Preparation of pyrido[2,3-d]pyrimidin-7-one derivatives as Raf inhibitors for the treatment of cancer.

Abstract

Title compds. I [R1 = H, NH2, (un)substituted NH-alkyl, NH-cycloalkyl, etc.; R2 = H, halo, Me, CH2F, etc.; one of R3 and R4 = H, and the other = -NH-C(O)-(NH)x-(CH2)y-R6, wherein x and y independently = 0-1; R5 = H, (un)substituted alkyl, alkenyl, alkynyl, etc.; R6 = (un)substituted aryl or heteroaryl], and their tautomers or pharmaceutically acceptable salts, are prepd. and disclosed. These compds. are inhibitors or kinases such as Raf, including compds. that show anti-proliferative activity, including against tumor cells, and are useful in the treatment of diseases including cancer. E.g., II was prepd. by amidation of 4-chloro-3-(trifluoromethyl)benzoic acid with 6-(5-amino-2-chlorophenyl)-2-[[2-(dimethylamino)ethyl]amino]-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (prepn. given). Compds. of the invention were tested for their in vitro inhibitory activity against protein kinases. E.g., all tested compds. inhibited c-Raf and p38 from about 70% to about 100%. [on SciFinder(R)]