Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides

Abstract

The present disclosure relates to bifunctional compounds, 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 bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand whichbinds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disordersthat result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

Description

[0001] Cross References to Related Applications [0002] This disclosure claims priority to U.S. Provisional Application No. 62 / 438,803, filed December 23, 2016, and U.S. Provisional Application No. 62 / 582,698, filed November 7, 2017, both of which are incorporated by reference in their entirety This article. [0003] incorporated by reference [0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016; U.S. Patent Application 15 / 206,497, filed July 11, 2016; U.S. Patent Application Serial No. 62 / 406,888, filed April 11; U.S. Patent Application Serial No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application Publication No. .2016 / 0058872 published U.S. Patent Application Serial No. 14 / 792,414 filed July 6, 2015; U.S. Patent Application Serial No. 14 / 371,956; and US Patent Application Serial No. 15 / 074,820, filed March 18, 2016, published as US Patent Application Publication No. 2016 / 0...

AI Technical Summary

Problems solved by technology

Currently marketed agents also bind wild-type BRaf and cause its paradoxical activation, leading to clinical complications

Furthermore, the family of low-activity class III BRaf mutations that signal through heterodimerization with CRaf, which accounts for 40% of BRaf mutations in non-small cell lung cancer (NSCLC) and sporadically occurs in other cancers, cannot be recognized by any currently approved or Clinical-stage BRaf inhibitors target

[0017] Therefore, non-specific effects and the inability to target and modulate RAF remain obstacles to the development of effective therapeutics

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