Journal of Medicinal Chemistry
Article
A solution of Na CO (2 M in H O, 10 mL) and H O (10 mL) was
added to a solution of compound 46 (1.0 g, 3.5 mmol), Pd(ally)Cl2
10% mmol), sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-
biphenyl-3-sulfonate hydrate (sSPhos) (20% mmol), and potassium
benzyltrifluoroborate (1.39 g, 7.0 mmol) in toluene (25 mL). The
reaction mixture was stirred at room temperature for 30 min and then
heated to 110 °C and stirred for 3−4 h. All volatiles were removed, and
the residue was dissolved in EtOAc. The organic layer was washed with
water and brine prior to being dried and concentrated. The residue was
(s, 2H), 4.00 (s, 2H), 2.90−2.82 (m, 1H), 2.75 (s, 3H), 1.26 (d, J = 7.2
2
3
2
2
1
3
Hz, 6H). C NMR (100 MHz, MeOD) 142.9, 139.5, 132.4, 129.7,
129.33, 129.30, 127.7, 119.7, 105.5, 71.9, 69.2, 62.7, 34.5, 23.1, 22.7,
12.4. ESI-MS: 364.33. UPLC: 4.88 min.
(
3-Benzyl-2-(3,3-dimethylbut-1-yn-1-yl)-9-methyl-4H,6H-thieno-
1
[
2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (13). H NMR (400 MHz,
MeOD) δ = 7.32−7.23 (m, 2H), 7.23−7.17 (m, 3H), 4.71 (s, 2H), 4.70
1
3
(
s, 2H), 4.00 (s, 2H), 2.75 (s, 3H), 1.32 (s, 9H). C NMR (100 MHz,
MeOD) 142.9, 139.6, 132.4, 129.7, 129.3, 129.1, 127.7, 119.6, 108.4,
1.5, 69.2, 62.7, 34.5, 31.0, 29.6, 12.4. ESI-MS: 378.38. UPLC: 5.24
min.
7
chromatographed on silica gel (DCM and MeOH) to afford compound
1
4
7
2
2
(800 mg, 77%). H NMR (400 MHz, CDCl ) δ 7.40−7.30 (m, 3H),
3
3
-Benzyl-2-(cyclopropylethynyl)-9-methyl-4H,6H-thieno[2,3-e]-
.20 (d, J = 7.2 Hz, 2H), 6.82 (s, 1H), 4.79 (s, 2H), 4.73 (s, 2H), 3.88 (s,
H), 2.75 (s, 3H). Retention time: 4.37 min; ESI-MS [M + H] :
1
+
[1,2,4]triazolo[3,4-c][1,4]oxazepine (14). H NMR (400 MHz,
MeOD) δ = 7.32−7.23 (m, 2H), 7.23−7.15 (m, 3H), 4.69 (s, 2H),
98.10. UPLC: 3.4 min.
4
.67 (s, 2H), 4.00 (s, 2H), 2.74 (s, 3H), 1.62−1.51 (m, 1H), 1.02−0.91
3
-Benzyl-2-isopropyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]-
13
1
(m, 2H), 0.81−0.73 (m, 2H). C NMR (100 MHz, MeOD) 155.4,
triazolo[3,4-c][1,4]oxazepine (5). H NMR (400 MHz, MeOD) δ 7.30
d, J = 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.1 Hz, 2H),
1
6
53.0, 143.1, 139.6, 132.2, 129.7, 129.3, 127.7, 119.8, 103.8, 69.0, 67.4,
2.7, 34.5, 12.4, 9.6, 1.0. ESI-MS: 362.40. UPLC: 4.77 min.
(
4
3
.72 (s, 2H), 4.66 (s, 2H), 4.00 (s, 2H), 3.50−3.43 (m, 1H), 2.81 (s,
H), 1.34 (d, J = 6.8 Hz, 6H). ESI-MS: 340.02. UPLC: 5.9 min.
3
-Benzyl-2-(cyclobutylethynyl)-9-methyl-4H,6H-thieno[2,3-e]-
1
[
1,2,4]triazolo[3,4-c][1,4]oxazepine (15). H NMR (400 MHz,
MeOD) δ = 7.30−7.22 (m, 2H), 7.24−7.14 (m, 3H), 4.70 (s, 2H),
.69 (s, 2H), 4.00 (s, 2H), 3.33−3.28 (m, 1H), 2.76 (s, 3H), 2.42−2.30
m, 2H), 2.26−2.12 (m, 2H), 2.25−1.90 (m, 2H), ESI-MS: 376.42.
UPLC: 5.41 min.
-Benzyl-2-(cyclopentylethynyl)-9-methyl-4H,6H-thieno[2,3-e]-
3
-Benzyl-9-methyl-2-(tetrahydro-2H-pyran-4-yl)-4H,6H-thieno-
1
[
2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (6). H NMR (400 MHz,
4
(
MeOD) δ 7.30 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.13 (d, J =
7
1
(
.1 Hz, 2H), 4.71 (s, 2H), 4.66 (s, 2H), 4.03 (s, 2H), 4.01−3.95 (m,
H), 3.65−3.42 (m, 3H), 3.40−3.35 (m, 1H), 2.78 (s, 3H), 1.97−1.69
m, 4H). ESI-MS: 382.09. UPLC: 4.9 min.
3
1
[
1,2,4]triazolo[3,4-c][1,4]oxazepine (16). H NMR (400 MHz,
MeOD) δ = 7.31−7.22 (m, 2H), 7.21−7.15 (m, 3H), 4.70 (s, 2H),
.68 (s, 2H), 4.00 (s, 2H), 2.97−2.90 (m, 1H), 2.75 (s, 3H), 2.05−1.96
3
-Benzyl-2-(tert-butyl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]-
1
triazolo[3,4-c][1,4]oxazepine (7). H NMR (400 MHz, MeOD) δ 7.30
t, J = 7.6 Hz, 3H), 7.22 (d, J = 6.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H),
4
(
1
6
(
4
2
1
3
m, 2H), 1.80−1.58 (m, 6H). C NMR (100 MHz, MeOD) 155.4,
.73 (s, 2H), 4.68 (s, 2H), 4.09 (s, 2H), 2.79 (d, J = 0.6 Hz, 3H), 2.22−
.10 (m, 1H), 1.11 (q, J = 5.0 Hz, 2H), 0.79 (q, J = 4.9 Hz, 2H). ESI-
MS: M + H 338.18.
53.1, 142.8, 139.6, 132.3, 129.7, 129.3, 129.0, 127.7, 119.9, 104.7, 72.2,
9.1, 62.7, 34.8, 34.5, 32.2, 25.9, 12.4. ESI-MS: 390.37. UPLC: 5.50
min.
-Benzyl-2-(cyclohexylethynyl)-9-methyl-4H,6H-thieno[2,3-e]-
General Procedure for Synthesis of Compounds 8 and 10−25.
3
The corresponding alkyne (2.0 equiv), Pd(PPh ) Cl (4.2 mg), CuI
1
3
2
2
[
1,2,4]triazolo[3,4-c][1,4]oxazepine (17). H NMR (400 MHz,
MeOD) δ = 7.32−7.28 (m, 2H), 7.23−7.15 (m, 3H), 4.70 (s, 2H),
.68 (s, 2H), 4.03 (s, 2H), 2.77−2.68 (m, 1H), 2.74 (s, 3H), 1.91−1.86
m, 2H), 1.78−1.67 (m, 2H), 1.61−1.48 (m, 3H), 1.46−1.34 (m, 3H).
(
2.3 mg), THF (1 mL), and Et N (1 mL) were added under N to a
3
2
flask charged with 47 (20 mg, 0.05 mmol). The reaction mixture was
stirred at 60 °C for 18 h. The reaction mixture was extracted with
EtOAc, and the organic layer was washed with brine, dried, and
concentrated. The residue was purified through HPLC to afford
compounds 8 and 10−25.
4
(
13
C NMR (100 MHz, MeOD) 155.3, 153.1, 142.9, 139.6, 132.3, 129.7,
1
2
29.32, 129.28, 127.7, 119.7, 104.3, 72.9, 69.1, 62.7, 34.5, 33.5, 31.0,
6.9, 25.6, 12.4. ESI-MS: 404.48. UPLC: 6.40 min.
3
-Benzyl-2-ethynyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo-
3
-Benzyl-9-methyl-2-(piperidin-4-ylethynyl)-4H,6H-thieno[2,3-
[
3,4-c][1,4]oxazepine (8). Obtained by coupling of 47 with TMS-
1
e][1,2,4]triazolo[3,4-c][1,4]oxazepine (18). H NMR (400 MHz,
DMSO) δ = 7.35−7.27 (m, 2H), 7.25−7.17 (m, 3H), 4.74 (s, 2H), 4.69
acetylene followed by treatment with TBAF to remove the TMS group.
H NMR (400 MHz, MeOD) δ 7.37−7.16 (m, 5H), 4.72 (s, 2H), 4.69
s, 2H), 4.22 (s, 1H), 4.10 (s, 2H), 2.76 (s, 3H). ESI-MS: 322.20.
1
(
3
4
s, 2H), 3.99 (s, 2H), 3.22−3.15 (m, 2H), 3.12−2.97 (m, 3H), 2.73 (s,
(
H), 2.66 (brs, 1H), 2.08−2.01 (m, 2H), 1.82−1.69 (m, 2H). ESI-MS:
UPLC: 4.9 min.
-Benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]-
oxazepine-2-carbonitrile (9). A flask was charged with compound 47
05.23. UPLC: 2.3 min.
3
3
-Benzyl-9-methyl-2-((1-methylpiperidin-4-yl)ethynyl)-4H,6H-
1
thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (19). H NMR (400
MHz, MeOD) δ = 7.36−7.22 (m, 2H), 7.22−7.15 (m, 3H), 4.70 (s,
2H), 4.67 (s, 2H), 4.04 (s, 2H), 3.57−3.50 (m, 2H), 3.09−2.93 (m,
(
1
1
20 mg, 0.05 mmol), K Fe(CN) (7 mg), CuI (2 mg), and 1-methyl-
3 6
H-imidazole (0.5 mL) under N . The reaction mixture was stirred at
2
40 °C for 18 h. The reaction mixture was extracted with EtOAc, and
the organic layer was washed with brine, dried, and concentrated. The
residue was purified through HPLC to afford compound 9 (45% yield).
H NMR (400 MHz, MeOD) δ 7.35 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.3
Hz, 1H), 7.27−7.20 (m, 2H), 4.77 (s, 2H), 4.76 (s, 2H), 4.18 (s, 2H),
.79 (s, 3H). ESI-MS: 323.20.
3
2
H), 2.87 (s, 3H), 2.72 (s, 3H), 2.09−2.01 (m, 2H), 1.96−1.83 (m,
H). ESI-MS: 419.51. UPLC: 1.77 min.
3
-Benzyl-9-methyl-2-((tetrahydro-2H-pyran-4-yl)ethynyl)-4H,6H-
1
1
thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (20). H NMR (400
MHz, MeOD) δ = 7.32−7.24 (m, 2H), 7.23−7.16 (m, 3H), 4.71 (s,
2H), 4.69 (s, 2H), 4.04 (s, 2H), 3.89−3.80 (m, 2H), 3.58−3.48 (m,
2H), 3.03−2.93 (m, 1H), 2.76 (s, 3H), 1.95−1.85 (m, 2H), 1.75−1.62
2
4
-(3-Benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c]-
1
13
[
1,4]oxazepin-2-yl)but-3-yn-1-ol (10). H NMR (400 MHz, MeOD) δ
(m, 2H). C NMR (100 MHz, MeOD) 155.4, 153.1, 143.3, 139.4,
7
4
3
.29 (t, J = 7.5 Hz, 2H), 7.25−7.15 (m, 3H), 4.72 (s, 2H), 4.69 (s, 2H),
.06 (s, 2H), 3.75 (t, J = 6.5 Hz, 2H), 2.75−2.70 (m, 5H). ESI-MS:
66.11.
132.4, 129.8, 129.5, 129.2, 127.7, 119.2, 102.4, 73.6, 69.2, 67.2, 62.7,
34.5, 33.1, 28.2, 12.4. ESI-MS: 406.40. UPLC: 4.27 min.
3-Benzyl-9-methyl-2-((1-methyl-1H-imidazol-5-yl)ethynyl)-
1
3
-(3-Benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c]-
4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (21).
H
1
[
(
=
1,4]oxazepin-2-yl)-N,N-dimethylprop-2-yn-1-amine (11). H NMR
400 MHz, MeOD) δ = 7.29 (dd, J = 7.0 Hz, J = 7.6 Hz, 2H), 7.21 (d, J
7.0 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 4.73 (s, 2H), 4.70 (s, 2H), 4.41
NMR (400 MHz, MeOD) δ = 7.32−7.24 (m, 2H), 7.23−7.16 (m,
3H), 4.71 (s, 2H), 4.69 (s, 2H), 4.04 (s, 2H), 3.89−3.80 (m, 2H),
3.58−3.48 (m, 2H), 3.03−2.93 (m, 1H), 2.76 (s, 3H), 1.95−1.85 (m,
1
3
13
(
s, 2H), 4.11 (s, 2H), 2.94 (s, 6H), 2.77 (s, 3H). C NMR (100 MHz,
MeOD) 146.4, 138.9, 132.6, 132.3, 129.9, 129.2, 127.9, 116.1, 87.0,
1.9, 69.0, 62.8, 48.4, 42.8, 34.6, 12.5. ESI-MS: 379.33. UPLC: 1.6 min.
-Benzyl-9-methyl-2-(3-methylbut-1-yn-1-yl)-4H,6H-thieno[2,3-
2H), 1.75−1.62 (m, 2H). C NMR (100 MHz, MeOD) 155.4, 153.1,
143.3, 139.4, 132.4, 129.8, 129.5, 129.2, 127.7, 119.2, 102.4, 73.6, 69.2,
67.2, 62.7, 34.5, 33.1, 28.2, 12.4. ESI-MS: 406.40. UPLC: 4.27 min.
3-Benzyl-9-methyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4H,6H-
8
3
1
1
e][1,2,4]triazolo[3,4-c][1,4]oxazepine (12). H NMR (400 MHz,
MeOD) δ = 7.31−7.22 (m, 2H), 7.24−7.15 (m, 3H), 4.70 (s, 2H), 4.69
thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (22). H NMR (400
MHz, MeOD) δ = 7.87 (s, 1H), 7.63 (s, 1H), 7.32−7.24 (m, 2H),
M
J. Med. Chem. XXXX, XXX, XXX−XXX