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; Rosemary F Zhang; Sidney Pitt; Guoxiang Shen; William J Pitts; Percy H Carter; Joel C Barrish; Steven G Nadler; Luisa M Salter-Cid; Murray McKinnon; Aberra Fura; Gary L Schieven; Stephen T Wrobleski

doi:10.1016/j.bmcl.2014.10.061

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

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5721-5726. doi: 10.1016/j.bmcl.2014.10.061. Epub 2014 Oct 24.

Authors

James J-W Duan¹, Zhonghui Lu², Bin Jiang², Bingwei V Yang², Lidia M Doweyko², David S Nirschl², Lauren E Haque², Shuqun Lin², Gregory Brown², John Hynes Jr², John S Tokarski², John S Sack², Javed Khan², Jonathan S Lippy², Rosemary F Zhang², Sidney Pitt², Guoxiang Shen², William J Pitts², Percy H Carter², Joel C Barrish², Steven G Nadler², Luisa M Salter-Cid², Murray McKinnon², Aberra Fura², Gary L Schieven², Stephen T Wrobleski³

Affiliations

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Electronic address: [email protected].
² Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
³ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Electronic address: [email protected].

PMID: 25453808
DOI: 10.1016/j.bmcl.2014.10.061

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.

Keywords: JAK inhibitor; JAK3; Janus kinase; Pyrrolo[1,2-b]pyridazine; TYK2.

MeSH terms

Administration, Oral
Animals
Drug Discovery*
Enzyme-Linked Immunosorbent Assay
Humans
Interferon-gamma / metabolism
Janus Kinase 1 / antagonists & inhibitors*
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 3 / antagonists & inhibitors*
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Structure
Protein Conformation / drug effects
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyridazines / chemistry*
Pyrroles / chemistry*
Structure-Activity Relationship
Tissue Distribution

Substances

Protein Kinase Inhibitors
Pyridazines
Pyrroles
Pyrrolopyridazine
Interferon-gamma
JAK1 protein, human
JAK2 protein, human
JAK3 protein, human
Janus Kinase 1
Janus Kinase 2
Janus Kinase 3