Cyclopropylamide compounds against parasites in fish

Abstract

The present invention relates to cyclopropylamide compounds which are useful in the treatment of parasitic infections in fish. The compounds have the formula (I): [Formula 1] TIFF2024511258000048.tif51170 has.

Description

[Technical field]

[0001] The present invention relates to the treatment or prevention of parasitic infections in animals. [Background technology]

[0002] Parasitic infection of fish is a major problem in commercial fish farming. Fish farmers who face parasite problems usually suffer significant financial losses and incur additional costs.

[0003] Fish lice are ectoparasites belonging to the subclass Copepoda that negatively impact fish, especially farmed salmonids, by feeding on the mucous membranes, skin, tissues and blood of the host fish. Fish lice can cause significant damage to the host fish, i.e. severe fin damage, skin erosions, bleeding and open wounds. Furthermore, fish lice can induce a chronic stress response in the fish, which in turn can predispose the fish to other diseases. Furthermore, fish lice appear to have immunomodulatory effects in the host fish and can act as vectors in the transmission of other fish diseases. The damage caused by parasitic infections from fish lice results in significant animal welfare issues, fish losses and increased costs. Fish lice infections are considered one of the most important disease problems in salmonid aquaculture, especially in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss).

[0004] Infestation with fish lice can also occur in other species of fish, for example sea bass, tilapia, carp, etc. In addition to the costs associated with treatment, lower classification ratings of slaughtered fish and reduced growth rates due to reduced feeding contribute to economic losses.

[0005] Fish lice, on the other hand, are widespread and encountered in all fish farming operations. Severe infections lead to fish mortality; more than 50% mortality due to fish lice infection has been reported in Norwegian fish farms. The degree of damage depends on the season and environmental factors, such as the salinity and average water temperature of the water. In the first phase, fish lice infection is seen in the appearance of the parasite attached to the fish, and later - even more obviously - from the damage caused to the skin and tissues. The most serious damage is observed in smolts that are just in the phase where they change from fresh water to sea water. This situation is even more aggravated by the specific conditions in fish farms where salmon of different age groups but the same weight class are kept together; here contaminated nets or cages are used; high salinity concentrations must be found; the flow through the nets and cages is minimal and the fish are kept in a very small space.

[0006] Many treatments already exist on the market to control fish lice, including bath treatments such as organophosphates (e.g., dichlorvos and azamethiphos) and pyrethroids (e.g., cypermethrin and deltamethrin), and feed treatments such as avermectins (e.g., ivermectin and emamectin benzoate) and growth regulators (e.g., lufenuron and teflubenzuron). However, resistance to many of these treatments has been observed and thus new treatments remain in demand, especially those with a longer duration of action.

[0007] Thus, there remains a need for new treatment options for controlling fish lice infestations in fish, particularly farmed fish populations, that are safe, selective for the target parasites, and capable of treating fish lice populations that are resistant or have reduced susceptibility to current products. The present invention provides a new treatment option for the control of fish lice in fish.

[0008] WO 2016 / 168056, WO 2016 / 168058, WO 2016 / 168059 and WO 2018 / 071327 disclose certain aromatic compounds as having insecticidal and acaricidal activity and thus useful in controlling agricultural plant pests, but none of these references exemplifies or describes their use in aquaculture.

[0009] Surprisingly, it has been found that aromatic cyclopropylamide compounds of formula (I) are effective for combating parasitic infections in fish, particularly fish lice infestations. Summary of the Invention

[0010] The present invention provides new methods and compositions for controlling parasites in fish.

[0011] The present invention relates to a compound of formula (I) for use in a method for controlling parasitic infections in fish. [ka] (In the formula, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; R 2 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 3 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 4 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 5 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; R 6 is H and (C 1 ~C 6 ) alkyl; R 7 is selected from the group consisting of H, F, Cl, Br and I; R 8 is selected from the group consisting of F, Cl, Br and I; R 9 is H and (C 1 ~C 6 ) alkyl; Q 1 is selected from the group consisting of O and S; Q 2 is selected from the group consisting of O and S; R 10 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl(C 1 ~C 6 )alkoxy, C(=O)(C 1 ~C 6 ) alkyl and (C 1 ~C 6 )AlkoxyC(=O)(C 1 ~C 6 ) alkyl; R 11 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2, (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; R 12 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; X 1 are N, NO and CR 13 is selected from the group consisting of R 13 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , CHO, (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and triazolyl; X 2 are N, NO and CR 14 is selected from the group consisting of R 14 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; X 3 is N(R 15 ) (substituted or unsubstituted phenyl), N(R 15 ) (substituted or unsubstituted heterocyclyl) and substituted or unsubstituted heterocyclyl; R 15 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl(C 1 ~C 6 )alkoxy, C(=O)(C 1 ~C 6 ) alkyl and (C 1 ~C 6 )AlkoxyC(=O)(C 1 ~C 6 ) alkyl; The substituted phenyl and substituted heterocyclyl are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C6 )Alkyl((C 1 ~C 6 ) alkyl)(=NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) having one or more substituents selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl, pyrrolopyridinyl and triazolyl; Each alkoxy, alkyl, haloalkoxy, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkenyl, cycloalkyl, halocycloalkenyl, halocycloalkyl, imidazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl is selected from the group consisting of F, Cl, Br, I, CN, OH, NH(C 1 ~C 6 ) alkyl, NH(C 3 ~C 6 )CycloalkylCH 2 O(C 1 ~C 6 ) alkyl, NH(C 3 ~C 6 )CycloalkylCH 2 O(C 1 ~C 6 )Haloalkyl, NHCH 2 (C3 ~C 6 ) Cycloalkyl, NH 2 , NO 2 , oxo, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy and C(O)O-(C 1 ~C 6 ) alkyl; R x1 H and (C 1 ~C 3 ) alkyl; R x2 is (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, halo(C 1 ~C 6 ) alkylphenyl, (C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) alkyl, O(C 1 ~C 6 ) haloalkyl, (C 1 ~C6 )Alkyl-O-(C 1 ~C 6 ) selected from the group consisting of haloalkyl, isoxazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, oxazolyl and pyrazolyl. This invention covers the compounds of the formula (I) and N-oxides, veterinarily acceptable acid addition salts, salt derivatives, solvates, ester derivatives, polymorphs, isotopes, stereoisomers and tautomers.

[0012] Suitable compounds for use according to the invention and embodiments include X 3 but, [ka] (In the formula, R 15 H and (C 1 ~C 6 ) alkyl; X 4 is N or CR 16 and R 16 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 5 is N or CR 17 and R 17 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 6 is N or CR 18 and R 18 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 7 is N or CR 19 and R 19 are H, F, I, Br, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 8 is N or CR 20 and R 20 are H, F, Cl, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; or R 18 and R 19 or R 17 and R 18 together they form a ring which is part of a bicyclic ring selected from the group consisting of pyrrolopyridinyl, pyrazolopyridinyl and azaindolyl, or X 7 is N and R18 Together with R, they form a 4- to 6-membered ring. 18 The ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S. It is a compound wherein

[0013] Suitable compounds for use according to the invention and embodiments include: R 1 is selected from the group consisting of H, F and Cl; R 2 H, F, Cl, Br, CH 3 , O.C.H. 3 and CF 3 selected from the group consisting of; R 3 H, F, Cl, Br and CHF 2 , C.F. 3 , OCF 3 selected from the group consisting of; R 4 H, F, Cl, Br, CN, CH 3 and CF 3 selected from the group consisting of; R 5 is H; R 6 is H; R 7 is selected from the group consisting of Cl and Br; R 8 is selected from the group consisting of Cl and Br; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R 13 is H, F, Cl and CH 3 selected from the group consisting of; R 14 is H or F; R 15 But H and CH 3 selected from the group consisting of; The compound is wherein Q1 and Q2 are O.

[0014] Suitable compounds for use according to the invention and embodiments include: R 1 is H; R 2 is selected from the group consisting of F and Cl; R 3 is selected from the group consisting of H, F and Cl; R 4 is selected from the group consisting of H, F and Cl; R 5 is H; R 6 is H; R 7 is Cl; R 8 is Cl; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R 13 is F, Cl and CH 3 selected from the group consisting of; R 14 is H; R 15 is H; The compound is wherein Q1 and Q2 are O.

[0015] In a suitable use of the present invention and / or any of its embodiments, the parasitic infection is a fish lice infection.

[0016] In suitable uses of the present invention and / or any of its embodiments, the parasite is at least one of Lepeophtheirus salmonis, Caligus celmensi, Caligus curtus, Caligus dussumieri, Caligus elongates, Caligus longicaudatus, Caligus rogercresseyi or Caligus stromii.

[0017] In a suitable use of the present invention and / or any of its embodiments, the parasitic infection may be due to copepodites, pre-adult or adult fish lice, or may be a mixed infection with various stages.

[0018] In a suitable use of the present invention and / or any of its embodiments, the infection rate of fish is on average 0.5 to 3 parasites per fish in a fish farm, preferably the parasites are adult female fish lice.

[0019] In a suitable use of the present invention and / or any of its embodiments, the method comprises administering to the fish a compound of formula (I) as defined in any of claims 1 to 4 by oral administration or by topical administration, for example by bath treatment or by intraperitoneal or intramuscular injection.

[0020] In a suitable use of the present invention and / or any of its embodiments, the method comprises administering to fish a compound of formula (I) as defined in any of claims 1 to 4 by oral administration, the oral administration comprising administering a medicated fish food comprising a therapeutically effective amount of the compound and fish food.

[0021] In a suitable use of the present invention and / or any of its embodiments, the method comprises administering a compound of formula (I) as defined in any of claims 1 to 4 by a bath treatment, the bath treatment comprising immersion of fish in water having a therapeutically effective amount of the compound.

[0022] In a suitable use of the present invention and / or any of its embodiments, the fish is a salmonid.

[0023] The present invention also relates to a premix comprising a compound of formula (I) as defined in any embodiment as described herein, the premix further comprising nutrients.

[0024] Suitably, the premix comprises nutrients in the form of pellets, which are coated with a composition comprising a compound of formula (I) as defined in any embodiment herein.

[0025] In a suitable embodiment, there is provided a medicated fish bait comprising a premix as defined herein and a fish bait.

[0026] In a preferred embodiment, the parasitic infection is an infection by fish lice.

[0027] In one embodiment, the present invention provides a composition comprising one or more compounds of formula (I) as described in any embodiment herein and a veterinarily acceptable formulation adjuvant for use to control parasitic infections in fish populations.

[0028] Another embodiment is a premix comprising nutrients, formulation supplements, and at least one compound of Formula (I) as described in any embodiment herein.

[0029] Another embodiment is a medicinal fish food comprising such a composition or premix as described in any embodiment herein and a nutritional fish food.

[0030] Further embodiments relate to kits comprising such a compound or composition as described in any embodiment herein and instructions for administration of the composition to fish.

[0031] A preferred embodiment relates to a kit comprising a premix and instructions for preparation of a medicated fish bait and / or instructions for administration of a medicated fish bait as described in any embodiment herein to a fish population for use in controlling fish lice infestations.

[0032] Another preferred embodiment relates to a kit comprising a preservative solution containing a compound or composition as described in any embodiment herein and instructions for preparation of medicated water for medicated bath treatment and / or instructions for immersion of fish to control fish lice infestation.

[0033] The inventors of the present invention have discovered a compound according to the invention for use in a method of controlling a parasitic infection in fish, in which a parasitic infection, in particular a fish lice infection, is prevented by the incorporation of an effective amount of a compound of formula (I) [ka] It has been discovered that the above-mentioned conditions can be treated or prevented by administering the compound of the formula (I) to a subject in need of treatment with an anti-inflammatory drug, such as a pulmonary artery disease, a pulmonary artery disease, or a pulmonary artery disease, as well as N-oxides, veterinarily acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, stereoisomers and tautomers of the compound of the formula (I).

[0034] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; R 2 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 3 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 4 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and S-(halo) 5 selected from the group consisting of; R 5 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; R 6 H and (C 1 ~C 6 ) alkyl; R 7 is selected from the group consisting of H, F, Cl, Br and I; R 8 is selected from the group consisting of F, Cl, Br and I; R 9 H and (C 1 ~C 6 ) alkyl; Q 1 is selected from the group consisting of O and S; Q 2 is selected from the group consisting of O and S; R 10 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl(C 1 ~C 6 )alkoxy, C(=O)(C 1 ~C 6) alkyl and (C 1 ~C 6 )AlkoxyC(=O)(C 1 ~C 6 ) alkyl; R 11 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2selected from the group consisting of; R 12 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; X 1 are N, NO and CR 13 is selected from the group consisting of R 13 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , CHO, (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 and triazolyl; X 2 are N, NO and CR 14 is selected from the group consisting of R 14 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 selected from the group consisting of; X 3 is N(R 15 ) (substituted or unsubstituted phenyl), N(R 15) (substituted or unsubstituted heterocyclyl) and substituted or unsubstituted heterocyclyl; R 15 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl(C 1 ~C 6 )alkoxy, C(=O)(C 1 ~C 6 ) alkyl and (C 1 ~C 6 )AlkoxyC(=O)(C 1 ~C 6 ) alkyl; The substituted phenyl and substituted heterocyclyl are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl)(=NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) having one or more substituents selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl, pyrrolopyridinyl and triazolyl; Each alkoxy, alkyl, haloalkoxy, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkenyl, cycloalkyl, halocycloalkenyl, halocycloalkyl, imidazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl is selected from the group consisting of F, Cl, Br, I, CN, OH, NH(C 1 ~C 6 ) alkyl, NH(C 3 ~C 6)CycloalkylCH 2 O(C 1 ~C 6 ) alkyl, NH(C 3 ~C 6 )CycloalkylCH 2 O(C 1 ~C 6 )Haloalkyl, NHCH 2 (C 3 ~C 6 ) Cycloalkyl, NH 2 , NO 2 , oxo, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy and C(O)O-(C 1 ~C 6 ) alkyl; R x1 is H and (C 1 ~C 3 ) alkyl; R x2 is (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6) alkylphenyl, halo(C 1 ~C 6 ) alkylphenyl, (C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) alkyl, O(C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) selected from the group consisting of haloalkyl, isoxazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, oxazolyl and pyrazolyl.

[0035] The advantage of such methods is that they are effective in both treating existing fish lice infestations and preventing new infestations, thus preventing the establishment of adult fish lice colonies, which are known to be the most damaging stage. The resistance-busting properties of such compounds are highly desirable.

[0036] Surprisingly, it has been found that the cyclopropylamide compounds of formula (I) as described in any embodiment herein are effective against juvenile and adult stages of fish lice in fish and can be used successfully while having low toxicity to the fish.

[0037] A further advantageous property of the compounds of formula (I) as described in any embodiment herein is that at the proposed concentrations they do not cause damage to other marine animals such as lobsters, oysters, crustaceans (except fish lice), fish and marine plants.

[0038] As shown in the examples, the administration of aromatic cyclopropylamide compounds of formula (I) as described herein can effectively control fish lice infestations using oral administration, especially when using medicated bait administration that includes the compounds of the present invention and fish bait.Furthermore, it has been shown that compounds of formula (I) as described herein can be effectively used to control resistant populations of fish parasites.

[0039] The present invention is therefore advantageous in the control of fish parasites, particularly fish lice, and allows for effective control of fish lice in fish populations.

[0040] The cyclopropylamide compounds of formula (I) or veterinarily acceptable salts thereof as described in any embodiment herein may be used to control parasitic infections in fish. Uses according to the invention are described in detail below.

[0041] The aromatic cyclopropylamide compounds of formula (I) may be referred to in the following description as compounds of formula (I) or compounds or molecules according to the invention.

[0042] In one embodiment of the present invention and / or in one embodiment thereof, X 3 teeth, [ka] (Wherein, R 15 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl(C 1 ~C 6 )alkoxy, C(=O)(C 1 ~C 6 ) alkyl and (C 1 ~C 6 )AlkoxyC(=O)(C 1 ~C 6 ) alkyl; X 4 are N, NO and CR 16 is selected from the group consisting of R 16 are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2, OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl) (= NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl; X 5 are N, NO and CR 17 is selected from the group consisting of R 17 are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2, (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl)(=NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl; X 6 are N, NO and CR 18 is selected from the group consisting of R 18 are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl) (= NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6)alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl; X 7 are N, NO and CR19 is selected from the group consisting of R 19 are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl)(=NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6 )AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl, and triazolyl; X 8 are N, NO and CR 20 is selected from the group consisting of R 20 are F, Cl, Br, I, H, CN, CHO, NHOH, NO, NO 2 , OH, NH 2 , (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, N=CH-phenyl, (C 1 ~C 6 )Alkyl-S(O)2 NH 2 , (C 1 ~C 6 )Haloalkyl-S(O) 2 NH 2 , (C 1 ~C 6 )Alkyl((C 1 ~C 6 ) alkyl)(=NO(C 1 ~C 6 ) alkyl), C(=NO(C 1 ~C 6 )Alkyl)(C 1 ~C 6 ) alkyl, C(O)(C 1 ~C 6 ) alkyl, C(O)NH(C 1 ~C 6 ) alkyl, C(O)NH phenyl, C(O)O(C 1 ~C 6 ) alkyl, CH(=NO(C 1 ~C 6 ) alkyl), NR x1 C(O)R x2 , N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 )Alkyl-O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )alkyl)(C(O)(C 1 ~C 6 ) haloalkyl), N((C 1 ~C 6 )alkyl)(C(O)O(C 1 ~C 6 ) alkyl), N((C 1 ~C 6 )Alkyl) 2 , N(C(O)O(C 1 ~C 6 )Alkyl) 2 , NH((C 1 ~C 6)AlkylC(O)(C 1 ~C 6 ) alkyl), NH(C 1 ~C 6 ) alkyl, NH(C 1 ~C 6 ) alkenyl, NH(C 1 ~C 6 )alkynyl, NH(C 1 ~C 6 ) alkylphenyl, NH(S(O) 2 (C 1 ~C 6 ) alkyl), S(=NCN)((C 1 ~C 6 ) alkyl), S(C 1 ~C 6 ) alkyl, S(C 1 ~C 6 ) haloalkyl, S(O)(=NCN)((C 1 ~C 6 ) alkyl), S(O)(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) haloalkyl, S(O) 2 (C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) selected from the group consisting of haloalkyl, SCN, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, thiazolyl, thienyl and triazolyl; Each alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxy, haloalkyl, halocycloalkyl, haloalkenyl, halocycloalkenyl and haloalkoxy is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , NO 2 , oxo, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy and C(O)O-(C 1 ~C 6 ) alkyl; or R 18 and R 19 or R 17 and R 18 together they form a ring which is part of a bicyclic ring selected from the group consisting of pyrrolopyridinyl, pyrazolopyridinyl, indenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, azaindolyl, benzisoxazolyl and benzothiazolyl; or X 5 is N and R 18 Together with R, they form a 4- to 6-membered ring. 18 the ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S; or X 6 is N and R 17 Together with R, they form a 4- to 6-membered ring. 17 the ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S; or X 6 is N and R 19 Together with R, they form a 4- to 6-membered ring. 19 the ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S; or X 7 is N and R 18 Together with R, they form a 4- to 6-membered ring. 18 The ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S; R x1 is H and (C 1 ~C 3 ) alkyl; R x2 is (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) halocycloalkenyl, (C 3 ~C 6 ) halocycloalkyl, (C 1 ~C 6 ) alkylphenyl, halo(C 1 ~C 6 ) alkylphenyl, (C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) alkyl, O(C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 ) selected from the group consisting of haloalkyl, isoxazolyl, isothiazolyl, furanyl, tetrahydrofuranyl, oxazolyl and pyrazolyl.

[0043] In one embodiment of the present invention and / or in accordance with an embodiment thereof, Q 1 is O or Q 2 is O or Q 1 and Q 2 are O respectively.

[0044] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl and (C 1 ~C 6 ) haloalkoxy.

[0045] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0046] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0047] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0048] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, Br, I, NH 2 , (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0049] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 are H, F, Cl, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0050] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 is selected from the group consisting of H, F and Cl.

[0051] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 is selected from the group consisting of H and F.

[0052] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 1 is H.

[0053] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and S-(halo) 5 is selected from the group consisting of:

[0054] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 1 ~C 6 ) haloalkoxy and S-(halo) 5 is selected from the group consisting of:

[0055] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkyl.

[0056] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, I, CN, and NH. 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkyl.

[0057] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, CN, and NH. 2 , (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0058] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0059] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 are H, F, Cl, Br, and CH 3 , CHF 2 and CF 3 is selected from the group consisting of:

[0060] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 2 is selected from the group consisting of H, F and Cl, preferably R 2 is F or Cl.

[0061] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and S-(halo) 5 is selected from the group consisting of:

[0062] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 1 ~C 6 ) haloalkoxy and S-(halo) 5 is selected from the group consisting of:

[0063] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0064] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, I, CN, and NH. 2 , (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0065] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, I, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0066] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 are H, F, Cl, Br, and CH 3 , CHF 2 and CF 3 Preferably, R 3 is H, F, Cl, Br and CHF 2 is selected from the group consisting of:

[0067] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 3 is selected from the group consisting of H, F, and Cl.

[0068] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 4 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 2 ~C6 ) alkenyl, (C 3 ~C 6 ) cycloalkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 3 ~C 6 ) halocycloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 3 ~C 6 ) halocycloalkenyl, (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 )Alkyl-S(O) 2 NH 2 and S-(halo) 5 is selected from the group consisting of:

[0069] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 4 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl, (C 1 ~C 6 ) haloalkoxy and S-(halo) 5 is selected from the group consisting of:

[0070] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 4 are H, F, Cl, Br, I, CN, and NH. 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0071] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 4 are H, F, Cl, Br, I, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0072] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 4 are H, F, Cl, Br, and CH 3 , CHF 2 and CF 3 Preferably, R 4 is selected from the group consisting of H, F and Cl, more preferably R 4 is Cl.

[0073] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 5 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl and (C 1 ~C 6 ) haloalkoxy.

[0074] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 5 are H, F, Cl, Br, and NH 2 , (C 1~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0075] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 5 are H, F, Cl, Br, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0076] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 5 is selected from the group consisting of H, F and Cl.

[0077] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 5 is H.

[0078] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 6 and R 9 , H, CH 3 and C.H. 2 CH 3 and each is selected from the group consisting of:

[0079] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 6 and R 9 are H, respectively.

[0080] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 7 and R 8 are each selected from the group consisting of Cl and Br.

[0081] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 7 and R 8 are Cl, respectively.

[0082] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 10 is H, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl and (C 1 ~C 6 ) haloalkyl.

[0083] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 10 is H, (C 1 ~C 6 ) alkyl.

[0084] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 10 H and CH 3 is selected from the group consisting of:

[0085] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 10 is H.

[0086] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 11 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0087] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 11 are H, F, Cl, Br, I, (C 1 ~C 6 ) alkyl and (C 1 ~C 6) haloalkyl.

[0088] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 11 are H, F, Cl, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0089] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 11 are H, F, Cl, CH 3 and CF 3 is selected from the group consisting of:

[0090] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 11 is H.

[0091] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 12 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl and (C 1 ~C 6 ) haloalkoxy.

[0092] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 12 are H, F, Cl, Br, I, CN, and NH. 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C1 ~C 6 ) haloalkoxy.

[0093] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 12 are H, F, Cl, Br, I, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0094] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 12 are H, F, Cl, CH 3 and CF 3 is selected from the group consisting of:

[0095] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 12 is H or F.

[0096] In one embodiment of the present invention and / or in one embodiment thereof, X 1 CR 13 It is.

[0097] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 ) haloalkoxy, S(C 1 ~C 6 ) alkyl, S(O)(C 1 ~C 6 ) alkyl, S(O) 2 (C 1 ~C 6 ) alkyl and triazolyl.

[0098] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , CHO, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl and (C 1 ~C 6 ) haloalkoxy.

[0099] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 are H, F, Cl, Br, I, NH 2 , (C 1 ~C 6 ) alkyl, ((C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) haloalkoxy.

[0100] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 are H, F, Cl, Br, and CH 3 , O.C.H. 3 and CF 3 is selected from the group consisting of:

[0101] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 are H, Cl, F, and CH 3 and OCH 3 is selected from the group consisting of:

[0102] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 13 is H, Cl, F and CH 3 Preferably, R13 is Cl, F and CH 3 is selected from the group consisting of:

[0103] In one embodiment of the present invention and / or in one embodiment thereof, X 2 CR 14 It is.

[0104] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 14 are H, F, Cl, Br, I, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 1 ~C 6 ) alkoxy, (C 1 ~C 6 ) haloalkyl, (C 2 ~C 6 ) haloalkenyl and (C 1 ~C 6 ) haloalkoxy.

[0105] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 14 are H, F, Cl, Br, I, NH 2 , (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0106] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 14 are H, F, Cl, CH 3 and CF 3 is selected from the group consisting of:

[0107] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 14 is selected from the group consisting of H, F or Cl.

[0108] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R14 is H or F, preferably H.

[0109] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 15 is H, (C 1 ~C 6 ) alkyl and (C 2 ~C 6 ) alkenyl.

[0110] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 15 is H and (C 1 ~C 6 ) alkyl.

[0111] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 15 H and CH 3 is selected from the group consisting of:

[0112] In one embodiment of the present invention and / or in one embodiment thereof, X 3 teeth, [ka] (In the formula, R 15 is H and (C 1 ~C 6 ) alkyl; X 4 is N or CR 16 and R 16 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 5 is N or CR 17 and R17 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 6 is N or CR 18 and R 18 are H, F, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 7 is N or CR 19 and R 19 are H, F, I, Br, Cl, NH 2 , CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1 ~C 6 ) haloalkoxy; X 8 is N or CR 20 and R 20 are H, F, Cl, CN, and NH. 2 , NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C 6 )alkoxy and (C 1~C 6 ) haloalkoxy; or R 18 and R 19 or R 17 and R 18 together they form a ring which is part of a bicyclic ring selected from the group consisting of pyrrolopyridinyl, pyrazolopyridinyl and azaindolyl, or X 7 is N and R 18 Together with R, they form a 4- to 6-membered ring. 18 The ring formed by contains 0, 1 or 2 heteroatoms selected from the group consisting of O, N and S. It is.

[0113] In one embodiment of the present invention and / or in one embodiment thereof, X 4 is N or CR 16 and R 16 are H, F, Cl, CN, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0114] In one embodiment of the present invention and / or in one embodiment thereof, X 5 is N or CR 17 and R 17 are H, F, Cl, NH 2 , (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0115] In one embodiment of the present invention and / or in one embodiment thereof, X 6 is N or CR 18 and R 18 are H, F, Cl, NH 2 ,CN,(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, (C 1 ~C6 )alkoxy and (C 1 ~C 6 ) haloalkoxy.

[0116] In one embodiment of the present invention and / or in one embodiment thereof, X 7 is N or CR 19 and R 19 are H, F, I, Br, Cl, NH 2 ,CN,(C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0117] In one embodiment of the present invention and / or in one embodiment thereof, X 8 is N or CR 20 and R 20 are H, F, Cl, CN, (C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0118] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 18 and R 19 or R 17 and R 18 together form a ring that is part of a bicyclic ring selected from the group consisting of pyrrolopyridinyl, pyrazolopyridinyl, and azaindolyl.

[0119] In one embodiment of the present invention and / or in one embodiment thereof, X 7 is N and R 18 Together with R, they form a 4- to 6-membered ring. 18 The ring formed by contains 0, 1 or 2 heteroatoms which are N.

[0120] In one embodiment of the present invention and / or in one embodiment thereof, X 4 is N or CR 16 and R 16 H, F, CN and (C 1~C 6 ) alkyl.

[0121] In one embodiment of the present invention and / or in one embodiment thereof, X 5 is N or CR 17 and R 17 are H, F, Cl, NH 2 and (C 1 ~C 6 ) alkyl.

[0122] In one embodiment of the present invention and / or in one embodiment thereof, X 6 is N or CR 18 and R 18 are H, F, Cl, NH 2 ,CN,(C 1 ~C 6 ) haloalkyl and (C 1 ~C 6 ) alkoxy.

[0123] In one embodiment of the present invention and / or in one embodiment thereof, X 7 is N or CR 19 and R 19 are H, F, I, Br, Cl, NH 2 ,CN,(C 1 ~C 6 ) alkyl and (C 1 ~C 6 ) haloalkyl.

[0124] In one embodiment of the present invention and / or in one embodiment thereof, X 8 is N or CR 20 and R 20 H, F, CN and (C 1 ~C 6 ) alkyl.

[0125] In one embodiment of the present invention and / or in accordance with an embodiment thereof, R 18 and R 19 or R 17 and R 18together form a ring that is part of a bicyclic ring selected from the group consisting of pyrrolopyridinyl, pyrazolopyridinyl, and azaindolyl.

[0126] In one embodiment of the present invention and / or in one embodiment thereof, X 7 is N and R 18 Together with R, they form a 4- to 6-membered ring. 18 The ring formed by contains 0, 1 or 2 heteroatoms which are N.

[0127] In one embodiment of the present invention and / or in one embodiment thereof, X 4 is N or CR 16 and R 16 is selected from the group consisting of H and F.

[0128] In one embodiment of the present invention and / or in one embodiment thereof, X 5 is N or CR 17 and R 17 is H.

[0129] In one embodiment of the present invention and / or in one embodiment thereof, X 6 is N or CR 18 and R 18 is selected from the group consisting of H and F.

[0130] In one embodiment of the present invention and / or in one embodiment thereof, X 7 is N or CR 19 and R 19 H and (C 1 ~C 6 ) alkyl.

[0131] In one embodiment of the present invention and / or in one embodiment thereof, X 8 is N or CR 20 and R 20 H, F and (C 1 ~C 6 ) alkyl.

[0132] In one embodiment of the present invention and / or its embodiments, R 1 is selected from the group consisting of H, F and Cl; R 2 are H, F, Cl, Br, and CH 3 , O.C.H. 3 and CF 3 selected from the group consisting of; R 3 is H, F, Cl, Br and CHF 2 , C.F. 3 , OCF 3 selected from the group consisting of; R 4 are H, F, Cl, Br, CN, and CH 3 and CF 3 selected from the group consisting of; R 5 is H; R 6 is H; R 7 is selected from the group consisting of Cl and Br; R 8 is selected from the group consisting of Cl and Br; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R 13 is H, F, Cl and CH 3 selected from the group consisting of; R 14 is H or F; R 15 H and CH 3 selected from the group consisting of; Q1 and Q2 are O.

[0133] In one embodiment of the present invention and / or its embodiments, R 1 is H; R 2 is selected from the group consisting of H, F and Cl; R 3is selected from the group consisting of H, F and Cl; R 4 is selected from the group consisting of H, F and Cl; R 5 is H; R 6 is H; R 7 is Cl; R 8 is Cl; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R 13 is F, Cl and CH 3 selected from the group consisting of; R 14 is H or F; R 15 H and CH 3 selected from the group consisting of; Q1 and Q2 are O.

[0134] In one embodiment of the present invention and / or its embodiments, R 1 is H; R 2 is selected from the group consisting of F and Cl; R 3 is selected from the group consisting of H, F and Cl; R 4 is selected from the group consisting of H, F and Cl; R 5 is H; R 6 is H; R 7 is Cl; R 8 is Cl; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R13 is F, Cl and CH 3 selected from the group consisting of; R 14 is H; R 15 is H; Q1 and Q2 are O.

[0135] In one embodiment of the present invention and / or in accordance with embodiments thereof, at least one of the following conditions is met: R 1 is selected from the group consisting of H, F and Cl; R 2 are H, F, Cl, Br, and CH 3 , O.C.H. 3 and CF 3 selected from the group consisting of; R 3 is H, F, Cl, Br and CHF 2 , C.F. 3 , OCF 3 selected from the group consisting of; R 4 are H, F, Cl, Br, CN, and CH 3 and CF 3 selected from the group consisting of; R 5 is H; R 6 is H; R 7 is selected from the group consisting of Cl and Br; R 8 is selected from the group consisting of Cl and Br; R 9 , R 10 and R 11 is H; R 12 is selected from the group consisting of H and F; R 13 is H, F, Cl and CH 3 selected from the group consisting of; R 14 is H or F; R 15 H and CH 3 selected from the group consisting of; Q1 and Q2 are O.

[0136] In one embodiment of the present invention and / or in accordance with embodiments thereof, at least one of the following conditions is met: R 1 is H; R 5 is H; R 6 is H; R 7 is Cl; R 8 is Cl; R 9 , R 10 and R 11 is H; R 15 H and CH 3 selected from the group consisting of; Q1 and Q2 are O.

[0137] In one embodiment of the present invention and / or in accordance with embodiments thereof, at least one of the following conditions is met: R 2 is selected from the group consisting of H, F and Cl; R 3 is selected from the group consisting of H, F and Cl; R 4 is selected from the group consisting of H, F and Cl; R 12 is selected from the group consisting of H and F; R 13 is F, Cl and CH 3 selected from the group consisting of; R 14 is H or F; R 15 H and CH 3 is selected from the group consisting of:

[0138] In one embodiment of the present invention and / or its embodiments, R 1 is H; R 5 is H; R 6is H; R 7 is Cl; R 8 is Cl; R 9 , R 10 and R 11 is H; R 15 H and CH 3 selected from the group consisting of; Q1 and Q2 are O.

[0139] In one embodiment of the present invention and / or its embodiments, R 2 is selected from the group consisting of H, F and Cl; R 3 is selected from the group consisting of H, F and Cl; R 4 is selected from the group consisting of H, F and Cl; R 12 is selected from the group consisting of H and F; R 13 is F, Cl and CH 3 selected from the group consisting of; R 14 is H or F.

[0140] Suitable compounds are any of those listed below.

[0141] [Table 1]

[0142] [Table 2]

[0143] [Table 3]

[0144] [Table 4]

[0145] [Table 5]

[0146] [Table 6]

[0147] [Table 7]

[0148] Further suitable compounds having advantageous properties are listed below.

[0149] [Table 8]

[0150] [Table 9]

[0151] [Table 10]

[0152] Salts, solvates, N-oxides and prodrugs A salt of the cyclopropylamide compound of formula (I) or another compound may be advantageous due to one or more physical properties of the salt, such as pharmaceutical stability at different temperatures and humidities; crystalline properties; and / or desired solubility in water, oil or other solvents. In some cases, the salt may be used as an aid in the isolation, purification and / or resolution of the compound. Acid and base salts can generally be formed, for example, by mixing the compound with an acid or base, respectively, using various methods known in the art. To the extent that the salt of the compound is intended to be administered in vivo (i.e., to an animal) for therapeutic benefit, the salt is pharma-ceutically acceptable.

[0153] Salts may also be advantageous in the synthesis of the compounds according to the invention, for example certain intermediates may be advantageously used in the form of their salts in the process of preparing the compounds according to the invention.

[0154] In general, acid addition salts can be prepared by reacting free base compounds with approximately stoichiometric amounts of inorganic or organic acids.Examples of inorganic acids that are often suitable for making (pharmaceutically acceptable) salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Examples of organic acids that are often suitable for making (pharmaceutically acceptable) salts generally include, for example, aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxy and sulfonic classes of organic acids. Specific examples of organic acids that are often suitable include cholic acid, sorbic acid, lauric acid, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, arylcarboxylic acids (e.g., benzoic acid), anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), alkylsulfonic acids (e.g., ethanesulfonic acid), arylsulfonic acids, and the like. Examples of suitable acids include sulphonic acid (e.g. benzenesulphonic acid), pantothenic acid, 2-hydroxyethanesulphonic acid, sulphanilic acid, cyclohexylaminosulphonic acid, β-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, alginic acid, butyric acid, camphoric acid, camphorsulphonic acid, cyclopentanepropionic acid, dodecylsulphuric acid, glycoheptanoic acid, glycerophosphoric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalsulphonic acid, oxalic acid, palmoic acid, pectic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, tosylic acid and undecanoic acid. In some such embodiments, for example, the salt comprises a salt of trifluoroacetic acid, mesylic acid or tosylic acid. In other embodiments, the salt comprises a hydrochloride salt.

[0155] Generally, base addition salts can be prepared by reacting a free acid compound with an approximately stoichiometric amount of an inorganic or organic base. Examples of base addition salts can include, for example, metallic salts and organic salts. Metallic salts include, for example, alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiologically acceptable metal salts. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. For example, a free acid compound can be mixed with sodium hydroxide to form such a base addition salt. Organic salts can be made from amines such as trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, ethanolamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing group can be C 1 ~C 6 - may be quaternized with agents such as alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aryl alkyl halides (e.g., benzyl and phenethyl bromides).

[0156] Solvates of the cyclopropylamide compounds of formula (I) or of another compound may be formed by aggregation of said compounds of formula (I) with solvent molecules, preferably in limited weight proportions, such as water, alcohols, e.g. ethanol, aromatic solvents, e.g. toluene, ether, halogenated organic solvents, e.g. dichloromethane, and the like.

[0157] N-oxides of a compound of formula (I) or another compound may be formed by oxidation of the N atom in an amine or an N-heterocycle, such as pyridine, with an oxidizing agent, such as hydrogen peroxide, a peracid or an inorganic oxidizing agent, such as potassium peroxymonosulfate (Oxone).

[0158] The present invention also includes prodrug derivatives of the cyclopropylamide compounds of formula (I). The term prodrug refers to a compound that is converted in vivo to produce the parent compound of the compound of formula (I). In vivo means that this conversion can occur in the host organism and / or the parasite, for example in the case of treating parasitic infection. Various forms of prodrugs are well known in the art. For example, when the group of formula (A) represents pyridine, it is possible to form pyridinium salts, such as acyloxyalkylpyridinium salts, which can provide advantages in terms of higher solubility for parenteral dosage forms, as described in SK Davidsen et al., J.of Med. Chem.37 4423-4429(1994).

[0159] Isomers The compounds according to the invention or their intermediates can exist in various isomeric forms. A reference to a compound according to the invention or an intermediate thereof always includes all possible isomeric forms of such compound.

[0160] In some embodiments, such compounds may have two or more isomers, such as optical isomers or stereoisomers. In some preferred embodiments, such compounds have the (E) configuration, and in other embodiments, the compounds have the (Z) configuration. In preferred embodiments, the compounds have the (E) configuration.

[0161] Unless otherwise stated, a compound structure that does not show a specific conformation is intended to encompass all possible conformational isomers of the compound, and includes less than all possible conformational isomers. Compounds with two chiral centers have four isomers: RR-, SS-, RS-, and SR-isomers. Such compounds can exist in several forms, namely, in the form of pure RR or SS or RS or SR isomers, or as mixtures, hereinafter referred to as "enantiomeric pairs", either RR / SS or RS / SR.

[0162] Cyclopropylamide compounds can exist as a racemic mixture of all four isomers (RR+SS+RS+SR) or in the form of a racemic mixture of enantiomer pairs (RR / SS) or (RS / SR). The isomers (RR) and (SS) are mirror images of each other and therefore enantiomers, which have the same chemical properties and melting points. (RS) and (SR) are also enantiomer pairs. However, the mirror images of (RR) and (SS) are not superimposable in (RS) and (SR). This relationship is called diastereomeric, and (RR) is a diastereomer to (RS).

[0163] Although structurally identical, isomers may have different effects in biological systems: one isomer may have a specific therapeutic activity, while another may have no therapeutic activity or may have an entirely different form of biological activity.

[0164] It has now surprisingly been found that parameters such as efficacy can be significantly improved by administering the pure or substantially pure RR-isomer of the present compound, or a pharma- ceutically acceptable salt thereof, while side effects can be substantially avoided.Accordingly, the applicants have found that by administering a therapeutically effective amount of the pure or substantially pure RR-isomer of the present compound, or a pharma- ceutically acceptable salt thereof.

[0165] Terms such as "pure RR-cyclopropylamide compound", "pure RR isomer of cyclopropylamide compound" and the like refer to cyclopropylamide compounds having the optical purity of the RR-cyclopropylamide compound of formula (I), i.e., 98% by weight or greater, meaning that the RR isomer is present in a concentration of 98% by weight or greater, while the total concentration (i.e., sum) of the corresponding RS-, SR- and SS-isomers is 2% by weight or less, based on the total amount of cyclopropyl compound present.

[0166] The terms "substantially pure RR-cyclopropylamide compound", "substantially pure RR isomer of cyclopropylamide compound" and the like refer to an optical purity of the RR-* cyclopropylamide compound that is 80% by weight or greater, meaning that the concentration of the RR-cyclopropylamide compound is 80% by weight or greater and the sum of the corresponding RS-, SR- and SS-isomers is 20% by weight or less, based on the total amount of cyclopropylamide compound present. In a more preferred embodiment, the "substantially pure RR-cyclopropylamide compound" contains 90% by weight or greater of the RR-cyclopropylamide compound and 10% by weight or less of the sum of the RS, SR and SS-isomers of the cyclopropylamide compound.

[0167] In an embodiment of the invention and / or embodiments thereof, the parasitic infection is a fish lice infection.

[0168] In one embodiment of the invention and / or embodiments thereof, the parasite is at least one of Lepeophtheirus salmonis, Caligus celmensi, Caligus curtus, Caligus dussumieri, Caligus elongates, Caligus longicaudatus, Caligus rogercresseyi or Caligus stromii.

[0169] In one embodiment of the invention and / or embodiments thereof, the parasitic infection is by copepodites, pre-adult or adult fish lice or is a mixed infection with various stages.

[0170] In one embodiment of the present invention and / or embodiments thereof, an existing parasitic infection in a fish population is treated.

[0171] In one embodiment of the invention and / or embodiments thereof, the parasite is an adult fish louse.

[0172] In one embodiment of the invention and / or embodiments thereof, the parasite is a juvenile fish louse.

[0173] In one embodiment of the invention and / or embodiments thereof, the infection rate of the fish population is on average 0.5 to 3 parasites per fish, preferably the parasites are adult female fish lice.

[0174] In one embodiment of the invention and / or embodiments thereof, the method comprises administering to fish an effective amount of a compound of formula (I) as defined in any embodiment herein to protect the fish from infection and / or re-infection by a parasite, preferably the parasite is a pre-adult or adult fish lice.

[0175] In one embodiment and / or embodiments thereof, the method comprises administering to the fish an effective amount of a compound of formula (I) as defined in any embodiment herein, wherein the time between administrations is from 2 to 8 weeks, preferably from 3 to 6 weeks, more preferably about 4 weeks.

[0176] In one embodiment of the invention and / or embodiments thereof, the parasite is resistant to macrocyclic lactone, organophosphate and / or pyrethroid antiparasitic agents, preferably the parasite is a fish louse.

[0177] In one embodiment of the invention and / or embodiments thereof, the method comprises administering to fish a compound of formula (I) as defined in any embodiment herein together with a physiologically active agent.

[0178] In one embodiment of the invention and / or embodiments thereof, the method comprises administering to the fish a compound of formula (I) as defined in any embodiment herein together with an antigen, optionally the compound and the antigen are administered together with an adjuvant.

[0179] In one embodiment of the invention and / or embodiments thereof, the method comprises administering to fish a compound of formula (I) as defined in any embodiment herein together with a further antiparasitic agent.

[0180] In one embodiment of the invention and / or embodiments thereof, the method comprises administering to the fish a compound of formula (I) as defined in any embodiment herein by oral administration, or by topical administration, or by medicated bath treatment, or by intraperitoneal or intramuscular injection, preferably by immersion of the fish in medicated water.

[0181] In one embodiment of the invention and / or embodiments thereof, the method comprises administering a compound of formula (I) as defined in any embodiment as described herein to fish by oral administration, wherein oral administration comprises administering a medicated fish food comprising the compound and fish food.

[0182] In one embodiment of the present invention and / or embodiments thereof, the medicinal fish bait is administered daily for a period of 3 to 7 days.

[0183] In one embodiment and / or embodiments thereof, the method comprises administering a compound of formula (I) as defined in any embodiment as described herein by a bath treatment, which comprises immersing the fish in water containing a therapeutically effective amount of the compound.

[0184] The present invention is also directed to a composition comprising a compound of formula (I) as defined in any one of the embodiments as described herein, and a veterinarily acceptable formulation adjuvant.

[0185] In one embodiment of the present invention and / or embodiments thereof, the composition comprises a solvent and optionally a solubilizer.

[0186] In one embodiment of the invention and / or embodiments thereof, the composition is in the form of a stock solution that is to be used to form a medicated solution containing an effective amount of the compound.

[0187] In one embodiment and / or embodiments thereof, the effective amount of the compound in medicinal water is from about 2 ppb to about 500 ppb.

[0188] In one embodiment of the invention and / or embodiments thereof, the method comprises administering the compound to the fish by medicated bath immersion of the fish.

[0189] In one embodiment of the invention and / or embodiments thereof, the method comprises administering the composition to the fish by oral administration via the feed.

[0190] The present invention is further directed to a premix comprising a compound of formula (I) as defined in any one of the embodiments as described herein and / or a composition as defined in any one of the embodiments as described herein, the premix further comprising nutrients.

[0191] In one embodiment of the present invention and / or embodiments thereof, the premix comprises nutrients in the form of pellets, which are coated with a composition comprising a compound of formula (I) as defined in any embodiment as described herein or are coated with a composition as defined in any embodiment as described herein.

[0192] In one embodiment of the present invention and / or embodiments thereof, the premix comprises nutrients in the form of pellets that are mixed with a composition comprising a compound of formula (I) as defined in any embodiment as described herein or with a composition as defined in any embodiment as described herein.

[0193] The present invention is further directed to a medicated fish bait. The medicated bait of the present invention and any of its embodiments comprises a composition as defined in any of the embodiments described herein or a premix as defined in any of the embodiments described herein and a fish bait.

[0194] Medicinal fish baits as described in the embodiments herein are useful in the methods as described in the embodiments herein.

[0195] The present invention is further directed to a kit comprising a composition as defined in any embodiment as described herein and instructions for administration of the composition to fish to control parasitic infections.

[0196] The kit may also include a premix as described herein, instructions for the preparation of a medicated fish bait as described herein, and instructions for administering the medicated fish bait to fish to control parasitic infections.

[0197] The kit may also include a preservative solution as described herein and instructions for preparation of medicated water for medicated bath treatments and instructions for immersion of fish to control parasitic infections.

[0198] definition The following definitions are important in connection with embodiments of the present invention.

[0199] definition "Parasite" A parasite is an organism that lives on or in another organism (usually called a host) causing harm to the host. As used herein, unless otherwise indicated, refers to endoparasites and ectoparasites. Endoparasites are parasites that live inside the body of their host and include helminths (e.g., trematodes, cestodes, and nematodes) and protozoa. Ectoparasites are organisms that feed through or on the skin of their host. In the present invention, the host animal is a fish.

[0200] "Fish", as used herein, unless otherwise indicated, refers to the taxonomic classes Chondrichthyes (cartilaginous fish, e.g., sharks and ray-finned fish) and Osteichthyes (bony fish), which live in water, have gills for breathing or skin covered with mucus, and may have scales. It includes food fish, breeding fish and aquarium fish, pond fish and farmed fish of all ages occurring in freshwater, marine (e.g., ocean) and brackish waters.

[0201] Non-limiting examples of food fish include carp, eel, trout, whitefish, salmon, roach, rudd, chub, arctic char, sturgeon, plaice, halibut, turbot, flounder, striped bass, yellowtail, grouper, cod, sole, tuna, red sea bream, sea bass, grey mullet, trevally, gilthead sea bream, tilapia, and catfish.

[0202] The present invention more particularly relates to marine fish and more particularly marine food fish, especially salmon.

[0203] Within the scope of the present invention, the term "salmon" is understood to include all representatives of the family Salmonidae, in particular the following species: Salmo salar (Atlantic salmon); Salmo trutta (brown or sea trout); Salmon gairdneri (rainbow trout); and Pacific salmon (Oncorhynchus): O. gorbuscha; O. keta; O. nekra; O. kisutch, O. tshawytscha and O. mason; and also artificially propagated species, such as Salvelinus spp. and Salmo clarkia.

[0204] The preferred hosts of the present invention are Atlantic and Pacific salmon and sea trout.

[0205] In another embodiment, the host fish is Mediterranean sea bass and / or sea bream. In another embodiment, the host fish is a freshwater fish, such as carp and / or freshwater trout. In another embodiment, the fish is tilapia.

[0206] Fish population means a group of individual fish maintained in a confined area, such as in seawater tanks, cages or nets. The cages and nets are fixed at the entrance to the ocean to allow a daily periodic water current to pass through them to ensure an adequate supply of oxygen and clean water.

[0207] The tanks have a continuous flow of seawater into and out of them, or at least scheduled flushes of fresh seawater, to ensure sufficient water quality and oxygen to keep the fish healthy. In this artificial environment, the fish are fed and provided with medication, if necessary, until they are mature enough for shipment as food fish or are selected for further breeding.

[0208] In one embodiment of the present invention, the compound of formula (I) or a salt, enantiomer or prodrug thereof is administered to a population of fish at the end of the freshwater phase or the beginning of the saltwater phase in fish farming.

[0209] According to another embodiment, the fish (salmon or sea trout) are maintained in seawater while the treatment takes place.

[0210] Fish lice According to the present invention, the compounds of formula (I) are particularly suitable for use in controlling fish parasitic crustaceans, such as fish lice. Thus, in one embodiment, the compounds of formula (I) are used to control fish parasitic crustaceans, particularly fish lice infestations.

[0211] Fish lice is the common name given to a group of fish-parasitic crustaceans that are ectoparasites called copepods that affect fish in saltwater. "Fish lice," as used herein, unless otherwise indicated, refers to a parasitic crustacean (copepod) that feeds through or on the mucus, skin and tissues of its host and is in the order Siphonostomatoida.

[0212] These include the families Caligidae and Lernanthropidae. Two representatives of the Caligidae family cause considerable losses in salmonid fish farming: Lepeophtheirus spp. and Caligus spp. (C). Species within Lepeophtheirus spp. (L) include, for example, Lepeophtheirus salmonis oncorhynchi, Lepeophtheirus salmonis Lernanthropus koyeri, and species within Caligus spp. include, for example, Caligus clemensi, Caligus curtus, Caligus dussumieri, Caligus elongatus, Caligus longicaudatus, Caligus rogercresseyi, and Caligus stromii. stromii and Caligus minimus.

[0213] L. salmonis is found only in the Northern Hemisphere. C. rogercresseyi is the most important species of fish lice in Chile affecting the salmon industry.

[0214] One representative of the family Lernanthropidae is of interest mainly in Mediterranean fish farming: Lernanthropus spp. Species within Lernanthropus spp. include, for example, Lernanthropus kroyeri, Lernanthropus callinomymicola, Lernanthropus indefinitus, Lernanthropus cynoscicola and Lernanthropus gisleri.

[0215] In one embodiment, the compounds are used to control fish lice infestations, wherein the fish lice are at least one of Lepeophtheirus salmonis, Caligus clemensi, Caligus curtus, Caligus dussumieri, Caligus elongatus, Caligus longicaudatus, Caligus rogercresseyi, or Caligus stromii, Caligus minimus, or Lernanthropus kroyeri.

[0216] In another embodiment, the compounds are used to control a crustacean parasitic infection in a fish, wherein the crustacean parasitic in the fish is at least one of Lepeophtheirus kroyeri and Caligus minimus.

[0217] It has now been found that the compounds of formula (I) are capable of controlling various stages of crustaceans parasitic on fish, in particular fish lice.

[0218] In one embodiment, the compounds of formula (I) are used to control fish lice infestations in crustaceans parasitic on fish, particularly copepodids, pre-adult or adult fish lice or mixed infections at various stages.

[0219] Fish-parasitic crustaceans, such as the ascarid fish louse, have both free-swimming (planktonic) and parasitic life cycles, all separated by molting.

[0220] The eggs hatch into nauplii I, which molt to a second nauplii stage; both nauplii depend on yolk stores for energy, do not feed, and are adapted to swimming. The next life cycle, the copepodid stage, is the infective stage, which seeks out suitable hosts, presumably by chemical and mechanosensory cues.

[0221] Transmission of caligid fish lice occurs during the copepod planktonic stage (larvae). Once the copepods have attached to a suitable host, they feed before molting into the caligid I stage. Fish lice continue their development through up to four caligid stages by molting. A distinctive feature of all caligid stages is that they are physically attached to the host by a structure called the frontal thread. Differences in the timing, method of production and physical structure of the frontal thread are found between individual species of fish lice.

[0222] Except for a brief period during molting, pre-adults and adult stages are mobile on the fish and in some cases may be transferred between host fish. The larger adult females occupy a relatively flat body surface on the posterior ventral and dorsal midline and in the head region.

[0223] The nauplii and copepodid stages do not feed until they are located on the host, living off internal food reserves. Once attached to the host, the copepodid stage begins to feed and develops into the first charimid stage. The copepods and charimid stages have developed digestive tracts and feed on the host mucus and tissue within their attachment (sessile stage). Pre-adult and adult fish lice, especially egg-laying females, are aggressive feeders, feeding in some cases from blood in addition to tissue and mucus.

[0224] As used herein, "juvenile fish lice" are the stage before an individual matures to the pre-adult and adult stages and includes the copepodid and charimid parasitic phages of fish lice.

[0225] As used herein, the term "sessile stage" refers to the juvenile and "mobile" stages - preadult and adult stages.

[0226] In one embodiment, existing infections of fish populations with motile stages such as adult fish lice stages and / or pre-adult stages are treated. This is particularly important as these parasite stages cause the most significant damage when feeding on fish.

[0227] Infection of a fish means that at least one member of the parasite stage is visible on the surface of the fish. In special cases, automated fish lice counting methods can be used to detect infection and the extent of fish lice infestation by parasite counting.

[0228] In an alternative preferred embodiment, existing infestations of fish populations with juvenile fish lice (sessile stage) are treated as determined by fish lice counting methods. Such control of juvenile fish lice infestations is desirable as control of the juvenile stage provides longer term efficacy as it protects the fish from pre-adult or adult development of fish lice in the fish, and especially from adult female fish lice.

[0229] In another embodiment, existing infestations of fish populations with juvenile fish lice (sessile stage) and adult stages (mobile stage) are treated.

[0230] In one embodiment, a single administration of a compound of formula (I) protects a fish population against reinfection with parasites, particularly fish lice, for a period of 4 weeks, allowing for a 4 week interval between treatments (i.e. the time between administrations is 4 weeks).

[0231] In one embodiment, the time between administrations is 2 to 8 weeks, preferably 3 to 6 weeks, more preferably about 4 weeks. Reinfection means that an individual has been infected with a particular parasite and then a different parasite infection is established on the same animal from its environment or contact with infected fish or equipment.

[0232] In another embodiment, the parasite is Argulus spp. Argulus (carp louse), Lernaea and Ergasilus, belonging to the class Crustacea, and considered to be important ectoparasites on fish. The parasitic copepods Argulus and Lernaea attach themselves to the body of the fish, their bodies are embedded in the scale capsule, and paired egg capsules protrude freely. Argulus spp. attach themselves to the body of the fish in particular by suckers and hooks, but can also swim freely in the water.

[0233] Control As used herein, the term "control" refers to reducing the number of parasites, particularly the number of fish parasitic crustaceans, particularly fish lice, eliminating parasites, particularly fish parasitic crustaceans, particularly fish lice, and / or preventing further infection, particularly by pre-adult and adult stages of fish parasitic crustaceans, particularly fish lice.

[0234] "Treatment" refers to preventative or reactive treatment, such as the control, elimination, protection from, and / or prevention of fish parasitic (such as fish lice) infection or conditions in fish or fish populations. The term includes lowering the average number of parasites (such as fish lice) infecting each fish in a fish population; or preventing an increase in the average number of parasites currently infecting each fish in a fish population; i.e., treating an existing parasitic infection or additionally or alternatively preventing the onset of symptoms associated with a parasitic infection, including reducing the severity of infection by a parasite (such as fish lice) or a disorder or condition or symptom associated with a parasitic infection. The term also includes preventing the recurrence of a fish parasitic infection or symptoms associated therewith, as well as references to "control" (e.g., killing, dissipating, expelling, incapacitating, preventing, removing, reducing, minimizing, and eradicating).

[0235] In most countries, salmon producers are obliged to regularly report their fish lice levels and treatment data. Local regulations call for weekly sampling of at least 5 fish per net pen, from a minimum of 6 net pens, for example, when water temperatures exceed 5°C. In all cases, fish-level fish lice counts are reported for the different parasite life cycles; charimus, pre-adult males and females, along with adult males (PAAM) and adult females (AF; both spawning and non-spawning). In Norway, fish populations are treated if an average of more than 0.5 adult female fish lice per fish is detected in an aquaculture facility, the entity that keeps the fish, also called the fish farming site. In Scotland, there is a mandatory requirement that if an average of 3 adult female fish lice per fish is found during weekly counts at any fish farming site, this must be reported.

[0236] In a preferred embodiment, compounds of formula (I) are used to control fish lice infestations in aquaculture facilities where the infestation rate in fish populations averages 0.5 to 3 adult female fish lice per fish.

[0237] Effective dose and route of administration As used herein, the term "effective amount" refers to the amount or dosage of a compound of formula (I) or a salt thereof to a fish or population of fish in single or multiple administrations that produces a desired effect.

[0238] In determining the effective amount, numerous factors are taken into consideration, including, but not limited to, the species of fish; the degree of parasitic infection; the response of the fish population; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of co-medications; and other appropriate circumstances.

[0239] A "therapeutically effective amount," as used herein, unless otherwise indicated, refers to an amount that (i) treats a particular parasitic infection, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular parasitic infection, or (iii) prevents or delays the onset of one or more symptoms of a particular parasitic infection as described herein.

[0240] The compounds of formula (I) or salts thereof may be administered to fish by any route which has the desired effect, including but not limited to oral administration, parenteral administration by intraperitoneal or intramuscular injection, or topical administration, for example in the form of a medicated bath.

[0241] Thus, in one embodiment, the compounds are applied to the fish by oral administration, topical administration, for example by a medicated bath treatment, which includes immersing the fish in water containing a therapeutically effective amount of the compound (medicated water) or injecting the fish by intraperitoneal or intramuscular injection.

[0242] In one embodiment, the fish are treated orally, e.g., via their food, or alternatively, topically, e.g., by bath treatment in a "medicated bath" in which the fish are placed and maintained for a period of time (minutes to hours), e.g., when transferred from one breeding tank to another.

[0243] In certain cases, treatment can also be performed parenterally, for example by injection, such as by intraperitoneal or intramuscular injection. It is also possible to treat, either transiently or continuously, the fish biotope, for example the net cage, the entire pond, the aquarium, the tank or the bath in which the fish are kept.

[0244] One aspect of the invention is a composition comprising one or more compounds of formula (I) and veterinarily acceptable formulation adjuvants for use in controlling parasitic infections in fish populations.

[0245] "Veterinarily acceptable," as used herein, unless otherwise indicated, indicates that a component must be chemically and / or toxicologically compatible with other components comprising the composition, the composition and / or the fish treated therewith. The term "pharmaceutical" acceptable has the same meaning as given for "veterinarily" acceptable.

[0246] The compositions include those suitable for the aforementioned routes of administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of veterinary medicine. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0247] The compound is administered in a composition adjusted for application. Compositions for oral administration may consist of, for example, a powder, granule, solution, emulsion or suspension that is mixed homogeneously with the feed as a feed additive, or a powder, granule, solution, emulsion or suspension that is administered in the form of a pill, such as a fish feed composition, with an outer coating that completely covers the active compound.

[0248] Compositions for bath application or for treating biotopes are powders, granules, solutions, emulsions or suspensions, tablets or the active compound itself.

[0249] The compositions are prepared in a manner known per se by mixing, granulating and / or molding the active compound, generally with solid or liquid carriers and, if necessary, with further adjuvants, such as emulsifiers or dispersing agents, solubilizers, colorants, antioxidants and / or preservatives.

[0250] Indeed, it is also possible, for example, to use forms of application in which the active compound is contained in a film matrix which dissolves readily in water or in a film in which it disperses over the application period.

[0251] The diluted compositions of the present invention are prepared by contacting the compound of formula (I) with the adjuvants of liquid and / or solid compositions by stepwise mixing and / or grinding so as to achieve optimal expression of the antiparasitic activity of the composition compatible with the application.

[0252] Bath application of the compositions of the invention to the parasites to be controlled can be carried out such that the composition is placed in the cage in the form of, for example, a solution, emulsion, suspension, powder or tablet, which is rapidly dissolved and dispersed by the movement of the fish and the current of the water.

[0253] Medicated bath treatment The compounds of formula (I) may be administered to fish by bath treatment, for example by placing the fish in a "medicated bath" and maintaining them for a period of time (minutes to hours), for example when transferring from one net pen or breeding tank to another.

[0254] Thus, in one embodiment, an effective amount of at least one compound of formula (I) is administered to the fish by topical administration, preferably by immersion of the fish in water containing a therapeutically effective amount of one or more compounds of formula (I). For use as a medicated bath treatment, a compound of formula (I) or a composition comprising at least one compound of formula (I), at least one compound of formula (I) may be dissolved or suspended in the water containing the fish and / or parasites, thereby forming a medicated water.

[0255] Another aspect of the present invention is a composition comprising at least one compound of formula (I) for dilution for use as a water bath immersion treatment to control parasitic infestations on fish from fish lice.

[0256] In one embodiment, such compositions comprise one or more compounds of formula (I) and veterinarily acceptable formulation adjuvants in the form of a stock solution for dilution in a volume of water to form medicated water for use as a bath immersion treatment. Preferably, the effective amount in the medicated water is from about 2 ppb to about 500 ppb.

[0257] In one embodiment, a stock solution is used, which is a concentrated solution of the compound in a liquid carrier containing a solvent and solubilizing agent, which can be diluted with a large amount of water.

[0258] In yet another embodiment of the invention, the composition is a stock solution of a compound of formula (I) for dilution in the volume of water to be used as a water bath immersion treatment to control parasitic fish lice infestations on fish.

[0259] In another aspect of the invention, a stock solution of a compound of formula (I) comprises a solvent and optionally a solubilizing agent.

[0260] The solvent may be a non-aqueous polar solvent such as methanol, ethanol, benzyl alcohol, isopropanol, acetone, methylene chloride, butyl diglycol, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, polyoxyethylated ethers, propylene glycol, ethylene glycol, and mixtures thereof. In another aspect of the invention, the non-aqueous polar solvent is selected from ethanol, benzyl alcohol, isopropanol, acetone, butyl diglycol, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, and mixtures thereof. In another aspect of the invention, the non-aqueous polar solvent is selected from benzyl alcohol, butyl diglycol, N-methyl-2-pyrrolidone, dimethylsulfoxide, and mixtures thereof.

[0261] The composition may further comprise solubilizers such as polyoxyethylene castor oil derivatives, polysorbates, (caprylic / capric) glycerides, poloxamers, polyoxyethylene alkyl ethers, polyoxylglycerides, sorbitan fatty acid esters, polyoxyethylated 12-hydroxystearic acid, propylene glycol esters, polyglycerol esters, polyvinylpyrrolidone, cyclodextrins, polyethylene glycols, glyceryl stearate, caprylic glycerides, glyceryl monooleate, capric glycerides, alcohol ethoxylates, and mixtures thereof.

[0262] The compound of formula (I) can be used to prepare immersion baths with different concentrations of the compound of formula (I) to achieve the required dosing concentration. The stock solution can be diluted at least once before mixing with the water or can be poured directly into the volume of water for treatment of the fish.

[0263] The concentration of the compound during application to the fish depends on the type and duration of treatment, and also on the age and condition of the fish being treated. Typical immersion times range from about 15 minutes to about 4 hours, preferably from about 15 minutes to 2 hours, and more preferably from about 30 minutes to about 1 hour.

[0264] The compounds of formula (I) may be used in a water bath in a therapeutically effective amount or concentrations in water of from about 2 ppb to about 500 ppb; or from about 5 ppb to about 500 ppb; or from about 5 ppb to about 250 ppb; or from about 5 ppb to about 200 ppb; or from about 5 ppb to about 100 ppb; or from about 5 ppb to about 90 ppb; or from about 5 ppb to about 80 ppb; or from about 5 ppb to about 60 ppb; or from about 5 ppb to about 50 ppb; or from about 5 ppb to about 40 ppb; or from about 5 ppb to about 25 ppb, based on the total volume of water.

[0265] All effective concentrations are in ppb measured in the volume of water (fresh, salt, brackish) for treating fish against copepod crustacean species, especially fish lice. The concentration is achieved by adding a volume of concentrated stock solution of the compound of formula (I), for example 50mg / ml or 100mg / ml, to the container containing the fish. Those skilled in the art can determine how much compound stock solution should be added, based on knowledge of the volume of the container containing the fish and the concentration of the stock solution.

[0266] Medicated bait, premix The active compounds in these compositions are used either in pure form as solid active compounds, e.g. of a specific particle size, or preferably together with - at least - one adjuvant conventionally used in formulation technology, e.g. an extender, generally a solvent or a solid carrier or a surface-active compound (surfactant).

[0267] The compounds may be added to the feed by simple mixing as pure compounds, such as powders, in the usual manner, or may be mixed with edible, non-toxic, veterinarily acceptable excipients in the form of veterinary compositions, which may be included as premixes in the form of solutions or suspensions, granules, pellets.

[0268] In one embodiment of the present invention, the compound of formula (I) or a salt thereof is administered in medicinal fish bait.

[0269] Thus, another embodiment is a composition comprising one or more compounds of formula (I) and a veterinarily acceptable formulation adjuvant for oral administration via the feed.

[0270] A specific composition is a "premix" that facilitates mixing of a uniform, relatively small amount of active ingredient in / on the fish food (on a tonne basis).

[0271] Thus, one aspect of the present invention is a premix comprising nutrients, formulation supplements, and at least one compound of formula (I).

[0272] In one embodiment, the nutritional fish food is in the form of pellets mixed with or coated with a composition comprising one or more compounds of formula (I) as defined in claim 1. Such compositions may contain the compounds of formula (I) as a solution or in a specific form.

[0273] Another aspect of the present invention is a medicated fish feed comprising the composition or premix and a nutritional fish feed. Such feed is prepared by a commercial feed mill according to veterinarian instructions or based on a label and shipped to the fish farm. Alternatively, such medicated feed is prepared at the fish farm.

[0274] In one embodiment, the medicinal fish bait is administered daily for a period of 3 to 14 days.

[0275] In one embodiment of the invention, the compound of formula (I) or a salt thereof is orally administered at a daily dose of 1-10 mg / kg of fish organism, preferably at a daily dose of 3-7 mg / kg of fish organism and most preferably at a daily dose of about 5 mg / kg of fish organism.

[0276] In one embodiment, the total treatment period during which the compound of formula (I) or a salt thereof is administered is 3 to 14 days (about 2 weeks), in one embodiment 3 to 7 days, in another embodiment 5 to 14 days, in another embodiment 5 to 10 days (about one and a half weeks), and preferably 7 days. During the total treatment period, the compound of formula (I) or a salt thereof may be administered, for example, every day or once every two days. Preferably, it is administered every day. In a preferred embodiment, administration is every day for 7 days.

[0277] In a preferred embodiment, the compound of formula (I) or a salt thereof is orally administered at a daily dose of 1-10 mg / kg of fish organism weight for 3-14 days (about 2 weeks). In another preferred embodiment, the compound of formula (I) or a salt thereof is orally administered at a daily dose of 3-7 mg / kg of fish organism weight for 5-10 days. In a more preferred embodiment, the compound of formula (I) or a salt thereof is orally administered at a daily dose of about 5 mg / kg of fish organism weight for 7 days.

[0278] It is understood that the amount of compound administered to fish to achieve the desired effect may vary due to the advantageous non-toxic properties of the compound. In one embodiment, the compound is orally administered at about 0.005-5000 mg / kg, particularly 0.01-500 mg / kg (i.e. mg compound / kg fish body weight / day). Furthermore, the compound may be administered at relatively high doses, such as 0.01 mg / kg, 0.1 mg / kg, 1 mg / kg, more than (i.e. higher than) 10 mg / kg, or even more than 100 mg / kg. The duration of administration may be from a few hours or days up to several years.

[0279] Thus, oral administration includes administering a medicated fish food containing the compound of formula (I) to a fish population. The fish food is generally in the form of a granule or pellet. Common ingredients of said fish food granules or pellets include fish meal, fish oil, vegetable proteins, sugars and polysaccharides (including mannans, glucans and alginates). In addition, excipients such as pigments, vitamins, minerals and binders may also be included.

[0280] The compound of formula (I) or its salt may be incorporated into the feed prior to pelleting, or alternatively, the compound of formula (I) or its salt may be coated onto granules or pellets, either on its own or in the form of a premix, which may contain, in addition to the active compound, one or more veterinarily acceptable excipients, such as starch, fumed silica, microcrystalline cellulose, lactose, and preservatives.

[0281] The compound can be incorporated into the feed mixture before pelleting. However, it is preferred to coat pellets or granules with the compound of formula (I). For example, commercially available fish pellets or granules are coated with the compound of formula (I) using a solution in a veterinary acceptable solvent, or alternatively, suspended in a carrier or with a premix containing the compound of formula (I) and one or more veterinary acceptable excipients such as starch, fumed silica (Aerosil®), microcrystalline cellulose, lactose, etc. In addition, typical preservatives may be present.

[0282] The concentration of the compound of formula (I) in the premix may be chosen within wide limits; for example, concentrations of the compound of formula (I) of 0.001 to 90% w / w, preferably 1 to 50% w / w and more preferably 5 to 15% w / w, according to further embodiments 0.001 to 10% w / w, preferably 0.05 to 5% w / w and in particular 0.15 to 2.5% w / w, based in each case on the total weight of the premix, have proven to be useful.

[0283] The feed pellets can be coated with the premix by the dry top-coating method. For this purpose, the premix is ​​added to the pellets and the resulting mixture is stirred / mixed to distribute the compound of formula (I) evenly on the pellets. According to an alternative top-coating method with further oil processing, fish or vegetable oil is added to the product of the above dry top-coating method with continuous mixing until the pellets are completely coated. According to yet another embodiment, called the vacuum coating method, the premix is ​​first dissolved / suspended in fish or vegetable oil before being sprayed on the pellets under vacuum. A solution is preferred.

[0284] After addition of the active ingredient to the fish feed, the pellets or granules contain, for example, from about 0.0005 to about 5% (w / w), preferably from about 0.001 to about 2.5% (w / w) and in particular from about 0.0025 to about 1.25% (w / w) of a compound of formula (I), based on the total weight of the fish feed.

[0285] In one embodiment of the invention, the amount of compound of formula (I) or a salt thereof present in the fish feed premix composition is from about 5 to about 20% (w / w), preferably from about 10 to about 15% (w / w) and most preferably about 12.5% ​​(w / w), in each case based on the total weight of the premix.

[0286] combination The compounds and compositions may also be used in combination with one or more other physiologically active agents.

[0287] Thus, in one embodiment, the compound is co-administered with additional physiologically active agents. Such combinations are selected based on the condition to be treated, the cross-reactivity of the components, and the pharmacological properties of the combination. For example, multifunctional agents, such as multivalent vaccines, are preferred in the treatment of fish, and thus the composition can be administered with antigens that target bacterial or viral diseases. In one embodiment, the compound of formula (I) is co-administered with one or more antigens, and optionally the compound and antigen are administered with an adjuvant.

[0288] These compounds and compositions may be administered together or in the same course of treatment as the compounds and compositions described herein. By concomitant administration is meant that the individual components of the combination may be administered either sequentially or simultaneously in separate or combined veterinary compositions.

[0289] While administration of a compound of formula (I) generally provides only long-term control of fish lice infestations, said control may in certain circumstances be further improved by use of a compound of formula (I) in combination with another physiologically active agent.

[0290] Such physiologically active agents may be either another anti-parasitic drug, particularly a fish lice repellent; a vaccine component comprising an antibiotic or an immunostimulant; or a bait component containing an immunomodulatory agent.

[0291] Such combination treatment may be required where the fish are already infected with mature parasites prior to treatment with the compound of formula (I) or where rapid elimination of the parasites is desired.

[0292] Thus, in one embodiment, the compound of formula (I) is co-administered with at least one further physiologically active agent.

[0293] Suitable antiparasitic agents are, for example, hydrogen peroxide; formaldehyde; organophosphates such as trichlorfon, malathion, dichlorvos or azamethiphos; macrocyclic lactones such as ivermectin, emamectin benzoate or moxidectin; pyrethroids such as cypermethrin or deltamethrin; neonicotinoids such as imidacloprid, nitenpyram, thiamethoxam or thiacloprid; spinosyns such as spinosad; IGRs such as epofenonane, triplen, methoprene or lufenuron or carbamates such as fenoxycarb.

[0294] When the compounds of formula (I) are used in combination with another compound active in controlling fish lice, said combination partner is preferably an organophosphate, a pyrethroid such as cypermethrin or deltamethrin, a macrocyclic lactone such as emamectin benzoate; hydrogen peroxide; or a neonicotinoid such as imidacloprid or thiacloprid.

[0295] In another embodiment, the combination partner is one or more isoxazoline compounds known in the art.Isoxazoline active agents are highly effective against various ectoparasites, and their combination with the compound of formula (I) expands the spectrum of efficacy against these parasites.Particularly useful isoxazoline active agents that can be combined with the compound include afoxolaner (containing substantially pure active enantiomers), sarolaner, fluralaner (containing substantially pure active enantiomers) and lotilaner.

[0296] These active agents may be selected from the group consisting of those described in U.S. Pat. No. 7,964,204, U.S. Pat. Appl. Pub. No. 2010 / 0254960A1, U.S. Pat. Appl. Pub. No. 2011 / 0159107, U.S. Pat. Appl. Pub. No. 2012 / 0309620, U.S. Pat. Appl. Pub. No. 2012 / 0030841, U.S. Pat. Appl. Pub. No. 2010 / 0069247, WO 2007 / 125984, WO 2012 / 086462, U.S. Pat. Nos. 8,318,757, 8,466,115, 8,618,126, and the like. Nos. 8,822,466, 8,383,659, 8,853,186, 9,221,835, U.S. Patent Application Publication No. 2011 / 0144349, U.S. Patent No. 8,053,452; U.S. Patent Application Publication No. 2010 / 0137612; U.S. Patent No. 8,410,153, U.S. Patent Application Publication No. 2011 / 152081, WO 2012 / 089623, WO 2012 / 089622, U.S. Patent No. 8,119,671; U.S. Patent No. 7,947,715;International Publication No. 2102 / 120135, International Publication No. 2012 / 107533, International Publication No. 2011 / 157748, U.S. Patent Application No. 2011 / 0245274, U.S. Patent Application Publication No. 2011 / 0245239, U.S. Patent Application Publication No. 2012 / 0232026, U.S. Patent Application Publication No. 2012 / 0077765, U.S. Patent Application Publication No. 2012 / 0035122, U.S. Patent Application Publication No. 2011 / 0251247, WO 2011 / 154433, WO 2011 / 154434, U.S. Patent Application Publication No. 2012 / 0238517, U.S. Patent Application Publication No. 2011 / 0166193, WO 2011 / 104088, WO 2011 / 104087, WO 2011 / 104089, U.S. Patent Application Publication No. 2012 / 015946, U.S. Patent Application Publication No. 2009 / 0143410, WO US Patent Application Publication No. 2007 / 123855A2, US Patent Application Publication No. 2011 / 0118212, US Patent No. 7,951,828 and US Patent No. 7,662,972, US Patent Application Publication No. 2010 / 0137372A1, US Patent Application Publication No. 2010 / 0179194A2, US Patent Application Publication No. 2011 / 0086886A2, US Patent Application Publication No. 2011 / 0059988A1, US Patent Application Publication No. 2010 / 0179195A1 , U.S. Patent Publication No. 2015 / 0126523, WO 2010 / 003923, WO 2010 / 003877, WO 2010 / 072602, WO 2014 / 134236, WO 2017 / 147352, U.S. Patent Nos. 7,897,630 and 7,951,828, each of which is incorporated herein by reference in its entirety;

[0297] Another combination partner is 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2-methyl-5-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436). This compound is known as tigolaner.

[0298] For example, a suitable combination treatment of the compound of formula (I) and another fish lice control agent can be carried out by first treating fish, particularly salmon, with the compound of formula (I) according to the feeding method and regime as described above, and then, for example, 3 months, preferably 5 months, more preferably 6 months and especially 9 months after the end of the feeding treatment of the compound of formula (I), with a further fish lice control agent; said second treatment can be topical, for example, by medicated bath treatment, or oral, for example, by feeding treatment, or preferably by injecting the further fish lice control agent into the fish. According to a preferred embodiment of this combination treatment, the feeding treatment with the compound of formula (I) is carried out at the end of the freshwater stage of salmon evolution or at the beginning of their saltwater stage.

[0299] The further combination treatment comprises first treating the fish, especially salmon, with a further fish lice control agent, followed by a feed treatment of the compound of formula (I) according to the invention as described above, for example 1 hour to 2 months later, preferably 1 hour to 1 month later or especially 1 week to 1 month later. According to a preferred embodiment of this combination treatment, the treatment with the further fish lice control agent is a medicated bath treatment, feed treatment or injection treatment, which is carried out at the beginning of the seawater season, for example 1 hour to 3 months, preferably 6 hours to 2 months.

[0300] According to a further embodiment of the invention, the feeding treatment with the compound of formula (I) is combined with vaccination of fish against typical bacterial or viral infections. Typical bacterial diseases to be treated by vaccination are, for example, vibriosis, furunculosis, wound disease, atypical Aeromonas salmonicida, pisirickettsiosis or ERM / yersiniosis. Examples of viral diseases to be treated are pancreatic disease / PDV, infectious pancreatic necrosis / IPNV or infectious salmon anemia / ISAV. The vaccine is generally applied by bath or feeding treatment or preferably by injection. Vaccination can be performed either immediately before, during or after feeding treatment of the fish with the compound of formula (I).

[0301] According to this embodiment of the combination treatment, the first treatment is a bath treatment with the compound of formula (I) followed by a feed treatment with hexaflumuron or lufenuron, a compound of formula (I) or emamectin, which may provide continuous protection against fish lice. According to another embodiment of the combination treatment, the first treatment is a feed treatment with hexaflumuron or lufenuron, a compound of formula (I) or emamectin, which may provide continuous protection against fish lice, followed by a bath treatment with the compound of formula (I).

[0302] In another embodiment, the compound of formula (I) is administered in combination with vitamins to improve the health of the animal.

[0303] Evidence for fish louse resistance to chemotherapeutic drugs is abundant worldwide.

[0304] Surprisingly, compounds of formula (I) have been found to be effective for controlling fish lice populations that have been identified as resistant to commercially available fish lice chemotherapeutic drugs from the organophosphate class, macrocyclic lactones, particularly avermectins and pyrethroids, as indicated in the examples with ***.

[0305] The term "resistance" as used herein refers to the reduced efficacy of a compound compared to untreated parasites, particularly fish lice. The first appearance of this phenomenon was reported in Norway, where tolerance to organophosphates, particularly azamethiphos, increased to the point of complete loss of their effectiveness by the mid-1990s. Treatment failures associated with pyrethroids were subsequently reported in Norway, Scotland and Ireland. Subsequent analyses based on bioassays confirmed reduced susceptibility to deltamethrin and cypermethrin. Recent tests based on bioassays confirmed the low susceptibility of C. rogercresseyi to pyrethroids. It is therefore particularly important to have new effective compounds available that can effectively control such resistant parasite populations.

[0306] Thus, in one embodiment, fish lice infestations with parasites exhibiting resistance to macrocyclic lactones, organophosphates and / or pyrethroids are controlled, where fish lice have been found to be resistant to macrocyclic lactones, organophosphates and / or pyrethroid antiparasitic agents, hi one embodiment, such fish lice populations are resistant to one or more of emamectin, deltamethrin or organophosphates.

[0307] kit Another aspect of the invention is a kit comprising a compound of formula (I) or a composition as described above containing such a compound, and instructions for administration of the composition to fish.

[0308] In one embodiment, the kit comprises instructions for preparation of the premix and medicated fish bait as described above and / or instructions for administration of the medicated fish bait to a fish population to control fish lice infestations as described in more detail above.

[0309] In another embodiment, the kit includes instructions for preparation of a preservative solution as described above and medicated water for medicated bath treatment and / or instructions for immersion of fish to control fish lice infestation as described in more detail above.

[0310] Working Example The following compounds were prepared. The compounds were synthesized according to the methods described in WO2016168059 and WO2018073127. [ka]

[0311] [Table 11]

[0312] [Table 12]

[0313] [Table 13]

[0314] [Table 14]

[0315] [Table 15]

[0316] [Table 16]

[0317] [Table 17]

[0318]

Table 18

[0319]

Table 19

[0320]

Table 20

[0321]

Table 21

[0322]

Table 22

[0323]

Table 23

[0324]

Table 24

[0325]

Table 25

[0326]

Table 26

[0327]

Table 27

[0328]

Table 28

[0329] [Table 29]

[0330] [Table 30]

[0331] [Table 31]

[0332] [Table 32]

[0333] [Table 33]

[0334] [Table 34]

[0335] [Table 35]

[0336] [Table 36] [Brief description of the drawings]

[0337] [Figure 1-1] The structures of compounds 1000 to 1394 are shown. [Figure 1-2] (As stated above.) [Figure 1-3] (As stated above.) [Figure 1-4](As stated above.) [Figure 1-5] (As stated above.) [Figure 1-6] (As stated above.) [Figure 1-7] (As stated above.) [Figure 1-8] (As stated above.) [Figure 1-9] (As stated above.) [Figure 1-10] (As stated above.) [Figure 1-11] (As stated above.) [Figure 1-12] (As stated above.) [Figure 1-13] (As stated above.) [Figure 1-14] (As stated above.) [Figure 1-15] (As stated above.) [Figure 1-16] (As stated above.) [Figure 1-17] (As stated above.) [Figure 1-18] (As stated above.) [Figure 1-19] (As stated above.) [Figure 1-20] (As stated above.) [Figure 1-21] (As stated above.) [Figure 1-22] (As stated above.) [Figure 1-23] (As stated above.) [Figure 1-24] (As stated above.) [Figure 1-25] (As stated above.) [Figure 1-26] (As stated above.) [Figure 1-27] (As stated above.) [Figure 1-28] (As stated above.) [Figure 1-29] (As stated above.) [Figure 1-30] (As stated above.) [Figure 1-31] (As stated above.) [Figure 1-32] (As stated above.) [Figure 1-33] (As stated above.) [Figure 1-34] (As stated above.) [Figure 1-35] (As stated above.) [Figure 1-36] (As stated above.) [Figure 1-37] (As stated above.) [Figure 1-38] (As stated above.) [Figure 1-39] (As stated above.) [Figure 1-40] (As stated above.) [Diagram 1-41] (As stated above.) [Figure 1-42] (As stated above.) [Figure 1-43] (As stated above.) [Figure 1-44] (As stated above.) [Figure 1-45] (As stated above.) [Figure 1-46] (As stated above.) [Figure 1-47] (As stated above.) [Figure 1-48] (As stated above.) [Figure 1-49] (As stated above.) [Figure 1-50] (As stated above.) [Figure 1-51] (As stated above.) [Figure 1-52] (As stated above.) [Figure 1-53] (As stated above.) [Diagram 1-54] (As stated above.) [Figure 1-55] (As stated above.) [Diagram 1-56] (As stated above.) [Diagram 1-57] (As stated above.) [Diagram 1-58] (As stated above.) [Diagram 1-59] (As stated above.) [Figure 1-60] (As stated above.) [Figure 1-61] (As stated above.) [Figure 1-62] (As stated above.) [Fig.1-63] (As stated above.) [Fig.1-64] (As stated above.) [Figure 1-65] (As stated above.) [Figure 1-66] (As stated above.) [Figure 1-67] (As stated above.) [Figure 1-68] (As stated above.) [Figure 1-69] (As stated above.) [Figure 1-70] (As stated above.) [Diagram 1-71] (As stated above.) [Diagram 1-72] (As stated above.) [Diagram 1-73] (As stated above.) [Diagram 1-74] (As stated above.) [Diagram 1-75] (As stated above.) [Diagram 1-76] (As stated above.) [Diagram 1-77] (As stated above.) [Diagram 1-78] (As stated above.) [Diagram 1-79] (As stated above.)

[0338] Chromatographic system: Column: Xbridge BEH C18 Waters, 2.1x50mm, 2.5μ Oven: 40°C Eluent: Solvent A: Water / HCO 2 H (0.05%); Solvent B: acetonitrile / HCO 2 H(0.05%) Flow rate: 0.8ml / min gradient:

[0339] [Table 37]

[0340] Operation time: 2.2 minutes + 0.5 minutes Equilibration time

[0341] [Table 38] EXAMPLES

[0342] Example 1 Juvenile Fish Louse Contact Assay Copepodids (juvenile fish lice stage of Lepeophtheirus salmonis) were exposed to seawater spiked with decreasing concentrations of the test compounds (dissolved in DMSO-seawater mixtures) for approximately 24 hours of continuous exposure and fish lice inhibition (% of dead + damaged copepodids) was assessed. In the negative (solvent) control group, the vitality of the parasites used was confirmed.

[0343] Results: The following compounds showed ≧80% inhibition at a test concentration of 100 nM: (* indicates 100% inhibition) 1001*, 1003, 1005*, 1008*, 1010*, 1016*, 1018*, 1020*, 1021*, 1022, 1026*, 1028*, 1030, 1031*, 1034*, 1039*, 1040*, 1045*, 1046*, 1047*, 1048*, 1049*, 1051*, 1055, 1057*, 1058*, 1060*, 1064*, 1069*, 1075*, 1076, 1079*, 1080*, 1081*, 1082*, 1083*, 1085*, 1095*, 1098*, 1101*, 1109*, 1124*, 1126*, 1132*, 1139*, 1156*, 1161*, 1168, 1179, 1181*, 1194*, 1204*, 1207*, 1213*, 1214*, 1216*, 1223*, 1225*, 1227*, 1243*, 1246, 1248*, 1291*, 1340, 1349, 1373*, 1379*, 1380*, 1381*, 1382*, 1384*, 1387*, 1388*, 1394*.

[0344] The following compounds showed ≧80% inhibition at a test concentration of 10 nM: (* indicates 100% inhibition) 1000*, 1004, 1007, 1011*, 1038, 1041*, 1042*, 1091*, 1092*, 1099*, 1100*, 1366*, 1367*, 1368*, 1370*, 1371*, 1372*, 1378*, 1383*, 1385*, 1386, 1389*, 1391, 1392*, 1393*.

[0345] The following compounds showed ≧80% inhibition at a test concentration of 1 nM: (* indicates 100% inhibition) 1087*, 1090*, 1094*, 1097*.

[0346] The following compounds showed ≥80% inhibition at test concentrations between 0.1 nM and 0.01 nM: (* indicates 100% inhibition): 1376*.

[0347] Example 2: Adult fish louse contact assay Motile stages of fish lice (i.e. pre-adults and adults of Lepeophtheirus salmonis) were exposed to seawater spiked with decreasing concentrations of test compounds (dissolved in PEG-seawater mixtures). Fish lice inhibition (% of dead + injured fish lice) was assessed after approximately 1 and 24 hours of continuous exposure in comparison to a negative (solvent) control group.

[0348] Results: The EC50 for the following compounds was ≦25 nM and >10 nM: 1003, 1007, 1039, 1087, 1092, 1378, 1379.

[0349] The EC50 for the following compounds was ≦10 nM and >1 nM: 1041, 1042, 1090, 1091, 1094, 1097, 1098, 1099, 1100, 1101, 1366, 1367, 1368, 1370, 1371, 1372, 1380, 1383, 1385, 1387, 1388, 1391, 1394.

[0350] The following compounds had an EC50 of ≦1 nM: 1006, 1376, 1389, 1392, 1393.

[0351] Example 3: Adult Caligus rogercresseyi fish louse contact assay Motile stages of fish lice (i.e. Caligus rogercresseyi (pre)adults) were exposed to seawater spiked with decreasing concentrations of test compounds (dissolved in PEG-seawater mixtures). After approximately 24 and 48 hours of continuous exposure, fish lice inhibition (% of dead + injured fish lice) was assessed in comparison to negative (vehicle) and untreated controls.

[0352] Results: EC of compound 1097 50 was 0.072 ppb after 24 hours and 0.035 ppb after 48 hours.

[0353] Example 4: Fish Lice Resistance Assay Fish lice resistance assays were performed using motile fish lice stages (i.e. pre-adults, adults) of several Lepeophtheirus salmonis isolates with known resistance profiles (i.e. fully susceptible, resistant to azamethiphos (OP), emamectin benzoate (ML), deltamethrin (SP)). Fish lice were exposed to seawater spiked with decreasing concentrations of test compounds (dissolved in PEG300 / seawater mixtures). Fish lice inhibition (% of dead + injured fish lice) was assessed after approximately 24 and 48 hours of continuous exposure, compared to the negative (solvent) control group.

[0354] Results: Compound 1097 inhibited susceptible isolates (EC 50 after 24 hours) and multiresistant isolates (EC 50 was equally effective against 1.96 ppb after 12 h and 0.64 ppb after 48 h).

[0355] Salmon - in vivo efficacy against fish lice Example 5: Efficacy Testing Using Gavage Salmon (Salmo salar) were treated with a single oral gavage at a dose of 5 mg / kg body weight / fish (day 0). The formulation used was DMSO 5% / fish oil 95%. A negative control group of salmon received the formulation vehicle only.

[0356] Fish were infected with Lepeophtheirus salmonis copepodids twice before treatment (i.e., around days -28 and -3) and once after treatment (i.e., day 17).

[0357] On day 7, fish were examined under sedation and the (pre)adult fish lice on each fish were counted and removed (treatment efficacy against (pre)adult fish lice from day -28 infestation).

[0358] Around day 28 (end of animal phase), fish were euthanized and the lice on each fish were classified (pre-adult or juvenile stage) and counted. The number of pre-adult and juvenile parasite stages corresponding to each infection time point were used to calculate efficacy, i.e., to assess efficacy of treatment with juvenile fish lice from infection on day -3 and efficacy of prevention from reinfection on day 17.

[0359] Efficacy is expressed as the % reduction in fish lice in the treatment group versus the control group using the Abbott formula.

[0360] Results: The therapeutic efficacy of the following compounds was ≥ 80% against (pre)adult fish lice: (* indicates 100% effectiveness) 1039, 1041*, 1042*, 1087, 1092, 1094, 1097*, 1099, 1100*, 1366*, 1367, 1368, 1370*, 1371*, 1372*, 1376*, 1378*, 1380, 1392*, 1393*, 1394*.

[0361] The therapeutic efficacy of the following compounds against juvenile fish lice was ≥ 80%: (* indicates 100% effectiveness) 1039, 1041*, 1042*, 1092, 1099*, 1100*, 1366*, 1367*, 1368*, 1370*, 1371*, 1372*, 1376*, 1378*, 1380, 1392, 1393, 1394*.

[0362] The following compounds had preventive efficacy of ≥80% at day 17 reinfection: (* indicates 100% effectiveness) 1097*, 1367, 1370, 1378*.

[0363] Example 6: Efficacy test using dietary administration Four test groups of fish were used (one group for evaluation of therapeutic efficacy, one for evaluation of preventive efficacy and their respective controls). Commercial fish feed pellets were coated with the formulated test compounds. DMSO 5% / fish oil 95% was used as the formulation. Salmon (Salmo salar) were treated orally at 1 mg / kg fish biomass via the coated feed for 7 consecutive days. Salmon in the negative control group were fed only the feed coated with the formulation excipient.

[0364] Fish in the treatment group were infected with Lepeophtheirus salmonis copepodids twice (around days -28 and -3) before treatment.

[0365] On or around day 8, fish were examined under sedation and the (pre)adult fish lice on each fish were counted and removed (assessment of treatment efficacy against (pre)adult fish lice from infestation on or around day -28).

[0366] Around day 25, fish were euthanized and the (pre)adult fish lice counted on each fish (assessment of treatment efficacy against juvenile fish lice from around day -3 infestation).

[0367] At two week intervals, fish from the prophylactic group were infected at several time points after treatment.

[0368] Approximately 3 weeks after each reinfestation, the fish were assessed for (pre-)adult fish lice. At each assessment, all (pre-)adult fish lice were removed from the fish.

[0369] The number of fish lice on the fish corresponding to each reinfection time point was used to calculate the preventive efficacy.

[0370] Efficacy is expressed as the % reduction in fish lice in the treatment group versus the control group using the Abbott formula.

[0371] Results: 100% therapeutic efficacy against (pre)adult and juvenile fish lice was achieved for compound 1097. Preventive efficacy against reinfection after treatment was 100% (D14), 99.9% (D28) and 86.0% (D42).

Claims

[Claim 1] formula 【Chemistry 3】 and N-oxides, veterinarily acceptable acid addition salts, salt derivatives, solvates, ester derivatives, polymorphs, isotopes, stereoisomers and tautomers of the compound selected from the group consisting of: 【Table 1】 【Table 2】

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