Isoxazoline oximes as antiparasitic agents

1. A compound of Formula (1)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, cyano, C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 alkoxy, C 0− C 6 alkyl C 3− C 6 cycloalkyl, and C 1− C 6 haloalkoxy;

R 2 is H, C 1− C 6 alkyl, C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, or C 0− C 6 alkyl heterocycle;

R 3 is H, C 1− C 6 alkyl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, C 2− C 6 alkenyl, C 0− C 6 alkyl phenyl, C 1− C 4 alkyl-O-phenyl, C 0− C 6 alkyl heterocycle, or C 0− C 6 alkyl heteroaryl;

each of R 2 and R 3 C 1− C 6 alkyl or C 0− C 6 alkylC 3− C 6 cycloalkyl can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R c , —SCN, or —C(O)NR a R b ; and

wherein R 2 and R 3 C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, or C 0− C 6 alkyl heterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR d , hydroxyl, C 1− C 6 alkoxy, C 1− C 6 alkyl, C 1− C 6 haloalkyl, —SH, —S(O) p R, C 1− C 6 haloalkoxy, Het, and phenyl;

R is C 1− C 6 alkyl or C 3− C 6 cycloalkyl each optionally substituted by at least one halo;

R a is hydrogen, C 1− C 6 alkyl, or C 0− C 3 alkylC 3− C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

R b is hydrogen, C 1− C 6 alkyl, C 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R;

or wherein R a and R b , with the N atom to which they are attached can form a 4-7 membered ring which may optionally include at least one additional heteroatom selected from N, O, and S;

R c is C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 haloalkylC 3− C 6 cycloalkyl, C 0− C 3 alkylC 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R b , —SCN, or —C(O)NR a R b ;

R d is hydrogen, C 1− C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1− C 6 alkoxy;

p is the integer 0, 1, or 2; and

is a bond that represents E and Z geometric isomers; stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

2. The compound of claim 1 wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, cyano, C 1− C 6 alkyl, C 1− C 6 haloalkyl, and C 0− C 6 alkyl C 3 -C 6 cycloalkyl.

3. The compound of claim 2 , wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, chloro, fluoro, bromo, cyano, C 1− C 6 alkyl, and C 1− C 6 haloalkyl; and

R 2 is H, C 1− C 6 alkyl, cyclopropyl, or C 1− C 6 alkyl substituted with halo.

4. The compound of claim 3 wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, chloro, fluoro, and C 1− C 6 haloalkyl; and

R 2 is H, C 1− C 6 alkyl, or —CF 3 .

5. The compound of claim 4 wherein

R 3 is H, C 1− C 6 alkyl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, or C 1− C 6 alkyl substituted with halo.

6. The compound of claim 5 wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, chloro, fluoro, and —CF 3 ;

R 2 is H, methyl, or —CF 3 , and

R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, —CH 2 CH 2 F, —CH 2 CF 3 , —CH 2 cyclopropyl, or —CH 2 CH 2 cyclopropyl.

7. A compound of claim 1 selected from

(E/Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(isopropoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)—N-(2-(tert-butoxyimino)ethyl)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(hydroxyimino)ethyl)-1-naphthamide;

(E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(hydroxyimino)propyl)-1-naphthamide;

(E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(methoxyimino)propyl)-1-naphthamide;

(E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(ethoxyimino)-3,3,3-trifluoropropyl)-1-naphthamide;

(E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(isopropoxyimino)propyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(hydroxyimino)ethyl)-1-naphthamide;

(Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)propyl)-1-naphthamide;

(E/Z)—N-(2-(ethoxyimino)ethyl)-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthamide;

(E/Z)—N-(2-(2-fluoroethoxyimino)ethyl)-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthamide;

(E/Z)—N-(2-(methoxyimino)ethyl)-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthamide;

(E/Z)-4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,4-difluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(ethoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-((2-fluoroethoxy)imino)ethyl)-1-naphthamide;

(E/Z)—N-(2-((cyclopropylmethoxy)imino)ethyl)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthamide;

(E/Z)-4-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide;

(E/Z)-4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide; and

(E/Z)-4-(5-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methoxyimino)ethyl)-1-naphthamide; stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

8. A composition comprising a therapeutic amount of a compound of Formula (1)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, cyano, C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 alkoxy, C 0− C 6 alkyl C 3− C 6 cycloalkyl, and C 1− C 6 haloalkoxy;

R 2 is H, C 1− C 6 alkyl, C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, or C 0− C 6 alkyl heterocycle;

R 3 is H, C 1− C 6 alkyl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, C 2− C 6 alkenyl, C 0− C 6 alkyl phenyl, C 1− C 4 alkyl-O-phenyl, C 0− C 6 alkyl heterocycle, or C 0− C 6 alkyl heteroaryl;

each of R 2 and R 3 C 1− C 6 alkyl or C 0− C 6 alkylC 3− C 6 cycloalkyl can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R c , —SCN, or —C(O)NR a R b ; and

wherein R 2 and R 3 C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, or C 0− C 6 alkyl heterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR d , hydroxyl, C 1− C 6 alkoxy, C 1− C 6 alkyl, C 1− C 6 haloalkyl, —SH, —S(O) p R, C 1− C 6 haloalkoxy, Het, and phenyl;

R is C 1− C 6 alkyl or C 3− C 6 cycloalkyl each optionally substituted by at least one halo;

R a is hydrogen, C 1− C 6 alkyl, or C 0− C 3 alkylC 3− C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

R b is hydrogen, C 1− C 6 alkyl, C 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R;

or wherein R a and R b , with the N atom to which they are attached can form a 4-7 membered ring which may optionally include at least one additional heteroatom selected from N, O, and S;

R c is C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 haloalkylC 3− C 6 cycloalkyl, C 0− C 3 alkylC 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R b , —SCN, or —C(O)NR a R b ;

R d is hydrogen, C 1− C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1− C 6 alkoxy;

p is the integer 0, 1, or 2; and

is a bond that represents E and Z geometric isomers, stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

9. The composition of claim 8 further comprising a pharmaceutically or veterinarily acceptable excipient, diluent, or carrier.

10. The composition of claim 9 further comprising at least one additional veterinary agent.

11. The composition of claim 10 wherein said additional veterinary agent is selected from the group consisting of eprinomectin, ivermectin, avermectin, abamectin, selamectin, doramectin, moxidectin, milbemycin oxime, an anthelmintic, DEET, derquantel, demiditraz, amitraz, fipronil, S-methoprene, pyriproxyfen, imidacloprid, indoxacarb, indoxacarb metabolites, metaflumizone, permethrin, amidoacetonitrile, pyrethrin, and spinosad, or mixtures thereof.

12. The composition of claim 11 wherein said additional veterinary agent is selected from ivermectin, avermectin, abamectin, selamectin, doramectin, moxidectin, or milbemycin oxime, and mixtures thereof.

13. The composition of claim 12 wherein said additional veterinary agent is selected from doramectin, moxidectin, milbemycin oxime, and mixtures thereof.

14. A method for the treatment of parasites in an animal comprising administering to said animal an effective amount of a compound of Formula (1)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, cyano, C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 alkoxy, C 0− C 6 alkyl C 3− C 6 cycloalkyl, and C 1− C 6 haloalkoxy;

R 2 is H, C 1− C 6 alkyl, C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, or C 0− C 6 alkyl heterocycle;

R 3 is H, C 1− C 6 alkyl, C 0− C 6 alkyl C 3− C 6 cycloalkyl, C 2− C 6 alkenyl, C 0− C 6 alkyl phenyl, C 1− C 4 alkyl-O-phenyl, C 0− C 6 alkyl heterocycle, or C 0− C 6 alkyl heteroaryl;

each of R 2 and R 3 C 1− C 6 alkyl or C 0− C 6 alkylC 3− C 6 cycloalkyl can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R c , —SCN, or —C(O)NR a R b ; and

wherein R 2 and R 3 C 0− C 6 alkyl phenyl, C 0− C 6 alkyl heteroaryl, or C 0− C 6 alkyl heterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR d , hydroxyl, C 1− C 6 alkoxy, C 1− C 6 alkyl, C 1− C 6 haloalkyl, —SH, —S(O) p R, C 1− C 6 haloalkoxy, Het, and phenyl;

R is C 1− C 6 alkyl or C 3− C 6 cycloalkyl each optionally substituted by at least one halo;

R a is hydrogen, C 1− C 6 alkyl, or C 0− C 3 alkylC 3− C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

R b is hydrogen, C 1− C 6 alkyl, C 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R;

or wherein R a and R b , with the N atom to which they are attached can form a 4-7 membered ring which may optionally include at least one additional heteroatom selected from N, O, and S;

R c is C 1− C 6 alkyl, C 1− C 6 haloalkyl, C 1− C 6 haloalkylC 3− C 6 cycloalkyl, C 0− C 3 alkylC 3− C 6 cycloalkyl, C 0− C 3 alkylphenyl, C 0− C 3 alkylheteroaryl, or C 0− C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1− C 6 alkoxy, C 1− C 6 haloalkoxy, C 1− C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R b , —SCN, or —C(O)NR a R b ;

R d is hydrogen, C 1− C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1− C 6 alkoxy;

p is the integer 0, 1, or 2; and

is a bond that represents E and Z geometric isomers, stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

15. The method of claim 14 wherein the compound is administered topically, orally, or by injection.

16. The method of claim 14 wherein said animal is a companion animal or livestock.

17. The method of claim 16 wherein the companion animal is a dog.

18. The method of claim 16 wherein livestock is bovine.

19. The method of claim 14 wherein the animal is a bird or fish.