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A. Nakao et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
5.1.33. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-
(ethylamino)ethyl]glycinamide hydrochloride (16n)
d6): d (ppm) 1.56–1.70 (m, 1H), 1.92–2.07 (m, 1H), 2.62 (s, 1.2H),
2.69 (s, 1.8H), 2.77–3.30 (m, 8H), 3.84–4.00 (m, 2H), 4.06–4.18
(m, 1H), 4.31 (d, J = 17.9, 0.6H), 4.44 (d, J = 17.9, 0.6H), 4.47 (d,
J = 17.4, 0.4H), 4.59 (d, J = 17.4, 0.4H), 4.65–4.75 (m, 0.4H), 5.18–
5.29 (m, 0.6H), 6.77–6.93 (m, 5H), 7.11–7.25 (m, 4H), 7.41 (d,
J = 9.2, 2H), 8.88 (d, J = 6.1, 0.6H), 8.91 (d, J = 6.1, 0.4H), 9.14 (br s,
1H), 9.36 (br s, 1H). 13C NMR (100 MHz, DMSO-d6): d (ppm)
27.44, 28.77, 29.58, 35.19, 35.50, 43.13, 43.20, 47.98, 48.04,
48.63, 52.91, 54.73, 54.90, 55.53, 57.35, 57.63, 116.96, 117.18,
118.59, 118.75, 119.12, 119.34, 123.13, 123.24, 124.16, 126.39,
126.49, 128.78, 128.89, 129.47, 129.51, 140.55, 140.96, 140.99,
142.34, 142.42, 142.99, 143.39, 156.40, 156.45, 169.41, 169.73,
169.89. LC–MS (ESI) m/z 567, 569 [M+H]+. HPLC purity: 99.30%.
HRMS (ESI) m/z calculated for C30H33Cl2N4O3 [M+H]+ 567.19242,
found 567.19287.
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16n (252 mg, 83%)
as a colorless solid. Mp 97–108 °C. 1H NMR (400 MHz, DMSO-d6):
d (ppm) 1.11–1.22 (m, 3H), 2.62 (s, 1.2H), 2.66 (s, 1.8H), 2.76–
3.09 (m, 8H), 3.26 (d, J = 6.0, 2H), 3.94, 3.95 (2s, 2H), 4.35 (s,
1.2H), 4.51 (s, 0.8H), 4.61–4.73 (m, 0.4H), 5.15–5.28 (m, 0.6H),
6.76–6.96 (m, 5H), 7.10–7.26 (m, 4H), 7.41 (d, J = 8.7, 2H), 8.64–
8.75 (m, 1H), 8.77 (br s, 2H). 13C NMR (100 MHz, DMSO-d6): d
(ppm) 10.82, 27.39, 28.76, 34.75, 35.18, 35.43, 41.68, 45.34,
52.96, 54.80, 54.91, 55.56, 57.14, 57.29, 117.16, 117.37, 118.63,
118.75, 119.10, 119.37, 123.05, 123.16, 124.15, 126.40, 126.49,
128.76, 128.86, 129.51, 140.54, 140.97, 142.53, 142.59, 143.01,
143.42, 156.38, 169.26, 169.48, 170.35. LC–MS (ESI) m/z 569, 571
[M+H]+. HPLC purity: 98.92%. HRMS (ESI) m/z calculated for
5.1.37. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-[(2S)-
pyrrolidin-2-ylmethyl]glycinamide hydrochloride (16r)
C
30H35Cl2N4O3 [M+H]+ 569.20807, found 569.20839.
5.1.34. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-
(isopropylamino)ethyl]glycinamide hydrochloride (16o)
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16r (117 mg, 75%) as
a colorless solid. Mp 113–125 °C. 1H NMR (400 MHz, DMSO-d6):
d (ppm) 1.43–1.59 (m, 1H), 1.71–1.93 (m, 3H), 2.61 (s, 1.2H),
2.65 (s, 1.8H), 2.82 (dd, J = 6.7, 16.4, 1.2H), 2.90 (dd, J = 6.7, 16.4,
0.8H), 2.95 (dd, J = 8.7, 16.4, 1.2H), 3.00 (dd, J = 8.7, 16.4, 0.8H),
3.05–3.19 (m, 2H), 3.20–3.51 (m, 3H), 3.96, 3.97 (2s, 2H), 4.36 (s,
1.2H), 4.52 (s, 0.8H), 4.59–4.71 (m, 0.4H), 5.15–5.26 (0.6H), 6.76–
6.94 (m, 5H), 7.11–7.24 (m, 4H), 7.42 (d, J = 8.7, 2H), 8.69 (br s,
1H), 8.85 (t, J = 5.4, 1H), 9.44 (br s, 1H). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 22.70, 26.95, 27.37, 28.75, 35.16, 35.42,
44.37, 52.95, 54.90, 55.03, 55.52, 57.16, 57.35, 58.70, 66.25,
117.08, 117.33, 118.68, 118.81, 119.07, 119.33, 123.00, 123.11,
124.15, 126.40, 126.45, 126.49, 128.74, 128.84, 129.51, 129.55,
140.54, 140.96, 142.28, 142.39, 143.00, 143.42, 156.28, 156.31,
169.25, 169.53, 170.53. LC–MS (ESI) m/z 581, 583 [M+H]+. HPLC
purity: 99.80%. HRMS (ESI) m/z calculated for C31H35Cl2N4O3
[M+H]+ 581.20807, found 581.20828.
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16o (96 mg, 61%) as
a colorless solid. Mp 93–101 °C. 1H NMR (400 MHz, DMSO-d6): d
(ppm) 1.19 (d, J = 6.2, 2.4H), 1.21 (d, J = 6.2, 3.6H), 2.62 (s, 1.2H),
2.66 (s, 1.8H), 2.72–3.07 (m, 6H), 3.19–3.34 (m, 3H), 3.94 (s,
1.2H), 3.95 (s, 0.8H), 4.34 (s, 1.2H), 4.51 (s, 0.8H), 4.61–4.72 (m,
0.4H), 5.16–5.27 (m, 0.6H), 6.78–6.86 (m, 3H), 6.87–6.95 (m, 2H),
7.11–7.25 (m, 4H), 7.41 (d, J = 9.3, 2H), 8.65–8.74 (m, 1H), 8.81
(br s, 2H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 18.33, 27.38,
28.77, 34.92, 35.20, 35.42, 42.85, 49.19, 52.97, 54.73, 54.83,
55.59, 57.12, 57.25, 117.23, 117.42, 118.69, 118.81, 119.13,
119.39, 122.97, 123.07, 124.15, 126.41, 126.49, 128.72, 128.81,
129.48, 129.51, 140.54, 140.97, 142.55, 142.60, 143.12, 143.51,
156.32, 156.35, 169.19, 169.39, 170.32. LC–MS (ESI) m/z 583, 585
[M+H]+. HPLC purity: 97.96%. HRMS (ESI) m/z calculated for
C
31H37Cl2N4O3 [M+H]+ 583.22372, found 583.22415.
5.1.38. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-[(2R)-
pyrrolidin-2-ylmethyl]glycinamide hydrochloride (16s)
5.1.35. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-(pipe-
ridin-3-yl)glycinamide hydrochloride (16p)
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16s (387 mg, 76%) as
a colorless solid. Mp 110–118 °C. 1H NMR (400 MHz, DMSO-d6):
d (ppm) 1.44–1.59 (m, 1H), 1.73–1.92 (m, 3H), 2.61 (s, 1.2H),
2.65 (s, 1.8H), 2.82 (dd, J = 6.7, 16.4, 1.2H), 2.90 (dd, J = 6.7, 16.4,
0.8H), 2.95 (dd, J = 8.7, 16.4, 1.2H), 3.00 (dd, J = 8.7, 16.4, 0.8H),
3.05–3.17 (m, 2H), 3.18–3.49 (m, 3H), 3.97 (s, 2H), 4.34 (s, 1.2H),
4.50 (s, 0.8H), 4.59–4.70 (m, 0.4H), 5.14–5.26 (0.6H), 6.76–6.94
(m, 5H), 7.11–7.24 (m, 4H), 7.42 (d, J = 8.7, 2H), 8.52 (br s, 1H),
8.87 (t, J = 5.1, 1H), 9.19 (br s, 1H). 13C NMR (100 MHz, DMSO-
d6): d (ppm) 22.71, 26.96, 27.36, 28.75, 35.16, 35.41, 44.34, 52.94,
54.89, 55.02, 55.52, 57.16, 57.35, 58.69, 117.08, 117.32, 118.67,
118.82, 119.07, 119.32, 122.99, 123.12, 124.15, 126.39, 126.44,
126.49, 128.73, 128.84, 129.50, 129.55, 140.54, 140.96, 142.29,
142.39, 142.99, 143.41, 156.31, 169.25, 169.52, 170.51. LC–MS
(ESI) m/z 581, 583 [M+H]+. HPLC purity: 98.85%. HRMS (ESI) m/z
calculated for C31H35Cl2N4O3 [M+H]+ 581.20807, found 581.20824.
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16p (131 mg, 73%)
as a colorless solid. Mp 124–136 °C. 1H NMR (400 MHz, DMSO-
d6): d (ppm) 1.22–1.37 (m, 1H), 1.55–1.86 (m, 3H), 2.50–2.60 (m,
1H), 2.60 (s, 1.2H), 2.67 (s, 1.8H), 2.72–3.16 (m, 7H), 3.77–3.90
(m, 1H), 3.93 (s, 2H), 4.34 (d, J = 18.0, 0.6H), 4.39 (d, J = 18.0,
0.6H), 4.48 (d, J = 18.0, 0.4H), 4.54 (d, J = 18.0, 0.4H), 4.61–4.72
(m, 0.4H), 5.14–5.26 (m, 0.6H), 6.77–6.94 (m, 5H), 7.11–7.25 (m,
4H), 7.42 (d, J = 9.3, 2H), 8.78 (d, J = 7.2, 1H), 8.96 (br s, 1H), 9.12
(br s, 1H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 20.27, 27.42,
27.67, 28.74, 35.16, 35.46, 42.49, 42.72, 45.80, 53.00, 54.98,
55.10, 55.49, 57.29, 57.52, 116.95, 117.16, 118.67, 118.79, 119.07,
119.31, 123.09, 123.17, 124.16, 126.39, 126.45, 126.50, 128.76,
128.86, 129.50, 129.56, 140.55, 140.94, 140.96, 142.18, 142.29,
143.03, 143.40, 156.37, 169.31, 169.44, 169.75. LC–MS (ESI) m/z
581, 583 [M+H]+. HPLC purity: 95.88%. HRMS (ESI) m/z calculated
for C31H35Cl2N4O3 [M+H]+ 581.20807, found 581.20836.
5.1.39. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-(piperi-
din-2-ylmethyl)glycinamide hydrochloride (16t)
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16t (369 mg, 84%) as
a colorless solid. Mp 124–134 °C. 1H NMR (400 MHz, DMSO-d6):
d (ppm) 1.20–1.44 (m, 2H), 1.46–1.75 (m, 4H), 2.60 (s, 1.2H), 2.65
5.1.36. N2-[5-Chloro-2-(4-chlorophenoxy)phenyl]-N2-{2-[2,3-
dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N1-(pyrro-
lidin-3-yl)glycinamide hydrochloride (16q)
The title compound was synthesized according to the method
described for the synthesis of 16m to afford 16q (106 mg, 68%)
as a colorless solid. Mp 136–146 °C. 1H NMR (400 MHz, DMSO-