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Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus Kinase (JAK) Inhibitors

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus Kinase (JAK) Inhibitors

James J-W Duan, Zhonghui Lu, Bin Jiang, Bingwei V Yang, Lidia M Doweyko, David S Nirschl, Lauren E Haque, Shuqun Lin, Gregory Brown, John Hynes Jr, John S Tokarski, John S Sack, Javed Khan, Jonathan S Lippy, etc.

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5721-5726.

PMID: 25453808

Abstract:

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42411949	Tyk2 active human			Price

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