790
Y. Takano et al. / Bioorg. Med. Chem. 14 (2006) 776–792
1
low powder (47%); mp >300 ꢁC; H NMR (DMSO-d6):
d 8.45 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.39 (dd,
J = 8.8, 1.0 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 6.920 (s,
1H), 6.916 (s, 1H), 6.88 (t, J = 7.3 Hz, 1H), 6.30 (t,
J = 5.4 Hz, 1H), 6.24 (t, J = 2.0 Hz, 1H), 4.17 (d,
J = 5.4 Hz, 2H); FAB(ꢀ)HRMS 470.1058 (ꢀ1.8 mmu).
Anal. Calcd for C22H16F3N5O4-1/2H2O: C, 55.00%; H,
3.57%; N, 14.58%. Found: C, 54.95%; H, 3.69%; N,
14.32%.
5.1.43. 3,4-Dihydro-3-oxo-6-trifluoromethyl-7-[3-(((4-tri-
fluoromethylphenylamino)carbonyl)aminomethyl)pyrrol-
1-yl]quinoxaline-2-carboxylic acid (27f). Following the
procedure described for compound 27a, the title com-
pound was prepared from compound 26 and 4-trifluo-
romethylphenyl isocyanate, brown powder (42%); mp
1
194–196 ꢁC; H NMR (DMSO-d6): d 8.91 (s, 1H), 7.89
(s, 1H), 7.77 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H), 7.57 (d,
J = 9.3 Hz, 2H), 6.93 (s, 2H), 6.49 (t, J = 5.4 Hz, 1H),
6.25 (t, J = 2.0 Hz, 1H), 4.20 (d, J = 4.9 Hz, 2H);
FAB(ꢀ)HRMS 538.0938 (ꢀ1.2 mmu).
5.1.39.
7-[3-(((3-Bromophenylamino)carbonyl)amino-
methyl)pyrrol-1-yl]-3,4-dihydro-3-oxo-6-trifluoromethyl-
quinoxaline-2-carboxylic acid (27b). Following the
procedure described for compound 27a, the title com-
pound was prepared from compound 26 and 3-brom-
ophenyl isocyanate, yellow powder (22%); mp
207–209 ꢁC; 1H NMR (DMSO-d6): d 8.69 (s, 1H),
7.90 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.22–7.15
(m, 2H), 7.06 (d, J = 7.3 Hz, 1H), 6.92 (s, 1H), 6.91
(s, 1H), 6.43 (t, J = 4.9 Hz, 1H), 6.24 (t, J = 2.0 Hz,
1H), 4.17 (d, J = 5.4 Hz, 2H); FAB(ꢀ)HRMS 548.0226
(+4.5 mmu).
5.1.44. 7-[3-(((3-Carboxyphenylamino)carbonyl)amino-
methyl)pyrrol-1-yl]-3,4-dihydro-3-oxo-6-trifluoromethyl-
quinoxaline-2-carboxylic acid (27g). Following the
procedure described for compound 27a, the title com-
pound was prepared from compound 26 and ethyl 3-iso-
cyanatobenzoate, yellow powder (20%); mp >300 ꢁC; 1H
NMR (DMSO-d6): d 8.70 (s, 1H), 8.05 (t, J = 1.5 Hz,
1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J = 8.3,
1.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.34 (t,
J = 7.8 Hz, 1H), 6.93 (s, 2H), 6.38 (t, J = 5.4 Hz, 1H),
6.25 (t, J = 2.0 Hz, 1H), 4.19 (d, J = 5.4 Hz, 2H);
FAB(ꢀ)HRMS 514.1017 (+4.3 mmu). Anal. Calcd for
C23H16F3N5O6-2H2O: C, 50.10%; H, 3.66%; N,
12.70%. Found: C, 50.21%; H, 3.67%; N, 12.71%.
5.1.40.
7-[3-(((4-Bromophenylamino)carbonyl)amino-
methyl)pyrrol-1-yl]-3,4-dihydro-3-oxo-6-trifluoromethyl-
quinoxaline-2-carboxylic acid (27c). Following the
procedure described for compound 27a, the title
compound was prepared from compound 26 and 4-
bromophenyl isocyanate, brown powder (49%); mp
196–198 ꢁC (decomp.); 1H NMR (DMSO-d6): d 8.62
(s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.38 (s, 4H), 6.92 (s,
1H), 6.91 (s, 1H), 6.37 (t, J = 5.4 Hz, 1H), 6.24 (t,
5.1.45. 7-[3-(((4-Carboxyphenylamino)carbonyl)amino-
methyl)pyrrol-1-yl]-3,4-dihydro-3-oxo-6-trifluorometh-
ylquinoxaline-2-carboxylic acid (27h). Following the
procedure described for compound 27a, the title com-
pound was prepared from compound 26 and ethyl 4-iso-
cyanatobenzoate, brown powder (20%); mp 234–236 ꢁC
(decomp.); 1H NMR (DMSO-d6): d 8.86 (s, 1H), 7.89 (s,
1H), 7.81 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.50 (d,
J = 8.8 Hz, 2H), 6.93 (s, 2H), 6.47 (t, J = 5.4 Hz, 1H),
6.25 (t, J = 2.0 Hz, 1H), 4.19 (d, J = 4.9 Hz, 2H);
FAB(ꢀ)HRMS 514.0968 (ꢀ0.6 mmu). Anal. Calcd for
C23H16F3N5O6-H2O: C, 51.79%; H, 3.40%; N, 13.13%.
Found: C, 51.91%; H, 3.43%; N, 12.82%.
J = 2.0 Hz,
1H),
4.17
(d,
J = 5.4 Hz,
2H);
FAB(ꢀ)HRMS 548.0144 (ꢀ3.7 mmu). Anal. Calcd for
C22H15BrF3N5O4- 4 H2O: C, 46.01%; H, 3.10%; N,
12.19%. Found: C3, 45.84%; H, 2.82%; N, 12.02%.
5.1.41. 3,4-Dihydro-7-[3-(((4-fluoroophenylamino)carbon-
yl)aminomethyl)pyrrol-1-yl]-3-oxo-6- trifluoromethylqui-
noxaline-2-carboxylic acid (27d). Following the
procedure described for compound 27a, the title com-
pound was prepared from compound 26 and 4-fluor-
ophenyl isocyanate, brown powder (43%); mp 168–
5.1.46. 3,4-Dihydro-3-oxo-7-[3-(((phenylamino)thiocar-
bonyl)aminomethyl)pyrrol-1-yl]-6-trifluoromethylquinox-
aline-2-carboxylic acid (28). Following the procedure
described for compound 27a, the title compound was
prepared from compound 26 and phenyl thioisocyanate,
yellow powder (47%); mp 198–200 ꢁC; 1H NMR
(DMSO-d6): d 9.54 (s, 1H), 7.90 (s, 1H), 7.86 (t,
J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.47–7.44 (m, 2H), 7.33–
7.29 (m, 2H), 7.09 (t, J = 7.3 Hz, 1H), 7.00 (s, 1H),
6.94 (s, 1H), 6.32 (t, J = 1.5 Hz, 1H), 4.56 (d,
J = 4.4 Hz, 2H); FAB(ꢀ)HRMS 486.0858 (+1.1 mmu).
1
170 ꢁC; H NMR (DMSO-d6): d 8.50 (s, 1H), 7.89 (s,
1H), 7.75 (s, 1H), 7.40 (dd, J = 8.8, 4.9 Hz, 2H), 7.08–
7.03 (m, 2H), 6.91 (s, 2H), 6.30 (t, J = 5.4 Hz, 1H),
6.23 (s, 1H), 4.17 (d, J = 5.4 Hz, 2H); FAB(ꢀ)HRMS
488.0985 (+0.3 mmu).
5.1.42. 3,4-Dihydro-7-[3-(((4-methoxyphenylamino)car-
bonyl)aminomethyl)pyrrol-1-yl]-3-oxo-6- trifluoromethyl-
quinoxaline-2-carboxylic acid (27e). Following the
procedure described for compound 27a, the title
compound was prepared from compound 26 and 4-
methoxyphenyl isocyanate, brown powder (46%);
5.1.47.
3,4-Dihydro-7-[3-((4-fluorophenylacetyl)amino-
methyl)pyrrol-1-yl]-3-oxo-6-trifluoromethylquinoxaline-
2-carboxylic acid (29). To a solution of compound 26
(200 mg, 478 lmol) and 4-fluorophenylacetic acid
(88.3 mg, 573 lmol) in DMF (5 mL) were added EDCI
(274 mg, 1.43 mmol) and Et3N (266 lL, 1.91 mmol),
and stirred for 18 h at room temperature. The reaction
was diluted with AcOEt, washed with water, dried over
Na2SO4, and evaporated. The residue was dissolved in
EtOH (5 mL) and 1 N KOH (600 lL, 600 lmol), and
1
mp 198–200 ꢁC; H NMR (DMSO-d6): d 8.26 (s, 1H),
7.89 (s, 1H), 7.76 (s, 1H), 7.29 (d, J = 9.3 Hz, 2H),
6.91 (s, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.23 (t,
J = 2.0 Hz, 1H), 6.20 (t, J = 5.4 Hz, 1H), 4.16 (d,
J = 5.4 Hz, 2H), 3.69 (s, 3H); FAB(ꢀ)HRMS 500.1165
(ꢀ1.6 mmu). Anal. Calcd for C23H18F3N5O5- 32 H2O: C,
52.28%; H, 4.01%; N, 13.25%. Found: C, 51.97%; H,
3.66%; N, 13.07%.