Imidazopyrazine-amide-based inhibitors

Recent patent disclosures reveal efforts to optimize within this template. The amide moiety has been cyclized to give dihydroisoquinolone inhibitors such as 9 and 10 [57]. Using various mono- and bicyclic core structure scaffolds, the amide has also been constrained in isoquinolone, 

Relatively high molecular weight is a feature of the chemotype exemplified by 4-11 and this can require creative formulation techniques. Pharmacokinetic properties of a lead candidate (structure unknown) from the same series that provided 10 were inadequate to provide sufficient exposures at high doses to support preclinical safety studies. However, cocrystal formulations with saccharin or gentisic acid improved water solubility by 50-fold and increased oral exposures up to 10-fold relative to traditional formulations at 20mg/kg [64]. 

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Publications describing Btk inhibitors are scarce [39], but a recent upturn in patent activity points to intensifying medicinal chemistry efforts. The field is dominated by two classes irreversible inhibitors and reversible inhibitors which are based on an imidazopyrazine-amide scaffold (Figure 2). 

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