Spirocyclic derivatives as antiparasitic agents
View Patent ↗The invention recites spirocyclic derivatives of Formula (V.1) or (V.2), stereoisomers thereof, veterinary acceptable salts thereof, compositions thereof, processes for making, and their use as a parasiticide for an animal. The variables A, B, V, Z, Y, W 1 , W 2 , W 3 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , n, and “ - - - ” are as described herein.
1. A compound of Formula (V.1) or Formula (V.2)
wherein
Y and Z are each independently C or N;
W 1 , W 2 , and W 3 are each independently C or N;
V is C, N, O, or S;
A taken together with Y and Z or V, Y, and Z is a 5- to 7-membered partially saturated or saturated carbocyclic or heterocyclic ring where the heterocyclic ring contains at least 1 to 3 heteroatoms selected from N, O, or S, and where ring A is optionally substituted with at least one substituent selected from oxo, ═S, ═NR 7 , halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy;
B is
wherein “ ” represents the point of attachment;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, hydroxyl, 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, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR;
R 3 is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 7 )R 5 , —C(NR 7 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 7 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy;
R 8 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, —S(O) p R c , or C 1 -C 6 alkoxy;
R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent;
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;
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, —SON, or —C(O)NR a R b ;
each of R 4 and R 5 C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety 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, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —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, —SON, or —C(O)NR a R b ; and
wherein each of R 4 and R 5 C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 7 , hydroxyl, C 1 -C 6 alkoxy, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy;
n is the integer 0, 1, or 2, and when n is 2, each R 2 may be identical or different from each other;
p is the integer 0, 1, or 2; and
“ ” is a single or double bond;
stereoisomers thereof, and veterinary acceptable salts thereof.
2. A composition comprising a therapeutic amount of a compound of Formula (V.1) or (Formula V.2) of claim 1 , and further comprising a veterinary acceptable excipient, diluent, carrier, or mixture thereof.
3. The compound of Formula (V.1) of claim 1 having Formula (V.1.2)
wherein X and W are each independently —O—, —S(O) p —, —NR 6 , —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—, and when X is —O—, —S(O) p —, or —NR 6 , then W is —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—, and when W is —O—, —S(O) p —, or —NR 6 , then X is —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—; and R 6 is hydrogen, C 1 -C 6 alkyl, hydroxyl, or C 1 -C 6 alkoxy; stereoisomers thereof, and veterinary acceptable salts thereof.
4. The compound of claim 3 having Formula (2.2)
wherein X is —O— or —S(O) p —; stereoisomers thereof, and veterinary acceptable salts thereof.
5. The compound of claim 4 wherein
X is —O—;
n is the integer 0;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
R 3 is C 1 -C 6 haloalkyl; and
R 4 is —C(O)R 5 , stereoisomers thereof, and veterinary acceptable salts thereof.
6. The compound of claim 5 wherein R 1a , R 1b , and R 1c are each independently hydrogen, halo, or C 1 -C 6 haloalkyl; and
R 3 is CF 3 , stereoisomers thereof, and veterinary acceptable salts thereof.
7. The compound of Formula (V.1) of claim 1 having Formula (V.1.6)
wherein X and W are each independently —O—, —S(O) p —, —NR 6 , —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—, and when X is —O—, —S(O) p —, or —NR 6 , then W is —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—, and when W is —O—, —S(O) p —, or —NR 6 , then X is —CH 2 —, —C(O)—, —C(NR 7 )—, or —C(S)—; and R 6 is hydrogen, C 1 -C 6 alkyl, hydroxyl, or C 1 -C 6 alkoxy, stereoisomers thereof, and veterinary acceptable salts thereof.
8. The compound of claim 7 having Formula (6.2)
wherein X is —O— or —S(O) p —; stereoisomers thereof, and veterinary acceptable salts thereof.
9. The compound of claim 8 wherein X is —O—;
n is the integer 0;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
R 3 is C 1 -C 6 haloalkyl;
R 4 is —C(O)R 5 ; and
R 5 is hydrogen or C 1 -C 6 alkyl, stereoisomers thereof, and veterinary acceptable salts thereof.
10. The compound of Formula (V.1) of claim 1 having Formula (3.2), (4.2), or (5.2)
wherein X is —O—;
n is the integer 0;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
R 3 is C 1 -C 6 haloalkyl; and
R 4 is —C(O)R 5 , stereoisomers thereof, and veterinary acceptable salts thereof.
11. A compound of claim 1 of Formula (V.1) selected from:
2-(methylsulfonyl)-1-(5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)ethanone;
2-methyl-1-(5-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)propan-1-one;
1-(5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
1-(5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one;
1-(5-(3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
5′-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-1-isobutyryl-3′H-spiro[azetidine-3,1′-[2]benzofuran];
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl) ethanone;
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-1-methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one;
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-1-methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one;
1-(5′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)propan-1-one;
1-(5′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one hydrochloride;
2-(methylsulfonyl)-1-(5′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)ethanone hydrochloride;
1-(5′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)methylsulfonylyethanone;
5′-[3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1yl]-1-isobutyryl-3′H-spiro[azetidine-3,1′-[2]benzofuran;
1-(5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
5′-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine-1-yl]-1-[(methylsulfonyl)acetyl]-3′H-spiro[azitidine-3,1′-[2]benzofuran];
5′-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1yl]-1-isobutyryl-3′H-spiro[azetidine-3,1′-[2]benzofuran;
1-isobutyryl-5′-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1yl]-3′H-spiro[azetidine-3,1′-[2]benzofuran;
5′-[3-(3,4,5-trichloro)-3-(trifluoromethyl)pyrrolidin-1-yl]-1-[(methylsulfonyl)acetyl]-3′H-spiro[azetidine-3,1′-[2]benzofuran];
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one;
1-(5′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone;
1-(5′-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-methylpropan-1-one;
1-(5′-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)propan-1-one; and
2-(methylsulfonyl)-1-(5′-(5-(3,4,5-trichlorophenyl)-5-(trifluoro methyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)ethanone, stereoisomers thereof, and veterinary acceptable salts thereof.
12. A composition comprising a compound of Formula (V.1.2), (V.1.3), (V.1.4), (V.1.5), or Formula (V.1.6)
wherein
X is —O— and W is —CH 2 —;
W 1 , W 2 , and W 3 are each independently C or N;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, hydroxyl, 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, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR;
R 3 is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 7 )R 5 , —C(NR 7 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 7 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy;
R 8 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, —S(O) p R c , or C 1 -C 6 alkoxy;
R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent;
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;
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, —SON, or —C(O)NR a R b ;
each of R 4 and R 5 C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety 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, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —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, —SON, or —C(O)NR a R b ; and
wherein each of R 4 and R 5 C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 7 , hydroxyl, C 1 -C 6 alkoxy, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy;
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, and veterinary acceptable salts thereof, and further comprising an acceptable veterinary acceptable excipient, diluent, carrier, or mixture thereof, and optionally, comprising at least one additional veterinary agent.
13. A method of treating a parasitic infection in an animal, comprising administering a therapeutically effective amount of a compound of Formula (V.1) or Formula (V.2)
wherein
Y and Z are each independently C or N;
W 1 , W 2 , and W 3 are each independently C or N;
V is C, N, O, or S;
A taken together with Y and Z or V, Y, and Z is a 5- to 7-membered partially saturated or saturated carbocyclic or heterocyclic ring where the heterocyclic ring contains at least 1 to 3 heteroatoms selected from N, O, or S, and where ring A is optionally substituted with at least one substituent selected from oxo, ═S, ═NR 7 , halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy;
B is
wherein “ ” represents the point of attachment;
R 1a , R 1b , and R 1c are each independently hydrogen, halo, hydroxyl, 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, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR;
R 3 is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 7 )R 5 , —C(NR 7 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;
R 7 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy;
R 8 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, —S(O) p R c , or C 1 -C 6 alkoxy;
R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent;
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;
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, —SON, or —C(O)NR a R b ;
each of R 4 and R 5 C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety 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, C 1 -C 6 alkyl, hydroxylC 1 -C 6 alkyl-, —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, —SON, or —C(O)NR a R b ; and
wherein each of R 4 and R 5 C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, ═NR 7 , hydroxyl, C 1 -C 6 alkoxy, hydroxylC 1 -C 6 alkyl-, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy;
n is the integer 0, 1, or 2, and when n is 2, each R 2 may be identical or different from each other;
p is the integer 0, 1, or 2; and
“ ” is a single or double bond;
stereoisomers thereof, and veterinary acceptable salts thereof, to treat a parasitic infection or infestation in an animal.
14. A compound of claim 1 selected from a compound of Formula, (2.2A), (3.2A), (4.2A), (5.2A), or (6.2A),
wherein
R 1a and R 1c are both Cl;
R 1b is H, Cl, or F;
R 5 is selected from the group consisting of methyl, ethyl, propyl, isobutyl, —CH 2 cyclopropyl, —CH 2 cyclobutyl, —CH 2 cyclopropyl, —CH 2 cyclobutyl, —CH 2 CF 3 , —CH 2 SCH 3 , —CH 2 S(O) CH 3 , —CH 2 S(O) 2 CH 3 , thietan-3-yl, 1-oxidothietan-3-yl, 1,1-dioxidothietan-3-yl, 1-cyclopropanol-1-yl, 1-trifluoromethylcyclopropan-1-yl, 1H-pyrazol-1-ylmethyl, 3-methyl-1H-pyrazol-1-ylmethyl, 1,1-difluorocycloprop-2-yl, and pyridin-2-ylmethyl;
R 8 is H or methyl, and
stereoisomers thereof, and veterinary acceptable salts thereof.
15. The method of claim 13 wherein said animal is a companion animal or livestock.
16. The method of claim 15 wherein said companion animal is a cat or dog and wherein said livestock is cattle.
17. The method of claim 13 wherein the therapeutically effective amount of a compound of Formula (V.1) or (V.2) is administered orally, topically, or by injection.