Histone deacetylase inhibitors with aryl-pyrazolyl-motifs
View Patent ↗The present invention relates to a novel class of histone deacetylase inhibitors with aryl-pyrazolyl motifs. The compounds of this invention can be used to treat cancer. The compounds of this invention are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The present invention further provides pharmaceutical compositions comprising the compounds of this invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the compounds of this invention in vivo.
1. A compound represented by the following structural Formula I:
wherein:
Ring B is heteroaryl or aryl;
R 1 is selected from hydrogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkynyl, or L 2 -R 2 , wherein R 2 is substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, L 2 is selected from a bond or C 1 -C 4 alkylene;
R 3 is OH, SH or NH 2 ;
R 4 is selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O)O—, C 1 -C 7 alkyl-O—C(═O)—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo group, hydroxyalkoxy, —NHSO 2 , —SO 2 NH, C 1 -C 7 alkyl-NHSO 2 —, C 1 -C 7 alkyl-SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino, C 1 -C 7 acylamino, amino-C 1 -C 7 alkyl, C 1 -C 7 alkylthio, perfluoro-C 1 -C 7 alkyl, perfluoro-C 1 -C 7 alkyloxy;
R 5 is selected from hydrogen, C 1 -C 10 alkyl, cycloalkyl, aryl or heterocyclyl, each of which is optionally substituted;
R 13 is selected from hydrogen or halo;
L 1 is a bond or (CH 2 ) r , ethenyl or cyclopropyl, wherein r is 1 or 2;
X 1 is selected from the group consisting of a covalent bond, L 3 -M 1 -L 2 -M 1 -L 3 , and L 2 -M 2 -L 2 wherein:
L 2 or L 3 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-(NH)—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-(S)—C 1 -C 4 -alkyl, and C 1 -C 4 -alkyl-(O)—C 1 -C 4 -alkyl, each of the alkyl is optionally substituted, provided that L 2 is not a chemical bond when X 1 is L 3 -M 1 -L 2 -M 1 -L 3 ;
M 1 , at each occurrence, is independently selected from the group consisting of —O—, —N(R 11 )—, —S—, —S(O)—, S(O) 2 —, —S(O) 2 N(R 11 )—, —N(R 11 )—S(O) 2 —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—N(R 11 ), —N(R 11 )—C(O)—, —C(S)—N(R 11 ), —N(R 11 )—C(S)—, —N(R 11 )—C(O)—O—, —O—C(O)—N(R 11 )—, —N(R 11 )—C(O)—N(R 11 )—, —N(R 11 )—C(S)—O—, —O—C(S)—N(R 11 )—, —N(R 11 )—C(S)—N(R 11 )—, R 11 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, aryl, aralkyl, C(O)R 12 or C 0 -C 6 alkyl-heterocyclyl, wherein the alkyl moieties are optionally substituted with —OH, —NH 2 , —N(H)CH 3 , —N(CH 3 ) 2 , or halo, wherein R 12 is an optionally substituted C 1 -C 4 alkyl, perfluoro-C 1 -C 4 -alkyl, phenyl or heterocyclic;
M 2 is selected from the group consisting of M 1 or heterocyclic, either of which rings optionally is substituted;
Y is N or CR 13 ;
t is 1, 2, 3 or 4; and
Provided that when R 3 is NH 2 , Y is CR 13 , R 13 is H, L 1 is CH 2 , Ring B is imidazolyl, X 1 is a bond, R 5 is hydrogen, t is 1, R 4 is methyl, then R 1 is not hydrogen;
or a stereoisomer or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 represented by the following structural Formula II:
wherein:
Ring B is heteroaryl or aryl;
R 1 is selected from hydrogen, C 1 -C 7 alkyl, or L 2 -R 2 , wherein R 2 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, L 2 is selected from a bond or C 1 -C 4 alkylene;
R 3 is OH, SH or NH 2 ;
R 4 is selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O)O—, C 1 -C 7 alkyl-O—C(═O)—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo group, hydroxyalkoxy, —NHSO 2 , —SO 2 NH, C 1 -C 7 alkyl-NHSO 2 —, C 1 -C 7 alkyl-SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino, C 1 -C 7 acylamino, amino-C 1 -C 7 alkyl, C 1 -C 7 alkylthio, perfluoro-C 1 -C 7 alkyl, perfluoro-C 1 -C 7 alkyloxy;
R 5 is selected from hydrogen, C 1 -C 10 alkyl, cycloalkyl, aryl or heterocyclyl, each of which is optionally substituted;
R 13 is selected from hydrogen or halo;
L 1 is a bond or (CH 2 ) r , ethenyl or cyclopropyl, wherein r is 1 or 2;
X 1 is selected from the group consisting of a covalent bond, L 3 -M 1 -L 2 -M 1 -L 3 , and L 2 -M 2 -L 2 wherein
L 2 or L 3 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-(NH)—C 1 -C 4 -alkyl, C 1 -C 4 -alkyl-(S)—C 1 -C 4 -alkyl, and C 1 -C 4 -alkyl-(O)—C 1 -C 4 -alkyl, each of the alkyl is optionally substituted, provided that L 2 is not a chemical bond when X 1 is L 3 -M 1 -L 2 -M 1 -L 3 ;
M 1 , at each occurrence, is independently selected from the group consisting of —O—, —N(R 11 )—, —S—, —S(O)—, S(O) 2 —, —S(O) 2 N(R 11 )—, —N(R 11 )—S(O) 2 —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)—N(R 11 ), —N(R 11 )—C(O)—, —C(S)—N(R 11 ), —N(R 11 )—C(S)—, —N(R 11 )—C(O)—O—, —O—C(O)—N(R 11 )—, —N(R 11 )—C(O)—N(R 11 )—, —N(R 11 )—C(S)—O—, —O—C(S)—N(R 11 )—, —N(R 11 )—C(S)—N(R 11 )—, R 11 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, aryl, aralkyl, C(O)R 12 or C 0 -C 6 alkyl-heterocyclyl, wherein the alkyl moieties are optionally substituted with —OH, —NH 2 , —N(H)CH 3 , —N(CH 3 ) 2 , or halo, wherein R 12 is an optionally substituted C 1 -C 4 alkyl, perfluoro-C 1 -C 4 -alkyl, phenyl or heterocyclic;
M 2 is selected from the group consisting of M 1 or heterocyclyl, either of which rings optionally is substituted;
t is 1, 2, 3 or 4; and
Provided that when R 3 is NH 2 , R 13 is H, L 1 is CH 2 , Ring B is imidazolyl, X 1 is a bond, R 5 is hydrogen, t is 1, R 4 is methyl, then R 1 is not hydrogen;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein Ring B is selected from phenyl, benzofuranyl, benzothiophenyl, thiazolyl, benzothiazolyl, furanyl, pyridyl, pyrimidyl, indolinyl, quinolinyl, thiophenyl, benzodioxyl, benzooxadiazolyl, quinoxalinyl, benzotriazolyl, benzoimidazolyl or benzooxazolyl.
4. The compound of claim 2 , wherein L 2 is a bond and R 2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyridyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, or substituted or unsubstituted naphthyl.
5. The compound according to claim 2 , wherein X 1 is selected from the group consisting of a C 0 -C 7 -alkyl-N(Z)—C 0 -C 7 -alkyl-, C 0 -C 7 -alkyl-O—C 0 -C 7 -alkyl-, C 0 -C 7 -alkyl-S—C 0 -C 7 -alkyl-, or —C 1 -C 7 -alkyl-, C 0 -C 7 -alkyl-NH—C(O)—C 0 -C 7 -alkyl-, C 0 -C 7 -alkyl-C(O)—NH—C 0 -C 7 -alkyl-, wherein Z is —H or —C 1 -C 7 -alkyl- optionally substituted with —OH, —NH 2 , or halo.
6. The compound according to claim 2 , wherein R 5 is phenyl, pyrimidinyl, pyridyl, naphthyl, dioxido-benzothienyl, pyrazolyl, benzoimidazolyl or benzothiazolyl, each of which is optionally substituted.
7. The compound according to claim 6 , wherein R 5 has from one and three substituents independently selected from the group consisting of OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O)O—, C 1 -C 7 alkyl-O—C(═O)—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo group, amide, hydroxyl-C 1 -C 7 -alkoxy, —NHSO 2 , —SO 2 NH, C 1 -C 7 alkyl-NHSO 2 —, C 1 -C 7 alkyl-SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino, C 1 -C 7 acylamino, amino-C 1 -C 7 alkyl, C 1 -C 7 alkylthio, perfluoro-C 1 -C 7 alkyl, perfluoro-C 1 -C 7 alkyloxy, thiol, di-C 1 -C 7 -alkylamino-C 1 -C 7 -alkoxy, aryl, or heterocyclic.
8. The compound according to claim 2 , wherein R 5 is substituted or unsubstituted C 1 -C 7 alkyl.
9. The compound of claim 8 , wherein R 5 has from one and three substituents independently selected from C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, halo, C 1 -C 4 haloalkyloxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkyl-C(═O)O—, C 1 -C 4 alkyl-C(═O)—, C 1 -C 4 alkynyl, amide, C 1 -C 4 hydroxyalkoxy, —NHSO 2 , —SO 2 NH, C 1 -C 4 alkyl-NHSO 2 —, C 1 -C 4 alkyl-SO 2 NH—, C 1 -C 4 alkylsulfonyl, —CN, NH 2 , N—C 1 -C 4 -alkylamino or N,N-di-C 1 -C 4 -alkylamino.
10. The compound of claim 2 represented by the following structural formula:
wherein:
R 1 is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl;
R 5 is selected from hydrogen, aryl, heteroaryl or C 1 -C 10 alkyl, each of which is optionally substituted;
R 13 is selected from hydrogen or halo;
L 1 is a bond;
m and n are independently selected from 0, 1, 2 or 3,
or pharmaceutically acceptable salt thereof.
11. The compound of claim 2 represented by the following structural formula:
wherein:
R 1 is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl;
R 13 is selected from hydrogen or halo;
L 1 is a bond;
or pharmaceutically acceptable salt thereof.
12. The compound of claim 2 represented by the following structural formula:
wherein Ring B, R 4 , R 3 , R 5 , R 13 , L 1 , t and X 1 are as defined in claim 2 ;
R 6 and R 10 are independently selected from hydrogen or fluoro, R 7 , R 8 or R 9 are independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 2 alkoxy, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkyloxy, C 1 -C 2 hydroxyalkyl, C 1 -C 2 alkenyl, C 1 -C 2 alkyl-C(═O)—, C 1 -C 2 alkynyl, halo group, hydroxyl-C 1 -C 2 -alkoxy, C 1 -C 2 aminoalkyl or C 1 -C 2 alkylamino.
13. The compound of claim 12 ,
wherein R 7 , R 8 and R 9 are independently selected from hydrogen, halo, methyl, methoxy or halomethyl;
R 4 is hydrogen.
14. A compound selected from:
Pyridin-3-ylmethyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
4-(aminomethyl)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
4-(acetylamino)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)nicotinamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-chlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-methoxyphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl {4-[({4-amino-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(2-fluorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-methylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
4-(acetylamino)-N-[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(2-naphthyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
4-(acetylamino)-N-[4-amino-1-(3-methylphenyl)-1H-pyrazol-3-yl]benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3-thienyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
4-(acetylamino)-N-[4-amino-1-(3-thienyl)-1H-pyrazol-3-yl]benzamide;
4-(acetylamino)-N-[4-amino-1-(2-naphthyl)-1H-pyrazol-3-yl]benzamide;
3-(acetylamino)-N-(4-amino-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-[4-amino-1-(3-chlorophenyl)-1H-pyrazol-3-yl]-4-{[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3,5-dichlorophenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-2-[methyl(2-phenylethyl)amino]-1,3-thiazole-5-carboxamide;
methyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)(1,3-benzoxazol-2-yl)acetate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-2-{[1-(4-methoxyphenyl)ethyl]amino}-1,3-thiazole-5-carboxamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[5-(3-cyanophenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{fluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(5-benzyl-1,3,4-oxadiazol-2-yl)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;
pyridin-3-ylmethyl[4-({[4-amino-1-(3,5-dimethylphenyl)-1H-pyrazol-3-yl]amino}carbonyl)benzyl]carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-1-benzothiophene-2-carboxamide;
2-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
benzyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
phenyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
2-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
isobutyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
(1,1-dioxido-1-benzothien-2-yl)methyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
2-chlorobenzyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
1-naphthyl (4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}benzyl)carbamate;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{[methyl(pyridin-4-yl)amino]methyl}benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(pyridin-4-ylamino)methyl]benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-({[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]amino}methyl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-({methyl[3-(methylamino)propyl]amino}methyl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-[(isobutylamino)methyl]benzamide;
4-(acetylamino)-N-(4-amino-5-fluoro-1-phenyl-1H-pyrazol-3-yl)benzamide;
N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{difluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide;
or
tert-butyl 4-(5-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)piperazine-1-carboxylate;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.