TRIAZINE DERIVATIVE AS COVALENT INHIBITORS OF PI3K

Kinase-targeted covalent inhibitors are usually irreversibly targeting noncatalytic cysteines in the ATP- binding site. These compounds are designed by directly introducing an electrophile on a reversible-inhibitor scaffold. Our invention relates to novel triazine compounds, containing chemical reactive groups (warheads), targeting a solvent exposed cysteine at > 10 A from the core reversible inhibitor. A variety of novel linkers have been designed and used to link the warhead with the reversible scaffold. We disclose a novel chemical space for drug-like covalent modifiers of phosphoinositide 3-kinase alpha (PI3Ka), an enzyme frequently altered in human malignancies. The invention relates to novel covalent inhibitors showing higher in vitro affinity, cellular potency and improved metabolic stability (rat liver microsomes). The compounds of the invention couldbe exploited as therapeutic agents and chemical probes useful for modulating cellular activities such as signal transduction, proliferation, differentiation and cell death.