D. Niculescu-Duvaz et al. / Bioorg. Med. Chem. 21 (2013) 1284–1304
1303
4.35.2. 6-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-
yl-3H-imidazol-4-yl}-2-fluoro-naphthalen-1-ol (1t)
Compound 61 (23 mg, 0.04 mol) was dissolved in 48% aq
Disclosure statement
l
This work was carried out as part of a research collaboration be-
tween the Institute of Cancer Research, The Wellcome Trust, Glaxo-
SmithKline and Cancer Research UK. Pease note that all authors
who are, or have been, employed by The Institute of Cancer Re-
search are subject to a ‘Rewards to Inventors Scheme’ that may re-
ward contributors to a programme that is subsequently licensed.
HBr (1 mL) and AcOH (1.6 mL) and the solution was heated to
120 °C in a sealed tube overnight. The solution was allowed to
cool to rt, diluted with water (5 mL) and washed with EtOAc.
The acidic layer was concentrated in vacuo and the the residue
purified by preparative HPLC to yield the TFA salt as a yellow
glue. Yield: 4.6 mg, 14%. 1H NMR (CD3OD), d: 3.02 (s, 6H,
N(CH3)2), 3.66 (t, J = 4.8, 2H, CH2), 4.46 (t, J = 4.8, 2H, CH2),
7.22 (d, J = 9.1, 2H, ArH), 7.36–7.51 (m, 2H, ArH), 7.63 (d,
J = 9.1, 1H, ArH), 8.04–8.14 (m, 5H, ArH), 8.41 (d, J = 8.6, 1H,
ArH), 8.56 (d, J = 6.4, 2H, ArH). LC–MS: Rf = 2.37 min; m/z 469
([M+H]+, 10), 235 (100). HRMS (EI): m/z calcd for C28H26FN4O2
([M+H]+): 469.2034; found: 469.2033.
Acknowledgments
This work was supported by the Wellcome Trust (Ref: 080333/
Z/06/Z), Cancer Research UK (Grant numbers C309/A11566, C309/
A8274 and C107/A10433), the Isle of Man Anti-Cancer Association
and The Institute of Cancer Research. We acknowledge NHS fund-
ing to the NIHR Biomedical Research Centre. We thank Professors
Workman and Blagg for their support. We are grateful to Meirion
Richards and Dr. Amin Mirza for technical support.
4.35.3. 7-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-
yl-1H-imidazol-4-yl}-quinolin-2-ol (1u)
Compound 65 (25 mg; 0.024 lmol) was deprotected using the
Supplementary data
general procedure to give the desired product as its HCl salt
(30 mg; quantitative). 1H NMR (CD3OD), d: 3.03 (s, 6H, N(CH3)2),
3.70 (t, J = 5.7, 2H, CH2), 4.54 (t, J = 5.7, 2H, CH2), 6.76 (d, J = 9.5,
1H, ArH), 7.39 (d, J = 8.2, 2H, ArH), 7.54 (d, J = 7.3, 1H, ArH), 7.69
(br, 1H, ArH), 7.93 (d, J = 7.3, 1H, ArH), 8.10 (d, J = 9.5, 1H, ArH),
8.18–8.30 (m, 4H, ArH), 8.89 (d, J = 4.5, 2H, ArH). LC–MS:
Rf = 2.09 min; m/z 452 ([M+H]+, 10), 226 (100). HRMS (EI): m/z
calcd for C27H25N5O2 ([M+H]+): 452.2086; found: 452.2083.
Supplementary data associated with this article can be found, in
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
2. Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.;
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Administered to Subjects with Locally Advanced or Metastatic Melanoma.
Tumors.
4.35.4. 6-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-
yl-3H-imidazol-4-yl}-quinolin-2-ol (1v)
Compound 68 (12 mg; 50 lmol) was deprotected using the gen-
eral procedure to give the desired product as its HCl salt (5 mg;
46%). 1H NMR (CD3OD), d: 3.02 (s, 6H, N(CH3)2), 3.67 (t, J = 5.0,
2H, CH2), 4.49 (t, J = 5.0, 2H, CH2), 6.71 (d, J = 9.5, 1H, ArH), 7.27
(d, J = 8.6, 2H, ArH), 7.55 (d, J = 8.6, 1H, ArH), 7.78 (d, J = 8.2, 1H,
ArH), 7.99–8.06 (m, 2H, ArH), 8.10–8.18 (m, 4H, ArH), 8.62–8.71
(d, J = 5.6, 2H, ArH). LC–MS: Rf = 2.21 min; m/z 452 ([M+H]+, 100),
276. HRMS (EI): m/z calcd for C27H26N5O2 ([M+H]+): 452.2087;
found: 452.2082.
4.35.5. 6-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-
yl-1H-imidazol-4-yl}-isoquinolin-1-ylamine (1x)
7. Puzanov, I.; Nathanson, K.L.; Chapman P.B. American Society of Clinical Oncology
Annual Meeting Abs 9021 2009.
Compound 74 (7 mg; 10 lmol) was heated in TFA (1.5 mL) at
8. Bollag, G.; Hirth, P.; Tsai, J.; Zhang, J.; Ibrahim, P. N.; Cho, H.; Spevak, W.; Zhang,
C.; Zhang, Y.; Habets, G.; Burton, E. A.; Wong, B.; Tsang, G.; West, B. L.; Powell,
B.; Shellooe, R.; Marimuthu, A.; Nguyen, H.; Zhang, K. Y. J.; Artis, D. R.;
Schlessinger, J.; Su, F.; Higgins, B.; Iyer, R.; D’Andrea, K.; Koehler, A.; Stumm, M.;
Lin, P. S.; Lee, R. J.; Grippo, J.; Puzanov, I.; Kim, K. B.; Ribas, A.; McArthur, G. A.;
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9. Yang, H.; Higgins, B.; Kolinsky, K.; Packman, K.; Go, Z.; Iyer, R.; Kolis, S.; Zhao,
S.; Lee, R.; Grippo, J. F.; Schostack, K.; Simcox, M. E.; Heimbrook, D.; Bollag, G.;
Su, F. Cancer Res. 2010, 70, 5518.
10. Chapman, P.; Hauschild, A.; Robert, C.; Haanen, J.; Ascierto, P. J. L.; Dummer, R.;
Garbe, C.; Testori, A.; Maio, M.; Hogg, D.; Lorigan, P.; Lebbe, C.; Jouary, T.;
Schadendorf, D.; Ribas, A.; O’Day, S.; Sosman, J.; Kirkwood, J.; Eggermont, A.;
Dreno, B.; Nolop, K.; Li, J.; Nelson, B.; Hou, J.; Lee, R.; Flaherty, K.; McArthur, A.;
Group, B.-S. N. Engl. J. Med. 2011, 364, 2507.
120 °C for 18 h. The acid was removed in vacuo and the residue
dissolved in water and washed with EtOAc. Evaporation of the
water gave the desired compound as the TFA salt (3.5 mg;
81%). 1H NMR (CD3OD), d: 3.02 (s, 6H, N(CH3)2), 3.65 (t, J = 4.5,
2H, CH2), 4.46 (t, J = 4.5, 2H, CH2), 7.22 (d, J = 8.6, 2H, ArH),
7.26 (d, J = 7.3, 1H, ArH), 7.64 (d, J = 7.3, 1H, ArH), 7.97 (d,
J = 7.7, 1H, ArH), 8.10 (d, J = 8.6, 4H, ArH), 8.20 (s, 1H, ArH),
8.56 (d, J = 8.2, 1H, ArH), 8.67 (br, 2H, ArH). LC–MS:
Rf = 1.87 min; m/z 451 ([M+H]+, 10), 226 (100). HRMS (EI): m/z
calcd for C27H28N6O ([M+H]+): 451.2240; found: 451.2242.
4.35.6. (2-{4-[5-(6-Fluoro-naphthalen-2-yl)-4-pyridin-4-yl-1H-
imidazol-2-yl]-phenoxy}-ethyl)-dimethyl-amine (1y)
11. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I.
J.; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J. J. Med. Chem.
2006, 49, 407.
12. Niculescu-Duvaz, I.; Roman, E.; Whittaker, S. R.; Friedlos, F.; Kirk, R.; Scanlon, I.
J.; Davies, L. C.; Niculescu-Duvaz, D.; Marais, R.; Springer, C. J. J. Med. Chem.
2008, 51, 3261.
13. Niculescu-Duvaz, D.; Gaulon, C.; Dijkstra, H. P.; Niculescu-Duvaz, I.; Zambon,
A.; Menard, D.; Suijkerbuijk, B. M.; Nourry, A.; Davies, L.; Manne, H.; Friedlos,
F.; Ogilvie, L.; Hedley, D.; Whittaker, S.; Kirk, R.; Gill, A.; Taylor, R. D.; Raynaud,
F. I.; Moreno-Farre, J.; Marais, R.; Springer, C. J. J. Med. Chem. 2009, 52, 2255.
14. Menard, D.; Niculescu-Duvaz, I.; Dijkstra, H. P.; Niculescu-Duvaz, D.;
Suijkerbuijk, B. M.; Zambon, A.; Nourry, A.; Roman, E.; Davies, L.; Manne, H.
A.; Friedlos, F.; Kirk, R.; Whittaker, S.; Gill, A.; Taylor, R. D.; Marais, R.; Springer,
C. J. J. Med. Chem. 2009, 52, 3881.
Compound 77 (50 mg; 0.1 mmol) was reacted as in the gen-
eral procedure to give the desired product (31 mg; 70%). 1H
NMR (CD3OD), d: 3.04 (s, 6H, N(CH3)2), 3.70 (t, J = 4.8, 2H,
CH2), 4.55 (t, J = 4.8, 2H, CH2), 7.41 (d, J = 8.6, 2H, ArH), 7.48
(t, J = 8.9, 1H, ArH), 7.73 (d, J = 7.9, 2H, ArH), 8.10 (d, J = 9.3,
2H, ArH), 8.24 (d, J = 7.3, 4H, ArH), 8.36 (s, 1H, ArH), 8.87
(d, J = 5.9, 2H, ArH). LC–MS: Rf = 2.57 min; m/z 453 ([M+H]+, 10),
227 (100). HRMS (EI): m/z calcd for
C
28H25FN4O ([M+H]+):
3.2090; found: 453.2079.