Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
A new class of pyrazolo derivative compounds having the formula where R and R 1 have the meanings given herein. The pyrazolo derivative compounds are useful in treating cell proliferative disorders caused by and/or associated with an altered cell cycle dependent kinase activity in mammals. The compounds may be provided in pharmaceutical compositions or in a kit.
1. A compound of formula (Ia)
wherein
R is a —COR a group, wherein R a is hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl;
R 1 is a group of formula (IIa)
wherein the cycle represents a 5 to 7 membered heterocyclic ring, wherein X, directly linked to the rest of the molecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of X and Y is other than a carbon atom; R c is, independently from each other and in any one of the free positions of the heterocyclic ring of formula (IIa), an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and n is 0 or an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
2. A compound of formula (Ia) according to claim 1 wherein R 1 is a group of formula (IIa) selected from:
wherein R, n and R c are as defined in claim 1 .
3. A compound of formula (Ia) according to claim 1 wherein R 1 is a group of formula (IIa) selected from:
wherein R, n and R c are as defined in claim 1 .
4. A compound, optionally in the form of a pharmaceutically acceptable salt, selected from the group consisting of:
N-{6,6-dimethyl-5-[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide,
N-{6,6-dimethyl-5-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide,
N-{6,6-dimethyl-5-[(1-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-cyclobutanebenzamide,
N-{6,6-dimethyl-5-[(1-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobeuzamide,
N-{6,6-dimethyl-5-[(4-methylpiperidin-1-yl)carbonyl]-2,4,5,6-tetrahydro pyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide,
3-methyl-N- [1,4,5,6-tetrahydro-6,6-dimethyl-5-[(1-methyl-4-piperidinyl) carbonyl]pyrrolo[3,4-c]pyrazole-3-yl]-butanamide, and
4-Chloro-N-[6,6-dimethyl-5-(4-pyrrolidin-1-yl-methyl-piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo [3 ,4-c]pyrazol-3-yl]-benzamide;
or a pharmaceutically acceptable salt thereof
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diuent.