Endoparasitic Depsipeptides

Patent metadata

Field	Value
Publication number	US-2020282016-A1
Application number	US-201816652136-A
Country	US
Kind code	A1
Filing date	Nov 28, 2018
Priority date	Nov 29, 2017
Publication date	Sep 10, 2020
Grant date	—

Abstract

wherein each of R1, R2, R3, R4, L1, and L2, are as defined herein. The present invention also contemplates compositions and methods of treatment as an endoparasiticide with a Formula (1) compound.

First claim

1 . A compound of Formula (1)

wherein
L 1 and L 2 are each individually and separately C 1 -C 4 alkylheteroaryl and C 1 -C 4 alkylheterocycle, wherein the heteroaryl moiety is a 5- or 6-member monocyclic aromatic ring or a 8- to 11-member fused aromatic ring each containing at least one heteroatom selected from N, O, and S; and the heterocycle moiety is a 4- to 6-member monocyclic saturated or partially saturated ring or a 8- to 11-member fused saturated or partially saturated ring, and wherein the heteroaryl and heterocycle moiety are N-linked to the alkyl;
and wherein the L 1 and L 2 alkyl moiety of the alkylheteroaryl and alkylheterocycle is optionally substituted with at least one substituent selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, and nitro; or at least two alkyl substitutions of each of the L 1 and L 2 alkyl moieties can join together to each form a C 3 -C 6 cycloalkyl ring;
or L 1 is absent;
and wherein the L 1 and L 2 heteroaryl and heterocycle moiety are each independently and separately optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are independently and separately optionally substituted with at least one substituent selected from hydroxyl, cyano, C 3 -C 6 cycloalkyl, —NR a R b , C 1 -C 4 alkoxy, morpholine, and phenyl; or halo, cyano, nitro, —NR a R b , oxo, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, saturated or partially saturated C 3 -C 6 cycloalkyl optionally substituted with at least one substituent selected from C 1 -C 3 alkyl, amino, cyano, halo, —OH, and C 1 -C 3 alkoxy; or phenyl optionally substituted with at least one substituent selected from halo, cyano, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy; or a saturated or partially saturated 4- to 6-membered heterocycle ring containing at least one heteroatom selected from N, O, and S and further optionally substituted with C 1 -C 4 alkyl; or a 5- to 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S and further optionally substituted with at least one substituent selected from halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 alkoxy; or —C(O)R, —COR, —C(O)OR, —CS(O) p R a , —C(O)NR a R b , —SR, —C(O)X, —OX, —S(O) p R, —S(O) p X, —CNR a C(O)R, CNR a C(O)OR, —CNR a R b , —CNH 2 (N)OH, —NR a C(O)R, —NR a C(O)OR, —NR a S(O) p R, —NR a C(O)NR a R b , —OR e —OR e NR a C(O)OR e , —OR e C(O)OH;
R is C 1 -C 6 alkyl, amino, C 1 -C 6 haloalkyl, phenyl optionally substituted with at least one substituent selected from C 1 -C 3 alkoxy, cyano, halo, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
R 1 , R 2 , R 3 , and R 4 are each separately and independently H and C 1 -C 6 alkyl;
R a and R b are each separately H, C 1 -C 6 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and phenyl optionally substituted with halo, amino, and C 1 -C 3 haloalkyl;
R e is C 1 -C 6 alkyl optionally substituted with halo, amino, C 3 -C 6 cycloalky, and C 1 -C 4 alkoxy;
X is an N-linked 4- to 6-membered saturated or partially saturated heterocyclic ring optionally containing at least one additional heteroatom selected from N, O, and S; or X is a 5- to 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S; or X is phenyl optionally substituted with at least one substituent selected from C 1 -C 4 haloalkyl, halo, amino, cyano, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy; or X is a saturated or partially saturated C 3 -C 6 cycloalkyl ring; and
p is the integer 0, 1, or 2, stereoisomers thereof, and veterinary acceptable salts thereof.

2 . A compound of Formula (1) of claim 1 that is a compound of Formula (1A1-1) or Formula (1A1-2)

stereoisomers thereof, and veterinary acceptable salts thereof.

3 . A compound of claim 2 that is a compound of Formula (1A1-2) stereoisomers thereof, and veterinary acceptable salts thereof.

4 . A compound of claim 2 that is a Formula (1A1-1) compound, stereoisomers thereof, and veterinary acceptable salts thereof.

5 . A compound of claim 4 , wherein each pyrazole is independently and separately optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, halo, cyano, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with at least one substituent selected from fluoro, chloro, methyl, and methoxy; C 1 -C 6 alkoxy, phenyl optionally substituted with at least one substituent selected from halo and methoxy; —C 1 -cyclopropyl, and C 2 -C 6 alkynl optionally substituted with cyclopropyl or phenyl, stereoisomers thereof, and veterinary acceptable salts thereof.

6 . A compound of claim 4 , that is a Formula (1A1-1) compound selected from any one of the compounds in Table 1b, stereoisomers thereof, and veterinary acceptable salts thereof.

7 . A compound of claim 6 that is a compound selected from the group consisting of:
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[(4-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)methyl]-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-chloro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8, 11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8, 11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(3-methylbut-1-yn-1-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(cycloprop

Assignees

• Zoetis Services Llc

Inventors

• Curtis Michael P
• Sheehan Susan M
• Kyne Graham M
• Bedore Matthew W
• Ewin Richard A
• Johnson Paul D
• Mctier Tom L
• Knauer Christoper S
• Vairagoundar Rajendran

Classifications

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title

• A61K38/15 Primary

  Depsipeptides; Derivatives thereof · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title