Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

Abstract

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2

“…To avoid significant hydrolysis of the ester functionality, it was important to run the reaction at a relatively low temperature (75 °C) and within a relatively short period of time (4 h). In the same manner, 41b was obtained from 40, which was prepared from 3-bromo-5-fluoro-2methoxyaniline (39). Treatment of 41a and 41b with 4,6dichloro-N-(methyl-d 3 )pyridazine-3-carboxamide (37) 53 in the presence of lithium bis(trimethylsilyl)amide resulted in chloropyridazine carboxamides 42a and 42b, which were then converted to 43a and 43b by Buchwald reaction.…”

“…The adverse effects of these drugs may be linked to the lack of specificity or selectivity. Tyk2 JH1 inhibitors such as 1 , 2 , 3 (PF-06700841), , and 4 (PF-06826647) (Figure ) have been reported, with 3 and 4 in clinical trial phases II and I, respectively. Like the JH1 inhibitors of other Jak family members, these inhibitors are only modestly selective as they also show significant activities against other Jak family members.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Interestingly, the initial SAR investigation showed that this platform could have a vertically flipped binding mode. Introduction of a 1‐methyl‐3‐pyrazolyl group at the 7‐position of 45 directed toward the solvent‐exposed region led to a significant improvement in TYK2‐inhibitory potency, and further modification resulted in the identification of 46 …”

Inherent formulation issues of kinase inhibitors

“…These include highly lipophilic moieties such as (substituted) phenyls, aromatic amines, biaryl constructs and heterocyclic aromatics. Using these structures as scaffolds, a great number of studies have designed new smKIs by adding different side groups [ [117][118][119]. Combining scaffolds to create a new multi-kinase-targeting smKI is also a commonly used strategy [120].…”