Spiroindoline Antiparasitic Derivatives

Patent metadata

Field	Value
Publication number	US-2016296499-A1
Application number	US-201415102384-A
Country	US
Kind code	A1
Filing date	Dec 22, 2014
Priority date	Dec 24, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

The invention describes novel spiropiperidines of Formula (1A), (1B), and (1C) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, processes for making, and their use in animals as an antiparasitic. The variables A, R 1 , R 2 , R 3 , R 4 , v, m, 5, and n are as described herein.

First claim

We claim:

1 . A compound of Formula (1A), Formula (1B), and Formula (1C)

wherein
A is a 5- or 6-membered partially saturated or saturated heterocyclic ring, or a 5- to 6-membered heteroaryl ring, or a 5- to 6-membered partially saturated or saturated carbocyclic ring, wherein the heterocyclic and heteroaryl ring each contain at least 1 to 3 heteroatoms selected from N, O, or S;
v is CH or N, wherein only one of v can be N;
R 1 is selected from the group consisting of C 0 -C 3 alkylaryl, C 0 -C 3 alkylheteroaryl, C 0 -C 3 alkylcycloalkyl, C 0 -C 3 alkylheterocycle, C 2 -C 4 alkenylaryl, C 2 -C 4 alkenylheteroaryl, C 2 -C 4 alkenylcycloalkyl, and C 2 -C 4 alkenylheterocycle; wherein each cycloalkyl, aryl, heteroaryl, or heterocycle R 1 moiety is individually and optionally substituted with at least one substituent selected from the group consisting of cyano, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, and heterocycle, wherein said R 3 cycloalkyl, aryl, heteroaryl, and heterocycle moieties are each individually and optionally substituted with at least one substituent selected from the group consisting of halo, hydroxyl, —NR 5 R 6 , nitro, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and isoxazole, wherein the isoxazole can be further substituted with at least one methyl;
R 4 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, C 3 -C 6 cycloalkyl, NR 5 R 6 , S(O) 2 CF 3 , S(O) 2 CH 3 , SCF 3 , SF 5 , nitro, phenyl, pyridin-2(1H)-one, heterocycle, and heteroaryl, and wherein the phenyl and heteroaryl moieties can be further optionally substituted with at least one substituent selected from the group consisting of halo, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
R 5 and R 6 are each independently selected from selected from H and C 1 -C 6 alkyl;
m is the integer 1, 2, 3, or 4;
n is the integer 0, 1, 2, 3, or 4, and when n is 2, 3, or 4, each R 4 may be identical or different from each other;

stereoisomers thereof, and veterinary acceptable salts thereof, with the proviso that when n is the integer 1, then R 4 is not fluoro or chloro at ring position 5 of Formula (1C); stereoisomers thereof, and veterinary acceptable salts thereof.

2 . The compound of claim 1 wherein ring A is selected from the group consisting of

wherein the broken line (----) represents the point of attachment.

3 . The compound of claim 2 that is a Formula (1A) compound, wherein
R 1 is C 2 alkenylphenyl, C 2 alkenylpyridinyl, or quinolinyl, each individually and optionally substituted with at least one substituent selected from the group consisting of cyano, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; and
R 2 is hydrogen; stereoisomers thereof, and veterinary acceptable salt thereof.

4 . A compound of claim 3 selected from the group consisting of:
(E)-N-((2-chloropyridin-4-yl)methyl)-1′-(3-(3,4-dichlorophenyl)allyl)-6,8-dihydrospiro[furo[3,4-g]indole-3,4′-piperidine]-1(2H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(3,4-dichlorophenyl)allyl)-2′,3′-dihydrospiro[piperidine-4,9′-[1,4]dioxino[2,3-e]indole]-7′(8′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(pyridin-4-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(pyrimidin-2-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-benzyl-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(4-fluorobenzyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(4-nitrobenzyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(4-hydroxybenzyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(pyrazin-2-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-(4-chlorobenzyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chlorothiazol-5-yl)methyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(thiazol-5-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(thiazol-2-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(thiazol-4-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-(cyclohexylmethyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(oxazol-4-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(oxazol-5-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-isobutylspiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-(cyclopropylmethyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-(cyclopentylmethyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(+/−)(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-((tetrahydrofuran-2-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(+/−)(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-((tetrahydrofuran-3-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(pyridin-3-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(3,4-dichlorophenyl)allyl)-N-(pyridazin-4-ylmethyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(4-fluorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(3,4-dichlorophenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(4-methoxyphenyl)allyl)spiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-1-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-2′-methylspiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-1-(3-(4-fluorophenyl)allyl)-2′-methylspiro[piperidine-4,8′-thiazolo[4,5-e]indole]-6′(7′H)-carboxamide;
(E)-N-((2-chloropyridin-4-yl)methyl)-2′-me

Assignees

• Zoetis Services Llc

Inventors

• Wendt John Adam
• Cox Mark
• Sheehan Susan M K
• Curtis Michael P
• Respondek Tomasz
• Ewin Richard Andrew
• Kyne Graham M
• Johnson Paul D

Classifications

• A01N43/90

  having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system · CPC title

• C07D471/20

  Spiro-condensed systems · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• A61P33/00

  Antiparasitic agents · CPC title