Tricyclic IndazolesA Novel Class of Selective Estrogen Receptor Degrader Antagonists

Herein, we report
the identification and synthesis of a series
of tricyclic indazoles as a novel class of selective estrogen receptor
degrader antagonists. Replacement of a phenol, present in our previously
reported tetrahydroisoquinoline scaffold, with an indazole group led
to the removal of a reactive metabolite signal in an in vitro glutathione
trapping assay. Further optimization, guided by X-ray crystal structures
and NMR conformational work, varied the alkyl side chain and pendant
aryl group and resulted in compounds with low turnover in human hepatocytes
and enhanced chemical stability. Compound 9 was profiled
as a representative of the series in terms of pharmacology and demonstrated
the desired estrogen receptor α degrader–antagonist profile
and demonstrated activity in a xenograft model of breast cancer.