FLUORO-SUBSTITUTED 3,5-DICYANO-4-(1H-INDAZOL-5-YL)-2,6-DIMETHYL-1,4-DIHYDROPYRIDINE DERIVATIVES AND METHODS OF USE THEREOF

Disclosed herein is a compound of formula (I) wherein is R1 hydrogen, fluoro, methyl or ethyl, R2 is methyl, difluoromethyl or trifluoromethyl, R3 is hydrogen or fluoro, R4 is hydrogen, methyl or ethyl, and is hydrogen or methyl; a salt thereof of the formula (I-A) wherein Q+ is an alkali metal cation or a quaternary ammonium cation; a process for the preparation thereof and the use thereof in the treatment of cancer. The process is characterised in that an indazolyl aldehyde of formula (II) is reacted with a ketonitrile of formula (II) in the presence of an acid, acid/base combination and/or dehydrating agent to give a compound of formula (IV) which is then condensed either with an enaminonitrile of formula (V) in the presence of a base to give a compound of formula (I-C) or dihydropyridine salt formation by treatment with an agent of formula (VIII) to yield the 1,4-dihydropyridinide salt of formula (I-A). Exemplary compounds include: rac-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-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; and 2,6-bis( difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile.