D. Zhang et al. / Bioorg. Med. Chem. 20 (2012) 5169–5180
5179
7.16. 6-Bromo-3H,4H-pyrido[2,3-d]pyrimidin-4-one (26)
References and notes
1. Stellrecht, C. M.; Gandhi, V. Cancer Lett. 2009, 280, 1.
2. Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande Woude, G. F. Nat. Rev. Mol.
Cell. Bio. 2003, 4, 915.
To a vial was charged with 2-amino-5-bromonicotinic acid 8
(1 g, 4.61 mmol) and 1.1 ml of formamide. The vial was capped
and heated at 150 °C for 30 min under microwave irradiation. To
the reaction mixture was added water. The precipitate was filtered
off and recrystallized from water to afford brown solid in 36% yield.
1H NMR (300 MHz, DMSO-d6) d 12.72 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H),
8.61 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H); MS (ESI, m/z): 225.8 [M+H]+.
3. Comoglio, P. M.; Giordano, S.; Trusolino, L. Nat. Rev. Drug Disc. 2008, 7, 504.
4. Liu, X. D.; Newton, R. C.; Scherle, P. A. Trend Mol. Med. 2010, 16, 37.
5. Schoffski, P.; Garcia, J. A.; Stadler, W. M.; Gil, T.; Jonasch, E.; Tagawa, S. T.; Smitt,
M.; Yang, X. Q.; Oliner, K. S.; Anderson, A.; Zhu, M.; Kabbinavar, F. Bju. Int. 2011,
108, 679.
6. Lu, R. M.; Chang, Y. L.; Chen, M. S.; Wu, H. C. Biomaterials 2011, 32, 3265.
7. Pacchiana, G.; Chiriaco, C.; Stella, M. C.; Petronzelli, F.; De Santis, R.; Galluzzo,
M.; Carminati, P.; Comoglio, P. M.; Michieli, P.; Vigna, E. J. Biol. Chem. 2010, 285,
36149.
7.17. 6-Bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-3H,4H-
8. Liu, L.; Zeng, W.; Wortinger, M.; Uhlik, M. T.; Stewart, J.; Tetreault, J.; Lu, J.;
Vaillancourt, P.; Tang, Y.; Wooldridge, J. Ejc. Suppl. 2010, 8, 74.
9. Okamoto, W.; Okamoto, I.; Tanaka, K.; Hatashita, E.; Yamada, Y.; Kuwata, K.;
Yamaguchi, H.; Arao, T.; Nishio, K.; Fukuoka, M.; Janne, P. A.; Nakagawa, K. Mol.
Cancer Ther. 2010, 9, 2785.
10. Schelter, F.; Kobuch, J.; Moss, M. L.; Becherer, J. D.; Comoglio, P. M.; Boccaccio,
C.; Kruger, A. J. Biol. Chem. 2010, 285, 26335.
11. Giordano, S. Curr. Opin. Mol. Ther. 2009, 11, 448.
12. van der Horst, E.; Chinn, L.; Wang, M.; Velilla, T.; Tran, H.; Madrona, Y.; Lam, A.;
Ji, M.; Hoey, T. C.; Sato, A. K. Neoplasia 2009, 11, 355.
13. Perk, L. R.; Walsum, M. S. V.; Visser, G. W. M.; Kloet, R. W.; Vosjan, M. J. W. D.;
Leemans, C. R.; Giaccone, G.; Albano, R.; Comoglio, P. M.; van Dongen, G. A. M.
S. Eur. J. Nucl. Med. Mol. I. 1857, 2008, 35.
14. Jin, H. K.; Yang, R. H.; Zheng, Z.; Romero, M.; Ross, J.; Bou-Reslan, H.; Carano, R.
A. D.; Kasman, I.; Mai, E.; Young, J.; Zha, J. P.; Zhang, Z. M.; Ross, S.; Schwall, R.;
Colbern, G.; Merchant, M. Cancer Res. 2008, 68, 4360.
pyrido[2,3-d]pyrimidin-4-one (27)
38.9 mg (0.97 mmol) of sodium hydride (60 percent in oil) was
added to an ice-cooled solution of 200 mg (0.88 mmol) of 6-bro-
mo-3H,4H-pyrido[2,3-d]pyrimidin-4-one 27 in 4 ml of DMF, and
the reaction medium is stirred for 10 min. Then 304.88 mg
(1.06 mmol) of 1-(2,6-dichloro-3-fluorophenyl)ethyl methanesul-
fonate 19 was added. The resulting mixture was heated at 80 °C
for 4 h. The ice-cold water was added to the reaction medium.
The mixture was extracted with ethyl acetate. The organic phase
was washed with water, brine, dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude product was purified by sil-
ica gel column chromatography (EA/PE, 1/5-1/2) to afford com-
pound 27 in 50% yield. 1H NMR (300 MHz, CDCl3) d 8.99 (d,
J = 2.4 Hz, 1H), 8.69 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 7.29–7.25 (m,
1H), 7.09–7.04 (m, 1H), 6.31 (q, J = 7.2 Hz, 1H), 2.01 (d, J = 7.2 Hz,
3H); MS (ESI, m/z): 415.7 [M+H]+.
15. Bottaro, D. P. Ann. Oncol. 2008, 19, 22.
16. Martens, T.; Schmidt, N. O.; Eckerich, C.; Fillbrandt, R.; Merchant, M.; Schwall,
R.; Westphal, M.; Lamszus, K. Clin. Cancer Res. 2006, 12, 6144.
17. Welsh, J.; Zhan, Y.; Likhacheva, A.; Komaki, R. Ejc. Suppl. 2010, 8, 162.
18. Youles, M.; Holmes, O.; Petoukhov, M. V.; Nessen, M. A.; Stivala, S.; Svergun, D.
I.; Gherardi, E. J. Mol. Biol. 2008, 377, 616.
19. Raymond, W. W.; Cruz, A. C.; Caughey, G. H. J. Biol. Chem. 2006, 281, 1489.
20. Atabey, N.; Gao, Y.; Yao, Z. J.; Breckenridge, D.; Soon, L.; Soriano, J. V.; Burke, T.
R.; Bottaro, D. P. J. Biol. Chem. 2001, 276, 14308.
7.18. tert-butyl 4-(4-{3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-
4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-6-yl}-1H-pyrazol-1-
yl)piperidine-1-carboxylate (29)
21. Schwall, R. H.; Chang, L. Y.; Godowski, P. J.; Kahn, D. W.; Hillan, K. J.; Bauer, K.
D.; Zioncheck, T. F. J. Cell. Biol. 1996, 133, 709.
22. Zificsak, C. A.; Theroff, J. P.; Aimone, L. D.; Albom, M. S.; Angeles, T. S.; Brown, R.
A.; Galinis, D.; Grobelny, J. V.; Herbertz, T.; Husten, J.; Kocsis, L. S.; LoSardo, C.;
Miknyoczki, S. J.; Murthy, S.; Rolon-Steele, D.; Underiner, T. L.; Wells-Knecht, K.
J.; Worrell, C. S.; Zeigler, K. S.; Dorsey, B. D. Bioorg. Med. Chem. Lett. 2011, 21,
660.
23. Weinberg, L. R.; Albom, M. S.; Angeles, T. S.; Husten, J.; Lisko, J. G.; McHugh, R.
J.; Milkiewicz, K. L.; Murthy, S.; Ott, G. R.; Theroff, J. P.; Tripathy, R.; Underiner,
T. L.; Zificsak, C. A.; Dorsey, B. D. Bioorg. Med. Chem. Lett. 2011, 21, 164.
24. Wang, Y.; Ai, J.; Wang, Y.; Chen, Y.; Wang, L.; Liu, G.; Geng, M.; Zhang, A. J. Med.
Chem. 2011, 54, 2127.
25. Katz, J. D.; Jewell, J. P.; Guerin, D. J.; Lim, J.; Dinsmore, C. J.; Deshmukh, S. V.;
Pan, B.-S.; Marshall, C. G.; Lu, W.; Altman, M. D.; Dahlberg, W. K.; Davis, L.;
Falcone, D.; Gabarda, A. E.; Hang, G.; Hatch, H.; Holmes, R.; Kunii, K.; Lumb, K.
J.; Lutterbach, B.; Mathvink, R.; Nazef, N.; Patel, S. B.; Qu, X.; Reilly, J. F.; Rickert,
K. W.; Rosenstein, C.; Soisson, S. M.; Spencer, K. B.; Szewczak, A. A.; Walker, D.;
Wang, W.; Young, J.; Zeng, Q. J. Med. Chem. 2011, 54, 4092.
Compound 29 was prepared in a similar manner as described
for compound 24m. Yield: 39.4%; 1H NMR (300 MHz, CDCl3) d
9.12 (d, J = 2.4 Hz, 1H), 8.65 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.85
(s, 1H), 7.78 (s, 1H), 7.29–7.25 (m, 1H), 7.09–7.03 (m, 1H), 6.34
(q, J = 7.5 Hz, 1H), 4.34–4.22 (m, 3H), 2.95–2.84 (m, 2H), 2.18–
2.13 (m, 2H), 2.03–1.86 (m, 5H), 1.47 (s, 9H); MS (ESI, m/z):
586.7 [M+H]+.
7.19. 3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-6-[1-(piperidin-
yl)-1H-pyrazol-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-4-one (30)
26. Cui, J. J.; Tran-Dube, M.; Shen, H.; Nambu, M.; Kung, P. P.; Pairish, M.; Jia, L.;
Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.;
Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q. H.; Zou, H. L.; Christensen, J.;
Mroczkowski, B.; Bender, S.; Kania, R. S.; Edwards, M. P. J. Med. Chem. 2011, 54,
6342.
27. Williams, D. K.; Chen, X. T.; Tarby, C.; Kaltenbach, R.; Cai, Z. W.; Tokarski, J. S.;
An, Y. M.; Sack, J. S.; Wautlet, B.; Gullo-Brown, J.; Henley, B. J.; Jeyaseelan, R.;
Kellar, K.; Manne, V.; Trainor, G. L.; Lombardo, L. J.; Fargnoli, J.; Borzilleri, R. M.
Bioorg. Med. Chem. Lett. 2010, 20, 2998.
Compound 30 was prepared as a white solid in a similar as de-
scribed for compound 14j. Yield: 85%; 1H NMR (400 MHz, CD3OD) d
9.19–9.18 (m, 1H), 8.82 (s, 1H), 8.58–8.56 (m, 1H), 8.33 (s, 1H), 8.05
(s, 1H), 7.41-7.36 (m, 1H), 7.25–7.20 (m, 1H), 6.33–6.28 (m, 1H),
4.66–4.59 (m, 1H), 3.60–3.57 (m, 2H), 3.28–3.20 (m, 2H), 2.39–
2.26 (m, 4H), 2.01 (s, J = 7.6 Hz, 3H); MS (ESI, m/z): 487.3 [M+H]+;
HRMS (ESI) calcd for C23H22Cl2FN6O ([M+H]+): 487.1216; found :
487.1211.
28. Cho, S. Y.; Han, S. Y.; Ha, J. D.; Ryu, J. W.; Lee, C. O.; Jung, H.; Kang, N. S.; Kim, H.
R.; Koh, J. S.; Lee, J. Bioorg. Med. Chem. Lett. 2010, 20, 4223.
29. Schroeder, G. M.; An, Y. M.; Cai, Z. W.; Chen, X. T.; Clark, C.; Cornelius, L. A. M.;
Dai, J.; Gullo-Brown, J.; Gupta, A.; Henley, B.; Hunt, J. T.; Jeyaseelan, R.; Kamath,
A.; Kim, K.; Lippy, J.; Lombardo, L. J.; Manne, V.; Oppenheimer, S.; Sack, J. S.;
Schmidt, R. J.; Shen, G.; Stefanski, K.; Tokarski, J. S.; Trainor, G. L.; Wautlet, B. S.;
Wei, D.; Williams, D. K.; Zhang, Y. R.; Zhang, Y. P.; Fargnoli, J.; Borzilleri, R. M. J.
Med. Chem. 2009, 52, 1251.
30. Raeppel, S.; Claridge, S.; Saavedra, O.; Gaudette, F.; Zhan, L. J.; Mannion, M.;
Zhou, N.; Raeppel, F.; Granger, M. C.; Isakovic, L.; Deziel, R.; Nguyen, H.;
Beaulieu, N.; Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.; Dubay, M.;
Rahil, J.; Wang, J.; Ste-Croix, H.; Macleod, A. R.; Besterman, J.; Vaisburg, A.
Bioorg. Med. Chem. Lett. 2009, 19, 1323.
Acknowledgments
We gratefully acknowledge financial support from National Ba-
sic Research Program of China (Grants 2009CB940903 and
2012CB518000), the National Natural Science Foundation of China
(Grants 20721003 and 81025017), and National S&T Major Projects
(2012ZX09103-101-072).
31. Porter, J.; Lumb, S.; Lecomte, F.; Reuberson, J.; Foley, A.; Calmiano, M.; le Riche,
K.; Edwards, H.; Delgado, J.; Franklin, R. J.; Gascon-Simorte, J. M.; Maloney, A.;
Meier, C.; Batchelor, M. Bioorg. Med. Chem. Lett. 2009, 19, 397.
32. Porter, J.; Lumb, S.; Franklin, R. J.; Gascon-Simorte, J. M.; Calmiano, M.; Le
Riche, K.; Lallemand, B.; Keyaerts, J.; Edwards, H.; Maloney, A.; Delgado, J.;
Supplementary data
Supplementary data associated with this article can be found, in