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T. Wichur, J. Godyn, I. Goral et al.
European Journal of Medicinal Chemistry 225 (2021) 113792
(17
mL, 0.18 mmol, 1 equiv), glacial acetic acid (15
m
L), NaBH3CN
3-formylpiperidine-1-carboxylate (38 mg, 0.18 mmol, 1 equiv),
(16 mg, 0.25 mmol, 1.4 equiv) in 3 mL of MeOH and THF mixture
(1:1). Purification: flash chromatography (5e10% MeOH in DCM).
Yield: 23 mg (31%), yellow oil. Purity 96% (UPLC/MS). 1H NMR
glacial acetic acid (3.6 mL), NaBH3CN (34 mg, 0.54 mmol, 3 equiv) in
2 mL MeOH. Purification: flash chromatography (5% MeOH in
DCM). Yield: 42 mg (45%), yellowish oil. Purity 97% (UPLC/MS). 1H
(300 MHz, CDCl3)
d
8.50e8.55 (m, 2H), 7.83e7.90 (m, 2H), 7.61 (d,
NMR (500 MHz, CDCl3) d 7.76e7.81 (m, 2H), 7.50e7.55 (m, 1H),
J ¼ 8.2 Hz, 1H), 7.37e7.56 (m, 4H), 7.25e7.30 (m, 2H), 7.21 (t,
J ¼ 8.2 Hz, 1H), 6.74e6.78 (m, 1H), 6.65 (d, J ¼ 7.6 Hz, 1H), 4.18 (t,
J ¼ 5.3 Hz, 2H), 3.89 (s, 2H), 3.05 (t, J ¼ 5.0 Hz, 2H), 1.91 (br. s., 1H).
7.39e7.45 (m, 2H), 7.23e7.29 (m, 1H), 7.12 (t, J ¼ 8.3 Hz, 1H), 6.49 (d,
J ¼ 8.0 Hz, 1H), 3.99e4.06 (m, 2H), 3.91 (t, J ¼ 8.6 Hz, 2H), 3.85 (d,
J ¼ 12.0 Hz, 1H), 3.68e3.79 (m, 1H), 2.90e2.97 (m, 2H), 2.83 (t,
J ¼ 8.6 Hz, 2H), 2.59e2.67 (m, 1H), 2.47e2.58 (m, 2H), 1.77e1.83 (m,
1H), 1.68 (br. s., 1H), 1.59 (dd, J ¼ 4.3, 9.5 Hz, 1H), 1.34e1.48 (m, 11H),
1.08e1.19 (m, 1H), 0.67e0.92 (m, 1H). Formula: C27H37N3O5S; MS:
m/z 516 (M þ Hþ).
13C NMR (75 MHz, CDCl3)
d 152.2, 149.8, 149.2, 138.2, 136.2, 133.8,
129.2, 126.7, 125.6, 124.8, 122.8, 121.2, 106.7, 106.1, 104.5, 67.6, 52.3,
48.1. Formula: C22H21N3O3S; MS: m/z 408 (M þ Hþ).
4.1.17.28. N-((5-Methylfuran-2-yl)methyl)-2-((1-(phenylsulfonyl)-
1H-indol-4-yl)oxy)ethan-1-amine (59). Following GP7, compound
59 was prepared using 2-((1-(phenylsulfonyl)-1H-indol-4-yl)oxy)
ethan-1-amine (14) (57 mg, 0.18 mmol, 1.3 equiv), 5-methyl-2-
4.1.17.32. 4-(((2-((1-(phenylsulfonyl)indolin-4-yl)oxy)ethyl)amino)
methyl)phenyl acetate (63). Following GP7, compound 63 was
prepared using 2-((1-(phenylsulfonyl)indolin-4-yl)oxy)ethan-1-
amine (21) (57 mg, 0.18 mmol, 1 equiv), 4-acetoxybenzaldehyde
furalaldehyde (14
mL, 0.14 mmol, 1 equiv), glacial acetic acid
(3.6 L), NaBH3CN (26 mg, 0.42 mmol, 3 equiv) in 2 mL MeOH.
m
(25 mL, 0.18 mmol, 1 equiv), glacial acetic acid (3.6 mL), NaBH3CN
Purification: flash chromatography (3% MeOH in DCM). Yield:
(34 mg, 0.54 mmol, 3 equiv) in 2 mL MeOH. Purification: flash
chromatography (5% MeOH in DCM), preparative HPLC. Yield:
10 mg (12%), white solid. Purity 100% (UPLC/MS). 1H NMR e
25 mg (44%), yellow oil. Purity 100% (UPLC/MS). 1H NMR (500 MHz,
CDCl3)
d
7.85 (d, J ¼ 8.0 Hz, 2H), 7.59 (d, J ¼ 8.0 Hz, 1H), 7.48e7.53
(m, 1H), 7.46 (d, J ¼ 4.0 Hz, 1H), 7.37e7.43 (m, 2H), 7.19 (t, J ¼ 8.0 Hz,
1H), 6.78 (d, J ¼ 4.0 Hz, 1H), 6.62 (d, J ¼ 8.0 Hz, 1H), 6.06 (d,
J ¼ 2.9 Hz,1H), 5.86 (d, J ¼ 1.7 Hz,1H), 4.15 (t, J ¼ 5.2 Hz, 2H), 3.80 (s,
2H), 3.05 (t, J ¼ 5.2 Hz, 2H), 2.23 (s, 3H), 2.09 (br. s., 1H). 13C NMR
formate salt (500 MHz, CDCl3)
d
8.20 (br. s., 1H), 7.78 (d, J ¼ 7.5 Hz,
2H), 7.48e7.55 (m, 1H), 7.39e7.45 (m, 2H), 7.35 (d, J ¼ 8.0 Hz, 2H),
7.28 (d, J ¼ 8.0 Hz,1H), 7.10 (t, J ¼ 8.0 Hz, 1H), 7.03 (d, J ¼ 8.0 Hz, 2H),
6.86 (br. s., 2H), 6.43 (d, J ¼ 8.6 Hz, 1H), 4.08 (t, J ¼ 4.6 Hz, 2H), 3.93
(s, 2H), 3.89 (t, J ¼ 8.3 Hz, 2H), 3.05 (t, J ¼ 4.6 Hz, 2H), 2.80 (t,
(126 MHz, CDCl3)
d 152.4, 151.8, 151.6, 138.3, 136.3, 133.9, 129.3,
126.8, 125.8, 124.9, 121.3, 108.1, 106.8, 106.5, 106.1, 104.7, 67.7, 47.8,
J ¼ 8.6 Hz, 2H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 169.3,
46.3, 13.7. Formula: C22H22N2O4S; MS: m/z 411 (M þ Hþ).
154.5, 150.7, 143.4, 136.8, 133.2, 132.0, 130.3, 129.3, 129.0, 127.2,
122.0, 119.1, 108.3, 106.7, 64.8, 51.2, 50.2, 46.0, 24.8, 21.1. Formula:
4.1.17.29. N-Benzyl-2-((1-(phenylsulfonyl)indolin-4-yl)oxy)ethan-1-
amine (60). Following GP7, compound 60 was prepared using 2-
((1-(phenylsulfonyl)indolin-4-yl)oxy)ethan-1-amine (21) (57 mg,
C
25H26N2O5S; MS: m/z 467 (M þ Hþ).
4.1.17.33. N-Benzyl-2-((1-(naphthalen-1-ylsulfonyl)-1H-indol-4-yl)
oxy)ethan-1-amine (64). Following GP7, compound 64 was pre-
pared using 2-((1-(naphthalen-1-ylsulfonyl)-1H-indol-4-yl)oxy)
ethan-1-amine (15) (55 mg, 0.15 mmol, 1 equiv), benzaldehyde
0.18 mmol, 1 equiv), benzaldehyde (18
mL, 0.18 mmol, 1 equiv),
glacial acetic acid (3.6 L), NaBH3CN (34 mg, 0.54 mmol, 3 equiv) in
m
2 mL MeOH. Purification: flash chromatography (4% MeOH in
DCM). Yield: 22 mg (30%), colourless oil. Purity 98% (UPLC/MS). 1H
(15 mL, 0.15 mmol, 1 equiv), glacial acetic acid (3 mL), NaBH3CN
NMR (500 MHz, CDCl3)
d
7.77e7.81 (m, 2H), 7.50e7.55 (m, 1H),
(28 mg, 0.45 mmol, 3 equiv) in 2 mL MeOH. Purification: flash
7.40e7.45 (m, 2H), 7.27e7.31 (m, 5H), 7.22e7.26 (m, 1H), 7.11e7.16
(m, 1H), 6.50 (d, J ¼ 8.0 Hz, 1H), 4.05 (t, J ¼ 5.2 Hz, 2H), 3.91 (t,
J ¼ 8.6 Hz, 2H), 3.83 (s, 2H), 2.96 (t, J ¼ 5.2 Hz, 2H), 2.82 (t, J ¼ 8.6 Hz,
chromatography (4% MeOH in DCM). Yield: 35 mg (51%), yellow oil.
Purity 97% (UPLC/MS). 1H NMR (500 MHz, CDCl3)
d 8.68e8.71 (m,
1H), 8.07 (dd, J ¼ 1.2, 7.5 Hz, 1H), 8.01 (d, J ¼ 8.6 Hz, 1H), 7.85 (d,
J ¼ 8.0 Hz, 1H), 7.69 (d, J ¼ 3.4 Hz, 1H), 7.60e7.64 (m, 1H), 7.53 (dt,
J ¼ 1.2, 7.5 Hz, 1H), 7.47 (t, J ¼ 8.3 Hz, 1H), 7.41 (d, J ¼ 8.6 Hz, 1H),
7.29e7.36 (m, 4H), 7.22e7.27 (m, 1H), 7.13 (t, J ¼ 8.3 Hz, 1H), 6.79 (d,
J ¼ 3.4 Hz,1H), 6.59 (d, J ¼ 8.0 Hz,1H), 4.16 (t, J ¼ 5.2 Hz, 2H), 3.87 (s,
2H), 3.05 (t, J ¼ 5.4 Hz, 2H), 2.08 (br. s., 1H). 13C NMR (126 MHz,
2H), 1.90 (br. s, 1H). 13C NMR (126 MHz, CDCl3)
d 155.4, 143.4, 140.0,
137.0,133.2,129.3,129.1,128.6,128.2,127.4,127.2,119.2,108.0,107.0,
67.6, 53.8, 50.3, 48.0, 25.0. Formula: C23H24N2O3S; MS: m/z 409
(M þ Hþ).
4.1.17.30. N-(3-Methylbenzyl)-2-((1-(phenylsulfonyl)indolin-4-yl)
oxy)ethan-1-amine (61). Following GP7, compound 61 was pre-
pared using 2-((1-(phenylsulfonyl)indolin-4-yl)oxy)ethan-1-amine
CDCl3) d 152.3, 139.9, 136.0, 135.4, 134.2, 133.9, 129.1, 129.0, 128.7,
128.4, 128.1, 128.1, 127.1, 127.0, 125.5, 125.2, 124.0, 123.9, 120.8,
106.4, 105.3, 104.3, 67.6, 53.6, 47.9. Formula: C27H24N2O3S; MS: m/z
457 (M þ Hþ).
(21) (57 mg, 0.18 mmol,1 equiv), m-tolualdehyde (21
mL, 0.18 mmol,
1 equiv), glacial acetic acid (3.6 L), NaBH3CN (34 mg, 0.54 mmol, 3
m
equiv) in 2 mL MeOH. Purification: flash chromatography (4%
4.1.17.34. N-(3-Methylbenzyl)-2-((1-(naphthalen-1-ylsulfonyl)-1H-
indol-4-yl)oxy)ethan-1-amine (65). Following GP7, compound 65
was prepared using 2-((1-(naphthalen-1-ylsulfonyl)-1H-indol-4-
yl)oxy)ethan-1-amine (15) (42 mg, 0.11 mmol, 1 equiv), m-tol-
MeOH in DCM). Yield: 43 mg (56%), pale yellow oil. Purity 95%
(UPLC/MS). 1H NMR (500 MHz, CDCl3)
d 7.78e7.82 (m, 2H),
7.52e7.56 (m, 1H), 7.41e7.46 (m, 2H), 7.30 (d, J ¼ 8.0 Hz, 1H),
7.18e7.22 (m, 1H), 7.05e7.17 (m, 4H), 6.52 (d, J ¼ 8.0 Hz, 1H), 4.06 (t,
J ¼ 5.2 Hz, 2H), 3.93 (t, J ¼ 8.3 Hz, 2H), 3.80 (s, 2H), 2.97 (t, J ¼ 5.4 Hz,
2H), 2.83 (t, J ¼ 8.6 Hz, 2H), 2.33 (s, 3H), 1.91 (br. s., 1H). 13C NMR
ualdehyde (13 mL, 0.11 mmol, 1 equiv), glacial acetic acid (2.2 mL),
NaBH3CN (21 mg, 0.33 mmol, 3 equiv) in 1.5 mL MeOH. Purification:
flash chromatography (4% MeOH in DCM). Yield: 24 mg (46%),
(126 MHz, CDCl3)
d
155.3, 143.2, 139.8, 138.1, 136.9, 133.1, 129.1,
yellow oil. Purity 96% (UPLC/MS). 1H NMR (500 MHz, CDCl3)
d 8.69
129.0, 128.8, 128.3, 127.8, 127.2, 125.0, 119.1, 107.8, 106.9, 67.5, 53.6,
(d, J ¼ 9.2 Hz, 1H), 8.07 (dd, J ¼ 1.2, 7.5 Hz, 1H), 8.01 (d, J ¼ 8.6 Hz,
1H), 7.85 (d, J ¼ 8.6 Hz, 1H), 7.69 (d, J ¼ 3.4 Hz, 1H), 7.60e7.64 (m,
1H), 7.51e7.56 (m,1H), 7.47 (t, J ¼ 7.7 Hz,1H), 7.40 (d, J ¼ 8.6 Hz,1H),
7.18e7.23 (m, 1H), 7.10e7.16 (m, 3H), 7.06 (d, J ¼ 7.5 Hz, 1H), 6.79 (d,
J ¼ 3.4 Hz,1H), 6.59 (d, J ¼ 8.0 Hz,1H), 4.16 (t, J ¼ 5.2 Hz, 2H), 3.84 (s,
2H), 3.05 (t, J ¼ 5.2 Hz, 2H), 2.32 (s, 3H), 2.16 (br. s., 1H). 13C NMR
50.2, 48.0, 24.9, 21.3. Formula: C24H26N2O3S; MS: m/z 423 (M þ Hþ).
4.1.17.31. Tert-butyl
3-(((2-((1-(phenylsulfonyl)indolin-4-yl)oxy)
ethyl)amino)methyl)piperidine-1-carboxylate (62). Following GP7,
compound 62 was prepared using 2-((1-(phenylsulfonyl)indolin-4-
yl)oxy)ethan-1-amine (21) (57 mg, 0.18 mmol, 1 equiv), tert-butyl
(126 MHz, CDCl3)
d 152.3, 139.7, 138.1, 136.0, 135.4, 134.2, 133.9,
22