D. Knez et al. / European Journal of Medicinal Chemistry 156 (2018) 598e617
611
A. It was purified by column chromatography using CH2Cl2/MeOH
4.5.9. ( )-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)
methyl)-N-(2-(dimethylamino)ethyl)-2-(pyridin-2-ylamino)
thiazole-4-carboxamide (16)
(v/v, 4/1) þ 0.3% NH3 (25% aq. sol) as eluent.
Yield: 20% (47 mg); pale yellow solid, mp 78e81 ꢁC; Rf ¼ 0.20
(CH2Cl2/MeOH ¼ 4/1 þ 0.3% NH3 (25% aq. sol), v/v); 1H NMR
(400 MHz, MeOD): 0.82e0.92 (m, 0.7H), 1.15e1.23 (m, 0.3H),
1.54e2.09 (m, 6H), 2.20 (bs, 3H), 2.45 (bs, 4H), 2.65e3.29 (m, 10H),
3.50e3.58 (m, 1H), 3.74e3.85 (m, 1H), 6.28e6.40 (m, 1H), 7.12e7.19
(m, 5H), 7.26e7.30 (m, 1H), 7.72 (dd, J ¼ 8.3, 1.2 Hz, 1H), resonances
for OH missing; ESI-HRMS m/z calcd. for C29H37N4O3 [MþH]þ
Compound 16 was synthesised from 7b (80 mg, 0.36 mmol, 1.0
eq.) via general procedure A. It was purified by column chroma-
tography using CH2Cl2/MeOH (v/v, 20/1) þ 0.3% NH3 (25% aq. sol) as
eluent.
Yield: 48% (88 mg); pale yellow solid, mp 88e91 ꢁC; Rf ¼ 0.38
(CH2Cl2/MeOH ¼ 9/1 þ 0.3% NH3 (25% aq. sol), v/v); 1H NMR
489.2866, found 489.2878; IR (ATR)
y
¼ 2932, 1630, 1577, 1523,
(400 MHz, CDCl3): d 0.76e1.10 (m, 1H), 1.41e1.70 (m, 3H), 1.89e2.26
1444, 1375, 1284, 1168, 1017, 811, 745 cmꢀ1; HPLC purity, 99.3% at
(m, 9H), 2.41e3.18 (m, 8H), 3.38e3.87 (m, 5H), 6.84e6.87 (m, 2H),
7.09e7.14 (m, 4H), 7.20e7.36 (m, 1H), 7.56 (t, J ¼ 7.3 Hz, 1H),
8.31e8.33 (m, 1H), 9.82 (bs, 1H); 13C NMR (100 MHz, CDCl3):
254 nm (tR ¼ 4.39 min).
d
24.81, 28.60, 35.33, 36.13, 36.77, 37.05, 44.99, 45.56, 46.84, 50.05,
51.95, 52.85, 55.43, 56.18, 56.41, 57.90, 63.39, 67.09, 110.58, 115.5,
116.09, 116.40, 124.29, 126.30, 128.09, 129.18, 137.78, 141.27, 141.55,
144.85, 146.65, 151.30, 159.40, 159.54, 165.05, 165.58; ESI-HRMS m/z
calcd. for C28H37N6OS [MþH]þ 505.2750, found 505.2760; IR (ATR)
4.5.7. ( )-N-((1-(2,3-Dihydro-1H-inden-2-yl)piperidin-3-yl)
methyl)-N-(2-(dimethylamino)ethyl)-6-hydroxy-2,5,7,8-
tetramethylchroman-2-carboxamide (14)
Compound 14 was synthesised from Trolox (0.070 mg,
0.28 mmol, 1.0 eq.) via general procedure A. It was purified by
column chromatography using CH2Cl2/MeOH (v/v, 9/1) as eluent, to
obtain a mixture of four diastereoisomers and enantiomers.
Yield: 9% (14 mg); white solid, mp 45e47 ꢁC; Rf ¼ 0.15 (CH2Cl2/
y
¼ 2932, 1605, 1537, 1479, 1455, 1409, 1305, 1223, 1150, 1053, 773,
741, 660 cmꢀ1; HPLC purity, 95.3% at 254 nm (tR ¼ 5.26 min).
4.5.10. ( )-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)
methyl)-N-(2-(dimethylamino)ethyl)-8-hydroxyimidazo[1,2-a]
pyridine-2-carboxamide (17)
MeOH ¼ 9/1, v/v); 1H NMR (400 MHz, CDCl3):
d 0.73e1.09 (m, 1.5H),
1.20e1.37 (m, 0.5H), 1.47e1.84 (m, 6H), 1.89e2.34 (m, 15H),
2.42e2.77 (m, 5H), 2.85e3.14 (m, 7H), 3.22e3.68 (m, 7H), 4.11e4.48
(m, 1H), 7.11e7.18 (m, 4H), resonance for OH missing; 13C NMR
Compound 17 was synthesised from 7c (71 mg, 0.40 mmol, 1.0
eq.) via general procedure A. The residue was purified by column
chromatography using CH2Cl2/MeOH (v/v, 9/1) þ 0.3% NH3 (25% aq.
sol) as eluent, and subsequently by reversed-phase column
chromatography.
(100 MHz, CDCl3):
d 12.09, 12.36, 13.07, 21.18, 24.10, 24.52, 25.82,
27.90, 28.44, 27.90, 28.44, 29.63, 31.87, 33.97, 34.95, 35.35, 36.12,
36.49, 36.78, 45.29, 45.64, 51.41, 51.77, 55.75, 57.80, 58.08, 66.60,
67.60, 79.50, 80.84, 118.56, 122.25, 124.34, 126.53, 126.68, 138.58,
140.64, 141.15, 141.70, 148.38, 154.61, 154.93, 173.57; ESI-HRMS m/z
calcd. for C33H48N3O3 [MþH]þ 534.3696, found 534.3709; IR (ATR)
Yield: 48% (75 mg); brown solid, mp 105e107 ꢁC; Rf ¼ 0.09
(CH2Cl2/MeOH ¼ 9/1 þ 0.3% NH3 (25% aq. sol), v/v); 1H NMR
(400 MHz, CDCl3): d 1.04e1.14 (m, 1H), 1.55e1.81 (m, 3H), 1.90e2.12
y
¼ 2933, 2854, 2767, 1714, 1631, 1459, 1406, 1373, 1237, 1194, 1096,
(m, 2H), 2.19e2.42 (m, 7H), 2.57e2.62 (m, 1H), 2.72e2.84 (m, 2H),
2.90e3.21 (m, 6H), 3.41e3.62 (m, 3H), 4.19e4.33 (m,1H), 6.53e6.65
(m, 2H), 7.04e7.11 (m, 4H), 7.51e7.60 (m, 1H), 7.90e8.03 (m, 1H),
1062, 1022, 935, 871, 743 cmꢀ1
;
HPLC purity (both di-
astereoisomers), 95.2% at 254 nm (tR ¼ 5.23 and 5.34 min).
9.40 (bs, 1H); 13C NMR (100 MHz, CDCl3):
d 24.81, 28.63, 29.62,
31.36, 35.37, 35.66, 36.42, 36.65, 36.95, 44.65, 45.22, 45.48, 46.22,
50.45, 51.67, 51.93, 52.17, 56.16, 56.42, 57.68, 66.63, 67.15, 105.37,
106.06, 114.72, 115.57, 116.19, 116.77, 117.42, 124.28, 126.27, 126.67,
138.92, 140.36, 141.12, 141.43, 148.80, 162.47, 164.40, 165.14; ESI-
4.5.8. ( )-(2 R)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)
methyl)-N-(2-(dimethylamino)ethyl)-4-(2-hydroxyphenyl)-2,5-
dihydrothiazole-2-carboxamide (15)
HRMS m/z calcd. for
C
27H36N5O2 [MþH]þ 462.2869, found
Compound 15 was synthesised from 7a (105 mg, 0.47 mmol, 1.0
eq.) via general procedure A. It was purified by column chroma-
tography using CH2Cl2/MeOH (v/v, 20/1) þ 0.3% NH3 (25% aq. sol) as
eluent.
462.2860; IR (ATR)
y
¼ 2932, 1612, 1537, 1458, 1294, 1241, 1159,
1048, 927, 734 cmꢀ1; HPLC purity, 95.7% at 254 nm (tR ¼ 4.47 min).
Yield: 42% (101 mg); pale orange solid, mp 45e47 ꢁC; Rf ¼ 0.55
4.5.11. ( )-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)
methyl)-N-(2-(dimethylamino)ethyl)-6-hydroxynicotinamide (18)
Compound 18 was synthesised from 6-hydroxynicotinic acid
(100 mg, 0.72 mmol,1.0 eq.) via general procedure A. It was purified
by column chromatography using CH2Cl2/MeOH (v/v, 4/1) þ 0.3%
NH3 (25% aq. sol) as eluent, and subsequently by reversed-phase
column chromatography.
(CH2Cl2/MeOH ¼ 9/1 þ 0.3% NH3 (25% aq. sol), v/v); 1H NMR
(400 MHz, CDCl3):
d 0.98e1.09 (m, 0.7H), 1.16e1.22 (m, 0.3H),
1.57e2.09 (m, 5H), 2.27 (s, 6H), 2.42e2.67 (m, 3H), 2.77e3.49 (m,
10H), 3.65e4.12 (m, 3H), 5.48e5.71 (m, 1H), 6.76e7.06 (m, 3H),
7.10e7.21 (m, 3H), 7.23e7.48 (m, 3H); 13C NMR (100 MHz, CDCl3):
d
24.53, 24.69, 24.83, 28.23, 28.59, 32.28, 32.47, 32.58, 32.63, 34.86,
34.96, 36.35, 36.41, 36.79, 36.82, 36.93, 36.98, 37.09, 44.58, 45.20,
45.57, 45.60, 45.88, 46.57, 49.00, 49.72, 51.77, 51.91, 51.95, 52.15,
55.87, 56.10, 56.20, 58.01, 58.14, 66.73, 67.03, 67.07, 67.22, 75.04,
75.30, 115.98, 116.00, 116.02, 116.05, 116.89, 116.93, 116.97, 117.13,
118.63, 118.94, 118.98, 124.04, 124.26, 126.02, 126.26, 126.33, 126.40,
127.96, 128.06, 128.14, 128.23, 128.84, 129.11, 129.21, 130.80, 133.15,
133.28, 133.34, 133.39, 134.09, 141.28, 141.30, 141.32, 141.45, 141.50,
158.68, 158.77, 158.84, 168.45, 168.67, 168.78, 173.66, 173.88, 173.90,
174.03; ESI-HRMS m/z calcd. for C29H39N4O2S [MþH]þ 507.2794,
Yield: 13% (39 mg); orange solid, mp 60e63 ꢁC; Rf ¼ 0.17
(CH2Cl2/MeOH ¼ 4/1 þ 0.3% NH3 (25% aq. sol), v/v); 1H NMR
(400 MHz, CDCl3): d 0.81e1.01 (m,1H),1.55e1.81 (m, 4H),1.97e2.29
(m, 9H), 2.40e2.52 (m, 2H), 2.77e2.94 (m, 4H), 3.01e3.09 (m, 3H),
3.30e3.40 (m, 2H), 3.45e3.55 (m, 2H), 6.57 (d, J ¼ 9.4 Hz, 1H),
7.11e7.18 (m, 4H), 7.51 (d, J ¼ 9.1 Hz, 1H), 7.59 (bs, 1H); 13C NMR
(100 MHz, CDCl3):
d 24.58, 28.39, 35.06, 36.57, 36.80, 45.60, 51.79,
55.37, 56.98, 66.80, 116.32, 119.90, 124.26, 124.32, 126.42, 135.23,
140.93, 141.29, 141.34, 164.65, 168.53; ESI-HRMS m/z calcd. for
found 507.2790; IR (ATR)
y
¼ 2934, 2767, 1648, 1622, 1592, 1486,
C
25H35N4O2 [MþH]þ 423.2760, found 423.2770; IR (ATR)
¼ 2933,
y
1453, 1288, 1254, 1219, 1155, 1118, 1034, 955, 817, 745, 670 cmꢀ1
;
2791, 1654, 1613, 1544, 1427, 1348, 1213, 1132, 1042, 932, 838, 744,
HPLC purity, 95.1% at 254 nm (tR ¼ 5.95 min).
659 cmꢀ1; HPLC purity, 98.4% at 254 nm (tR ¼ 3.71 min).