Journal of Medicinal Chemistry
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lyophilization. H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.27
7.16 (d, J = 7.6 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H), 2.85 (d, J = 4.8 Hz,
3H). MS (EI) for C18H16FN5O3S, found 402.1 (MH+).
(dd, J = 4.0, 1.2 Hz, 1H), 8.07 (t, J = 1.2 Hz, 1H), 7.87 (t, J = 1.6 Hz,
1H), 7.75 (t, J = 8.0 Hz, 1H), 7.67−7.65 (m, 3H), 7.47 (dd, J = 8.4, 1.6
Hz, 1H), 7.26 (dd, J = 8.4, 4.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.98
(s, 2H), 2.91−2.74 (m, 9H), 1.11 (d, J = 7.2 Hz, 6H). MS (EI) for
C28H30N6O2S found 515.1 (MH+).
3-Amino-6-(6-amino-5-(N-phenylsulfamoyl)pyridin-3-yl)-N-
methylpyrazine-2-carboxamide (14). 1H NMR (400 MHz,
DMSO-d6) δ 10.47 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.76 (q, J =
4.4 Hz, 1H), 8.66 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.61 (br s, 2H),
7.25−7.21 (m, 2H), 7.12 (d, J = 7.2 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H),
6.87 (s, 2H), 2.83 (d, J = 4.4 Hz, 3H). MS (EI) for C18H18N6O3S,
found 400.2 (MH+).
3-Amino-6-(4-chloro-3-(N-m-tolylsulfamoyl)phenyl)-N-
methylpyrazine-2-carboxamide (18). A solution of SO2/CuCl/
AcOH was formed by bubbling sulfur dioxide gas into acetic acid (424
mL) for 10 min at 0 °C to saturate and adding CuCl (7.15 g, 73.0
mmol). In a separate flask, an aqueous solution of NaNO2 (25.0 g,
0.362 mol) in H2O (380 mL) was added to a precooled (0 °C)
suspension of 5-bromo-2-chloroaniline (50.0 g, 242 mol) in conc. HCl
(aq., 380 mL). After stirring for 1 h, the reaction mixture was added to
the SO2/CuCl/AcOH solution at 0 °C via an addition funnel over 15
min. The ice bath was removed, and the reaction mixture was allowed
to stir at ambient temperature for 2 h, then diluted with H2O (1200
mL) and filtered. The off-white solid product was concentrated in
vacuo overnight to provide 63.6 g (91%) of 5-bromo-2-chlorobenzene-
1-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.3 Hz,
1H), 7.78 (dd, J = 8.5, 2.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H).
A mixture of 5-bromo-2-chlorobenzene-1-sulfonyl chloride (500
mg, 1.72 mmol), m-toluidine (202 mg, 1.89 mmol), pyridine (1.89
mmol, 153 μL), and CH2Cl2 (5 mL) was stirred for 30 min then
purified directly by flash chromatography (hexanes/ethyl acetate 4:1)
to provide 5-bromo-2-chloro-N-m-tolylbenzenesulfonamide (521 mg,
84%) as an off-white solid.
3-Amino-6-(4-chloro-3-(N-(3-fluorophenyl)sulfamoyl)-
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phenyl)-N-methylpyrazine-2-carboxamide (19). H NMR (400
MHz, DMSO-d6) δ 11.00 (s, 1H), 8.88 (s, 1H), 8.80 (d, J = 4.8 Hz,
1H), 8.62 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 8.4, 2.1 Hz, 1H), 8.34−
7.37 (m, 3H), 7.26 (dd, J = 15.1, 8.1 Hz, 1H), 7.10−6.91 (m, 2H),
6.82 (td, J = 8.5, 1.9 Hz, 1H), 2.86 (d, J = 4.8 Hz, 3H). MS (EI) for
C18H15ClFN5O3S, found 436.0 (MH+).
3-Amino-6-(4-chloro-3-(N-(3-methoxyphenyl)sulfamoyl)-
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phenyl)-N-methylpyrazine-2-carboxamide (20). H NMR (400
MHz, DMSO-d6) δ 10.69 (s, 1H), 8.83 (s, 1H), 8.77 (dd, J = 8.1, 4.9
Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.27−7.33
(m, 3H), 7.10 (t, J = 8.3 Hz, 1H), 6.78−6.62 (m, 2H), 6.61−6.48 (m,
1H), 3.61 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H). MS (EI) for
C19H18ClN5O4S, found 448.0 (MH+).
3-Amino-6-(4-chloro-3-(N-(3-(trifluoromethyl)phenyl)-
sulfamoyl)phenyl)-N-methylpyrazine-2-carboxamide (21). 1H
NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.86 (s, 1H), 8.80 (q,
J = 4.5 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.46 (dd, J = 8.4, 2.2 Hz, 1H),
8.27−7.52 (m, 3H), 7.54−7.40 (m, 3H), 7.42−7.26 (m, 1H), 2.86 (d, J =
4.8 Hz, 3H). MS (EI) for C19H15ClF3N5O3S, found 486.0 (MH+).
3-Amino-6-(4-chloro-3-(N-(3-chlorophenyl)sulfamoyl)-
A mixture of 5-bromo-2-chloro-N-m-tolylbenzenesulfonamide (521
mg, 1.44 mmol), bis(pinacolato)diboron (403 mg, 1.59 mmol),
Pd(dppf)Cl2·CH2Cl2 (105 mg, 0.129 mmol), potassium acetate (423
mg, 4.32 mmol), and dioxane (10 mL) was heated to 90 °C in a sealed
tube. After 3 h, the reaction mixture was cooled to ambient
temperature, and 3-amino-6-bromo-N-methylpyrazine-2-carboxamide
(100 mg, 0.433 mmol), Pd(dppf)Cl2·CH2Cl2 (42 mg, 0.051 mmol),
triethylamine (238 μL, 1.84 mmol), N,N-dimethylformamide (2 mL),
and H2O (2 mL) were added. The reaction mixture was heated to
85 °C. After 2 h, the mixture was filtered through celite and purified
directly by reverse phase HPLC (acetonitrile/aqueous ammonium
acetate buffer solution; 10−90% gradient) to provide 18 (121 mg, 65%
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phenyl)-N-methylpyrazine-2-carboxamide (22). H NMR (400
MHz, DMSO-d6) δ 11.00 (s, 1H), 8.86 (s, 1H), 8.81 (q, J = 4.6 Hz,
1H), 8.62 (s, 1H), 8.46 (dd, J = 8.4, 2.2 Hz, 1H), 8.35−7.34 (m, 3H),
7.25−7.19 (m, 2H), 7.14 (ddd, J = 8.2, 2.1, 0.9 Hz, 1H), 7.05 (ddd, J =
8.0, 2.0, 0.9 Hz, 1H), 2.86 (d, J = 4.8 Hz, 3H). MS (EI) for
C18H15Cl2N5O3S, found 452.0 (MH+).
3-Amino-6-(4-chloro-3-(N-(2-chlorophenyl)sulfamoyl)-
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phenyl)-N-methylpyrazine-2-carboxamide (23). H NMR (400
MHz, DMSO-d6) δ 10.29 (s, 1H), 8.88−8.63 (m, 2H), 8.46 (d, J =
10.2 Hz, 1H), 8.41 (s, 1H), 8.12−7.55 (m, 3H), 7.43 (d, J = 7.8 Hz,
1H), 7.34−7.14 (m, 3H), 2.83 (d, J = 4.8 Hz, 3H). MS (EI) for
C18H15Cl2N5O3S, found 451.7 (MH+).
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in 2 steps) as an off-white solid. H NMR (400 MHz, DMSO-d6) δ
10.60 (s, 1H), 8.83 (s, 1H), 8.79 (dd, J = 12.0, 4.0 Hz, 1H), 8.57 (d,
J = 2.2 Hz, 1H), 8.41 (dd, J = 8.4, 2.1 Hz, 1H), 7.88 (s, 1H), 7.64−
7.37 (m, 2H), 7.08 (t, J = 7.8 Hz, 1H), 7.02−6.88 (m, 2H), 6.79 (d, J =
7.9 Hz, 1H), 2.85 (d, J = 4.8 Hz, 3H), 2.16 (s, 3H). MS (EI) for
C19H18ClN5O3S, found 431.8 (MH+).
Compounds 7−8, 12−14, and 19−36 were prepared by a
procedure similar to that described for the synthesis of compound 18.
3-Amino-N-methyl-6-(3-(N-phenylsulfamoyl)phenyl)-
pyrazine-2-carboxamide (7). 1H NMR (400 MHz, CD3OD) δ 8.61
(s, 1H), 8.30−8.22 (m, 2H), 7.72−7.70 (m, 1H), 7.55 (t, J = 7.6 Hz,
1H), 7.24−7.20 (m, 2H), 7.12−7.04 (m, 3H), 2.97 (s, 3H). MS (EI)
for C18H17N5O3S, found 382.1 (MH+).
3-Amino-6-(4-chloro-3-(N-(4-chlorophenyl)sulfamoyl)-
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phenyl)-N-methylpyrazine-2-carboxamide (24). H NMR (400
MHz, DMSO-d6) δ 10.86 (s, 1H), 8.85 (s, 1H), 8.79 (q, J = 4.8 Hz,
1H), 8.57 (d, J = 2.2 Hz, 1H), 8.45 (dd, J = 8.4, 2.2 Hz, 1H), 8.30−
7.43 (m, 3H), 7.28 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 2.85
(d, J = 4.8 Hz, 3H). MS (EI) for C18H15Cl2N5O3S, found 452.0
(MH+).
3-Amino-6-(3-(N-(3-chlorophenyl)sulfamoyl)phenyl)-N-
methylpyrazine-2-carboxamide (25). 1H NMR (400 MHz,
CD3OD) δ 8.65 (s, 1H), 8.35 (t, J = 1.7 Hz, 1H), 8.32−8.24 (m,
1H), 8.06−7.40 (m, 6H), 7.24−7.13 (m, 2H), 7.09−7.00 (m, 2H),
2.98 (s, 3H). MS (EI) for C18H16ClN5O3S, found 416.1 (MH+).
3-Amino-6-(4-chloro-3-(N-(2-chloro-4-fluorophenyl)-
sulfamoyl)phenyl)-N-methylpyrazine-2-carboxamide (26). 1H
NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.76 (s, 2H), 8.48 (d,
J = 6.2 Hz, 1H), 8.38 (s, 1H), 7.97−7.53 (m, 3H), 7.46 (dd, J = 8.5, 2.9
Hz, 1H), 7.29 (dd, J = 9.0, 5.7 Hz, 1H), 7.22−7.14 (m, 1H), 2.83 (d, J =
4.8 Hz, 3H). MS (EI) for C18H14Cl2FN5O3S, found 469.7 (MH+).
3-Amino-6-(4-chloro-3-(N-(2-chloro-3-fluorophenyl)-
sulfamoyl)phenyl)-N-methylpyrazine-2-carboxamide (27). 1H
NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.89−8.69 (m, 2H),
8.48 (dd, J = 8.4, 2.1 Hz, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.14−7.49 (m,
3H), 7.40−7.19 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 2.83 (d, J = 4.8 Hz,
3H). MS (EI) for C18H14Cl2FN5O3S, found 469.7 (MH+).
3-Amino-6-(4-chloro-3-(N-phenylsulfamoyl)phenyl)-N-meth-
ylpyrazine-2-carboxamide (8). H NMR (400 MHz, DMSO-d6) δ
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10.69 (s, 1H), 8.84 (s, 1H), 8.79 (q, J = 4.6 Hz, 1H), 8.57 (d, J = 2.4
Hz, 1H), 8.43 (dd, J = 8.4, 2.4 Hz, 1H), 7.82 (br s, 2H), 7.70 (d, J =
8.0 Hz, 1H), 7.24−7.15 (m, 4H), 7.00−6.96 (m, 1H), 2.85 (d, J = 5.2
Hz, 3H). MS (EI) for C18H16ClN5O3S, found 418.0 (MH+).
3-Amino-6-(4-methoxy-3-(N-phenylsulfamoyl)phenyl)-N-
methylpyrazine-2-carboxamide (12). 1H NMR (400 MHz,
DMSO-d6) δ 10.07 (s, 1H), 8.75 (q, J = 4.6 Hz, 1H), 8.73 (s, 1H),
8.35 (dd, J = 8.4, 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.63 (br s,
2H), 7.23 (d, J = 8.8 Hz, 1H), 7.20−7.11 (m, 4H), 6.96−6.92 (m,
1H), 3.94 (s, 3H), 2.84 (d, J = 4.8 Hz, 3H). MS (EI) for
C19H19N5O4S, found 414.0 (MH+).
3-Amino-6-(4-chloro-3-(N-(2,4-dichlorophenyl)sulfamoyl)-
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phenyl)-N-methylpyrazine-2-carboxamide (28). H NMR (400
3-Amino-6-(4-fluoro-3-(N-phenylsulfamoyl)phenyl)-N-meth-
ylpyrazine-2-carboxamide (13). 1H NMR (400 MHz, DMSO-d6) δ
10.68 (s, 1H), 8.83−8.79 (m, 2H), 8.50−8.47 (m, 1H), 8.41−8.37 (m,
1H), 7.78 (br s, 2H), 7.51 (t, J = 9.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H),
MHz, DMSO-d6) δ 10.44 (s, 1H), 8.87−8.56 (m, 2H), 8.58−8.28 (m,
2H), 7.91−7.19 (m, 6H), 2.84 (d, J = 4.8 Hz, 3H). MS (EI) for
C18H14Cl3N5O3S, found 483.7 (MH−).
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dx.doi.org/10.1021/jm300403a | J. Med. Chem. 2012, 55, 5467−5482