SAR studies of 6-(arylamino)-4,4-disubstituted-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones as progesterone receptor antagonists

We previously disclosed that 6-aryl benzoxazin-2-ones were PR modulators. In a continuation of this work we examined the SAR of new 6-arylamino benzoxazinones and found the targets 1–25, with an extra amino linker between the pendent 6-aryl groups and benzoxazinone or benzoxazine-2-thione core, were PR antagonists. A series of compounds with substituents at the 1- and 4-positions as well as different 6-aryl groups were prepared and tested in the T47D cell alkaline phosphatase assay. Interestingly, the SAR unveiled from the 6-arylamino benzoxazinones was quite different from those of their parent compounds. For example, in contrast to the 6-aryl benzoxazinones, methyl substitution at the 1-position significantly increased the potency of 6-arylamino benzoxazinones. Several 6-arylamino benzoxazinones (e.g., 12, IC50 = 5.0 nM) had low nanomolar in vitro potency as PR antagonists in the T47D cell alkaline phosphatase assay.

Graphical abstractInsertion of a NH linker at the 6-position of 6-aryl benzoxazinones, the progesterone receptor (PR) modulators, led to exclusively PR antagonists (1–25) in a progesterone induced alkaline phosphatase assay in the T47D cells.Figure optionsDownload full-size imageDownload as PowerPoint slide