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Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1 H -imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo , which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1 H -imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Presented herein is an effective preparation of succinimide spiro-fused sultams through the coupling reaction of N -(phenylsulfonyl)acetamides with maleimides. It is deduced that this reaction should proceed through a cascade process including Rh(III)-catalyzed C(sp 2 )-H bond cleavage of N -(phenylsulfonyl)acetamide, maleimide double bond insertion into the C-Rh bond, β-hydride elimination, reductive elimination, and intramolecular aza-Michael addition. Notably, this cascade procedure features simultaneous annulation and spirocyclization through traceless fusion of the directing group into target product by using air as an economical oxidant to assist the regeneration of the active Rh(III) catalyst. This new method has several advantages including readily accessible starting materials with broad scope, significantly reduced synthetic steps, redox-neutral conditions, high atom-economy, and sustainability.

Rh(III)-catalyzed coupling between acrylic acids and yndienones has been realized for the synthesis of cis -hydrobenzofuranone. The reaction proceeded in excellent regio- and stereoselectivity under mild and redox-neutral conditions via a sequence of carboxylic acid-directed olefinic C-H activation, alkyne insertion, and Michael addition. Representative products were found to exhibit cytotoxicity toward the A549 cancer cell line at micromolar levels.