Fluoro-substituted 3,5-dicyano-4-(1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine derivatives and methods of use thereof
View Patent ↗The present invention relates to novel fluoro-substituted 3,5-dicyano-4-(1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine derivatives having protein tyrosine kinase inhibitory activity, to a process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions, particularly cancer and other proliferative disorders.
1. A compound of formula (I)
wherein
R 1 is hydrogen, fluoro, methyl or ethyl,
R 2 is methyl, difluoromethyl or trifluoromethyl,
R 3 is hydrogen or fluoro,
R 4 is hydrogen, methyl or ethyl,
and
R 5 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
2. The compound of formula (I) according to claim 1 , wherein
R 5 is hydrogen,
or a pharmaceutically acceptable salt thereof.
3. The compound of formula (I) according to claim 1 , wherein
R 1 is hydrogen or fluoro,
or a pharmaceutically acceptable salt thereof.
4. The compound of formula (I) according to claim 1 , wherein
R 1 is hydrogen or fluoro,
R 2 is methyl or difluoromethyl,
R 3 is hydrogen or fluoro,
R 4 is hydrogen or methyl,
and
R 5 is hydrogen,
or a pharmaceutically acceptable salt thereof.
5. The compound of formula (I) according to claim 1 , wherein the compound is selected from the group consisting of
rac-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
(4R)-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
(4S)-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
rac-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
(4R)-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
(4S)-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
2,6-Bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile;
2,6-Bis(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile;
and
rac-4-(6-Fluoro-1H-indazol-5-yl)-2-methyl-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
or a pharmaceutically acceptable salt thereof.
6. A salt of a compound of formula (I) according to claim 1 , having a formula (I-A)
wherein
R 1 , R 2 , R 3 and R 4 have the meanings defined in claim 1 ,
and
Q + is an alkali metal cation or a quaternary ammonium cation.
7. The salt of formula (I-A) according to claim 6 , wherein
Q + is a sodium or potassium cation or a 2-hydroxyethyltrimethyl ammonium (choline) cation.
8. The salt of formula (I-A) according to claim 6 , wherein
Q + is a 2-hydroxyethyltrimethyl ammonium (choline) cation.
9. A pharmaceutical composition comprising a compound as defined in claim 1 , and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising a salt as defined in claim 6 , and a pharmaceutically acceptable excipient.