2,6-BIS(((1H-BENZODIMIDAZOL-2-YL)THIO)METHYL)PYRIDINE AND N2,N6-DIBENZYLPYRIDINE-2,6-DICARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS PHOSPHOINOSITIDE 3-KINASE (PI3K) INHIBITORS FOR TREATING CANCER

摘要

2,6-bis(((lH-benzo[d]imidazol-2-yl)thio)methyl)pyridine and N2, N6-dibenzylpyridine-2, 6-dicarboxamide derivatives and related compounds as phosphoinositide 3-kinase (PI3K) inhibitors for treating cancer. The present invention relates to pharmaceutically active 2,6- bis(((lH-benzo[d]imidazol-2-yl)thio)methyl)pyridine, N2,N6- dibenzylpyridine-2, 6-dicarboxamide and N2,N6-bis(3-hydroxyphenyl) pyridine-2, 6-dicarboxamide, as well as to derivatives thereof, and to structurally related compounds. These compounds are phosphoinositide 3-kinase inhibitors (PI3K) and useful in treating or preventing cancerous diseases. The invention further relates methods of manufacturing such compounds as well as to pharmaceutical compositions and formulations comprising such compounds, optionally together with other pharmaceutically active compounds. The invention further relates to a method for determining the activity of PI3Kalpha or PI3Kalpha mutants, which method includes: a) providing a solid phase which is functionalized by immobilization of GST-GRPl-molecules onto the solid phase, b) performing a PI3Kalpha or PI3Kalpha mutant catalyzed enzyme reaction to convert PIP2 to PIP3, c) adding competitor PIP3 carrying a detectable label or reporter molecule, and d) determining enzyme activity based on the amount of PIP3 obtained in step b) which competes with competitor PIP3 for binding to the functionalized solid phase.