Ubiquitin ligase inhibitors
View Patent ↗This invention describes compounds useful as ubiquitin ligase inhibitors. The compounds of the invention are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved. The invention also provides for pharmaceutical compositions comprising the compounds described in the invention for the treatment of conditions that require inhibition of ubiquitin ligases. Furthermore, the invention provides for methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a compound according to the invention.
1. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from CF 3 -phenyl, 1-chloro-4-fluorophenyl, 2,4-difluorophenyl, 3,5-dichlorophenyl;
R 2 is H, C 1 -C 6 -hydrocarbyl, or aryl;
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl; and
Y is —O—, —S—, —S(O)—, or —SO 2 —;
wherein each of the aryl, and hydrocarbyl group of R 2 is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 ; and
provided that the compound is not the following combination:
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
R 9
3,5-dichlorophenyl
H
Cl
Cl
NO 2
H
Cl
H
H.
2. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 together with the nitrogen atom to which they are both attached form a piperidinyl which is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 4 -hydrocarbyl-C(O)—, oxo, C 1 -C 3 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 3 -hydrocarbyl-O—, C 1 -C 3 -hydrocarbyl, mono- to per-halogenated C 1 -C 3 -hydrocarbyl, aryl-O—, —CN, —NO 2 , or —SO 2 ;
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F; and
Y is —O—, —S—, —S(O)—, or —SO 2 —.
3. The compound according to claim 2 wherein the piperidinyl is 3,5-dimethylpiperidinyl.
4. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 3 -hydrocarbyl-C(═NH)- which is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 4 -hydrocarbyl-C(O)—, oxo, C 1 -C 3 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 3 -hydrocarbyl-O—, C 1 -C 3 -hydrocarbyl, mono- to per-halogenated C 1 -C 3 -hydrocarbyl, aryl-O—, —CN, —NO 2 , or —SO 2 ;
R 2 is H, C 1 -C 6 -hydrocarbyl, or aryl;
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl; and
Y is —O—, —S—, —S(O)—, or —SO 2 —;
wherein each of the aryl, and hydrocarbyl group of R 2 is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 ;
provided that the compound is not one of the following combinations:
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
R 9
H
Cl
Cl
NO 2
H
Cl
H
H.
5. The compound according to claim 4 wherein R 1 is CH 3 —C(═NH)—.
6. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 4 -C 10 -hydrocarbyl-NH—CO—C 6 H 4 - which is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 4 -hydrocarbyl-C(O)—, oxo, C 1 -C 3 -hydrocarbyl-(O)—, mono- to per-halogenated C 1-3 -hydrocarbyl-O—, C 1 -C 3 -hydrocarbyl, mono- to per-halogenated C 1 -C 3 -hydrocarbyl, aryl-O—, —CN, —NO 2 , or —SO 2 ;
R 2 is H, C 1 -C 6 -hydrocarbyl, or aryl;
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl; and
Y is —O—, —S—, —S(O)—, or —SO 2 —;
wherein each of the aryl, and hydrocarbyl group of R 2 is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 .
7. The compound according to claim 4 wherein R 1 is cyclopropyl-CH 2 —NH—CO-phenyl.
8. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
—CH 3
CH 3 CH 2 —
HC≡C—C(CH 3 ) 2 —
CN—(CH 2 ) 2 —
R 2 is H, C 1 -C 6 -hydrocarbyl, or aryl;
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl; and
Y is —O—, —S—, —S(O)—, or —SO 2 —;
wherein each of the aryl, and hydrocarbyl group of R 2 is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 ; and
provided that the compound is not one of the following combinations:
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
R 9
H
Cl
Cl
NO 2
H
Cl
H
H
H
Cl
Cl
NO 2
H
Cl
H
H
H
Cl
H
NO 2
H
Cl
H
H
3,5-dichlorophenyl
H
Cl
Cl
NO 2
H
Cl
H
H
3-chloro,4-fluorophenyl
H
Cl
Cl
NO 2
H
Cl
H
H
cyclohexyl
H
H
H
NO 2
H
H
H
H
CH 3
H
H
H
NO 2
H
H
H
H.
9. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1-6 -hydrocarbyl, C 5 -C 12 -heterocyclyl-C 0 -C 6 -hydrocarbyl, aryl-C 1 -C 6 -hydrocarbyl, C 5 -C 12 -heteroaryl-C 0 -C 6 -hydrocarbyl, —C(═X)-L 1 -R 10 , C 4 -C 10 -hydrocarbyl-NH—C(O)—C 6 H 4 —, aryl-oxy-C 1 -C 6 -hydrocarbyl-, aryl-oxy-aryl-SO 2 —, (CH 3 ) 2 N—C 1 -C 6 -hydrocarbyl, (NH 2 )(NH)C—NH—(CH 2 ) 3 —CH(NH 2 CO)—, or ═C(R 13 )(R 14 );
X is ═O, ═S, or ═NH;
L 1 is a covalent bond, —NH—, —O—, —S—, or C 1 -C 3 -hydrocarbyl;
R 10 is —C 1 -C 6 -hydrocarbyl, C 5 -C 12 -heterocyclyl, aryl, or C 5 -C 12 -heteroaryl;
R 2 is selected from H—, —CH 3 , —Cl, CH 3 CH 2 —,
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl; and
Y is —O—, —S—, —S(O)—, or —SO 2 —;
wherein each of the aryl, heterocyclyl, and hydrocarbyl group of R 1 is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 ; and
provided that the compound is not one of the following combinations:
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
R 9
H
Cl
Cl
NO 2
H
Cl
H
H
H
Cl
Cl
NO 2
H
Cl
H
H
H
Cl
H
NO 2
H
Cl
H
H
—CH 3
NO 2
H
NO 2
H
H
H
H
—CH 3
—CH 3
Cl
H
NO 2
H
H
H
H
H
H
H
NO 2
H
H
H
H
3,5-dichlorophenyl
H
Cl
Cl
NO 2
H
Cl
H
H
3-chloro,4-fluorophenyl
H
Cl
Cl
NO 2
H
Cl
H
H
cyclohexyl
H
H
H
NO 2
H
H
H
H
CH 3
CH 3
H
H
NO 2
H
H
H
H
CH 3
H
H
H
NO 2
H
H
H
H
CH 3 CH 2
CH 3
Cl
Cl
NO 2
H
H
H
H
CH 3 C═O
H
H
H
NO 2
H
H
H
H.
10. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 together with the nitrogen to which they are both covalently bound form a moiety selected from
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F; and
Y is —O—, —S—, —S(O)—, or —SO 2 —.
11. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 together are
R 3 is —H, —Cl, or —NO 2 ;
R 4 is —H, —Cl, or —NO 2 ;
R 5 is —H or —NO 2 ;
R 6 is —H or —Cl;
R 7 is —H or —Cl;
R 8 is —H or —Cl;
R 9 is —H or —F; and
Y is —O—, —S—, —S(O)—, or —SO 2 —.
12. A compound selected from:
4-(2-chloro-6-nitrophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
4-{[4-(2-chloro-6-nitrophenoxy)phenyl]sulfonyl}morpholine;
{3-chloro-2-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}amine;
4-(2-amino-6-chlorophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
N-{3-chloro-2-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}-2,2,2-trifluoroacetamide;
4-(2-chloro-6-nitrophenoxy)-N-(1-phenylethyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide;
4-(2-chloro-6-nitrophenoxy)-N-(1,1-dimethylpropyl)benzenesulfonamide;
N-(3-aminopropyl)-4-(2-chloro-6-nitrophenoxy)-N-methylbenzenesulfonamide;
4-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}morpholine;
1-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}piperidine;
1-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}pyrrolidine;
4-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}-2,6-dimethylmorpholine;
3,5-dichloro-N-(3-chloro-4-fluorophenyl)-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,4-difluorophenyl)benzenesulfonamide;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-3,5-dimethylpiperidine;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,5-dichlorophenyl)benzenesulfonamide;
4-chloro-N-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}benzene-carboximidamide;
2-chloro-N-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}ethanimidamide;
N-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}pyridine-3-carboximidamide;
N-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}pyridine-4-carboximidamide;
N-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}ethanimidamide;
4-(2-chloro-6-nitrophenoxy)benzenesulfonamide;
4-(2-chloro-6-nitrophenoxy)-N-[(1E)-(dimethylamino)methylene]benzenesulfonamide;
4-(2-chloro-6-nitrophenoxy)-N-(1,1-dimethylpropyl)benzenesulfonamide;
N-(3-aminopropyl)-4-(2-chloro-6-nitrophenoxy)-N-methylbenzenesulfonamide;
4-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}morpholine;
1-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}piperidine;
1-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}pyrrolidine;
4-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}-2,6-dimethylmorpholine;
4-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}morpholine;
3,5-dichloro-N-(3-chloro-4-fluorophenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,4-difluorophenyl)benzenesulfonamide;
4-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-2,6-dimethylmorpholine;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-4-methylpiperidine;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-3,5-dimethylpiperidine;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}piperidine;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}pyrrolidine;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,5-dichlorophenyl)benzenesulfonamide;
3,5-dichloro-N-(3-chloro-2-methylphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{[(3,4-dichlorophenyl)amino]carbonothioyl}benzene sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[(1Z)-[(4-chlorophenyl)amino](hydroxy-amino)methylene]benzenesulfonamide;
N-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}pyridine-4-carboximidamide;
2-chloro-N-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}ethanimidamide;
4-chloro-N-{[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl}benzenecarboximidamide;
N-(3-bromophenyl)-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-phenylbenzenesulfonamide;
{2-chloro-6-[4-(morpholin-4-ylsulfonyl)phenoxy]benzyl}amine;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-(4-chlorobenzyl)benzenesulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-benzyl-N-methylbenzenesulfonamide;
{2-[4-(morpholin-4-ylsulfonyl)phenoxy]-1,3-phenylene}dimethanamine;
4-[2,6-bis(aminomethyl)phenoxy]-N-phenylbenzenesulfonamide;
4-(2-chloro-6-nitrophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
p4-{[4-(2-chloro-6-nitrophenoxy)phenyl]sulfonyl}morpholine;
3-chloro-2-[4-(morpholin-4-ylsulfonyl)phenoxy]aniline;
4-(2-amino-6-chlorophenoxy)-N-(4-fluorophenyl)benzenesulfonamide;
N-{3-chloro-2-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}-2,2,2-trifluoroacetamide;
4-(2-chloro-6-nitrophenoxy)-N-(1-phenylethyl)benzenesulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-(2,4-dichlorophenyl)benzenesulfonamide;
3,5-dichloro-N-[(1E)-(dimethylamino)methylene]-4-(4-nitrophenoxy)benzene-sulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-(1,2,2-trimethylpropyl)benzenesulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-phenylbenzenesulfonamide;
1-{2-chloro-6-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}methanamine;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-(4-chlorobenzyl)benzenesulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-benzyl-N-methylbenzenesulfonamide;
{2-[4-(morpholin-4-ylsulfonyl)phenoxy]-1,3-phenylene}dimethanamine;
4-[2,6-bis(aminomethyl)phenoxy]-N-phenylbenzenesulfonamide;
3,5-dichloro-N-[(1E)-(dimethylamino)methylene]-4-(4-nitrophenoxy)benzene-sulfonamide;
4-[2-(aminomethyl)-3-chlorophenoxy]-N-(1,2,2-trimethylpropyl)benzenesulfonamide;
N-(3-fluorophenyl)-4-(4-nitrophenoxy)benzenesulfonamide;
4,4′-oxybis(N,N-diethylbenzenesulfonamide);
1-{[4-(4-nitrophenoxy)phenyl]sulfonyl}piperidine;
1-methyl-4-{[4-(4-nitrophenoxy)phenyl]sulfonyl}piperazine;
4-chloro-N-{4-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}benzenesulfonamide;
N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide;
4-(4-nitrophenoxy)-N-phenylbenzenesulfonamide;
4,4′-oxybis[N-(3-nitrophenyl)benzenesulfonamide];
N-(3-nitrophenyl)-4-phenoxybenzenesulfonamide;
N-(3-acetylphenyl)-4-(4-nitrophenoxy)benzenesulfonamide;
N-(2-methoxyphenyl)-4-(4-nitrophenoxy)benzenesulfonamide;
1-{[4-(4-nitrophenoxy)phenyl]sulfonyl}indoline;
1,1′-[oxybis(4,1-phenylenesulfonyl)]dipiperidine;
4-{[4-(4-nitrophenoxy)phenyl]sulfonyl}morpholine;
N,N-diethyl-4-(4-nitrophenoxy)benzenesulfonamide;
4,4′-oxybis(N,N-diethylbenzenesulfonamide);
1,1′-[oxybis(4,1-phenylenesulfonyl)]dipiperidine;
N-{4-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}-4-phenoxybenzamide;
N-{4-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}-4-nitrobenzamide;
4,4′-oxybis[N-(4-methylphenyl)benzenesulfonamide];
4-{[4-(4-nitrophenoxy)phenyl]sulfonyl}morpholine;
N-(3-nitrophenyl)-4-phenoxybenzenesulfonamide;
N-(3-acetylphenyl)-4-(4-nitrophenoxy)benzenesulfonamide;
4-({4-[2,6-dinitro-4-(trifluoromethyl)phenoxy]phenyl}sulfonyl)morpholine;
1-({4-[2,6-dinitro-4-(trifluoromethyl)phenoxy]phenyl}sulfonyl)-4-methylpiperazine;
4-[2,6-dinitro-4-(trifluoromethyl)phenoxy]-N-(pyridin-2-ylmethyl)benzenesulfonamide;
N-(5-chloropyridin-2-yl)-4-phenoxybenzenesulfonamide;
1-{[4-(2,4-dichlorophenoxy)-2-fluorophenyl]sulfonyl}piperidine;
N-(cyclopropylmethyl)-2-({[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}amino)benzamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[3-(3,5-dichlorophenoxy)propyl]benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-(2,4-dichlorophenyl)ethyl]benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(pyridin-4-ylmethyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-isopropoxyphenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-methylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-cyanophenyl)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)-benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-methylphenyl)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)-N-(4-nitrophenyl)benzenesulfonamide;
1-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-2,6-dimethylpiperidine
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-mesityl-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)benzenesulfonamide;
3,5-dichloro-N-(3-chloro-2-methylphenyl)-4-(2-chloro-4-nitrophenoxy)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-mesitylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,6-dimethylphenyl)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,6-dimethylphenyl)benzenesulfonamide;
3,5-dichloro-N-(3-chloro-2-methylphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{[(3,4-dichlorophenyl)amino]carbonothioyl}benzene sulfonamide;
methylN-(4-chlorophenyl)-N′-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}imidothio carbamate;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[(1Z)-[(4-chlorophenyl)amino](hydroxyamino)methylene]benzenesulfonamide;
N-(cyclopropylmethyl)-3-({[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}amino)benzamide;
N-(cyclopropylmethyl)-4-({[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}amino)benzamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-chlorophenyl)benzenesulfonamide;
3,5-dichloro-N-(3-chloro-4-methoxyphenyl)-4-(2-chloro-4-nitrophenoxy)-N-(1,3-dichloro-2-(2-chloro-4-nitrophenoxy)-5-sulfonylbenzene)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-chlorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,3,4-trimethoxyphenyl)benzene-sulfonamide;
N-(3-bromophenyl)-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-isopropyl-6-methylphenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-methylphenyl)benzenesulfonamide;
N-1,3-benzodioxol-5-yl-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-methoxyphenyl)benzenesulfonamide;
3,5-dichloro-N-(5-chloro-2-methoxyphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-3-thienylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-fluoro-3-methoxyphenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,4-dichlorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-1H-indol-7-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-cyanophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,4-dimethoxyphenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-1H-indol-6-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-1H-indol-5-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-dibenzo[b,d]furan-4-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,5-difluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,3-dichlorophenyl)benzenesulfonamide;
N-biphenyl-3-yl-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-5-yl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3,4-difluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-fluoro-4-methylphenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,4,5-trifluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-cyanophenyl)benzenesulfonamide;
3,5-dichloro-N-(3-chloro-4-methoxyphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-N-(4-chloro-2,5-dimethoxyphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,5-dichlorophenyl)benzenesulfonamide;
N-(4-bromopyridin-2-yl)-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,6-dimethoxypyridin-3-yl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-chloropyridin-3-yl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-methoxyphenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-iodophenyl)benzenesulfonamide;
N-{[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl]sulfonyl}-3-nitrobenzene-carboximidamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[[(4-chlorophenyl)amino](imino)methyl]benzene sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-chloro-2-nitrophenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-pyridin-2-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4,6-dibromopyridin-2-yl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-quinolin-8-ylbenzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2-fluoro-5-nitrophenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,3-dihydro-1H-inden-2-yl)benzene-sulfonamide;
N-[(1H-benzimidazol-2-ylamino)(imino)methyl]-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzene sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-methyl-3-(trifluoromethyl)phenyl]benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-methyl-5-(trifluoromethyl)phenyl]benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,6-di-tert-butylphenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-fluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-fluoro-2-methylphenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[5-fluoro-2-(trifluoromethyl)phenyl]benzene sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(4-fluoro-2-methylphenyl)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(2,6-difluorophenyl)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(5-fluoro-2-methylphenyl)benzene-sulfonamide;
N-{3-chloro-4-[2,6-dinitro-4-(trifluoromethyl)phenoxy]phenyl}-4-methylbenzenesulfonamide;
4-chloro-N-{3-chloro-4-[2,6-dinitro-4-(trifluoromethyl)phenoxy]phenyl}benzene-sulfonamide;
3,5-dichloro-N-[5-chloro-2-(trifluoromethyl)phenyl]-4-(2,4-dichlorophenoxy)benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-(3-iodo-4-methylphenyl)benzene-sulfonamide;
3,5-dichloro-N-(2-chloro-4-methylphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3,5-dichloro-N-(5-chloro-2-methylphenyl)-4-(2-chloro-4-nitrophenoxy)benzene-sulfonamide;
3-chloro-N-(2-fluoro-5-nitrophenyl)-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
3-chloro-N-(2,5-dichlorophenyl)-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
3-chloro-N-(2,5-difluorophenyl)-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
3-chloro-N-(2,5-dichloropyridin-3-yl)-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
3-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene sulfonamide;
3-chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene sulfonamide;
3-chloro-N-[4-fluoro-2-(trifluoromethyl)phenyl]-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene sulfonamide;
3-chloro-N-[5-chloro-2-(trifluoromethyl)phenyl]-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene sulfonamide;
3-chloro-N-(2,6-difluorophenyl)-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
N-(3-bromophenyl)-3-chloro-4-[4-nitro-2-(trifluoromethyl)phenoxy]benzene-sulfonamide;
2,5-dichloro-N-[4-(4-nitrophenoxy)phenyl]benzenesulfonamide;
3-chloro-2-methyl-N-[4-(4-nitrophenoxy)phenyl]benzenesulfonamide;
3-chloro-N-[4-(4-nitrophenoxy)phenyl]benzenesulfonamide;
2,5-dichloro-N-[4-(4-chlorophenoxy)phenyl]benzenesulfonamide;
2,5-dichloro-N-{4-[2-chloro-5-(trifluoromethyl)phenoxy]-2-fluorophenyl}benzene-sulfonamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-2,5-dichlorobenzenesulfonamide;
2,5-dichloro-N-[4-(2,4,6-trichlorophenoxy)phenyl]benzenesulfonamide;
N-acetyl-N-[3-chloro-4-(2,6-dichloro-4-{[(3-chlorophenyl)amino]sulfonyl}phenoxy)phenyl]acetamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-3-chloro-2-methylbenzenesulfonamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-3-chlorobenzenesulfonamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-4-fluorobenzenesulfonamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-4-(trifluoromethoxy)benzenesulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-(1H-pyrrol-1-yl)phenyl]benzene-sulfonamide;
N-{4-[2-chloro-5-(trifluoromethyl)phenoxy]-2-fluorophenyl}-4-fluorobenzene-sulfonamide;
N-{4-[2-chloro-5-(trifluoromethyl)phenoxy]-2-fluorophenyl}-4-methoxybenzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[2-(trifluoromethoxy)phenyl]benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[3-(trifluoromethoxy)phenyl]benzene-sulfonamide;
3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{4-[2-chloro-5-(trifluoromethyl)phenoxy]-2-fluorophenyl}benzenesulfonamide;
N-[3-bromo-4-(4-fluorophenoxy)phenyl]-3,5-dichloro-4-(2-chloro-4-nitrophenoxy) benzenesulfonamide;
or a pharmaceutically acceptable salt thereof.
13. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein
R 200 is —S(O) 2 —N(R 1 )(R 2 );
R 1 is phenyl substituted with halogen, trifluoromethoxy or both,
R 2 is hydrogen;
R 3 is halo;
R 400 is halo;
R 5 is NO 2 ;
R 35 is —H;
R 6 is —H;
R 7 is halo;
R 17 is —H or —C 1 -C 6 -hydrocarbyl;
R 18 is —H, C 1 -C 6 -hydrocarbyl, —C(O)R 19 , —SO 2 R 19 , C(O)NHR 19 , CSNHR 19 , CNNHR 19 , or CO 2 R 19 ;
R 19 is —H, —OH, or C 1 -C 3 -hydrocarbyl;
wherein each of the aryl, heteroaryl, heterocyclyl, and hydrocarbyl groups above is optionally substituted by one or more groups selected from halo, —OH, —NH 2 , C 1 -C 6 -hydrocarbyl-C(O)—, oxo, C 1 -C 6 -hydrocarbyl-(O)—, mono- to per-halogenated C 1 -C 6 -hydrocarbyl-O—, C 1 -C 6 -hydrocarbyl, mono- to per-halogenated C 1 -C 6 -hydrocarbyl, —CN, —NO 2 , —NO, —NH 2 , —NH—C(O)R 18 , or —SO 2 ;
provided that when R 35 is H, the compound is not one of the following combinations:
R 1
R 2
R 3
R 400
R 5
R 6
R 7
3,5-dichlorophenyl
H
Cl
Cl
NO 2
H
Cl
3-chloro-4-fluorophenyl
H
Cl
Cl
NO 2
H
Cl.
14. A compound selected from:
N-(2-bromo-5-(trifluoromethoxy)phenyl)-3,5-dichloro-4-(2-chloro-4-nitrophenoxy)benzenesulfonamide;
N-(3-bromo-4-(4-fluorophenoxy)phenyl)-3-chlorobenzamide; and
1-(3-bromo-4-(4-fluorophenoxy)phenyl)-3-(3-chlorophenyl)urea.