US 2009/0023745 A1Published application

Substituted Pyrazolo[4,3-c]Pyridine Derivatives Active as Kinase Inhibitors

AssigneeNerviano Medical Sciences S.R.L.

InventorsTiziano Bandiera, Andrea Lombardi Borgia, Paolo Polucci, Manuela Villa, Marcella Nesi, Mauro Angiolini, Mario Varasi

Life of this patent

Estimating the term…

Abstract

Substituted pyrazolo[4,3-c]pyridine derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with a dysregulated protein kinase activity, like cancer.

Claims26

Dependent claims

A compound of formula (I):

wherein:
R is an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl or aryl;
R1 is selected from hydrogen, halogen, nitro, NHCOR4, NHSO2R10, NR5R6, OR7, R8R9N—C1-C6 alkyl, R7O—C1-C6 alkyl and an optionally further substituted straight or branched C1-C6 alkyl, wherein:
R4 is selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, NR8R9, R8R9N—C1-C6 alkyl and R7O—C1-C6 alkyl;
R5 and R6, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, R8R9N—C2-C6 alkyl and R7O—C2-C6 alkyl;
R7 is selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl and R8R9N—C2-C6 alkyl;
R8 and R9, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl and aryl, and R8 and R9, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycloalkyl group;
R10 is an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl or aryl;
A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a maximum of two of A, B, D and E representing a nitrogen atom, CR2 or CR3, wherein:
R2 and R3 are independently selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally further substituted straight or branched C1-C6 alkyl, R8R9N—C1-C6 alkyl and R7O—C1-C6 alkyl, wherein R7, R8 and R9 are as defined above;
Ra and Rb are independently hydrogen or methyl, with the proviso that when Ra, Rb, and R1 are hydrogen atoms, then at least one of A, B, D and E is nitrogen;
or isomers, tautomers, carriers, metabolites, prodrugs or pharmaceutically acceptable salt thereof.

9 more elements

A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:

1H-Pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
1H-Pyrrole-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
1-Methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
Tetrahydro-pyran-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-H1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
Furan-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-ethyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;
1H-Pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
1H-Pyrrole-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
1-Methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;
1H-Pyrrole-2-carboxylic acid {5-dimethylamino-2-[5-(pyridine-3-sulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-phenyl}-amide;
1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-phenyl}-amide;
1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-phenyl}-amide;
1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide;
1H-Pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;
1-Methyl-1H-pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-7,7-dimethyl-4,5,6,7-tetrahydro-H1H-pyrazolo[4,3-c]pyridin-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(2-dimethylamino-1-methyl-ethylamino)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-isopropyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(2-pyrrolidin-1-yl-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-propyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
4-[(2-Diethylamino-ethyl)-methyl-amino]-N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-((2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-ylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[(2-dimethylamino-ethyl)-ethyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(2-diisopropylamino-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[methyl-(2-pyrrolidin-1-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-{[2-(isopropyl-methyl-amino)-ethyl]-methyl-amino}-2-(tetrahydro-pyran-4-ylamino)-benzamide;
4-(2-Diethylamino-1-methyl-ethylamino)-N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[methyl-(2-morpholin-4-yl-ethyl)-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-fluoro-piperidin-1-ylmethyl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and
N-[5-(3,5-Difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide.

37 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A compound of formula (I):

wherein:
R is an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl or aryl;
R1 is selected from hydrogen, halogen, nitro, NHCOR4, NHSO2R10, NR5R6, OR7, R8R9N—C1-C6 alkyl, R7O—C1-C6 alkyl and an optionally further substituted straight or branched C1-C6 alkyl, wherein:
R4 is selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, NR8R9, R8R9N—C1-C6 alkyl and R7O—C1-C6 alkyl;
R5 and R6, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, R8R9N—C2-C6 alkyl and R7O—C2-C6 alkyl;
R7 is selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl and R8R9N—C2-C6 alkyl;
R8 and R9, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl and aryl, and R8 and R9, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycloalkyl group;
R10 is an optionally further substituted straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl or aryl;
A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a maximum of two of A, B, D and E representing a nitrogen atom, CR2 or CR3, wherein:
R2 and R3 are independently selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally further substituted straight or branched C1-C6 alkyl, R8R9N—C1-C6 alkyl and R7O—C1-C6 alkyl, wherein R7, R8 and R9 are as defined above;
Ra and Rb are independently hydrogen or methyl, with the proviso that when Ra, Rb, and R1 are hydrogen atoms, then at least one of A, B, D and E is nitrogen;
or isomers, tautomers, carriers, metabolites, prodrugs or pharmaceutically acceptable salt thereof.

9 more elements