C. Xia, Z. Yao, L. Xu et al.
European Journal of Medicinal Chemistry 220 (2021) 113484
(yield: 40e77%).
13C NMR (150 MHz, DMSO‑d6)
d 170.42, 158.49, 149.49, 146.56,
A suspension of m2 and palladium on carbon (10 wt%) was
exposed to an atmosphere of hydrogen (balloon) overnight (~20 h).
Analysis of the crude reaction mixture by TLC confirmed the for-
mation of the desired product. The slurry was filtered through
diatomite, and the filtrate was concentrated under reduced pres-
sure to give m3 (yield: 80e98%).
HATU (1 equiv) was added over 2e5 min to a solution of m3 (1
equiv) and DIPEA (2 equiv) in DMSO. The reaction mixture was
stirred at room temperature for 30e50 min. Addition of water
resulted in the formation of a precipitate. The mixture was cooled
in an ice bath for 15e30 min and then filtered. The collected solid
was washed with water and dried in vacuum to afford m4 (yield:
30e50%).
145.49, 138.88, 137.57, 132.28, 129.06, 129.00, 127.09, 125.77, 124.75,
79.07, 54.09, 35.81. HRMS (ESI, positive) m/z calcd for C19H19N6O3
[MþH]þ 379.1519; found 379.1539. HPLC analysis: retention
time ¼ 7.57 (3), 7.63 (4) min; peak area, >95%.
4.2.3. 5-Benzyl-N-(1,7-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido
[2,3-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (5 and
6)
White solid (30 mg, yield: 82%). m.p.: 96.0e97.9 ꢀC. 1H NMR
(300 MHz, DMSO‑d6)
d
8.50 (d, J ¼ 7.2 Hz, 1H), 7.86 (d, J ¼ 8.1 Hz,
1H), 7.30 (m, 6H), 4.86 (dt, J ¼ 15.3, 7.5 Hz, 1H), 4.66 (t, J ¼ 10.2 Hz,
1H), 4.51 (dd, J ¼ 9.6, 7.5 Hz, 1H), 4.12 (s, 2H), 3.28 (s, 3H), 2.44 (s,
3H). 13C NMR (151 MHz, DMSO‑d6)
d 168.71, 155.25, 154.92, 133.70,
The iodomethane, iodoethane or iodomethane-d3 (1.2 equiv)
was added dropwise over 15e30 min to a solution of m4 (1 equiv)
and Cs2CO3 (1.4 equiv) in DMF stirred under nitrogen at room
temperature. The reaction mixture was stirred at room tempera-
ture for another 16e20 h. TLC showed that the reaction was
completed. The reaction mixture was poured into cold water, which
formed a solid. The resultant solid was filtered, and the filter was
washed with water and dried in vacuum to afford m5 (yield:
40e70%).
129.05, 128.64, 127.16, 121.86, 75.31, 49.13, 40.55, 35.09, 23.62.
HRMS (ESI, positive) m/z calcd for C20H21N6O3 [MþH]þ 393.1675;
found 393.1679. HPLC analysis: retention time ¼ 6.92 (5), 6.97 (6)
min; peak area, >95%.
4.2.4. 5-Benzyl-N-(1,8-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido
[2,3-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (7 and
8)
White solid (28 mg, yield: 76%). m.p.: 121.3e122.5 ꢀC. 1H NMR
A one-necked flask, equipped with a magnetic stirrer bar was
charged with m5 (1 equiv), Lawesson’s reagent (0.55 equiv) and
toluene. The reaction was stirred at 115 ꢀC overnight. Upon
completion (monitored by TLC), toluene was removed under vac-
uum to provide the crude product. Purification of the crude ma-
terial by silica gel chromatography (10e25% EtOAc in petroleum
ether) afforded m6 (yield: 30e60%).
A solution of m5 or m6 (1 equiv) in DCM was treated with HCl
(4 N in dioxane, 5 equiv). Evolution of gas was observed, and the
reaction mixture was stirred at room temperature for 4e8 h. The
resulting solid was filtered off, washed with DCM, and dried to give
m7 or m8 (yield: 50e90%).
(600 MHz, DMSO‑d6) d 8.53 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H),
7.36e7.23 (m, 5H), 4.87 (dt, J ¼ 16.8, 7.8 Hz, 1H), 4.66 (t, J ¼ 9.6 Hz,
1H), 4.56e4.47 (m, 1H), 4.13 (s, 2H), 3.31 (s, 3H), 2.34 (s, 3H). 13C
NMR (150 MHz, DMSO‑d6)
d 168.81, 154.18, 145.41, 133.72, 132.31,
131.00, 129.05, 127.17, 75.27, 55.35, 49.24, 35.02, 17.59. HRMS (ESI,
positive) m/z calcd for C20H21N6O3 [MþH]þ 393.1675; found
393.1691. HPLC analysis: retention time ¼ 8.07 (7), 8.10 (8) min;
peak area, >95%.
4.2.5. 5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b]
[1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (9 and 10)
White solid (19 mg, yield: 75%). m.p.: 75.7e77.3 ꢀC. 1H NMR
HATU (1 equiv) was added in one portion to a solution of 5-
benzyl-4H-1,2,4-triazole-3-carboxylic acid (1.2 equiv) and DIPEA
(2 equiv) in DMSO. After 5e10 min of stirring at room temperature,
a solution of m7 or m8 (1 equiv) in DMSO was added dropwise to
the reaction. The reaction mixture was allowed to stir at room
temperature for 45e90 min, at which time TLC analysis indicated
the reaction was completed. The reaction mixture was extracted
with EtOAc. The combined organic solution was washed with brine
and concentrated in vacuum to give the crude product. This was
purified using silica gel chromatography (eluting with 5e10%
MeOH in DCM) to give the target compounds 1e26 (yield: 70e90%).
(300 MHz, DMSO‑d6)
(dd, J ¼ 4.8, 1.5 Hz, 1H), 7.76e7.62 (m, 1H), 7.39e7.13 (m, 6H),
4.91e4.63 (m, 2H), 4.56e4.45 (m, 1H), 4.14 (s, 2H), 3.35 (s, 3H). 13
NMR (150 MHz, DMSO‑d6) 169.36, 149.56, 145.52, 144.96, 136.18,
130.11, 129.47, 129.05, 128.67, 127.21, 127.16, 126.94, 76.24, 49.66,
40.89, 33.08. HRMS (ESI, positive) m/z calcd for C19H19N6O3 [MþH]þ
379.1519; found 379.1517. HPLC analysis: retention time ¼ 7.23 (9),
7.29 (10) min; peak area, >95%.
d
14.36 (s, 1H), 8.53 (d, J ¼ 6.0 Hz, 1H), 8.36
C
d
4.2.6. 5-Benzyl-N-(5-methyl-4-thioxo-2,3,4,5-tetrahydrobenzo[b]
[1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (11 and 12)
White solid (21 mg, yield: 75%). m.p.: 124.9e127 ꢀC. 1H NMR
4.2.1. 5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]
oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (1 and 2)
White solid (23 mg, yield: 80%). m.p.: 109.4e110.8 ꢀC. 1H NMR
(600 MHz, DMSO‑d6)
d
14.36 (s, 1H), 8.53 (d, J ¼ 8.4 Hz, 1H), 7.62
(dd, J ¼ 7.2, 1.8 Hz, 1H), 7.42 (m, 2H), 7.37e7.24 (m, 6H), 5.00 (q,
J ¼ 9.0 Hz, 1H), 4.43 (d, J ¼ 8.4 Hz, 2H), 4.16 (s, 2H), 3.80 (s, 3H). 13
C
(300 MHz, DMSO‑d6)
d
14.39 (s, 1H), 8.41 (s, 1H), 7.50 (dd, J ¼ 7.1,
NMR (150 MHz, DMSO‑d6) d 199.57, 158.42, 156.88, 156.52, 149.89,
2.3 Hz, 1H), 7.36e7.20 (m, 8H), 4.82 (dt, J ¼ 11.5, 7.8 Hz, 1H), 4.59 (t,
J ¼ 10.7 Hz, 1H), 4.40 (dd, J ¼ 9.8, 7.7 Hz, 1H), 4.12 (s, 2H), 3.31 (s,
137.88, 136.91, 129.64, 129.11, 129.05, 128.87, 127.30, 126.81, 126.57,
124.71, 122.95, 79.07, 53.66, 44.76, 32.24. HRMS (ESI, positive) m/z
calcd for C20H20N5O2S [MþH]þ 394.1338; found 394.1316. HPLC
analysis: retention time ¼ 8.19 (11), 8.14 (12) min; peak area, >95%.
3H). 13C NMR (75 MHz, DMSO‑d6)
d 168.97, 149.94, 136.91, 129.05,
127.68, 127.16, 126.23, 124.05, 122.95, 76.35, 49.23, 35.29, 32.87.
HRMS (ESI, positive) m/z calcd for C20H20N5O3 [MþH]þ 378.1566;
found 378.1573. HPLC analysis: retention time ¼ 7.40 (1), 7.50 (2)
min; peak area, >95%.
4.2.7. 5-Benzyl-N-(4-thioxo-2,3,4,5-tetrahydrobenzo[b][1,4]
oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (13 and 14)
White solid (15 mg, yield: 77%). m.p.: 124.7e126.5 ꢀC. 1H NMR
4.2.2. 5-Benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]
[1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (3 and 4)
White solid (15 mg, yield: 70%). m.p.: 119.1e120.7 ꢀC. 1H NMR
(300 MHz, DMSO‑d6)
7.33e7.04 (m, 9H), 4.75 (dt, J ¼ 14.7, 7.5 Hz, 1H), 4.54e4.32 (m, 2H),
4.08 (s, 2H). 13C NMR (150 MHz, DMSO‑d6)
200.92, 170.81, 149.96,
d 14.32 (s, 1H), 10.11 (s, 1H), 8.37 (s, 1H),
d
(300 MHz, DMSO‑d6)
d
14.47 (s, 1H), 8.12 (dd, J ¼ 7.5, 1.5 Hz, 1H),
136.90, 131.89, 129.06, 128.30, 127.23, 125.35, 123.75, 122.75, 78.33,
60.22, 29.45. HRMS (ESI, positive) m/z calcd for C19H18N5O2S
[MþH]þ 380.1181; found 380.1184. HPLC analysis: retention
7.84 (dd, J ¼ 4.8, 1.5 Hz, 1H), 7.30 (m, 6H), 7.01 (dd, J ¼ 7.5, 5.1 Hz,
1H), 5.53e5.33 (m, 1H), 4.47e4.23 (m, 2H), 4.13 (s, 2H), 3.05 (s, 3H).
7