Reversible Carboxamide-Mediated Internal Activation at C(6) of 2-Chloro-4-anilino-1H-pyrrolo[2,3-d]pyrimidines Stanley D. Chamberlain, Roseanne M. Gerding, Huangshu Lei, Ganesh Moorthy, Samarjit Patnaik, Aniko ´ M. Redman, Kirk L. Stevens, Joseph W. Wilson, Bin Yang, and J. Brad Shotwell* GlaxoSmithKline, Oncology R&D, 5 Moore DriVe, Research Triangle Park, North Carolina 27709 jbs26900@gsk.com ReceiVed September 18, 2008 A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1′)-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1′) constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines. Structures possessing aminopyrimidines are remarkably gen- eral in their ability to potently inhibit a variety of protein kinases via a direct 2-point interaction with the kinase hinge. Potent inhibition of a number of anticancer/anti-inflammation kinase targets including AurA/B, 1 IGF-1R/IR, 2 FAK, 2 VEGF, 3 ALK, 2 SYK, 4 IKK, 5 and JAK 6 by 2,4-bisanilino pyrimidines is well- documented. The development of this class of inhibitors has been aided by straightforward chemical syntheses wherein 2,4- dichloropyrimidines are versatile starting materials, allowing sequential derivatization of both chlorides via S N AR displace- ments with functionalized anilines. We recognized the potential for the corresponding 4,6-bisanilino-1H-pyrrolo[2,3-d]pyrim- idines to bind to kinases in an analogous manner, with a 3-point contact to the kinase hinge, and expected that chemical diversification of known dichloro-pyrrolopyrimidine 1 via sequential chloride displacements would proceed smoothly in analogy to chemistry reported for 2,4-dichloropyrimidines. 1-6 We were especially interested in 1H-pyrrolo[2,3-d]pyrimidines 2 containing side-chain carboxamides and herein describe our successful synthetic efforts toward this class of potential kinase inhibitors. Dichloride 1 was prepared according to previous reports 8 and readily derivatized by acid- or base-mediated addition of anilines 2 and 3 to afford C(4)-substituted pyrrolopyrimidines 4 and 5 in reasonable yields (Scheme 1). Exposure of 4 to aniline 6 and hydrochloric acid, quenching with ammonium hydroxide, and subsequent detosylation, afforded C(6) derivative 8 in good yield. In contrast, chloride 5 proved refractory toward acid- catalyzed, electrophilic aromatic substitution, and preparation of 9 using palladium-catalyzed methods proved extremely capricious (Scheme 2). In general, pyrrolopyrimidines are much more resistant toward S N AR displacements than corresponding simple pyrimidine substrates, with their reduced electrophilicity apparently a result of the electronic impact of the pendant pyrrole. As such, within (1) Burdick, D.; Liang, J. Pyrimidine Kinase Inhibitors. WO 2007/120339 A1, December 15, 2006. (2) (a) Liu, T.; LaFortune, T.; Honda, T.; Ohmori, O.; Hatakeyama, S.; Meyer, T.; Jackson, D.; Groot, J.; Yung, W. Mol. Cancer Ther. 2007, 6, 1357. (b) Galkin, A.; Melnick, J.; Kim, S.; Hood, T.; Nanxin, L.; Lintog, L.; Xia, G.; Steensma, R.; Chopiuk, G.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P.; Gray, N.; Warmuth, M. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 270. (c) Imbach, P.; Kawahar, E.; Konishi, K.; Matsuura, N.; Miyake, T.; Ohmori, O.; Roesel, J.; Teno, N.; Umemura, I. Pyrimidine Derivatives. WO 2006/021454 A2, August 27, 2004. (d) Garcia-Echeverria, C.; Kanazawa, T.; Kawahara, E.; Masuya, K.; Matsuura, N.; Miyake, T.; Ohmori, O.; Umemura, I.; Steensma, R.; Chopiuk, G.; Jiang, J.; Wan, Y.; Ding, Q.; Zhang, Q.; Gray, N.; Karanewsky, D. 2,4- Pyrimidinediamines Useful in the Treatment of Neoplastic Diseases, Inflammatory and Immune System Disorders. WO 2005/016894 A1, September 24, 2003. (3) (a) Sammond, D.; Nailor, K.; Veal, J.; Nolte, R.; Wang, L.; Knick, V.; Rudolph, S.; Truesdale, A.; Nartey, E.; Stafford, J.; Kumar, R.; Cheung, M. Bioorg. Med. Chem. Lett. 2005, 15, 3519. (b) Kumar, R.; Knick, V.; Rudolph, S.; Johnson, J.; Crosby, R.; Crouthamel, M.; Hopper, T.; Miller, C.; Harrington, L.; Onori, J.; Mullin, R.; Gilmer, T.; Truesdale, A.; Epperly, A.; Boloor, A.; Stafford, J.; Luttrell, D.; Cheung, M. Mol. Cancer Ther. 2007, 6, 2012. (4) Atkinson, F.; Campos, S.; Harrison, L.; Parr, N.; Patel, V.; Vitulli, G. 1H-Indazol-4-yl-2,4-pyrimidinediamine Derivatives. WO 2007/085540 A1, June 9, 2006. (5) Wagnon, J.; Nguefack, J.; Jegham, S.; Bosch, M.; Bouaboula, M.; Casellas, P.; Tonnerre, B.; Olsen, J.; Mignani, S. Novel 2,4-Dianilinopyrimidine Derivatives, The Preparation Thereof, Their Use as Medicaments, Pharmaceutical Compositions and, in Particular, as IKK Inhibitors. WO 2007/006926 A2, November 25, 2005. (6) Hui, L.; Argade, A.; Tso, K.; Thota, S.; Carroll, D.; Sran; A.; Copper, R.; Singh, R.; Bhamidipati, S.; Masuda, E.; Taylor, V. Compositions and Methods for Inhibition of the JAK Pathway. WP 2007/098507 A2, October 19, 2006. (7) TFE ) trifluoroethanol. (8) Gore, P.; Patel, V. K.; Walker, A.; Woodrow, M. Pyrrolopyrimidine Derivatives as Syk Inhibitors and Their Preparation, Pharmaceutical Composi- tions, and Use in the Treatment of Inflammatory and Allergic Diseases. WO 2007042298 A1, April 19, 2007. SCHEME 1. Synthesis of Carboxamides 4 and 5 7 10.1021/jo8020693 CCC: $40.75  2008 American Chemical Society J. Org. Chem. 2008, 73, 9511–9514 9511 Published on Web 11/11/2008