Inhibitors of Akt activity
View Patent ↗The present invention is directed to compounds which contain substituted naphthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention. These substituted naphthyridines have unexpected advantageous properties when compared to other naphthyridines reported in PCT publication WO2003/086394, such unexpected advantageous properties may include increased cellular potency/solubility, greater selectivity, enhanced pharmacokinetic properties, lack of off target activity and so on.
1. A compound selected from:
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
2-(4-{[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
6-Methyl-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]-methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
6-(2-Hydroxyethyl)-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-Phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,7-naphthyridin-8(7H)-one;
2-(4-{[4-(1,3-Benzoxazol-2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[445-pyridin-2-yl-2H-tetrazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-1,2,3-triazol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-pyrrol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-oxadiazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,3-thiazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(3-pyrimidin-4-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
2-(4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
2-(4-{[4-fluoro-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
2-(4-{[4-hydroxy-4-(1-pyridin-2-yl-1H-pyrazol-4-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-2-ylpiperidine-4-carboxamide;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrimidin-2-ylpiperidine-4-carboxamide;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrazin-2-ylpiperidine-4-carboxamide;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrimidin-4-ylpiperidine-4-carboxamide;
3-Phenyl-2-(4-{[4-(3-pyridin-2-yl-1H-pyrrol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-Phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-pyrazol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-Phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(pyrimidin-2-ylamino)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-Phenyl-2-{4-[(4-pyridin-4-ylpiperidin-1-yl)methyl]phenyl}-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-{4-[(4-phenylpiperidin-1-yl)methyl]phenyl}-1,6-naphthyridin-5(6H)-one;
2-(4-{[4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(4-pyridin-2-yl-M-imidazol-1-yl)piperidin-1-yl]methyl}phenyl-1,6-naphthyridin-5(6H)-one;
5-methoxy-3-phenyl-2-(4-{[3-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridine;
3-phenyl-2-(4-{[3-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
5-methoxy-3-phenyl-2-(4-{[(3R,4R)-3-methyl-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridine;
3-phenyl-2-(4-{[(3R,4R)-3-methyl-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
(3R)-N-(4-fluorophenyl)-1-[4-(5-methoxy)-3-phenyl-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-carboxamide;
(3R)-N-(4-fluorophenyl)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-carboxamide;
(3R)-N-(3-fluorophenyl)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-carboxamide;
3-phenyl-2-(4-{[3-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
(3R)-N-(2-fluorophenyl)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-carboxamide;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-4-ylpyrrolidine-3-carboxamide;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-3-ylpyrrolidine-3-carboxamide;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-2-ylpyrroldine-3-carboxamide;
2,2,2-trifluoro-N-{(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyridin-3-yl}acetamide;
3-Phenyl-2-(4-{[(3S)-3-(2-thienylcarbonyl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
{(3S)-1-[4-(5-Methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzyl]pyrrolidin-3-yl}(2-thienyl)methanone;
N-{1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-yl}-N′-phenylurea;
N-{1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidin-3-yl}-N′-pyridin-4-ylurea;
2-[4-({4-[5-(6-Hydroxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(2-pyridin-2-yl-1,3-thiazol-4-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(2-pyridin-3-yl-1H-imidazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-imidazol-4-yl)piperidine-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperazine;
1-[4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzyl]-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperazine;
1-{1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)phenyl]ethyl}-445-pyridin-2-yl-4-h-1,2,4-triazol-3-yl)piperidine;
2-[4-({4-[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one;
2-[4-({3-[4-(dimethylamino)phenyl]pyrrolidin-1-yl}methyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
2-[4-({4-[5-(6-chloropyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one;
3-phenyl-2-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one; and
3-phenyl-2-(4-{[4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2. The salt of a compound according to claim 1 which is selected from:
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
2-(4-{[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(61)-one HCl;
2-(4-{[4-(1,3-Benzoxazol-2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[445-pyridin-2-yl-2H-tetrazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-1,2,3-triazol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-pyrrol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-oxadiazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,3-thiazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(3-pyrimidin-4-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
2-(4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
2-(4-{[4-fluoro-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
2-(4-{[4-hydroxy-4-(1-pyridin-2-yl-1H-pyrazol-4-yl)piperidin-1-yl]methyl}phenyl)-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-2-ylpiperidine-4-carboxamide TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrimidin-2-ylpiperidine-4-carboxamide TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrazin-2-ylpiperidine-4-carboxamide TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyrimidin-4-ylpiperidine-4-carboxamide TFA;
3-Phenyl-2-(4-{[4-(3-pyridin-2-yl-1H-pyrrol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
3-Phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-pyrazol-1-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
3-Phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
3-phenyl-2-(4-{[3-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyrrolidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
(3R)-N-(2-fluorophenyl)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidine-3-carboxamide TFA;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-4-ylpyrrolidine-3-carboxamide TFA;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-3-ylpyrroldine-3-carboxamide TFA;
(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-N-pyridin-2-ylpyrrolidine-3-carboxamide TFA;
2,2,2-trifluoro-N-{(3R)-1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyridin-3-yl}acetamide TFA;
N-{1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]pyrrolidin-3-yl}-N′-pyridin-4-ylurea TFA;
2-[4-({4-[5-(6-Hydroxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one HCl;
3-phenyl-2-(4-{[4-(2-pyridin-2-yl-1,3-thiazol-4-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(2-pyridin-3-yl-1H-imidazol-5-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(1-pyridin-2-yl-1H-imidazol-4-yl)piperidine-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl]-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperazine TFA;
1-[4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzyl]-4-(5-pyridin-2-yl-4H-1,2,4-triazol-3-yl)piperazine TFA;
1-{1-[4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)phenyl]ethyl}-445-pyridin-2-yl-4h-1,2,4-triazol-3-yl)piperidine Formatic Acid;
2-[4-({4-[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one TFA; 2-[4-({3-[4-(dimethylamino)phenyl]pyrrolidin-1-yl}methyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
3-phenyl-2-(4-{[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA;
2-[4-({4-[5-(6-chloropyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl]methyl)phenyl}-3-phenyl-1,6-naphthyridin-5(6H)-one TFA;
3-phenyl-2-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
3-phenyl-2-(4-{[4-(5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one TFA; and
3-phenyl-2-(4-{[4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one HCl;
or a stereoisomer thereof.
3. A compound below:
wherein:
Q is
optionally substituted with
and
R 1 is H;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
4. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3 .