US 2014/0235675 A1Published application

3-oxo-2,3-dihydro-1h-indazole-4-carboxamide derivatives as parp-1 inhibitors

AssigneeNerviano Medical Sciences S.R.L.

InventorsGianluca Mariano Enrico Papeo, Daniela Borghi, Michele Caruso, Helena Posteri, Mikhail Yurievitch Krasavin

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Abstract

There are provided 3-oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP-1 with respect to poly (ADP-ribose) polymerase PARP-2. The compounds of this invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

Claims23

Dependent claims

A compound of formula (I):

wherein
R1 is an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2 is hydrogen, COR4 or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R3 is hydrogen, halogen, cyano, nitro, NHCOR4, COR4, NR5R6, NR5COR4, OR7, SR7, SOR10, SO2R10, NHSOR10, NHSO2R10, or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, R8R9N—C1-C6 alkyl and R8O—C1-C6 alkyl;
R4 is hydrogen, NR5R7, OR7, SR7, or an optionally substituted group selected from linear or branched C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, R8R9N—C1-C6 alkyl and R8O—C1-C6 alkyl;
R5 and R6 are independently hydrogen, or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, R8R9N—C1-C6 alkyl and R8O—C1-C6 alkyl, or R5 and R6, taken together with the nitrogen to which they are bonded, form an optionally substituted heterocyclyl group;
R7 is hydrogen, COR5, SOR10, SO2R10 or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, R8R9N—C1-C6 alkyl, R8O—C1-C6 alkyl, heterocyclyl-C1-C6 alkyl, aryl-C1-C6 alkyl and heteroaryl-C1-C6 alkyl, wherein R5 is as defined above;
R8 and R9 are independently hydrogen, COR4 or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl and heteroaryl, or R8 and R9, taken together with the nitrogen to which they are bonded, form an optionally substituted heterocyclyl group, wherein R4 is as defined above;
R10 is hydrogen, NR5R6, OR7 or an optionally substituted group selected from linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, R8R9N—C1-C6 alkyl and R8O—C1-C6 alkyl, wherein R5, R6, R7, R8 and R9 are as defined above;
or a pharmaceutically acceptable salt thereof.

7 more elements

A compound of formula (I) or a salt thereof, selected from the group consisting of:

3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclopentylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclopentylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-2-(1-methylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-ethylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-(1-propylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-ethylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(propan-2-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclobutylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclobutylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclobutylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(4,4-dichlorocyclohexyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
6-chloro-2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylazetidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylazetidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
6-chloro-2-(1-cyclohexylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylazetidin-3-yl)-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(cyclohexylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-benzylpiperidin-4-yl)-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(cyclohexylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-benzylpiperidin-4-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-[4-(piperidin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-(1-phenylpiperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(1H-pyrrol-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-{1-(1H-pyrrol-3-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(furan-3-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(furan-3-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-1-(1H-pyrrol-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-[1-(pyridin-4-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-[1-(pyridin-3-yl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[4-(pyridin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-ethyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
2-(1-cyclohexylpiperidin-4-yl)-1-ethyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2[4-(pyridin-4-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-ethyl-6-fluoro-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-3-oxo-2[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
6-fluoro-1-methyl-3-oxo-2-[4-(pyridin-3-yl)phenyl]-2,3-dihydro-1H-indazole-4-carboxamide,
3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
1-methyl-3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide,
2-[1-(furan-2-ylmethyl)piperidin-4-yl]-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide, and
2-[1-(furan-2-ylmethyl)piperidin-4-yl]-1-methyl-3-oxo-2,3-dihydro-1H-indazole-4-carboxamide.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/233,963Filed 18 Jul 2012
Priority: EP 11175355.426 Jul 2011
Published: 21 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/4188
1,3-Diazoles: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61P 9/00
Drugs for disorders of the cardiovascular system