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J ¼ 1.9 Hz, 6H), 3.39 (t, J ¼ 6.2 Hz, 2H), 2.88 (s, 2H), 1.97 (t, 1H), 7.42 (s, 1H), 7.29 (d, J ¼ 6.1 Hz, 2H), 7.20 (d, J ¼ 8.6 Hz, 1H),
J ¼ 10.6 Hz, 2H), 1.85 – 1.71 (m, 3H), 1.46 – 1.32 (m, 2H). 13 C NMR 3.44 (s, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 3.17 (t, J ¼ 6.1 Hz, 2H), 2.78
(126 MHz, DMSO-d6): d 166.57, 162.57, 160.64, 154.56, 135.32,
(d, J ¼ 11.2 Hz, 2H), 1.91 (t, J ¼ 10.7 Hz, 2H), 1.63 (t, J ¼ 17.2 Hz, 3H),
1.23 (dd, J1 ¼ 14.0, J2 ¼ 9.1 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6):
132.35, 130.94, 130.88, 129.83, 127.97, 121.16, 115.33, 115.16,
107.31, 107.10, 61.96, 53.36, 45.34, 36.28, 30.35, 27.57, 27.47.
HRMS (ESI): calcd. for C23H27FN4O2 [M þ H]þ 411.2196,
found 411.2190.
d 166.57, 154.57, 142.28, 132.35, 131.59, 130.77, 130.10, 129.84,
128.11, 127.97, 122.01, 121.16, 107.33, 107.11, 61.98, 53.40, 45.32,
36.21, 30.35, 27.58, 27.48. HRMS (ESI): calcd. for C23H27BrN4O2
[M þ H]þ 471.1395, found 471.1386.
4.1.5.11. N-((1–(2-chlorobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-2-
oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9k). White
solid, yield: 90%, m.p. 156–158 ꢁC. 1H NMR (300MHz, DMSO-d6): d
9.17 (s, 1H), 8.46 (s, 1H), 7.68 (d, J ¼ 2.5Hz, 1H), 7.64 (s, 1H), 7.60 (s,
1H), 7.55–7.48 (m, 2H), 7.22 (d, J ¼ 8.6 Hz, 1H), 4.43 (d, J ¼ 5.0 Hz,
2H), 3.44 (d, J ¼ 11.8Hz, 2H), 3.37 (d, J ¼ 2.0 Hz, 6H), 3.21 (s, 2H),
1.89 (d, J ¼ 12.6Hz, 3H), 1.45 (d, J ¼ 11.5Hz, 2H), 1.21 (d, J ¼ 17.9Hz,
2H). 13 C NMR (126 MHz, DMSO-d6): d 166.78, 154.57, 135.30, 134.22,
132.49, 132.18, 130.43, 129.88, 128.21, 127.72, 121.18, 107.37,
107.06, 56.86, 52.54, 46.38, 33.99, 27.61, 27.50, 26.40, 26.34. HRMS
(ESI): calcd. for C23H27ClN4O2 [M þ H]þ 427.1901, found 427.1892.
4.1.5.16. N-((1–(4-bromobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9p). White
solid, yield: 69%, m.p. 165–167 ꢁC. 1H NMR (300 MHz, CDCl3): d
7.50 (d, J ¼ 9.3 Hz, 1H), 7.46–7.40 (m, 2H), 7.32 (d, J ¼ 4.4 Hz, 2H),
7.20 (d, J ¼ 8.3 Hz, 1H), 6.96 (d, J ¼ 8.1 Hz, 1H), 6.30 (s, 1H), 3.52 (s,
2H), 3.45 (d, J ¼ 1.6 Hz, 6H), 3.39 (t, J ¼ 6.2 Hz, 2H), 2.98–2.85 (m,
2H), 2.04– 1.87 (m, 3H), 1.75 (d, J ¼ 13.0 Hz, 2H), 1.38 (dd, J1 ¼ 13.6,
J2 ¼ 9.4 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6): d 166.57, 154.56,
138.71, 132.34, 131.44, 131.26, 129.83, 129.15, 128.55, 127.97,
127.22, 121.16, 120.19, 107.31, 107.10, 61.99, 53.46, 53.40, 45.33,
36.28, 36.24, 30.35, 27.57, 27.47. HRMS (ESI): calcd. for
C23H27BrN4O2 [M þ H]þ 471.1395, found 471.1384.
4.1.5.12. N-((1–(3-chlorobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9l). White
1
solid, yield: 76%, m.p. 134–136 ꢁC. H NMR (300 MHz, DMSO-d6): d
4.1.6. General procedure for the synthesis of target com-
pounds 11a–11f
8.36 (t, J ¼ 5.7 Hz, 1H), 7.65 (dd, J1 ¼ 4.2, J2 ¼ 2.7 Hz, 2H), 7.36 –
7.32 (m, 2H), 7.31 (s, 1H), 7.27 (s, 1H), 7.20 (d, J ¼ 8.6 Hz, 1H), 3.45
(s, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 3.17 (t, J ¼ 6.2 Hz, 2H), 2.78 (d,
J ¼ 11.3 Hz, 2H), 1.91 (t, J ¼ 10.6 Hz, 2H), 1.63 (t, J ¼ 17.1 Hz, 3H),
1.27 – 1.16 (m, 2H). 13 C NMR (126 MHz, DMSO-d6): d 166.57,
154.56, 141.99, 133.33, 132.34, 130.46, 129.82, 128.69, 127.94,
127.72, 127.20, 121.16, 107.34, 107.12, 62.02, 53.41, 45.32, 36.21,
30.35, 27.58, 27.48. HRMS (ESI): calcd. for C23H27ClN4O2 [M þ H]þ
427.1901, found 427.1899.
Intermediates 10a–10f (0.3 g, 1.0 equiv.) and PyBOP (1.3 equiv.)
and DIPEA(2.0 equiv.) were added to 6 ml of DMF and stirred at
room temperature for 20 min. Then, intermediates 4a, 4g, 4m (1.0
equiv.) were added and stirred at room temperature for 4 h. After
completion of the reaction, the reaction mixture was quenched
with water. The aqueous phase was extracted with CH2Cl2
(3 ꢃ 15 ml). The CH2Cl2 layer was then washed with brine and
dried over anhydrous Na2SO4. After concentration, the crude prod-
uct was purified by silica gel column chromatograph (CH2Cl2/
methanol ¼ 80:1) to give target compounds 11a–11f.
4.1.5.13. N-((1–(4-chlorobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-2-
oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9m). White
solid, yield: 75%, m.p. 127–129 ꢁC. 1H NMR (300 MHz, DMSO-d6): d
8.36 (t, J ¼ 5.6 Hz, 1H), 7.65 (dd, J1 ¼ 4.3, J2 ¼ 2.6 Hz, 1H), 7.37 (d,
J ¼ 8.4 Hz, 2H), 7.31 (d, J ¼ 8.6 Hz, 2H), 7.20 (d, J ¼ 8.6 Hz, 1H), 3.42
(s, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 3.17 (t, J ¼ 6.2 Hz, 2H), 2.78 (d,
J ¼ 11.2Hz, 2H), 1.90 (t, J ¼ 10.5Hz, 2H), 1.65 (d, J ¼ 12.7Hz, 3H),
1.22 (dd, J1 ¼ 14.9, J2 ¼ 8.5 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6): d
166.57, 154.56, 138.30, 132.35, 131.69, 130.87, 129.83, 128.52,
127.96, 121.16, 107.21, 61.94, 53.40, 45.33, 36.25, 30.36, 27.53. HRMS
(ESI): calcd. for C23H27ClN4O2 [M þ H]þ 427.1901, found 427.1894.
4.1.6.1. N-((1–(4-methoxybenzyl)piperidin-4-yl)methyl)-1H-indole-
5-carboxamide (11a). White solid, yield: 67%, m.p. 89–90 ꢁC. 1H
NMR (500 MHz, DMSO-d6): d 8.34 (t, J ¼ 5.4 Hz, 1H), 8.12 (s, 1H),
7.62 (d, J ¼ 8.5 Hz, 1H), 7.41 (s, 2H), 7.34 (d, J ¼ 7.5 Hz, 3H), 7.28 (d,
J ¼ 6.7 Hz, 1H), 6.51 (s, 1H), 3.63 (s, 3H), 3.53–3.46 (m, 2H), 3.17 (s,
2H), 2.91 (d, J ¼ 10.0 Hz, 2H), 2.14 (s, 2H), 1.70 (d, J ¼ 13.2 Hz, 2H),
1.64 (s, 1H), 1.29 (d, J ¼ 11.7 Hz, 3H). 13 C NMR (126 MHz, DMSO-
d6): d 167.87, 137.77, 129.84, 128.71, 127.89, 127.41, 127.02,
126.11, 120.99, 120.25, 114.19, 111.25, 102.47, 61.96, 55.54, 52.90,
44.95, 35.69, 29.44. HRMS (ESI): calcd. for C23H27N3O2 [M þ H]þ
378.2181, found 378.2179.
4.1.5.14. N-((1–(2-bromobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9n). White
1
solid, yield: 75%, m.p. 137–139 ꢁC. H NMR (300 MHz, DMSO-d6): d
4.1.6.2. N-((1–(4-methoxybenzyl)piperidin-4-yl)methyl)-1H-indazole-
5-carboxamide (11b). White solid, yield: 65%, m.p. 78–79 ꢁC. 1H
NMR (500 MHz, DMSO-d6): d 13.33 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H),
8.19 (s, 1H), 7.85 (d, J ¼ 8.7 Hz, 1H), 7.57 (d, J ¼ 8.7 Hz, 1H), 7.34 (d,
J ¼ 7.9 Hz, 2H), 6.92 (d, J ¼ 8.3 Hz, 2H), 3.75 (s, 5H), 3.19 (s, 2H),
3.00 (d, J ¼ 9.1 Hz, 2H), 2.31 (s, 2H), 1.74 (d, J ¼ 13.0 Hz, 2H), 1.69 (s,
1H), 1.37 (d, J ¼ 11.1 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6): d
167.10, 159.41, 135.14, 131.68, 127.55, 125.75, 122.76, 120.93,
114.19, 55.54, 52.24, 44.76, 27.05. HRMS (ESI): calcd. for
C22H26N4O2 [M þ H]þ 379.2134, found 379.2124.
8.37 (t, J ¼ 5.5 Hz, 1H), 7.66 (dd, J1 ¼ 4.2, J2 ¼ 2.7 Hz, 2H), 7.58 (d,
J ¼ 8.0 Hz, 1H), 7.50 – 7.45 (m, 1H), 7.37 (t, J ¼ 7.4 Hz, 1H), 7.19 (dd,
J1 ¼ 8.1, J2 ¼ 4.8 Hz, 2H), 3.51 (s, 2H), 3.37 (s, 3H), 3.36 (s, 3H), 3.18
(t, J ¼ 6.2 Hz, 2H), 2.83 (d, J ¼ 11.0 Hz, 2H), 2.02 (t, J ¼ 10.7 Hz, 2H),
1.65 (t, J ¼ 14.9 Hz, 3H), 1.22 (d, J ¼ 9.5 Hz, 2H). 13 C NMR (126 MHz,
DMSO-d6): d 166.58, 154.57, 138.16, 132.89, 132.35, 131.11, 129.83,
129.18, 128.00, 127.94, 124.28, 121.17, 107.36, 107.13, 61.95, 53.60,
45.31, 36.20, 30.39, 27.59, 27.49. HRMS (ESI): calcd. for
C23H27BrN4O2 [M þ H]þ 471.1395, found 471.1384.
4.1.5.15. N-((1–(3-bromobenzyl)piperidin-4-yl)methyl)-1,3-dimethyl-
4.1.6.3. N-((1–(2-chlorobenzyl)piperidin-4-yl)methyl)-1H-indazole-5-
2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (9o). White
1
1
solid, yield: 78%, m.p. 143–145 ꢁC. H NMR (300 MHz, DMSO-d6): d carboxamide (11c). White solid, yield: 78%, m.p. 89–90 ꢁC. H NMR
8.36 (t, J ¼ 5.6 Hz, 1H), 7.65 (dd, J1 ¼ 4.2, J2 ¼ 2.7 Hz, 2H), 7.48 (s, (500 MHz, DMSO-d6):d 13.27 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.86