Design and Synthesis of New Pyrazolo[1,5-c]quinazolin-5-amines as Potential TLR7/8 Modulators.

Multiple heterocyclic scaffolds have been found to exhibit agonist or antagonist activity at toll-like receptors (TLRs) with varying degrees of selectivity for the subtypes. TLR7 and 8 agonists are potentially valuable vaccine adjuvants while antagonists show useful activity against autoimmune diseases and cancer. A pyrazolo[1,5-c]quinazoline based compound 23, an unexplored scaffold in the domain of TLR7/8, was synthesized by analogy with lead agonists and antagonists from the literature. Compound 23 exhibited moderate agonist activity for both TLR7 and TLR8. The effect of structural modifications at the C1, C8, C9, and C10 position of the pyrazolo[1,5-c]quinazoline scaffold on hTLR7/8 activity was investigated by synthesizing a focused library of compounds. Although none of the compounds had agonist activity, three compounds were found to be dual TLR7/8 antagonists. These findings add to the existing structure-activity relationship knowledge of the tricyclic TLR7/8 modulators that will aid subsequent discovery and optimization of new drug candidates.