Src homology 2 domain–containing inositol 5-phosphatase 1 (SHIP1), encoded by gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia, which modulates downstream cellular proliferation, survival, and chemotaxis. Here, we report the optimization and characterization of a pyridyl–pyrazole-piperidine scaffold as a basis for SHIP1 ligands that demonstrate cellular target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure–activity relationship studies guided by biochemical and cellular assays using multiple human and murine SHIP1 protein constructs and cells identified compound 32 as a SHIP1-active ligand. To ensure that the cellular activity of compound 32 is not due to kinase inhibition in general within the context of BV2 mouse microglia cells, we executed a kinome profiling study of compound 32 compared to crizotinib as a positive control using BV2 cell lysates.