3-heterocyclyl-indole derivatives as inhibitors of glycogen synthase kinase-3 (GSK-3)
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Abstract
Compounds of formula Ia or Ib
wherein P; R1; R2; m; and n are as defined in the application, salts thereof, processed for their preparation, new intermediates used therein, pharmaceutical formulations containing said compounds and the use of said compounds in therapy.
6 Citations
9 Claims
- 1. A compound having the formula Ia;
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6. A compound selected from:
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2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-6-carbonitrile hydrochloride; 6-(6-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide hydrochloride; 6-(6-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)nicotinamide hydrochloride; 6-(6-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-(dimethylamino)ethyl)-N-methylnicotinamide hydrochloride; 6-(6-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide hydrochloride; 2-Hydroxy-3-[5-(piperazine-1-sulfonyl)pyridin-2-yl]-1H-indole-6-carbonitrile hydrochloride; 2-Hydroxy-N-(2-methoxyethyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-(pyridin-2-ylmethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-(2-thienylmethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-1H-indole-5-carboxamide hydrochloride; N-[2-(Acetylamino)ethyl]-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxybenzyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-[4-(trifluoromethyl)benzyl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-[2-(trifluoromethyl)benzyl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-[2-(trifluoromethoxy)benzyl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-[4-(trifluoromethoxy)benzyl]-1H-indole-5-carboxamide hydrochloride; 3-{5-[(Diethylamino)methyl]pyridin-2-yl}-2-hydroxy-N-(2-thienylmethyl)-1H-indole-5-carboxamide hydrochloride; 3-{5-[(Diethylamino)methyl]pyridin-2-yl}-2-hydroxy-N-(pyridin-2-ylmethyl)-1H-indole-5-carboxamide hydrochloride; 3-{5-[(Diethylamino)methyl]pyridin-2-yl}-2-hydroxy-N-(2-methoxyethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-(tetrahydrofuran-2-ylmethyl)-1H-indole-5-carboxamide hydrochloride; N-Benzyl-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-N-propyl-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxyphenyl)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(4-methoxyphenyl)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(pyridin-3-ylmethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(pyridin-4-ylmethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(pyridin-2-ylmethyl)-1H-indole-5-carboxamide hydrochloride; N-[2-(Aminosulfonyl)ethyl]-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-[2-(methylsulfonyl)ethyl]-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 3-(5-Cyanopyridin-2-yl)-2-hydroxy-N-{2-[(4-methylpiperazin-1-yl)sulfonyl]ethyl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-sulfonamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxyethyl)-3-(5-nitropyridin-2-yl)-1H-indole-5-carboxamide hydrochloride; N-(2-Cyanoethyl)-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-[2-(1H-imidazol-4-yl)ethyl]-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-Benzyl-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-propyl-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxyethyl)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-[2-(Dimethylamino)ethyl]-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 3-(5-Cyanopyridin-2-yl)-2-hydroxy-N-(2-methoxyethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-methyl-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 6-Bromo-2-hydroxy-N-methyl-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 6-Bromo-2-hydroxy-N-isopropyl-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 6-Bromo-2-hydroxy-N-(2-methoxyethyl)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 6-Bromo-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(tetrahydrofuran-2-ylmethyl)-1H-indole-5-carboxamide hydrochloride; 6-Bromo-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(2-pyrrolidin-1-ylethyl)-1H-indole-5-carboxamide hydrochloride; N-[3-(Dimethylamino)propyl]-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxyethyl)-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-pyridin-3-yl-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(2-methoxybenzylamide)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(3-methoxybenzylamide)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-N-(4-methoxybenzylamide)-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-(Cyanomethyl)-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; N-(2-Furylmethyl)-2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-6-carbonitrile hydrochloride; 2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile hydrochloride; 2-Hydroxy-3-{5-[(3-oxopiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-6-carbonitrile hydrochloride; 2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-6-carbonitrile hydrochloride; 3-{6-[2-(Diisopropylamino)ethoxy]pyrimidin-4-yl}-2-hydroxy-1H-indole-6-carbonitrile hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxylic acid hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-(2-thienylmethyl)-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-[2-(2-thienyl)ethyl]-1H-indole-5-carboxamide hydrochloride; N-[2-(Acetylamino)ethyl]-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-(2-Cyanoethyl)-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-[2-(Aminosulfonyl)ethyl]-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; N-(Cyanomethyl)-2-hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carboxamide hydrochloride; 2-Hydroxy-3-[5-(4-methylpiperazine-1-sulfonyl)pyridin-2-yl]-1H-indole-5-carboxylic acid carbamoylmethylamide hydrochloride; 2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-N-[2-(methylsulfonyl)ethyl]-1H-indole-5-carboxamide hydrochloride; 3-(5-Diethylaminomethyl-pyridin-2-yl)-2-hydroxy-1H-indole-5-carboxylic acid (2-methanesulfonyl-ethyl)-amide hydrochloride; 2-Hydroxy-3-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-1H-indole-5-carboxylic acid (thiophen-2-ylmethyl)-amide dihydrochloride, or 2-Hydroxy-3-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-1H-indole-5-carboxylic acid benzylamide dihydrochloride; or a free base of any foregoing hydrochloride, or a tautomer thereof, or a pharmaceutically acceptable salt of any said free base. - View Dependent Claims (8, 9)
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7. A compound selected from:
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3-(4-Cyanopyridin-2-yl)-2-hydroxy-N-(2-methoxyethyl)-1H-indole-5-carboxamide; 2-Hydroxy-3-[5-(4-methylpiperazine-1-sulfonyl)pyridin-2-yl]-1H-indole-5-carboxylic acid (2-carbamoylethyl)amide; 2-Hydroxy-3-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-1H-indole-5-carboxylic acid methyl ester; or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
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Specification