J.W. Lee, J. Park, J. Kim et al.
European Journal of Medicinal Chemistry 216 (2021) 113298
Compound 43 was prepared by the general procedure B. 1H-
Pyrazolo[3,4-b]pyridine-3-carboxylic acid was used as an acid
source and compound 9 was used as an aniline source. Yield: 13%;
mobile phase of MPLC purification: MeOH/DCM; yellow caramel;
7.54 (d, J ¼ 8.3 Hz, 1H), 7.50 (s, 1H), 7.11 (d, J ¼ 8.3 Hz, 1H), 3.63 (s,
2H), 2.50e2.42 (m, 10H), 2.25 (s, 3H), 1.08 (t, J ¼ 6.9 Hz, 3H); 13C
NMR (150 MHz, CDCl3)
d 164.8, 161.2, 141.8, 136.4, 136.2, 135.2,
133.7, 130.8, 130.3, 129.0 (q, J ¼ 31.5 Hz), 125.1, 125.0, 124.9, 124.0 (q,
J ¼ 272.9 Hz), 123.1, 120.1, 117.2, 114.4, 58.0, 53.0, 52.8, 52.3, 17.1,
11.8; IR (Neat): 3133, 2941, 2819, 2208, 2187, 2083, 2043, 1898,1657,
1603, 1564, 1526, 1494, 1450, 1409, 1313, 1251, 1208, 1162, 1118,
1055, 1013, 928, 840, 816, 755, 676, 658 cmꢁ1; HRMS (ESI): m/z
calcd for C26H30F3N6O2 [MþH]þ 515.2377, found 515.2374.
1H NMR (600 MHz, Methanol-d4)
d
8.66 (dd, J ¼ 8.3,1.4 Hz,1H), 8.59
(dd, J ¼ 4.8, 1.2 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J ¼ 8.3 Hz, 1H), 8.12 (d,
J ¼ 1.4 Hz, 1H), 7.97 (d, J ¼ 8.3 Hz, 1H), 7.56 (dd, J ¼ 8.3, 2.1 Hz, 1H),
7.36 (dd, J ¼ 7.8, 4.2 Hz,1H), 7.29 (d, J ¼ 8.3 Hz,1H), 4.58 (s, 2H), 3.75
(s, 2H), 2.57e2.46 (m, 8H), 2.36 (s, 3H), 1.11 (t, J ¼ 7.2 Hz, 3H); 13C
NMR (150 MHz, Methanol-d4)
d 167.0, 162.5, 153.9, 150.8, 142.7,
142.3, 139.3, 138.1, 136.8, 135.4, 132.8, 132.1, 131.7, 130.0 (q, J ¼
30.2 Hz), 129.6, 126.4 (q, J ¼ 5.9 Hz), 125.6 (q, J ¼ 271.5 Hz), 120.0,
119.9, 118.8, 115.5, 59.1, 53.7, 53.7, 53.3, 17.5, 11.7; IR (Neat): 3401,
3320, 2918, 2819, 2117, 1689, 1667, 1621, 1605, 1533, 1500, 1449,
1409, 1390, 1337, 1316, 1301, 1279, 1265, 1241, 1161, 1118, 1047, 1010,
974, 956, 943, 922, 894, 877, 850, 840, 808, 789, 775, 749, 713, 699,
674, 664 cmꢁ1; HRMS (ESI): m/z calcd for C29H31F3N7O2 [MþH]þ
566.2486, found 566.2506.
4.1.39. N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)
benzamido)-2-methylphenyl)-1H-imidazole-2-carboxamide (47)
Compound 47 was prepared by the general procedure B. 1H-
Imidazole-2-carboxylic acid was used as an acid source and com-
pound 9 was used as an aniline source. Yield: 37%; mobile phase of
MPLC purification: MeOH/DCM; pale yellow solid; m.p.:
223e224 ꢀC; 1H NMR (600 MHz, Acetone-d6)
d 9.84 (s, 1H), 9.25 (s,
1H), 8.41e8.39 (m, 1H), 8.34 (s, 1H), 8.28 (d, J ¼ 8.3 Hz, 1H), 8.00 (d,
J ¼ 8.3 Hz, 1H), 7.77e7.75 (m, 1H), 7.26 (d, J ¼ 8.3 Hz, 1H), 3.76 (s,
2H), 3.10e2.60 (m,10H), 2.37 (s, 3H),1.12 (t, J ¼ 7.2 Hz, 3H); 13C NMR
4.1.36. N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)
benzamido)-2-methylphenyl)-1H-pyrazole-3-carboxamide (44)
Compound 44 was prepared by the general procedure B. Pyr-
azole-3-carboxylic acid was used as an acid source and compound 9
was used as an aniline source. Yield: 53%; mobile phase of MPLC
purification: MeOH/DCM; white solid; m.p.: 126e128 ꢀC; 1H NMR
(150 MHz, Acetone-d6)
d 164.7, 156.9, 142.5, 142.2, 138.4, 136.1 (q,
J ¼ 281.6 Hz), 131.9, 131.6, 131.2, 130.3, 128.9 (q, J ¼ 30.2 Hz), 126.2,
125.9, 125.8, 124.8, 117.4, 114.4, 114.3, 58.7, 54.1, 53.6, 52.8, 17.1, 12.5;
IR (Neat): 3211, 2948, 2817, 2102, 1688, 1647, 1602, 1554, 1526, 1496,
1454, 1417, 1379, 1351, 1313, 1278, 1254, 1217, 1164, 1150, 1117, 1055,
1013, 943, 925, 909, 888, 868, 808, 786, 751, 676, 654 cmꢁ1; HRMS
(600 MHz, CDCl3) d 8.81 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H),
7.96 (d, J ¼ 8.3 Hz,1H), 7.80 (d, J ¼ 8.3 Hz,1H), 7.61 (d, J ¼ 7.6 Hz,1H),
7.50 (d, J ¼ 2.1 Hz,1H), 7.09 (d, J ¼ 8.3 Hz,1H), 6.79 (d, J ¼ 2.1 Hz,1H),
3.64 (s, 2H), 2.51e2.45 (m, 10H), 2.16 (s, 3H), 1.10 (t, J ¼ 7.2 Hz, 3H);
(ESI): m/z calcd for
515.2378.
C
26H30F3N6O2 [MþH]þ 515.2377, found
13C NMR (150 MHz, CDCl3)
d
164.8, 160.5, 146.6, 141.6, 136.4, 135.6,
4.1.40. N-(2-methyl-5-(6-(trifluoromethyl)nicotinamido)phenyl)
imidazo[1,2-b]pyridazine-3-carboxamide (48)
Compound 48 was prepared by the general procedure B. Com-
pound 21 was used as an acid source and compound 12 was used as
an aniline source. Yield: 83%; mobile phase of MPLC purification:
MeOH/DCM; white solid; m.p.: 313e314 ꢀC; 1H NMR (600 MHz,
133.6, 130.8, 130.6, 130.5, 130.3, 128.9 (q, J ¼ 30.2 Hz), 126.1, 125.1,
123.9 (q, J ¼ 271.4 Hz), 117.5, 114.8, 106.1, 57.9, 52.9, 52.7, 52.2, 17.0,
11.7; IR (Neat): 3211, 2942, 2818, 2103, 1997, 1657, 1604, 1530, 1448,
1409, 1359, 1303, 1251, 1210, 1162, 1117, 1055, 1013, 927, 854, 814,
756, 675 cmꢁ1; HRMS (ESI): m/z calcd for C26H30F3N6O2 [MþH]þ
515.2377, found 515.2376.
DMSO‑d6)
d
10.63 (s,1H),10.43 (s,1H), 9.27 (s,1H), 8.88 (t, J ¼ 2.1 Hz,
1H), 8.61e8.58 (m, 2H), 8.46 (d, J ¼ 2.1 Hz, 1H), 8.41e8.39 (m, 1H),
8.07 (d, J ¼ 8.3 Hz, 1H), 7.60 (d, J ¼ 8.3 Hz, 1H), 7.54e7.52 (m, 1H),
7.29 (d, J ¼ 8.3 Hz, 1H), 2.42 (s, 3H); 13C NMR (150 MHz, DMSO‑d6)
4.1.37. N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)
benzamido)-2-methylphenyl)-1-methyl-1H-pyrazole-3-
carboxamide (45)
d
162.5, 155.7, 149.1, 148.0 (q, J ¼ 34.5 Hz), 144.3, 140.8, 139.0, 137.6,
Compound 45 was prepared by the general procedure B. 1-
Methyl-1H-pyrazole-3-carboxylic acid was used as an acid source
and compound 9 was used as an aniline source. Yield: 73%; mobile
phase of MPLC purification: MeOH/DCM; pale yellow solid; m.p.:
136.7, 136.1, 133.6, 130.1, 127.1, 123.2 (q, J ¼ 244.2 Hz), 122.1, 120.3,
119.2, 118.5, 116.6, 114.0, 17.1; IR (Neat): 3307, 3056, 2113, 1663,
1649, 1625, 1604, 1560, 1532, 1477, 1452, 1429, 1391, 1336, 1301,
1287, 1237, 1187, 1168, 1146, 1119, 1082, 1061, 1028, 1005, 984, 925,
903, 881, 865, 813, 797, 762, 743, 704, 675 cmꢁ1; HRMS (ESI): m/z
calcd for C21H16F3N6O2 [MþH]þ 441.1281, found 441.1278.
133e135 ꢀC; 1H NMR (600 MHz, CDCl3)
d 8.69 (s, 1H), 8.28 (s, 1H),
8.24 (s, 1H), 8.13 (s, 1H), 7.99 (d, J ¼ 8.3 Hz, 1H), 7.89 (d, J ¼ 8.3 Hz,
1H), 7.78 (d, J ¼ 8.3 Hz, 1H), 7.38 (t, J ¼ 2.1 Hz, 1H), 7.19 (d, J ¼ 8.3 Hz,
1H), 6.80 (t, J ¼ 1.7 Hz, 1H), 3.96 (s, 3H), 3.70 (s, 2H), 2.55e2.47 (m,
10H), 2.32 (s, 3H), 1.12 (t, J ¼ 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
4.1.41. N-(2-methyl-5-(6-(trifluoromethyl)nicotinamido)phenyl)
imidazo[1,2-a]pyridine-3-carboxamide (49)
Compound 49 was prepared by the general procedure B. Com-
pound 27 was used as an acid source and compound 12 was used as
an aniline source. Yield: 23%; mobile phase of MPLC purification:
EtOAc/Hex; white solid; m.p.: 200e202 ꢀC; 1H NMR (600 MHz,
d
164.4, 160.0, 146.7, 141.7, 136.6, 136.2, 133.9, 132.1, 130.9, 130.8,
130.2, 129.2 (q, J ¼ 30.2 Hz), 125.0 (q, J ¼ 5.9 Hz), 124.1 (q, J ¼
285.8 Hz), 124.0, 116.8, 113.5, 107.2, 58.0, 53.0, 52.8, 52.3, 39.4, 17.1,
11.8; IR (Neat): 3305, 2948, 2813, 2165, 2095, 1997, 1658, 1603, 1531,
1503, 1450, 1409, 1359, 1312, 1234, 1164, 1119, 1055, 1014, 924, 843,
756, 709, 675 cmꢁ1; HRMS (ESI): m/z calcd for C27H32F3N6O2
[MþH]þ 529.2533, found 529.2529.
DMSO‑d6)
d
10.68 (s,1H), 9.97 (s,1H), 9.47 (d, J ¼ 6.9 Hz,1H), 9.26 (d,
J ¼ 1.4 Hz, 1H), 8.60 (s, 1H), 8.58 (dd, J ¼ 7.9, 1.7 Hz, 1H), 8.11 (d, J ¼
7.6 Hz, 1H), 7.90 (d, J ¼ 2.1 Hz, 1H), 7.79 (d, J ¼ 9.0 Hz, 1H), 7.61 (dd,
J ¼ 8.3, 2.1 Hz, 1H), 7.54e7.51 (m, 1H), 7.31 (d, J ¼ 8.3 Hz, 1H), 7.19
(td, J ¼ 6.9, 1.4 Hz, 1H), 2.27 (s, 3H); 13C NMR (150 MHz, DMSO‑d6)
4.1.38. N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)
benzamido)-2-methylphenyl)-1H-imidazole-4-carboxamide (46)
Compound 46 was prepared by the general procedure B. 1H-
Imidazole-4-carboxylic acid was used as an acid source and com-
pound 9 was used as an aniline source. Yield: 63%; mobile phase of
MPLC purification: MeOH/DCM; white solid; m.p.: 155e157 ꢀC; 1H
d
162.7, 158.8, 149.3, 148.1 (q, J ¼ 33.0 Hz), 147.1, 137.9, 137.6, 136.6,
135.7, 133.7, 130.5, 129.7, 127.6, 127.4, 121.4 (q, J ¼ 273.0 Hz), 120.6,
118.7, 118.2,117.9, 117.3, 114.2, 17.5; IR (Neat): 3207, 2114, 2019, 1985,
1966, 1659, 1640, 1619, 1521, 1488, 1448, 1416, 1333, 1309, 1263,
1218, 1179, 1140, 1084, 1029, 939, 893, 860, 839, 809, 787, 759, 721,
706 cmꢁ1; HRMS (ESI): m/z calcd for C22H17F3N5O2 [MþH]þ
440.1329, found 440.1328.
NMR (600 MHz, CDCl3)
d 8.97 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 8.09
(s, 1H), 7.95 (d, J ¼ 8.3 Hz, 1H), 7.81 (d, J ¼ 7.6 Hz, 1H), 7.59 (s, 1H),
12