Co-crystal screening data and machine learning models allows prediction of the most likely co-formers to use for new molecules.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER + breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f ]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

No abstract

The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates.