An efficient and concise synthesis of a selective small molecule non-peptide inhibitor of cathepsin L: KGP94.

[Display omitted] • New routes include the synthesis of a key phenolic-protected, functionalized benzophenone intermediate. • An alternative approach enables access to the new analogue. • Inexpensive starting materials, mild conditions, and excellent overall yield. • Reasonable, reliable, and suitable method for both bench and industrial scales. KGP94 is a potent, selective, and competitive inhibitor of the lysosomal endopeptidase enzyme (Cathepsin L) currently in preclinical trials for the treatment of metastatic cancer, which is a leading cause of cancer-associated death. Herein, we report two new synthetic routes for synthesizing the target compound through four consecutive steps, using a Weinreb amide approach starting from a common 3-bromobenzoyl chloride. A key step in the approach is a coupling reaction of a readily available Grignard reagent with amide 4 to produce 6 , a previously unreported coupling pattern. These new strategies offer an efficient and alternative approach to synthesis of target compound with an excellent overall yield. [ABSTRACT FROM AUTHOR]