Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors Mark J. Wall, Jinsheng Chen, Sanath Meegalla, Shelley K. Ballentine, Kenneth J. Wilson Renee L. DesJarlais, Carsten Schubert, Margery A. Chaikin, Carl Crysler, Ioanna P. Petrounia, Robert R. Donatelli, Edward J. Yurkow, Lisa Boczon, Marie Mazzulla, Mark R. Player, Raymond J. Patch, Carl L. Manthey, Christopher Molloy, Bruce Tomczuk and Carl R. Illig * Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA Received 14 December 2007; revised 21 January 2008; accepted 23 January 2008 Available online 30 January 2008 Abstract—A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domai rophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imid yl)-2-quinolone-6-carbonitrile 21b, has an IC 50 of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model. Ó 2008 Elsevier Ltd. All rights reserved. The macrophage colony-stimulating factor-1 receptor (FMS) is the cell surface receptor for colony-stimulating factor-1 (CSF-1), which controls growth and differentia- tion of the monocyte/macrophage lineage. 1 FMS is a member ofthe type III receptor tyrosine kinases that also includes FLT-3, PDGFR, and KIT. Macrophages are thought to play an important role in several diseases, including cancer and inflammation. For example, of the severalleukocytelineagespresentin the rheumatoid arthritis synovium, increased levels of macrophages best correlate with disease severity and response to therapy. 2 In addition,expression ofFMS in breast cancerhas been linked to poor survivability and increased tumor size, where presumably the receptor is involved in local invasion and metastasis. 3–5 Consequently there is signif- icant interest in modulating the CSF-1 pathway and sev- eral structuralclassesof small-molecule inhibitors of FMS have been reported. 6–11 We have recently published an X-ray crystal structure of the FMS kinase domain in complex with two classes of inhibitors. 11 In this paper we describe the synthesis and optimization of one of these classes of compounds, the 2-quinolones, shown in Figure 1. A high-throughput screen using Thermofluor Ò technol- ogy 12 produced quinolone 1, with an IC 50 of 1 lM for FMS. Initial chemistry efforts began by synthesizing analogueswith substitution in the 3- and 6-positions of the quinolone. These compounds could be readily prepared by condensation of 2-aminophenyl ketones 2 with a-substituted acetic acids in phosphorus oxychlo- ride to give the corresponding 2-chloroquinolines 3 that are subsequently hydrolyzed to the corresponding quin- olones 4 in aqueous acetic acid according to the proce- dures outlined in Scheme 1. The aminophenyl ketones 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.088 Keywords: FMS; cFMS; Colony-stimulating factor-1 receptor; CSF-1; M-CSF; 2-Quinolones. * Corresponding author. Tel.: +1 610 458 6057; fax: +1 610 458 8249; e-mail: cillig@prdus.jnj.com N H Cl O O O 3 4 6 1 FMS IC 50 = 1 µ M Figure 1.Thermofluor Ò HTS screening hit. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 2097–2102