1403458-80-9

Upstream product

• 1403459-00-6 tert-butyl (2R)-2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate 
• 1403458-59-2 tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate 
• 1403458-58-1 tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate 
• 1403458-64-9 methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 1296271-33-4 methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate 

Downstream Products

• 1403458-46-7 8-[(2R)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide 

Relevant academic research and scientific papers

Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours

Attempts to lock the active conformation of compound 4, a PI3Kβ/δ inhibitor (PI3Kβ cell IC50 0.015?μM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kβ/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kβ cell IC50 0.0011?μM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014?μM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kβ/δ preclinical candidates.

CHROMENONE DERIVATIVES

The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, n and R6 has any of the meanings defined hereinbe