Carboxamide-4-quinoline compounds with anthelmintic activity

Abstract

The present invention provides a novel carboxamide-4-quinoline compound that can be used as a pharmaceutical agent, particularly in the treatment and prevention of helminth-induced diseases in animals.

Description

Technical Field

[0001] The present invention relates to the field of veterinary medicine, and more particularly to compounds having anthelmintic activity. In particular, the present invention relates to novel compounds useful in the prevention and treatment of diseases caused by helminths.

Background Art

[0002] Parasitic diseases in animals cause great pain and economic losses worldwide. Therefore, the treatment of parasitic infections remains an important global issue.

[0003] Parasites (helminths) are known to cause helminth infections (helminthiases) in humans and animals. There are many species of these parasites, which are broadly classified into the following groups: flatworms, acanthocephalans, tapeworms, flukes, and nematodes. Helminths mainly inhabit the digestive tract, but may also be found in the host's cardiovascular system and other organs, where they cause physiological damage.

[0004] Helminths, particularly gastrointestinal (GI) nematodes, are important in livestock production, especially in ruminants such as cattle and sheep. The greatest impact is a reduction in voluntary feed intake, followed by a decrease in the absorption of essential nutrients and digestive function. This has an adverse effect on livestock production, resulting in significant economic losses to agriculture and livestock industries worldwide.

[0005] With the increasing use of anthelmintics, resistance to various parasites, particularly gastrointestinal parasites, has also spread and is now widespread. This represents a major threat to the sustainability of modern ruminant livestock production, resulting in reduced productivity, impaired animal health and welfare, and increased greenhouse gas emissions through increased parasite infections and farm inputs.

[0006] The ability of parasites to survive treatment that is generally effective at the recommended dosage poses a significant threat to the future control of helminth parasites in animals such as ruminants, horses, poultry, and pets. This is particularly true for nematodes (roundworms). Treatment with anthelmintics kills helminths whose phenotype is sensitive to the drug, but resistant parasites survive and leave behind their "resistance" genes. Resistant species accumulate, ultimately resulting in treatment failure.

[0007] Another example of an important disease caused by helminths is canine filariasis (also known as cardiovascular filariasis), which is an endemic, severe, and often fatal disease in parts of North America, South America, Europe, Asia, and Australia. This disease is caused by the parasitic nematode Dirofilaria immitis, whose adult worms live in the heart, lungs, and associated blood vessels of the host animal, causing severe lung disease, heart failure, and damage to other internal organs such as the liver and kidneys. Canine filariasis is known to affect pets, particularly dogs (considered the definitive host). Dirofilaria immitis is often referred to as "canine heartworm," but it also infects cats, as well as ferrets, wolves, coyotes, jackals, foxes, bears, and seals, and very rarely, humans (zoonosis).

[0008] At least 70 species of mosquitoes can serve as intermediate hosts. The genera Aedes, Anopheles, and Culex are the most common genera as vectors.

[0009] Like most parasites, the life cycle of Dirofilaria immitis includes various life forms. The adult form of this parasite is very large and inhabits the heart and pulmonary arteries of animals. Male helminths are typically about 12-20 cm long and 0.7-0.9 mm wide. Female helminths are about 25-31 cm long and 1.0-1.3 mm wide. After mating with a male helminth, sexually mature female helminths produce microfilariae that are only about 300 μm long and 7 μm wide. Microfilariae pass through the capillary bed and enter the canine vascular system at a rate of about 10 per mL of blood. 3 ~about 10 5 The parasite circulates at a concentration of one microfilariae. If a dog is kept in an insect-free environment, the parasite's life cycle does not progress. However, if a female mosquito ingests microfilariae while feeding on an infected dog, the microfilariae develop into larvae within the mosquito's body. The microfilariae go through two larval stages (L1 and L2) and finally become the mature third-stage larva (L3), which is the infectious larval stage. These L3 larvae are then about 1.1 mm in length and reinfect dogs through mosquito bites. Therefore, it is this L3 stage that causes the initial infection. Just three days after infection, the L3 larva molts into the fourth larval stage (L4), and then becomes the fifth stage or immature adult. These immature adults travel through the circulatory system to the heart and pulmonary artery, where they mature and reproduce. This causes the female worm to produce microfilariae in the blood.

[0010] Currently, macrocyclic lactones, such as ivermectin (sold under trade names Heartgard, Iverhart, etc.), milbemycin oxime (Interceptor Flavor Tabs and Sentinel Flavor Tabs), and moxidectin (Proheart 6 and Proheart 12), are used to prevent heartworm disease in dogs.

[0011] Therefore, new anthelmintic compounds are needed. Further challenges that need to be overcome include the toxicity and safety of existing compounds for both animals and users, their efficacy (potency and duration), bioavailability, pharmacokinetics, and pharmacodynamics.

[0012] WO2021 / 122911A1 describes compounds containing a quinoline structure that have anthelmintic activity. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] WO2021 / 122911A1 [Overview of the project] [Problems that the invention aims to solve]

[0014] Therefore, the object of the present invention is to provide a novel compound that can be effectively used against parasitic nematodes, particularly against animal parasitic nematodes.

[0015] Such novel compounds are desirable to be compatible with standard antiparasitic treatments in animals. Furthermore, it is desirable to provide a pharmaceutical composition containing the novel compound that can be easily administered to animals. [Means for solving the problem]

[0016] In a first embodiment, the present invention relates to formula (I): [ka] [During the ceremony, R A Each of these is independently selected from Cl, F, OCF3, methyl, methoxy, or trifluoromethyl, or each of two adjacent substituents R AThis forms a five-membered or six-membered ring containing zero, one, or two N atoms, wherein the ring may be substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy, and trifluoromethyl; n is between 0 and 5; R B [This is H or CH3] The present invention provides compounds represented by or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs thereof.

[0017] In a second embodiment, the present invention provides a method for producing a compound represented by formula (I), wherein the method is: Formula (A): [ka] [In the formula, R A [and n have the meanings defined in any of the embodiments described herein] The compound represented by formula (B): [ka] [In the formula, R B [This is H or CH3] This step includes reacting the compound with the compound represented by .

[0018] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) and at least one pharmaceutically acceptable excipient.

[0019] In another embodiment, the present invention provides compounds according to the present invention for use as pharmaceuticals.

[0020] The present invention further provides compounds according to the present invention for use in the treatment or prevention of diseases caused by parasitic nematodes in animals.

[0021] The present invention further provides the use of a compound according to the present invention for producing a medicament for treating or preventing diseases caused by parasitic nematodes in animals.

[0022] In a further aspect, the present invention provides a method for treating or preventing a disease caused by a parasitic nematode, wherein the method comprises administering to a warm-blooded animal an effective amount of a compound according to the present invention or a composition according to the present invention and optionally an effective amount of one or more additional active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] [Figure 1] FIG. 1 shows the plasma profiles of compounds 1, 3, 5 according to some embodiments of the present invention and comparative compounds C151, C243, C254 after oral administration to dogs at 10 mg / kg body weight. [Figure 2] FIG. 2 shows the plasma profiles of compounds 1, 3, 5, 6 according to some embodiments of the present invention and comparative compounds C151, C243, C254 after intravenous administration to dogs at 1 mg / kg body weight. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention relates to a compound of formula (I):

Chemical formula

[0025] Two adjacent R A The 5-membered or 6-membered ring formed by this can be aryl, heteroaryl, or cycloalkyl, preferably aryl or heteroaryl. Examples include a phenyl ring, or pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, etc., preferably phenyl or pyridine. The phenyl ring and two adjacent R A The ring system formed by this can be selected from the group consisting of naphthyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, indole, isoindole, benzimidazole, and indazole; preferably, it can be selected from the group consisting of naphthyl and quinoline.

[0026] In some embodiments, R A R is one or more substituents on the phenyl ring, where these are independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, preferably independently selected from Cl or F. The integer n is selected from the range of 0 to 5, preferably from the range of 1 to 3, more preferably from 1 or 2, and most preferably from 2. If n is 0, the phenyl ring is unsubstituted. If n is 1 to 5, the phenyl ring has 1 to 5 R A It is substituted with, and the remaining C atoms in the phenyl ring are not substituted. B is H or CH3, preferably H.

[0027] The present invention also relates to pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs of the compound represented by formula (I).

[0028] In some embodiments, R B It is hydrogen.

[0029] In some of these embodiments, n can be 3, and the substituent R AR can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. A The substituted phenyl ring can be selected from the group consisting of 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-fluoro-3,5-dichlorophenyl, 2,3-difluoro-5-chlorophenyl, 3,5-dichloro-4-fluorophenyl, 2-chloro-3,5-difluorophenyl, 3,4,5-trichlorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl, and preferably from the group consisting of 2,3,5-trifluorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl.

[0030] In some of these embodiments, n can be 3, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and preferably independently selected from Cl or F. A The substituted phenyl ring can be selected from the group consisting of 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-fluoro-3,5-dichlorophenyl, 2,3-difluoro-5-chlorophenyl, 3,5-dichloro-4-fluorophenyl, 2-chloro-3,5-difluorophenyl, 3,4,5-trichlorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl, and preferably from the group consisting of 2,3,5-trifluorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl.

[0031] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. AThe substituted phenyl ring can be selected from the group consisting of 2,3-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl, 5-chloro-2-fluorophenyl, and 2-chloro-5-fluorophenyl, preferably selected from the group consisting of 2,3-dichlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3,5-dichlorophenyl, and 5-chloro-2-fluorophenyl, and more preferably selected from the group consisting of 3-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, and 2,3-dichlorophenyl.

[0032] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl. AThe phenyl rings substituted with are 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3- It can be selected from the group consisting of chloro-5-trifluoromethylphenyl and 3-fluoro-5-trifluoromethylphenyl, preferably from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, and 5-chloro-2-methoxyphenyl, and more preferably from the group consisting of 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, and 3-chloro-2-methoxyphenyl.

[0033] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl, or trifluoromethoxy. AThe phenyl ring is 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoro-3-trifluoromethoxyphenyl, 2-fluoro-5- It can be selected from the group consisting of trifluoromethoxy, 2-chloro-3-trifluoromethoxy, and 2-chloro-5-trifluoromethoxy, preferably from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-fluoro-5-trifluoromethoxy, and more preferably from the group consisting of 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, and 2-chloro-5-trifluoromethoxy.

[0034] In some of these embodiments, n can be 1, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. AThe phenyl ring substituted can be selected from the group consisting of 3-fluorophenyl and 3-chlorophenyl, and preferably from the group consisting of 3-chlorophenyl.

[0035] In some of these embodiments, n can be 1, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl, or trifluoromethoxy, and preferably independently selected from Cl or F. A The phenyl ring substituted can be selected from the group consisting of 3-fluorophenyl and 3-chlorophenyl, and preferably from the group consisting of 3-chlorophenyl.

[0036] In some of these embodiments, the phenyl ring has two adjacent R rings that form a 5-membered or 6-membered aromatic ring or a heteroaromatic ring. A It is substituted with the phenyl ring and two adjacent R A The ring system formed by this is selected from the group consisting of naphthyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, indole, isoindole, benzimidazole, and indazole; preferably selected from the group consisting of naphthyl and quinoline.

[0037] In some embodiments, R B This is CH3 (methyl group).

[0038] In some of these embodiments, n can be 3, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. AThe substituted phenyl ring can be selected from the group consisting of 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-fluoro-3,5-dichlorophenyl, 2,3-difluoro-5-chlorophenyl, 3,5-dichloro-4-fluorophenyl, 2-chloro-3,5-difluorophenyl, 3,4,5-trichlorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl, and preferably from the group consisting of 2,3,5-trifluorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl.

[0039] In some of these embodiments, n can be 3, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, trifluoromethoxy, or trifluoromethyl, and preferably independently selected from Cl or F. A The substituted phenyl ring can be selected from the group consisting of 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-fluoro-3,5-dichlorophenyl, 2,3-difluoro-5-chlorophenyl, 3,5-dichloro-4-fluorophenyl, 2-chloro-3,5-difluorophenyl, 3,4,5-trichlorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl, and preferably from the group consisting of 2,3,5-trifluorophenyl, 2,3,5-trichlorophenyl, and 2,3-dichloro-5-fluorophenyl.

[0040] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. AThe substituted phenyl ring can be selected from the group consisting of 2,3-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl, 5-chloro-2-fluorophenyl, and 2-chloro-5-fluorophenyl, preferably selected from the group consisting of 2,3-dichlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3,5-dichlorophenyl, and 5-chloro-2-fluorophenyl, and more preferably selected from the group consisting of 3-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, and 2,3-dichlorophenyl.

[0041] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl. AThe phenyl ring substituted with can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl, 2-chloro-3-methylphenyl, 2-chloro-3-methylphenyl It can be selected from the group consisting of xyphenyl, 3-chloro-5-trifluoromethylphenyl, and 3-fluoro-5-trifluoromethylphenyl, preferably from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, and 5-chloro-2-methoxyphenyl, and more preferably from the group consisting of 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, and 3-chloro-2-methoxyphenyl.

[0042] In some of these embodiments, n can be 2, and the substituent R A Each of these can be independently selected from Cl, F, methyl, methoxy, trifluoromethyl, or trifluoromethoxy. AThe phenyl ring substituted with can be selected from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-chloro-3-trifluoromethylphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 3-chloro-5-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl The group can be selected from toxic, 2-fluoro-5-trifluoromethoxy, 2-chloro-3-trifluoromethoxy, and 2-chloro-5-trifluoromethoxy, preferably from the group consisting of 2-fluoro-5-trifluoromethylphenyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-methoxyphenyl, 2-fluoro-5-trifluoromethoxy, and more preferably from the group consisting of 2-fluoro-5-trifluoromethyl, 3-chloro-2-methylphenyl, 3-chloro-2-methoxyphenyl, and 2-chloro-5-trifluoromethoxy.

[0043] In some of these embodiments, n can be 1, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, or trifluoromethyl, and preferably independently selected from Cl or F. AThe phenyl ring substituted can be selected from the group consisting of 3-fluorophenyl and 3-chlorophenyl, and preferably from the group consisting of 3-chlorophenyl.

[0044] In some of these embodiments, n can be 1, and the substituent R A R can be independently selected from Cl, F, methyl, methoxy, trifluoromethoxy, or trifluoromethyl, and preferably independently selected from Cl or F. A The substituted phenyl ring can be selected from the group consisting of 3-fluorophenyl and 3-chlorophenyl, and preferably from the group consisting of 3-chlorophenyl.

[0045] In some embodiments, the compound is of formula (C): [ka] [During the ceremony, R1, R2, R3 and R C Each of these is independently selected from H, Cl, F, OCF3, methyl, methoxy, and trifluoromethyl, or R1, R2, R3, and R C Each of two adjacent substituents selected from the above forms a five-membered or six-membered ring containing zero, one, or two N atoms, wherein the ring may be substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy, and trifluoromethyl; and, R B [This is H or CH3] It is represented as follows.

[0046] In some embodiments, R1 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy, and trifluoromethyl, preferably from Cl, F, methyl, and methoxy, more preferably from F or Cl, and most preferably from Cl.

[0047] In some embodiments, R2 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy, and trifluoromethyl, preferably selected from H, Cl, and F, and more preferably it is Cl.

[0048] In some embodiments, R3 is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy, and trifluoromethyl, preferably selected from H, Cl, and trifluoromethyl, more preferably selected from H or Cl, and most preferably it is H.

[0049] In some embodiments, R C The element is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy, and trifluoromethyl, preferably selected from H or F, and more preferably selected from H.

[0050] Representative compounds represented by formula (C) are shown in Table C.

[0051] [Table 1]

[0052] In some embodiments, the compound is selected from a list consisting of compounds 1 to 28.

[0053] In some embodiments, the compound is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28, preferably selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 15, 17, 23, and 27, more preferably selected from compounds 1, 2, 3, 5, 6, 7, 8, 17, and 23, and even more preferably selected from compounds 1, 3, 5, 6, 7, 8, and 23 or compounds 1, 3, 5, 7, 8 or compounds 1, 5, and 23. Most preferably, the compound is compound 1 or 5. In some embodiments, the compound is compound 1. In other embodiments, the compound is compound 5.

[0054] In one embodiment, the compound is of formula (II): [ka] It is represented by, or by, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof.

[0055] In some embodiments, R1, R2, and R3 are each independently selected from H, Cl, F, OCF3, methyl, methoxy, and trifluoromethyl, or R1 and R2 form a 5-membered or 6-membered ring containing 0, 1, or 2 N atoms, wherein the ring may be substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy, and trifluoromethyl; and, R B It is either H or CH3.

[0056] In some embodiments, R1, R2, and R3 are independently selected from H, Cl, F, methyl, methoxy, and trifluoromethyl, respectively. B This is as shown above.

[0057] In some embodiments, R1 is selected from H, Cl, F, methyl, methoxy, and trifluoromethyl, preferably from Cl, F, methyl, and methoxy, more preferably from F or Cl, and most preferably from Cl.

[0058] In some embodiments, R2 is selected from H, Cl, F, methyl, methoxy, and trifluoromethyl, preferably selected from H, Cl, and F, and more preferably it is Cl.

[0059] In some embodiments, R3 is selected from H, Cl, F, methyl, methoxy, and trifluoromethyl, preferably selected from H, Cl, and trifluoromethyl, more preferably selected from H or Cl, and most preferably it is H.

[0060] In some embodiments, R C The element is selected from H, Cl, F, methyl, methoxy, trifluoromethoxy, and trifluoromethyl, preferably selected from H and F, and more preferably selected from H.

[0061] Representative compounds represented by formula (II) are shown in Table A.

[0062] [Table 2]

[0063] In some embodiments, the compound is selected from a list consisting of compounds 1 to 17.

[0064] In some embodiments, the compound is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17, preferably selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, and 17, more preferably selected from compounds 1, 3, 5, 6, and 7, even more preferably selected from compounds 1, 3, 5, 6 or compounds 1, 4, 5, and most preferably selected from compound 1.

[0065] In one embodiment, the compound is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 3).

[0066] In another embodiment, the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 5).

[0067] In yet another embodiment, the compound is N-(8-(2-chloro-3-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 6).

[0068] In yet another embodiment, the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 1).

[0069] In a further embodiment, the compound is N-(8-(3,5-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 10).

[0070] In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-yl)quinoline-4-carboxamide (compound 2).

[0071] In a further embodiment, the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)-2-methylquinoline-4-carboxamide (compound 7).

[0072] In a further embodiment, the compound is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)-2-methylquinoline-4-carboxamide (compound 17).

[0073] In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-(trifluoromethyl)phenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 4).

[0074] In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-methoxyphenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 11).

[0075] In a further embodiment, the compound is N-(8-(2-chloro-5-methoxyphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 12).

[0076] In a further embodiment, the compound is N-(8-(2-chloro-5-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 13).

[0077] In a further embodiment, the compound is N-(8-(2-chloro-5-(trifluoromethyl)phenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 14).

[0078] In a further embodiment, the compound is N-(8-(3-chloro-2-methylphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 8).

[0079] In a further embodiment, the compound is N-(8-(3-chloro-2-methoxyphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 9).

[0080] In a further embodiment, the compound is N-(8-(5-chloro-2-methylphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 15).

[0081] In a further embodiment, the compound is N-(8-(5-chloro-2-methoxyphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 16).

[0082] In a further embodiment, the compound is N-(8-(2,3-difluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 18).

[0083] In a further embodiment, the compound is N-(8-(2,5-difluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 19).

[0084] In a further embodiment, the compound is N-(8-(2-chloro-5-methylphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 20).

[0085] In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-5-methylphenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 21).

[0086] In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(2,4,5-trifluorophenyl)quinoline-3-yl)quinoline-4-carboxamide (compound 22).

[0087] In a further embodiment, the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)-2-methylquinoline-4-carboxamide (compound 23).

[0088] In a further embodiment, the compound is N-(7-fluoro-8-(5-fluoro-2-methylphenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 24).

[0089] In a further embodiment, the compound is N-(7-fluoro-8-(2-fluoro-3-methoxyphenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 25).

[0090] In a further embodiment, the compound is N-(8-(2-chloro-5-(trifluoromethoxy)phenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (compound 26).

[0091] In a further embodiment, the compound is N-(7-fluoro-4-morpholino-8-(naphthalene-1-yl)quinoline-3-yl)quinoline-4-carboxamide (compound 27).

[0092] In a further embodiment, the compound is N-(7'-fluoro-4'-morpholino-[5,8'-biquinoline]-3'-yl)quinoline-4-carboxamide (compound 28).

[0093] The compounds represented by formula (I), formula (II), or formula (C) can be prepared by general synthetic routes known to those skilled in the art, specific examples of which are described in more detail in the examples.

[0094] In particular, the compound represented by formula (I) is Formula (A): [ka] [In the formula, R A And n has the meaning defined in any of the embodiments described above. The compound represented by formula (B): [ka] [In the formula, R B [This is H or CH3] It can be obtained by a reaction that includes a step of reacting with a compound represented by .

[0095] In particular, R A Each of these is preferably independently selected from Cl, F, OCF3, methyl, methoxy, or trifluoromethyl, or each of two adjacent substituents R AIt can form a 5-membered or 6-membered ring containing 0, 1, or 2 N atoms, where the ring may be substituted with one or more groups selected from Cl, F, OCF3, methyl, methoxy, and trifluoromethyl; and n is 0 to 5.

[0096] In this context, "halogen" refers to a compound having a -COHal group, where Hal is selected from F, Cl, Br, and I, and preferably from Cl.

[0097] The compounds represented by formulas (A) and (B) are commercially available or available in synthetic droplet form. In one embodiment of the present invention and / or its embodiments, an amine represented by formula (A) and an acid or halogen represented by formula (B) can form the corresponding amide group in an organic solvent, optionally in the presence of a coupling agent or an auxiliary alkaline compound.

[0098] A coupling agent can generally be considered a substance that promotes the formation of an ester or amide. The coupling agent reacts with a carboxyl group to form a reactive intermediate, which then further reacts with an alcohol or amine to form the final product, i.e., an ester or amide. In one embodiment of the present invention and / or its embodiments, the coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCxHCl), and carbonyldiimidazole (CDI). More preferably, the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0099] In one embodiment of the present invention and / or its embodiments, the process can be carried out in the presence of an auxiliary alkaline compound. Suitable alkaline compounds include, but are not limited to, pyridines such as 4-(dimethylamino)pyridine (DMAP), amidines such as 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), and amines such as triethylamine and diisopropylethylamine (DIPEA), with triethylamine being preferred.

[0100] Organic solvents are known to those skilled in the art. Suitable organic solvents for the process according to the present invention include, for example, acetonitrile, dioxane, tetrahydrofuran (THF), and dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and dichloromethane, with dichloromethane being preferred.

[0101] In one embodiment of the present invention and / or its embodiments, the process can be carried out at a temperature of 5 to 120°C, preferably at a temperature of 20 to 100°C.

[0102] In alternative embodiments and / or embodiments thereof of the present invention, a halide of compound B is used. For example, the carboxylic acid represented by formula (B) can be reacted with thionyl chloride or oxalyl chloride (preferably oxalyl chloride) to form the corresponding acid chloride. The corresponding acid chloride can then be reacted with the amine represented by formula (A) to obtain the compound represented by formula (I).

[0103] In alternative embodiments and / or embodiments thereof of the present invention, the alternative process can be carried out in an organic solvent and / or in the presence of an auxiliary alkaline compound. Suitable organic solvents may be, for example, acetonitrile, toluene, dioxane, tetrahydrofuran, chloroform, or dichloromethane. With regard to the auxiliary alkaline compound, the same applies as above, with pyridine, DMAP, triethylamine, and diisopropylethylamine being preferred, and triethylamine being the most preferred.

[0104] The present invention also provides pharmaceutically acceptable salts, solvates, polymorphs, or prodrugs of the compound represented by formula (I).

[0105] The terms "salt" or "salts" refer to acid-added or base-added salts of the compounds of the present invention. "Salts" particularly includes "pharmaceutically acceptable salts," which refer to salts that retain the biological efficacy and properties of the compounds of the present invention and are not generally biologically or otherwise undesirable. In particular, the compounds of the present invention can form acid salts based on the presence of an amino group.

[0106] Pharmacologically acceptable acid addition salts include inorganic and organic acids (e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlortheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfonate) It can be formed using salts such as salts, malates, maleates, malons, mandelates, mesylates, methylsulfates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propions, stearates, succinates, sulfosalicylates, tartrates, tosylates, and trifluoroacetates.

[0107] Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0108] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of the compound represented by formula (I) with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water, in an organic solvent, or in a mixture of both. Generally, it is preferable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, if possible.

[0109] The solvate of a compound can be considered as a compound to which an organic solvent or water has adhered. An organic solvent refers to one known to those skilled in the art. When water is adhering to a compound, the corresponding compound is known as a hydrate.

[0110] As used herein and as commonly understood by those skilled in the art, the term "polymorph" refers to different crystalline forms of the same molecular entity. Therefore, the solvates and hydrates discussed above, due to their differing chemical compositions, are not included in the definition of polymorphs and are instead referred to as "pseudopolymorphs."

[0111] The term "prodrug" refers to a compound that, for example, is rapidly converted in vivo by hydrolysis in the blood to produce the parent compound represented by formula (I) above. A detailed discussion can be found in "T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series" and "Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987".

[0112] The term "pharmaceutically acceptable prodrug," as used herein, refers to a prodrug of the present invention that, within the bounds of appropriate medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., is commensurate with a reasonable benefit-risk ratio, and is effective for its intended use, as well as, where possible, the zwitterionic form of the present invention.

[0113] The compounds of the present invention have been shown to be active against various types of helminths, including gastroenteric nematodes and heartworms. Therefore, the compounds of the present invention are particularly suitable as active ingredients in anthelmintic compositions. The compounds have been shown to exhibit selective activity against at least the larvae of Ascaridia, Oesophagostomum, Haemonchus, and Dirofilaria, while the likelihood of target-related adverse reactions in mammals (e.g., humans) is low.

[0114] Furthermore, the compound possesses beneficial physicochemical properties, such as water solubility. Improved water solubility is a desirable characteristic in the design of pharmacoactive compounds.

[0115] Administration and dosage form The compounds according to the present invention can be administered in various dosage forms. The term “dosage form” means that the compounds according to the present invention are formulated into products suitable for administration to animals via a hypothetical route of administration. Such dosage forms are, as may be referred to herein, “formulations” or “pharmaceutical compositions.”

[0116] In any case, the type of formulation selected for the dosage form will depend on the target animal, the specific intended purpose, and the physical, chemical, and biological properties of the compound according to the present invention.

[0117] The pharmaceutical compositions and / or embodiments thereof of the present invention can be administered to animals via various routes of administration.

[0118] One possible route of administration is the oral route, where the compounds according to the present invention are administered by mouth. Suitable oral administration forms include liquids (e.g., drench formulations, feed or drinking water formulations), semi-solids (e.g., pastes, gels), and solids (e.g., tablets, capsules, powders, granules, chewable treats, premixes, and medicated blocks).

[0119] In one embodiment of the present invention and / or its embodiments, the veterinary composition is an oral composition.

[0120] The liquid dosage forms of the compound are generally solutions, suspensions, or emulsions. A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. A suspension consists of insoluble solid particles dispersed in a liquid medium, where the solid particles make up about 0.5% to about 30% of the suspension. The liquid may be aqueous, oily, or both. An emulsion is a heterogeneous dispersion in which an immiscible liquid is contained within another liquid; its stability depends on the emulsifier.

[0121] Many veterinary compositions are known to be suitable for oral administration to animals, but they vary depending on the animal species. For small ruminants such as sheep, medicinal active ingredients are traditionally administered orally in solid form (e.g., tablets or boluses) or liquid form via their feed or drinking water. For larger herds of sheep and cattle, the use of oral liquid medications is the most common form of oral administration, especially when administering anthelmintic compounds.

[0122] "Drenching" means administering a potentially slightly viscous liquid composition containing the compound and pharmaceutically acceptable excipients orally using a specific drenching gun that delivers the composition into the throat of an animal (sheep). When administering the composition in the drinking water of an animal recipient or as a liquid, it may be convenient to use a solution formulation or a suspension formulation. This formulation may be, for example, a concentrated suspension mixed with water, or a dry preparation mixed and suspended in water.

[0123] The dry powder (or granules) for reconstitution is reconstituted as a solution or suspension using a diluent (e.g., water) immediately before administration. The main advantage of this administration method is that it overcomes the problem of instability in the solution or suspension state.

[0124] The liquid administration form may include, in addition to the active compound, pharmaceutically acceptable excipients commonly used in the art, such as inert diluents, such as water or another solvent; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, and fragrances.

[0125] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders and granules, chewable treats, premixes, and medicated blocks. In such a solid dosage form, the active compound is carried out with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or (a) fillers or bulking agents (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic), (c) humectants (e.g., glycerol), (d) disintegrants (e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate), (e) solution retarding agents (e.g., paraffin), (f) absorption enhancers (e.g., quaternary ammonium compounds), (g) wetting agents (h) an absorbent (e.g., kaolin and bentonite clay), and (i) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), and mixtures thereof, to be mixed. In the case of capsules, tablets and pills, the dosage form may also contain a buffer.

[0126] The active compound may also be in a microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical field, e.g., enteric coatings, release-controlled coatings, and other coatings). In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, as is common practice, e.g., tableting lubricants and other tableting aids, e.g., magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffers. These may contain opacifiers and may be compositions that release only the active ingredient, or preferentially the active ingredient, in a delayed manner, in a specific part of the intestinal tract. Examples of embedding compositions include polymers and waxes.

[0127] Taking advantage of the unique anatomical structure of the rumen's forestomach, several controlled-release delivery systems have been developed for intraruminal administration. Intraruminal boluses are specific formulations for ruminants (such as cattle, sheep, goats, buffalo, camels, and deer). They are veterinary delayed-release delivery systems that remain in the rumen's rumen-reticular sac for extended periods, with the therapeutic active substance within exhibiting a predictable delayed-release pattern. Such intraruminal boluses are typically administered using a drug gun or another appropriate device.

[0128] Semi-solid oral formulations (pastes or gels) are generally administered directly into the animal's mouth using an applicator, or mixed with feed.

[0129] Solid oral formulations are administered to animals either directly (tablets, capsules, boluses), mixed with feed, or via medicated feed blocks.

[0130] When an oral formulation is administered to a non-human animal via feed, it can be supplied, for example, as a standalone feed, or as a chewable treat or soft chew. Alternatively (or additionally), it can be uniformly dispersed in the animal recipient's normal feed, used as a top dressing, or used in the form of solid pellets, pastes, or liquids added to finished feed. When an oral formulation is administered as a feed additive, it may be convenient to prepare a “premix” in which the oral formulation is dispersed in a small amount of liquid or solid carrier. This “premix” can be dispersed in the animal’s normal feed, for example, using a conventional mixer.

[0131] Soft Chews for dogs are a chewable dosage form that enhances drug acceptance and encourages voluntary ingestion by animals. The term "soft chew" or "soft chewable drug" is intended to refer to a veterinary drug unit dose that is solid at room temperature, soft enough for dogs to chew after oral administration, and functionally requires sufficient chewing due to the product exhibiting certain plastic rheological behavior and texture during the chewing process in the mouth.

[0132] Alternatively, the compounds according to the present invention can be administered via parenteral administration routes, for example, topically (e.g., via spot-on, pour-on, or spray) or parenterally (e.g., by subcutaneous injection, intravenous injection, intramuscular injection, etc.).

[0133] In one embodiment of the present invention and / or its embodiments, the veterinary composition is an injectable composition.

[0134] Injectable compositions, such as sterile aqueous or sterile oily suspensions for injection, can be prepared according to known techniques using appropriate dispersants or wetting and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, or emulsions (e.g., solutions in 1,3-butanediol) in non-toxic, parenterally administered diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or synthetic diglycerides, can be used. In addition, fatty acids such as oleic acid are also used in the preparation of injectable preparations. Injectable formulations are preferably administered subcutaneously.

[0135] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by mixing in a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium before use.

[0136] To prolong the effects of a drug, it is often desirable to slow down the absorption of the drug via subcutaneous or intramuscular injection. Subcutaneous administration is preferred.

[0137] This can be achieved using suspensions of crystalline or amorphous materials with low water solubility. In this case, the absorption rate of the drug depends on its dissolution rate, which may depend on the crystal size and morphology. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle. Depot formulations for injection are manufactured by forming a microcapsule matrix of the drug within a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of drug to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0138] Alternatively, solid implants can be administered by injection (e.g., subcutaneous implants).

[0139] In one embodiment of the present invention and / or its embodiments, the veterinary composition is a topical composition. For example, the compounds according to the present invention can be administered topically using a transdermal formulation (i.e., a formulation that passes through the skin of an animal).

[0140] For example, the pore-on method or spot-on method involves applying the formulation to a specific location on the skin or fur (e.g., the animal's neck or spine). This can be achieved, for example, by applying a swab or drop of the pore-on or spot-on formulation to a relatively small area of ​​the recipient animal's skin or fur.

[0141] The concentration of the compound according to the present invention in the applicable dosage form may vary considerably depending on the route of administration. Generally, the concentration of the compound according to the present invention in the composition or embodiment thereof is 1 to 70% by weight, based on the total weight of the composition. In some embodiments, the concentration is 1 to 50% by weight, or 10 to 50% by weight. In other embodiments, the concentration is 35 to 65% by weight, 40 to 60% by weight, 45 to 55% by weight, or about 50% by weight.

[0142] Pharmaceutical composition In another embodiment, the present invention provides a pharmaceutical composition.

[0143] The pharmaceutical compositions and / or embodiments thereof of the present invention comprise an effective amount of one or more (preferably one) compounds according to the present invention and at least one pharmaceutically acceptable excipient. The composition may contain one or more compounds according to the present invention. The pharmaceutical composition is particularly a veterinary composition and may also be referred to as a (veterinary) dosage form.

[0144] In the veterinary compositions and / or embodiments thereof of the present invention, the compounds and / or embodiments thereof are formulated together with one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients must be suitable for the (veterinary) dosage form and route of administration.

[0145] Pharmaceutically acceptable excipients are known to those skilled in the art. For example, they are described in "Gennaro, Remington: The Science and Practice of Pharmacy" (20 th As described in the 2000 edition, all such pharmaceutically acceptable excipients must be substantially pure and non-toxic pharmaceutically or veterinarily in the amounts used and must be compatible with the active ingredient.

[0146] In one preferred embodiment and / or embodiment thereof of the present invention, the one or more pharmaceutically acceptable excipients are selected from carriers, binders, antioxidants, buffers, sugar components, surfactants, lubricants, stabilizers, flow agents, disintegrants, and preservatives and mixtures thereof.

[0147] Where used herein, the term “carrier” means a non-toxic, inert, solid, semi-solid, or liquid filler or diluent that holds / encapsulates any type of material. Some examples of materials that can function as pharmaceutically acceptable carriers are, but are not limited to, the following: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; esters, e.g., ethyl oleate and ethyl laurate; agar.

[0148] A binder is a substance that has the ability to bond other substances. If the binder is a polymer, the binder has a melting point or glass transition temperature (T) in the range of 25 to 100°C (preferably 35 to 85°C, particularly 40 to 70°C). g It is a component that has a glass transition temperature (T). The glass transition temperature is the temperature at which a polymer becomes brittle when cooled and soft when heated. This is because hydrophilic polymers have a glass transition temperature (T g This means that at temperatures above 5°C, the material becomes soft and can be plastically deformed without fracturing. The glass transition temperature or melting point can be measured by methods known to those skilled in the art.

[0149] In one preferred embodiment and / or the embodiment thereof, the binder is selected from polyethylene glycol, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymer, microcrystalline wax, glycerol monostearate, hydrogenated castor oil, polyethylene glycol glycerol hydroxystearate, polysaccharides, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylate, polyvinylpyrrolidone-polyacetate copolymer, and mixtures thereof.

[0150] Antioxidants are substances used to inhibit oxidation. Suitable antioxidants for inclusion in veterinary dosage forms include, but are not limited to, ascorbic acid, glutathione, tocopherol and its esters, tert-butylhydroquinone (TBHQ), butylhydroxyanisole (BHA, also known as 2-tert-butyl-4-hydroxyanisole, 3-tert-butyl-4-hydroxyanisole, or mixtures thereof), and butylhydroxytoluene (BHT, also known as 2,6-di-tert-butyl 4-methylphenol). In one preferred embodiment and / or embodiments thereof of the present invention, the amount of antioxidant contained in the veterinary dosage form may be in the range of 0.001 to 1.00% by weight.

[0151] Buffers are substances that maintain or adjust the pH value of a product. Non-exclusive examples of buffers include bicarbonates, dihydrogen phosphates, and hydrogen phosphates.

[0152] Sugar components are used in oral administration forms to sweeten the taste of the product. They include natural sugars (carbohydrates) and sugar substitutes. In one preferred embodiment of the present invention and / or its embodiments, the amount of sugar component included in the veterinary administration form may be in the range of 1 to 10% by weight.

[0153] In particular, in oral administration forms, surfactants can be considered as substances that reduce the interfacial tension between two phases. Common surfactants include alkyl sulfates (e.g., sodium lauryl sulfate), alkyltrimethylammonium salts, and alcohol ethoxylates. In one preferred embodiment and / or embodiments thereof of the present invention, the amount of surfactant included in the veterinary administration form may be in the range of 0.1 to 10.0% by weight.

[0154] Lubricants can generally be considered substances suitable for reducing friction, such as static friction, sliding friction, and rolling friction. The lubricant is preferably a stearate or fatty acid, and more preferably an alkaline earth metal salt such as magnesium stearate. In one preferred embodiment and / or embodiment thereof of the present invention, the amount of lubricant included in the veterinary dosage form may be in the range of 0.1 to 10.0% by weight.

[0155] Stabilizers are pharmaceutically acceptable excipients that help preserve the product. Examples include, but are not limited to, alginates, carrageenan, gelatin, pectin, and natural gums. In one preferred embodiment and / or of the present invention, the amount of stabilizer included in the veterinary dosage form may be in the range of 0.01 to 3.0% by weight.

[0156] Fluids (also called fluidity enhancers) can be used to improve fluidity. Traditionally, talc was used as a fluidity enhancer, but it has now been almost completely replaced by colloidal silica. In one preferred embodiment and / or embodiments thereof of the present invention, the amount of fluid included in the veterinary dosage form may be in the range of 1 to 3% by weight.

[0157] A disintegration agent (also called a disintegrant) is a compound (generally a compound in a solid dosage form) that enhances the ability of a dosage form (preferably a tablet) to disintegrate into smaller fragments when in contact with a liquid (preferably water). Non-limiting examples of disintegrants include sodium carboxymethyl starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl glycolate, with sodium starch glycolate being preferred. In one preferred embodiment and / or embodiments thereof of the present invention, the surfactant included in the veterinary dosage form may be in the range of 1.0 to 7.0% by weight.

[0158] Preservatives are substances that can be added to prevent degradation due to microbial growth or undesirable chemical changes. Non-limiting examples include lactic acid, benzoic acid, benzoates, and hydroxybenzoates. In one preferred embodiment and / or embodiment thereof of the present invention, the amount of preservative included in the veterinary dosage form may be in the range of 0.01 to 1.0% by weight.

[0159] The pharmaceutical compositions of the present invention can be manufactured by processes known in the art. These processes include, for example, various known mixing processes, dissolution processes, granulation processes, emulsification processes, encapsulation processes, capture processes, and lyophilization processes. The optimal formulation depends, for example, on the form of administration and route of administration (e.g., oral, parenteral by injection, topical).

[0160] Solid dosage forms can be prepared, for example, by tightly and homogeneously mixing the compound with fillers, binders, lubricants, flow enhancers, disintegrants, flavorings (e.g., sweeteners), buffers, preservatives, pharmaceutical-grade dyes or pigments, and release control agents.

[0161] Oral administration forms other than solids can be prepared by mixing the compound with, for example, one or more solvents, thickeners, surfactants, preservatives, stabilizers, resins, fillers, binders, lubricants, flow enhancers, disintegrants, cosolvents, sweeteners, flavorings, buffers, suspending agents, and pharmaceutical-grade dyes or pigments.

[0162] How to use The compounds of the present invention can be used as pharmaceuticals for controlling parasitic infestations in animals, particularly as veterinary antiparasitic agents. The present invention is understood to further include the use of the compounds and / or embodiments thereof described in this application in the manufacture of pharmaceuticals for controlling parasitic infestations in animals or for treating or preventing diseases caused by parasitic nematodes in animals. The present invention also includes a method for treating or preventing diseases caused by parasitic nematodes, the method comprising administering to an animal an effective amount of the compounds or compositions according to the present invention and optionally an effective amount of at least one other active ingredient.

[0163] The expression "control of helminth parasites" means reducing or eradicating the number of parasites in animals, and / or partially or completely suppressing the occurrence of parasitic infestations in animals. This can be achieved, for example, by killing, repelling, exterminating, neutralizing, deterring, removing, mitigating, or minimizing the parasites. The effects of a compound may be, for example, ovicidal, larvicidal, or adulticidal, or a combination thereof. Furthermore, the effect may manifest by directly killing the parasites immediately or after a certain period of time (for example, during molting or by killing the eggs). The effect may also manifest indirectly, alternatively (or additionally), for example, by reducing the number of eggs laid and / or lowering the hatching rate.

[0164] The compounds according to the present invention act against animal parasites, particularly endoparasites. Endoparasites refer to parasites that inhabit the internal organs or tissues of a host. The term “endoparasite” particularly includes helminths such as tapeworms, nematodes, or trematodes, and protozoa such as coccidia. Endoparasites include nematode pests that commonly infect animals, and include their egg, larval, and adult stages. Such parasites include helminths (roundworms, hookworms, tapeworms, and heartworms), and such parasites are commercially important because they cause serious diseases in animals.

[0165] The term "(parasitic) infection" encompasses conditions associated with or caused by one or more (parasitic) pathogens. These conditions include clinical (parasitic) and subclinical states. Therefore, the term "treatment of parasitic infection" encompasses both the treatment of parasitic diseases and subclinical states. Treatment of parasitic infection generally means reducing the parasitic burden (e.g., helminths) in animals to a level that does not result in economic loss.

[0166] Subclinical conditions are typically those in which animals infected with parasites do not directly present with clinical symptoms but cause economic losses. Such economic losses may result from, for example, reduced growth in young animals, decreased feed efficiency, reduced weight gain in meat-producing animals, reduced milk production in ruminants, decreased egg production in laying hens, or reduced wool production in sheep.

[0167] The term "parasitic disease" refers to clinically evident pathological conditions and diseases associated with or resulting from infection by one or more parasites, such as parasitic gastroenteritis or anemia in ruminants (e.g., sheep or goats) or colic in horses.

[0168] In preferred embodiments, the compounds according to the present invention are used to prevent or treat helminthic infections, for example, infections caused by one or more helminths selected from the following groups: (a) tapeworms, for example, species of the genera Anaplocephala; Dipylidium; Diphyllobothrium; Echinococcus; Moniezia; Taenia; (b) trematodes, for example, species of the genera Dicrocoelium; Fasciola; Paramphistomum; Schistosoma; or (c) nematodes, for example, Acanthocheilonema species; Aelurostrongylus species; Ancylostoma species; Angiostrongylus species; Anecator species; Ascaridia species; Ascaris species; Brugia species; Bunostomum species ;Capillaria sp.;Chabertia sp.;Cooperia sp.;Crenosoma sp.;Cyathostomum sp.;Cylicocyclus sp.;Cylicodontophorus sp.;Cylicostephanus sp.;Crateros tomum species; Dictyocaulus species; Dipetalonema species; Dirofilaria species; Dracunculus species; Enterobius species; Filaroides species; Habronema species; Haemonchus species; Heteraki s species;Hyostrongylus species;Metastrongylus species;Meullerius species;Necator species;Nematodirus species;Nippostrongylus species;Oesophagostomum species;Onchocerca species;On cocercidae species;Ostertagia species;Oxyuris species;Parascaris species;Spirocerca species;Stephanurus species;Strongylus species;Syngamus species;Toxocara species;Strongyloides species Species; Teladorsagia species; Toxascaris species; Trichinella species; Trichuris species; Trichostrongylus species; Triodontophorous species; Uncinaria species and / or Wuchereria species;Preferably, nematodes; especially species of the genera Dirofilaria, Haemonchus, Ascaridia, Strongylus, Cyathostomum, Ostertagia, Cooperia, Trichostrongylus, Nematodirus, Teladorsagia, Oesophagostomum, Ancylostoma, and Toxocara; especially Dirofilaria immitis.

[0169] In particular, the compounds according to the present invention are effective against parasitic nematodes, and more specifically against roundworms. More specifically, the compounds according to the present invention are effective against Dirofilaria immitis, Angiostrongylus vasorum, gastrointestinal nematodes such as Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Spirocerca lupi, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, and pulmonary nematodes such as Dictyocaulus viviparus, Aelurostrongylus It is effective against abstrusus and crenosoma vulpis.

[0170] In one embodiment, the compound according to the present invention is effective against Dirofilaria immitis and Angiostrongylus vasorum, and preferably against Dirofilaria immitis.

[0171] In another embodiment, the compound is administered to gastrointestinal nematodes, such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus effective against Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi.

[0172] In another embodiment, the compound is effective against lung nematodes, such as Dictyocaulus viviparus, Aelurostrongylus abstrusus, and Crenosoma vulpis.

[0173] As used herein, the terms “treat” or “cure” are understood to encompass prophylactic treatment, metaphylactic and therapeutic treatment, or curative treatment. Prophylactic or metaphylactic treatment, i.e., deworming, is commonly used to prevent helminth infections and control parasitic infections in animals. Furthermore, helminths can infect humans and therefore pose a threat to human health. Prophylactic treatment also includes treatments administered at regular intervals, for example, 1 to 6 times per year, or 2 to 4 times per year, or 1 to 4 times per month. Metaphylactic treatment includes, for example, treating all animals in a group that are in contact with each other within the same area, to prevent the spread of parasites to other animals when many animals are diagnosed with helminth infections.

[0174] In therapeutic or curative treatment, the compound is administered after a clinical diagnosis. This method reduces the cost of anthelmintics and significantly reduces the possibility of resistance selection by treating only some animals, thereby ensuring the presence of susceptible parasite populations within the group. However, its drawback is that it requires regular monitoring, which increases the labor input.

[0175] The present invention provides compounds or veterinary compositions according to the present invention for use as pharmaceuticals.

[0176] In one embodiment, the compound or veterinary composition according to the present invention is used to treat helminthic infections in animals, such as filariasis, particularly canine heartworm disease.

[0177] In another embodiment, the compounds or veterinary compositions according to the present invention are used to treat animal infections caused by gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, and Oxyuris equi.

[0178] The compounds or veterinary compositions according to the present invention are used in the manufacture of pharmaceuticals. In preferred embodiments, the compounds or veterinary compositions according to the present invention are used in the manufacture of pharmaceuticals for the treatment of helminthic infections, such as filariasis, in particular canine heartworm disease.

[0179] In another embodiment, the compounds or veterinary compositions according to the present invention are used to manufacture pharmaceuticals for treating infections caused by gastrointestinal nematodes such as Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Copeeria oncophora, Copeeria punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, and Oxyuris equi.

[0180] Furthermore, the present invention also provides the use of the compounds of the present invention or veterinary compositions according to the present invention for the manufacture of pharmaceuticals for the treatment of helminthic infections (e.g., filariasis, and in particular, canine heartworm disease) or infections caused by gastrointestinal nematodes (e.g., Ascaridia galli, Oesophagostomum dentatum, Haemonchus contortus). Preferably, the compounds of the present invention or the veterinary compositions according to the present invention are used to manufacture pharmaceuticals for treating helminthic infections (e.g., filariasis, and especially canine heartworm disease) or infections caused by gastrointestinal nematodes (e.g., Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi).

[0181] Furthermore, the present invention relates to parasitic organisms, preferably helminths [preferably one or more types of helminths selected from the following group: (a) Tapeworms: for example, species of the genera Anaplocephala; Dipylidium; Diphyllobothrium; Echinococcus; Moniezia; Taenia; (b) Trematodes, for example, species of the genera Dicrocoelium; Fasciola; Paramphistomum; Schistosoma; or (c) Nematodes, for example, Acanthochei lonema species;Aelurostrongylus species;Ancylostoma species;Anecator species;Angiostrongylus species;Ascaridia species;Ascaris species;Brugia species;Bunostomum species;Capillar ia species;Chabertia species;Cooperia species;Crenosoma species;Cyathostomum species;Cylicocyclus species;Cylicodontophorus species;Cylicostephanus species;Craterostomum species ;Dictyocaulus species;Dipetalonema species;Dirofilaria species;Dracunculus species;Enterobius species;Filaroides species;Habronema species;Haemonchus species;Heterakis species;H yostrongylus sp.; Metastrongylus sp.; Meullerius sp.; Necator sp.; Nematodirus sp.; Nippostrongylus sp.; Oesophagostomum sp.; Onchocerca sp. ercidae species;Ostertagia species;Oxyuris species;Parascaris species;Spirocerca species;Stephanurus species;Strongylus species;Syngamus species;Toxocara species;Strongyloides species ;Teladorsagia species;Toxascaris species;Trichinella species;Trichuris species;Trichostrongylus species;Triodontophorous species;Uncinaria species, and / or Wuchereria species;More preferably, the present invention also provides compounds or compositions for use in the treatment of disorders / diseases caused by nematodes, particularly species of the genera Dirofilaria, Haemonchus, Strongylus, Cyathostomum, Ostertagia, Cooperia, Trichostrongylus, Nematodirus, Teladorsagia, Oesophagostomum, Ancylostoma, and Toxocara; in particular, Dirofilaria immitis.

[0182] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used to treat diseases caused by helminthic infections (e.g., filariasis, particularly canine heartworm disease) or gastrointestinal nematodes (e.g., Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Ostertagia ostertagi, Copeeria oncophora, Copeeria punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Haemonchus contortus, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi) or pulmonary nematodes (e.g., Dictyocaulus It is used in the treatment of diseases caused by viviparus, Aelurostrongylus abstrusus, and Crenosoma vulpis.In preferred embodiments of the present invention, or in such embodiments, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, where the helminths are species of the genera Dirofilaria, Ascaridia, Oesophagostomum, Haemonchus, Ancylostoma, Toxocara, Angiostrongylus, Crenosoma, Spirocerca, Aelurostrongylus, Ostertagia, Cooperia, Trichostrongylus, Nematodirus, Teladorsagia, Chabertia, Parascaris, Oxyuris, Dictyocaulus, Aelurostrongylus, Crenosoma, and Cyathostomum, and more specifically, Dirofilaria repens, Dirofilaria immitis, Ascaridia galli, and Oesophagostomum. venulosum, Haemonchus contortus, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemon Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

[0183] In preferred embodiments of the present invention, the compounds or compositions according to the present invention are used in the treatment of gastric torsion.

[0184] In preferred embodiments or embodiments thereof of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, where the helminths are species of the genus Haemonchus, in particular Haemonchus placei and Haemonchus contortus.

[0185] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of toxocariasis. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, wherein the helminths are species of the genus Toxocara, and in particular Toxocara canis.

[0186] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of duodenal worm disease. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, wherein the helminths are species of the genus Anchylostoma, and in particular Ancylostoma caninum.

[0187] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of ascariosis. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, where the helminth is Ascaridia galli.

[0188] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of intestinal nodule disease. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, wherein the helminths are species of the genus Oesophagostomum, in particular Oesophagostomum venulosum, Oesophagostomum radiatum, and Oesophagostomum dentatum.

[0189] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of trichomeriasis. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, wherein the helminths are species of the genus Trichostrongylus, and in particular Trichostrongylus axei and Trichostrongylus colubriformis.

[0190] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of Ostertagia ostertagi. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, where the helminths are species of the genus Ostertagia, and in particular Ostertagia ostertagi.

[0191] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of cooperationosis. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, wherein the helminths are species of the genus Cooperia, and in particular Cooperia oncophora and Cooperia punctata.

[0192] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of helminthic diseases caused by infection with the genus Nematodirus. In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of disorders / diseases caused by helminths, where the helminths are species of the genus Nematodirus, and in particular Nematodirus helvetianus and Nematodirus spathiger.

[0193] In preferred embodiments of the present invention, the compounds or compositions of the present invention are used in the treatment of helminthic diseases caused by infection with the genus Teladorsagia.

[0194] The compounds according to the present invention and compounds corresponding to their use according to the present invention are intended to be used to treat animals, including humans and non-human animals, in particular non-human mammals. Such non-human mammals include, for example, domestic mammals (e.g., pigs, domestic ruminants, e.g., cattle, sheep, goats), laboratory mammals (e.g., mice, rats, gerbils), companion mammals (e.g., dogs, cats, horses), and wild and zoo mammals (e.g., water buffalo, deer). Furthermore, the compounds are also considered suitable for treating non-mammals, such as poultry (e.g., turkeys, chickens, ducks) and fish (e.g., salmon, trout, carp).

[0195] The inventors have shown that the compounds of the present invention, as previously disclosed and defined, are particularly suitable for the treatment of helminthic infections, for example, gastric torsion, trichonodiasis, or enterotocytosis (especially in sheep or cattle), or Ostertag's gastric worm disease or Cooperiosis (especially in cattle), or Duodenal worm disease (especially in dogs), or Toxocariasis (especially in dogs), and for the treatment of filariasis (especially in dogs or cats), and especially in canine heartworm disease (especially in dogs).

[0196] The compounds or veterinary compositions according to the present invention are administered to treat or prevent disorders / diseases caused by one or more helminths selected from the group consisting of: (a) Tapeworms: e.g., species of the genera Acanthocheilonema; Anaplocephala; Dipylidium; Diphyllobothrium; Echinococcus; Moniezia; Taenia; (b) Trematodes, e.g., species of the genera Dicrocoelium; Fasciola; Paramphistomum; Schistosoma; or (c) Nematodes, e.g., species of the genera Aelurostrongylus; Ancylostoma; Anecator; Angiostrongylus; Asc aridia sp.; Ascaris sp.; Brugia sp.; Bunostomum sp.; Capillaria sp.; Chabertia sp.; Cooperia sp.; Crenosoma sp.; Cyathostomum sp. Genus species;Dictyocaulus species;Dipetalonema species;Dirofilaria species;Dracunculus species;Enterobius species;Filaroides species;Habronema species;Haemonchus species;Heterakis species;Hyostrongylus species;Metastrongylus species;Meullerius species.Necator species; Nematodirus species; Nippostrongylus species; Oesophagostomum species; Onchocerca species; Oncocercidae species; Ostertagia species; Oxyuris species; Parascaris species; Spirocer ca species; Stephanurus species; Strongylus species; Syngamus species; Toxocara species; Strongyloides species; Teladorsagia species; Toxascaris species; Trichinella species; Trichuris species; Trichostr Species of the genera *ongylus*; *Triodontophorous*; *Uncinaria*; and / or *Wuchereria*; more preferably, nematodes, especially *Dirofilaria*; *Haemonchus*; *Strongylus*; *Cyathostomum*; *Ostertagia*; *Cooperia*; *Trichostrongylus*; *Nematodirus*; *Teladorsagia*; *Oesophagostomum*; *Ancylostoma*; *Toxocara*; especially *Dirofilaria immitis*.

[0197] In particular, the compounds or veterinary compositions according to the present invention are administered to treat or prevent disorders / diseases caused by one or more helminths selected from the group consisting of: (a) tapeworms, e.g., Monezia expansa; (b) trematodes, e.g., Fasciola hepatica, Fascioloides magna, Dicrocoelium dentriticum, Paramphistomum cervi; and (c) nematodes: Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Haemonchus placei, Haemonchus contortus, Nematodirus helvetianus, Nematodirus spathiger, Trichostrongylus colubriformis, Trichostrongylus circumcincta, Oesophagostomum venulosum, Chabertia ovina, Teladorsagia circumcincta, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Dictyocaulus viviparus, Dictyocaulus filaria, Dirofilaria immitis, Dirofilaria repens.

[0198] More preferably, the compounds or veterinary compositions according to the present invention are administered to treat or prevent infections caused by helminths, for example, to treat or prevent gastric torsion, enterotocytosis, trichomycosis (especially in sheep or cattle), or Ostertag's gastric worm disease or Cooperiosis (especially in cattle), or duodenal worm disease (especially in dogs), or toxocariasis (especially in dogs), or filariasis (especially in dogs or cats), and especially canine heartworm disease (in dogs).

[0199] As used herein, the term “treatment” refers to reversing, alleviating, or inhibiting the progression of a disease, disorder, or condition. In the case of helminthic infections, for example, in the case of filariasis, and especially in the case of canine heartworm disease, this means that the clinical symptoms (impairment of lung, heart, liver, and / or kidney function) are alleviated.

[0200] Accordingly, the present invention provides a method for treating diseases caused by helminths (e.g., nematodes), wherein the method comprises administering a therapeutically effective amount of a compound or composition according to the present invention to an animal (particularly a sheep or a dog). In other words, the present invention provides a method for treating helminthic infections, such as filariasis, particularly canine heartworm disease, wherein the method comprises administering a therapeutically effective amount of a compound or composition according to the present invention to a mammal in need of such treatment.

[0201] The present invention also covers methods for treating animals having diseases caused by nematodes, wherein the method comprises administering an effective amount of a compound or composition and / or embodiment thereof according to the present invention to a subject in need of such treatment, wherein the nematode is at least one selected from the following groups: species of the genera Ascaridia, Oesophagostomum, Haemonchus, Dirofilaria, Ancylostoma, Toxocara, Angiostrongylus, Crenosoma, Spirocerca, Aelurostrongylus, Ostertagia, Copeeria, Trichostrongylus, Nematodirus, Teladorsagia, Chabertia, Parascaris, Oxyuris, Dictyocaulus, Aelurostrongylus, Crenosoma, Cyathostomum, in particular Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Dirofilaria repens, Dirofilaria immitis, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyuris equi, Dictyocaulusviviparus, Aelurostrongylus abstrusus, Crenosoma vulpis. More specifically, the subject is warm-blooded animals, in particular mammals, more specifically sheep, cattle, horses, dogs or cats, in particular dogs or cats.

[0202] The present invention also relates to a method for treating a mammal (preferably a cattle, sheep, horse, cat, or dog) suffering from a disease caused by helminths (particularly nematodes), wherein the method comprises administering an effective amount of the compound or composition and / or embodiments thereof according to the present invention to a subject in need of such treatment, wherein the nematode is at least one selected from the following groups: species of the genera Ascaridia, Oesophagostomum, Haemonchus, Dirofilaria, Ancylostoma, and Tox. ocara sp., Angiostrongylus sp., Crenosoma sp., Spirocerca sp., Aelurostrongylus sp., Ostertagia sp., Cooperia sp., Trichostrongylus sp., Nematodirus sp. Species, Teladorsagia sp., Chabertia sp., Parascaris sp., Oxyuris sp., Dictyocaulus sp., Aelurostrongylus sp., Crenosoma sp., Cyathostomum sp., especially Ascaridia galli, Oesophagostomum venulosum, Haemonchus contortus, Dirofilaria repens, Dirofilaria immitis, Ancylostoma caninum, Toxocara canis, Angiostrongylus vasorum, Crenosoma vulpis, Spirocerca lupi, Aelurostrongylus abstrusus, Ostertagia ostertagi, Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus placei, Nematodirus helvetianus, Nematodirus spathiger, Nematodirus filicolis, Nematodirus battus, Teladorsagia circumcincta, Chabertia ovina, Parascaris equorum, Oxyurisequi, Dictyocaulus viviparus, Aelurostrongylus abstrusus, Crenosoma vulpis.

[0203] According to the compounds of the present invention and / or therapeutic methods according to embodiments thereof, diseases caused by helminths, in particular diseases caused by nematodes, in particular diseases caused by nematodes (wherein said nematodes are at least one selected from the group Ascaridia, Oesophagostomum, Haemonchus, Dirofilaria, Ancylostoma, Toxocara, Angiostrongylus, Crenosoma, Spirocerca, Aelurostrongylus, Ostertagia, Cooperia, Trichostrongylus, Nematodirus, Teladorsagia, Chabertia, Parascaris, Oxyuris, Dictyocaulus, Aelurostrongylus, Crenosoma, and Cyathostomum), can be treated or prevented in mammals (especially dogs) by administering to the animal an effective amount of the compounds of the present invention necessary to achieve the desired result for a period of time necessary to achieve the desired result.

[0204] In one embodiment, the parasitic nematode is a gastroenterinary nematode, and the target animal is selected from the group consisting of dogs, cats, ruminants, horses, and poultry.

[0205] A preferred use of the compounds or compositions according to the present invention is in cattle. The compounds or compositions according to the present invention can be used in animals of various weights, including animals weighing more than 50 kg (for example, animals weighing between 50 and 1200 kg).

[0206] A preferred use of the compounds or compositions according to the present invention is in small ruminants such as sheep. The compounds or compositions according to the present invention can be used in animals of various weights, including animals weighing more than 45 kg (for example, animals weighing 50 to 100 kg).

[0207] A preferred use of the compounds or compositions according to the present invention is in horses. The compounds or compositions according to the present invention can be used in animals of various weights, including animals weighing more than 100 kg (for example, 100 to 1000 kg).

[0208] In one embodiment, the animal to be treated is a sheep, and the disease to be treated is a helminth infection, such as gastric torsion, trichomycosis, or enterococcal infection, particularly gastric torsion. In another embodiment, the animal is a sheep, and the disease to be treated is trichomycosis. In yet another embodiment, the animal is a sheep, and the disease to be treated is enterococcal infection.

[0209] In one embodiment, the animal to be treated is a cattle, and the disease to be treated is a helminthic infection, such as gastric torsion, trichomycosis, Ostertag's gastric worm disease, or cooperationosis, in particular Ostertag's gastric worm disease. In another embodiment, the animal is a cattle, and the disease to be treated is trichomycosis. In another embodiment, the animal is a cattle, and the disease to be treated is gastric torsion. In another embodiment, the animal is a cattle, and the disease to be treated is cooperationosis.

[0210] Another preferred use of the compounds or compositions according to the present invention is in pets, such as cats and dogs, and in particular in dogs. The compounds or compositions according to the present invention can be used in animals of various body weights.

[0211] Other typical animals that can be treated with the compounds or compositions according to the present invention are small pets such as cats. In one embodiment, the compounds or compositions according to the present invention are used to treat diseases in dogs or cats, for example, severe lung disease, heart failure and damage to other internal organs caused by Dirofilaria, more specifically by Dirofilaria immitis.

[0212] In some embodiments, the parasitic nematode belongs to the genus Dirofilaria, and the animals to be treated are selected from cats and dogs.

[0213] In other embodiments, the animal to be treated is a dog, and the disease to be treated is filariasis, particularly canine heartworm disease.

[0214] In other embodiments, the animal to be treated is a cat, and the disease to be treated is filariasis, particularly canine heartworm disease.

[0215] In other embodiments, the animal to be treated is a dog, and the disease to be treated is duodenal worm infection.

[0216] In other embodiments, the animal to be treated is a dog, and the disease to be treated is toxocariasis.

[0217] The frequency of administration depends on several factors and may be a single dose, or, depending on the protective period, may be once a week, once a month, once every two months, once every three months, once every four months, once every six months, once every nine months, or once a year. In some embodiments, the frequency of administration may be, for example, once a week, once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every nine months, or once every twelve months, or it may be an equivalent frequency expressed in days or weeks that approximates such frequencies.

[0218] The compound of the present invention is intended to be administered once a month. However, by using a sustained-release formulation, administration may be possible once every two, three, four, five, or six months.

[0219] In one embodiment, the present invention treats or controls existing parasitic infestations in animals. In another embodiment, the present invention treats or controls existing parasitic infestations in animals and protects the animals from further parasitic infestations.

[0220] Another embodiment is a method for protecting an animal at risk of parasitic infection or developing a parasitic disease, the method comprising administering to the animal an effective amount of at least one compound and / or embodiment thereof using a single dose.

[0221] The term “parasitic disease” refers to clinically evident pathological conditions and diseases directly related to or caused by parasitism by one or more parasites, such as gastric torsion, ascariasis, enterococcal disease, or heartworm disease. It also encompasses pathological conditions or diseases related to or caused by one or more pathogens transmitted by a vector, such as heartworm disease caused by a mosquito, which is the vector. Other examples include parasitic gastroenteritis or anemia in ruminants (e.g., sheep and goats), or colic in horses.

[0222] The expression "prevention of parasitic diseases" means suppressing the development of parasitic diseases in animals. Generally, control of parasitic infestations (which include parasitic diseases) is achieved by administering an effective amount of the compound according to the present invention.

[0223] In one embodiment, the present invention provides a composition comprising an effective amount of the compound and / or embodiments thereof, which is used to treat and / or protect animals from parasitic infestations, wherein the composition is administered to an animal diagnosed with or suspected of being parasitic. In one embodiment, the composition is administered to an animal at risk of parasitic infestation to protect the animal from such infestation.

[0224] The compounds according to the present invention are useful in pharmaceuticals, particularly in pharmaceuticals for treating and controlling parasitic infestations in animals. In such pharmaceuticals, there exist compounds and / or embodiments thereof at concentrations that are administered as an effective dose to the animals in need. "Effective dose" is the amount or quantity of the compound necessary to cause a measurable reduction in the parasitic population infesting an animal, and / or to inhibit the progression of parasitic infestation in an animal (whether overall, partially, or to at least alleviate the clinical symptoms of the affected animal).

[0225] This amount can be easily determined by observing or detecting the number of parasites in the animal before and after contact with the compound. If the compound exerts its effect through ingestion / ingestion by the parasite, the effective amount generally constitutes the amount that results in a blood concentration that is generally toxic to the target parasite.

[0226] The difference in numerical values ​​in such counts performed before and after treatment indicates the efficacy of the administered dose; for example, the number of parasites decreases by an amount ranging from 5% to approximately 100% after the initial administration.

[0227] Therefore, while a 100% or near-100% reduction is the target, a reduction of approximately 50% in the number of parasites can already be considered a significant reduction. This is because even such a modest reduction can already alleviate certain symptoms in affected animals and / or restore them to improved economic productivity levels.

[0228] In one embodiment, an effective amount of the active agent achieves at least about 80% or at least about 90% efficacy against the target parasite. In a particular preferred embodiment, the efficacy is at least about 95%.

[0229] In preferred embodiments, the reduction in parasitism to animals, or the control and / or reduction achieved, relates to a reduction of at least 50, 60, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or even 100% of the number of a particular type of parasite, in an order of increasing preference.

[0230] In certain cases (for example, the prevention of Dirofilaria immitis), the term "effective dose" can represent a high efficacy of 100%. In one embodiment, the efficacy against Dirofilaria immitis is 100%.

[0231] The duration of activity or efficacy (i.e., "knockdown," onset of activity, and / or sustained effect) is a primary concern when selecting an antiparasitic product. The duration of a compound's effectiveness against parasites is crucial for determining the necessary treatment interval.

[0232] In one embodiment, the compound of the present invention provides approximately 100% efficacy against parasites for about one month or more.

[0233] In other embodiments, the compounds of the present invention exhibit efficacy against parasites for approximately 3 months or more, approximately 8 months or more, or approximately 9 months or more, with approximately 100% efficacy.

[0234] In other embodiments, the compounds of the present invention exhibit efficacy against parasites with at least about 90% effectiveness for about 10 months or more, about 11 months or more, or even about 12 months or more.

[0235] Therefore, one embodiment of the present invention is a method in which the compound is administered monthly.

[0236] Therefore, in another embodiment of the present invention, the compound is administered once every six weeks.

[0237] Therefore, in another embodiment of the present invention, the compound is administered once every two months.

[0238] Therefore, in another embodiment of the present invention, the compound is administered once every 10 weeks.

[0239] Therefore, in another embodiment of the present invention, the compound is administered once every 3 months.

[0240] Therefore, in another embodiment of the present invention, the compound is administered once every 6 months.

[0241] Therefore, in another embodiment of the present invention, the compound is administered once every 9 months.

[0242] In particular, the compound is particularly suitable for use in preventing canine filariasis in mammals. Canine filariasis is prevented when the Dirafilaria larvae present in the host mammalian body are not allowed to grow into adult worms. Mammals include dogs, cats, wolves, coyotes, jackals, foxes, ferrets, bears, seals, and sea lions, particularly dogs and cats, and more particularly dogs.

[0243] In particular, the compound is particularly suitable for use in dogs to prevent canine filariasis in dogs by eliminating the tissue stage of Dirofilaria immitis larvae over a one-month (30-day) period after infection.

[0244] The present invention further provides the use of a compound according to the present invention for manufacturing a medicament for preventing canine filariasis in animals.

[0245] Examples of anticipated combination therapies In one embodiment of the present invention or an embodiment thereof, the veterinary composition of the present invention and / or an embodiment thereof contains an effective amount of the compound of the present invention and / or an embodiment thereof as a single active ingredient.

[0246] In another embodiment of the present invention, the veterinary composition and / or embodiment of the present invention comprises an effective amount of the compound and / or embodiment of the present invention in combination with one or more other (known) active ingredients.

[0247] The compounds of the present invention can be administered as a single active ingredient in a pharmaceutical composition, or in combination with at least one other additional antiparasitic agent (which forms a parasitic agent that provides a broader range of veterinary utility). Accordingly, the present invention also envisions a combination veterinary pharmaceutical composition that contains an effective amount of the compounds of the present invention in combination with at least one other additional antiparasitic agent, and may further include at least one veterinarily acceptable excipient.

[0248] These one or more other active ingredients may have an anthelmintic or antiparasitic spectrum similar to that of the compounds of the present invention in order to synergistically enhance the treatment of infections covered by the spectrum of the compounds of the present invention.

[0249] Alternatively, if parasitism by multiple parasite species is suspected, and another active ingredient with a different spectrum is required in addition to the compound of the present invention, one or more other known active ingredients may have a different antiparasitic spectrum than the compound of the present invention.

[0250] The treatment may include administering a composition comprising the compound of the present invention and one or more further known active ingredients, or administering the compound of the invention, followed by or prior to administering one or more additional active ingredients.

[0251] Accordingly, the methods and pharmaceutical compositions of the present invention encompass methods in which the compound according to the present invention is the sole active ingredient administered to the recipient animal. However, the methods and compositions also encompass methods in which the compound is administered in combination with one or more other pharmaceutically acceptable active ingredients. These other active ingredients may target the same and / or different parasites and conditions.

[0252] Examples of active ingredients that can be administered in combination with the compounds of the present invention include pharmaceutically acceptable anthelmintics, insecticides, and acaricides, insect growth regulators, and antiprotozoal agents.

[0253] In one embodiment of this specification, arylpyrazole compounds, such as phenylpyrazole, can be incorporated into the veterinary compositions herein. Arylpyrazoles are known in the art and may be suitable for combination with the compound represented by formula (I) in the compositions described herein. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patents 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 incorporated herein by reference). A particularly preferred arylpyrazole activator is fipronil.

[0254] In another embodiment, the composition described herein may advantageously contain one or more isoxazoline compounds known in the art. Isooxazoline activators are highly effective against a variety of ectoparasites, and when combined with the compound represented by formula (I), the range of efficacy against these parasites will be extended.

[0255] Particularly useful isoxazoline activators that can be combined with the compound include aafoxolaner (containing a substantially pure active enantiomer), sarolaner, fluralaner (containing a substantially pure active enantiomer), and lotilaner. Another combination partner is 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazole-3-yl]pyrazole-4-yl]benzamide (CAS RN 1621436). This compound is known as tigolanel.

[0256] In another embodiment, the composition described herein may advantageously include one or more SLO-1 modulator compounds known in the art. SLO-1 modulator activators are highly effective against a variety of parasites, and when combined with compounds represented by formula (I), the range of efficacy against these parasites will be extended. Particularly useful SLO-1 modulator activators that can be combined with such compounds include WO2017 / 178416, WO2018 / 087036, WO2018 / 197401, WO2019 / 002132, WO2019 / 025341, WO2019 / 115768, WO2019 / 215182, WO2020 / 14068, WO2020 / 131629, WO2020 / 131631, and WO2020 / 083 These include compounds disclosed in 971, WO2021 / 018839, WO2021 / 204930, WO2023 / 036821, WO2023 / 036821, WO2020 / 191091, WO2021 / 242581, WO2023 / 073641, WO2020 / 247747, WO2022 / 106469 and WO2022 / 117783 (all of which are incorporated herein by reference in their entirety).

[0257] The additional active compound is preferably a pharmaceutically acceptable insecticide or acaricide. Examples of such pharmaceutically acceptable insecticides and acaricides include acetamiprid, acetoprole, amitraz, amidoflumet, avermectin, azadirachtin, bifenthrin, bifenazate, buprofezin, bistriflurone, chlorfenapyr, chlorfluazurone, chlorantraniliprole, chlorpyrifos, chromafenozide, clothianidin, cyantraniliprole, cyflumetofen, β-cyfluthrin, cyhalothrin, λ-cyhalothrin, and simiazole. Cypermethrin, cyromazine, deltamethrin, demiditraz, diafenthiuron, diazinon, diflubenzuron, dimefluthrin, dinotefuran, emamectin, esfenvalerate, ethiprole, phenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamide, flubendiamide, flucitrinate, tau-fluvalinate, flufenoxuron, halofenozide, hexaflumuron, imidacloprid, indoxacarb, lufenuron, metaflumizone, methoprene, metofluthrin, methoxyfenozide, nitenpyram, novaron, nobiflumuron Examples include permethrin, fosmet, profluthrin, protrefenbut, pymetrozine, pyrafluprole, pyrethrin, pyridaryl, pyrifluquinazon, pyriproxyfen, rotenone, ryanodine, spinetram, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, tolfenpyrad, tralomethrin, the above isoxazolines, and triflumulon. General references discussing antiparasitic drugs such as insecticides and acaricides include, for example, "The Pesticide Manual, 13th Edition, CDS Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, UK (2003)".

[0258] The compounds described herein can be combined with anthelmintic compounds, and more preferably with anthelmintic compounds selected from the group consisting of: SLO-1 regulatory depsipeptide compounds, e.g., emodepside and the SLO-1 modulators described above; avermectins (e.g., ivermectin, selamectin, doramectin, abamectin and eprinomectin); milbemycins (moxidectin and milbemycin oxime); pro-benzoimidazoles (e.g., Febantel, netobimine, and thiophanates; benzimidazole derivatives, e.g., triclabendazole or thiazobenzoimidazole derivatives (e.g., thiabendazole and cambendazole), or carbamate benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide), mebendazole, oxyfendazole, parbendazole, oxybendazole, flubendazole); imidazothiazoles (e.g., rebamizole and tetramizole); tetrahydropyrimidine (Morantel and pyrantel), organophosphate esters (e.g., trichlorfon, haloxone, dichlorvos, and naphthalophos); salicylanilides (e.g., closantel, oxyclozanide, lafoxanide, and niclosamide); nitrophenol compounds (e.g., nitroxynyl and nitroscanate); benzenedisulfonamides (e.g., chlorthrone); pyrazineisoquinolines (e.g., praziquantel and epsiplantel); heterocyclic compounds (e.g., piperazine, diethylcarbamate) Zin, dichlorophene, and phenothiazine; arsenic compounds (e.g., thiaacetal samide, melorsamine, and arsenamide); cyclooctadepsipeptides (e.g., emodepside); paraherbicamides (e.g., derquaternel); and aminoacetonitrile compounds (e.g., monepantel, AAD1566); tripenzimidines (amidine compounds); amidine compounds (e.g., amidantel and tripenzimidine) [these include all pharmaceutically acceptable forms such as salts, solvates, or N-oxides].

[0259] Preferred combinations include (a) one compound selected from the group of compounds represented by formula (I) as defined elsewhere herein (or its enantiomer, salt, solvate, N-oxide or prodrug), and (b) anthelmintic avermectins (e.g., ivermectin, selamectin, doramectin, abamectin, emamectin, and eprinomectin); milbemycins (moxidectin, and milbemycin oxime); pro-benzimidazoles (e.g., febantel, netobimine, and Thiophanates); Benzimidazole derivatives, e.g., thiazolbenzimidazole derivatives (e.g., thiabendazole and cambendazole), carbamate benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide), mebendazole, oxyfendazole, parbendazole, oxybendazole, flubendazole, and triclabendazole); Imidazothiazoles (e.g., rebamizole and tetramizole); Tetrahydropyrimidines (morantel, (and pyrantel), organophosphate esters (e.g., trichlorfon, haloxone, dichlorvos, and naphthalophos); salicylanilides (e.g., closantel, oxyclozanide, lafoxanide, and niclosamide); nitrophenol compounds (e.g., nitroxynyl and nitroscanate); benzenedisulfonamides (e.g., chlorthrone); pyrazineisoquinolines (e.g., praziquantel and epsiplantel); heterocyclic compounds (e.g., piperazine, diethylcarbamazine) It contains one compound selected from the group consisting of: dichlorophene, phenothiazine; arsenic compounds (e.g., thiaacetal samide, melorsamine, and arsenamide); cyclooctadepsipeptides (e.g., emodepside); paraherbicamides (e.g., derquaternel); aminoacetonitrile compounds (e.g., monepantel, AAD1566); tripenzimidine (amidine compound); and amidantel (amidine compound) [these include all pharmaceutically acceptable forms such as salts].

[0260] A preferred combination is at least one compound selected from the group of compounds represented by formula (I) as defined elsewhere herein, * Furlaraner, afoxolaner, salolaner, rotillaner, tigolaner; and / or, * Closantel, oxyclozanide, lafoxanide, niclosamide; and / or * Nitroxynil, nitroscanate, chlorsulolone; and / or, * Praziquantel, Esiplantel; and / or, * Emodepsid, Del Quantel, Monet Panther; It includes.

[0261] In one embodiment, the compounds described herein can be combined with antiparasitic cyclopropylamide compounds disclosed in WO2022 / 161972, WO2022 / 162001, and WO2022 / 162016 (all of which are incorporated herein in their entirety by reference).

[0262] The compounds described herein can be combined with pharmaceutically acceptable insect growth regulators. Such pharmaceutically acceptable insect growth regulators include, for example, methoprene, pyriproxyfen, tetrahydroazadirachtin, chlorfluazurone, cyromazine, diflubenzuron, fluazurone, flucycloxurone, flufenoxurone, hexaflumurone, lufenuron, ifenulone, tebufenozide, and triflumuron. These compounds tend to provide both initial and sustained treatment of parasitic infestation at all stages of insect development (including eggs) on animal subjects and within the environment of animal subjects.

[0263] The compounds described herein can be combined with a pharmaceutically acceptable antiprotozoal agent. Such pharmaceutically acceptable antiprotozoal agents include, for example, triazinones (e.g., toltrazuril and ponazuril), and triazinediones (e.g., clazuril, diclazuril, and retrazuril).

[0264] In some intended embodiments, the compound is administered together with a pyridylmethylamine derivative (e.g., the pyridylmethylamine derivative discussed in European Patent Application No. EP0539588 or International Patent Application Publication No. WO2007 / 115643).

[0265] In some intended embodiments, the compound is administered together with nodulisporic acid and its derivatives (e.g., the compounds discussed in U.S. Patent Nos. 5,399,582; 5,945,317; 5,962,499; 5,834,260; 6,221,894; or 5,595,991; or WO1996 / 29073).

[0266] In some intended embodiments, the compound is administered together with a dihydroazole compound (e.g., the compound discussed in WO2010 / 75591).

[0267] Other antiparasitic compounds intended to be useful in combination therapy with these compounds include, for example: imidazo[1,2-b]pyridazine compounds discussed in U.S. Patent Application Publication No. 2005-0182059; 1-(4-mono- and di-halomethylsulfonylphenyl)-2-acylamino-3-fluoropropanol compounds discussed in U.S. Patent No. 7,361,689; and trifluoromethanesulfoneanilide oxime ether compounds discussed in U.S. Patent No. 7,312,248. n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and n-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide compounds discussed in U.S. Patent Publication No. 2006-0281695; and 2-phenyl-3-(1H-pyrrole-2-yl)acrylonitrile compounds discussed in U.S. Patent Publication No. 2006 / 0128779; WO Patent Application Publication No. 2005-085216, WO2007 / 026965, WO2007 / 070606, WO2007 / 075459, WO2007 / 079162, WO2007 / 105814, WO2007 / 125984, WO2008 / 019760, WO2008 / 122375, Isooxazoline compounds discussed in WO2008 / 150393, WO2009 / 002809, WO2009 / 003075, WO2009 / 022746, WO2009 / 035004, WO2009 / 045999, WO2009 / 051956, and WO2009 / 035004.

[0268] Alternatively, the other additional active ingredients are not antiparasitic drugs.

[0269] Examples of non-antiparasitic active ingredients that may be administered in combination with the compounds of the present invention include anti-inflammatory drugs, anti-infective drugs, hormones, and immunobiological preparations for disease prevention (e.g., vaccines and antisera).

[0270] In intended combination therapy, the compounds according to the present invention may be administered before, simultaneously with, and / or after, the other active ingredient. Furthermore, the compounds according to the present invention may be administered in the same composition as the other active ingredient and / or in a different composition. Furthermore, the compounds according to the present invention and the other active ingredient may be administered via the same and / or different routes of administration.

[0271] When the compounds according to the present invention are administered in combination therapy, the weight ratio of the active ingredients can vary over a wide range. Factors influencing this ratio include, for example, the specific compound; the nature of the other active ingredient administered in combination therapy; the route of administration of the compound and the other active ingredient; the target condition and pathogen; the type of animal (e.g., species and breed), age, size, sex, diet, activity and condition; and pharmacological considerations, such as the activity, potency, pharmacokinetic and toxicity profiles of the compound and the other active ingredient. In some intended embodiments, for example, the weight ratio of the compound to the other active ingredient is, for example, about 1:3000 to about 3000:1. In some such examples, the weight ratio is about 1:300 to about 300:1. In other such examples, the weight ratio is about 1:30 to about 30:1.

[0272] The present invention also includes, for example, a kit suitable for use in carrying out the therapeutic methods described above. The kit comprises an effective amount of one or more compounds of the present invention and additional components. The additional components may be, for example, one or more of the following: another component (e.g., an excipient or active ingredient), a device for combining the compounds of the present invention with another component and / or for administering the compounds of the present invention, or a diagnostic tool.

[0273] Since many forms of the present invention may best suit the requirements of a particular application, this detailed description of preferred embodiments is intended solely to inform those skilled in the art of the present invention, its principles and practical applications, so that they may adapt or apply the present invention in many forms. This detailed description and its specific examples illustrate preferred embodiments of the present invention, but are intended to be illustrative only.

[0274] The present invention is therefore not limited to the preferred embodiments described herein and can be modified in various ways. Furthermore, for the sake of brevity and readability, only some combinations of embodiments are explicitly described, but it should be understood that other combinations of embodiments are also intended.

[0275] The present invention will be further described by the following non-limiting embodiments. [Examples]

[0276] Examples Chromatography system: Column: Xbridge BEH C18 Waters, 2.1 × 50 mm, 2.5 μm Oven: 40℃ Eluent: Solvent A: Water / HCO2H (0.05%); Solvent B: Acetonitrile / HCO2H (0.05%) Flow rate: 0.8mL / min gradient:

[0277] [Table 3]

[0278] Example 1 - Synthesis of N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide (Compound 1) [ka]

[0279] 1. Diethyl 2-(((2-bromo-3-fluorophenyl)amino)methylene)malonate 2-bromo-3-fluoroaniline (61.7 g, 325 mmol) was dissolved in ethanol (310 mL) together with diethyl 2-(ethoxymethylene)-malonate (65.0 mL, 325 mmol), and the mixture was stirred under reflux for 5 hours. The mixture was cooled to room temperature, diluted with 150 mL of ethanol, and the resulting precipitate was isolated by filtration. The solid residue was washed with ethanol (3 × 100 mL) and dried to obtain the title compound as a solid. MS (ESI) 362.0 [M+H] + .

[0280] 2. Ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate Diethyl 2-(((2-bromo-3-fluorophenyl)amino)methylene)malonate (60.0 g, 167 mmol) was combined with Dowsam® A (180 mL), and the mixture was stirred at 250 °C for 3 hours. The mixture was cooled to room temperature and diluted with 1500 mL of n-heptane. The resulting precipitate was isolated by filtration, washed with n-heptane (3 × 100 mL), and dried to obtain the title compound as a solid. MS (ESI) 315.9 [M+H] + .

[0281] 3. 8-Bromo-7-fluoro-4-hydroxyquinoline-3-carboxylic acid Ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate (44.4 g, 0.12 mol) was suspended in a solution of sodium hydroxide (40.2 g, 1 mol) dissolved in water (430 mL), and the mixture was stirred under reflux for 1 hour. The mixture was cooled to room temperature and acidified with hydrochloric acid (5 M, 221 mL, 1.1 mol) while stirring. The resulting precipitate was isolated by filtration, washed with water (3 × 100 mL), and dried to obtain the title compound as a solid. MS (ESI) 287.9 ​​[M+H] + .

[0282] 4. 8-Bromo-7-fluoroquinoline-4-ol 8-Bromo-7-fluoro-4-hydroxyquinoline-3-carboxylic acid (33.0 g, 102 mmol) was suspended in Dowsam® A (330 mL), and the mixture was stirred at 260 °C. After 5 hours, the mixture was cooled to 60 °C and diluted with 1200 mL of n-heptane. The mixture was cooled to room temperature, the resulting precipitate was isolated by filtration, washed with n-heptane (3 × 300 mL), and dried to obtain the title compound as a solid. MS (ESI) 243.9 [M+H] + .

[0283] 5. 8-Bromo-7-fluoro-3-nitroquinoline-4-ol 8-Bromo-7-fluoroquinoline-4-ol (34.6 g, 143 mmol) was combined with propionic acid (170 mL) and heated to 100°C. While stirring, nitric acid (65%, 24.6 mL, 0.357 mol) was added dropwise over 15 minutes at 100°C. After the addition was complete, the mixture was stirred at 125°C. After 90 minutes, the mixture was cooled to room temperature, ethanol (170 mL) was added, followed by water (510 mL). The resulting precipitate was isolated by filtration, washed with a 3:1 mixture of water and ethanol (200 mL), and dried under reduced pressure at 40°C to obtain the title compound as a solid. MS (ESI) 288.0 [M+H] + .

[0284] 6. 4-(8-bromo-7-fluoro-3-nitroquinoline-4-yl)morpholine 8-Bromo-7-fluoro-3-nitroquinoline-4-ol (6 g, 20.90 mmol) was combined with chloroform (70 mL) and dimethylformamide (1.8 mL, 23 mmol). Thionyl chloride (1.83 mL, 25 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred under reflux for 4 hours and cooled to 0°C. Triethylamine (5.83 mL, 41.8 mmol) was then slowly added, followed by morpholine (2.73 mL, 31.4 mmol). The reaction mixture was heated again under reflux and stirred overnight at the reflux temperature. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with water, HCl (1 M), and saturated sodium bicarbonate solution. The organic layer was dehydrated with MgSO4 and concentrated under reduced pressure. The solid residue was suspended in ethyl acetate, and the mixture was stirred at 45°C for 45 minutes. The precipitate was isolated by filtration, washed with n-pentane, and dried to obtain the title compound as a solid. MS (ESI) 358.0 [M+H] + .

[0285] 7. 4-(8-(2,3-dichlorophenyl)-7-fluoro-3-nitroquinoline-4-yl)morpholine 4-(8-bromo-7-fluoro-3-nitroquinoline-4-yl)morpholine (5 g, 14 mmol), tetrakis(triphenylphosphine)palladium (1.62 g, 1.4 mmol), and sodium carbonate (5.95 g, 56.2 mmol) were combined with 1,4-dioxane (160 mL) and water (40 mL), which had been degassed under argon. The mixture was heated to 110°C, and then, while stirring, (2,3-dichlorophenyl)boronic acid (9.34 g, 42.1 mmol), dissolved in 1,4-dioxane (40 mL), was added dropwise over 2.5 hours. Stirring was continued at 110°C, and then the mixture was poured into water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The extracts were combined and washed with saturated sodium bicarbonate aqueous solution and brine, dehydrated with MgSO4, and concentrated under reduced pressure. The residue was treated with methyl tert-butyl ether (120 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure to approximately 30 mL, the resulting precipitate was isolated by filtration and washed with methyl tert-butyl ether. The mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography (silica, dichloromethane / ethyl acetate gradient 100:1 → 80:20). The product was combined with the above-mentioned isolated precipitate to obtain the title compound as a solid. MS (ESI) 442.0 [M+H] + .

[0286] 8. 8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-amine 4-(8-(2,3-dichlorophenyl)-7-fluoro-3-nitroquinoline-4-yl)morpholine (5.14 g, 11.8 mmol) was dissolved in a mixture of tetrahydrofuran (86 mL) and methanol (12 mL) under argon. Carbon-supported platinum (5%, sulfide, 0.46 g, 0.118 mmol) was added, the flask was sealed with a septum, the mixture was purged with argon, then with hydrogen, and stirred overnight at ambient temperature under a hydrogen atmosphere. The mixture was filtered through a Celite cake and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, the resulting residue was dissolved in DCM (10 mL), and treated with methyl tert-butyl ether (10 mL). The resulting precipitate was isolated by filtration, washed with methyl tert-butyl ether, and dried to obtain the title compound as a solid. MS (ESI) 392.0 [M+H] + .

[0287] 9. Quinoline-4-carbonyl chloride Quinoline-4-carboxylic acid (2.5 g, 14.44 mmol) was combined with dichloromethane (48 mL). Dimethylformamide (0.224 mL, 2.89 mmol) was added, followed by oxalyl chloride (1.39 mL, 15.88 mmol), and the mixture was stirred at room temperature. After 90 minutes, the mixture was concentrated under reduced pressure to obtain a solid, which was used directly in the next step.

[0288] 10. N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide 8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-amine (4.71 g, 12 mmol) was dissolved in dichloromethane (96 mL), and the resulting solution was cooled to 0°C. Triethylamine (4.18 mL, 30 mmol) was added, followed by quinoline-4-carbonyl chloride (HCl salt, 3.01 g, 13.2 mmol), and the mixture was stirred at ambient temperature. After 5 hours, an additional quinoline-4-carbonyl chloride (HCl salt, 0.547 g, 2.4 mmol) was added, and stirring was continued for 2 hours. The reaction mixture was diluted with water (50 mL), and the layers were separated. The organic layer was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL), dehydrated with MgSO4, and concentrated to dryness under reduced pressure. The residue was combined with methyl tert-butyl ether (50 mL) and dichloromethane (20 mL), and the resulting mixture was concentrated at 45°C with stirring. The precipitate was filtered off, suspended in acetonitrile (50 mL), heated at 80°C for 30 minutes, filtered off, and combined with methyl tert-butyl ether (50 mL). The resulting mixture was stirred at 45°C for 3 hours, the precipitate was filtered off, dried, and combined with ethanol (50 mL). The mixture was stirred at 80°C for 1 hour, cooled to 0°C, and the resulting precipitate was isolated by filtration and dried under reduced pressure to obtain the title compound as a solid.

[0289] Using the same procedure as described above, representative compounds represented by formula (C) shown in Table 1 were prepared.

[0290] [ka]

[0291] [Table 4]

[0292] Example 2 - In vitro test In the following examples, the compounds according to the present invention are compared with prior art compounds C146, C151, C243, C254, and C399 (disclosed as compounds 146, 151, 243, 254, and 399, respectively, in WO2021 / 122911A1). These compounds were examined using the following in vitro assays.

[0293] In vitro assay: Ascaridia galli and Oesophagostumum dentatum Ascaridia galli (chicken intestinal roundworm), larval stage 3 ("L3"); and Oesophagostumum dentatum (porcine nodular worm), larval stages 3 and 4 ("L3" and "L4", respectively), were suspended in a nutrient medium, and 20 larvae per well were distributed into a 96-well plate. DMSO solutions of the compound were added to the wells at progressively decreasing concentrations. The anthelmintic effect was confirmed by microscopic examination and determined by the minimum effective concentration (MEC). MEC is the concentration at which at least one larva dies, changes in motility, or changes in development.

[0294] In vitro assay: Haemonchus contortus Solutions of compounds were prepared by gradually decreasing their concentration in DMSO, diluted in nutrient medium, and distributed into 96-well microtiter plates. Desheathed L3 larvae of Haemonchus contortus were incubated in a water bath at 37°C for 20 minutes, separated by centrifugation, and added at a rate of 300-350 larvae / well. After 7 days of incubation, motility was evaluated using an automated microscope. Ivermectin was used as a positive control, and DMSO as a negative control. EC2 values ​​were expressed for the concentrations of individual compounds that reduced motility by 50% compared to the positive control. 50 The value was calculated.

[0295] In vitro assay: Dirofilaria immitis L1 Approximately 100–300 microfilariae of *Dirofilaria immitis* were added to microtiter plate wells containing varying concentrations of test compounds in nutrient medium and DMSO. After incubation for 3 days, activity was evaluated as a reduction in motility compared to DMSO as a negative control. The compounds were tested in two replicates. Based on the concentration-response curve, EC was used. 50 The value was calculated.

[0296] In vitro assay: Dirofilaria immitis L4 Ten D. immitis L4 larvae were added to microtiter plate wells containing varying concentrations of the test compound in nutrient medium and DMSO. After incubation for 3 days, activity was evaluated as a reduction in motility compared to DMSO as a negative control. Each compound was tested in two replicates. Based on the concentration-response curve, EC2 was calculated. 50 The value was calculated.

[0297] The results are shown in Table 2.

[0298] [Table 5]

[0299] Table 2 shows that compounds 1 to 28 are effective against the larvae of Ascaridia, Oesophagostomum, Haemonchus, and Dirofilaria.

[0300] In vitro assay: Agonist activity in D. immitis slo-1 channel and human Maxi K channel (BK channel) To confirm the potential agonist activity of the compound, we used either Dirofilaria immitis slo-1 (Accession No JQ730003; pcDNA::Dimslo1) or a stably transfected CHO KI cell line expressing a human Maxi K channel (subunit KCNMA1 / KCNMB1; Ponte et al, Molecular Pharmacology 2012, 81(4), 567-577).

[0301] In the fluorescence membrane potential staining assay, cells were seeded at a concentration of 10,000 cells / well (20,000 cells / well for non-human cells) in 25 μL of medium in a black 384-well plate (clear bottom) and cultured for 20–24 hours (37°C, 5% CO2). 25 μL of FMP staining agent (Blue-Tyrode's) was added to each well and incubated at room temperature for 30 minutes. The cells were then incubated with 12.5 μL of diluted test compound for a further 10 minutes.

[0302] To measure membrane potential, the prepared cell plate and KCl solution plate were placed in a FLIPR Tetra (Molecular Device). Baseline fluorescence was recorded for 20 seconds (excitation wavelength 510-545 nm, fluorescence wavelength 565-625 nm). 12.5 μL of KCl solution was added to initiate ion influx into the cells (final assay concentration of KCl-Tyrode: 70 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.8 mM NaH2PO4, 5 mM glucose, 28 mM Hepes, pH 7.4, including voltage-sensitive dye). Stimulation (%) was calculated as value 2 / value 1 × 100 (value 1: pre-stimulation FLIPR signal (average recording time 5-10 seconds), value 2: post-stimulation FLIPR signal (average recording time 120-140 seconds)). Total measurement time: 150 seconds.

[0303] EC 50 Values ​​were measured in three replicates using a compound dilution series. Data were confirmed in at least two independent studies. Data were processed using ActivityBase XE Runner software (IDBS) for curve fitting and semi-maximal effective concentration calculations. The results are shown in Table 3.

[0304] [Table 6]

[0305] Table 3 shows that compounds 1 to 28 have a low probability of causing target-related adverse reactions in hosts such as mammals (e.g., humans).

[0306] In vitro assay: Water solubility A stock solution of the compound was prepared in DMSO (1% by weight). An aliquot (5 μL) of the stock solution was added to 10 mL of 10 mM phosphate buffer solution (pH 7). The resulting suspension was gently inverted and shaken at room temperature for 72 hours. To remove undissolved particles, the suspension was allowed to stand for 24 hours, and then centrifuged (4000 rpm, 5 minutes). The supernatant was separated and analyzed by HPLC-UV / MS. The concentration of the compound was determined by comparing the UV signal with the calibration curve of the same individual test compound.

[0307] [Table 7]

[0308] As can be seen from Table 4, the water solubility of compound 1 at pH 7 is at least 10 times higher than that of comparative example C151. For compound 2, its water solubility is approximately 100 times higher than that of comparative example C399.

[0309] Example 3 - In vivo efficacy against A. viteae in gerbils Efficacy was evaluated by experimentally infecting immunosuppressed gerbils (Meriones unguiculatus) with 80 filariae nematode Acanthocheilonema viteae L3 larvae. On days 5, 6, and 7 post-infection, the animals were treated orally with the test compound at a dose of 10 mg / kg body weight once daily. Ten weeks after infection, the gerbils were euthanized, and the larval load was measured. Efficacy was calculated using Abbott's formula as the reduction in the average number of larvae in the treated group compared to the infected group in the untreated group (negative control).

[0310] The compound of the present invention was also tested in this study. The results are shown in Table 5.

[0311] [Table 8]

[0312] Example 4 - In vivo efficacy against A. viteae in gerbils In another study, the efficacy was evaluated in gerbils using the same procedure as described above. The results are shown in Table 6.

[0313] [Table 9]

[0314] Compound 1 is understood to exhibit higher efficacy against A. viteae than comparative compounds C151, C254, and C399. In the case of Dirofilaria, 100% efficacy is desirable for effective protection of animals. Therefore, it is extremely important that this filaria model exhibits the highest possible efficacy.

[0315] Example 5 - In vivo efficacy against A. viteae in gerbils Efficacy was evaluated by experimentally infecting immunosuppressed gerbils (Meriones unguiculatus) with 80 filariae nematode Acanthocheilonema viteae L3 larvae. On days 5, 6, and 7 post-infection, the animals were treated orally with the test compound at a dose of 10 mg / kg body weight once daily. Ten weeks after infection, the gerbils were euthanized, and the larval load was measured. Efficacy was calculated using Abbott's formula as the reduction in the average number of larvae in the treated group compared to the untreated control group (negative control).

[0316] The compound of the present invention was also tested in this study. The results are shown in Table 7.

[0317] [Table 10]

[0318] As can be understood, compound 10 exhibits higher efficacy than comparative example C146 of Example 3, and compound 2 exhibits higher efficacy than comparative example C399 of both Example 3 and Example 4.

[0319] Example 6 - Pharmacodynamic studies in sheep The efficacy of compound 1 and C151 (compound 151 in WO2021 / 122911A1, used as a comparative example) was confirmed after subcutaneous administration to gastrointestinal nematodes in sheep. Sheep approximately 12-16 weeks old were infected orally with L3 larvae of Haemonchus contortus (approximately 4,000 individuals) and L3 larvae of Trichostrongylus colubriformis (approximately 6,000 individuals). All sheep included in this study were negative for roundworm eggs in qualitative fecal examinations performed before parasitism.

[0320] Three sheep were assigned to each treatment group. The sheep in treatment group 1 remained untreated and served as a negative control group. The sheep in the other treatment groups were treated by subcutaneous injection with compound 1 or compound C151 at a dose of 10 mg / kg body weight 33 or 34 days after infection.

[0321] Seven days after treatment, all sheep were necropped, and their abomasum and small intestine were processed to recover parasites. All sheep in the untreated control group had sufficient infection with *H. contortus* and *T. colubriformis*. The efficacy of each treatment group was calculated relative to the untreated control group.

[0322] The results are shown in Table 7.

[0323] [Table 11]

[0324] As can be seen from Table 7, the potency of compound 1 is significantly higher than that of the comparative compound C151, which is known from prior art.

[0325] Example 7 - Pharmacokinetic study in dogs The pharmacokinetic behavior of the test compound was evaluated by administering it to beagle dogs.

[0326] The test compound was dissolved in a suitable vehicle (pharmaceutically acceptable excipient) or a mixture thereof. Dogs were divided into administration groups (intravenous administration group n=4, oral administration group n=5) and administered the compound orally (dose = 10 mg / kg) or intravenously as a bolus (dose = 1 mg / kg). Blood samples were collected at predetermined time points after administration (for oral administration: 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 32, 48, 72, 120, 168 hours). The samples were processed to obtain plasma, rapidly frozen, and stored at -75°C until analysis. To quantitatively analyze the test compound, the samples were thawed, deproteinized, and analyzed by HPLC-MS / MS using a calibration curve.

[0327] Figure 1 shows the plasma profiles after oral administration of compounds 1, 3, 5, C151, C254, and C243 at a dose of 10 mg / kg body weight. All compounds shown in Figure 1 were administered using the same vehicle and dose.

[0328] As can be seen from Figure 1, compounds 1, 3, and 5 showed unexpectedly significant higher exposure levels (expressed as higher plasma concentrations) after oral administration compared to comparative compounds C151 and C254. Compound C243 also showed high exposure levels, but its efficacy was insufficient in vitro (Table 2).

[0329] Figure 2 shows the plasma profiles after intravenous administration of compounds 1, 3, 5, 6, C151, C243, and C254 at 1 mg / kg body weight. All compounds shown in Figure 1 were administered using the same vehicle and dose. As can be seen from Figure 2, compounds 1, 3, 5, and 6 showed unexpectedly significantly higher exposure levels (expressed as higher plasma concentrations) after intravenous administration compared to the comparative compounds C151 and C243.

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, R Ａ These are Cl, F, and OCF, respectively. ３ R is independently selected from methyl, methoxy, or trifluoromethyl, or each of two adjacent substituents R. Ａ It forms a five-membered or six-membered ring containing zero, one, or two N atoms, where the ring is composed of Cl, F, and OCF ３ , may be substituted with one or more groups selected from methyl, methoxy, and trifluoromethyl; n is between 0 and 5; R Ｂ is H or CH ３ is] A compound represented by or a pharmaceutically acceptable salt, solvate, polymorph, or prodrug thereof.

2. Formula (C): 【Chemistry 2】 [During the ceremony, R １ 、 R ２ 、 R ３ and R Ｃ are each independently selected from H, Cl, F, OCF ３ , methyl, methoxy and trifluoromethyl, or R １ , R ２ , R ３ and R Ｃ Two adjacent substituents each selected from form a 5- or 6-membered ring containing 0, 1 or 2 N atoms, where the ring may be substituted with one or more groups selected from Cl, F, OCF ３ , methyl, methoxy and trifluoromethyl; and, R Ｂ is H or CH ３ is] The compound according to claim 1, represented by [the specified compound].

3. Formula (II): 【Transformation 3】 [During the ceremony, R １ , R ２ and R ３ These are H, Cl, F, and OCF, respectively. ３ , independently selected from methyl, methoxy and trifluoromethyl, or R １ and R ２ It forms a five-membered or six-membered ring containing zero, one, or two N atoms, where the ring is composed of Cl, F, and OCF ３ , may be substituted with one or more groups selected from methyl, methoxy and trifluoromethyl; and, R Ｂ is H or CH ３ is] The compound according to claim 1 or 2, represented by the following:

4. R １ , R ２ and R ３ However, each is independently selected from H, Cl, F, methyl, methoxy, and trifluoromethyl, and R Ｂ is H or CH ３ The compound according to claim 3.

5. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(3-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

6. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

7. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(2-chloro-3-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

8. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

9. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(2,3-dichlorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)-2-methylquinoline-4-carboxamide.

10. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(3-chloro-2-methylphenyl)-7-fluoro-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

11. The compound according to any one of claims 1 to 4, wherein the compound is N-(8-(5-chloro-2-fluorophenyl)-7-fluoro-4-morpholinoquinoline-3-yl)-2-methylquinoline-4-carboxamide.

12. The compound according to any one of claims 1 to 4, wherein the compound is N-(7-fluoro-8-(2-fluoro-5-(trifluoromethyl)phenyl)-4-morpholinoquinoline-3-yl)quinoline-4-carboxamide.

13. A method for producing the compound according to any one of claims 1 to 12, wherein formula (A): 【Chemistry 4】 [During the ceremony, R Ａ These are Cl, F, and OCF, respectively. ３ R is independently selected from methyl, methoxy, or trifluoromethyl, or each of two adjacent substituents R. Ａ It forms a five-membered or six-membered ring containing zero, one, or two N atoms, where the ring is composed of Cl, F, and OCF ３ , may be substituted with one or more groups selected from methyl, methoxy, and trifluoromethyl; n is between 0 and 5. The compound represented by formula (B): 【Transformation 5】 [In the formula, R Ｂ is H or CH ３ is] The method comprising the step of reacting with a compound represented by or a halide thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, further comprising one or more additional active ingredients.

16. A compound according to any one of claims 1 to 12, for use as a pharmaceutical.

17. A compound according to any one of claims 1 to 12, for use in the treatment or prevention of diseases caused by parasitic nematodes in animals.

18. A compound for use according to claim 17, wherein the parasitic nematode is a gastroenteric nematode, and the animal is selected from the group consisting of dogs, cats, ruminants, horses, and poultry.

19. A compound for use according to claim 17, wherein the parasitic nematode belongs to the genus Dirofilaria, and the animal is selected from cats and dogs.

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