Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors†

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an in vivo tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles.