Heterocyclic-fused pyrimidine derivatives as modulators of PIKK related kinase signaling, and their preparation and pharmaceutical compositions.

Abstract

Disclosed are compds. of formula I, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR). Compds. of formula I wherein A is a (un)substituted 5- to 8-membered heterocyclic ring and (un)substituted heterobicyclic ring; R1and R2 together with the atoms they are attached to form a 5- to 8-membered satd. heterocyclic ring; B is (un)substituted phenylene and (un)substituted 5- to 6-membered heteroarylene; D is NHCONH2 and derivs., NH2 and derivs., CONH2 and derivs., OCO2H and derivs., etc.; and pharmaceutically acceptable salts thereof, are claimed. Example compd. II was prepd. by N-arylation of 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-chloropyrimidine. All the invention compds. were evaluated for their kinase modulatory activity. From the assay, it was detd. that compd. II exhibited Ki value of ≤ 100 nM. [on SciFinder(R)]