H), 5.24 (q, J = 7.2 Hz, 1H), 4.28-4.22 (m, 2H), 3.62-3.57 (m, 1H), 2.57 (s, 3H), 2.30-2.16 (m, 1H), 2.11-1.95 (m, 1H), 1.55 (t, J = 7.4 Hz, 6H) 276 (300 MHz, CDCl3, ppm) δ 8.36 (s, 1H), 7.28-7.22 (m, 2H), 7.19-7.16 (m, 2H), 7.03-6.95 (m, 2H), 6.91-6.88 (m, 1H), 6.09 (d, J = 7.2 Hz, 1H), 5.39 (q, J = 7.5 Hz, 1H), 4.41-4.35 (m, 1H), 4.24-4.17 (m, 1H), 3.77-3.72 (m, 1H), 2.44-2.39 (m, 1H), 2.28-2.24 (m, 1H), 1.68 (t, J = 6.9 Hz, 6H) 279 (300 MHz, DMSO-d6, ppm) δ 8.99 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 7.58-7.43 (m, 2H), 7.43-7.25 (m, 2H), 7.24-7.12 (m, 1H), 6.93 (t, J = 6.9 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.45 (s, 1H), 5.26-5.16 (m, 2H), 4.30-4.17 (m, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 2.23-2.09 (m, 1H), 2.00-1.95 (m, 1H) 293 (300 MHz, CDCl3, ppm) δ 8.16 (d, J = 3.6 Hz, 1H), 7.60 (dd, J = 7.5, 1.5 Hz, 1H), 7.40-7.29 (m, 2H), 6.99-6.89 (m, 2H), 6.83-6.79 (m, 1H), 6.24-6.22 (m, 1H), 5.36-5.33 (m, 1H), 4.34-4.28 (m, 1H), 4.19-4.11 (m, 1H), 3.79-3.74 (m, 1H), 2.46 (s, 3H), 2.39-2.30 (m, 1H), 2.23-2.07 (m, 1H), 1.72-1.58 (m, 6H) 294 (300 MHz, CDCl3, ppm) δ 8.27 (s, 1H), 7.58 (d, J = 1.8 Hz, 2H), 7.42 (t, J = 1.8 Hz, 1H), 7.01-6.90 (m, 2H), 6.84-6.80 (m, 1H), 6.31 (br s, 1H), 5.39-5.34 (m, 1H), 4.36-4.30 (m, 1H), 4.24-4.17 (m, 1H), 3.79-3.75 (m, 1H), 2.63 (s, 3H), 2.42-2.36 (m, 1H), 2.22-2.16 (m, 1H), 1.64 (t, J = 6.6 Hz, 6H) 295 (300 MHz, CDCl3, ppm) δ 8.37 (s, 1H), 7.53-7.51 (m, 3H), 7.26-7.23 (m, 1H), 7.02-6.95 (m, 1H), 6.92-6.89 (m, 1H),6.06 (d, J = 7.2 Hz, 1H), 5.43-5.37 (s, 1H), 4.42-4.35 (m, 1H), 4.24-4.17 (m, 1H), 3.77-3.70 (m, 1H), 2.47-2.41 (m, 1H),2.27-2.22 (m, 1H), 1.68 (t, J = 6.6 Hz, 6H) 296 (300 MHz, CDCl3, ppm) δ 8.37 (s, 1H), 7.53-7.51 (m, 3H), 7.00-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.04 (d, J = 7.8 Hz, 1H), 5.43-5.37 (m, 1H), 4.38-4.33 (m, 1H), 4.26-4.12 (m, 1H), 3.76-3.71 (m, 1H), 1.68 (t, J = 6.9 Hz, 6H) 304 (300 MHz, CDCl3, ppm) δ 8.40 (s, 1H), 8.16 (s, 2H), 7.42 (t, J = 2.1 Hz, 1H), 7.03-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.06 (d, J = 7.8 Hz, 1H), 5.48-5.32 (m, 1H), 4.39-4.33 (m, 1H), 4.24-4.18 (m, 1H), 3.76-3.69 (m, 1H), 2.46-2.39 (m, 1H), 2.29-2.18 (m, 1H), 1.72-1.68 (m, 6H) 305 (400 MHz, chloroform-d, ppm) δ: 8.37 (s, 1H), 7.66 (s, 2H), 7.55 (s, 1H), 7.01-6.84 (m, 4H), 6.10 (d, J = 8.3 Hz, 1H), 5.35 (d, J = 8.3 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.15 (m, 1H), 3.81-3.74 (m, 1H), 2.44-2.38 (m, 1H), 2.21-2.20 (m, 1H), 1.70-1.55 (m, 6H) 307 (300 MHz, CDCl3, ppm): δ 8.86 (s, 1H), 7.33-7.30 (m, 2H), 7.04-6.80 (m, 5H), 5.69 (s, 1H), 5.50-5.30 (m, 2H), 4.35-4.30 (m, 1H), 4.25-4.00 (m, 1H), 2.68 (s, 3H), 2.45-2.25 (m, 4H), 2.20-2.10 (m, 1H) 308 (300 MHz, CDCl3, ppm): δ 8.84 (s, 1H), 7.63 (s, 2H), 7.46 (s, 1H), 7.02- 6.78 (m, 4H), 5.68 (s, 1H), 5.45-5.31 (m, 2H), 4.37-4.30 (m, 1H), 4.21-4.07 (m, 1H), 2.66 (s, 3H), 2.45-2.30 (m, 4H), 2.20-2.10 (m, 1H) 322 (300 MHz, CDCl3, ppm): δ 8.52 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 7.80 (s, 1H), 7.70-7.60 (m, 1H), 7.40-7.20 (m, 2H), 7.05-6.95 (m, 1H), 6.93-6.87 (m, 1H), 6.20-6.00 (m, 1H), 5.45-5.30 (m, 1H), 4.45-4.35 (m, 1H), 4.30-4.15 (m, 1H), 3.83-3.74 (m, 1H), 2.71 (s, 3H), 2.52-2.37 (m, 1H), 2.30-2.15 (m, 1H), 1.75-1.65 (m, 6H) 344 (300 MHz, CDCl3, ppm): δ 8.23 (s, 1H), 7.14-6.91 (m, 4H), 6.90-6.75 (m, 1H), 6.10 (d, J = 7.8 Hz, 1H), 5.45-5.31 (m, 1H), 4.45-4.32 (m, 1H), 4.30-4.10 (m, 1H), 3.85-3.65 (m, 1H), 2.54 (s, 3H), 2.44-2.30 (m, 1H), 2.24-2.17 (m, 1H), 1.67 (t, J = 6.6 Hz, 6H) 345 (300 MHz, chloroform-d, ppm): δ 8.23 (s, 1H), 7.28-7.20 (m, 2H), 7.10-7.00 (m, 2H), 6.99-6.93 (m, 1H), 6.90-6.87 (m, 1H), 6.11 (d, J = 7.2 Hz, 1H), 5.40-5.30 (m, 1H), 4.40-4.34 (m, 1H), 4.24-4.15 (m, 1H), 3.85-3.74 (m, 1H), 2.53 (s, 3H), 2.50-2.35 (m, 1H), 2.30-2.15 (m, 1H), 1.66 (t, J = 6.6 Hz, 6H) 364 (300 MHz, chloroform-d, ppm): δ 8.47 (s, 1H), 8.34-8.24 (m, 2H), 7.60 (d, J = 1.8 Hz, 2H), 7.42 (t, J = 1.8 Hz, 1H), 6.79 (d, J = 5.7 Hz, 1H), 6.55-6.40 (m, 1H), 5.47-5.40 (m, 1H), 4.49-4.41 (m, 1H), 4.40-4.25 (m, 1H), 3.82-3.70 (m, 1H), 2.64 (s, 3H), 2.50-2.25 (m, 2H), 1.68-1.64 (m, 6H) 527 (300 MHz DMSO-d6, ppm): δ 8.08 (s, 1H), 7.15-7.44 (m, 3H), 7.00-6.79 (m, 2H), 6.10 - 6.21 (m, 1H), 5.36 - 5.43 (m, 1H), 4.30 - 4.49 (m, 1H), 4.10 - 4.18 (m, 1H), 2.40-2.38 (m, 4H), 2.28-2.26 (m, 1H), 1.80 (bs, 9H) 528 (300 MHz, DMSO-d6, ppm) δ 9.18 (d, J = 8.1 Hz, 1H), 8.37 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.26-5.20 (m, 1H), 4.30-4.14 (m, 2H), 3.61-3.51 (m, 1H), 2.30 (s, 3H), 2.22-2.17 (m, 1H), 2.08-2.01 (m, 1H), 1.59-1.56 (m, 6H) A402 (400 MHz, DMSO-d6, ppm) δ 9.19 (d, J = 8.62 Hz, 1H) 8.46 (s, 1H) 7.77 (d, J = 1.90 Hz, 2H) 7.68 (t, J = 1.96 Hz, 1H) 7.45 (d, J = 2.41 Hz, 1H) 7.36 (dd, J = 8.68, 2.47 Hz, 1H) 6.83 (d, J = 8.74 Hz, 1H) 4.81 (d, J = 8.62 Hz, 1H) 4.29 (d, J = 11.28 Hz, 1H) 3.72 - 3.76 (m, 1H) 3.48 - 3.58 (m, 1H) 2.54 (s, 3H) 1.54 (dd, J = 8.36, 7.10 Hz, 6H) 0.89 - 0.99 (m, 1H) 0.75 (dt, J = 9.03, 4.67 Hz, 1H) 0.66 - 0.72 (m, 1H) 0.59 - 0.66 (m, 1H) A403 (400 MHz, DMSO-d6) δ ppm 9.14 (d, J = 8.11 Hz, 1H) 8.56 (s, 1H) 7.96 (d, J = 1.90 Hz, 2H) 7.69 (t, J = 1.90 Hz, 1H) 7.34 (d, J = 7.10 Hz, 1H) 7.18 (t, J = 7.69 Hz, 1H) 6.93 (t, J = 7.16 Hz, 1H) 6.80 (d, J = 8.24 Hz, 1H) 5.19 - 5.29 (m, 1H) 4.65 (s, 2H) 4.18 - 4.33 (m, 2H ) 3.57 - 3.66 (m, 1H) 2.13 - 2.27 (m, 1H) 1.97 - 2.13 (m, 1H) 1.55 (dd, J = 10.77, 6.97 Hz, 6H) A404 (400 MHz, DMSO-d6) δ ppm 9.18 (d, J=8.11 Hz, 1 H) 8.66 (s, 1 H) 7.84 (t, J=1.90 Hz, 1 H) 7.68 (d, J=1.90 Hz, 2 H) 7.33 (d, J=6.97 Hz, 1 H) 7.17 (t, J=7.77 Hz, 1 H) 6.92 (t, J=7.17 Hz, 1 H) 6.80 (d, J=8.11 Hz, 1 H) 5.21 - 5.27 (m, 1 H) 4.25 - 4.31 (m, 1 H) 4.18 - 4.25 (m, 1 H) 3.58 (dt, J=13.94, 6.97 Hz, 1 H) 2.17 - 2.25 (m, 1 H) 2.00 - 2.08 (m, 1 H) 1.54 (dd, J=11.79) A406 (400 MHz, DMSO-d6, ppm) δ 9.15 (d, J = 7.98 Hz, 1H), 8.34 (s, 1H), 7.66 - 7.71 (m, 2H), 7.57 - 7.64 (m, 1H), 7.31 (d, J = 6.97 Hz, 1H), 7.16 (t, J = 7.66 Hz, 1H), 6.91 (t, J = 7.15 Hz, 1H), 6.78 (d, J = 8.27 Hz, 1H), 5.19 - 5.25 (m, 1H), 4.18 - 4.30 (m, 2H), 3.35 - 3.61 (m, 3H), 2.56 - 2.66 (m, 1H), 2.15 - 2.32 (m, 1H), 2.01 - 2.09 (m, 1H), 1.51 - 1.59 (m, 6H) A407 (400 MHz, DMSO-d6, ppm) δ 9.12 (d, J = 8.11 Hz, 1H), 8.39 (s, 1H), 7.62 - 7.70 (m, 1H), 7.14 - 7.36 (m, 4H), 6.91 (t, J = 7.19 Hz, 1H), 6.79 (d, J = 8.11 Hz, 1H), 5.23 (br d, J = 7.48 Hz, 1H), 4.17 - 4.32 (m, 2H), 3.51 - 3.62 (m, 1H), 2.03 - 2.39 (m, 5H), 1.57 - 1.54 (m, 6H) A410 (400 MHz, DMSO-d6, ppm) δ 9.11 (d, J = 8.11 Hz, 1H), 8.44 - 8.52 (m, 1H), 7.93 (m, 1H), 7.15 - 7.73 (m, 4H), 6.92 (m, 1H), 6.76 - 6.80 (m, 1H), 4.04 - 5.27 (m, 4H), 3.52 - 3.66 (m, 1H), 2.51 - 2.53 (m, 2H), 2.36 - 2.46 (m, 1H), 1.98 - 2.26 (m, 2H), 1.46 - 1.61 (m, 5H) A411 (400 MHz, DMSO-d6, ppm) δ ppm 9.14 (d, J = 8.24 Hz, 1H) 8.47 (s, 1H) 7.77 (d, J = 1.90 Hz, 2H) 7.68 (t, J = 1.90 Hz, 1H) 7.37 (d, J = 7.73 Hz, 1H) 7.07 - 7.19 (m, 3H) 5.22 - 5.29 (m, 1H) 3.57 - 3.64 (m, 3H) 3.03 - 3.20 (m, 2H) 2.54 (s, 3H) 2.14 - 2.31 (m, 2H) 1.55 (br d, J = 6.97 Hz, 3H) 1.52 (br d, J = 6.97 Hz, 3H) A412 (400 MHz, DMSO-d6, ppm) δ 9.10 (d, J = 8.11 Hz, 1H), 8.40 (s, 1H), 6.77 - 7.76 (m, 9H), 5.19 - 5.28 (m, 1H), 3.55 - 4.66 (m, 5H), 2.00 - 2.49 (m, 2H), 1.52 - 1.56 (m, 6H) A413 (400 MHz, DMSO-d6, ppm) δ 9.11 (d, J = 7.98 Hz, 1H), 8.37 (s, 1H), 7.63 - 7.71 (m, 1H), 7.46 (m, 1H), 7.26 - 7.34 (m, 2H), 7.16 (t, J = 7.74 Hz, 1H), 6.92 (t, J = 7.41 Hz, 1H), 6.79 (d, J = 7.60 Hz, 1H), 5.23 (br d, J = 7.73 Hz, 1H), 4.25 (m, 2H), 3.37 - 3.67 (m, 3H), 2.35 - 2.46 (m, 1H), 2.16 - 2.26 (m, 1H), 2.04 (br s, 1H), 1.56 - 1.53 (m, 6H) A414 (400 MHz, DMSO-d6, ppm) δ 9.15 (d, J = 7.98 Hz, 1H) 8.54 (s, 1H) 7.78 (d, J = 1.90 Hz, 2H) 7.68 (t, J = 1.90 Hz, 1H) 7.35 (d, J = 2.41 Hz, 1H) 7.22 (dd, J = 8.74, 2.66 Hz, 1H) 6.84 (d, J = 8.74 Hz, 1H) 5.23 (q, J = 6.42 Hz, 1H) 3.88 - 4.34 (m, 2H) 3.60 (spt, J = 6.91 Hz, 1H) 2.55 (s, 3 H) 1.94 - 2.24 (m, 2H) 1.55 (dd, J = 10.39, 6.97 Hz, 6H) A415 (400 MHz, DMSO-d6) δ ppm 9.35 (d, J = 8.62 Hz, 1H), 8.57 (s, 1H), 7.57 - 7.85 (m, 7H), 5.52 (m, 1H), 3.57 - 3.81 (m, 3H), 2.53 - 2.69 (m, 4H), 1.55 - 1.50 (m, 7H) A416 (400 MHz, DMSO-d6, ppm) δ 9.35 (d, J = 8.62 Hz, 1H), 8.57 (s, 1H), 7.57 - 7.85 (m, 7H), 5.52 (m, 1H), 3.57 - 3.81 (m, 3H), 2.53 - 2.69 (m, 4H), 1.55 - 1.50 (m, 7H) A417 (400 MHz, DMSO-d6, ppm) δ 9.37 (d, J = 8.36 Hz, 1H), 8.61 (s, 1H), 7.78 - 7.89 (m, 3H), 7.61 - 7.71 (m, 3H), 5.48 - 5.55 (m, 1H), 3.57 - 3.84 (m, 3H), 2.54 - 2.68 (m, 5H), 1.58 (d, J = 6.97 Hz, 3H), 1.54 (br d, J = 6.84 Hz, 3H) A418 (400 MHz, DMSO-d6, ppm) δ 9.37 (d, J = 8.36 Hz, 1H), 8.61 (s, 1H), 7.78 - 7.89 (m, 3H), 7.61 - 7.71 (m, 3H), 5.48 - 5.55 (m, 1H), 3.57 - 3.84 (m, 3H), 2.54 - 2.68 (m, 5H), 1.58 (d, J = 6.97 Hz, 3H), 1.54 (br d, J = 6.84 Hz, 3H) 419 (300 MHz, DMSO-d6, ppm) δ 8.50 (s, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.45 - 7.50 (m, 1H), 7.10 - 7.28 (m, 1H), 6.98 - 6.89 (m, 2H), 6.10 - 6.05 (m, 1H), 5.45 - 5.40 (m, 1H), 4.50 - 4.10 (m, 2H) 3.80-3.70 (m, 1H), 2.40-2.21 (m, 2H), 1.65-1.58 (m, 6H) A419 (400 MHz, DMSO-d6, ppm) δ 9.17 (d, J = 7.98 Hz, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 7.67 - 7.78 (m, 3H), 5.28 - 5.35 (m, 1H), 3.58 (m, 1H), 2.68 - 2.80 (m, 2H), 2.52 - 2.55 (m, 3H), 1.51 - 2.16 (m, 10H) A420 (400 MHz, DMSO-d6, ppm) δ 9.17 (d, J = 7.98 Hz, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 7.67 - 7.78 (m, 3H), 5.28 - 5.35 (m, 1H), 3.58 (m, 1H), 2.68 - 2.80 (m, 2H), 2.52 - 2.55 (m, 3H), 1.51 - 2.16 (m, 10H) A423 (400 MHz, DMSO-d6, ppm) δ 11.72 - 12.10 (m, 1H), 9.07 (d, J = 8.11 Hz, 1H), 8.37 (s, 1H), 7.66 - 7.79 (m, 3H), 5.21 (d, J = 6.72 Hz, 1H), 3.54 - 3.65 (m, 1H), 2.53 - 2.60 (m, 4H), 1.51 - 2.14 (m, 14H) A424 (400 MHz, DMSO-d6, ppm) δ 11.72 - 12.10 (m, 1H), 9.07 (d, J = 8.11 Hz, 1H), 8.37 (s, 1H), 7.66 - 7.79 (m, 3H), 5.21 (d, J = 6.72 Hz, 1H), 3.54 - 3.65 (m, 1H), 2.53 - 2.60 (m, 4H), 1.51 - 2.14 (m, 14H) A425 (400 MHz, DMSO-d6, ppm) δ 9.42 (d, J = 7.86 Hz, 1H), 8.57 (s, 1H), 7.67 - 7.81 (m, 5H), 5.45 (d, J = 6.46 Hz, 1H), 3.56 - 4.22 (m, 3H), 2.54 - 2.57 (m, 3H), 1.50 - 2.32 (m, 10H) A426 (400 MHz, DMSO-d6, ppm) δ 9.42 (d, J = 7.86 Hz, 1H), 8.57 (s, 1H), 7.67 - 7.81 (m, 5H), 5.45 (d, J = 6.46 Hz, 1H), 3.56 - 4.22 (m, 3H), 2.54 - 2.57 (m, 3H), 1.50 - 2.32 (m, 10H) A428 (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 8.24 Hz, 1H), 8.39 (s, 1H), 7.67 - 7.80 (m, 1H), 7.67 (s, 1H), 5.40 (br d, J = 2.66 Hz, 1H), 3.36 - 3.70 (m, 2H), 2.76 - 3.16 (m, 2H), 2.53 - 2.57 (m, 2H), 2.50 - 2.67 (m, 2H), 2.08 - 2.39 (m, 1H), 1.23 - 1.55 (m, 6H) A429 400 MHz, DMSO-d6, ppm) δ 9.00 (t, J = 4.06 Hz, 2H), 8.38 (s, 1H), 7.76 (d, J = 1.77 Hz, 1H), 7.67 (s, 1H), 5.45 (d, J = 5.07 Hz, 1H), 3.60 - 3.77 (m, 1H), 2.72 - 3.47 (m, 4H), 2.53 - 2.56 (m, 2H), 2.34 - 2.46 (m, 1H), 1.42 - 1.58 (m, 6H) A430 (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 8.24 Hz, 1H), 8.39 (s, 1H), 7.67 - 7.80 (m, 1H), 7.67 (s, 1H), 5.40 (br d, J = 2.66 Hz, 1H), 3.36 - 3.70 (m, 2H), 2.76 - 3.16 (m, 2H), 2.53 - 2.57 (m, 2H), 2.50 - 2.67 (m, 2H), 2.08 - 2.39 (m, 1H), 1.23 - 1.55 (m, 6H) A431 (400 MHz, DMSO-d6, ppm) δ 8.82 (br t, J = 5.39 Hz, 1H) 8.40 (s, 1H) 7.77 (d, J = 1.65 Hz, 2H) 7.66 - 7.73 (m, 1H) 7.20 (d, J = 8.36 Hz, 1H) 6.55 - 6.60 (range, 1H) 6.48 - 6.54 (range, 1H) 4.38 (br d, J = 5.45 Hz, 2H) 3.81 (s, 3H) 3.76 (s, 3H) 3.50 (dt, J = 13.88, 6.88 Hz, 1H) 2.53 (s, 3H) 1.50 (d, J = 6.84 Hz, 6H) A432 (400 MHz, DMSO-d6, ppm) δ 9.15 (d, J = 7.86 Hz, 1H), 8.62 (s, 1H), 7.62 - 7.82 (m, 5H), 6.98 (d, J = 8.49 Hz, 1H), 5.26 (m, 1H), 3.77 - 4.43 (m, 2H), 3.34 - 3.70 (m, 1H), 2.33 - 2.43 (m, 1H), 1.98 - 2.31 (m, 2H), 1.55 (m, 6H) A433 (400 MHz, DMSO-d6, ppm) δ 9.55 (d, J = 7.60 Hz, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.24 (m, 1H), 7.97 (d, J = 8.11 Hz, 1H), 7.68 - 7.80 (m, 3H), 5.89 (d, J = 7.10 Hz, 1H), 3.70 - 4.29 (m, 3H), 2.53 - 2.57 (m, 3H), 1.45 - 1.54 (m, 6H) A434 (400 MHz, DMSO-d6, ppm) δ 9.55 (d, J = 7.60 Hz, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.24 (m, 1H), 7.97 (d, J = 8.11 Hz, 1H), 7.68 - 7.80 (m, 3H), 5.89 (d, J = 7.10 Hz, 1H), 3.70 - 4.29 (m, 3H), 2.53 - 2.57 (m, 3H), 1.45 - 1.54 (m, 6H) A435 (400 MHz, DMSO-d6, ppm) δ 9.11 (d, J = 8.49 Hz, 1H), 8.37 (s, 1H), 7.38 - 7.79 (m, 4H), 6.82 (d, J = 5.07 Hz, 1H), 5.27 (d, J = 6.59 Hz, 1H), 3.36 - 3.67 (m, 1H), 2.53 - 2.62 (m, 5H), 1.52 - 2.14 (m, 10H) A436 (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H) 8.05 (br s, 1 H) 7.80 (br s, 1 H) 7.77 (d, J=1.90 Hz, 2 H) 7.68 (t, J=1.84 Hz, 1 H) 3.56 - 3.67 (m, 1 H) 2.54 (s, 3 H) 1.53 (d, J=6.97 Hz, 6 H) A437 (400 MHz, DMSO-d6, ppm) δ 9.11 (d, J = 8.49 Hz, 1H), 8.37 (s, 1H), 7.38 - 7.79 (m, 4H), 6.82 (d, J = 5.07 Hz, 1H), 5.27 (d, J = 6.59 Hz, 1H), 3.36 - 3.67 (m, 1H), 2.53 - 2.62 (m, 5H), 1.52 - 2.14 (m, 10H) A438 (400 MHz, DMSO-d6, ppm) δ 9.32 (d, J = 7.6 Hz, 1H), 8.42 (s, 1H), 8.10 - 8.17 (m, 3H), 7.64 - 7.83 (m, 1H), 7.21 - 7.31 (m, 2H), 5.66 - 5.77 (m, 1H), 4.93 (t, J = 9.4 Hz, 1H), 4.48 (m, 1H), 3.35 - 3.73 (m, 1H), 2.52 - 2.69 (m, 3H), 1.50 - 1.63 (m, 6H) A439 400 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 8.11 Hz, 1H), 8.44 (s, 1H), 7.66 - 7.79 (m, 3H), 6.94 - 7.17 (m, 2H), 6.52 - 6.63 (m, 2H), 3.88 - 5.17 (m, 1H), 2.53 - 3.60 (m, 7H), 1.44 - 2.33 (m, 8H) A440 400 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 8.11 Hz, 1H), 8.44 (s, 1H), 7.66 - 7.79 (m, 3H), 6.94 - 7.17 (m, 2H), 6.52 - 6.63 (m, 2H), 3.88 - 5.17 (m, 1H), 2.53 - 3.60 (m, 7H), 1.44 - 2.33 (m, 8H) A441 (400 MHz, DMSO-d6, ppm) δ 8.94 (d, J = 8.36 Hz, 1H), 8.43 (s, 1H), 7.66 - 7.80 (m, 3H), 6.87 - 7.36 (m, 2H), 5.09 - 5.17 (m, 1H), 3.37 - 3.78 (m, 1H), 2.53 - 2.77 (m, 5H), 2.23 - 2.41 (m, 1H), 1.51 - 2.09 (m, 9H) A442 (400 MHz, DMSO-d6, ppm) δ 9.32 (d, J = 7.6 Hz, 1H), 8.42 (s, 1H), 8.10 - 8.17 (m, 3H), 7.64 - 7.83 (m, 1H), 7.21 - 7.31 (m, 2H), 5.66 - 5.77 (m, 1H), 4.93 (t, J = 9.4 Hz, 1H), 4.48 (m, 1H), 3.35 - 3.73 (m, 1H), 2.52 - 2.69 (m, 3H), 1.50 - 1.63 (m, 6H) A443 (400 MHz, DMSO-d6, ppm) δ 8.94 (d, J = 8.36 Hz, 1H), 8.43 (s, 1H), 7.66 - 7.80 (m, 3H), 6.87 - 7.36 (m, 2H), 5.09 - 5.17 (m, 1H), 3.37 - 3.78 (m, 1H), 2.53 - 2.77 (m, 5H), 2.23 - 2.41 (m, 1H), 1.51 - 2.09 (m, 9H) A445 (400 MHz, DMSO-d6, ppm) δ 9.21 (d, J = 7.35 Hz, 1H), 8.44 (s, 1H), 7.66 - 7.78 (m, 3H), 7.30 (d, J = 8.24 Hz, 1H), 6.51 (m, 1H), 6.47 (d, J = 2.15 Hz, 1H), 5.65 (br d, J = 4.56 Hz, 1H), 4.81 (m, 1H), 4.40 (m, 1H), 3.56 - 3.74 (m, 4H), 2.52 - 2.55 (m, 3H), 1.50 - 1.59 (m, 6H) A446 (400 MHz, DMSO-d6, ppm) δ 9.21 (d, J = 7.35 Hz, 1H), 8.44 (s, 1H), 7.66 - 7.78 (m, 3H), 7.30 (d, J = 8.24 Hz, 1H), 6.51 (m, 1H), 6.47 (d, J = 2.15 Hz, 1H), 5.65 (br d, J = 4.56 Hz, 1H), 4.81 (m, 1H), 4.40 (m, 1H), 3.56 - 3.74 (m, 4H), 2.52 - 2.55 (m, 3H), 1.50 - 1.59 (m, 6H) A447 (400 MHz, DMSO-d6, ppm) δ 9.28 (d, J = 7.35 Hz, 1H), 8.46 (s, 1H), 7.66 - 7.79 (m, 3H), 7.43 (d, J = 7.35 Hz, 1H), 7.24 (t, J = 7.41 Hz, 1H), 6.94 (t, J = 7.41 Hz, 1H), 6.87 (d, J = 7.98 Hz, 1H), 5.72 - 5.80 (m, 1H), 4.80 (t, J = 9.19 Hz, 1H), 4.29 - 4.38 (m, 1H), 3.58 (m, 1H), 2.53 - 2.56 (m, 3H), 1.50 - 1.60 (m, 6H) A448 (400 MHz, DMSO-d6, ppm) δ 9.20 (d, J = 7.35 Hz, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 7.67 - 7.80 (m, 3H), 5.21 - 5.27 (m, 1H), 4.28 - 4.43 (m, 2H), 3.58 (m, 1H), 2.52 - 2.67 (m, 3H), 2.00 - 2.45 (m, 2H), 1.52 (m, 6H) A451 (400 MHz, DMSO-d6, ppm) δ 9.20 (d, J = 7.35 Hz, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 7.67 - 7.80 (m, 3H), 5.21 - 5.27 (m, 1H), 4.28 - 4.43 (m, 2H), 3.58 (m, 1H), 2.52 - 2.67 (m, 3H), 2.00 - 2.45 (m, 2H), 1.52 (m, 6H) A452 (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 8.49 Hz, 1H), 8.53 (s, 1H), 7.78 (d, J = 1.90 Hz, 2H), 7.68 (t, J = 1.84 Hz, 1H), 7.36 (d, J = 7.73 Hz, 1H), 7.17 (t, J = 7.71 Hz, 1H), 6.92 (t, J = 7.26 Hz, 1H), 6.76 (d, J = 8.11 Hz, 1H), 5.32 (m, 1H), 3.52 - 3.62 (m, 1H), 2.52 - 2.58 (m, 3H), 2.21 (m, 1H), 1.80 - 1.89 (m, 1H), 1.23 - 1.61 (m, 12H) A453 (400 MHz, DMSO-d6, ppm) δ 9.28 (d, J = 7.35 Hz, 1H), 8.46 (s, 1H), 7.66 - 7.79 (m, 3H), 7.43 (d, J = 7.35 Hz, 1H), 7.24 (t, J = 7.41 Hz, 1H), 6.94 (t, J = 7.41 Hz, 1H), 6.87 (d, J = 7.98 Hz, 1H), 5.72 - 5.80 (m, 1H), 4.80 (t, J = 9.19 Hz, 1H), 4.29 - 4.38 (m, 1H), 3.58 (m, 1H), 2.53 - 2.56 (m, 3H), 1.50 - 1.60 (m, 6H) A454 (400 MHz, DMSO-d6, ppm) δ 9.17 (d, J = 8.11 Hz, 1H) 8.54 (s, 1H) 7.78 (d, J = 1.77 Hz, 2H) 7.68 (t, J = 1.90 Hz, 1H) 7.54 (d, J = 7.98 Hz, 1H) 7.36 (dd, J = 7.86, 1.52 Hz, 1H) 7.31 (d, J = 1.52 Hz, 1H) 5.30 (q, J = 6.67 Hz, 1H) 4.24 - 4.39 (m, 2H) 3.50 - 3.65 (m, 1H) 2.55 (s, 3H) 2.15 - 2.31 (m, 1H) 1.99 - 2.15 (m, 1H) 1.54 (dd, J = 11.09, 6.91 Hz, 6H) A455 (400 MHz, DMSO-d6, ppm) δ 9.41 (d, J = 7.35 Hz, 1H), 8.51 (s, 1H), 8.27 - 8.42 (m, 2H), 7.66 - 7.79 (m, 4H), 5.82 - 5.90 (m, 1H), 4.93 (t, J = 9.38 Hz, 1H), 3.61 - 4.54 (m, 1H), 2.53 - 2.58 (m, 3H), 1.48 - 1.53 (m, 3H), 1.45 - 1.51 (m, 4H) A456 (400 MHz, DMSO-d6, ppm) δ 9.41 (d, J = 7.35 Hz, 1H), 8.51 (s, 1H), 8.27 - 8.42 (m, 2H), 7.66 - 7.79 (m, 4H), 5.82 - 5.90 (m, 1H), 4.93 (t, J = 9.38 Hz, 1H), 3.61 - 4.54 (m, 1H), 2.53 - 2.58 (m, 3H), 1.48 - 1.53 (m, 3H), 1.45 - 1.51 (m, 4H) A457 (400 MHz, DMSO-d6, ppm) δ 9.33 (d, J = 7.10 Hz, 1H), 8.52 (s, 1H), 7.66 - 7.79 (m, 3H), 7.48 (s, 1H), 7.20 - 7.28 (m, 1H), 6.90 (d, J = 8.49 Hz, 1H), 5.73 (br d, J = 5.20 Hz, 1H), 4.85 (t, J = 9.25 Hz, 1H), 4.43 (m, 1H), 3.35 - 3.63 (m, 1H), 2.53 - 2.56 (m, 3H), 1.50 - 1.53 (m, 6H) A458 (400 MHz, DMSO-d6, ppm) δ 9.33 (d, J = 7.10 Hz, 1H), 8.52 (s, 1H), 7.66 - 7.79 (m, 3H), 7.48 (s, 1H), 7.20 - 7.28 (m, 1H), 6.90 (d, J = 8.49 Hz, 1H), 5.73 (br d, J = 5.20 Hz, 1H), 4.85 (t, J = 9.25 Hz, 1H), 4.43 (m, 1H), 3.35 - 3.63 (m, 1H), 2.53 - 2.56 (m, 3H), 1.50 - 1.53 (m, 6H) A472 (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 8.49 Hz, 1H), 8.53 (s, 1H), 7.78 (d, J = 1.90 Hz, 2H), 7.68 (t, J = 1.84 Hz, 1H), 7.36 (d, J = 7.73 Hz, 1H), 7.17 (t, J = 7.71 Hz, 1H), 6.92 (t, J = 7.26 Hz, 1H), 6.76 (d, J = 8.11 Hz, 1H), 5.32 (m, 1H), 3.52 - 3.62 (m, 1H), 2.52 - 2.58 (m, 3H), 2.21 (m, 1H), 1.80 - 1.89 (m, 1H), 1.23 - 1.61 (m, 12H) 560 (400 MHz, chloroform-d, ppm) δ: 8.35 (s, 1H), 7.51 (s, 2H), 7.65 (s, 1H), 7.29-7.21 (m, 2H), 7.01-6.84 (m, 3H), 6.20 (d, J = 8.3 Hz, 1H), 6.08-6.07 (m, 1H), 5.40 (d, J = 8.3 Hz, 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)

[0372] [Preparation Example] [3] [:] Example compounds A400, A401, A405, and A459 were prepared according to process 8, wherein the reactants were adapted from known reactions in the literature. For example, see 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.

[0373] [ ] [process] [8]

[0374] [ ] [Description of Key Steps: Synthesis] [3] [-(] [3] [,] [5] [-] [Dichlorophenyl] [)-] [8] [-(] [4] [,] [4] [-] [Difluorocyclohexyl] [)-] [2] [-] [Methylimidazo] [[] [1] [,] [2] [-] [b] []] [despair] [𠯤] [-] [7] [-] Methyl formate [(] [8] [-] [6] [)] [ ] A mixture of 90 mg (0.3 mmol) of methyl 3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]-dalcetin-7-carboxylate (8-5) in 5 mL of DMSO was treated with 200 mg (1.0 mmol) of zinc sulfite and cooled in an ice bath. 185 µL (1 mmol) of 2-methyl-propyl-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 evaporated mixture was purified by column chromatography (silicone; CyH / EtOAc) and solvent was removed under vacuum to give 900 mg (74%) of a yellow oily product. (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).

[0375] The conversion of compound 8-6 to the product can be achieved as in process 4 by hydrolyzing the methyl ester into a carboxylic acid, followed by coupling the acid with the desired amine.

[0376] As mentioned above, compounds A400, A401 and A405 are prepared using the process described in step 8. [Compound] [, 1 , ] [H NMR] [Spectrum] A400 (400 MHz, DMSO-d6) δ ppm 9.12 (d, J=7.98 Hz, 1 H) 8.69 (s, 1 H) 7.79 (d, J=1.90 Hz, 2 H) 7.71 - 7.75 (m, 1 H) 7.34 (d, J=7.73 Hz, 1 H) 7.18 (t, J=7.67 Hz, 1 H) 6.92 (t, J=7.09 Hz, 1 H) 6.80 (d, J=8.11 Hz, 1 H) 5.14 - 5.22 (m, 1 H) 4.24 - 4.34 (m, 1 H) 4.13 - 4.24 (m, 1 H) 2.67 (dt, J=3.68, 1.84 Hz, 1 H) 2.56 (s, 3 H) 2.27 (t, J=19.33 Hz, 3 H) 2.10 - 2.21 (m, 1 H) 1.96 - 2.08 (m, 1 H A401 (400 MHz, DMSO-d6) δ ppm 9.34 (d, J=8.11 Hz, 1 H) 8.84 (s, 1 H) 7.80 (d, J=1.90 Hz, 2 H) 7.74 - 7.77 (m, 1 H) 7.33 (d, J=7.10 Hz, 1 H) 7.19 (t, J=7.10 Hz, 1 H) 6.93 (t, J=7.03 Hz, 1 H) 6.81 (d, J=8.11 Hz, 1 H) 5.16 - 5.23 (m, 1 H) 4.23 - 4.33 (m, 1 H) 4.14 - 4.23 (m, 1 H) 2.58 (s, 3 H) 2.16 - 2.27 (m, 1 H) 1.98 - 2.07 (m, 1 H) A405 (400 MHz, DMSO-d6) δ ppm 9.29 (d, J=7.98 Hz, 1 H) 8.77 (s, 1 H) 7.80 (d, J=1.90 Hz, 2 H) 7.73 (d, J=1.90 Hz, 1 H) 7.60 (t, J=52.00 Hz, 1 H) 7.36 (d, J=6.97 Hz, 1 H) 7.16 - 7.21 (m, 1 H) 6.92 (td, J=7.45, 1.08 Hz, 1 H) 6.81 (d, J=8.11 Hz, 1 H) 5.19 - 5.25 (m, 1 H) 4.19 - 4.31 (m, 2 H) 2.58 (s, 3 H) 2.15 - 2.24 (m, 1 H) 2.03 - 2.11 (m, 1 H

[0377] [Preparation Example] [4] [:] Example 304-0 was prepared according to the following procedure 9. Similarly, compound 321 can be prepared in the same manner by someone skilled in this art.

[0378] [ ] [process] [9]

[0379] [ ] [1.] [synthesis] [2-(3,5-] [Dichlorophenyl] [)-8-] [Hydroxyimidazole] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(9-2)] Ethyl 2-bromo-8-hydroxyimidazo[1,2-b]-dichlorophenyl-7-carboxylate (3-6, 2.0 g, 0.007 mmol, 1.0 equivalent) and 3,5-dichlorophenylcarboxylate were placed in a 500 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Acid (1.6 g, 0.008 mmol, 1.2 equivalents), K₂CO₃ (2.1 g, 0.015 mmol, 2.2 equivalents), dialkylene (100.0 mL), H₂O (20.0 mL), Pd(dtbpf)Cl₂ (0.27 g, 0.000 mmol, 0.06 equivalents). The solution was stirred in an oil bath at 100 °C for 1 hour. The reaction was then quenched by adding 100 mL of water. The solid was collected by filtration. This yielded 2.1 g (85.3%) of ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]-diethyl-7-carboxylate (9-2) as a grayish-white solid. (ES, m / z): 352 [M+H]+.

[0380] [ ] [2.] [synthesis] [8-] [bromine] [-2-(3,5-] [Dichlorophenyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(9-3)] Ethyl 2-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]-diethyl-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 equivalent) were placed in a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 80 °C overnight. The 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 saturated Na2CO3. The resulting solution was extracted with 3 × 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:10). This yields 810 mg (34.4%) of ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]tadalafil-7-carboxylate (9-3) as a grayish-white solid. (ES, m / z): 414 [M+H]+.

[0381] [ ] [3.] [synthesis] [2-(3,5-] [Dichlorophenyl] [)-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(9-4)] Ethyl 8-bromo-2-(3,5-dichlorophenyl)imidazo[1,2-b]pyroxene-7-carboxylate (9-3, 1800.0 mg, 4.4 mmol, 1.0 equivalent), K3PO4 (2761.5 mg, 13.0 mmol, 3.0 equivalent), 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-(prop-1-en-2-yl)-1,3,2-dioxoboron (801.6 mg, 4.8 mmol, 1.1 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 hour. The reactants were then quenched by adding 20 mL of water. The solution was extracted with 3 × 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:10). This yielded 0.55 g (33.7%) of ethyl 2-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]-tert-7-carboxylate (9-4) as a grayish-white solid. (ES, m / z): 376 [M+H]+.

[0382] [ ] [4.] [synthesis] [2-(3,5-] [Dichlorophenyl] [)-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(9-5)] Ethyl 2-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-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 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert H2 atmosphere (g). The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The filtrate was concentrated. This yielded 450 mg (82.4%) of ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylate (9-5) as a grayish-white solid. (ES, m / z): 378 [M+H]+.

[0383] [ ] [5.] [synthesis] [3-] [chlorine] [-2-(3,5-] [Dichlorophenyl] [)-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(9-6)] Ethyl 2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-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 equivalent) were placed in a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 50 °C overnight. The resulting mixture was concentrated. The residue was applied to a silicone column and dissociated with EA / PE (1 / 20). This yielded 106.6 mg (97.7%) of ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylate as a grayish-white solid (9-6). (ES, m / z): 412 [M+H]+.

[0384] [ ] [6.] [synthesis] [3-] [chlorine] [-2-(3,5-] [Dichlorophenyl] [)-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(9-7)] Place ethyl 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-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 equivalent) into a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at room temperature. Adjust the pH of the solution to 3–4 with HCl (1 mol / L). Extract the resulting solution with 3 × 10⁻⁶ mL of ethyl acetate and combine the organic layers. Dry the organic phase in an oven under reduced pressure and concentrate. This produces 78 mg (88.1%) of 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylic acid (9-7) as a grayish-white solid. (ES, m / z): 384 [M+H]+.

[0385] [ ] [7.] [synthesis] [3-] [chlorine] [-2-(3,5-] [Dichlorophenyl] [)-N-[(4S)-6-] [fluorine] [-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [304-0)] Place (4S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-amine dihydrochloride (51.0 mg, 0.2 mmol, 1.2 equivalents), 3-chloro-2-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyroxyl-7-carboxylic acid (9-7, 68.0 mg, 0.2 mmol, 1.0 equivalents), DMF (5.0 mL), DIEA (45.7 mg, 0.35 mmol, 2.0 equivalents), and HATU (100.8 mg, 0.3 mmol, 1.5 equivalents) into a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at room temperature. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from ACN:H2O=72 to ACN:H2O=95 over 7 minutes; detector, 254 nm. This yielded 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]pyridine-7-methamide (304-0) as a grayish-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).

[0386] 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)

[0387] [Preparation Example] [5] [:]Prepared according to process 10: Example 174: [process]

[10]

[0388] [ ] [1.] [synthesis] [N-(5-)] [chloride] [𠯤] [-3-] [base] [)-1,1-] [Diphenylmethyleneimine] [(10-2)) ] Place 3,5-dichlorodichlorodiphenyl ether (10⁻¹, 500.0 mg, 3.4 mmol, 1.0 equivalent), diphenylmethyleneimine (675.2 mg, 3.7 mmol, 1.1 equivalent), XantPhos (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 dimethyl ether (5 mL) into a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution in an oil bath at 90 °C for 3 hours. Filter off the solids. Concentrate the resulting mixture. This produces 3 mL (30.4%) of N-(5-chlorodiphenyl-3-yl)-1,1-diphenylmethyleneimine (10⁻²), which is a brown oily substance.

[0389] [ ] [2.] [synthesis] [5-] [chloride] [𠯤] [-3-] [amine] [ ] [ ] N-(5-chlorodiphenyl-3-yl)-1,1-diphenylmethyleneimine (10⁻², 10.0 mL) and HCl (3M) (15.0 mL) were placed in a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. 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. This produced 15 mL of 5-chlorodiphenyl-3-amine (5⁻¹), which was a brown oil.

[0390] [ ] [3.] [synthesis] [7-] [Clomidazol] [[1,2-b]] [despair] [𠯤] [(10-4)] [ ] 5-chloropyrazo-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 with 3 × 50 mL of ethyl acetate, and the organic layer was washed with 3 × 50 mL of brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silicone column with ethyl acetate / petroleum ether (2:3). This produced 2.2 g (12.4%) of 7-chloroimidazolo[1,2-b]pyrazo-3-amine (10⁻⁴) as a yellow oil.

[0391] [4.] [synthesis] [7-] [chlorine] [-3-] [Ioimidazole] [[1,2-b]] [despair] [𠯤] [(10-5)] 7-chloro-3-iodoimidazole[1,2-b]dal (1.0 g, 7.0 mmol, 1.0 equivalent), NIS (2.2 g, 10.0 mmol, 1.5 equivalent), and DMF (10 mL) were placed in a 50 mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction mixture was then quenched by adding 20 mL of water. The solution was extracted with 3 × 20 mL concentrated ethyl acetate. The residue was fed onto a silicone column with ethyl acetate / petroleum ether (2:1). This produced 800 mg (43.9%) of 7-chloro-3-iodoimidazole[1,2-b]dal as a yellow oil.

[0392] [ ] [5.] [synthesis] [7-] [chlorine] [-3-(2,6-] [Difluorophenyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [(10-6)] [ ] Place 7-chloro-3-iodoimidazole[1,2-b]dalte (10⁻⁵, 400.0 mg, 1.4 mmol, 1.0 equivalent) and 2,6-difluorophenyl into a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. 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), H2O (2.5 mL). The resulting solution was stirred at room temperature for 1 hour overnight. The resulting mixture was concentrated. The residue was applied to a silicone column containing ethyl acetate / petroleum ether (1:3). This produced 150 mg (39.4%) of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]tadalafil (10-6) as a white solid.

[0393] [ ] [6.] [synthesis] [3-(2,6-] [Difluorophenyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Methyl formate [(10-7)] 130.0 mg (0.5 mmol, 1.0 equivalent) of 7-chloro-3-(2,6-difluorophenyl)imidazo[1,2-b]tadalafil (10⁻⁶), 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 placed in a 50 mL pressure tank reactor. 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 silicone column containing ethyl acetate / petroleum ether (1:3). This produced 95 mg (67.1%) of methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]tadalafil-7-carboxylate (10⁻⁷) as a white solid. [ ]

[0394] [ ] [7.] [synthesis] [3-(2,6-] [Difluorophenyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(10-8)] [ ] Methyl 3-(2,6-difluorophenyl)imidazo[1,2-b]tadalafil-7-carboxylic acid (10⁻⁷, 85.0 mg, 0.3 mmol, 1.0 equivalent), NaOH (58.7 mg, 1.5 mmol, 5.0 equivalent), MeOH (9 mL), and H₂O (3 mL) were placed in a 40 mL round-bottom flask. The resulting solution was stirred at room temperature for 3 hours. The solution was diluted with 20 mL of water. The pH of the solution was adjusted to 3-4 with HCl (3 mol / L). The solution was extracted with 3 × 20 mL of ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. This yielded 65 mg (80.4%) of 3-(2,6-difluorophenyl)imidazo[1,2-b]tadalafil-7-carboxylic acid (10⁻⁸) as a white solid.

[0395] [ ] [8.] [synthesis] [3-(2,6-] [Difluorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [174)] [ ] Place 3-(2,6-difluorophenyl)imidazo[1,2-b]pyro-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 equivalent), HATU (165.79 mg, 0.436 mmol, 2 equivalent), DIEA (84.5 mg, 0.6 mmol, 3.0 equivalent), and DMF (3 mL) into a 40 mL round-bottom flask. Stir the resulting solution at room temperature for 2 hours. The crude product was purified by preparative HPLC under the following conditions (Waters-2767): column, X-bridge RP18, 5 µm, 19 × 100 mm; mobile phase, water containing 0.03% ammonia and CH3CN (30% CH3CN increased to 70% within 15 minutes); detector, UV 254 nm. This yielded 19.4 mg (21.9%) of 3-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]imidazo[1,2-b]pyridine-7-methylamine (174) as a white solid. (300 MHz, CDCl3, ppm) δ 8.95 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.55-7.45 (m, 1H), 7.25-7.24 (m, 1H), 7.17-7.08 (m, 4H), 6.91-6.81 (m, 2H), 5.43-5.39 (m, 1H), 4.35-4.25 (m, 2H), 2.41-2.31 (m, 1H), 2.28-2.21 (m, 1H).

[0396] [Preparation Example] [6] Example 277 was prepared according to the following procedure 11: [process]

[11]

[0397] [ ] [1.] [synthesis] [8-] [chlorine] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(271-1)] Ethyl 8-hydroxy-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (3-7, 2.8 g, 12.6 mmol, 1.0 equivalent), DMF (8.0 uL, 103.4 mmol, 8.2 equivalent), and CHCl3 (55.0 mL) were placed in a 100 mL round-bottom flask. Then, (COCl)2 (8.0 g, 63.1 mmol, 5.0 equivalent) was added dropwise at room temperature with stirring. 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, C18 silica gel; mobile phase, 0.1% FA / water and CH3CN (increased from 10% CH3CN to 70% over 12 minutes). Detector, UV 254 nm, 220 nm. This produces 537 mg (17.2%) of ethyl 8-chloro-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (271-1) as a yellow solid.

[0398] [ ] [2.] [synthesis] [2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-2)] Place ethyl 8-chloro-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (271-1,480.0 mg, 2.0 mmol, 1.0 equivalent), dimethyl ether (19.0 mL), H₂O (4.8 mL), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoboron (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) into a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at 80 °C. Dilute the resulting solution with 10 mL of water. The resulting solution was extracted with 2 × 20 mL of ethyl acetate, and the organic layers were combined. The mixture was washed with 2 × 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silicone column with ethyl acetate / petroleum ether (0-20%). This produced 370 mg (73.0%) of ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]-diethyl-7-carboxylate (4-2) as a brown solid.

[0399] [ ] [3.] [synthesis] [3-] [bromine] [-2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(11-4)] Ethyl 2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-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 equivalent) were placed in a 40 mL round-bottom flask. The resulting solution was stirred at 65 °C for 30 minutes. The solution was diluted with 20 mL of water. The resulting solution was extracted with 2 × 20 mL of dichloromethane and the organic layers were combined. The mixture was washed with 2 × 20 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated. This yielded 491 mg (95.4%) of ethyl 3-bromo-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate as a brown solid (11-4).

[0400] [ ] [4.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(11-5)] Place ethyl 3-bromo-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyroxene-7-carboxylate (11-4,490.0 mg, 1.5 mmol, 1.0 equivalent), dimethyl ether (10.0 mL), H2O (2.5 mL), and 3,5-difluorophenyl into a 50 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Acid (477.4 mg, 3.0 mmol, 2.0 equivalent), K2CO3 (626.7 mg, 4.535 mmol, 3.0 equivalent), Pd(dtbpf)Cl2 (98.5 mg, 0.15 mmol, 0.1 equivalent). The resulting solution was stirred at 100 °C for 30 minutes. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2 × 50 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was fed onto a silicone column with ethyl acetate / petroleum ether (0-15%). This produced 442 mg (80.2%) of ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate (11-5) as a yellow-green solid.

[0401] [ ] [5.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(11-6)] Place ethyl 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-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 equivalent) into a 50 mL three-necked round-bottom flask. Stir the resulting solution at room temperature for 1 hour. Concentrate the resulting mixture. Adjust the pH of the solution to 3 with HCl (2 mol / L). Extract the resulting solution with 2 × 20 mL of ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate. This produces 401 mg (89.0%) of 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylic acid (11-6) as a yellow solid.

[0402] [ ] [6.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-2-] [methyl] [-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(11-7)] Place 3-(3,5-difluorophenyl)-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyroxyl-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), DIEA (471.0 mg, 3.6 mmol, 3.0 equivalent), and HATU (692.8 mg, 1.8 mmol, 1.5 equivalent) into a 50 mL three-necked round-bottom flask. Stir the resulting solution 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% NH4HCO3 / water and CH3CN (increased from 30% CH3CN to 80% over 10 minutes); detector, UV 254 nm, 220 nm. This yielded 520 mg (92.0%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyrazol-7-methylamine (11-7) as a green solid.

[0403] [ ] [7.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-(2-] [Hydroxypropyl] [-2-] [base] [)-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(11-8)] Place 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-8-(prop-1-en-2-yl)imidazo[1,2-b]pyridine-7-methylamine (11-7, 200.0 mg, 0.4 mmol, 1.0 equivalent), ethanol (8.0 mL), toluene (8.0 mL), NaBH4 (32.9 mg, 0.9 mmol, 2.0 equivalent), and Mn(OAc)3·2H2O (9.3 mg, 0.03 mmol ... 10.8 mg (0.03 mmol, 0.08 equivalent) of 2-[(1E)-([3-[(E)-[(2-hydroxyphenyl)methylene]amino]-2,2-dimethylpropyl]imino]methyl]phenol (0.03 mg, 0.08 equivalent). O2 (g) was introduced into the above. The resulting solution was stirred at room temperature for 4 hours. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2 × 20 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 2 × 20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This yielded 250 mg (crude) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropyl-2-yl)-2-methylimidazo[1,2-b]pyridine-7-methylamine (11-8) as a yellow oil.

[0404] [ ] [8.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-(2-] [Fluoropropyl] [-2-] [base] [)-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [277)] Place 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-hydroxypropyl-2-yl)-2-methylimidazo[1,2-b]-dalbin-7-methamide (11-8, 200.0 mg, 0.4 mmol, 1.0 equivalent) and DCM (10.0 mL) into a 25 mL three-necked round-bottom flask. Then, add DAST (134.7 mg, 0.8 mmol, 2.0 equivalent) dropwise with stirring at room temperature. Stir the resulting solution at room temperature for 1 hour. Concentrate the resulting mixture. Purify the crude product using Prep-Flash under the following conditions: column, C18 silica gel; mobile phase, 0.1% TFA / water and CH3CN (increased from 50% CH3CN to 100% over 10 minutes). Detector, UV 254 nm, 220 nm. This produces 9.5 mg (4.6%) of 3-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-(2-fluoroprop-2-yl)-2-methylimidazo[1,2-b]tadalafil-7-methoxyamine (277) as a white solid. (300 MHz, CDCl3, ppm) δ 8.26 (s, 1H), 7.35-7.33 (m, 1H), 7.29-7.19 (m, 3H), 6.98-6.85 (m, 3H), 5.94 (d, J = 7.5 Hz, 1H), 5.32-5.29 (m, 1H), 4.38-4.33 (m, 1H), 4.23-4.18 (m, 1H), 2.62 (s, 3H), 2.40-2.24 (m, 2H), 2.15 (d, J = 6.3 Hz, 3H), 2.08 (d, J = 6.3 Hz, 3H).

[0405] [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 by means of the process shown in process 12 below.

[0406] [ ] [process]

[12] [ ]

[0407] [ ] [1.] [synthesis] [8-] [Level 3 Butyl] [-3-(3,5-] [Dichlorophenyl] [)-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(12-2)] [ ] LiBr (6.9 g, 791.9 mmol, 7.5 equivalents) was added to a stirred mixture of ethyl 8-bromo-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (12-1, 30.0 g, 105.6 mmol, 1.0 equivalent) in THF (750.00 mL) at 0 °C under a nitrogen atmosphere. CuI (150.8 g, 791.9 mmol, 7.5 equivalents) was added dropwise to the mixture at 0 °C over 30 minutes. The resulting mixture was stirred at 0 °C for another 30 minutes. Tertiary butylmagnesium (310.5 mL, 527.9 mmol, 5.0 equivalents) was added dropwise to the mixture at 0 °C for 1 hour. The resulting mixture was stirred at 0 °C for another 5 minutes. The reaction was quenched at 0 °C by adding saturated NH4Cl (aqueous solution) (400 mL). The mixture was extracted with EtOAc (2 × 800 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture of ethyl 8-tert-butyl-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (12-2.33 g, crude product) was used directly in the next step without further purification.

[0408] [ ] [2.] [synthesis] [3-] [bromine] [-8-] [Level 3 Butyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(12-3)] NBS (19.0 g, 107.1 mmol, 1.0 equivalent) was added to a stirred solution of ethyl 8-tributyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (12-2, 28.0 g, 107.1 mmol, 1.0 equivalent) in CHCl3 (300.0 mL). The mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The mixture was then cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using PE / EtOAc (3:1) to give ethyl 3-bromo-8-tributyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (12-3, 29.5 g, 80.9%) as a yellow solid.

[0409] [ ] [synthesis] [8-] [Level 3 Butyl] [-3-(3,5-] [Dichlorophenyl] [)-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(12-4)] [ ] At room temperature under a nitrogen atmosphere, ethyl 3-bromo-8-tributyl-2-methylimidazo[1,2-b]-dichlorophenyl 7-carboxylate (12-3, 26.0 g, 76.4 mmol, 1.0 equivalent) and 3,5-dichlorophenyl K₂CO₃ (31.7 g, 229.2 mmol, 1.0 equivalent) and Pd(dtbpf)Cl₂ (4980.7 mg, 7.6 mmol, 0.1 equivalent) were added to a stirred mixture of acid (14.5 g, 76.4 mmol, 1.0 equivalent) in THF (240.0 mL) and H₂O (60.0 mL). The mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The mixture was then cooled to room temperature. The mixture was concentrated under vacuum. The resulting mixture was diluted with water (800 mL). The mixture was extracted with EtOAc (2 × 800 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by dissolution with PE / EtOAc (8:1) using silicone column chromatography to obtain ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (12-4, 19 g, 61.2%) as a grayish-white solid.

[0410] [ ] [3.] [synthesis] [8-] [Level 3 Butyl] [-3-(3,5-] [Dichlorophenyl] [)-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(12-5)] [ ] Place ethyl 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (12-4, 18.0 g, 44.3 mmol, 1.0 equivalent), MeOH (100.0 mL, 344.3 mmol, 28.0 equivalent), THF (100.0 mL), H₂O (200.0 mL), and KOH (53.1 g, 1329.0 mmol, 30.0 equivalent) into a 250 mL round-bottom flask. Stir the resulting solution at 80 °C for 48 hours. Concentrate the mixture under vacuum. Dilute the resulting solution with 50 mL of water. Adjust the pH of the solution to 4 with HCl (2 mol / L). Collect the solid by filtration. Dry the solid in an oven under reduced pressure. This produces 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (12-5,18 g, crude product), which is a grayish-white solid.

[0411] [ ] [4.] [synthesis] [8-] [Level 3 Butyl] [-3-(3,5-] [Dichlorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(] [Compound] [306)] DIEA (17.4 g, 134.8 mmol, 3.0 equivalent) and HATU (20.5 g, 53.9 mmol, 1.2 equivalent) were added to a stirred mixture of 8-tert-butyl-3-(3,5-dichlorophenyl)-2-methylimidazo[1,2-b]pyran-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 equivalent) in DMF (80.0 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise to 300 mL of H2O. The precipitate was collected by filtration and washed with water (2 × 20 mL). The residue was dissolved in MeCN (200 mL). 800 mL of H2O was then added dropwise. The precipitated solid was collected by filtration. The 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]pyridine-7-methylamine (306 g, 17.2 g, 75.1%), which was 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) [Compound] [, 1 , ] [H NMR] [spectrum] 297 (300 MHz, CDCl3, ppm): δ 8.04 (s, 1H), 7.55 (d, J = 1.8 Hz, 2H), 7.38 (s, 1H), 6.98-6.88 (m, 2H), 6.12 (d, J = 6.9 Hz, 1H), 5.29 (t, J = 5.4 Hz, 1H), 4.34-4.29 (m, 1H), 4.18-4.11 (m, 1H), 2.59 (s, 1H), 2.38-2.31 (m, 1H), 2.19-2.14 (m, 1H), 1.75 (s, 9H) 298 (300 MHz, CDCl3, ppm) δ 8.16 (s, 1H), 7.50-7.46 (m, 3H), 7.26-7.19 (m, 2H), 6.97-6.91 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.06 (d, J = 7.2 Hz, 1H), 5.33-5.31 (m, 1H), 4.38-4.33 (m, 1H), 4.21-4.13 (m, 1H), 2.39-2.34 (m, 1H), 2.26-2.21 (m, 1H), 1.76 (s, 9H) 298-0 (300 MHz, CDCl3, ppm) δ 8.16 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.52-7.47 (m, 3H), 6.99-6.93 (m, 2H), 6.90-6.79 (m, 1H), 6.05 (d, J = 7.5 Hz, 1H), 5.34 (q, J = 5.7 Hz, 1H), 4.37-4.34 (m, 1H), 4.19-4.16 (m, 1H), 2.48-2.32 (m, 1H), 2.28-2.12 (m, 1H), 1.79 (s, 9H) 299 (300 MHz, CDCl3, ppm) δ 8.18 (s, 1H), 7.53-7.49 (m, 3H), 6.99-6.93 (m, 2H), 6.87-6.82 (m, 1H), 6.09 (d, J = 7.5 Hz, 1H), 5.37-5.31 (m, 1H), 4.39-4.32 (m, 1H), 4.22-4.14 (m, 1H), 2.42-2.36 (m, 1H), 2.24-2.18 (m, 1H), 1.79 (s, 9H) 299-0 (300 MHz, CDCl3, ppm) 8.16 (s, 1H), 7.60 (s, 1H), 7.57-7.44 (m, 3H), 6.96 (t, J = 8.1 Hz, 2H), 6.92-6.79 (m, 1H), 6.07 (d, J = 7.8 Hz, 1H), 5.35 (q, J = 5.7 Hz, 1H), 4.37-4.34 (m, 1H), 4.24-4.11 (m, 1H), 2.44-2.40 (m, 1H), 2.30-2.13 (m, 1H), 1.79 (s, 9H) 418 (300 MHz, DMSO-d6, ppm) δ 8.33 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.35 (s, 1H) 7.25-7.15 (m, 3H), 6.99-6.85 (m, 1H), 6.84-6.80 (m, 1H), 6.25 - 6.20 (m, 1H), 5.35 - 5.30 (m, 1H), 4.36-4.15 (m, 2H), 2.50-2.22 (m, 2H), 1.73 (s, 9H) 420 (300 MHz DMSO-d6, ppm): δ 8.15 (s, 1H), 7.75 (s, 2H) 7.44 (s, 1H), 7.00-6.79 (m, 2H), 6.15 - 6.30 (m, 1H), 5.25 - 5.32 (m, 1H), 4.30 - 4.47 (m, 1H), 4.10 - 4.15 (m, 1H), 2.40-2.38 (m, 1H), 2.25-2.10 (m, 1H), 1.80 (bs, 9H) 523 (300 MHz DMSO-d6, ppm): δ 8.08 (s, 1H), 7.15-7.44 (m, 3H), 7.00-6.79 (m, 2H), 6.10 - 6.21 (m, 1H), 5.36 - 5.43 (m, 1H), 4.30 - 4.49 (m, 1H), 4.10 - 4.18 (m, 1H), 2.40-2.38 (m, 4H), 2.28-2.26 (m, 1H), 1.80 (bs, 9H) 524 (300 MHz DMSO-d6, ppm): δ 9.20 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 7.48-7.42 (m, 2H), 7.36-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.92 (t, J = 7.5, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.19-5.16 (m, 1H), 4.28-4.19 (m, 2H), 2.35 (s, 3H), 2.20-2.18 (m, 1H), 2.10-2.00 (m, 1H), 1.68 (s, 9H) 525 300 MHz DMSO-d6, ppm): δ 9.20 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 7.74-7.68 (m, 1H), 7.47-7.42 (m, 1H), 7.37-7.34 (m, 1H), 7.21-7.15 (m, 1H), 6.94-6.90(m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.20-5.17 (m, 1H), 4.28-4.19 (m, 3H), 2.43 (s, 3H), 2.19-2.16 (m, 1H), 2.05-1.99 (m, 1H), 1.68 (s, 9H) 526 (300 MHz DMSO-d6, ppm): δ 8.31 (s, 1H), 7.47-7.44 (m, 2H), 7.26-6.79 (m, 5H), 5.41 (bss, 1H), 4.36 (bs, 2H), 2.55 (bs, 3H), 2.40-2.38 (m, 1H), 2.28-2.26 (m, 1H), 1.80 (bs, 9H) 571 (300 MHz, CDCl3, ppm) δ 8.11 (s, 1H), 7.28-7.21 (m, 2H), 6.97-6.85(m, 4H), 6.12-6.10 (m, 1H), 5.35-5.32 (m, 1H), 4.39-4.33 (m, 1H), 4.22-4.14 (m, 1H), 2.42-2.35 (m, 1H), 2.27-2.21(m, 1H), 1.78 (s, 9H) 572 (400 MHz, CD3OD, ppm) δ 8.21 (s, 1H), 7.48 (d, J = 6.3 Hz, 2H), 7.31 (d, J = 5.7 Hz, 1H), 7.16 (t, J = 5.7 Hz, 1H), 6.94 (t, J = 5.7 Hz, 1H), 6.82 (d, J = 5.7 Hz, 1H), 5.28 (bt, J = 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.23-4.17 (m, 1H), 2.30-2.23 (m, 1H), 2.19-2.14 (m, 1H), 1.75 (s, 9H) 573 (300 MHz, CDCl3, ppm) δ 8.11 (s, 1H), 7.24-7.17 (m, 2H), 7.13-7.03 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.09-6.08 (m, 1H), 5.32-5.30 (m, 1H), 4.36-4.33 (m, 1H), 4.19-4.14 (m, J = 10.5 Hz, 1H), 2.39-2.36 (m, 1H), 2.23-2.20 (m, 1H), 1.75 (s, 9H) 574 (300 MHz, CDCl3, ppm) δ 8.12 (d, J = 3.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.25-7.10 (m, 2H), 6.99-6.93 (m, 1H), 6.90-6.87 (m, 1H), 6.10 (m, 1H), 5.35-5.34 (m, 1H), 4.39-4.36 (m, 1H), 4.22-4.15 (m, 1H), 2.43-2.36 (m, 1H), 1.79 (s, 9H) A472 (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 8.49 Hz, 1H), 8.53 (s, 1H), 7.78 (d, J = 1.90 Hz, 2H), 7.68 (t, J = 1.84 Hz, 1H), 7.36 (d, J = 7.73 Hz, 1H), 7.17 (t, J = 7.71 Hz, 1H), 6.92 (t, J = 7.26 Hz, 1H), 6.76 (d, J = 8.11 Hz, 1H), 5.32 (m, 1H), 3.52 - 3.62 (m, 1H), 2.52 - 2.58 (m, 3H), 2.21 (m, 1H), 1.80 - 1.89 (m, 1H), 1.23 - 1.61 (m, 12H)

[0412] [Preparation Example] [8] The following compounds can be synthesized by using the process shown in step 13: 320, 320-0, 513, 513-0, 514, 514-0. [process]

[13]

[0413] [ ] [1.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(4-5)] Place THF (5.0 mL), H2O (1.0 mL, 0.06 mmol, 0.18 equivalents), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyroxyl-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.0 equivalents), and 3,5-difluorophenyl into a 40 mL round-bottom flask. Acid (145.0 mg, 0.9 mmol, 3.0 equivalent), Pd(dtbpf)Cl2 (20.0 mg, 0.03 mmol, 0.1 equivalent), K2CO3 (85.0 mg, 0.6 mmol, 2.0 equivalent). The resulting solution was stirred at 70 °C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:6). This produced 90 mg (81.7%) of ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyroxyl-7-carboxylate (4-5) as a white solid.

[0414] [ ] [2.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(4-6)] Add 1.0 mL of H₂O, 5.0 mL of EtOH, ethyl 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (4-5, 90.0 mg, 0.25 mmol, 1.0 equivalent), and 60.0 mg of LiOH (2.5 mmol, 10.0 equivalent) to a 40 mL round-bottom flask. Stir the resulting solution at 50 °C for 2 hours. Adjust the pH to 4 using HCl (6 mol / L). Extract the resulting solution with 3 × 20 mL of ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under vacuum. This yields 70 mg (84.4%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (4-6) as a white solid.

[0415] [ ] [3.] [synthesis] [N-[3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [base] []] [Tributyl carbamate] [(13-1)] Place 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]pyroxyl-7-carboxylic acid (4-6, 70.0 mg, 0.2 mmol, 1.0 equivalents), DPPA (70.0 mg, 0.25 mmol, 1.2 equivalents), and TEA (24.0 mg, 0.2 mmol, 1.1 equivalents) into a 40 mL round-bottom flask. Stir the resulting solution at 50 °C for 3 hours. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, increased from H2O:ACN = 90:10 to H2O:ACN = 20:80 over 15 minutes; detector, 254 nm. This yielded 65 mg (76.4%) of N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-yl]aminocarbamate tributyl ester (13-1) as a white solid.

[0416] [ ] [4.] [synthesis] [3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [amine] [(13-2)] Place 1,4-dimethylalkanes (4M, 5.00 mL) containing HCl (gas) and N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tert-7-yl]aminocarbamate tributyl ester (13-1, 65.0 mg, 0.2 mmol, 1.0 equivalent) in a 50 mL round-bottom flask. Stir the resulting solution at 40 °C for 2 hours. Concentrate the mixture under vacuum. This yields 40 mg (81.9%) of 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tert-7-amine (13-2) as a white solid.

[0417] [ ] [5.] [synthesis] [(4S)-N-[3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [base] []-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [Methamide and] [(4R)-N-[3-(3,5-] [Difluorophenyl] [)-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [base] []-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [Methionine] [(320)] [and] [320-0) ] Place DCM (2.0 mL), 3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]pyroxyl-7-amine (13-2, 25.0 mg, 0.08 mmol, 1.0 equivalent), (4S)-3,4-dihydro-2H-1-benzopyran-4-carbazyl chloride (50.0 mg, 0.2 mmol, 3.0 equivalent), and DIEA (0.5 mg, 0.004 mmol, 0.05 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 1 hour. Concentrate the resulting mixture under vacuum. 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 over 20 minutes; detector, 254 nm. This produces 9.3 mg (24.3%) of (4S)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-yl]-3,4-dihydro-2H-1-benzopyran-4-methylamine (320) as a white solid and 11 mg (26.0%) of (4R)-N-[3-(3,5-difluorophenyl)-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-yl]-3,4-dihydro-2H-1-benzopyran-4-methylamine (320-0).1H NMR at 320 MHz (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 of 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). [Compound] [, 1 , ] [H NMR] [Spectrum] 514 (300 MHz, CDCl3, ppm) δ 8.68 (s, 1H), 8.67 (bs, 1H), 8.44 (bs, 1H), 7.66 (bs, 1H), 7.63 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.50 (s, 1H), 6.94 (bs, 1H), 4.54-4.50 (m, 1H), 4.35-4.27 (m, 1H), 4.05 (bs, 1H), 3.71-3.62 (m, 1H), 2.74-2.69 (m, 1H), 2.59 (s, 3H), 2.30-2.20 (m, 1H), 1.32-1.29 (m, 6H)

[0418] [Preparation Example] [9] Compounds 323 and 323-0 can be synthesized according to the process described in step 14 below. [process]

[14]

[0419] [ ] [1.] [synthesis] [3-] [Level 3 Butyl] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(14-2a)] [and] [3-] [Isobutyl] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(14-2b)] Place THF (3.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]pyroxene-7-carboxylate (4-4, 100.0 mg, 0.3 mmol, 1.00 equivalent), di-tert-butylzinc (4.0 mL, 2.0 mmol, 6.5 equivalent), and Pd(PPh3)4 (40.0 mg, 0.03 mmol, 0.1 equivalent) into an 8 mL round-bottom flask. Stir the resulting solution overnight at 80 °C. Concentrate the mixture under vacuum. Apply the residue to a silicone column with ethyl acetate / petroleum ether (1:4). This produces 20 mg (mixture) of ethyl 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]tadala-7-carboxylate (14-2a) and ethyl 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]tadala-7-carboxylate (14-2b).

[0420] [ ] [2.] [synthesis] [3-] [Level 3 Butyl] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(14-3a)] [and] [3-] [Isobutyl] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(14-3b)] Place 1.0 mL of H₂O, 5.0 mL of EtOH, a mixture of ethyl 3-tributyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylate (a mixture of 14-2a and 14-2b, 20.0 mg, 0.06 mmol, 1.00 equivalent), and 40.0 mg of NaOH (1.00 mmol, 15.2 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at 80 °C for 2 hours. Adjust the pH to 4 using HCl (6 mol / L). The solution was extracted with 3 × 20 mL of ethyl acetate, the organic layer was combined, dried with anhydrous sodium sulfate, and concentrated under vacuum. This produced 12 mg (mixture) of 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (14-3a) and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (14-3b) as a white solid.

[0421] [ ] [3.] [synthesis] [3-] [Level 3 Butyl] [-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(323)] [and] [N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-2-] [methyl] [-3-(2-)] [Methylpropyl] [)-8-(] [C] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(323-0)] Place in a 50 mL round-bottom flask a mixture of DMF (1.0 mL, 12.9 mmol, 237.2 equivalents), 3-tert-butyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid and 3-isobutyl-8-isopropyl-2-methylimidazo[1,2-b]tadalafil-7-carboxylic acid (a mixture of 14-3a and 14-3b, 15.0 mg, 0.05 mmol, 1.0 equivalents), (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (10.0 mg, 0.06 mmol, 1.2 equivalents), HATU (35.0 mg, 0.09 mmol, 1.7 equivalents), and DIEA (17.0 mg, 0.1 mmol, 2.4 equivalents). Stir the resulting solution 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 over 20 minutes; detector, 254 nm. The product was obtained. This produces 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]tadalafil-7-methamide (323) as a white solid and 5 mg (21%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methyl-3-(2-methylpropyl)-8-(propyl-2-yl)imidazo[1,2-b]tadalafil-7-methamide (323-0).323-1H NMR: (300 MHz chloroform-d, ppm): δ 8.22 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.99-6.96 (m, 1H), 6.91-6.88 (m, 1H), 6.11-5.90 (m, 1H), 5.45-5.30 (m, 1H), 4.41-4.37 (m, 1H), 4.30-4.14 (m, 1H), 3.90-.70 (m, 1H), 2.68 (s, 3H), 2.50-2.30 (s, 1H), 2.30-2.15 (m, 1H), 1.75-1.70 (m, 6H), 1.55 (s, 9H); 323-0 of 1H 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). .

[0422] [Preparation Example]

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

[0423] [ ] [process]

[15]

[0424] [ ] [1.] [synthesis] [8-] [Isopropyl] [-2-] [methyl] [-3-(] [piperidine] [-1-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(15-1)] To an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, place toluene (2.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]-diethyl-7-carboxylate (4-4, 70.0 mg, 0.2 mmol, 1.0 equivalent), piperidine (120.0 mg, 1.4 mmol, 6.6 equivalent), Pd2(dba)3 (35.0 mg, 0.04 mmol, 0.2 equivalent), BINAP (38.0 mg, 0.06 mmol, 0.3 equivalent), and Cs2CO3 (200.0 mg, 0.6 mmol, 2.9 equivalent). Stir the resulting solution at 120 °C for 2 hours. Concentrate the resulting mixture under vacuum. The residue was applied to a silicone column together with ethyl acetate / petroleum ether (1:5). This produced 60 mg (84.6%) of ethyl 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]tadalafil-7-carboxylate (15-1) as a yellow solid.

[0425] [ ] [2.] [synthesis] [8-] [Isopropyl] [-2-] [methyl] [-3-(] [piperidine] [-1-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(15-2)] Place i-PrOH (1.0 mL, 0.02 mmol), THF (1.0 mL), H2O (1.0 mL), ethyl 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyroxyl-7-carboxylate (15-1, 70.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH·H2O (30.0 mg, 0.7 mmol, 3.4 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at 50 °C for 1 hour. Adjust the pH to 4 using HCl (6 mol / L). Extract the resulting solution with 3 × 20 mL ethyl acetate, combine the organic layers, dry with anhydrous sodium sulfate, and concentrate under vacuum. This produces 60 mg (93.7%) of 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]tadala-7-carboxylic acid (15-2) in the form of a yellow solid.

[0426] [ ] [3.] [synthesis] [N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [methyl] [-3-(] [piperidine] [-1-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(324)] Place DMA (3.0 mL), 8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]pyroxyl-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 equivalent), HATU (113.0 mg, 0.3 mmol, 1.5 equivalent), and DIEA (51.0 mg, 0.4 mmol, 2.0 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 1 hour. The mixture was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silicone; mobile phase, increased from H2O:ACN=50:50 to H2O:ACN=10:90 over 20 min; detector, 254 nm. This produced 36.4 mg (42.3%) of N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-isopropyl-2-methyl-3-(piperidin-1-yl)imidazo[1,2-b]tadalafil-7-methoxyamine (324) as a yellow solid. (300 MHz, chloroform-d, ppm): δ 8.19 (s, 1H), 7.33-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.97-6.90 (m, 1H), 6.89-6.80 (m, 1H), 6.10-6.02 (m, 1H), 5.40-5.30 (m, 1H), 4.38-4.34 (m, 1H), 4.22-4.10 (m, 1H), 3.79-3.76 (m, 1H), 3.30-3.20 (m, 4H), 2.52 (s, 3H), 2.50-2.35 (m, 1H), 2.30-2.15 (m, 1H), 1.80-1.70 (m, 4H), 1.65-1.58 (m, 8H). [Compound] [, 1 , ] [H NMR] [Spectrum] 325 (300 MHz, chloroform-d, ppm): δ 8.20 (s, 1H), 7.34-7.27 (m, 1H), 7.25-7.21 (m, 1H), 6.98-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.15-6.00 (m, 1H), 5.40-5.30 (m, 1H), 4.45-4.34 (m, 1H), 4.24-4.15 (m, 1H), 3.91-3.83 (m, 4H), 3.80-3.70 (m, 1H), 3.40-3.20 (m, 4H), 2.52 (s, 3H), 2.49-2.32 (m, 1H), 2.30-2.15 (m, 1H), 1.70-1.50 (m, 6H) 369 (300 MHz, DMSO-d6, ppm) δ 8.98 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.30-5.15 (m, 1H), 4.25 (brs, 2H), 3.90 (s, 1H), 3.62-3.50 (m, 1H), 3.40-3.31 (m, 2H), 2.73 (brs, 1H), 2.42 (s, 3H), 2.30-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.75-1.40 (m, 11H) 372-0 (300 MHz, chloroform-d, ppm): δ 8.20 (s, 1H), 7.35-7.30 (m, 1H), 7.26-7.20 (m,1H), 6.99-6.93 (m, 1H), 6.88 (dd, J = 7.2, 1.2 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 5.45-5.35 (m, 1H), 4.40-4.33 (m, 1H), 4.24-4.18 (m, 1H), 3.80-3.70 (m, 1H), 3.50-3.30 (m, 4H), 2.53 (s, 3H), 2.41-2.32 (m, 1H), 2.27-2.15 (m, 1H), 2.13-1.98 (m, 4H), 1.62 (t, J = 7.2 Hz, 6H) 373 (300 MHz, DMSO-d6, ppm): δ 9.01 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.32 (d, J = 6.6 Hz, 1H), 7.20-7.14 (m, 1H), 6.95-6.89 (m, 1H), 6.80 (d, J = 6.6 Hz, 1H), 5.25-5.19 (m, 1H), 4.27-4.22 (m, 2H), 3.58-3.53 (m, 1H), 3.41-3.30 (m, 4H), 2.38 (s, 3H), 2.25-2.15 (m, 1H), 2.12-1.96 (m, 1H), 1.52-1.46 (m, 6H), 0.88 (t, J = 6.3 Hz, 4H), 0.14 (s, 6H)

[0427] [Preparation Example]

[11] Compounds 327, 326, 326-0, 365, 370, and 371 can be prepared by the process shown in step 16 below: [process]

[16]

[0428] [ ] [1.] [synthesis] [8-] [Isopropyl] [-2-] [methyl] [-3-[4-(] [Trifluoromethyl] [)] [ring] [hex-1-] [ene] [-1-] [base] []] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(16-1)] Place dimethyl ether (2.0 mL), H₂O (0.4 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]-dimethyl-7-carboxylate (4-4, 100.00 mg, 0.3 mmol, 1.0 equivalent), and 4-(trifluoromethyl)cyclohexyl-1-en-1-yl into an 8 mL round-bottom flask. Acid (120.0 mg, 0.6 mmol, 2.0 equivalents), Pd(dtbpf)Cl2 (20.0 mg, 0.03 mmol, 0.1 equivalents), K2CO3 (100.0 mg, 0.7 mmol, 2.4 equivalents). The resulting solution was stirred at 80 °C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column with ethyl acetate / petroleum ether (1:5). This produced 110 mg (90.7%) of ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]tadalafil-7-carboxylate (16-1) as a yellow solid.

[0429] [ ] [2.] [synthesis] [8-] [Isopropyl] [-2-] [methyl] [-3-[4-(] [Trifluoromethyl] [)] [Self-Expression] [-1-] [ene] [-1-] [base] []] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(16-2)] Place 2.0 mL of i-PrOH, 2.0 mL of THF, 1.0 mL of H₂O, ethyl 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyrrolidone-7-carboxylate (16-1, 110.0 mg, 0.3 mmol, 1.0 equivalent), and 70.0 mg of LiOH (2.9 mmol, 10.5 equivalent) into a 50 mL round-bottom flask. Stir the resulting solution at 50 °C for 1 hour. Adjust the pH of the solution to 4 with HCl (6 mol / L). Extract the resulting solution with 3 × 20 mL of ethyl acetate, combine the organic layers, dry with anhydrous sodium sulfate, and concentrate under vacuum. This produces 90 mg (88.0%) of 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]tadala-7-carboxylic acid (16-2) as a white solid.

[0430] [ ] [3.] [synthesis] [N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [methyl] [-3-[4-(] [Trifluoromethyl] [)] [Self-Expression] [-1-] [ene] [-1-] [base] []] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(327)] Place DMF (5.0 mL), 8-isopropyl-2-methyl-3-[4-(trifluoromethyl)cyclohex-1-en-1-yl]imidazo[1,2-b]pyrrolidone-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) into a 40 mL round-bottom flask. Stir the resulting solution 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 over 20 minutes; detector, 254 nm. This yielded 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]pyridine-7-methylamine (327) as a white solid. (300 MHz, chloroform-d, ppm): δ 8.20 (s, 1H), 7.35-7.30 (m, 1H), 7.25-7.17 (m, 1H), 7.10-6.84 (m, 2H), 6.15-5.90 (m, 2H), 5.45-5.30 (m, 1H), 4.44-4.31 (m, 1H), 4.23-4.19 (m, 1H), 3.83-3.72 (m, 1H), 2.75-2.55 (m, 3H), 2.53 (s, 3H), 2.50-2.35 (m, 3H), 2.29-2.13 (m, 3H), 1.63 (d, J = 6.6 Hz, 6H).

[0431] [ ] [4.] [synthesis] [N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [methyl] [-3-[(1r,4r)-4-(] [Trifluoromethyl] [)] [Cyclohexyl] []] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methamide and] [N-((S)-]octodecane [-4-] [base] [)-8-] [Isopropyl] [-2-] [methyl] [-3-((1s,4R)-4-(] [Trifluoromethyl] [)] [Cyclohexyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(326)] [and] [326-0) ] Place EA (5.0 mL), 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]pyrazol-7-methylamine (327, 50.0 mg, 0.10 mmol, 1.0 equivalent), and aqueous solution Pd / C (50.0 mg) into a 50 mL round-bottom flask. Introduce H2 (g) into the mixture at room temperature. Stir the resulting solution at room temperature for 2 hours. Filter off the solid. Concentrate the resulting mixture under vacuum. 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 over 20 minutes; detector, 254 nm. The racemic product was purified by column chromatography: XA-YMC Cellulose-SC, 4.6*100mm, 3 μm; mobile phase A / mobile phase B: n-hexane / EtOH = 70 / 30; flow rate: 1 mL / min; gradient: 30B to 30B over 10 min; 254 nm; injection volume: 1 mL; this yielded 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]pyridine-7-methylamine and 8.0 mg of [other products]. (15.8%) N-((S)-chroman-4-yl)-8-isopropyl-2-methyl-3-((1s,4R)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-b]tadalafil-7-methylamine (326 and 326-0) is a white solid. Stereochemical description is assumed.1H NMR spectrum of 326: (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); 1H NMR spectrum of 326-0: (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 ... 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). . [Compound] [, 1 , ] [H NMR] [spectrum] 365 (300 MHz, CDCl3, ppm): δ 8.25 (s, 1H), 7.31-7.28 (m, 1H),7.26-7.20 (m, 1H), 6.99-6.94 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.06 (d, J = 7.2 Hz, 1H), 5.40-5.30 (m, 1H), 4.40-4.30 (m, 1H), 4.24-4.10 (m, 1H), 3.80-3.70 (m, 1H), 2.54 (s, 3H), 2.49-2.33 (m, 1H), 2.25-2.15 (m, 1H), 2.05-1.90 (m, 1H),1.64-1.56 (m, 6H), 1.15-1.05 (m, 2H), 0.95-0.80 (m, 2H) 370 (300 MHz, CDCl3, ppm): δ 8.25 (s, 1H), 7.34-7.31 (m, 1H), 7.27-7.22 (m, 1H), 6.99-6.95 (m, 1H), 6.89 (d, J = 8.1 Hz 1H), 6.16 (brs, 1H), 5.45-5.35 (m, 1H), 4.40-4.34 (m, 1H), 4.28-4.18 (m, 1H), 4.16-4.09 (m, 2H), 3.80 (brs, 1H), 3.63-3.47 (m, 3H), 2.61 (s, 3H), 2.60-2.15 (m, 4H), 1.75-1.70 (m, 2H), 1.62 (t, J = 6.6 Hz, 6H) 371 (300 MHz, CDCl3, ppm): δ 8.22 (s, 1H), 7.31-7.28 (m, 1H), 7.24-7.21 (m, 1H), 6.99-6.94 (m, 1H), 6.90-6.87 (m, 1H), 6.07-6.05 (m, 1H), 5.41-5.35 (m, 1H), 4.41-4.34 (m, 1H), 4.27-4.17 (m, 1H), 3.78-3.74 (m, 1H), 3.38-3.29 (m, 1H), 2.56 (s, 3H), 2.54-2.22 (m, 6H), 2.03-1.86 (m, 4H), 1.62 (t, J = 6.9 Hz, 6H)

[0432] [Preparation Example]

[12] Compound 352 was prepared according to the process shown in step 17 below: [process]

[17]

[0433] [ ] [1.] [synthesis] [3-[5-] [bromine] [-1-[(] [Tertiary butoxycarbonyl] [)] [Amine] []] [Imidazole] [-2-] [base] []-3-] [Ethyl propionate] [(17-2)] THF (85.0 g, 1178.8 mmol, 26.3 equivalents), ethyl 5-bromo-1-[(tributoxycarbonyl)amino]imidazolium-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 placed in a 1000 mL round-bottom flask. Then, t-BuOK (500 mL) was added fractionally at 0 °C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then quenched by adding NH4Cl (aqueous solution). The resulting solution was extracted with 3 × 200 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then applied to a silicone column with ethyl acetate / petroleum ether (1:4). This produces 13 g (77.0%) of ethyl 3-[5-bromo-1-[(tri-butoxycarbonyl)amino]imidazol-2-yl]-3-sideoxypropionate (17-2), which is a colorless oil.

[0434] [ ] [2.] [synthesis] [3-] [bromine] [-8-] [Hydroxyimidazole] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(17-3)] DCM (100.0 mL, 1573.0 mmol, 59.2 equivalents), ethyl 3-[5-bromo-1-[(tributoxycarbonyl)amino]imidazol-2-yl]-3-t-oxypropionate (17-2, 10.0 g, 26.6 mmol, 1.0 equivalent), and DMF-DMA (9.0 g, 75.5 mmol, 2.8 equivalents) were placed in a 500 mL round-bottom flask. The resulting solution was stirred at 40 °C for 2 hours. The reaction was then quenched by adding water / ice. The resulting solution was extracted with 2 × 100 mL MTBE and the aqueous layers were combined. The pH of the solution was adjusted to 4 with HCl (4 mol / L). The solid was collected by filtration. This yielded 5 g (65.7%) of ethyl 3-bromo-8-hydroxyimidazo[1,2-b]thalassyl-7-carboxylate (17-3) as a white solid.

[0435] [ ] [3.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Hydroxyimidazole] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(17-4)] I. In a 40 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere, place H₂O (1.0 mL), NMP (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]-dichlorophenyl-7-carboxylate (17-3,400.0 mg, 1.398 mmol, 1.0 equivalent), and 3,5-dichlorophenyl Acid (320.1 mg, 1.7 mmol, 1.2 equivalents), Pd(dtbpf)Cl2 (70.0 mg, 0.1 mmol, 0.08 equivalents), Cs2CO3 (1.2 g, 3.7 mmol, 2.6 equivalents). The resulting solution was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature, and then 5 ml of H2O was added. The solid was collected by filtration. This produced 300 mg (crude) of ethyl 3-(3,5-dichlorophenyl)-8-hydroxyimidazo[1,2-b]-tert-7-carboxylate (17-4) as a yellow solid.

[0436] [ ] [4.] [synthesis] [8-] [chlorine] [-3-(3,5-] [Dichlorophenyl] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(17-5)] To a 40 mL round-bottom flask, add 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]-dichloro-7-carboxylate (17-4, 200.0 mg, 0.6 mmol, 1.0 equivalents), and (COCl)2 (400.0 mg, 3.1 mmol, 5.5 equivalents). Stir the resulting solution at 80 °C for 22 hours. Concentrate the mixture under vacuum. Wash the mixture with 10 × 10 mL ACN:H2O = 1:1. Collect the solid by filtration. This produces 110 mg (52.3%) of ethyl 8-chloro-3-(3,5-dichlorophenyl)imidazo[1,2-b]tadalafil-7-carboxylate (17-5) as a yellow solid.

[0437] [ ] [5.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-(] [C] [-1-] [ene] [-2-] [base] [)] [Imidazolidine] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(17-6)] Place the following substances into 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]pyroxene-7-carboxylate (17.5, 110.0 mg, 0.3 mmol, 1.0 equivalents), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoboron (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). The resulting solution was stirred at 80°C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column containing ethyl acetate / petroleum ether (1:3). This produced 80 mg (71.6%) of ethyl 3-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate (17-6) as a yellow solid.

[0438] [ ] [6.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [(17-7)] Place EA (5.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-(prop-1-en-2-yl)imidazo[1,2-b]tadalafil-7-carboxylate (17-6, 80.0 mg, 0.21 mmol, 1.0 equivalent), and PtO2 (40.0 mg, 0.2 mmol, 0.8 equivalent) into a 50 mL round-bottom flask. Introduce H2 (g) into the mixture using a balloon. Stir the resulting solution at 50 °C for 1 hour. Collect the solid by filtration. Concentrate the mixture under vacuum. This yields 60 mg of ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylate (17-7) as a yellow solid.

[0439] [ ] [7.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(17-8)] EtOH (2.0 mL), H₂O (0.50 mL), ethyl 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylic acid (17-7, 60.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH (30.0 mg, 1.2 mmol, 7.9 equivalent) were placed in an 8 mL round-bottom flask. The resulting solution was stirred at 50 °C for 1 hour. The reaction was then quenched by adding water / ice. The pH of the solution was adjusted to 4 with HCl (6 mol / L). The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 40 mg (72.0%) of 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]tadalafil-7-carboxylic acid (17-8) as a white solid.

[0440] [ ] [8.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(352)] Place DMF (4.0 mL), 3-(3,5-dichlorophenyl)-8-isopropylimidazo[1,2-b]pyroxen-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 equivalent), HATU (70.0 mg, 0.2 mmol, 1.6 equivalent), and DIEA (46.0 mg, 0.4 mmol, 3.1 equivalent) into an 8 mL round-bottom flask. Stir the resulting solution 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 over 20 minutes; detector, 254 nm. This yielded 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]pyridine-7-methamide (352 mg / mL) 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).

[0441] [Preparation Example]

[13] [:] Compound 366 was prepared according to process 18 shown below: [process]

[18]

[0442] [ ] [1.] [synthesis] [3-] [Cyano] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Ethyl formate [ ] DMAC (5.0 mL), ethyl 3-bromo-8-isopropyl-2-methylimidazo[1,2-b]-diethyl-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 equivalent), Pd₂(dba)₃ (50.5 mg, 0.05 mmol, 0.2 equivalent), and Zn (100.1 mg, 1.5 mmol, 5.0 equivalent) were placed in a 20 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 2 hours. The reactants were then quenched by adding water. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, the organic layer was combined, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was then applied to a silicone column with ethyl acetate / petroleum ether (1:5). This produced 40 mg (47.9%) of ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]-ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]-ethyl 3-carboxylate (18-1) as a yellow oil.

[0443] [ ] [2.] [synthesis] [3-] [Cyano] [-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(18-2)] EtOH (1.0 mL), H₂O (0.5 mL), ethyl 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyro-7-carboxylic acid (18-1, 40.0 mg, 0.15 mmol, 1.0 equivalent), and LiOH (30.0 mg, 1.2 mmol, 8.5 equivalent) were placed in an 8 mL round-bottom flask. 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 with 3 × 20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 25 mg (69.7%) of 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyro-7-carboxylic acid (18-2) as a yellow oil.

[0444] [ ] [3.] [synthesis] [3-] [Cyano] [-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Isopropyl] [-2-] [Methylimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(366)] [ ] Place 2 mL of DMF, 3-cyano-8-isopropyl-2-methylimidazo[1,2-b]pyro-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 equivalent), and DIEA (28.0 mg, 0.2 mmol, 2.1 equivalent) into an 8 mL round-bottom flask. Stir the resulting solution 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 = 70:30 to H2O:ACN = 10:90 over 20 minutes; detector, 254 nm. This yielded 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]pyridine-7-methamide (366) as a white solid. (300 MHz, CDCl3, ppm): δ 8.35 (s, 1H), 7.25-7.20 (m, 2H), 6.97-6.92 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.20-6.10 (m, 1H), 5.39-5.33 (m, 1H), 4.41-4.32 (m, 1H), 4.27-4.14 (m, 1H), 3.69-3.59 (m, 1H), 2.62 (s, 3H), 2.45-2.35 (m, 1H), 2.29-2.18 (m, 1H), 1.65-1.55 (m, 6H).

[0445] [Preparation Example]

[14] Compounds 394, 397-0, 395, and 398 can be synthesized according to the following procedure 19: [process]

[19]

[0446] [ ] [1.] [synthesis] [3-] [bromine] [-8-] [ethoxyimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Methyl formate [(19-1)] [ ] Add DMF (5.0 mL), ethyl 3-bromo-8-hydroxyimidazo[1,2-b]-dichloro-7-carboxylate (17-3, 150.0 mg, 0.5 mmol, 1.0 equivalent), iodomethane (200.0 mg, 1.3 mmol, 2.4 equivalent), and K₂CO₃ (210.0 mg, 1.5 mmol, 2.9 equivalent) to a 40 mL round-bottom flask. Stir the resulting solution at 70 °C for 1 hour. Purify the mixture by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silicone; mobile phase, increased from H₂O:ACN = 90:10 to H₂O:ACN = 40:60 over 15 minutes; detector, 254 nm. This produces 80 mg (48.6%) of methyl 3-bromo-8-ethoxyimidazolium[1,2-b] tert-7-carboxylate (19-1), a white solid.

[0447] [ ] [2.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [ethoxyimidazo] [[1,2-b]] [despair] [𠯤] [-7-] Methyl formate [(19-2)] [ ] Place THF (5.0 mL), H2O (1.0 mL), methyl 3-bromo-8-ethoxyimidazo[1,2-b]-dichlorophenyl ester (19-1,80.0 mg, 0.25 mmol, 1.0 equivalent), and 3,5-dichlorophenyl into an 8 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Acid (56.0 mg, 0.3 mmol, 1.1 equivalents), Pd(dtbpf)Cl2 (30.0 mg, 0.05 mmol, 0.2 equivalents), K2CO3 (100.0 mg, 0.7 mmol, 2.8 equivalents). The resulting solution was stirred at 80 °C for 2 hours. The mixture was concentrated under vacuum. The residue was applied to a silicone column containing ethyl acetate / petroleum ether (1:3). This produced 20 mg (20.6%) of methyl 3-(3,5-dichlorophenyl)-8-ethoxyimidazo[1,2-b]pyroxyl-7-carboxylate (19-2) as a white solid.

[0448] [ ] [3.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-8-] [Methoxyimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Formic acid] [(19-3)] [ ] EtOH (5.0 mL), H₂O (2.0 mL), ethyl 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]-diethyl-7-carboxylic acid (19-2, 70.0 mg, 0.2 mmol, 1.0 equivalent), and LiOH (40.0 mg, 1.7 mmol, 8.7 equivalent) were placed in a 40 mL round-bottom flask. 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 with 3 × 20 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 40 mg (61.9%) of 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]-diethyl-7-carboxylic acid (19-3) as a white solid.

[0449] [ ] [4.] [synthesis] [3-(3,5-] [Dichlorophenyl] [)-N-[(4S)-3,4-] [Dihydrogen] [-2H-1-] [Benzopyran] [-4-] [base] []-8-] [Methoxyimidazo] [[1,2-b]] [despair] [𠯤] [-7-] [Methionine] [(394)] [ ] Place DMF (3.0 mL), 3-(3,5-dichlorophenyl)-8-methoxyimidazo[1,2-b]pyro-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 equivalent), and DIEA (35.9 mg, 0.3 mmol, 2.3 equivalent) into an 8 mL round-bottom flask. Stir the resulting solution 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 = 70:30 to H2O:ACN = 10:90 over 20 minutes; detector, 254 nm. This yielded 12 mg (21.6%) of 3-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-8-methoxyimidazo[1,2-b]-4-methylamine (394 mg / mL) 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). [Compound] [, 1 , ] [H NMR] [spectrum] 397-0 (300 MHz, DMSO-d6, ppm) δ 10.1 (s, 1H), 9.15 (s, 1H), 7.95 (s, 2H), 7.65 - 7.60 (m, 2H), 7.35 - 7.40 (m, 1H) 7.20-7.15 (m, 1H), 6.99-6.85 (m, 2H), 6.20 - 6.00 (m, 1H), 5.70 - 5.30 (m, 3H), 4.36-4.25 (m, 2H), 3.20 (br, 1H), 2.45-2.20 (m, 2H) 395 (300 MHz, DMSO-d6, ppm) δ 10.05 (d, J = 15 Hz, 1H), 9.25 (s, 1H), 8.95 (s, 1H), 8.25 (s, 2H), 7.85 - 7.80 (m, 1H), 7.35 - 7.15 (m, 1H) 7.00 - 6.80 (m, 2H), 5.25 - 5.18 (m, 1H), 4.36-4.15 (m, 2H), 2.25-2.02 (m, 2H) 398 (300 MHz, CDCl3, ppm): δ 10.11 (d, J = 7.8 Hz, 1H), 9.12 (s, 1H), 7.93 (d, J = 1.9 Hz, 2H), 7.53 (s, 1H), 7.53-7.50 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.21-7.16 (m, 1H), 6.94-6.85 (m, 2H), 5.48-5.44 (m, 1H), 4.97-4.88 (m, 2H), 4.37-4.30 (m, 2H), 2.37-2.32 (m, 1H), 2.24-2.19(m, 1H), 1.64 (t, J = 7.2 Hz, 3H)

[0450] [PREPARATION EXAMPLE]

[15] Compounds 450...

Claims

1. A compound of formula (Ie) or a pharmaceutically or veterinarily acceptable salt thereof: wherein: Each R10 is independently a halogen; R1 is, as appropriate, a substituted C1-C6 alkyl, a substituted 4- to 6-membered cycloalkyl, a substituted 4- to 6-membered cycloalkenyl, or -NRaRb, wherein Ra and Rb are independently H or, as appropriate, substituted C1-C6 alkyl; or Ra and Rb may, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S and may be substituted as appropriate; R2 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl; each R4 is independently hydrogen, halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R5 and R6 are independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl; R' is hydrogen or C1-C4 alkyl; R8 is hydrogen or C1-C4 alkyl; R9 and R9' are independently halogens or C1-C4 haloalkyl groups; W is CR5R6; Z is CR5R6, O, or S; Y2, Y3, Y4, and Y5 are independently CR4 or N; a is 0 or 1; and m is 0, 1, 2, or 3; wherein each of the substituents, when it appears, is independently one or more halogens, hydroxyl groups, C1-C4 alkyl groups, or C1-C4 haloalkyl groups.

2. The compound of claim 1 or its pharmaceutically or veterinarily acceptable salt, wherein m is 2 or 3.

3. The compound of claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, wherein each R10 is independently chlorine or fluorine and m is 2 or 3.

4. The compound of claim 1 or a pharmaceutically or veterinary acceptable salt thereof, wherein R1 is, as appropriate, a substituted C1-C6 alkyl, a substituted 4- to 6-membered cycloalkyl, or -NRaRb, wherein Ra and Rb may, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclic group, which may include one or two additional heteroatoms selected from the group consisting of N, O, and S and may be substituted as appropriate.

5. The compound of claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, wherein R2 is a halogen or a C1-C3 alkyl group.

6. The compound of claim 1 or its pharmaceutically or veterinarily acceptable salt, wherein: Each R10 is independently chlorine or fluorine; m is 2 or 3; R1 is a C1-C4 alkyl group, a 4- to 6-membered cycloalkyl group, or -NRaRb, wherein Ra and Rb may form a 4-, 5-, or 6-membered heterocyclic group with the nitrogen to which they are attached, the heterocyclic group may include one or two additional heteroatoms selected from the group consisting of N, O, and S and may be substituted, wherein each of the substituents is independently one or more chlorine, fluorine, hydroxyl, methyl, or trifluoromethyl groups; R2 is halogen or methyl; each R4 is independently hydrogen or halogen; W is CH2; Z is O; and R9 and R9' are each independently chlorine or fluorine.

7. The compound of claim 6 or its pharmaceutically or veterinarily acceptable salt, wherein: R1 is a C1-C4 alkyl group that has been substituted, as appropriate.

8. The compound of claim 6 or its pharmaceutically or veterinarily acceptable salt, wherein: R1 is a substituted 4- to 6-membered cycloalkyl group, depending on the situation.

9. The compound of claim 6 or its pharmaceutically or veterinarily acceptable salt, wherein: R1 is NRaRb, where Ra and Rb can form a 4-, 5-, or 6-membered heterocyclic group together with the nitrogen to which they are attached. The heterocyclic group may include one or two additional heteroatoms selected from the group consisting of N, O, and S, and may be substituted by one or more chlorine, fluorine, or hydroxyl groups as appropriate.

10. The compound of claim 7 or its pharmaceutically or veterinarily acceptable salt, wherein: m is 3; R1 is isopropyl or tributyl; R2 is methyl; and R9 and R9' are each fluorine.

11. The compound of claim 8 or its pharmaceutically or veterinarily acceptable salt, wherein: m is 3; R1 is substituted cyclobutyl or cyclopentyl as appropriate; R2 is methyl; and R9 and R9' are each fluorine.

12. The compound of claim 9 or its pharmaceutically or veterinarily acceptable salt, wherein: m is 3; R1 is NRaRb, wherein Ra and Rb may form a 4-, 5-, or 6-membered heterocyclic group together with the nitrogen to which they are attached, the heterocyclic group may include an additional heteroatom selected from the group consisting of N, O, and S and may be substituted by one or more chlorine, fluorine, or hydroxyl groups as appropriate; R2 is methyl; and R9 and R9' are each fluorine.

13. The compound of claim 12 or a pharmaceutically or veterinarily acceptable salt thereof, wherein R1 is, as appropriate, a substituted azacyclobutane, a substituted pyrrolidyl, a substituted piperidinyl, or a substituted urinyl, wherein the one or more of the substituents are, as appropriate, hydroxyl or fluorine.

14. A veterinary composition comprising an effective amount of any one of claims 1 to 13 of a compound or a pharmaceutically or veterinarily acceptable salt thereof and a veterinarily acceptable carrier for killing parasites.

15. A veterinary composition comprising an effective amount of a compound of any one of claims 1 to 13 or a pharmaceutically or veterinarily acceptable salt thereof, one or more additional active agents, and a veterinarily acceptable carrier.

16. Use of a compound of any one of claims 1 to 13 or a pharmaceutically or veterinary acceptable salt thereof for the preparation of an agent for the treatment, control and / or prevention of endoparasitic infections in animals.

17. Use of a compound of any one of claims 1 to 13 or a pharmaceutically or veterinary acceptable salt thereof for the preparation of an agent for the treatment, control and / or prevention of parasitic infections or infestations in animals.

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