Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3K delta Inhibitors: Part II-Benzimidazole Derivatives

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: alpha, beta, gamma, delta) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K delta, displaying IC50 values ranging from 1.892 to 0.018 mu M. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3K delta), good selectivity (for PI3K delta relative to other PI3K isoforms: PI3K alpha/delta = 79; PI3K beta/delta = 1415; PI3K gamma/delta = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.