Thienopyrimidine Ureas as Multitargeted RTK Inhibitors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6081
Compound 82 was prepared following the same sequence as
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-3-chloro-
phenyl]-N′-(3-methylphenyl)urea (89). Compound 89 was
prepared following the same sequence as described for the
1
described for the synthesis of 11 by replacing 2 with 34a. H
NMR (DMSO-d6) δ 2.29 (s, 3H), 4.04 (s, 2H), 6.79-6.82 (d, J
) 7.5 Hz, 1H), 7.14-7.19 (t, J ) 7.8 Hz, 1H), 7.24-7.33 (m,
3H), 7.35-7.37 (d, J ) 8.4 Hz, 2H), 7.53-7.56 (td, J ) 2.1, 7.8
Hz, 1H), 7.63-7.66 (d, J ) 8.4 Hz, 2H), 8.27 (s, 1H), 8.34-
8.35 (d, J ) 1.8 Hz, 1H), 8.42-8.44 (dd, J ) 1.5, 4.8 Hz, 1H),
8.67 (s, 1H), 8.89 (s, 1H); MS (ESI) m/z 467 (M + H)+. Anal.
(C26H22N6OS‚0.2H2O) C, H, N.
1
synthesis of 11 by substituting 41b for 2. H NMR (DMSO-
d6) δ 2.29 (s, 3H), 6.82 (d, J ) 7.5 Hz, 1H), 7.18 (t, J ) 7.5 Hz,
1H), 7.23-7.26 (m, 1H), 7.31-7.34 (s, br, 1H), 7.41-7.42 (m,
2H), 7.49 (s, 1H), 7.91 (s, br, 1H), 8.33 (s, 1H), 8.75 (s, 1H),
9.05 (s, 1H); MS (ESI) m/z 409.9, 411.9 (M + H)+. Anal. (C20H16-
ClN5O‚0.5H2O) C, H, N.
N-{4-[4-Amino-6-(pyridin-4-ylmethyl)thieno[2,3-d]-
pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea (83).
Compound 83 was prepared following the same sequence as
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-3-meth-
oxyphenyl]-N′-(3-methylphenyl)urea (90). Compound 90
was prepared following the same sequence as described for
11 by substituting 41c for 2. The crude material was purified
by preparative HPLC using the conditions described for the
purification of 51 to provide the title compound as the
1
described for the synthesis of 11 by replacing 2 with 34b. H
NMR (DMSO-d6) δ 2.28 (s, 3H), 3.32 (s, 2H), 6.79-6.82 (d, J
) 7.5 Hz, 1H), 7.13-7.30 (m, 5H), 7.32-7.35 (d, J ) 8.4 Hz,
2H), 7.61-7.64 (d, J ) 8.4 Hz, 2H), 8.28 (s, 1H), 8.45-8.47
(dd, J ) 4.2, 1.5 Hz, 2H), 8.67 (s, 1H), 8.88 (s, 1H); MS (ESI)
m/z 467 (M + H)+; HRMS (FAB) Calcd for C26H23N6OS
467.1654, found 467.1649.
1
trifluoroacetate salt. H NMR (DMSO-d6) δ 2.29 (s, 3H), 3.72
(s, 3H), 6.81 (d, J ) 7.1 Hz, 1H), 7.05 (dd, J ) 8.1, 2.0 Hz,
1H), 7.14-7.25 (m, 3H), 7.34 (s, 1H), 7.38 (s, 1H), 7.50 (d, J )
2.0 Hz, 1H), 8.36 (s, 1H), 8.67 (s, 1H), 8.93 (s, 1H); MS (ESI)
m/z 406.0 (M + H)+. Anal. (C21H19N5O2S‚1.0CF3CO2H‚0.2H2O)
C, H, N.
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-2-fluoro-
phenyl]-N′-(3-methylphenyl)urea (91). Compound 91 was
prepared following the same sequence as described for the
synthesis of 51 by replacing 42 with 3′-fluoroacetophenone.
1H NMR (DMSO-d6) δ 2.30 (s, 3H), 6.83 (d, J ) 7.1 Hz, 1H),
7.18 (t, J ) 7.6 Hz, 1H), 7.23-7.27 (m, 2H), 7.32 (s, br, 1H),
7.39 (dd, J ) 12.0, 1.9 Hz, 1H), 7.49 (s, 1H), 8.30 (d, J ) 8.5
Hz, 1H), 8.34 (s, 1H), 8.70 (d, J ) 2.7 Hz, 1H), 9.06 (s, 1H);
MS (ESI) m/z 394 (M + H)+. Anal. (C20H16FN5OS) C, H, N.
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-2-chloro-
phenyl]-N′-(3-methylphenyl)urea (92). Compound 92 was
prepared following the same sequence as described for the
synthesis of 51 by replacing 42 with 3′-chloroacetophenone.
1H NMR (DMSO-d6) δ 2.30 (s, 3H), 6.83 (d, J ) 7.1 Hz, 1H),
7.19 (apparent t, J ) 7.6 Hz, 1H), 7.26 (d, J ) 8.1 Hz, 1H),
7.33 (s, 1H), 7.39 (dd, J ) 8.7, 2.2 Hz, 1H), 7.52 (s, 1H), 7.58
(d, J ) 2.0 Hz, 1H), 8.34 (d, J ) 8.8 Hz, 1H), 8.34 (s, 1H), 8.44
(s, 1H), 9.43 (s, 1H); MS (ESI) m/z 410 (M + H)+. Anal. (C20H16-
ClN5OS‚0.7H2O) C, H, N.
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-2-meth-
oxyphenyl]-N′-(3-methylphenyl)urea (93). Compound 93
was prepared following the same sequence as described for
the synthesis of 11 by substituting 41d for 2. 1H NMR (DMSO-
d6) δ 2.29 (s, 3H), 3.94 (s, 3H), 6.80 (d, J ) 7.5 Hz, 1H), 7.01
(dd, J ) 8.3, 1.7 Hz, 1H), 7.12 (d, J ) 1.7 Hz, 1H), 7.17 (t, J )
7.8 Hz, 1H), 7.24 (d, J ) 8.5 Hz, 1H), 7.32 (s, 1H), 7.46 (s,
1H), 8.29 (d, J ) 8.5 Hz, 1H), 8.34 (s, 1H), 8.38 (s, 1H), 9.31
(s, 1H); MS (ESI) m/z 406 (M + H)+. Anal. (C21H19N5O2S‚
0.7H2O) C, H, N.
N-(11-Amino-5,6-dihydro-7-thia-8,10-diazabenzo[c]-
fluoren-3-yl)-N′-(3-methylphenyl)urea (94). Compound 94
was prepared following the same sequence as described for
the synthesis of 51 by substituting 1-tetralone for 42. 1H NMR
(DMSO-d6) δ 2.28 (s, 3H), 2.91 (m, 4H), 6.6-7.0 (s, br, 2 H),
6.79 (d, J ) 7.1 Hz, 1H), 7.16 (m, 1H), 7.23 (d, J ) 8.1 Hz,
1H), 7.32 (s, 1H), 7.40 (m, 2H), 7.54 (d, J ) 1.7 Hz, 1H), 8.30
(s, 1H), 8.61 (s, 1H), 8.72 (s, 1H); MS (ESI) m/z 402 (M + H)+.
Anal. (C22H19N5OS‚0.7H2O) C, H, N.
N-[4-(4-Amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)-
phenyl]-N′-[3-(trifluoromethyl)phenyl]urea (95). Com-
pound 95 was prepared using the same procedure as described
for the synthesis of 74 by substituting 3-trifluoromethylphenyl
isocyanate for m-tolyl isocyanate. 1H NMR (DMSO-d6) δ 9.18
(s, 1H), 9.06 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.50-7.70 (m,
4H), 7.32 (d, J ) 8.4 Hz, 3H), 2.62 (q, J ) 7.5 Hz, 2H), 1.98 (t,
J ) 7.5 Hz, 3H). Anal. (C22H18F3N5OS‚0.9CH2Cl2) C, H, N.
N-{4-[4-Amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimi-
din-5-yl]phenyl}-N′-(3-methylphenyl)urea (84). Compound
84 was prepared following the same sequence as described for
the synthesis of 11 by replacing 2 with 36a, except that the
reaction of the corresponding amino nitrile with formamide
was conducted in a Smith Synthesizer microwave (70 min at
180 °C) to form the pyrimidine ring and that the tert-
butyldimethylsilyl group was removed with tetrabutylammo-
nium fluoride (TBAF) (in THF at room temperature) in the
1
last step. H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.75-2.80 (t, J
) 6.6 Hz, 2H), 3.54-3.60 (m, 2H), 4.85-4.89 (t, J ) 5.7 Hz,
1H), 6.79-6.82 (d, J ) 7.5 Hz, 2H), 7.14-7.19 (t, J ) 7.5 Hz,
1H), 7.24-7.32 (m, 4H), 7.61-7.63 (d, J ) 8.4 Hz, 2H), 8.26
(s, 1H), 8.67 (s, 1H), 8.87 (s, 1H); MS (ESI) m/z 420 (M + H)+.
Anal. (C22H21N5O2S‚0.4H2O) C, H, N.
N-{4-[4-Amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimi-
din-5-yl]phenyl}-N′-(3-methylphenyl)urea (85). Compound
85 was prepared following the same sequence as described for
11 by replacing 2 with 4-methoxy-1-(4-nitrophenyl)butan-1-
one, which was prepared using the same procedure as de-
scribed for the synthesis of ketone 36a by substituting
3-methoxypropyl iodide for 35a. 1H NMR (DMSO-d6) δ 2.29
(s, 3H), 2.83-2.87 (t, J ) 6.6 Hz, 2H), 3.22 (s, 3H), 3.47-3.52
(t, J ) 6.6 Hz, 2H), 6.79-6.82 (d, J ) 7.5 Hz, 2H), 7.14-7.19
(t, J ) 7.5 Hz, 1H), 7.24-7.32 (m, 4H), 7.61-7.64 (d, J ) 9.0
Hz, 2H), 8.27 (s, 1H), 8.67 (s, 1H), 8.87 (s, 1H); MS (ESI) m/z
434 (M + H)+.
N-{4-[4-Amino-6-(3-hydroxypropyl)thieno[2,3-d]pyri-
midin-5-yl]phenyl}-N′-(3-methylphenyl)urea (86). Com-
pound 86 was prepared following the same sequence as
described for the synthesis of 84 by substituting 36b for 36a.
1H NMR (DMSO-d6) δ 1.70 (m, 2H), 2.29 (s, 3H), 2.68 (m, J )
6.27 Hz, 2H), 3.37 (t, J ) 6.27 Hz, 2H), 6.81 (d, J ) 7.80 Hz,
1H), 7.17 (t, J ) 7.63 Hz, 1H), 7.23-7.33 (m, 4H), 7.62 (d, J )
8.81 Hz, 2H), 8.27 (s, 1H), 8.69 (s, 1H), 8.90 (s, 1H); MS (ESI)
m/z 434 (M + H)+.
N-(4-{4-Amino-6-[2-(dimethylamino)ethyl]thieno[2,3-
d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea (87).
Compound 87 was prepared following the same sequence as
1
described for the synthesis of 11 by substituting 39 for 2. H
NMR (DMSO-d6) δ 2.11 (s, 6H), 2.29 (s, 3H), 2.42-2.46 (t, J )
7.2 Hz, 2H), 2.72-2.77 (t, J ) 6.0 Hz, 2H), 6.79-6.82 (d, J )
7.5 Hz, 1H), 7.14-7.19 (t, J ) 7.5 Hz, 1H), 7.24-7.32 (m, 4H),
7.61-7.64 (d, J ) 6.6 Hz, 2H), 8.26 (s, 1H), 8.67 (s, 1H), 8.87
(s, 1H); MS (ESI) m/z 447 (M + H)+.
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)-3-fluoro-
phenyl]-N′-(3-methylphenyl)urea (88). Compound 88 was
prepared following the same sequence as described for the
synthesis of 11 by substituting 41a for 2. 1H NMR (500 MHz,
DMSO-d6) δ 2.29 (s, 3H), 6.82 (d, J ) 7.5 Hz, 1H), 7.18 (t, J )
7.8 Hz, 1H), 7.25 (d, J ) 10.0 Hz, 1H), 7.27 (dd, J ) 8.6, 2.0
Hz, 1H), 7.32 (s, 1H), 7.37 (t, J ) 8.4 Hz, 1H), 7.52 (s, 1H),
7.66 (dd, J ) 12.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.75 (s, 1H), 9.09
(s, 1H); MS (ESI) m/z 394.0 (M + H)+. Anal. (C20H16FN5OS‚
0.2H2O) C, H, N.
N-[4-(4-Aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-
(3-chlorophenyl)urea (96). Compound 96 was prepared
using the same procedure as described for the synthesis of 76
by substituting 3-chlorophenyl isocyanate for m-tolyl isocyan-
1
ate. H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.34 (s, 1H), 7.73 (s,
1H), 7.61 (d, J ) 8.4 Hz, 2H), 7.44 (s, 1H), 7.40 (d, J ) 8.4 Hz,