Identification of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model.

We herein report the structural optimization and structure-activity relationship (SAR) studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all the obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity (KD) of 0.004 μM and an enzymatic IC50 value of 0.011 μM, and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, Compound 22b exhibited excellent anti-metastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.