Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1 Christopher A. Hurley a,⇑ , Wade S. Blair g , Richard J. Bull a , Christine Chang g , Peter H. Crackett a , Gauri Deshmukh d , Hazel J. Dyke a , Rina Fong f , Nico Ghilardi e , Paul Gibbons c , Peter R. Hewitt a , Adam Johnson g , Tony Johnson a , Jane R. Kenny d , Pawan Bir Kohli g , Janusz J. Kulagowski a , Marya Liimatta g , Patrick J. Lupardus f , Robert J. Maxey a , Rohan Mendonca c , Raman Narukulla a , Rebecca Pulk c , Savita Ubhayakar d , Anne van Abbema g , Stuart I. Ward a , Bohdan Waszkowycz b , Mark Zak c a Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom b Department of Computer Aided Drug Design, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom c Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States d Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States e Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States f Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States g Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States article info Article history: Received 22 February 2013 Revised 5 April 2013 Accepted 6 April 2013 Available online 17 April 2013 Keywords: Janus kinase JAK1 JAK2 JAK1 inhibitor abstract The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which dis- play nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previ- ously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib). Ó 2013 Elsevier Ltd. All rights reserved. Cytokine signaling pathways mediate a broad range of biologi- cal functions, including many aspects of inflammation and immu- nity. 1 Types I and II cytokine receptors lack kinase activity and instead transmit their signals through the receptor-associated Ja- nus kinases (JAK1, JAK2, JAK3, and TYK2). 2,3 When stimulated, cytokine receptor complexes activate specific combinations of JAKs in well-defined patterns, 4 leading to further activation of signal transducer and activator of transcription (STAT) proteins residing in the cytoplasm. Upon JAK-mediated tyrosine phosphorylation, the STATs dimerise and are translocated to the nucleus where they regulate transcription of specific target genes. 5,6 Because of the importance of the JAK/STAT pathways in cytokine signaling, target- ing of JAK kinases is envisioned to be useful in the treatment of a variety of diseases including rheumatoid arthritis (RA), 7 myelopro- liferative disorders 8 and cancer. 9 Current evidence suggests that immuno-relevant cytokines (such as IL-6 and the c c cytokines) play a pivotal role in RA disease pathogenesis. 10,11 The approved pan-JAK inhibitor tofacitinib (1, Fig. 1) has undergone extensive evaluation for RA and has demon- strated efficacy in various clinical trials, likely due to its suppres- sion of the IL-6 and c c cytokine pathways. 12 Additionally, a humanized monoclonal antibody (tocilizumab) targeting the IL-6 pathway has been approved for the treatment of moderate to se- vere RA. 13 Although IL-6 activates JAK1, JAK2, and TYK2, knockout studies in mice have demonstrated that JAK1 plays a particularly important role in signal transduction. 14 Additionally, JAK1 has been shown to play a critical and potentially dominant role in the transduction of c c cytokine signaling. 15 Finally, inhibition of JAK2 is associated with anemia, 16 thus limiting its suppression may be beneficial. We, therefore, desired to develop potent JAK1 inhibitors with reduced inhibition of JAK2 to maximize anti-RA ef- fects while limiting the potential for anemia. We previously reported the identification and preparation of novel fused imidazo-pyrrolopyridine tricyclic JAK inhibitors, such as compound 2 (Fig. 1), that exhibited modest selectivity for JAK1 over the JAK2 isoform. 17 However, some members of this structural class were compromised by low in vitro permeability in MDCK cells and inadequate oral exposure in rat pharmacokinetic studies. In an effort to circumvent the problems faced with com- pounds such as 2, we undertook an exploration to find suitable imidazo-pyrrolopyridine scaffold replacements. One restriction 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.04.018 ⇑ Corresponding author. Tel.: +44 1279 645 645; fax: +44 1279 645 646. E-mail address: Chris.Hurley@glpg.com (C.A. Hurley). Bioorganic & Medicinal Chemistry Letters 23 (2013) 3592–3598 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl