Discovery and Development of CNS-Penetrant IRAK4 Inhibitors

Key words

IRAK4 - pyridones - CNS-Penetrant

Significance

Interleukin-1 Receptor Associated Kinase 4 (IRAK4) inhibitors are emerging therapeutics for the treatment of neurological disorders. In this work, Bolduc, Peterson and co-workers describe the property driven optimization of previous lead compound 1 to compound 24, which has improved potency, solubility and brain penetration. Challenging chemistry was enabled to the synthesis of the bridged ether ring and access complex 3-amino-2-pyridone analogues, leading to identification of the potent cis-fluorocyclopropyl pyridone structure in compound 24.

Comment

Compounds were designed to decrease lipophilicity and increase F _sp ³, with the goal of improving solubility and brain penetration. Swapping the imidazolopyrimidine 5,6-heterocyclic core in 1 with an azaindazole core improved potency, solubility, and MDR1 efflux ratio. The bridged ether ring improved potency, metabolic stability, and solubility. A challenging Cadogan cyclization was optimized to enable the scalable installation of the bridged ether onto the azaindazole core in 55% yield. Replacement of pyrazolopyrimidine amide in 1 with an N-alkylpyridone reduced eLogD and introduced an opportunity to increase F _sp ³ . A one-pot Knoevenagel, Michael addition and nitro reduction approach developed in a previous report by the authors (Org. Lett. 2022, 24, 6133) was utilized to access diverse 3-amino-2-pyridone analogues leading to identification of the potent cis-fluorocyclopropyl derivative 24.

Publication History

Article published online:
25 July 2024