4024 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Goldberg et al.
and washed with saturated aqueous NaHCO3, water and brine, dried
(MgSO4), filtered, and concentrated in vacuo. Flash column
chromatography on silica gel (1:13 MeOH/CH2Cl2) afforded the
title compound as a white solid (54 mg, 70%). 1H NMR (DMSO-
d6, 400 MHz): δ 1.3 (s, 9H), 3.0 (s, 3H), 3.7 (s, 3H), 6.5 (d, 1H,
J ) 9 Hz), 6.7 (s, 2H), 7.3 (d, 1H, J ) 2 Hz), 7.4 (d, 1H, J ) 2
Hz), 7.5-7.6 (m, 2H), 7.9 (d, 1H, J ) 7 Hz), 8.0 (d, 1H, J ) 9
Hz), 8.4 (s, 1H), 8.6 (s, 1H), 9.2 (s, 1H), 10.1 (s, 1H), 10.3 (s, 1H).
HPLC purity: system A, tR 8.94 min (99%). ESMS m/z ) 568 [M
+ H]+.
anesulfonylamino-2-methoxy-phenyl)-amide (18): Compound 18
was prepared as described above (50%, off-white solid). 1H NMR
(DMSO-d6, 400 MHz): δ 1.2 (s, 9H), 2.3-2.4 (m, 6H), 3.0 (s,
3H), 3.4-3.5 (m, 2H), 3.6 (t, 4H, J ) 4 Hz), 3.7 (s, 3H), 4.0 (s,
3H), 6.5 (d, 1H, J ) 9 Hz), 7.0-7.1 (m, 3H), 7.2 (d, 1H, J ) 2
Hz), 7.4 (s, 1H), 7.5 (d, 1H, J ) 2 Hz), 7.6 (dd, 1H, J ) 8, 2 Hz),
7.9 (d, 1H, J ) 8 Hz), 8.7 (d, 1H, J ) 2 Hz), 9.2 (s, 1H), 9.8 (s,
1H), 10.0 (s, 1H). HPLC purity: system A, tR 9.86 min (97%).
ESMS m/z ) 678 [M + H]+.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl-
carbamoyl)-benzo[b]thiophen-7-yl]-6-cyclopropylamino-nicotinamide
(19): Compound 19 was prepared as described above to provide
the title compound as an off-white solid (71%). 1H NMR (DMSO-
d6, 400 MHz): δ 0.4-0.5 (m, 2H), 0.7-0.8 (m, 2H), 1.3 (s, 9H),
2.5-2.6 (m, 1H), 3.0 (s, 3H), 3.7 (s, 3H), 6.7 (d, 1H, J ) 9 Hz),
7.2 (d, 1H, J ) 2 Hz), 7.4 (d, 1H, J ) 2 Hz), 7.5-7.6 (m, 3H), 7.9
(dd, 1H, J ) 6, 2 Hz), 8.0 (d, 1H, J ) 9 Hz), 8.3 (s, 1H), 8.7 (d,
1H, J ) 2 Hz), 9.2 (s, 1H), 10.1 (s, 1H), 10.3 (s, 1H). HPLC
purity: system A, tR 9.42 min (99%). ESMS m/z ) 608 [M +
H]+.
7-[(6-Cyclopropylamino-pyridine-3-carbonyl)-amino]-1-
methyl-indole-2-carboxylic Acid (5-tert-Butyl-3-methanesulfo-
nylamino-2-methoxy-phenyl)-amide (20): Compound 20 was
prepared as described above (45%, off-white solid). 1H NMR
(DMSO-d6, 400 MHz): δ 0.4-0.5 (m, 2H), 0.7-0.8 (m, 2H), 1.2
(s, 9H), 2.5-2.6 (m, 1H), 3.0 (s, 3H), 3.7 (s, 3H), 4.0 (s, 3H), 6.6
(d, 1H, J ) 9 Hz), 7.1-7.2 (m, 2H), 7.3 (d, 1H, J ) 2 Hz), 7.4 (s,
1H), 7.5 (d, 1H, J ) 2 Hz), 7.6 (d, 1H, J ) 2 Hz), 7.7 (dd, 1H, J
) 7, 2 Hz), 8.0 (d, 1H, J ) 7 Hz), 8.7 (d, 1H, J ) 2 Hz), 9.1 (s,
1H), 9.8 (s, 1H), 10.0 (s, 1H). HPLC purity: system A, tR 9.33
min (99%), system B, tR 3.18 min (99%). ESMS m/z ) 605 [M +
H]+. Anal. Calcd for C31H36N3O5S: C, 61.57; H, 6.00; N, 13.90.
Found: C, 61.11; H, 5.94; N, 13.46.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl-
carbamoyl)-benzo[b]thiophen-7-yl]-6-(cyclopropylmethyl-amino)-nicotinamide
(21): Compound 21 was prepared as described above (68%, off-
white solid). 1H NMR (DMSO-d6, 400 MHz): δ 0.2-0.3 (m, 2H),
0.4-0.5 (m, 2H), 1.0-1.1 (m, 1H), 1.2 (s, 9H), 3.0 (s, 3H), 3.1-
3.2 (m, 2H), 3.7 (s, 3H), 4.0 (s, 3H), 6.5 (d, 1H, J ) 9 Hz), 7.2 (d,
1H, J ) 2 Hz), 7.3 (s, 1H), 7.4 (d, 1H, J ) 2 Hz), 7.5-7.6 (m,
2H), 7.8 (dd, 1H, J ) 2, 7 Hz), 7.9 (d, 1H, J ) 9 Hz), 8.3 (s, 1H),
8.7 (d, 1H, J ) 2 Hz), 9.2 (s, 1H), 10.1 (s, 1H), 10.2 (s, 1H). HPLC
purity: system A, tR 9.63 min (99%). ESMS m/z ) 622 [M +
H]+. Anal. Calcd for C31H35N5O5S2: C, 59.88; H, 5.67; N, 11.26.
Found: C, 59.47; H, 5.65; N, 11.14.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phe-
nylcarbamoyl)-benzo[b]thiophen-7-yl]-6-methylamino-nicotina-
mide (12): Prepared as described above (30%, off-white solid).
1H NMR (DMSO-d6, 400 MHz): δ 1.3 (s, 9H), 2.8 (d, 3H, J ) 4
Hz), 3.3 (s, 3H), 3.7 (s, 3H), 6.5 (d, 1H, J ) 8 Hz), 7.2 (s, 1H), 7.4
(s, 1H), 7.5 (d, 2H, J ) 4 Hz), 7.8 (d, 1H, J ) 6 Hz), 7.9 (dd, 2H,
J ) 8, 6 Hz), 8.3 (d, 1H, J ) 6 Hz), 8.7 (s, 1H), 9.2 (s, 1H), 10.2
(s, 1H), 10.3 (s, 1H). HPLC purity: system A, tR 9.03 min (99%),
system B, tR 2.98 min (99%). ESMS m/z ) 582 [M + H]+.
1-Methyl-7-[(6-methylamino-pyridine-3-carbonyl)-amino]-in-
dole-2-carboxylic Acid (5-tert-Butyl-3-methanesulfonylamino-
2-methoxy-phenyl)-amide (13): Compound 13 was prepared as
described above (30%, off-white solid). 1H NMR (DMSO-d6, 400
MHz): δ 1.2 (s, 9H), 2.8 (d, 3H, J ) 5 Hz), 3.0 (s, 3H), 3.7 (s,
3H), 4.0 (s, 3H), 6.5 (d, 1H, J ) 9 Hz), 7.0-7.1 (m, 2H), 7.2-7.3
(m, 1H), 7.4 (d, 1H, J ) 2 Hz), 7.5 (s, 1H), 7.6 (d, 1H, J ) 2 Hz),
7.7 (dd, 1H, J ) 8, 2 Hz), 7.9 (d, 1H, J ) 8 Hz), 8.7 (s, 1H), 9.1
(s, 1H), 9.8 (s, 1H), 10.0 (s, 1H). ESMS m/z ) 579 [M + H]+.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxyphenyl-
carbamoyl)-benzo[b]thiophen-7-yl]-6-dimethylamino-nicotina-
mide (14): Compound 14 was prepared as described above (50%,
1
off-white solid). H NMR (DMSO-d6, 400 MHz): δ 1.2 (s, 9H),
3.0 (s, 3H), 3.1 (s, 6H), 3.7 (s, 3H), 6.7 (d, 1H, J ) 9 Hz), 7.2 (d,
1H, J ) 2 Hz), 7.4 (s, 1H), 7.5-7.6 (m, 2H), 7.8 (dd, 1H, J ) 9,
3 Hz), 8.1 (dd, 1H, J ) 9, 3 Hz), 8.3 (s, 1H), 8.7 (d, 1H, J ) 2
Hz), 9.2 (s, 1H), 10.1 (s, 1H), 10.3 (s, 1H). HPLC purity: system
A, tR 8.94 min (97%). ESMS m/z ) 596 [M + H]+.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phe-
nylcarbamoyl)-benzo[b]thiophen-7-yl]-6-(2-dimethylamino-ethy-
lamino)-nicotinamide (15): Compound 15 was prepared as de-
1
scribed above (34%, off-white solid). H NMR (DMSO-d6, 400
MHz): δ 1.2 (s, 9H), 2.2 (s, 6H), 2.4-2.5 (m, 2H), 3.0 (s, 3H),
3.4-3.5 (m, 2H), 3.7 (s, 3H), 6.9 (d, 1H, J ) 9 Hz), 7.2 (d, 1H, J
) 2 Hz), 7.3 (d, 1H, J ) 2 Hz), 7.4-7.5 (m, 2H), 7.8 (dd, 1H, J
) 6.0, 2 Hz), 7.9 (dd, 1H, J ) 9, 2 Hz), 8.3 (s, 1H), 8.7 (d, 1H, J
) 2 Hz), 9.2 (br s, 1H), 10.1 (s, 1H), 10.2 (s, 1H). HPLC purity:
system A, tR 8.54 min (99%), system B, tR 2.61 min (99%). ESMS
m/z ) 639 [M + H]+.
7-{[6-(2-Dimethylamino-ethylamino)-pyridine-3-carbonyl]-
amino}-1-methyl-indole-2-carboxylic Acid (5-tert-Butyl-3-meth-
anesulfonylamino-2-methoxy-phenyl)-amide (16): Compound 16
was prepared as described above (42%, off-white solid). 1H NMR
(DMSO-d6, 400 MHz): δ 1.2 (s, 9H), 2.1 (s, 6H), 2.3-2.4 (m,
2H), 3.0 (s, 3H), 3.4-3.5 (m, 2H), 3.7 (s, 3H), 4.0 (s, 3H), 6.5 (d,
1H, J ) 9 Hz), 7.0-7.1 (m, 3H), 7.2-7.3 (m, 1H), 7.4 (d, 1H, J
) 2 Hz), 7.5 (d, 1H, J ) 2 Hz), 7.6 (d, 1H, J ) 7, 2 Hz), 7.9 (d,
1H, J ) 7 Hz), 8.7 (d, 1H, J ) 2 Hz), 9.1 (s, 1H), 9.8 (s, 1H), 10.0
(s, 1H). HPLC purity: system A, tR 8.38 min (99%). ESMS m/z )
636 [M + H]+.
7-{[6-(Cyclopropylmethyl-amino)-pyridine-3-carbonyl]-amino}-
1-methyl-indole-2-carboxylic Acid (5-tert-Butyl-3-methanesulfo-
nylamino-2-methoxy-phenyl)-amide (22): Compound 22 was
prepared as described above (63%, off-white solid). 1H NMR
(DMSO-d6, 400 MHz): δ 0.2-0.3 (m, 2H), 0.4-0.5 (m, 2H), 0.9-
1.0 (m, 1H), 1.2 (s, 9H), 3.0 (s, 3H), 3.2 (t, 2H, J ) 6 Hz), 3.7 (s,
3H), 4.0 (s, 3H), 6.5 (d, 1H, J ) 9 Hz), 7.0-7.1 (m, 2H), 7.2 (d,
1H, J ) 2 Hz), 7.3-7.4 (m, 2H), 7.5 (d, 1H, J ) 2 Hz), 7.6 (dd,
1H, J ) 7, 2 Hz), 7.9 (dd, 1H, J ) 7, 2 Hz), 8.6 (d, 1H, J ) 2 Hz),
9.1 (s, 1H), 9.8 (s, 1H), 10.0 (s, 1H). HPLC purity: system A, tR
9.67 min (98%). ESMS m/z ) 619 [M + H]+.
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl-
carbamoyl)-benzo[b]thiophen-7-yl]-6-(2-methoxy-ethylamino)-nicotinamide
(23): Compound 23 was prepared as described above (55%, off-
1
N-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phe-
nylcarbamoyl)-benzo[b]thiophen-7-yl]-6-(2-morpholin-4-yl-ethy-
lamino)-nicotinamide (17): Compound 17 was prepared as de-
white solid). H NMR (DMSO-d6, 400 MHz): δ 1.2 (s, 9H), 3.1
(s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 4H), 3.7 (s, 3H), 6.6 (d, 1H, J )
9 Hz), 7.2 (d, 1H, J ) 2 Hz), 7.3 (s, 1H), 7.4 (d, 1H, J ) 2 Hz),
7.5-7.6 (m, 2H), 7.8 (dd, 1H, J ) 6, 2 Hz), 7.9 (dd, 1H, J ) 9, 2
Hz), 8.3 (s, 1H), 8.7 (d, 1H, J ) 2 Hz), 9.2 (s, 1H), 10.1 (s, 1H),
10.3 (s, 1H). HPLC purity: system A, tR 9.13 min (98%). ESMS
m/z ) 626 [M + H]+. Anal. Calcd for C30H35N5O6S2: C, 57.58;
H, 5.64; N, 11.19. Found: C, 57.60; H, 5.61; N, 10.92.
1
scribed above (40%, off-white solid). H NMR (DMSO-d6, 400
MHz): δ 1.2 (s, 9H), 2.3-2.4 (m, 6H), 3.0 (s, 3H), 3.4-3.5 (m,
2H), 3.6-3.7 (m, 4H), 3.8 (s, 3H), 6.5 (d, 1H, J ) 9 Hz), 7.1-7.2
(m, 1H), 7.3 (d, 1H, J ) 2 Hz), 7.4 (d, 1H, J ) 2 Hz), 7.5-7.6 (m,
2H), 7.8 (dd, 1H, J ) 9, 2 Hz), 7.9 (dd, 1H, J ) 9, 2 Hz), 8.3 (s
1H), 8.7 (d, 1H, J ) 2 Hz), 9.3 (br s, 1H), 10.1 (s, 1H), 10.3 (s,
1H). ESMS m/z ) 681 [M + H]+.
7-{[6-(2-Methoxy-ethylamino)-pyridine-3-carbonyl]-amino}-
1-methyl-indole-2-carboxylic Acid (5-tert-Butyl-3-methanesulfo-
nylamino-2-methoxy-phenyl)-amide (24): Compound 24 was
prepared as described above (50%, off-white solid). 1H NMR
1-Methyl-7-{[6-(2-morpholin-4-yl-ethylamino)-pyridine-3-car-
bonyl]-amino}-indole-2-carboxylic Acid (5-tert-Butyl-3-meth-