Benzothiophene inhibitors of MK2. Part 2: Improvements in kinase selectivity and cell potency David R. Anderson * , Marvin J. Meyers * , Ravi G. Kurumbail, Nicole Caspers, Gennadiy I. Poda, Scott A. Long, Betsy S. Pierce, Matthew W. Mahoney, Robert J. Mourey, Mihir D. Parikh Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, MO 63017, USA article info Article history: Received 6 October 2008 Revised 3 February 2009 Accepted 5 February 2009 Available online 8 February 2009 Keywords: MK2 MAPKAP-K2 Kinase inhibitor abstract Optimization of kinase selectivity for a set of benzothiophene MK2 inhibitors provided analogs with potencies of less than 500 nM in a cell based assay. The selectivity of the inhibitors can be rationalized by examination of X-ray crystal structures of inhibitors bound to MK2. Ó 2009 Elsevier Ltd. All rights reserved. In Part 1 of this Letter we described a new class of benzothio- phene inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2). While these compounds were potent inhibitors of MK2 with sub-micromolar cellular potencies, selectiv- ity against other kinases, including CDK2, was not achieved. In this Letter, strategies used to improve the selectivity of this class of inhibitors are described. Previously we had disclosed that placing a rigid group near the hinge binding element resulted in remarkable selectivity enhance- ment for a different chemical class of MK2 inhibitors. 1 For example, compound 1 was found to possess good selectivity against a num- ber of kinases, and this selectivity was attributed to the rigid aryl group attached to the 2-position of the pyridine. Based on this precedent, we sought to modify the hinge binding element in the benzothiophene class (e.g., 2) to provide an attachment point for this selectivity element as shown in 3. To assess this hypothesis, compounds were prepared with an additional ring fused to the benzothiophene ring, which would provide a rigid attachment point for a selectivity element. To verify that the hetero atom, as part of an additional fused ring, could be an effective hinge-binding element, compounds without the selec- tivity element were first prepared (Fig. 1). The synthesis of furan and dihydro–furan analogs is shown in Scheme 1. Chlorobenzothiophene 4 2 was demethylated with BBr 3 and alkylated with allyl bromide to provide 5. Heating 5 to 200 °C in diethylaniline regioselectively provided 6 in quantitative yield. Treatment of 6 with OsO 4 /NaIO 4 gave a tautomeric mixture of 7 and 8. This mixture was converted to furan 9 by dehydration in phosphoric acid. Dihydrofuran 10 was prepared by sodium boro- hydride reduction, mesylate formation of the resulting primary alcohol and cyclization with sodium bicarbonate. Chlorobenzothi- ophenes 9 and 10 were then elaborated as described in Part 1 of this series by Buchwald coupling with 11, followed by deprotection and cyclization to afford diazapenes 12 and 13. 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.02.017 * Corresponding authors. Tel.: +1 636 247 7651 (D.R.A.). E-mail address: david.r.anderson@pfizer.com (D.R. Anderson). 1 N HN NH O R Selectivity Element S NH HN O X 3 S NH HN O O 2 R Hinge-binding Element Hinge-binding Element Figure 1. Rationale for improving selectivity of benzothiophene inhibitors of MK2. Bioorganic & Medicinal Chemistry Letters 19 (2009) 4882–4884 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl