Journal of Medicinal Chemistry
Article
1H), 3.21−3.28 (m, 1H), 3.15 (t, J = 6.90 Hz, 2H), 1.77−1.87 (m, 1H),
1.58−1.69 (m, 1H). MS (m/z) 432.1 (M + H+).
d4) δ 8.06 (d, J = 8.53 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.53 (dd, J =
2.01, 8.53 Hz, 1H), 7.44−7.50 (m, 1H), 7.23−7.35 (m, 3H), 3.93 (dd, J
= 4.39, 9.41 Hz, 1H), 3.83 (dd, J = 6.53, 9.29 Hz, 1H), 3.17−3.24 (m,
1H), 3.10 (t, J = 6.90 Hz, 2H), 1.73−1.83 (m, 1H), 1.55−1.65 (m, 1H).
13C NMR (101 MHz, methanol-d4) δ 159.07, 138.86, 136.77, 132.49,
132.03, 131.14, 130.41, 127.30, 124.37, 119.65, 118.15, 117.29, 112.84,
72.26, 47.70, 39.60, 33.10. MS (m/z) 414.0 (M + H+). HRMS (ES+)
(C17H17Cl2N3O3S + H+) m/z = 414.0446 observed, 414.0446
calculated.
N-(3-Amino-4-(2-cyanophenoxy)butyl)-2,4-dichlorobenzenesul-
fonamide (26). Compound 26 was prepared analogously to compound
3 and was purified by HPLC (20−60%) to afford 26 (54.7 mg, 33%) as
a pale orange foam: 1H NMR (400 MHz, methanol-d4) δ 8.05 (d, J =
8.53 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.61−7.67 (m, 2H), 7.51 (dd, J
= 2.01, 8.53 Hz, 1H), 7.15−7.18 (m, 1H), 7.11 (dt, J = 0.75, 7.53 Hz,
1H), 4.07 (dd, J = 4.52, 9.29 Hz, 1H), 3.96 (dd, J = 6.27, 9.29 Hz, 1H),
3.25−3.32 (m, 1H), 3.12 (t, J = 7.03 Hz, 2H), 1.79−1.89 (m, 1H),
1.63−1.73 (m, 1H). MS (m/z) 414.0 (M + H+).
N-(3-Amino-4-(3-fluorophenoxy)butyl)-2,4-dichlorobenzenesul-
fonamide (27). Compound 27 was prepared analogously to compound
3 and was purified by HPLC (20−60%) to afford 27 (100 mg, 61%) as a
sticky light orange oil: 1H NMR (400 MHz, methanol-d4) δ 8.06 (d, J =
8.53 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.53 (dd, J = 2.01, 8.53 Hz,
1H), 7.24−7.32 (m, 1H), 6.73−6.77 (m, 1H), 6.66−6.72 (m, 2H), 3.90
(dd, J = 4.52, 9.29 Hz, 1H), 3.80 (dd, J = 6.40, 9.41 Hz, 1H), 3.18−3.26
(m, 1H), 3.09 (t, J = 7.03 Hz, 2H), 1.73−1.83 (m, 1H), 1.56−1.66 (m,
1H). MS (m/z) 407.0 (M + H+).
N-(3-Amino-4-(3-chlorophenoxy)butyl)-2,4-dichlorobenzenesul-
fonamide (28). Compound 28 was prepared analogously to compound
3 and was purified by HPLC (20−60%) to afford 28 (21.5 mg, 41%) as
a light orange oil: 1H NMR (400 MHz, methanol-d4) δ 8.05 (d, J = 8.53
Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.53 (dd, J = 2.26, 8.53 Hz, 1H),
7.23−7.29 (m, 1H), 6.95−6.98 (m, 2H), 6.87 (ddd, J = 1.00, 2.32, 8.47
Hz, 1H), 3.89 (dd, J = 4.50, 9.30 Hz, 1H), 3.79 (dd, J = 6.40, 9.30 Hz,
1H), 3.17−3.24 (m, 1H), 3.09 (t, J = 6.90 Hz, 2H), 1.73−1.82 (m, 1H),
1.56−1.66 (m, 1H). MS (m/z) 423.0 (M + H+).
N-(3-Amino-4-(m-tolyloxy)butyl)-2,4-dichlorobenzenesulfona-
mide (29). Compound 29 was prepared analogously to compound 3
and was purified by HPLC (20−60%) to afford 29 (52 mg, 47%) as a
sticky light orange solid: 1H NMR (400 MHz, methanol-d4) δ 8.05 (d, J
= 8.53 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.52 (dd, J = 2.01, 8.53 Hz,
1H), 7.15 (t, J = 7.78 Hz, 1H), 6.67−6.79 (m, 3H), 3.86 (dd, J = 4.50,
9.30 Hz, 1H), 3.76 (dd, J = 6.40, 9.30 Hz, 1H), 3.15−3.23 (m, 1H), 3.09
(t, J = 7.03 Hz, 2H), 2.32 (s, 3H), 1.73−1.82 (m, 1H), 1.55−1.65 (m,
1H). MS (m/z) 403.0 (M + H+).
N-(3-Amino-4-(3-methoxyphenoxy)butyl)-2,4-dichlorobenzene-
sulfonamide (30). Compound 30 was prepared analogously to
compound 3 and was purified by HPLC (20−60%) to afford 30
(45.5 mg, 46%) as a light yellow oil: 1H NMR (400 MHz, methanol-d4)
δ 8.05 (d, J = 8.28 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.52 (dd, J = 2.13,
8.41 Hz, 1H), 7.14−7.19 (m, 1H), 6.47−6.55 (m, 3H), 3.87 (dd, J =
4.50, 9.30 Hz, 1H), 3.74−3.80 (m, 4H), 3.16−3.23 (m, 1H), 3.09 (t, J =
7.03 Hz, 2H), 1.73−1.82 (m, 1H), 1.56−1.65 (m, 1H). MS (m/z)
419.0 (M + H+).
(S)-N-(3-Amino-4-(2-amino-5-cyanophenoxy)butyl)-2,4-dichlor-
obenzenesulfonamide (31). The procedures to synthesize compound
6 were followed to prepare the intermediate, (S)-tert-butyl (3-((tert-
butoxycarbonyl)amino)-4-(5-cyano-2-nitrophenoxy)butyl)((2,4-
dichlorophenyl)sulfonyl)carbamate (0.211 g, 0.32 mmol), which was
dissolved in DCM (3.2 mL) and treated with zinc dust (0.209 g, 3.20
mmol) and acetic acid (0.183 mL, 3.20 mmol). After 23 h, additional
zinc dust (0.209 g) and acetic acid (0.183 mL) were added. After an
additional 24 h, the reaction was filtered. Then, 10% Na2CO3 (5 mL)
was slowly added to the filtrate, which was washed with DCM (2 X 3
mL). The combined organic extracts was concentrated and purified
using FC (0−35% EtOAc/hexanes, 25 g silica) to afford (S)-tert-butyl
(4-(2-amino-5-cyanophenoxy)-3-((tert-butoxycarbonyl)amino)-
butyl)((2,4-dichlorophenyl)sulfonyl)carbamate (192 mg, 72% yield,
75% purity) as an orange oil: MS (m/z) 629.0 (M + H+). To a solution
of (S)-tert-butyl (4-(2-amino-5-cyanophenoxy)-3-((tert-
(S)-N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-2-nitroben-
zenesulfonamide (19). Compound 19 was prepared analogously to
compound 14 and was purified using FC (0−9% (10% NH4OH in
MeOH)/DCM, 40 g silica) to afford 19 (98 mg, 69%, two steps) as a
glassy yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.95−8.04 (m,
1H), 7.85−7.90 (m, 1H), 7.82 (t, J = 8.28 Hz, 1H), 7.13 (dd, J = 1.80,
11.80 Hz, 1H), 6.95 (dd, J = 1.80, 8.80 Hz, 1H), 3.75−3.95 (m, 4H),
2.95−3.14 (m, 3H), 1.61−1.71 (m, 1H), 1.35−1.48 (m, 1H). MS (m/
z) 409.1 (M + H+).
(S)-N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-4-chloro-2-
(trifluoromethyl)benzenesulfonamide (20). Compound 20 was
prepared analogously to compound 12 and was purified using HPLC
(20−60%) to afford 20 (19.6 mg, 9%, two steps) as a sticky colorless
solid: 1H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 8.53 Hz, 1H),
7.97 (d, J = 2.01 Hz, 1H), 7.85 (dd, J = 2.01, 8.53 Hz, 1H), 7.67 (t, J =
8.16 Hz, 1H), 6.91−7.00 (m, 2H), 4.01 (dd, J = 4.39, 9.41 Hz, 1H), 3.90
(dd, J = 6.50, 9.30 Hz, 1H), 3.19−3.26 (m, 1H), 3.15 (t, J = 6.90 Hz,
2H), 1.76−1.86 (m, 1H), 1.58−1.68 (m, 1H). MS (m/z) 466.1 (M +
H+).
(S)-N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-4-cyano-2-
(trifluoromethyl)benzenesulfonamide (21). Compound 21 was
prepared analogously to compound 12 and was purified using HPLC
(25−50%) then FC (0−10% MeOH/DCM, 4 g silica) to afford 21
(23.5 mg, 11%, two steps) as a glassy pale orange solid: 1H NMR (400
MHz, methanol-d4) δ 8.33−8.37 (m, 2H), 8.21 (dd, J = 1.50, 8.30 Hz,
1H), 7.65−7.70 (m, 1H), 6.93−7.00 (m, 2H), 4.02 (dd, J = 4.39, 9.41
Hz, 1H), 3.91 (dd, J = 6.40, 9.41 Hz, 1H), 3.11−3.26 (m, 3H), 1.77−
1.87 (m, 1H), 1.59−1.69 (m, 1H). 13C NMR (101 MHz, chloroform-d)
1
3
δ 164.55 (d, JCF = 258.2 Hz), 163.54 (d, JCF = 11.0 Hz), 143.36,
3
3
135.84, 134.41 (d, JCF = 2.2 Hz), 132.33, 131.91 (q, JCF = 6.4 Hz),
129.03 (q, 2JCF = 34.5 Hz), 122.00 (q, 1JCF = 275.7 Hz), 116.71, 116.14,
114.16, 111.615 (d, 3JCF = 2.9 Hz), 102.85 (d, 2JCF = 23.5 Hz), 93.73 (d,
2JCF = 16.1 Hz), 74.09, 50.99, 42.48, 31.60. 19F NMR (376 MHz,
chloroform-d) δ −58.35 (s, 3F), −103.71 (s, 1F). MS (m/z) 457.1 (M
+ H+). HRMS (ES+) (C19H16F4N4O3S + H+) m/z = 457.0959
observed, 457.0957 calculated.
(S)-N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-2-chloro-4-
(trifluoromethyl)benzenesulfonamide (22). Compound 22 was
prepared analogously to compound 12 and was purified using FC
(0−100% EtOAc/hexanes, then 0−10% MeOH/EtOAc, 12 g silica) to
1
afford 22 (56 mg, 30%, two steps) as a sticky light orange solid: H
NMR (400 MHz, methanol-d4) δ 8.28 (d, J = 8.28 Hz, 1H), 7.97 (d, J =
1.00 Hz, 1H), 7.82−7.85 (m, 1H), 7.64−7.69 (m, 1H), 6.91−6.99 (m,
2H), 4.00 (dd, J = 4.39, 9.41 Hz, 1H), 3.89 (dd, J = 6.53, 9.50 Hz, 1H),
3.19−3.26 (m, 1H), 3.12 (t, J = 7.03 Hz, 2H), 1.74−1.84 (m, 1H),
1.57−1.67 (m, 1H). MS (m/z) 466.1 (M + H+).
N-(3-Amino-4-phenoxybutyl)-2,4-dichlorobenzenesulfonamide
(23). Compound 23 was prepared analogously to compound 3 and was
purified by HPLC (20−60%) to afford 23 (81.5 mg, 45%) as a light
orange solid: 1H NMR (400 MHz, methanol-d4) δ 8.05 (d, J = 8.53 Hz,
1H), 7.70 (d, J = 2.01 Hz, 1H), 7.52 (dd, J = 2.01, 8.53 Hz, 1H), 7.25−
7.31 (m, 2H), 6.89−6.97 (m, 3H), 3.88 (dd, J = 4.52, 9.29 Hz, 1H), 3.78
(dd, J = 6.50, 9.30 Hz, 1H), 3.17−3.24 (m, 1H), 3.09 (t, J = 7.03 Hz,
2H), 1.74−1.83 (m, 1H), 1.56−1.66 (m, 1H). MS (m/z) 389.1 (M +
H+).
N-(3-Amino-4-(4-cyanophenoxy)butyl)-2,4-dichlorobenzenesul-
fonamide (24). Compound 24 was prepared analogously to compound
3 and was purified by HPLC (20−60%) to afford 24 (98.6 mg, 40%) as
a sticky colorless oil: 1H NMR (400 MHz, methanol-d4) δ 8.05 (d, J =
8.53 Hz, 1H), 7.70 (d, J = 2.01 Hz, 1H), 7.66−7.70 (m, 2H), 7.53 (dd, J
= 2.01, 8.53 Hz, 1H), 7.06−7.11 (m, 2H), 3.98 (dd, J = 4.39, 9.41 Hz,
1H), 3.88 (dd, J = 6.53, 9.29 Hz, 1H), 3.21−3.28 (m, 1H), 3.10 (t, J =
6.90 Hz, 2H), 1.74−1.84 (m, 1H), 1.57−1.67 (m, 1H). MS (m/z)
414.0 (M + H+).
N-(3-Amino-4-(3-cyanophenoxy)butyl)-2,4-dichlorobenzenesul-
fonamide (25). Compound 25 was prepared analogously to compound
3 and was purified using FC (0−4% MeOH/DCM, 12 g silica) to afford
25 (50 mg, 36%) as a sticky white solid: 1H NMR (400 MHz, methanol-
L
J. Med. Chem. XXXX, XXX, XXX−XXX