F. Lovering et al. / Bioorg. Med. Chem. 17 (2009) 3342–3351
3351
7. Ben-Levy, R.; Hooper, S.; Wilson, R.; Paterson, H. F.; Marshall, C. J. Curr. Bio.
1998, 8, 1049.
8. Engel, A.; Kotlyarov, A.; Gaestel, M. EMBO 1998, 17, 3363.
9. Lukas, S. M.; Kroe, R. R.; Wildeson, J.; Peet, G. W.; Frego, L.; Davidson, W.;
Ingraham, R. H.; Pargellis, C. A.; Labadia, M. E.; Werneburg, B. G. Biochemistry
2004, 43, 9950.
HPLC purity (method 1: 99%, method 2: 99%); HRMS: calcd for
C21H18N6O2 (M+H)+, 387.15640; found 387.1563.
4.5.36. N-{4-[(3,4-Dioxo-2-{[(1R)-1-phenylethyl]amino}-
cyclobut-1-en-1-yl)amino]pyridin-2-yl}acetamidedione (53)
10. Kotlyarov, A.; Armin Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk,
H.-D.; Gaestel, M. Nat. Cell Biol. 1999, 1, 94.
A
reaction vessel containing 3-[(2-chloropyridin-4-yl)amino]-
11. Neininger, A.; Kontoyiannis, D.; Kotlyarov, A.; Winzen, R.; Eckert, R.; Volk, H.-
D.; Holtmann, H.; Kollias, G.; Gaestel, M. J. Biol. Chem. 2002, 277, 3065.
12. Brook, M.; Tchen, C. R.; Santalucia, T.; McIlrath, J.; Arthur, J. S. C.; Saklatvala, J.;
Clark, A. R. Mol. Cell Biol. 2006, 26, 2408.
13. Hitti, E.; Iakovleva, T.; Brook, M.; Deppenmeier, S.; Gruber, A. D.; Radzioch, D.; Clark,
A. R.; Blackshear, P. J.; Kotlyarov, A.; Gaestel, M. Mol. Cell Biol. 2006, 26, 2399.
14. Wang, X.; Xu, L.; Wang, H.; Young, P. R.; Gaestel, M.; Feuerstein, G. Z. J. Biol.
Chem. 2002, 277, 43968.
15. Shiroto, K.; Otani, H.; Yamamoto, F.; Huang, C.-K.; Maulik, N.; Das, D. K. J. Mol.
Cell Cardiol. 2005, 38, 93.
16. Hegen, M.; Gaestel, M.; Nickerson-Nutter, C. L.; Lin, L.-L.; Telliez, J.-B. J.
Immunol. 2006, 177, 1913.
17. Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier, W. F.; Lee, L.; Liu,
S.; Sambandam, A.; Snider, P. A.; Masih, L. Bioorg. Med. Chem. Lett. 2005, 15,
1587.
18. Anderson, D. R.; Meyers, M. J.; Vernier, W. F.; Mahoney, M. W.; Kurumbail, R.
G.; Caspers, N.; Poda, G. I.; Schindler, J. F.; Reitz, D. B.; Mourey, R. J. J. Med. Chem.
2007, 50, 2647.
4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.1 g,
0.3 mmol), acetamide (0.08 g, 1.4 mmol), Pd2dba (0.04 g, 0.04 mmol),
XPHOS (0.04 g, 0.08 mmol) and cesium carbonate (0.2 g, 0.62 mmol)
was purged with nitrogen. Dioxane/DMF (1.2 mL, 5:1, degassed) was
then added. The reaction was stirred under microwave irradiation at
150 °C for 2 h. The reaction mixture was filtered through a plug of silica
(1% triethylamine/10%MeOH/DCM) and concentrated. Purification by
RP-HPLC (CH3CN/H2O) afforded the title compound as an off white so-
lid (0.02 g, 19%). 1H NMR (DMSO-d6) d ppm 1.59 (d, J = 6.8 Hz, 3H),
5.21–5.34 (m, 1H), 7.25–7.47 (m, 5H), 7.64 (d, J = 3.3 Hz, 1H), 7.81 (s,
1H), 8.17 (d, J = 6.1 Hz, 1H), 8.34 (s, 1H), 10.13 (s, 1H), 10.62 (s, 1H);
HPLC purity (method 1: 97%, method 2: 98%); HRMS: calcd for
C19H18N4O3 (M+H)+, 351.14517; found 351.1453.
19. Trujillo, J. I.; Meyers, M. J.; Anderson, D. R.; Hegde, S.; Mahoney, M. W.; Vernier,
W. F.; Buchler, I. P.; Wu, K. K.; Yang, S.; Hartmann, S. J.; Reitz, D. B. Bioorg. Med.
Chem. Lett. 2007, 17, 4657.
4.5.37. N-{4-[(3,4-Dioxo-2-{[(1R)-1-phenylethyl]amino}-
cyclobut-1-en-1-yl)amino]pyridin-2-yl}nicotinamide (54)
20. Wu, J.-P.; Wang, J.; Abeywardane, A.; Andersen, D.; Emmanuel, M.; Gautschi, E.;
Goldberg, D. R.; Kashem, M. A.; Lukas, S.; Mao, W.; Martin, L.; Morwick, T.;
Moss, N.; Pargellis, C.; Patel, U. R.; Patnaude, L.; Peet, G. W.; Skow, D.; Snow, R.
J.; Ward, Y.; Werneburg, B.; White, A. Bioorg. Med. Chem. Lett. 2007, 17, 4664.
21. Cherry, M.; Williams, D. H. Curr. Med. Chem. 2004, 11, 663.
22. Di, L.; Kerns, E. H.; Li, S. Q.; Carter, G. T. Int. J. Pharm. 2007, 335, 1.
23. The illustration was rendered using the Schrodinger Suite by reading in the
PDB file and treating it using the Protein Preparation workflow to optimize the
placement of protons.
24. Butera, J. A.; Antane, M. M.; Antane, S. A.; Argentieri, T. M.; Freeden, C.;
Graceffa, R. F.; Hirth, B. H.; Jenkins, D.; Lennox, J. R.; Matelan, E.; Norton, N. W.;
Quagliato, D.; Sheldon, J. H.; Spinelli, W.; Warga, D.; Wojdan, A.; Woods, M. J.
Med. Chem. 2000, 43, 1187.
25. Gilbert, A. M.; Antane, M. M.; Argentieri, T. M.; Butera, J. A.; Francisco, G. D.;
Freeden, C.; Gundersen, E. G.; Graceffa, R. F.; Herbst, D.; Hirth, B. H.; Lennox, J.
R.; McFarlane, G.; Norton, N. W.; Quagliato, D.; Sheldon, J. H.; Warga, D.;
Wojdan, A.; Woods, M. J. Med. Chem. 2000, 43, 1203.
26. Adam, F.; Littke, G. C. F. Angew. Chem., Int. Ed. 2002, 41, 4176.
27. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
28. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2004, 43, 1871.
A
reaction vessel containing 3-[(2-chloropyridin-4-yl)amino]-
4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.1 g,
0.3 mmol), nicotinamide (0.07 g, 0.6 mmol), Pd2dba (0.28 g,
0.03 mmol), XANTPHOS (0.036 g, 0.06 mmol) and potassium
phosphate (tribasic, fluka brand, 0.12 g, 0.57 mmol) was purged
with nitrogen. Dioxane/DMF (1.2 mL, 5:1, degassed) was then
added. The reaction was stirred under microwave irradiation at
150 °C for 2 h. The reaction mixture was filtered through a plug
of silica (1% triethylamine/10%MeOH/DCM) and concentrated.
Purification by RP-HPLC (CH3CN/H2O) afforded the title com-
pound (0.028 g, 22%) as an off white solid. 1H NMR (DMSO-d6) d
ppm 1.61 (d, J = 6.82 Hz, 3H) 5.28–5.34 (m, 1H) 7.29–7.46 (m,
5H) 7.54 (ddd, J = 7.89, 4.86, 0.88 Hz, 1H) 7.68 (d, J = 4.29 Hz, 1H)
8.03 (d, J = 1.77 Hz, 1H) 8.27 (d, J = 5.56 Hz, 1H) 8.33 (ddd,
J = 8.08, 2.02, 1.77 Hz, 1H) 8.75 (dd, J = 4.80, 1.52 Hz, 1H) 9.12
(dd, J = 2.27, 0.76 Hz, 1H) 10.13 (s, 1H) 11.08 (s, 1H) HPLC purity
(method 1: 100%, method 2: 100%); HRMS: calcd for C23H19N5O3
(M+H)+, 414.15607; found 414.1562.
29. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653.
30. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481.
31. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
32. Alkyl acids generally have pKa’s in the 4–5 range, however squaric acids are
much more acidic, with a pKa values of 0.54 and 3.48 (Schwartz, L. M.; Howard,
L. O. J. Phys. Chem. 1971, 75, 1798). Thus squaric amides are likely to be
significantly more acidic than alkyl amides.
Acknowledgements
The authors would like to thank Li Di and Susan Petusky for
the Cyp450 data and Jennifer Gale and Jenny Togias for kinase
selectivity data. The authors would also like to thank Steve Tam
for helpful discussions. Protein crystallization data were collected
at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID
(or 22-BM) beamline at the Advanced Photon Source, Argonne
National Laboratory. Supporting institutions may be found at
Source was supported by the U. S. Department of Energy, Office
of Science, Office of Basic Energy Sciences, under Contract No.
W-31-109-Eng-38.
33. West, R.; Niu, H. Y. J. Am. Chem. Soc. 1963, 85, 2589.
34. Sato, K.; Seio, K.; Sekine, M. J. Am. Chem. Soc. 2002, 124, 12715.
35. Underwood, K. W.; Parris, K. D.; Federico, E.; Mosyak, L.; Czerwinski, R. M.;
Shane, T.; Taylor, M.; Svenson, K.; Liu, Y.; Hsiao, C. L.; Wolfrom, S.; Maguire, M.;
Malakian, K.; Telliez, J. B.; Lin, L. L.; Kriz, R. W.; Seehra, J.; Somers, W. S.; Stahl,
M. L. Structure 2003, 11, 627.
36. Huse, M.; Kuriyan, J. Cell 2002, 109, 275.
37. Liao, J. J. L. J. Med. Chem. 2007, 50, 409.
38. Taylor, S. S.; Yang, J.; Wu, J.; Haste, N. M.; Radzio-Andzelm, E.; Anand, G.
Biochim. Biophys. Acta 2004, 1697, 259.
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A.; Muller-Tiemann, B.; Egner, U. J. Mol. Biol. 2007, 369, 735.
41. ALogP was calculated using Pipeline Pilot from Scitegic.
42. Goldberg, D. R.; Choi, Y.; Cogan, D.; Corson, M.; DeLeon, R.; Gao, A.;
Gruenbaum, L.; Hao, M. H.; Joseph, D.; Kashem, M. A.; Miller, C.; Moss, N.;
Netherton, M. R.; Pargellis, C. P.; Pelletier, J.; Sellati, R.; Skow, D.; Torcellini, C.;
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