By: Crew, Andrew P.; Hornberger, Keith R.; Wang, Jing; Dong, Hanqing; Qian, Yimin; Crews, Craig M.; Jaime-Figueroa, Saul
United States, US10723717 B2 2020-07-28 | Language: English, Database: CAplus
The disclosure relates to bifunctional compounds of formula I, which find utility as modulators of rapidly accelerated fibrosarcoma
(RAF, such as c-RAF, A-RAF and/or B-RAF, the target protein). In particular, the present disclosure is directed to bifunc tional
compounds I, wherein ULM is a small mol. E3 ubiquitin ligand binding moiety that binds to E3 ubiquitin ligase selected from a group
consisting of Von Hippel-Lindau, inhibitors of apoptosis proteins or mouse double- minute homolog 2 ligand; PTM is a small mol.
that binds the target protein RAF; L is a bond and a chem. linking moiety; and their pharmace utically acceptable salts, enantiomers,
stereoisomers, solvates, polymorphs and prodrugs thereof, are claimed. Thus, compound II was prepared by a multistep procedure
(procedure given). The invention compounds were evaluated for their B- RAF degradation activity. From the assay, it was determined
that compound II exhibited DC value in the range of < 100 n M to > 50 nM and D value of > 70%.