S. Hou, X. Yang, Y. Tong et al.
European Journal of Medicinal Chemistry 211 (2021) 113114
0.69 mmol), key intermediate 8-d (140 mg, 0.69 mmol) and 4-
133.78, 132.30, 127.25, 124.40, 123.26, 120.11, 119.65, 115.70, 111.09,
(4,4,5,5-tetramethyl-1,3,2-
dioxaborolane-2-yl)-1H-pyrazole
106.12, 48.34, 23.71. HRMS-EI m/z [M þ H]þ calcd for C24H22N7Oþ:
(134 mg, 0.69 mmol) according to a similar procedure described for
424.1880,
found:
424.1882.
HPLC
analysis:
retention
the synthesis of compound 16. White solid, 99 mg, yield: 35%. mp
time ¼ 4.597 min, 98.75%.
159e161 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d: 12.92 (s, 1H), 11.88 (s,
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(1H-
pyrazol-4-yl)-1H-indole-2-carboxamide (27) Compound 27 was
prepared from 7-bromo-1H-indole-2-carboxylic acid 27-a (177 mg,
0.74 mmol), key intermediate 8-d (150 mg, 0.74 mmol) and 4-
1H), 10.66 (s, 1H), 8.89 (s, 1H), 8.23 (d, J ¼ 8.2 Hz, 1H), 8.04 (t,
J ¼ 8.0 Hz, 2H), 7.85 (d, J ¼ 7.6 Hz,1H), 7.68 (d, J ¼ 8.3 Hz,1H), 7.62 (s,
1H), 7.54 (s, 1H), 7.38 (d, J ¼ 8.3 Hz, 1H), 5.72e5.53 (m, 1H), 1.47 (d,
J ¼ 6.6 Hz, 6H). 13C NMR (100 MHz, DMSO‑d6)
d
160.53, 151.85,
(4,4,5,5-tetramethyl-1,3,2-dioxa
(143 mg, 0.74 mmol) according to a similar procedure described for
borolan-2-yl)-1H-pyrazole
150.52, 146.67, 143.66, 139.88, 138.36, 131.18, 129.80, 125.88, 122.80,
122.51, 119.57, 115.65, 108.48, 106.60, 48.37, 23.70. HRMS-EI m/z
[M þ H]þ calcd for C22H21N8Oþ: 413.1833, found: 413.1834. HPLC
analysis: retention time ¼ 3.465 min, 97.54%.
the synthesis of compound 16. White solid, 94 mg, yield: 31%. mp
170e173 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d: 13.12 (s, 1H), 11.04 (s,
1H), 10.93 (s, 1H), 8.89 (s, 1H), 8.27 (d, J ¼ 11.1 Hz, 1H), 8.04 (t,
J ¼ 7.8 Hz,1H), 7.81 (d, J ¼ 6.9 Hz, 1H), 7.61 (d, J ¼ 8.1 Hz, 1H), 7.49 (s,
1H),7.41 (d, J ¼ 7.2 Hz,1H), 7.15 (s, 1H), 7.13 (t, J ¼ 5.7 Hz,1H), 6.85 (s,
1H), 5.40 (s, 1H), 1.45 (d, J ¼ 5.4 Hz, 6H). 13C NMR (100 MHz,
6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-(6-(4-isopropyl-4H-
1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-2-carboxamide (22)
Compound 22 was prepared from 6-bromo-1H-indole-2-carboxylic
acid 22-a (188 mg, 0.79 mmol), key intermediate 8-d (160 mg,
0.79 mmol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (210 mg, 0.79 mmol) according
to a similar procedure described for the synthesis of compound 16.
White solid,130 mg, yield: 34%. mp 230e232 ꢀC .1H NMR (400 MHz,
DMSO‑d6)
d 160.20, 151.94, 150.64, 146.64, 143.53, 139.97, 134.90,
132.26, 128.22, 123.59, 121.29, 120.48, 119.82, 118.92, 117.92, 115.70,
108.77, 48.35, 23.65. HRMS-EI m/z [M þ H]þ calcd for C22H21N8Oþ:
413.1833,
found:
413.1830.
HPLC
analysis:
retention
time ¼ 4.040 min, 95.24%.
DMSO‑d6)
d
11.97 (s, 1H), 10.70 (s, 1H), 8.89 (s, 1H), 8.39 (s, 1H), 8.23
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(pyr-
idin-4-yl)-1H-indole-2-carboxamide (28) compound 28 was
prepared from 7-bromo-1H-indole-2-carboxylic acid 28-a (159 mg,
0.66 mmol), key intermediate 8-d (134 mg, 0.66 mmol) and 4-
(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)pyridine (135 mg,
0.66 mmol) according to a similar procedure described for the
synthesis of compound 16. White solid, 100 mg, yield: 36%, mp
(d, J ¼ 8.3 Hz, 1H), 8.04 (t, J ¼ 8.0 Hz, 1H), 7.94 (s, 1H), 7.85 (d,
J ¼ 7.6 Hz, 1H), 7.69 (q, J ¼ 6.0 Hz, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.39
(dd, J ¼ 8.3, 1.2 Hz, 1H), 5.79e5.66 (m, 1H), 5.58 (q, J ¼ 5.9 Hz, 1H),
3.55e3.41 (m, 1H), 3.28e3.20 (m, 1H), 1.65 (d, J ¼ 6.0 Hz, 3H), 1.47
(d, J ¼ 6.8 Hz, 6H), 1.06 (t, J ¼ 7.0 Hz, 3H). 13C NMR (100 MHz,
DMSO‑d6)
d 160.58, 151.91, 150.55, 146.69, 143.63, 139.85, 138.35,
136.71, 131.46, 129.18, 126.13, 125.34, 123.71, 122.86, 119.36, 115.70,
108.62, 106.66, 86.87, 63.51, 48.39, 23.69, 21.63, 15.20. HRMS-EI m/z
[M þ H]þ calcd for C26H29N8Oþ2 : 485.2408, found: 485.2408. HPLC
analysis: retention time ¼ 4.616 min, 96.72%.
278e280 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d 11.58 (s, 1H), 10.84 (s,
1H), 8.90 (s, 1H), 8.73 (s, 2H), 8.25 (d, J ¼ 8.6 Hz, 1H), 8.06 (d,
J ¼ 7.7 Hz, 1H), 7.82 (d, J ¼ 7.4 Hz, 2H), 7.72 (s, 2H), 7.59 (s, 1H), 7.39
(d, J ¼ 6.9 Hz, 1H), 7.28 (d, J ¼ 7.6 Hz, 1H), 5.57 (s, 1H), 1.46 (d,
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1-
(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indole-2-
carboxamide (23) Compound 23 was prepared from 6-bromo-1H-
indole-2-carboxylic acid 23-a (141 mg, 0.59 mmol), key interme-
diate 8-d (120 mg, 0.59 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-
J ¼ 6.2 Hz, 6H). 13C NMR (100 MHz, DMSO‑d6)
d 160.07, 151.85,
150.59, 150.55, 150.52, 146.67, 146.08, 143.54, 140.04, 134.78, 132.74,
128.50, 125.38, 124.30, 123.98, 121.35, 119.88, 115.62, 108.28, 48.33,
23.65. HRMS-EI m/z [M þ H]þ calcd for C24H22N7Oþ: 424.1880,
found: 424.1880. HPLC analysis: retention time ¼ 5.000 min,
95.04%.
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-pyrazole
(164 mg, 0.59 mmol) according to a similar procedure described for
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-7-(thi-
ophen-3-yl)-1H-indole-2-carboxamide (29) Compound 29 was
prepared from 7-bromo-1H-indole-2-carboxylic acid 29-a (165 mg,
0.69 mmol), key intermediate 8-d (140 mg, 0.69 mmol) and 4,4,5,5-
tetramethyl-2-(thiophen-3- yl)-1,3,2-dioxaborolane (145 mg,
0.69 mmol) according to a similar procedure described for the
synthesis of compound 16. White solid, 91 mg, yield: 31%. mp
the synthesis of compound 16. White solid, 79 mg, yield: 27%. mp
269e272 ꢀC. 1H NMR (400 MHz, DMSO‑d6)
d 11.87 (s, 1H), 10.64 (s,
1H), 8.90 (s, 1H), 8.27 (s, 1H), 8.23 (d, J ¼ 8.1 Hz, 1H), 8.04 (t,
J ¼ 8.0 Hz,1H), 7.89 (s, 1H), 7.85 (d, J ¼ 7.6 Hz,1H), 7.69 (d, J ¼ 8.4 Hz,
1H), 7.60 (s, 1H), 7.55e7.52 (m, 1H), 7.36 (dd, J ¼ 8.4, 1.3 Hz, 1H),
5.75e5.65 (m, 1H), 4.48e4.36 (m, 1H), 4.02e3.96 (m, 2H),
3.49e3.42 (m, 2H), 2.05e1.97 (m, 4H), 1.47 (d, J ¼ 6.7 Hz, 6H). 13
C
178e181 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d 11.13 (s, 1H), 10.90 (s,
NMR (100 MHz, DMSO‑d6)
d
160.62, 151.87, 150.59, 146.69, 143.60,
1H), 8.89 (s, 1H), 8.26 (d, J ¼ 7.8 Hz, 1H), 8.05 (t, J ¼ 8.0 Hz, 1H), 7.98
(dd, J ¼ 2.8, 1.3 Hz, 1H), 7.82 (d, J ¼ 7.0 Hz, 1H), 7.76 (dd, J ¼ 5.0,
2.9 Hz, 1H), 7.70 (d, J ¼ 7.8 Hz, 1H), 7.59e7.52 (m, 2H), 7.41 (dd,
J ¼ 7.2, 0.9 Hz, 1H), 7.24e7.15 (m, 1H), 5.58e5.52 (m, 1H), 1.46 (d,
139.89, 138.36, 136.23, 131.22, 129.57, 126.01, 125.37, 122.92, 119.40,
115.64, 108.38, 106.41, 66.42, 57.80, 48.36, 33.43, 23.66. HRMS-EI m/
z [M þ H]þ calcd for C27H29N8O2þ: 497.2408, found: 497.2408. HPLC
analysis: retention time ¼ 3.932 min, 96.98%.
J ¼ 6.7 Hz, 6H). 13C NMR (100 MHz, DMSO‑d6)
d 160.11, 151.89,
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(pyr-
idin-3-yl)-1H-indole-2-carboxamide (24) Compound 24 was
prepared from 6-bromo-1H-indole-2-carboxylic acid 24-a (153 mg,
0.64 mmol), key intermediate 8-d (130 mg, 0.64 mmol) and 3-
(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (131 mg,
0.64 mmol) according to a similar procedure described for the
synthesis of compound 16. White solid, 78 mg, yield: 29%. mp
150.65, 146.68, 143.53, 140.00, 138.88, 134.95, 132.35, 128.39,
128.36, 127.18, 124.64, 123.51, 121.85, 121.64, 121.28, 119.88, 115.61,
108.53, 48.33, 23.66. HRMS-EI m/z [M þ H]þ calcd for C23H21N6OSþ:
429.1492,
found:
429.1492.
HPLC
analysis:
retention
time ¼ 7.333 min, 96.70%.
(R)-N-(6-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)
pyridin-2-yl)-1H-indole-2-carboxamide (18) Step A: Compound
18-a was prepared from compound 8-c (500 mg, 1.90 mmol) and
(R)-2-aminopropan-1-ol (712 mg, 9.5 mmol, 5.0 eq) according to a
similar procedure described for the synthesis of compound 8 (step
280e283 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d 12.07 (s, 1H), 10.74 (s,
1H), 8.91 (d, J ¼ 11.9 Hz, 2H), 8.59 (d, J ¼ 4.3 Hz, 1H), 8.24 (d,
J ¼ 8.1 Hz, 1H), 8.13 (d, J ¼ 8.0 Hz, 1H), 8.05 (t, J ¼ 7.9 Hz, 1H), 7.86
(dd, J ¼ 8.0, 2.3 Hz, 2H), 7.76 (s, 1H), 7.64e7.60 (m, 1H), 7.54 (dd,
J ¼ 7.9, 4.9 Hz, 1H), 7.49e7.43 (m, 1H), 5.78e5.65 (m, 1H), 1.48 (d,
C). White solid, 255 mg, yield: 61%. 1H NMR (300 MHz, CDCl3)
d 8.36
(s, 1H), 7.54 (t, J ¼ 8.1 Hz, 1H), 7.42 (d, J ¼ 7.4 Hz, 1H), 6.57 (d,
J ¼ 8.2 Hz, 1H), 5.32e5.21 (m, 1H), 4.68 (s, 2H), 4.01 (d, J ¼ 11.4 Hz,
1H), 3.86e3.40 (m, 2H), 1.52 (d, J ¼ 6.8 Hz, 3H). MS (ESI) [M þ H]þ:
J ¼ 6.7 Hz, 6H). 13C NMR (100 MHz, DMSO‑d6)
d 160.47, 151.78,
150.50, 148.57, 148.26, 146.73, 143.64, 139.93, 138.15, 137.03, 134.72,
12