4466 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18
Hasegawa et al.
Methyl N-(5-(4-((2-Chloro-5-(trifluoromethyl)phenyl)amino-
carbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate (18).
General procedure A was utilized using 3c and 2-chloro-5-
trifluoromethylphenyl isocyanate leading to 18 as a brown solid
(69%): 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.53 (s, 1H),
8.65 (d, 1H), 8.57 (s, 1H), 7.71 (d, 1H), 7.45 (d, 2H), 7.37 (m,
2H), 7.01 (s, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); LC-
MS m/z 520 (M + 1), 522 (M + 3), 99.9%. Further treatment with
HCl in methanol gave HCl salt: C23H18F3N5O4‚HCl‚H2O. Elemental
analysis (C, H, N): C calcd 48.10, found 47.83; H calcd 3.51, found
3.47; N calcd 12.20, found 12.23.
Methyl N-(5-(4-((3-Ethylphenyl)aminocarbonylamino)phenoxy)-
1H-benzimidazol-2-yl)carbamate (19). General procedure A was
utilized using 3c and 3-ethylphenyl isocyanate leading to 19 as a
brown solid (71%): 1H NMR (DMSO-d6) δ 11.60 (brs, 2H), 8.71
(s, 1H), 8.67 (s, 1H), 7.42 (d, J ) 9.0 Hz, 2H), 7.37 (d, J ) 8.5
Hz, 1H), 7.31-6.98 (m, 4H), 6.92 (d, J ) 9.0 Hz, 2H), 6.83-6.77
(m, 2H), 3.75 (s, 3H), 2.57 (m, 2H), 1.17 (t, 3H); LC-MS m/z 446
(M + 1), 96.5%.
Methyl N-(5-(4-((3-Bromophenyl)aminocarbonylamino)phen-
oxy)-1H-benzimidazol-2-yl)carbamate (20). General procedure A
was utilized using 3c and 3-bromophenyl isocyanate leading to 20
as a brown solid (64%): 1H NMR (DMSO-d6) δ 12.2-11.0 (brs,
2H), 9.11 (s, 1H), 8.93 (s, 1H), 7.84 (s, 1H), 7.42 (d, J ) 9.1 Hz,
2H), 7.37 (d, J ) 8.6 Hz, 1H), 7.31 (m, 1H), 7.22 (t, J ) 8.5 Hz,
1H), 7.13 (d, J ) 8.5 Hz, 1H), 7.00 (d, J ) 3.0 Hz, 1H), 6.92 (d,
J ) 9.1 Hz, 2H), 6.79 (dd, J ) 7.5 and 2.5 Hz, 1H), 3.74 (s, 3H);
LC-MS m/z 496 (M + 1), 498 (M + 3), 99.7%.
Methyl N-(5-(4-((3-Chlorophenyl)aminocarbonylamino)phen-
oxy)-1H-benzimidazol-2-yl)carbamate (21). General procedure A
was utilized using 3c and 3-chlorophenyl isocyanate leading to 21
as a brown solid (75%): 1H NMR (DMSO-d6) δ 11.60 (brs, 2H),
9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, J ) 9.0 Hz, 2H),
7.38 (d, J ) 9.0 Hz, 1H), 7.32-7.24 (m, 2H), 7.01 (m, 2H), 6.93
(d, J ) 9.0 Hz, 2H), 6.80 (dd, J ) 7.5 and 2.5 Hz, 1H), 3.75 (s,
3H); LC-MS m/z 452 (M + 1), 454 (M + 3), 99.9%.
Methyl N-(5-(4-((2,5-Difluorophenyl)aminocarbonylamino)-
phenoxy)-1H-benzimidazol-2-yl)carbamate (22). General proce-
dure A was utilized using 3c and 2, 5-difluorophenyl isocyanate,
leading to 22 as a brown solid (90%): 1H NMR (DMSO-d6) δ
12.0-11.0 (brs, 2H), 9.09 (s, 1H), 8.71 (s, 1H), 8.04 (m, 1H), 7.42
(d, J ) 9.0 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 1H), 7.29 (m, 1H), 7.00
(d, J ) 2.5 Hz, 1H), 6.93 (d, J ) 9.0 Hz, 2H), 6.82 (m, 1H), 6.79
(dd, J ) 8.5 and 2.5 Hz, 1H), 3.74 (s, 3H); LC-MS m/z 454 (M +
1), 94.4%.
Methyl N-(5-(4-((3-(Trifluoromethylthio)phenyl)aminocar-
bonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate (23). Gen-
eral procedure A was utilized using 3c and 3-trifluoromethyl-
thiophenyl isocyanate leading to 23 as a brown solid (69%): 1H
NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.96 (s, 1H), 8.73 (s,
1H), 7.98 (s, 1H), 7.55 (d, J ) 9.0 Hz, 1H), 7.46-7.42 (m, 1H),
7.43 (d, J ) 9.0 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 1H), 7.29 (d, J )
7.5 Hz, 1H), 7.00 (d, J ) 2.0 Hz, 1H), 6.92 (d, J ) 9.0 Hz, 2H),
6.79 (dd, J ) 8.5 and 2.0 Hz, 1H), 3.74 (s, 3H); LC-MS m/z 518
(M + 1), 99.1%.
and SnCl2 (350 mg, 1.5 mmol) in DMF (3 mL) were stirred
overnight. The mixture was washed with aq NaHCO3, extracted
with AcOEt, dried over MgSO4, and evaporated to give a crude
product. It was eluted through SCX ion exchange column with
MeOH-NH3 to give 25 as a brown solid (33 mg, 41%): 1H NMR
(DMSO-d6) δ 11.65 (sbr, 2H), 8.99 (s, 1H), 8.22 (s, 1H), 7.44 (dd,
J ) 7.0 and 2.0 Hz, 1H), 7.41 (d, J ) 9.0 Hz, 2H), 7.36 (d, J )
9.0 Hz, 1H), 6.99 (brs, 1 H), 6.91 (d, J ) 9.0 Hz, 2H), 6.85 (dd,
J ) 11 and 9.0 Hz, 1H), 6.78 (dd, J ) 9.0 and 2.0 Hz, 1H), 6.10
(m, 1H), 3.74 (s, 3H); MS m/z 451 (M + 1), 95%.
Methyl N-(5-(4-((3-Carboxyphenyl)aminocarbonylamino)-
phenoxy)-1H-benzimidazol-2-yl)carbamate (26). General proce-
dure A was utilized using 3c and 3-ethoxycarbonylphenyl isocyanate
leading to N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)-
phenoxy)-1H-benzimidazol-2-yl)carbamate as a brown solid (82%).
Hydrolysis of the product (100 mg) with 1 N NaOH (1 mL) in
EtOH (1 mL) and THF (2 mL) gave 26 as an off-white solid (84
mg, 90%): 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.97 (brs,
1H), 8.77 (brs, 1H), 8.12 (s, 1H), 7.64 (d, J ) 9.0 Hz, 1H), 7.54
(d, J ) 8.0 Hz, 1H), 7.44 (d, J ) 8.8 Hz, 2H), 7.38 (m, 2H), 7.00
(d, J ) 2.0 Hz, 1H), 6.92 (d, J ) 8.8 Hz, 2H), 6.79 (dd, J ) 8.5
and 2.5 Hz, 1H), 3.74 (s, 3H); MS m/z 462 (M + 1), 96.9%.
Methyl N-(5-(4-((3-(Trifluoromethyl)phenyl)aminothiocar-
bonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate (27). Gen-
eral procedure A was utilized using 3c and 3-trifluoromethylphenyl
isothiocyanate leading to 27 as a brown solid (60%): 1H NMR
(DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.95 (s, 1H), 9.92 (s, 1H), 7.95
(s, 1H), 7.75 (d, J ) 7.0 Hz, 1H), 7.55 (t, J ) 7.5 Hz, 1H), 7.44
(d, J ) 7.5 Hz, 1H), 7.39 (m, 1H), 7.38 (d, J ) 9.0 Hz, 2H), 7.06
(s, 1H), 6.93 (d, J ) 9.0 Hz, 2H), 6.81 (dd, J ) 8.5 and 2.2 Hz,
1H), 3.75 (s, 3H); MS m/z 502 (M + 1), 95.0%.
Methyl (5-(4-((2-(3-Trifluoromethyl)phenyl)acetylamido)-
phenoxy)-1H-benzoimidazol-2-yl)carbamate (28). A mixture of
3c (130 mg, 0.44 mmol), 3-trifluoromethylphenylacetic acid (135
mg, 0.65 mmol), HBTU (250 mg, 0.65 mmol), and triethylamine
(130 mg, 1.3 mmol) in DMF (2.5 mL) was stirred for 4 h. The
precipitate formed was collected by filtration and dried in vacuo.
It was loaded on a SCX ion exchange column, washed with MeOH,
and eluted with MeOH-NH3. The solution stood still to form a
precipitate. Filtration afforded 28 (9.4 mg, 5%): 1H NMR (DMSO-
d6) δ 10.2 (s, 1H), 7.70 (s, 1H), 7.62 (m, 3H), 7.55 (d, J ) 9.0 Hz,
2H), 7.37 (d, J ) 8.0 Hz, 1H), 6.99 (d, J ) 2.5 Hz, 1H), 6.91 (d,
J ) 8.8 Hz, 2H), 6.77 (dd, J ) 8.8 and 2.5 Hz, 1H), 3.76 (m, 2H),
3.74 (s, 3H); LC-MS m/z 485 (M + 1), 99.0%.
Methyl (6-(4-(2-(2-Fluoro-5-(trifluoromethyl)phenylamino)-
2-oxoethyl)phenoxy)-1H-benzoimidazol-2-yl)carbamate (29). A
mixture of 6c (210 mg, 0.5 mmol) and 1,3-bis(methoxycarbonyl)-
2-methyl-2-thiopseudourea (108 mg, 0.53 mmol) in EtOH (5 mL)
was refluxed overnight. After cooling, the insoluble material was
collected by filtration and dried in vacuo to give desired compound
29 (174 mg, 68%): 1H NMR (DMSO-d6) δ 11.63 (brs, 2H), 10.28
(s, 1H), 8.44 (d, J ) 7.6 Hz, 1H), 7.51-7.54 (m, 2H), 7.39 (d, J
) 8.6 Hz, 1H), 7.30 (d, J ) 8.6 Hz, 2H), 7.04 (d, J ) 2.0 Hz, 1H),
6.91 (d, J ) 8.6 Hz, 2H), 6.80 (dd, J ) 8.6 and 2.3 Hz, 1H), 3.74
(brs, 5H); LC-MS m/z 503 (M + 1), 98.8%.
Methyl N-(5-(4-((3-Methylthiophenyl)aminocarbonylamino)-
phenoxy)-1H-benzimidazol-2-yl)carbamate (24). General proce-
dure A was utilized using 3c and 3-methylthiophenyl isocyanate
leading to 24 as a brown solid (77%): 1H NMR (DMSO-d6) δ
12.2-11.2 (brs, 2H), 8.67 (s, 1H), 8.64 (s, 1H), 7.46 (s, 1H), 7.41
(d, J ) 9.0 Hz, 2H), 7.36 (d, J ) 8.5 Hz, 1H), 7.21 (t, J ) 8.0 Hz,
1H), 7.13 (d, J ) 9.0 Hz, 1H), 6.99 (d, J ) 2.0 Hz, 1H), 6.92 (d,
J ) 9.0 Hz, 2H), 6.84 (d, J ) 8.5 Hz, 1H), 6.78 (dd, J ) 8.5 and
2.2 Hz, 1H), 3.74 (s, 3H), 2.45 (s, 3H); LC-MS m/z 464 (M + 1),
99.9%.
Methyl N-(5-(4-((2-Fluoro-5-aminophenyl)aminocarbonyl-
amino)phenoxy)-1H-benzimidazol-2-yl)carbamate (25). General
procedure A was utilized using 3c and 2-fluoro-5-nitrophenyl
isocyanate leading to N-(5-(4-((2-fluoro-5-nitrophenyl)aminocar-
bonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate as a yellow
solid (90%). The HCl salt of the compound (95 mg, 0.18 mmol)
Methyl N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)amino-
carbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate (30).
General procedure A was utilized using 3a and 2-fluoro-5-
(trifluoromethyl)phenyl isocyanate leading to 30 as a brown solid
(44%): 1H NMR (DMSO-d6) δ 11.67 (brs, 2H), 9.23 (s, 1H), 8.80
(s, 1H), 8.54 (d, J ) 2.5 Hz, 1H), 7.48 (t, J ) 2.3 Hz, 1H), 7.41
(m, 2H), 7.26 (t, J ) 2.3 Hz, 1H), 7.14 (d, J ) 8.5 Hz, 1H), 7.08
(d, J ) 8.5 Hz, 2H), 6.84 (d, J ) 8.5 Hz, 1H), 6.61 (d, J ) 8.1 Hz,
1H), 3.75 (s, 3H); LC-MS m/z 504 (M + 1), 94%.
Methyl N-(5-(5-((2-Fluoro-5-(trifluoromethyl)phenyl)amino-
carbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carba-
mate (31). General procedure A was used utilizing 7c and 2-fluoro-
5-trifluoromethylphenyl isocyanate leading to 31 as a brown solid
(47%): 1H NMR (DMSO-d6) δ 12.0-11.1 (brm, 2H), 9.21(s, 1H),
8.96 (d, J ) 2.76 Hz, 1H), 8.58 (dd, J ) 5.3 and 2.0 Hz, 1H), 8.15
(d, J ) 2.8 Hz, 1H), 8.00 (dd, J ) 6.1 and 2.8 Hz 1H), 7.51 (t, J