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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.
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Citations
52 Claims
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1-41. -41. (canceled)
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42. A method of prevention and/or treatment of conditions associated with glycogen synthase kinase-3, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound of formula Ia
wherein the compound is in the form of a base or a pharmaceutically acceptable salt thereof, and wherein: -
P is a 6-membered ring containing one nitrogen; R1 is hydrogen; R2 is C0-6alkylcyano; R3 is C0-6alkylNR4R5; m is 1; n is 1; R4 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, C1-6alkylNR14R15, and a 5- or 6-membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclic group is optionally substituted by a group Y; R5 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, and C1-6alkylNR14R15; or R4 and R5 together with the N to which they are attached may form a 6-membered heterocyclic group containing one nitrogen and one oxygen; and wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, and C0-6alkylheteroaryl group defined under R2 to R5 is optionally substituted by one or more groups Z; R14 and R15 are independently selected from hydrogen, C1-6alkyl, and C0-6alkylC3-6cycloalkyl, wherein R14 and R15 optionally together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms independently selected from N, O, and S, wherein the heterocyclic group is optionally substituted by a group Y; Z is independently selected from the group consisting of oxo, halogen, nitro, CN, OR16, C1-6alkyl, C0-6alkylaryl, C0-6alkylC3-6cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC1-6alkylNR16R17, NR16R17, CONR16R17NR16(CO)R17, O(CO)C1-6alkyl, (CO)OC1-6alkyl, COR16, (SO2)NR16R17, SO2R16, SOR16, (CO)C1-6alkylNR16R17, (SO2)C1-6alkylNR16R17, phenyl, heteroaryl, and a 5- or 6-membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, wherein the phenyl, heteroaryl, and heterocyclic groups are optionally substituted by a group Y; Y is selected from the group consisting of oxo, halogen, nitro, CN, OR16, C1-6alkyl, C0-6alkylaryl, C0-6alkylC3-6cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC1-6alkylNR16R17, NR16R17, CONR16R17, NR16(CO)R17, O(CO)C1-6alkyl, (CO)OC1-6alkyl, COR16, (SO2)NR16R17, SO2R16, SOR16, (CO)C1-6alkylNR16R17 (SO2)C1-6alkylNR16R17, phenyl, C0-6alkylaryl, and heteroaryl, wherein the phenyl, C0-6alkylaryl, and heteroaryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, CN, OR16, C1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy; R16 and R17 are independently selected from hydrogen and C1-6alkyl, and wherein R16 and R17 optionally together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms independently selected from N, O, and S. - View Dependent Claims (43, 44, 45, 46, 47, 48, 49, 50, 51, 52)
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 C1-6alkyl, C0-6alkylaryl, 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, in the form of a base or a pharmaceutically acceptable salt thereof.
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44. A method according to claim 42 wherein in said compound of formula Ia,
P is pyridyl; - R2 is CN;
R3 is C0-6alkylNR4R5;
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,in the form of a base or a pharmaceutically acceptable salt thereof.
- R2 is CN;
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45. A method according to claim 42 wherein in said compound of formula Ia, R4 and R5 together form a 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O,
in the form of a base or a pharmaceutically acceptable salt thereof. -
46. A method according to claim 42 wherein in said compound of formula Ia is a compound selected from:
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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.
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47. A method according to claim 42 wherein in said compound of formula Ia is a compound selected from:
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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-ylpiperidin-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; or a pharmaceutically acceptable salt thereof.
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48. A method of prevention and/or treatment according to claims 42 wherein said condition associated with glycogen synthase kinase-3 is selected from:
- dementia, Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, Frontotemporal dementia Parkinson'"'"'s Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies and dementia pugilistica.
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49. A method according to claim 48, wherein the condition is Alzheimer'"'"'s Disease.
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50. A method of prevention and/or treatment according to claim 42 wherein said condition is selected from:
- amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington'"'"'s Disease, postencephalitic parkinsonism, progressive supranuclear palsy, Pick'"'"'s Disease, Niemann-Pick'"'"'s Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia or cognitive disorders.
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51. A method of prevention and/or treatment according to claim 42 wherein said condition is selected from:
- predemented states, Mild Cognitive Impairment, Age-Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment, vascular dementia, dementia with Lewy bodies or Frontotemporal dementia.
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52. A method according to claim 50 wherein the condition is Bipolar Disease.
Specification