title: Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.
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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Electronic address: james.duan@bms.com.
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Bingwei V
authors.initials: BV
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Lidia M
authors.initials: LM
authors.lastname: Doweyko
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Nirschl
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haque
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Lin
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Brown
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hynes
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lippy
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Rosemary F
authors.initials: RF
authors.lastname: Zhang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Shen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pitts
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Salter-Cid
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Electronic address: stephen.wrobleski@bms.com.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; D007371:Interferon-gamma; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3
keywords: JAK inhibitor; JAK3; Janus kinase; Pyrrolo[1,2-b]pyridazine; TYK2