3-Heterocyclyl-indole inhibitors of glycogen synthase kinase-3

• US 7,399,780 B2
• Filed: 03/28/2003
• Issued: 07/15/2008
• Est. Priority Date: 03/28/2002
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Xue, Yafeng, Berg, Stefan, Hellberg, Sven, Nylöf, Martin
• Primary Examiner(s): McKane; Joseph
• Assistant Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US10/509,268
• Publication Number:
  US 20050153987A1
• Time in Patent Office: 1,936 Days
• Field of Search: 514/415, 514/418, 548/469, 548/484
• US Class Current: 514/415
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present invention provides new compounds of formula Ia and Ib: as well as a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Claims

1. A compound of formula Ia,

2. A compound according to claim 1, wherein:

R⁵ is C_1-6alkylNR¹⁴R¹⁵, and

R⁴ selected from hydrogen, C_1-6alkyl;

or

R⁴ and R⁵ together with the N to which they are attached form a 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O, wherein said heterocyclic group may optionally be substituted by a group Y;

and wherein R¹⁴ and R¹⁵ may together form a 5-membered heterocyclic group containing one or more heteroatoms, selected independently from N, and O;

Y is selected from C_1-6alkyl, C_0-6alkylaryl, NR¹⁶R¹⁷, phenyl, wherein the phenyl may be optionally substituted with nitro and trifluoromethyl;

wherein R¹⁶ and R¹⁷ may together form a 5-membered heterocyclic group containing one N heteroatom.

3. A compound according to claim 1, wherein P is pyridyl;

R² is CN;

R³ is C_0-6alkylNR⁴R⁵;

wherein R⁴ and R⁵ may together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O.

4. A compound according to claim 3, wherein R⁴ and R⁵ together form a 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O.

5. A compound selected from:

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbonitrile;

3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol, or

2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

or a pharmaceutically acceptable salt thereof.

6. A compound selected from:

2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-pyrrolidin-1-yl)piperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;

6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;

6-Bromo-3[-5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

5-Bromo-3[-5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

3-Fluoro-3[-5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonitrile;

3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol;

5-(2-Furyl)-3[-5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-ol;

6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide;

6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamide;

5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-2-ol;

3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-indol-2-ol;

6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indol-2-ol;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;

6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile;

5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol, or

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carbonitrile;

p1 or a pharmaceutically acceptable salt thereof.

7. A hydrochloride salt of a compound according to claim 6.

8. 6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrollindin-1-ylethyl)nicotinamide;

6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)nicotinamide;

2-Hydroxy-3-(5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-thiazol-4-yl)-1H-indol-2-ol, or

3-{5-[(4-Methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol;

or a pharmaceutically acceptable salt thereof.

9. A fumarate salt of a compound according to claim 8.

10. A compound that is 2-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 5-14 in association with at least one pharmaceutically acceptable carrier or diluent.

11. A compound that is 2-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}methyl)pyridin-2-yl]-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

12. A compound that is 2-Hydroxy-3[-5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof.

13. A compound that is 3[-5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol or a pharmaceutically acceptable salt thereof.

14. A compound that is 3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-oxazol-5-yl)-1H-indol-2-ol or a pharmaceutically acceptable salt thereof.