N. Suzuki et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1601–1606
1605
O
O
Cl
F
O
O
l, m
k
I
n
NH
N
HN
N
Cl
H3C
OEt
I
H3C
N
H3C
N
N
38
39
H3C
40
O
F
o
R
HN
Cl
N
H3C
N
41
O
O
O
F
F
MeO
HN
N
Cl
N
HN
N
Cl
p
q, r, s
39
O
N
N
H3C
H3C
42
20
Scheme 2. Reagents and conditions: (k) formamidine acetate (1.2 equiv), Na (2.2 equiv), EtOH, rt, 75%; (l) ICl (1 equiv), AcOH, 60 °C, 100%; (m) POCl3 (2 equiv), toluene, rt,
35%; (n) ArNH2 (1 equiv), EtOH, reflux, 54%; (o) alkyne (1.5 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N (5 equiv), DMF, 80 °C, 50–90%; (p) phenylvinylbronic acid
pinacol ester (1.2 equiv), Pd(OAc)2 (10 mol %), PPh3 (30 mol %), 2 M K2CO3 (4 equiv), DMF, 100 °C, 65%; (q) LiAlH4 (1.5 equiv), THF, rt, 77%; (r) MnO2 (10 equiv), THF, rt, 77%; (s)
morpholine (4 equiv), NaBH(OAc)3 (4 equiv), AcOH (1 equiv), rt to 50 °C, 82%.
5. Fabian, M. A.; Biggs, W. H., III; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.;
34. Reduction of 34 with LiAlH4, followed by Swern oxidation pro-
vided the aldehyde 35. Horner–Wadsworth–Emmons reaction of
35 with phosphonates afforded the acrylate 36. Hydrolysis of 36
with NaOH followed by condensation with the amines provided
the acrylamide analogues (37).
Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.;
Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.;
Lai, A. G.; Lelias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L.
M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. Nat. Biotechnol. 2005, 23, 329.
6. Liao, J. J. J. Med. Chem. 2007, 50, 409.
7. (a) Bergman, E.; Forsell, P.; Persson, E. M.; Knutson, L.; Dickinson, P.; Smith, R.;
Swaisland, H.; Farmer, M. R.; Cantarini, M. V.; Lennernäs, H. Int. J. Pharm. 2007,
341, 134; (b) Koch, K. M.; Reddy, N. J.; Cohen, R. B.; Lewis, N. L.; Whitehead, B.;
Mackay, K.; Stead, A.; Beelen, A. P.; Lewis, L. D. J. Clin. Oncol. 2009, 27, 1191; (c)
Bubendorf, A. G.; Hennig, M.; Hidber, P.; Rimmler, G.; Rohrer, F. WO
2004072049 A1.
The synthetic route to 5-alkynyl analogues and compound 20 is
shown Scheme 2. 6-Methyl pyrimidone (38) was obtained by the
reaction of ethyl acetoacetate with formamidine acetate under ba-
sic condition. Treatment of 38 with ICl was followed by chlorina-
tion with POCl3 to give 5-iodo-4-chloro-6-methylpyrimidine (39).
The reaction of 39 with the 4-benzyloxy aniline provided 40. Sono-
gashira coupling reaction of 40 with alkynes provided 5-alkynyl
analogues (41). On the other hand, Suzuki–Miyaura coupling reac-
tion of 39 with phenylvinylborate provided compound 42. Conver-
sion of the terminal methyl ester into aldehyde, followed by
reductive amination with morpholine provided compound 20.
In summary, we have described early SARs leading to novel
alkenyl and alkynyl pyrimidine compounds which have effective
EGFR/Her-2 dual inhibitory activity. The key modification was
the introduction of a 5-alkenyl or alkynyl moiety that contained
hydrophilic groups at the appropriate position. Although acrylam-
ide and aliphatic alkyne analogues did not exhibit potent antipro-
liferative activity against BT474, we found that introducing an
aromatic ring into the terminal hydrophilic part could improve cel-
lular activity. Further exploration of these 4-anilinopyrimidine
derivatives as EGFR/Her-2 dual inhibitors will be reported in due
course.
8. (a) Gavai, A. V.; Fink, B. E.; Fairfax, D. J.; Martin, G. S.; Rossiter, L. M.; Holst, C. L.;
Kim, S.-H.; Leavitt, K. J.; Mastalerz, H.; Han, W.-C.; Norris, D.; Goyal, B.;
Swaminathan, S.; Patel, B.; Mathur, A.; Vyas, D. M.; Tokarski, J. S.; Yu, C.;
Oppenheimer, S.; Zhang, H.; Marathe, P.; Fargnoli, J.; Lee, F. Y.; Wong, T. W.;
Vite, G. D. J. Med. Chem. 2009, 52, 6527; (b) Rheault, T. R.; Caferro, T. R.;
Dickerson, S. H.; Donaldson, K. H.; Gaul, M. D.; Goetz, A. S.; Mullin, R. J.;
McDonald, O. B.; Petrov, K. G.; Rusnak, D. W.; Shewchuk, L. M.; Spehar, G. M.;
Truesdale, A. T.; Vanderwall, D. E.; Wood, E. R.; Uehling, D. E. Bioorg. Med. Chem.
Lett. 2009, 19, 817; (c) Lin, R.; Johnson, S. G.; Connolly, P. J.; Wetter, S. K.;
Binnun, E.; Hughes, T. V.; Murray, W. V.; Pandey, N. B.; Moreno-Mazza, S. J.;
Adams, M.; Fuentes-Pasquera, S. A.; Middleston, S. A. Bioorg. Med. Chem. Lett.
2009, 19, 2333.
9. (a) Waterson, A. G.; Stevens, K. L.; Reno, M. J.; Zhang, Y.-M.; Boros, E. E.;
Frederic, B.; Rastagar, A.; Uehling, D. E.; Dickerson, S. H.; Reep, B.; McDonald, O.
B.; Wood, E. R.; Rusnak, D. W.; Alligood, K. J.; Rudolph, S. K. Bioorg. Med. Chem.
Lett. 2006, 16, 2419; (b) Xu, G.; Searle, L. L.; Hughes, T. V.; Beck, A. K.; Connolly,
P. J.; Abad, M. C.; Neepe, M. P.; Struble, G. T.; Springer, B. A.; Emanuel, S. L.;
Gruninger, R. H.; Pandey, N.; Adams, M.; Moreno-Mazza, S.; Fuentes-Pesquera,
A. R.; Middleton, S. A.; Greenberger, L. M. Bioorg. Med. Chem. Lett. 2008, 18,
3495; (c) Xu, G.; Abad, M. C.; Connolly, P. J.; Neeper, M. P.; Struble, G. T.;
Springer, B. A.; Emanuel, S. L.; Pandey, N.; Gruninger, R. H.; Adams, M.; Moreno-
Mazza, S.; Fuentes-Pesquera, A. R.; Middleton, S. A. Bioorg. Med. Chem. Lett.
2008, 18, 4615; (d) Hughes, T. V.; Xu, G.; Wetter, S. K.; Connolly, P. J.; Emanuel,
S. L.; Karnachi, P.; Pollack, S. R.; Pandey, N.; Adams, M.; Moreno-Mazza, S.;
Middleton, S. A.; Greenberger, L. M. Bioorg. Med. Chem. Lett. 2008, 18, 4896.
10. Wakeling, A. E.; Guy, S. P.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Barker, A.
J.; Gibson, K. H. Cancer Res. 2002, 62, 5749.
References and notes
11. Moyer, J. D.; Barbacci, E. G.; Iwata, K. K.; Arnold, L.; Boman, B.; Cunningham, A.;
DiOrio, C.; Doty, J.; Morin, M. J.; Moyer, M. P.; Neveu, M.; Pollack, V. A.;
Pustilnik, L. R.; Reynolds, M. M.; Slaon, D.; Theleman, A.; Miller, P. Cancer Res.
1997, 57, 4838.
12. (a) Zhang, Y.-M.; Cockerill, S.; Guntrip, S. B.; Rusnak, D.; Smith, K.; Vanderwall,
D.; Wood, E.; Lackey, K. Bioorg. Med. Chem. Lett. 2004, 14, 111; (b) Rusnak, D.
W.; Affleck, K.; Cockerill, S. G.; Stubberfield, C.; Harris, R.; Page, M.; Smith, K. J.;
1. Supuran, C. T.; Scozzafava, A. Expert Opin. Ther. Patents 2004, 14, 35.
2. Olayioye, M. A.; Neve, R. M.; Lane, H. A.; Hynes, N. E. EMBO J. 2000, 19, 3159.
3. Kersemaekers, A.-M. F.; Fleuren, G. J.; Kenter, G. G.; Van den Broek, L. J. C. M.;
Uljee, S. M.; Hermans, J.; Van de Vijver, M. J. Clin. Cancer Res. 1999, 5, 577.
4. Rusnak, D. W.; Lackey, K.; Affleck, K.; Wood, E. R.; Alligood, K. J.; Rhodes, N.;
Keith, B. R.; Murray, D. M.; Glennon, K.; Knight, W. B.; Mullin, R. J.; Gilmer, T. M.
Mol. Cancer Ther. 2001, 1, 85.