IP Library › Granted Patent US 9,061,013

Granted Patent B2

US 9,061,013 · App. 14/005,943 · Granted Jun 23, 2015

Isoxazoline derivatives as antiparasitic agents

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Quick Facts

Patent No.: US 9,061,013
App. No.: 14/005,943
Granted: Jun 23, 2015
Kind: B2

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Abstract

This invention recites isoxazoline substituted derivatives of Formula (1) stereoisomers thereof, geometric isomers thereof, veterinarily acceptable salts 5 thereof, compositions thereof, and their use as a parasiticide in animals. The variables A, W, R 1a, R 1b, R 1c, R 2, R 3, R 5, and n are as described herein.

Claims (133)

1. A compound of Formula (1)

wherein

A is phenyl, naphthyl, or heteroaryl where said heteroaryl contains 1 to 4 heteroatoms each independently selected from N, O and S;

W is N or CR c ;

R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or —S(O) p R;

R 2 is halo, cyano, C 1 -C 6 alkyl, nitro, hydroxyl, —C(O)NH 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or —OR;

R 3 is —C(X)NR a R 4 or —NR a C(X)R 4 , where X is O, S, or NR 6 ;

R 4 is hydrogen, C 1 -C 6 alkyl, 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; wherein said phenyl, heteroaryl, and heterocycle moieties are optionally substituted with one or more substituents selected from cyano, halo, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 1 -C 6 haloalkoxy;

R 5 is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NH 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;

R 6 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, S(O) p R, or C 1 -C 6 alkoxy;

R and R′ are each independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

R a is hydrogen, C 1 -C 6 alkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C(O)R 4 , or C(O)OR; wherein the alkyl and alkylcycloalkyl moiety 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 of which may be optionally substituted with at least one halo;

R c is halo, hydroxyl, cyano, C 1 -C 5 alkyl, or C 1 -C 5 haloalkyl;

each of R, R 2 , R 3 , and R 4 C 1 -C 6 alkyl or C 0 -C 3 alkylC 3 -C 6 cycloalkyl can be optionally and independently substituted by one or more substituents selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl-, and C 1 -C 6 haloalkoxy, and wherein R 4 C 1 -C 6 alkyl and C 0 -C 3 alkylC 3 -C 6 cycloalkyl can be further optionally substituted by —S(O) p R b , —NR a R b , —NR a C(O)R b , —SC(O)R′, or —C(O)NR a R b ;

n is the integer 0, 1, or 2, and when n is 2, each R 2 may be identical or different from each other; and

p is the integer 0, 1, or 2;

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

2. The compound of claim 1 having Formula (2) or (6)

wherein

Y and Z are each independently C or N, and Y and Z are not both N;

stereoisomers thereof, and veterinarily acceptable salts thereof.

3. The compound of claim 2 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 2 is halo, cyano, C 1 -C 6 alkyl, or hydroxyl;

R 5 is trifluoromethyl; and

R a is hydrogen or C 1 -C 6 alkyl optionally substituted by cyano or at least one halo substituent;

stereoisomers thereof, and veterinarily acceptable salts thereof.

4. The compound of claim 3 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, cyano, or trifluoromethyl;

R 2 is halo, cyano, methyl, or hydroxyl;

R a is hydrogen, methyl, or ethyl; and

R 4 is C 1 -C 6 alkyl, 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; wherein said phenyl, heteroaryl, and heterocycle moieties are optionally substituted with one or more substituents selected from cyano, halo, hydroxyl, or C 1 -C 6 alkyl; and wherein the R 4 C 1 -C 6 alkyl or C 0 -C 3 alkylC 3 -C 6 cycloalkyl can be optionally and independently substituted by one or more substituents selected from cyano, halo, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —S(O) p R b , —C(O)NR a R b , —NR a C(O)R b , and hydroxyC 1 -C 6 alkyl-;

stereoisomers thereof, and veterinarily acceptable salts thereof.

5. The compound of claim 4 wherein

Y and Z are both carbon;

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, or trifluoromethyl;

R a is hydrogen or methyl;

R 4 is C 1 -C 6 alkyl or C 0 -C 3 alkylC 3 -C 6 cycloalkyl, each optionally substituted by one or more substituents selected from halo, hydroxyl, C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl-, —C(O)NR a R b , —NR a C(O)R b , and —S(O) p R b ; and

n is the integer 0;

stereoisomers thereof, and veterinarily acceptable salts thereof.

6. The compound of claim 1 having Formula (7) or (11)

wherein

Y and Z are each independently C or N, and Y and Z are not both N,

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

7. The compound of claim 6 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 2 is halo, cyano, C 1 -C 6 alkyl, or hydroxyl;

R 5 is trifluoromethyl;

R a is hydrogen or C 1 -C 6 alkyl optionally substituted by cyano or at least one halo substituent; and

R c is halo, hydroxyl, cyano, or C 1 -C 5 haloalkyl;

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

8. The compound of claim 7 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, cyano, or trifluoromethyl;

R 2 is halo, cyano, methyl, or hydroxyl;

R a is hydrogen, methyl, or ethyl;

R c is halo, hydroxyl, or trifluoromethyl; and

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

9. The compound of claim 8 wherein

Y and Z are both carbon;

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, or trifluoromethyl;

R a is hydrogen or methyl;

R c is fluoro, chloro, hydroxyl, or trifluoromethyl;

n is the integer 0;

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

10. A compound selected from the group consisting of

3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (2,2,2-trifluoro-ethyl)-amide;

3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid cyclopropylamide;

3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid methylamide;

3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid dimethylamide;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid cyclopropylamide;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (2,2,2-trifluoro-ethyl)-amide;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid methylamide;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid dimethylamide;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid;

3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethylamide;

3-fluoro-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanecarboxamide;

1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid cyclopropylamide;

1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methylamide;

1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (2,2,2-trifluoro-ethyl)amide;

1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}azetidine-3-carboxylic acid dimethylamide;

1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid methylamide;

1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (2,2,2-trifluoro-ethyl)-amide;

1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid cyclopropylamide;

1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid dimethylamide;

N-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutyl)cyclopropanecarboxamide; and

N-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutyl)-2-(methylsulfonyl)acetamide;

stereoisomers thereof, geometric isomers thereof, and veterinarily acceptable salts thereof.

11. A pharmaceutical or veterinary composition comprising a therapeutic amount of a compound of Formula (1)