Bolduc PN,
*,
Pfaffenbach M,
Evans R,
Xin Z,
Henry KL,
Gao F,
Fang T,
Silbereis J,
Rebollar JV,
Li P,
Chodaparambil JV,
Metrick C,
Peterson EA.
*
Biogen, Cambridge, USA
A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant
Aza-indazole IRAK4 Inhibitors.
ACS Med. Chem. Lett. 2024;
15: 714-721
DOI:
10.1021/acsmedchemlett.4c00102
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.
