202
X. Li et al. / European Journal of Medicinal Chemistry 134 (2017) 185e206
under vacuum, the residue was dissolved with CH2Cl2, and washed
with saturated NaHCO3 (2 ꢂ 30 mL) and brine (2 ꢂ 30 mL), dried
over Na2SO4 overnight, and the solvent was evaporated under
vacuum. The crude material was purified via flash chromatography
to afford the compound 3 (0.16 g, 30%). Mp: 212e214 ꢁC$1H NMR
synthetic method for 3, compound 10d gave 11d as a white solid,
31% yield. Mp: 187e189 ꢁC. 1H NMR (400 MHz, DMSO-d6)
10.99 (s,
d
1H), 9.75 (s, 1H), 8.94e8.81 (m, 1H), 8.68 (d, J ¼ 8.2 Hz, 1H), 8.63 (d,
J ¼ 4.6 Hz, 1H), 8.04e7.94 (m, 4H), 7.63e7.59 (m, 2H), 7.34 (d,
J ¼ 8.0 Hz, 1H), 7.30 (t, J ¼ 7.1 Hz, 2H), 7.20 (d, J ¼ 7.5 Hz, 1H),
7.12e7.10 (m, 1H), 7.05 (t, J ¼ 7.5 Hz, 1H), 6.98e6.91 (m, 2H), 6.80 (d,
J ¼ 7.6 Hz, 1H), 6.61 (t, J ¼ 7.3 Hz, 1H), 5.05 (s, 2H), 4.90e4.85 (m,
1H), 4.45e4.25 (m, 2H), 3.33e3.28 (m, 2H). 13C NMR (100 MHz,
(400 MHz, DMSO-d6)
d 10.81 (s, 1H), 10.51 (s, 1H), 9.61 (s, 1H), 8.55
(d, J ¼ 7.7 Hz, 1H), 7.98 (d, J ¼ 8.6 Hz, 2H), 7.86 (d, J ¼ 8.8 Hz, 2H),
7.77 (d, J ¼ 8.7 Hz, 3H), 7.32 (d, J ¼ 8.0 Hz,1H), 7.28 (d, J ¼ 1.9 Hz,1H),
7.18 (d, J ¼ 7.4 Hz, 1H), 7.07 (t, J ¼ 7.2 Hz, 1H), 7.03e6.94 (m, 4H),
6.84e6.77 (m,1H), 6.62 (t, J ¼ 7.1 Hz,1H), 5.03 (s, 2H), 4.94e4.88 (m,
1H), 3.80 (s, 3H), 3.29e3.20 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
DMSO-d6)
d 171.58, 165.62, 163.69, 149.83, 148.94, 143.20, 138.36,
136.62, 133.54, 128.30, 128.12, 127.84, 127.19, 126.81, 124.18, 122.27,
121.36, 119.00, 118.71, 116.89, 116.80, 111.84, 109.91, 54.06, 42.46,
28.74. HRMS (AP-ESI) m/z calcd for C31H28N6O3 [MþH]þ 533.2296,
found 533.2299.
d
171.97, 166.40, 165.23, 162.19, 143.26, 142.30, 136.54, 129.86,
129.57, 129.12, 127.74, 127.13, 126.86, 126.58, 124.30, 124.17, 121.42,
119.13, 119.06, 118.71, 117.06, 116.82, 113.89, 111.80, 110.67, 55.83,
55.66, 27.97. HRMS (AP-ESI) m/z calcd for C32H29N5O4 [MþH]þ
548.2292, found 548.2293.
3.1.17.6. (S)-N-(1-((4-((2-aminophenyl)carbamoyl)benzyl)amino)-3-
(1H-indol-3-yl)-1-oxopropan-2-yl)pyrazine-2-carboxamide
(11e).
Using the synthetic method for 3, compound 10e gave 11e as a
3.1.17.2. (S)-4-((3-(1H-indol-3-yl)-2-(4-methoxybenzamido)prop-
anamido)methyl)-N-(2-aminophenyl)benzamide (11a). Using the
synthetic method for 3, compound 10a gave 11a as a white solid,
white solid, 36% yield. Mp: 206e208 ꢁC. 1H NMR (400 MHz, DMSO-
d6)
d
10.84 (s, 1H), 9.64 (s, 1H), 9.17 (s, 1H), 8.87 (d, J ¼ 2.1 Hz, 1H),
8.80 (t, J ¼ 5.7 Hz, 1H), 8.72e8.70 (m, 2H), 7.92 (d, J ¼ 7.9 Hz, 2H),
7.62 (d, J ¼ 7.9 Hz,1H), 7.37e7.28 (m, 3H), 7.18 (d, J ¼ 7.7 Hz,1H), 7.15
(s, 1H), 7.05 (t, J ¼ 7.5 Hz, 1H), 7.01e6.90 (m, 2H), 6.80 (d, J ¼ 7.9 Hz,
1H), 6.62 (t, J ¼ 7.4 Hz, 1H), 5.07 (s, 2H), 4.87 (dd, J ¼ 13.8, 7.3 Hz,
1H), 4.38 (d, J ¼ 5.6 Hz, 2H), 3.32e3.26 (m, 2H). 13C NMR (100 MHz,
32% yield. Mp: 187e188 ꢁC$1H NMR (400 MHz, DMSO-d6)
d 10.80 (s,
1H), 9.64 (s, 1H), 8.70 (t, J ¼ 5.9 Hz, 1H), 8.41 (d, J ¼ 7.9 Hz, 1H), 7.92
(d, J ¼ 8.1 Hz, 2H), 7.84 (d, J ¼ 8.8 Hz, 2H), 7.70 (d, J ¼ 7.8 Hz, 1H),
7.39e7.30 (m, 3H), 7.22 (d, J ¼ 2.0 Hz, 1H), 7.18 (d, J ¼ 7.6 Hz, 1H),
7.06 (t, J ¼ 7.4 Hz, 1H), 7.01e6.96 (m, 4H), 6.83e6.77 (m, 1H), 6.63 (t,
J ¼ 7.4 Hz, 1H), 5.09 (s, 2H), 4.80e4.74 (m, 1H), 4.39 (d, J ¼ 5.8 Hz,
DMSO-d6)
d 171.38, 165.63, 162.88, 148.19, 144.70, 143.89, 143.81,
143.29, 143.20, 136.62, 133.59, 128.25, 127.81, 127.36, 127.13, 126.93,
124.23, 124.00, 121.43, 118.97, 118.76, 116.97, 116.77, 111.83, 110.03,
54.18, 42.51, 28.44. HRMS (AP-ESI) m/z calcd for C30H27N7O3
[MþH]þ 534.2248, found 534.2248.
2H), 3.28e3.12 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
d 172.57,
166.24, 165.65, 162.11, 143.57, 143.10, 136.58, 133.47, 129.81, 128.22,
127.75, 127.23, 127.13, 126.92, 126.81, 124.18, 124.11, 121.36, 118.98,
118.71, 117.11, 116.86, 113.82, 111.80, 111.04, 55.82, 54.93, 42.39,
28.05. HRMS (AP-ESI) m/z calcd for C33H31N5O4 [MþH]þ 562.2449,
found 562.2449.
3.1.17.7. (S)-N-(1-((4-((2-aminophenyl)carbamoyl)benzyl)amino)-3-
(1H-indol-3-yl)-1-oxopropan-2-yl)thiophene-2-carboxamide (11f).
Using the synthetic method for 3, compound 10f gave 11f as a white
solid, 34% yield. Mp: 134e136 ꢁC. 1H NMR (400 MHz, DMSO-d6)
3.1.17.3. (S)-N-(2-aminophenyl)-4-((2-(4-(dimethylamino)benza-
mido)-3-(1H-indol-3-yl)propanamido)methyl)benzamide
Using the synthetic method for 3, compound 10b gave 11b as a
white solid, 28% yield. 1H NMR (400 MHz, DMSO-d6)
10.80 (s, 1H),
(11b).
d
10.81 (s, 1H), 9.67 (s, 1H), 8.76 (t, J ¼ 5.9 Hz, 1H), 8.65 (d, J ¼ 8.1 Hz,
1H), 8.00e7.86 (m, 3H), 7.78e7.67 (m, 2H), 7.33 (d, J ¼ 8.1 Hz, 3H),
7.21e7.18 (m, 2H), 7.15e7.13 (m, 1H), 7.06 (t, J ¼ 7.1 Hz, 1H), 6.99 (t,
J ¼ 7.4 Hz, 2H), 6.82 (d, J ¼ 7.9 Hz, 1H), 6.65 (t, J ¼ 7.1 Hz, 1H), 5.31 (s,
2H), 4.78e4.73 (m, 1H), 4.39 (d, J ¼ 5.8 Hz, 2H), 3.19e3.13 (m, 2H).
d
9.70 (s, 1H), 8.65 (t, J ¼ 5.9 Hz, 1H), 8.15 (d, J ¼ 7.9 Hz, 1H), 7.92 (d,
J ¼ 8.1 Hz, 2H), 7.73 (d, J ¼ 8.9 Hz, 2H), 7.70 (d, J ¼ 7.8 Hz, 1H),
7.35e7.31 (m, 3H), 7.21e7.19 (m, 2H), 7.08e7.97 (m, 3H), 6.85 (d,
J ¼ 7.3 Hz, 1H), 6.69e6.67 (m, 3H), 5.53 (s, 2H), 4.78e4.73 (m, 1H),
4.39 (d, J ¼ 5.8 Hz, 2H), 3.22e3.12 (m, 2H). 13C NMR (100 MHz,
13C NMR (100 MHz, DMSO-d6)
d 172.24, 165.67, 161.59, 143.50,
142.70, 140.11, 136.57, 133.47, 131.39, 129.09, 128.31. 128.24, 127.70,
127.25, 127.14, 126.94, 124.31, 124.21, 121.39, 118.98, 118.74, 117.42,
117.06, 111.82, 110.84, 54.83, 42.41, 28.09. HRMS (AP-ESI) m/z calcd
for C30H27N5O3S [MþH]þ 538.1907, found 538.1903.
DMSO-d6)
d 172.82, 166.64, 165.70, 152.65, 143.66, 136.57, 133.37,
129.32, 128.23, 127.78, 127.24, 127.19, 126.94, 124.63, 124.15, 121.34,
121.20, 118.97, 118.69, 117.86, 117.36, 111.79, 111.12, 54.80, 42.37,
28.08. HRMS (AP-ESI) m/z calcd for C34H34N6O3 [MþH]þ 575.2765,
found 575.2767.
3.1.17.8. (S)-N-(1-((4-((2-aminophenyl)carbamoyl)benzyl)amino)-3-
(1H-indol-3-yl)-1-oxopropan-2-yl)furan-2-carboxamide
(11
g).
Using the synthetic method for 3, compound 10g gave 11g as a
3.1.17.4. (S)-4-((3-(1H-indol-3-yl)-2-(4-(trifluoromethyl)benzamido)
white solid, 36% yield. Mp: 202e204 ꢁC. 1H NMR (400 MHz, DMSO-
propanamido)methyl)-N-(2-aminophenyl)benzamide
Using the synthetic method for 3, compound 10c gave 11c as a
white solid, 34% yield. 1H NMR (400 MHz, DMSO-d6)
10.81 (s, 1H),
(11c).
d6)
d
10.81 (s, 1H), 9.64 (s, 1H), 8.74 (t, J ¼ 5.9 Hz, 1H), 8.32 (d,
J ¼ 8.1 Hz, 1H), 7.92 (d, J ¼ 8.0 Hz, 2H), 7.85e7.78 (m, 1H), 7.67 (d,
J ¼ 7.8 Hz, 1H), 7.33 (d, J ¼ 8.1 Hz, 3H), 7.22e7.13 (m, 3H), 7.06 (t,
J ¼ 7.4 Hz, 1H), 6.98 (t, J ¼ 7.4 Hz, 2H), 6.80 (d, J ¼ 7.8 Hz, 1H),
6.66e6.57 (m, 2H), 5.01 (s, 2H), 4.79e4.73 (m, 1H), 4.39 (d,
J ¼ 5.7 Hz, 2H), 3.24e3.15 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
d
9.68 (s, 1H), 8.89 (d, J ¼ 7.9 Hz, 1H), 8.78 (t, J ¼ 5.8 Hz, 1H), 8.06 (d,
J ¼ 8.1 Hz, 2H), 7.93 (d, J ¼ 8.0 Hz, 2H), 7.83 (d, J ¼ 8.2 Hz, 2H), 7.71
(d, J ¼ 7.8 Hz, 1H), 7.35e7.32 (m, 3H), 7.25e7.15 (m, 2H), 7.11e7.04
(m, 1H), 7.01e6.98 (m, 2H), 6.83 (d, J ¼ 7.8 Hz,1H), 6.66 (t, J ¼ 7.4 Hz,
1H), 5.37 (s, 2H), 4.84e4.79 (m, 1H), 4.41 (d, J ¼ 5.6 Hz, 2H),
d
172.04, 165.65, 158.10, 148.00, 145.54, 143.37, 136.59, 133.54,
128.23, 127.73, 127.29, 127.13, 126.93, 124.19, 123.99, 121.40, 118.96,
118.74, 116.97, 116.75, 114.22, 112.29, 111.82, 110.64, 54.12, 42.44,
28.13. HRMS (AP-ESI) m/z calcd for C30H27N5O4 [MþH]þ 522.2136,
found 522.2137.
3.23e3.11 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
d 172.15, 165.63,
143.50, 143.08, 138.29, 136.57, 133.46, 128.90, 128.26, 127.67, 127.20,
126.94, 125.66, 124.22, 124.08, 121.40, 118.98, 118.73, 117.11, 116.86,
111.83, 110.86, 55.16, 42.39, 27.99. HRMS (AP-ESI) m/z calcd for
C
33H28F3N5O3 [MþH]þ 600.2217, found 600.2220.
3.1.17.9. (S)-N-(1-((6-((2-aminophenyl)amino)-6-oxohexyl)amino)-
3-(1H-indol-3-yl)-1-oxopropan-2-yl)-4-methoxybenzamide
(19).
3.1.17.5. (S)-N-(1-((4-((2-aminophenyl)carbamoyl)benzyl)amino)-3-
(1H-indol-3-yl)-1-oxopropan-2-yl)picolinamide (11d). Using the
Using the synthetic method for 3, compound 18 gave 19 as a white
solid, 31% yield. Mp: 133e135 ꢁC. 1H NMR (400 MHz, DMSO-d6)