Development of CXCR3 antagonists. Part 4: Discovery of 2-amino-(4-tropinyl)quinolines Roland L. Knight, * Daniel R. Allen, Helen L. Birch, Gayle A. Chapman, Frances C. Galvin, Louise A. Jopling, Christopher J. Lock, Johannes W. G. Meissner, David A. Owen, Gilles Raphy, Robert J. Watson and Sophie C. Williams UCB Inflammation Discovery, Granta Park, Great Abington, Cambridge CB21 6GS, United Kingdom Received 10 October 2007; revised 19 November 2007; accepted 19 November 2007 Available online 28 November 2007 Abstract—The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropan porating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitab for studying the role of CXCR3 in models of disease. Ó 2007 Elsevier Ltd. All rights reserved. CXCR3 is a chemokine receptor which is mainly ex- pressed on CD4+ and CD8+ T cells with a Th 1 pheno- type, and in addition, is also expressed on B cells, naturalkiller (NK) cells,malignant T cells and astro- cytes.Interaction occurswith the threechemokines, MIG (CXCL9), IP-10 (CXCL10) and ITAC (CXCL11), which are induced primarily by IFN-c and are produced by macrophages and other cell types at sites of inflam- mation.Antagonism of this receptor has shown reduc- tion of disease severity in animal models of arthritis, 1,2 IBD, 3 diabetes 4 and transplant rejection. 5 Studies in hu- man patientshave implicated CXCR3 in rheumatoid arthritis, multiple sclerosis, diabetes, transplant rejection and COPD, 6 whilst the receptor has also been shown to drive chemotaxis of mast cells to airway smooth muscle in asthma. 7 In our previous publications, 8 we described the develop- ment of urea piperidine 1b (Fig. 1) from the screening hit 1a. This molecule,incorporatingthe homotropene amide moiety, showed promising potency, physicochem- ical properties and pharmacokinetics. Replacement of the central piperidine ring with a tropane was found to furtherimprove the potency and drug-like properties in this series. 8b We had also found 9 that in the azole derivative1c wecould replace thearyl urea moiety and retain activity against CXCR3. Going forward, our goal was to develop a series of non- urea derivatives which matched the potency and proper- ties of compounds such as 1b. This paper describes the development of very potent and drug-like CXCR3 antagonists from the benzazole template 1c. Initial work focused on investigating whether the bene- fits afforded by the homotropene moiety in 1b would lead to similar improvements in azole 1c. Incorporation of the homotropene amide right-hand side to the ben- zazole template was carried out according to Scheme 1 by the condensation of 2-chlorobenzothiazole with 1- BOC-4-methyl-aminopiperidine to give 2, followed by cleavage of the BOC group with HCl in MeOH to afford 3. Reductive alkylation with the BOC-homotropene 4 8b afforded 5,which was converted to the corresponding acetyl amide 6 by subsequentdeprotectionand acetylation. Comparison of compound 6 with compounds 1b and 1c is illustrated in Table 1 below. We were encouraged to find that compound 6 gave sim- ilar potency compared to 1c thus demonstrating that the homotropene group was well tolerated in thisseries whilst having significantly lower log D. Overall 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.11.075 Keywords:Chemokine;CXCR3; Quinoline;Tropane;Tool reagent; Inflammation. * Corresponding author. Tel.: +44 0 1223 896562; fax: +44 0 1223 896400; e-mail: roland.knight@ucb-group.com Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 629–633