Discovery of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cells and is a negative regulator of T cell receptor (TCR) signaling. Recent studies have demonstrated that HPK1 is a promising therapeutic target for cancer immunotherapy. However, despite significant progress in the development of HPK1 inhibitors, none of them has been approved for cancer therapy. Development of HPK1 inhibitors with a structurally distinct scaffold is still needed. Herein, we describe the design and synthesis of a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d]pyrimidine scaffold, exemplified by 31. Compound 31 showed potent inhibitory activity against HPK1 with an IC value of 3.5 nM and favorable selectivity within a panel of kinases. It also potently inhibited the phosphorylation level of SLP76, a substrate of HPK1, and enhanced the IL-2 secretion in Jurkat cells (human T cell leukemia). Our findings provide new clues for further optimization and development to generate HPK1 inhibitors for cancer immunotherapy.