Pyrrolotriazine derivatives as kinase inhibitors, and their preparation. pharmaceutical compositions, and inhibition of kinase activity of growth factor receptors VEGFR-2 and FGFR-1 making them useful as anticancer agents.

Abstract

The invention provides compds. of formula I, and pharmaceutically acceptable salts thereof. Compds. I where X is O, CO2, CO, OCONH, S, SO, SO2, or X is absent; R1 is H, (un)substituted alkyl, alkenyl, alkynyl, (hetero)aryl, heterocyclo, (hetero)aralkyl, or heterocycloalkyl derivs.; R2 = H, or (un)substituted alkyl; R3 is (un)substituted aminocarbonylaryl derivs., and the corresponding stereoisomers, pharmaceutical acceptable salts, esters, prodrugs, or solvates thereof are claimed in this invention. The formula I compds. inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anticancer agents. The formula I compds. are also useful for the treatment of other diseases assocd. with signal transduction pathways operating through growth factor receptors. Chloro compd. II underwent nucleophilic substitution with N-cyclopropyl-3-amino-4-fluorobenzamide to provided invention compd. III. Compds. I inhibit the VEGFR-2 and FGFR-1 with an IC50 value between 0.01 and 10 μM, and the preferred compds. have IC50 values less than 0.3 μM. These compds. were selective against VEGFR-2 and FGFR-1 kinase enzymes, and they have minimal activity against CDK-2 kinase and LCK and Src kinases, where the activity against these kinases was >1 μM. [on SciFinder(R)]