Pyridyl derivatives as histone deacetylase inhibitors
View Patent ↗The present invention relates to a novel class of pyridyl and pyrimidinyl derivatives. The pyridyl and pyrimidinyl compounds can be used to treat cancer. The pyridyl and pyrimidinyl compounds can also inhibit histone deacetylase and 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 compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the pyridyl and pyrimidinyl derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the pyridyl and pyrimidinyl derivatives in vivo.
1. A compound with the formula
wherein Ar is phenyl, thienyl or pyridyl, optionally substituted with halo,
methyl, methoxy, amino, hydroxyl or halomethyl;
R 1 and R 2 are independently H, OH, halo, NH 2 , C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R 3 is independently H, 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-C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, 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 or di(C 1 -C 7 )alkylamino;
R 4 is —NR 6 R 7 ;
R 5 is independently H, 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)O—, C 1 -C 2 alkyl-C(═O)—, C 1 -C 2 alkynyl, halo, hydroxyalkoxy, C 1 -C 2 alkyl-NHSO 2 —, C 1 -C 2 alkyl-SO 2 NH—, C 1 -C 2 alkylsulfonyl, C 1 -C 2 alkylamino or di(C 1 -C 2 )alkylamino;
R 6 is independently H, or C 1 -C 4 alkyl;
R 7 is —(CR a 2 ) s C(O)(CR a 2 ) q R 13 , or —(CR a 2 ) s C(O)O(CR a 2 ) q R 12 ;
R 12 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, heteroaryl, aryl or heterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, heterocyclic or aryl is optionally substituted with aryl, heteroaryl, halo, C 1 -C 4 alkyl, N(R 6 ) 2 , OH, C 1 -C 4 alkoxy or C 1 -C 4 haloalkyl;
R 13 is H, C 2 -C 7 alkyl, C 3 -C 6 cycloalkyl, heteroaryl, or aryl, wherein the cycloalkyl, heteroaryl or aryl is optionally substituted with aryl, heteroaryl, halo, C 1 -C 4 alkyl, N(R 6 ) 2 , OH, C 1 -C 4 alkoxy or C 1 -C 4 haloalkyl;
R a is independently H or C 1 -C 4 alkyl;
Ring B is aryl or heteroaryl;
p is 1, 2, 3 or 4;
s and q are independently 0, 1, 2, 3, or 4;
t is independently 1, 2, 3 or 4;
L 1 is (CH 2 ) r , ethenyl or cyclopropyl, wherein r is 0, 1 or 2;
X is OH or NH 2 ;
or a stereoisomer or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein
Ar is
R 1 and R 2 are H;
R 3 is H;
R 4 is —NR 6 R 7 ;
R 5 is H;
R 6 is H or C 1 -C 4 alkyl;
R 7 is —C(O)O(CR a 2 ) q R 12 ;
R 12 is H, C 1 -C 4 alkyl, cycloalkyl, aryl, or heteroaryl;
R 17 and R 21 are independently hydrogen or fluoro;
R 18 , R 19 or R 20 are independently hydrogen, halo, methyl, methoxy or halomethyl;
R 22 , R 23 and R 24 are independently hydrogen, methyl, amino, hydroxyl or halo;
R a is independently H or C 1 -C 4 alkyl;
Ring B is aryl or heteroaryl;
q is independently 0, 1 or 2;
t is independently 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
L 1 is a bond;
X is NH 2 ;
or a stereoisomer or pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein Ar is phenyl, and all other substituents are defined in claim 2 .
4. The compound of claim 2 , wherein Ring B is
and all other substituents are defined in claim 2 .
5. A compound with the formula
Ar is
R 1 and R 2 are independently H, OH, halo, NH 2 , C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R 3 is H;
R 4 is —NR 6 R 7 ;
R 5 is H;
R 6 is H or C 1 -C 4 alkyl;
R 7 is —C(O)O(CR a 2 ) q R 12 ;
R 12 is aryl, or heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 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-C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, 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 or di(C 1 -C 7 )alkylamino, aryl, heterocyclic or cycloalkyl;
R 17 and R 21 are independently hydrogen or fluoro;
R 18 , R 19 or R 20 are independently hydrogen, halo, methyl, methoxy or halomethyl;
R 22 , R 23 and R 24 are independently hydrogen, methyl, amino, hydroxyl or halo;
R a is independently H or C 1 -C 4 alkyl;
Ring B is aryl or heteroaryl;
q is independently 0, 1 or 2;
t is independently 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
L 1 is a bond;
X is NH 2 ;
or a stereoisomer or pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein R 12 is phenyl or 2-pyridyl, wherein the phenyl or pyridyl is optionally substituted with 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)O—, C 1 -C 2 alkyl-C(═O)—, C 1 -C 2 alkynyl, halo, hydroxyalkoxy, C 1 -C 2 alkyl-NHSO 2 —, C 1 -C 2 alkyl-SO 2 NH—, C 1 -C 2 alkylsulfonyl, C 1 -C 2 alkylamino or di(C 1 -C 2 )alkylamino;
q is 1 or 2;
R a is H or C 1 -C 2 alkyl;
and all other substituents are as defined in claim 5 .
7. The compound of claim 6 , wherein R 12 is phenyl; and all other substituents are as defined in claim 6 .
8. The compound of claim 6 , wherein R 12 is 2-pyridyl; and all other substituents are as defined in claim 6 .
9. The compound of claim 7 or 8 , wherein Ar is
10. The compound of claim 7 or 8 , wherein Ar is phenyl.
11. The compound of claim 7 or 8 , wherein R 1 and R 2 are H; R a is H; R 6 is H, and q is 1.
12. The compound of claim 7 or 8 , wherein Ring B is
13. A compound selected from:
pyridin-3-ylmethyl{[4-({[3-amino-6-(2-thienyl)pyridin-2yl]amino}carbonyl)phenyl]methyl}carbamate;
methyl [(4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}phenyl)methyl]carbamate;
Pyridin-3-ylmethyl [(4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}phenyl)methyl]carbamate;
4-(Acetylamino)-N-(3-amino-6-phenylpyridin-2-yl)benzamide;
ethyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
1-methylethyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
propyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
2-methylpropyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
phenyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
phenylmethyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
4-[(acetylamino)methyl]-N-(3-amino-6-phenylpyridin-2-yl l)benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-[(propanoylamino)methyl]benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-[(butanoylamino)methyl]benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(cyclopropylcarbonyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(2-methylpropanoyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(2,2-dimethylpropanoyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(3-methylbutanoyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(cyclobutylcarbonyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(3-phenylpropanoyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(cyclohexylcarbonyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(cyclopentylcarbonyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(phenylacetyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(phenylcarbonyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(pyridin-2-ylacetyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(pyridin-3-ylacetyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(pyridin-4-ylacetyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(3-pyridin-3-ylpropanoyl)amino]methyl}benzamide;
pyridin-2-ylmethyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
N-(3-amino-6-phenylpyridin-2-yl)-4-({[(methylamino)carbonyl]amino}methyl)benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-({[(ethylamino)carbonyl]amino}methyl)benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-[(isobutylamino)methyl]benzamide;
N-(3-amino-6-phenylpyridin-2-yl)-4-{[(2-methoxy-1-methylethyl)amino]methyl}benzamide;
N-(3-amino-6-phenylpyridin-2-yl)benzamide;
N-(3-amino-6-phenyl-2-pyridinyl)-4-(1,1-dimethylethyl)benzamide;
benzoic acid, methyl 4-[[(3-amino-6-phenyl-2-pyridinyl)amino]carbonyl]benzoate;
4-(aminomethyl)-N-(3-amino-6-phenyl-2-pyridinyl)benzamide;
2-methoxyethyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate;
tert-Butyl (4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}benzyl)carbamate; and
tert-Butyl (4-{[(2-amino-5-phenylpyridin-3-yl)amino]carbonyl}benzyl)carbamate;
or a stereoisomer or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
15. The compound of claim 1 that is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 that is
or a stereoisomer or pharmaceutically acceptable salt thereof.
17. The compound of claim 1 that is
or a stereoisomer or pharmaceutically acceptable salt thereof.
18. The compound of claim 1 that is
or a stereoisomer or pharmaceutically acceptable salt thereof.
19. The compound of claim 1 that is
or a stereoisomer or pharmaceutically acceptable salt thereof.