8
F. Fernandez Diaz-Rullo et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
4
.2.2. tert-Butyl-N-[(1S)-4-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-
4.2.6. tert-Butyl N-[(1S)-4-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-
benzofuran-5-yl)sulfonyl]carbamimidamido}-1-[(pyridine-3-
ylmethyl)carbamoyl]butyl]carbamate (3f)
benzo-5-furanyl)sulfonyl]carbamimidamido}-1-{[1-(pyridine-4-yl)
ethyl]carbamoyl}butyl]carbamate (3b)
Aminopyridine used was 4-(1-aminoethyl)pyridine 2b (41
.34 mmol). Final product was a white solid (130 mg; 74%). R
l
0.5
L;
Aminopyridine used was 3-(aminomethyl)pyridine 2f (35
l
L;
0.5
3
(DCM/MeOH 9:1); H NMR (CDCl , 400 MHz) d 8.47 (s, 1H), 8.40–
0
(
f
0.34 mmol). Final product was a white solid (162 mg; 94%). R
f
1
1
3
DCM/MeOH 9:1); H NMR (CDCl , 400 MHz) d 8.47–8.51 (m,
2
1
H), 7.76–7.86 (m, 1H), 7.25 (m, 2H), 6.33 (bs, 3H), 5.78–5.85 (m,
H), 4.97–5.02 (q, J = 6.9 Hz, 1H), 4.26 (m, 1H), 3.23 (m, 2H), 2.97
8.41 (m, 1H), 7.97 (bs, 1H), 7.58–7.60 (m, 1H), 7.16–7.19 (dd,
J = 4.9, 7.6 Hz, 1H), 6.42 (bs, 3H), 5.85–5.87 (m, 1H), 4.38–4.43
(dd, J = 5.9, 15.3 Hz, 1H), 4.31–4.36 (dd, J = 5.9, 15.3 Hz, 1H), 4.21
(m, 1H), 3.12–3.26 (m, 2H), 2.94 (s, 2H), 2.54 (s, 3H), 2.46 (s, 3H),
2.08 (s, 3H), 1.78–1.80 (m, 1H), 1.51–1.61 (m, 3H), 1.46 (s, 6H),
1.37 (s, 9H); C NMR (CDCl , 100 MHz) d 173.1, 158.9, 156.6,
3
156.0, 148.7, 148.2, 138.3, 135.6, 134.4, 132.6, 132.2, 124.7,
123.6, 117.6, 86.5, 79.8, 53.9, 43.2, 40.7, 40.2, 30.1, 29.7, 28.6,
(
s, 1H), 2.59 (s, 3H), 2.51 (s, 3H), 2.11 (s, 3H), 1.63–1.80 (m, 1H),
13
1
1
1
4
.53–1.55 (m, 3H), 1.41–1.48 (m, 18H);
3
C NMR (CDCl ,
00 MHz) d 173.3, 173.1, 158.5, 156.7, 156.4, 154.3, 148.8, 148.6,
1
3
38.0, 133.0, 132.1, 124.6, 121.6, 117.1, 86.3, 79.3, 54.4, 42.6,
0.0, 29.2, 29.0, 27.4, 25.7, 20.3, 20.2, 18.2, 17.1, 11.2; MS (ESI)
+
m/z calculated for [C31
H
46
N
6
O
6
S+H ] = 631.3, found 631.2.
2
O
42 6
8.3, 25.7, 19.3, 18.0, 12.5; MS (ESI) m/z calculated for [C29H N -
S+H ] = 617.3, found 617.2; [a] in CHCl = -5.0 (c = 1.0).
6 D 3
+
20
4
4
.2.3. tert-butyl-N-[(1S)-1-[methyl(pyridine-4-ylmethyl)carbamoyl]-
-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
4
.2.7. tert-Butyl N-[(1S)-4-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-
yl)sulfonyl]carbamimidamido}butyl]carbamate (3c)
Aminopyridine used was 4-[(methylamino)methyl]pyridine 2c
in its dihydrochloride salt (66 mg; 0.34 mmol). 4.9 eq. of TEA
benzofuran-5-yl)sulfonyl]carbamimidamido}-1-{[1-(pyridine-3-yl)
ethyl]carbamoyl}butyl]carbamate (3g)
Aminopyridine used was 3-(1-aminoethyl)pyridine 2g (41
0.34 mmol). Final product was a white solid (132 mg; 75%). R
lL;
(
191
lL; 1.37 mmol) were added instead. Forms rotamers giving
1
f
0.5
multiple peaks on the NMR. H NMR spectrum was acquired at
8
1
1
3
(DCM/MeOH 9:1); H NMR (CDCl
8.37 (m, 1H), 7.81–7.91 (m, 1H), 7.61 (m, 1H), 7.12–7.18 (m, 1H),
.39 (bs, 3H), 5.85–5.95 (m, 1H), 4.95–4.98 (m, 1H), 4.12–4.18
m, 1H), 3.14–3.37 (m, 2H), 2.91 (s, 2H), 2.53 (s, 3H), 2.46 (s, 3H),
3
, 400 MHz) d 8.50 (s, 1H), 8.36–
0 °C. C NMR reported is acquired at 25 °C. Final product was a
0.5 (DCM/MeOH 9:1); 1H NMR
white solid (121 mg; 69%). R
DMSO-d , 400 MHz, 80 °C) d 8.50–8.51 (m, 2H), 7.19–7.20 (m,
H), 6.54–6.58 (bs, 2H), 6.43 (s, 2H), 4.59–4.63 (m, 2H), 4.40–
.41 (m, 1H), 2.97–3.08 (m, 10 H), 2.47 (s, 3H), 2.04 (s, 3H),
f
6
(
(
6
2
4
1
1
1
5
2
O
2
.05 (s, 3H), 1.57–1.71 (m, 4H), 1.42 (s, 9H), 1.33–1.35 (m, 9H);
C NMR (CDCl , 100 MHz) d 172.1, 158.8, 156.6, 156.6, 156.0,
3
48.1, 148.1, 147.9, 147.6, 139.6, 139.3, 138.3, 138.3, 134.2,
34.1, 132.7, 132.2, 130.9, 128.8 124.7, 123.6, 123.6, 117.6, 86.4,
1
3
.48–1.64 (m, 4H), 1.43 (s, 6H), 1.39 (s, 9H); 1 C NMR (CDCl
00 MHz) d 172.8, 158.7, 156.3, 156.2, 155.8, 150.3, 150.1, 145.8,
45.6, 138.3, 133.0, 132.2, 124.6, 122.4, 121.7, 117.5, 86.4, 80.1,
2.3, 50.6, 49.9, 43.2, 40.8, 35.3, 34.4, 30.8, 30.4, 28.6, 28.3, 28.2,
3
3
,
1
1
7
1
9.8, 53.8, 47.1, 43.2, 40.4, 29.7, 28.6, 28.3, 28.3, 25.6, 21.8, 21.6,
+
9.4, 18.0, 12.5; MS (ESI) m/z calculated for [C31
H
46
N
6
O
6
S+H ]
46 6
5.0, 24.9, 19.3, 17.9, 12.5; MS (ESI) m/z calculated for [C31H N -
+
20
= 631.3, found 631.2.
6
D 3
S+H ] = 631.3, found 631.2; [a] in CHCl = 0 (c = 1.0).
4
4
.2.8. tert-Butyl N-[(1S)-1-[methyl(pyridine-3-ylmethyl)carbamoyl]-
-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
4
[
.2.4. Methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{1-
(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]
carbamimidamido}pentanamido]-3-(pyridin-4-yl)propanoate (3d)
yl)sulfonyl]carbamimidamido}butyl]carbamate (3h)
Aminopyridine used was 3-[(methylamino)methyl]pyridine 2h
Aminopyridine used was methyl (2S)-2-amino-3-(4-pyridinyl)
1
(
42
l
L; 0.34 mmol). Forms rotamers. H NMR spectrum was
propanoate 2d (61 mg; 0.34 mmol). Final product was a white solid
13
acquired at 80 °C. C NMR reported is acquired at 25 °C. Final pro-
1
(
100 mg; 52%). R
f
0.6 (DCM/MeOH 9:1); H NMR (CDCl
3
, 400 MHz)
1
duct was a white solid (132 mg; 75%). R
NMR (DMSO-d , 400 MHz, 80 °C) d 8.48 (m, 2H), 7.61–7.63 (d,
J = 7.8 Hz, 1H), 7.31–7.34 (dd, J = 4.7, 7.6 Hz, 1H), 6.43–6.58 (m,
4
2
9
1
1
4
1
f
0.5 (DCM/MeOH 9:1); H
d 8.36–8.38 (m, 2H), 7.60 (bs, 1H), 7.05–7.07 (m, 2H), 6.04–6.25
bs, 3H), 5.55–5.57 (m, 1H), 4.73–4.78 (q, J = 7.3 Hz, 1H), 4.10 (m,
6
(
1
2
1
1
1
3
H), 3.63 (s, 3H), 3.08–3.13 (m, 3), 2.93–2.99 (m, 1H), 2.88 (s,
H), 2.50 (s, 3H), 2.43 (s, 3.15), 2.02 (s, 3H), 1.66 (m, 1H), 1.43–
H), 4.40–4.63 (m, 3H), 3.05–3.09 (m, 4H), 2.95–2.97 (m, 5H),
.47 (s, 3H), 2.04 (s, 3H), 1.47–1.66 (m, 4H), 1.44 (s, 6H), 1.39 (s,
13
.66 (m, 3H), 1.38 (s, 6H), 1.32 (s, 9H);
C NMR (CDCl
3
,
13
3
H); C NMR (CDCl , 100 MHz) d 172.6, 158.7, 156.3, 156.1,
00 MHz) d 172.7, 171.5, 158.8, 156.5, 155.9, 149.6, 146.1, 138.3,
32.7, 132.2, 124.7, 117.6, 86.4, 79.9, 53.9, 52.6, 52.5, 43.2, 40.4,
6.7, 29.9, 28.6, 28.3, 25.4, 19.3, 18.0, 12.5; MS (ESI) m/z calculated
49.2, 149.0, 148.5, 138.3, 135.7, 134.8, 133.0, 132.4, 132.2,
31.8, 130.9, 128.8, 124.6, 123.8, 117.4, 86.4, 80.0, 50.9, 49.9,
9.1, 43.2, 40.8, 35.0, 34.0, 30.8, 30.5, 28.6, 28.3, 28.3, 24.9, 19.3,
+
20
for [C33
H
48
N
6
O
8
S+H ] = 689.3, found 689.2; [
a]
D
in CHCl
3
= -2.0
+
7.9, 12.5; MS (ESI) m/z calculated for [C31
H
46
N
6
O
6
S+H ] = 631.3,
(
c = 1.0).
20
D 3
found 631.2; [a] in CHCl = -6.0 (c = 1.0).
4
.2.5. tert-Butyl-N-[(1S)-4-{1-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-
4.2.9. Methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{1-
[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
yl)sulfonyl]carbamimidamido}pentanamido]-3-(pyridine-3-yl)
propanoate (3i)
benzofuran-5-yl)sulfonyl]carbamimidamido}-1-[(pyridine-4-
yl)carbamoyl]butyl]carbamate (3e)
Aminopyridine used was 4-aminopyridine 2e (32 mg;
0
.34 mmol). Final product was a white solid (104 mg; 62%). R
f
0.5
Amounts used were doubled: Boc-
0.57 mmol), HATU (304 mg; 0.80 mmol), TEA (232
methyl (2R)-2-amino-3-(3-pyridinyl)propanoate 2i (122 mg;
0.68 mmol).White solid (237 mg; 60%). R 0.6 (DCM/MeOH 9:1);
, 400 MHz) d 8.40–8.42 (m, 2H), 7.63–7.65 (bs,
1H), 7.56–7.58 (d, J = 7.8 Hz, 1H), 7.19–7.22 (dd, J = 7.8, 4.9 Hz,
1H), 6.30–6.53 (bs, 3H), 5.79–5.80 (bs, 1H), 4.77–4.83 (m, 1H),
4.12 (m, 1H), 3.70 (s, 3H), 3.17–3.22 (m, 3H), 2.99–3.05 (m, 1H),
L
-Arg(Pbf)-OH (300 mg;
1
(
DCM/MeOH 9:1); H NMR (CDCl
3
, 400 MHz) d 9.68 (bs, 1H),
l
L; 1.66 mmol),
8
5
3
6
1
1
1
.44–8.45 (d, J = 6.1 Hz, 2H), 7.64 (m, 2H), 6.26 (bs, 2H), 5.67–
.69 (m, 1H), 4.59 (m, 1H), 3.33 (m, 2H), 2.98 (s, 2H), 2.61 (s,
H), 2.54 (s, 3H), 2.12 (s, 3H), 1.93 (m, 1H), 1.69 (m, 3H), 1.49 (s,
f
1
H NMR (CDCl
3
1
3
H), 1.45 (s, 9H); C NMR (CDCl
3
, 100 MHz) d 172.4, 159.0,
56.6, 156.2, 150.2, 145.7, 138.4, 132.3, 132.2, 124.9, 117.8,
14.2, 86.6, 80.2, 54.6, 43.2, 40.2, 29.7, 28.6, 28.3, 25.7, 19.4,
+
8.0, 12.5; MS (ESI) m/z calculated for [C29
H
42
N
6
O
6
S+H ] = 603.3,
2.96 (s, 2H), 2.60 (s, 3H), 2.52 (s, 3H), 2.10 (s, 3H), 1.55–1.73 (m,
2
0
13
found 603.2; [
a]
D
in CHCl
3
= +6.0 (c = 1.0).
3
4H), 1.47 (s, 6H), 1.39 (s, 9H); C NMR (CDCl , 100 MHz) d 172.6,