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Evaluation of WO2015042088 A1 - a novel urea-based scaffold for TrkA inhibition

ABSTRACT Tropomyosin receptor kinases (TrkA/B/C) are involved in the development and maintenance of the nervous system. TrkA is a target for chronic pain treatment due to the central position of the nerve growth factor (NGF)/TrkA pathway in nociception. Clinical evidence points toward mutated oncogenic Trk fusion proteins retaining intact kinase domains as relevant targets for cancer treatment. Merck pursues Trk inhibitors for inflammatory and neuropathic pain treatment and has previously reported type I and II selective pan-Trk inhibitors. This is the fifth filing by Merck disclosing urea-based Trk inhibitor series. This application claims nonsymmetric 1-(9H-fluoren-9-yl)urea and 1-(9H-xanthen-9-yl)urea derivatives containing a wide range of 5- and 6-membered bi- or tri-heterocyclic fragments as TrkA inhibitors for the treatment of Trk-related conditions. The exemplified compounds display IC50 values ranging from 27 to 4800 nM against TrkA. The TrkA inhibitors claimed confirm the emergence of nonsymmetric ureas lacking the hinge-binding motif as a favored Trk inhibitor structure. The compounds exemplified will likely be structurally optimized in the future. Despite the lack of selectivity profiling, the progression of the Trk inhibitor scaffold exploration by Merck also suggests that the compounds disclosed in this patent likely constitute non–adenosine triphosphate (ATP) competitive type III pan-Trk inhibitors.