Journal of Medicinal Chemistry
Article
1.32−1.21 (1H, m), 1.13 (3H, d, J = 4.6 Hz, HMe Linker), 0.86 (3H, d, J
= 6.5 Hz, Hδ Leu), 0.80 (3H, d, J = 6.5 Hz, Hδ Leu); 13C NMR (100
MHz, DMSO-d6): δ 175.3, 172.7, 171.1, 170.3, 138.3, 129.0, 128.1,
126.2, 55.1, 52.9, 49.5, 41.1, 38.1, 37.7, 36.2, 30.6, 25.0, 24.2, 22.4, 22.2,
17.7, 15.3; HRMS [M + Na]+ calcd for C23H34N4O4: 467.2629, found:
467.2640.
(6S,9S,12R)-4-Benzyl-6-isobutyl-9,12-dimethyl-1,4,7,10-tet-
raza-2,5,8,11-cyclopentadecanetetrone (Nphe-2R). 1H NMR
(400 MHz, DMSO-d6): δ 8.37 (1H, d, J = 8.0 Hz), 8.27 (1H, d, J =
5.3 Hz), 7.43−7.34 (2H, m), 7.34−7.26 (1H, m), 7.22−7.13 (2H, m),
7.03−6.95 (1H, m), 5.07 (1H, d, J = 17.1 Hz), 4.46−4.28 (2H, m),
4.28−4.19 (1H, m), 4.05−3.94 (1H, m), 3.16 (1H, d, J = 16.2 Hz),
3.04−2.82 (2H, m), 2.20−2.10 (1H, m), 2.06−1.95 (1H, m), 1.82−
1.68 (1H, m), 1.68−1.54 (1H, m), 1.54−1.37 (3H, m), 1.22 (3H, d, J =
7.2 Hz), 0.87 (3H, d, J = 6.7 Hz), 0.73 (3H, d, J = 2.7 Hz), 0.72 (3H, d, J
= 2.6 Hz); 13C NMR (100 MHz, DMSO-d6): δ 174.2, 173.1, 171.5,
167.6, 137.4, 128.8, 127.4, 126.7, 51.3, 50.7, 50.4, 47.8, 44.1, 40.2, 31.7,
31.4, 29.5, 24.0, 22.9, 21.9, 18.1, 16.6; HRMS [M + Na]+ calcd for
C23H34N4O4: 467.2629, found: 467.2624.
1.71−1.61 (2H, m, H4 Linker), 1.25−1.22 (2H, m, H3 Linker), 1.20
(3H, d, J = 6.8 Hz, Hβ Ala), 0.91 (3H, d, J = 6.7 Hz, HMe Linker), 0.90
(3H, d, J = 6.3 Hz, Hδ Nleu), 0.84 (3H, d, J = 6.7 Hz, Hα Nleu); 1H
NMR (400 MHz, CDCl3): δ 7.34−7.19 (5H, m), 7.25 (1H, d, J = 7.2
Hz, HN Phe), 6.39 (1H, d, J = 8.9 Hz, HN Ala), 5.70 (1H, br s, HN
Linker), 5.05−4.95 (1H, m, Hα Ala), 4.67 (1H, dd, J = 13.5, 0.9 Hz, Hα
Nleu), 4.50 (1H, dt, J = 9.2, 7.5 Hz, Hα Phe), 3.61−3.49 (1H, m, H5
Linker), 3.44 (1H, dd, J = 14.4, 8.0 Hz, Hβ Nleu), 3.15 (1H, d, J = 13.7
Hz, Hα Nleu), 3.09−3.05 (2H, m, Hβ Phe), 3.03−2.94 (1H, m, Hβ
Nleu), 2.84−2.75 (1H, m, H5 Linker), 2.47−2.38 (1H, m, H2 Linker),
1.96−1.85 (1H, m, Hγ Nleu), 1.59−1.51 (2H, m, H4 Linker), 1.35 (3H,
d, J = 6.7 Hz, Hβ Ala), 1.33−1.25 (3H, m, H3 Linker), 1.08 (3H, d, J =
6.7 Hz, HMe Linker), 0.95 (3H, d, J = 6.7 Hz, Hδ Nleu), 0.92 (3H, d, J =
6.8 Hz, Hδ Nleu); 13C NMR (100 MHz, DMSO-d6): δ 175.4, 175.0,
171.0, 169.4, 138.7, 129.1, 128.9, 128.3, 128.2, 126.3, 56.3, 55.5, 51.4,
44.2, 37.8, 36.2, 32.0, 27.5, 26.0, 20.0, 19.9, 19.8, 17.4, 17.2; HRMS [M
+ Na]+ calcd for C23H34N4O4: 467.2629, found: 467.2626.
(3S,6S,12R)-3-Benzyl-6-isobutyl-10-methyl-12-methyl-
1,4,7,10-tetraza-2,5,8,11-cyclopentadecanetetrone (Nala-2R).
1H NMR (400 MHz, DMSO-d6): δ 8.84 (1H, d, J = 5.5 Hz), 7.37 (1H,
(6S,9S,12S)-4-Benzyl-6-isobutyl-9,12-dimethyl-1,4,7,10-tet-
raza-2,5,8,11-cyclopentadecanetetrone (Nphe-2S). 1H NMR
(400 MHz, DMSO-d6): δ 8.77 (1H, d, J = 6.2 Hz, HN Leu), 8.06
(1H, d, J = 8.7 Hz, HN Ala), 7.46−7.12 (5H, m), 6.89 (1H, s, HN
Linker), 5.32 (1H, br s), 5.18 (1H, d, J = 15 Hz), 4.68−4.57 (1H, m, Hα
Phe), 4.56−4.47 (1H, m, Hα Ala), 4.40−4.21 (1H, m, Hα Leu), 3.77
(1H, d, J = 15.0 Hz, Hβ Phe), 3.21−3.09 (1H, m, H5 Linker), 3.00−2.90
(1H, m, H5 Linker), 2.69−2.68 (m, 1H), 2.48−2.38 (1H, m, H2
Linker), 2.35−2.30 (1H, dt, 3.7, 1.8 Hz), 1.70−1.58 (1H, m, H4
Linker), 1.58−1.48 (1H, m, Hβ Leu), 1.48−1.39 (1H, m, Hγ Leu),
1.33−1.21 (3H, m, H3 Linker), 1.17 (3H, d, J = 7.0 Hz, Hβ Ala), 1.14−
1.07 (1H, m, H4 Linker), 0.93 (3H, d, J = 6.7 Hz, HMe Linker), 0.91−
0.83 (2H, m), 0.66 (3H, d, J = 6.3 Hz, Hδ Leu), 0.41 (3H, d, J = 4.3 Hz,
d, J = 9.4 Hz), 7.32−7.13 (5H, m), 6.36 (1H, d, J = 9.4 Hz), 4.46−4.35
(1H, m), 4.28 (1H, d, J = 15.0 Hz), 3.83−3.73 (1H, m), 3.60 (1H, d, J =
15.0 Hz), 3.21 (3H, s), 2.95−2.86 (1H, m), 2.86−2.79 (1H, m), 2.71−
2.62 (1H, m), 1.82−1.68 (1H, m), 1.65−1.53 (1H, m), 1.48−1.36 (1H,
m), 1.32−1.05 (4H, m), 0.97 (3H, d, J = 6.7 Hz), 0.80 (3H, d, J = 6.5
Hz), 0.74 (3H, 6.5 Hz); 13C NMR (100 MHz, DMSO-d6): δ 178.1,
172.8, 171.9, 171.1, 138.8, 129.2, 128.7, 126.7, 54.1, 53.5, 40.6, 40.4,
40.2, 39.7, 39.5, 39.3, 39.2, 25.0, 24.5, 23.3, 21.3, 18.8; HRMS [M +
Na]+ calcd for C23H34N4O4: 467.2629, found: 467.2626.
(3S,6S,12S)-3-Benzyl-6-isobutyl-10-methyl-12-methyl-
1,4,7,10-tetraza-2,5,8,11-cyclopentadecanetetrone (Nala-2S).
1H NMR (400 MHz, DMSO-d6): δ 8.29 (1H, d, J = 4.3 Hz, HN
1
Hδ Leu); H NMR (400 MHz, CDCl3): δ 7.41−7.17 (5H, m), 6.98
Leu), 8.06 (1H, d, J = 8.7 Hz, HN Phe), 7.32−7.11 (5H, m), 6.87 (1H,
dd, J = 6.7, 2.2 Hz, HN Linker), 4.49 (1H, d, J = 17.8 Hz, Hα Nala), 4.34
(1H, ddd, J = 11.2, 8.8, 4.1 Hz, Hα Phe), 3.81 (1H, d, J = 17.7 Hz, Hα
Nala), 3.82−3.75 (1H, m, Hα Leu), 3.29−3.23 (2H, m, Hβ Phe and H5
Linker), 2.84 (1H, dd, J = 14.1, 11.4 Hz), 2.83−2.78 (1H, m, H5
Linker), 2.72 (3H, s, HMe Linker), 2.69−2.65 (1H, m, H2 Linker),
1.62−1.50 (1H, m, H3 Linker), 1.47−1.38 (2H, m, H4 Linker), 1.36−
1.22 (2H, m, Hβ Leu and Hγ Leu), 1.21−1.06 (2H, m, Hβ Leu and H3
Linker), 0.96 (3H, d, J = 6.7 Hz, HMe Linker), 0.79 (3H, d, J = 6.2 Hz,
(1H, br s, HN Leu), 6.57−6.47 (1H, m, HN Linker), 5.87 (1H, d, J = 7.7
Hz, HN Ala), 5.34 (1H, d, J = 17.1 Hz, Hβ Phe), 4.81−4.73 (1H, m, Hα
Leu), 4.70 (1H, d, J = 14.9 Hz, Hα Nphe), 4.57−4.54 (1H, m, Hα Ala),
4.50 (1H, d, J = 17.1 Hz, Hβ Nphe), 3.51−3.41 (1H, m, H5 Linker),
3.34 (1H, d, J = 14.9 Hz, Hα Nphe), 3.08−2.95 (1H, m, H5 Linker),
2.27−2.12 (1H, m, H2 Linker), 1.64−1.57 (2H, m, H3 Linker), 1.54−
1.40 (3H, m, H4 Linker and Hγ Leu), 1.36 (3H, d, J = 6.8 Hz, Hβ Ala),
1.15 (3H, d, J = 6.7 Hz, HMe Linker), 0.76 (3H, d, J = 6.7 Hz, Hδ Leu),
0.59 (3H, d, J = 6.5 Hz, Hδ Leu); 13C NMR (100 MHz, DMSO-d6): δ
174.9, 168.0, 138.0, 128.8, 128.5, 127.6, 127.3, 126.5, 52.5, 38.6, 37.5,
31.6, 25.8, 23.7, 23.1, 22.9, 22.0, 20.9, 19.7, 18.1, 17.2, 15.1; HRMS [M
+ Na]+ calcd for C23H34N4O4: 467.2629, found: 467.2622.
1
Hδ Leu), 0.71 (3H, d, J = 6.3 Hz, Hδ Leu); H NMR (400 MHz,
CDCl3): δ 7.42 (1H, br s, HN Phe), 7.35−7.13 (1H, br s, NH Linker and
NH Leu), 4.65 (1H, br s, Hα Phe), 4.13−3.98 (1H, m), 3.86 (1H, br s,
Hα Leu), 3.62−3.48 (2H, m, H5 Linker), 3.47−3.38 (1H, m, Hβ Phe),
3.18 (3H, s, Hβ Nala), 3.13−3.04 (2H, m, H5 Linker and Hβ Phe), 2.93
(2H, s), 2.89−2.78 (1H, m, H2 Linker), 1.80−1.66 (2H, br s, H3
Linker), 1.54−1.45 (1H, br s, Hγ Leu), 1.16 (3H, d, J = 6.7 Hz, HMe
Linker), 0.95−0.78 (6H, m, Hδ Leu); 13C NMR (100 MHz, DMSO-
d6): δ 175.9, 171.8, 170.8, 169.9, 138.6, 128.9, 128.0, 126.0, 54.0, 53.9,
51.2, 35.9, 34.8, 34.4, 30.3, 23.8, 22.2, 17.1; HRMS [M + Na]+ calcd for
C23H34N4O4: 467.2629, found: 467.2632.
(3S,6S,9S,13R)-3-Benzyl-6-isobutyl-9,13-dimethyl-1,4,7,10-
tetraza-2,5,8,11-cyclopentadecanetetrone (Ø-3R). 1H NMR
(400 MHz, DMSO-d6): δ 8.22−8.06 (3H, m), 7.54 (1H, t, J = 5.3
Hz), 7.29−7.11 (5H,m), 4.20−4.12 (1H, m), 3.95−3.86 (1H, m),
3.28−3.18 (1H, m), 3.13 (1H, dd, J = 13.8, 5.2 Hz), 2.99−2.88 (2H,
m), 2.14−2.04 (1H, m), 1.92−1.83 (1H, m), 1.74−1.61 (1H, m),
1.53−1.23 (5H, m), 1.21 (3H, d, J = 7.3 Hz), 0.89 (3H, d, J = 6.8 Hz),
0.82−0.73 (6H, m); 13C NMR (100 MHz, DMSO-d6): δ 172.9, 172.3,
171.2, 170.4, 138.5, 129.0, 128.1, 126.1, 55.3, 53.1, 49.9, 42.4, 40.4,
40.0, 36.4, 36.0, 35.6, 28.5, 24.3, 22.5, 22.2, 20.9, 17.2; HRMS [M +
Na]+ calcd for C23H34N4O4: 467.2629, found: 467.2639.
(3S,9S,12R)-3-Benzyl-7-isobutyl-9,12-dimethyl-1,4,7,10-tet-
raza-2,5,8,11-cyclopentadecanetetrone (Nleu-2R). 1H NMR
(400 MHz, DMSO-d6): δ 8.79 (1H, d, J = 9.2 Hz), 8.41 (1H, s),
8.31 (1H, d, J = 8.5 Hz), 8.21 (1H, d, J = 1.9 Hz), 7.78−7.68 (1H, d, J =
7.9 Hz), 7.48−7.39 (1H, m), 7.32−7.14 (10H, m), 4.69−4.55 (2H, m),
4.48−4.38 (1H, m), 4.32−4.23 (2H, m), 4.20−4.09 (1H, d, J = 18.3
Hz), 3.20−3.11 (2H, m), 3.10−3.01 (2H, m), 3.00−2.81 (2H, m),
2.80−2.69 (2H, m), 2.27−2.03 (3H, m), 1.95−1.82 (1H, m), 1.79−
1.52 (4H, m), 1.47−1.28 (3H, m), 1.21 (3H, d, J = 7.0 Hz), 1.17 (3H, d,
J = 6.7 Hz), 1.08 (3H, d, J = 7.2 Hz), 0.93 (3H, d, J = 6.8 Hz), 0.89 (3H,
d, J = 6.7 Hz), 0.82 (3H, d, J = 6.7 Hz), 0.75 (3H, d, J = 6.7 Hz), 0.68
(3H, d, J = 6.7 Hz); 13C NMR (100 MHz, DMSO-d6): δ 176.2, 175.6,
174.02, 170.4, 169.1, 167.9, 138.7, 138.3, 129.2, 129.0, 128.2, 128.1,
126.2, 55.5, 55.0, 54.9, 53.8, 50.7, 44.6, 42.0, 38.4, 36.2, 31.6, 30.8, 27.2,
26.5, 25.8, 20.1, 19.9, 19.7, 17.2, 16.7, 16.4; HRMS [M + Na]+ calcd for
C23H34N4O4: 467.2629, found: 467.2625.
(3S,9S,12S)-3-Benzyl-7-isobutyl-9,12-dimethyl-1,4,7,10-tet-
raza-2,5,8,11-cyclopentadecanetetrone (Nleu-2S). 1H NMR
(400 MHz, DMSO-d6): δ 8.36 (1H, d, J = 8.2 Hz, HN Phe), 7.99
(1H, d, J = 8.0 Hz, HN Ala), 7.46−7.36 (1H, m, HN Linker), 7.30−7.15
(5H, m), 4.72−4.65 (1H, m, Hα Ala), 4.25−4.19 (1H, m, Hα Phe), 4.16
(1H, d, J = 14.0 Hz, Hα Nleu), 3.48−3.39 (1H, m, Hβ Nleu), 3.29−3.24
(1H, m, Hα Nleu), 3.19−3.11 (1H, m, Hβ Phe), 3.11−3.08 (1H, m, Hβ
Nleu), 3.07−2.96 (2H, m, H5 Linker), 2.75 (1H, dd, J = 14.3, 10.9 Hz,
Hβ Phe), 2.34−2.31 (1H, m, H2 Linker), 1.93−1.85 (1H, m, Hγ Nleu),
(3S,6S,9S,13S)-3-Benzyl-6-isobutyl-9,13-dimethyl-1,4,7,10-
tetraza-2,5,8,11-cyclopentadecanetetrone (Ø-3S). 1H NMR
(400 MHz, DMSO-d6): δ 8.52 (1H, d, J = 7 Hz), 8.17−8.05 (1H,
m), 8.05−7.93 (1H, m), 7.30−7.13 (5H, m), 6.90−6.80 (1H, m),
4.39−4.30 (1H, m), 4.08−3.91 (2H, m), 3.27 (1H, dd, J = 13.9, 4.5
Hz), 2.87−2.75 (2H, m), 2.21 (1H, d, J = 10.8 Hz), 1.89−1.63 (3H, m),
1.49−1.38 (1H, m), 1.38−1.34 (1H, m), 1.32 (3H, d, J = 7.2 Hz),
5377
J. Med. Chem. 2021, 64, 5365−5383