Preparation of 3-substituted 1H-pyrrolo[2,3-b]pyridine and 1H-pyrrolo[3,2-b]pyridine compounds as mTOR kinase and PI3 kinase inhibitors.

Abstract

Title compds. I [A = O, S, or CH2; dash line = optional second carbon-to-carbon bond; D = C-R6 or N; E = C-R9 or N; R1, R2, R3, and R4 independently = H or (un)substituted alkoxy; R5 = H, alkyl, aryl, etc.; R6 and R9 independently = H, alkoxy, (un)substituted alkyl, etc.; R7 and R8 when taken together can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the two carbon atoms to which it is attached, forms a 5- to 7-membered heterocycle contg. two oxygen atoms; R10 = H or (un)substituted alkyl; R11 = H or alkyl], and their geometric isomers or pharmaceutically acceptable salts, are prepd. and disclosed. Thus, e.g., II was prepd. by reacting 1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (prepn. given) with 4,6-dihydroxybenzofuran-3-one in the presence of HCl at the temp. of 90°C. The invention compds. were tested in PI3K fluorescence polarization assay and mTOR enzyme assay, e.g., II exhibited IC50 value of 64 nM and 41.5 nM for PIK3-α and mTOR kinase, resp. As inhibitors of mTOR and PIK3, I should prove useful for the treatment of PI3K-related and mTOR-related disorders such as cancer, restenosis, atherosclerosis, arthritis, etc. [on SciFinder(R)]