Journal of Medicinal Chemistry
Article
1.49 (ddt, J = 7.3, 14.6, 29.7 Hz, 2H), 1.35−1.23 (m, 1H);
ESMS m/z: 429.3 (M − H2O + H)+.
8.5, 6.3 Hz, 1H), 4.21 (dd, J = 8.6, 2.2 Hz, 1H), 3.13 (dd, J =
13.7, 6.0 Hz, 1H), 2.87 (dd, J = 13.7, 8.8 Hz, 1H), 2.65 (t, J =
7.7 Hz, 1H), 2.41−2.29 (m, 1H), 2.14 (ddd, J = 10.0, 6.0, 1.8
Hz, 1H), 1.98 (t, J = 5.5 Hz, 1H), 1.88 (tt, J = 5.6, 2.9 Hz,
1H), 1.81 (dt, J = 14.1, 2.5 Hz, 1H), 1.71 (dt, J = 13.4, 6.7 Hz,
1H), 1.48 (d, J = 10.3 Hz, 1H), 1.41 (s, 3H), 1.33 (m, 12H),
0.96−0.83 (s, 9H); ESMS m/z: 513.4 (M + H)+.
((R)-3-Phenyl-1-((R)-3-phenyl-2-(pyrazine-2-
carboxamido)propanamido)propyl)boronic acid (11e, 9 mg,
93% yield). 1H NMR (400 MHz, methanol-d4): δ 9.18 (s, 1H),
8.80 (s, 1H), 8.70 (s, 1H), 7.34−7.27 (m, 4H), 7.25−7.19 (m,
3H), 7.18−7.08 (m, 3H), 5.14−5.03 (m, 1H), 3.28−3.21 (m,
2H), 2.61 (q, J = 7.1, 8.4 Hz, 2H), 2.50 (t, J = 7.1 Hz, 1H),
1.88−1.71 (m, 1H), 1.70−1.46 (m, 1H); ESMS m/z: 415.2
(M − H2O + H)+.
tert-Butyl((R)-1-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-
trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-
yl)butyl)amino)-1-oxopropan-2-yl)carbamate (8b, 118 mg,
1
((R)-2-Phenyl-1-((R)-3-phenyl-2-(pyrazine-2-
carboxamido)propanamido)ethyl)boronic acid (11f, 9 mg,
69% yield). H NMR (400 MHz, methanol-d4): δ 4.40−4.24
(m, 1H), 4.18 (dd, J = 8.8, 2.3 Hz, 1H), 2.70 (t, J = 7.7 Hz,
1H), 2.43−2.27 (m, 1H), 2.22−2.07 (m, 1H), 1.95 (t, J = 5.6
Hz, 1H), 1.86 (td, J = 5.7, 2.9 Hz, 1H), 1.80 (d, J = 6.0 Hz,
1H), 1.76 (d, J = 5.8 Hz, 1H), 1.49−1.46 (m, 1H), 1.45 (s,
9H), 1.41 (s, 1H), 1.39 (s, 1H), 1.37 (s, 3H), 1.35 (d, J = 7.2
Hz, 3H), 1.29 (s, 3H), 0.93 (dd, J = 6.6, 1.9 Hz, 6H), 0.88 (s,
3H); ESMS m/z: 437.4 (M + H)+.
1
86% yield). H NMR (400 MHz, methanol-d4): δ 9.17 (d, J
= 6.5 Hz, 1H), 8.87−8.72 (m, 1H), 8.69 (d, J = 2.2 Hz, 1H),
7.38−7.23 (m, 5H), 7.23−7.15 (m, 3H), 7.15−7.07 (m, 1H),
7.03−6.97 (m, 1H), 5.12−4.98 (m, 1H), 3.27−3.16 (m, 2H),
2.93−2.73 (m, 2H), 2.68−2.30 (m, 1H); ESMS m/z: 401.20
(M − H2O + H)+.
((R)-2-Cyclohexyl-1-((R)-2-(pyrazine-2-carboxamido)-
tert-Butyl((R)-1-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-
trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-
yl)butyl)amino)-1-oxobutan-2-yl)carbamate (8c, 131 mg, 75%
1
pentanamido)ethyl)boronic acid (12a, 9 mg, 45% yield). H
NMR (400 MHz, methanol-d4): δ 9.24 (d, J = 1.4 Hz, 1H),
8.82 (d, J = 2.5 Hz, 1H), 8.73 (dd, J = 2.5, 1.5 Hz, 1H), 4.87−
4.80 (m, 1H), 2.76 (t, J = 6.9 Hz, 1H), 1.98−1.85 (m, 2H),
1.76−1.66 (m, 4H), 1.59−1.40 (m, 3H), 1.40−1.31 (m, 3H),
1.30−1.17 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H), 0.97−0.77 (m,
2H); ESMS m/z: 359.3 (M − H2O + H)+.
1
yield). H NMR (400 MHz, methanol-d4): δ 4.28−4.09 (m,
2H), 2.69 (t, J = 7.8 Hz, 1H), 2.33 (ddt, J = 11.1, 8.9, 2.5 Hz,
1H), 2.19−2.06 (m, 1H), 1.95 (t, J = 5.6 Hz, 1H), 1.86 (dq, J
= 5.6, 2.8 Hz, 1H), 1.82 (d, J = 12.4 Hz, 1H), 1.79 (d, J = 3.5
Hz, 1H), 1.77 (d, J = 3.2 Hz, 1H), 1.75 (d, J = 6.9 Hz, 1H),
1.66 (dt, J = 14.4, 7.6 Hz, 1H), 1.45 (s, 9H), 1.40−1.38 (m,
1H), 1.37 (s, 3H), 1.36−1.34 (m, 1H), 1.29 (s, 3H), 0.97 (t, J
= 7.4 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H), 0.88 (s, 3H); ESMS
m/z: 451.4 (M + H)+.
((R)-4-Phenyl-1-((R)-2-(pyrazine-2-carboxamido)-
1
pentanamido)butyl)boronic acid (12d, 15 mg, 84% yield). H
NMR (400 MHz, methanol-d4): δ 9.23 (d, J = 1.5 Hz, 1H),
8.82 (d, J = 2.5 Hz, 1H), 8.72 (dd, J = 2.5, 1.5 Hz, 1H), 7.25−
7.19 (m, 2H), 7.19−7.15 (m, 2H), 7.14−7.09 (m, 1H), 4.83
(dd, J = 8.9, 5.7 Hz, 1H), 2.69−2.53 (m, 3H), 2.04−1.80 (m,
2H), 1.80−1.61 (m, 2H), 1.61−1.34 (m, 4H), 0.99 (t, J = 7.4
Hz, 3H); ESMS m/z: 381.3 (M − H2O + H)+.
tert-Butyl((R)-1-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-
trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-
yl)butyl)amino)-1-oxopentan-2-yl)carbamate (8d, 125 mg,
1
70% yield). H NMR (400 MHz, methanol-d4): δ 4.25 (dd,
((R)-3-Phenyl-1-((R)-2-(pyrazine-2-carboxamido)-
pentanamido)propyl)boronic acid (12e, 29 mg, 62% yield). 1H
NMR (500 MHz, methanol-d4): δ 9.14 (d, J = 1.5 Hz, 1H),
8.70 (d, J = 2.5 Hz, 1H), 8.64−8.58 (m, 1H), 7.17−7.05 (m,
4H), 7.02 (td, J = 7.0, 3.3 Hz, 1H), 4.77−4.74 (m, 1H), 2.62−
2.48 (m, 3H), 1.93−1.79 (m, 2H), 1.74 (ddt, J = 13.3, 9.7, 6.6
Hz, 1H), 1.63 (ddt, J = 13.7, 9.4, 6.6 Hz, 1H), 1.38 (m, 2H),
0.89 (t, J = 7.4 Hz, 3H); ESMS m/z: 367.2 (M − H2O + H)+.
((R)-2-Phenyl-1-((R)-2-(pyrazine-2-carboxamido)-
J = 9.0, 5.7 Hz, 1H), 4.17 (dd, J = 8.8, 2.3 Hz, 1H), 2.72−2.66
(m, 1H), 2.40−2.29 (m, 1H), 2.17−2.08 (m, 1H), 1.95 (t, J =
5.6 Hz, 1H), 1.90−1.82 (m, 1H), 1.81−1.78 (m, 1H), 1.78−
1.76 (m, 1H), 1.76−1.71 (m, 1H), 1.71−1.64 (m, 1H), 1.64−
1.57 (m, 1H), 1.48 (s, 1H), 1.45 (s, 9H), 1.42−1.38 (m, 2H),
1.37 (s, 3H), 1.36−1.33 (m, 1H), 1.29 (s, 3H), 0.96 (t, J = 7.4
Hz, 3H), 0.93 (d, J = 6.2 Hz, 6H), 0.88 (s, 3H); ESMS m/z:
465.4 (M + H)+.
1
tert-Butyl((R)-1-(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-
trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-
yl)butyl)amino)-1-oxohexan-2-yl)carbamate (8e, 86 mg, 46%
pentanamido)ethyl)boronic acid (12f, 24 mg, 45% yield). H
NMR (500 MHz, methanol-d4): δ 9.13 (dd, J = 1.5, 6.9 Hz,
1H), 8.71 (dd, J = 2.5, 4.9 Hz, 1H), 8.60 (ddd, J = 1.5, 2.5, 6.6
Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 7.11−6.98 (m, 4H), 4.71−
4.64 (m, 1H), 2.88−2.74 (m, 2H), 2.52 (td, J = 9.3, 14.2 Hz,
1H), 1.87−1.72 (m, 2H), 1.46−1.26 (m, 2H), 0.93−0.83 (m,
3H); ESMS m/z: 353.2 (M − H2O + H)+.
1
yield). H NMR (400 MHz, methanol-d4): δ 4.23 (t, J = 7.4
Hz, 1H), 4.17 (dd, J = 8.7, 2.3 Hz, 1H), 2.68 (t, J = 7.7 Hz,
1H), 2.42−2.28 (m, 1H), 2.18−2.05 (m, 1H), 1.95 (t, J = 5.6
Hz, 1H), 1.89−1.83 (m, 1H), 1.82−1.78 (m, 1H), 1.78−1.70
(m, 2H), 1.69−1.56 (m, 1H), 1.48 (s, 1H), 1.45 (s, 9H), 1.38
(s, 2H), 1.37 (s, 3H), 1.36 (s, 4H), 1.29 (s, 3H), 0.96−0.89
(m, 9H), 0.88 (s, 3H); ESMS m/z: 479.4 (M + H)+.
((R)-1-((R)-2-(Pyrazine-2-carboxamido)pentanamido)-
1
pentyl)boronic acid (12g, 19 mg, 36% yield). H NMR (400
MHz, methanol-d4): δ 9.24 (d, J = 1.5 Hz, 1H), 8.82 (d, J = 2.5
Hz, 1H), 8.73 (dd, J = 1.5, 2.5 Hz, 1H), 4.88−4.81 (m, 1H),
2.59 (t, J = 7.3 Hz, 1H), 2.04−1.86 (m, 2H), 1.59−1.28 (m,
8H), 1.00 (t, J = 7.4 Hz, 3H), 0.96−0.87 (m, 3H); ESMS m/z:
319.2 (M − H2O + H)+.
tert-Butyl((R)-3-methyl-1-(((R)-3-methyl-1-((3aS,4S,6-
S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d]-
[1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxobutan-2-yl)-
1
carbamate (8f, 118 mg, 66% yield). H NMR (400 MHz,
methanol-d4): δ 4.17 (dd, J = 8.8, 2.3 Hz, 1H), 4.07 (d, J = 7.2
Hz, 1H), 2.68 (t, J = 7.7 Hz, 1H), 2.34 (ddd, J = 14.2, 6.9, 4.5
Hz, 1H), 2.18−2.09 (m, 1H), 2.09−2.00 (m, 1H), 1.96 (t, J =
5.6 Hz, 1H), 1.86 (tt, J = 5.6, 3.0 Hz, 1H), 1.82−1.78 (m, 1H),
1.78−1.70 (m, 1H), 1.47 (s, 1H), 1.45 (s, 9H), 1.38 (s, 1H),
1.37 (s, 3H), 1.35 (s, 1H), 1.29 (s, 3H), 0.96 (s, 3H), 0.95−
Synthesis of Compounds 8a−i, 13. Compounds 8a−i, 13
were prepared using general procedure A. tert-Butyl((R)-1-
(((R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-
4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-
oxo-3-phenylpropan-2-yl)carbamate (8a, 64 mg, 95%). 1H
NMR (400 MHz, methanol-d4): δ 7.26 (m, 5H), 4.51 (dd, J =
4865
J. Med. Chem. 2021, 64, 4857−4869