US 7,683,067 B2Granted

3-heterocyclyl-indole derivatives as inhibitors of glycogen synthase kinase-3 (GSK-3)

AssigneeAstraZeneca AB

InventorsStefan Berg, Sven Hellberg

Life of this patent

Estimating the term…

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.

Claims9

Dependent claims

A compound having the formula Ia;

P represents a 6-membered heteroaromatic ring containing one or two heteroatoms;
R1 is hydrogen;
R2 is cyano;
R3 is (SO2)NR4R5;
wherein R4 and R5 may together form a 4-, 5-, 6- or 7-membered heterocyclic group containing one or more heteroatoms selected independently from N, O and S, wherein said heterocyclic group is substituted by a group Y;
R8 and R9 are independently selected from:
hydrogen and C1-6alkyl or R8 and R9 may together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms, selected independently from N, O and S;
Y is selected from:
oxo, C2-6alkylOR8, C0-6alkylheteroaryl, OR8 and C2-6alkylNR8R9;
m is 1;
n is 1;
or a salt, or a tautomer thereof.

9 more elements

A compound selected from:

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.

75 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/572,778Filed 21 Sep 2004
Priority: SE 030254624 Sep 2003
Published: US 2008/0275041 A16 Nov 2008
Granted: 23 Mar 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 15/00
Drugs for genital or sexual disorders

Family

US 2008/0275041 A1Pre-grant publication · published 6 Nov 2008
US 7,683,067 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/572,778Filed 21 Sep 2004

Priority

SE 030254624 Sep 2003

Published

US 2008/0275041 A16 Nov 2008

Granted

23 Mar 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 15/00
Drugs for genital or sexual disorders