Journal of Medicinal Chemistry
Article
M + H, loss of tert-butyl); 1H NMR (500 MHz, DMSO) 10.54
(s, 1H), 7.62−7.72 (m, 2H), 7.28−7.38 (m, 1H), 6.39−6.53 (m, 1H),
6.27−6.35 (m, 1H), 5.79−5.86 (m, 1H), 3.86 (s, 3H), 3.38−3.44 (m, 4H),
2.95−3.13 (m, 4H), 1.37 (s, 9H); 13C NMR (126 MHz, DMSO-d6)
δ 163.8, 157.4, 153.6, 145.0, 131.9, 131.4, 128.2, 119.3, 110.4, 103.0, 79.3,
55.8, 45.5, 28.0.
4-(4-Acryloylamino-2-methylbenzenesulfonyl)piperazine-1-
carboxylic Acid tert-Butyl Ester (29d). MS (ES+) m/z (M + 23)
432; δH (500 MHz, DMSO-d6) 10.49 (1H, s), 7.61−7.82 (3H, m),
6.41−6.51 (1H, m), 6.25−6.36 (1H, m), 5.83 (dd, J = 10.09, 1.65 Hz,
1H), 3.38 (4H, br s), 2.93−3.02 (4H, m), 2.54 (3H, s), 1.37 (9H, s).
4-(4-Acryloylamino-2-fluorobenzenesulfonyl)piperazine-1-
carboxylic Acid tert-Butyl Ester (29f). MS (ES+) m/z (M + 23)
436; HRMS (ES+) m/z 310.1228 (310.1225 calcd for C19H27N3O5S,
M + H, loss of tert-butyl); 1H NMR (250 MHz, DMSO) 7.80 (dd, J =
12.94, 1.98 Hz, 1H), 7.66 (t, J = 8.38 Hz, 1H), 7.38 (dd, J = 8.76, 1.90 Hz,
1H), 6.21−6.40 (m, 2H), 5.74 (dd, J = 6.24, 5.63 Hz, 1H), 3.31−3.48
(m, 5H), 3.01 (t, J = 4.72 Hz, 4H), 1.24−1.37 (m, 9H); 13C NMR
(126 MHz, DMSO-d6) δ 163.7, 153.5, 143.1, 138.6, 131.4, 131.3, 128.8,
128.1, 122.4, 116.4, 79.3, 45.0, 28.0, 20.7.
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 2-Trifluoromethylbenzyl Ester (16s). MS (ES+) m/z (M + 1)
498; HRMS (ES+) m/z 498.1298 (498.1311 calcd for
1
C22H22F3N3O5S, M + H); H NMR (500 MHz, DMSO) 10.60 (br s,
1H), 7.91 (d, J = 8.83 Hz, 1H), 7.48−7.79 (m, 4H), 6.40−6.53 (m, 1H),
6.26−6.37 (m, 1H), 5.78−5.92 (m, 1H), 5.18 (s, 2H), 3.48 (br s, 4H),
2.87 (br s, 4H); 13C NMR (126 MHz, DMSO-d6) δ 162.6, 152.6,
142.3, 133.3, 131.7, 130.2, 128.9, 127.7, 127.5, 127.4, 127.1, 125.4
(q, J = 30 Hz), 124.9 (q, J = 6 Hz), 123.0 (q, J = 274 Hz), 118.0, 62.0,
44.5, 41.6 (br).
N-(4-{4-[2-(2-Phenoxyphenyl)acetyl]piperazine-1-sulfonyl}-
phenyl)acrylamide (16t). MS (ES+) m/z (M + 1) 506; HRMS
1
(ES+) m/z 506.1755 (506.1750 calcd for C27H27N3O5S, M + H); H
NMR (500 MHz, DMSO) 10.62 (s, 1H), 7.93 (d, J = 8.83 Hz, 2H),
7.66 (d, J = 8.83 Hz, 2H), 7.15−7.31 (m, 4H), 6.91−7.08 (m, 2H),
6.72−6.85 (m, 3H), 6.43−6.55 (m, 1H), 6.25−6.39 (m, 1H), 5.77−
5.92 (m, 1H), 3.43−3.66 (m, 6H), 2.74 (t, J = 4.73 Hz, 3H); 13C
NMR (126 MHz, DMSO-d6) δ 168.4, 163.8, 156.9, 154.2, 143.4,
131.9, 131.4, 129.7, 128.9, 128.5, 128.3, 127.5, 123.6, 122.9, 119.2,
118.8, 117.8, 45.8, 45.7, 44.5, 40.5, 33.6.
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 2-Methylbenzyl Ester (16u). MS (ES+) m/z (M + 1) 444;
HRMS (ES+) m/z 444.1597 (444.1593 calcd for C22H25N3O5S,
M + H); 1H NMR (500 MHz, DMSO) 10.58 (s, 1H), 7.91 (d, J = 8.67
Hz, 2H), 7.68 (d, J = 8.83 Hz, 2H), 7.00−7.29 (m, 4H), 6.40−6.50
(m, 1H), 6.26−6.37 (m, 1H), 5.83 (dd, J = 10.17, 1.66 Hz, 1H), 5.02
(s, 2H), 3.46 (br s, 4H), 2.80−2.95 (m, 4H), 2.22 (s, 3H); 13C NMR
(126 MHz, DMSO-d6) δ 163.8, 154.1, 143.4, 136.4, 134.4, 131.4,
130.1, 128.9, 128.6, 128.6, 128.2, 128.1, 125.8, 119.2, 65.1, 45.7, 42.7,
18.4.
4-(4-Acryloylamino-2-chlorobenzenesulfonyl)piperazine-1-
carboxylic Acid tert-Butyl Ester (29g). MS (ES+) m/z (M + 1)
423; δH (250 MHz, DMSO-d6) 10.68 (1H, s), 8.07 (d, J = 2.13 Hz,
1H), 7.90 (d, J = 8.83 Hz, 1H), 7.70 (dd, J = 8.76, 2.06 Hz, 1H), 6.24−
6.53 (2H, m), 5.74−5.96 (1H, m), 3.33−3.42 (4H, m), 3.02−3.18
(4H, m), 1.36 (9H, s).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 2,3-Difluorobenzyl Ester (16o). Phosgene (0.5 mL, 20%
solution in toluene) was added in one portion to a stirred solution of
2,3-difluorobenzyl alcohol (0.2 g, 1.36 mmol) in THF (2 mL), and the
resulting mixture was stirred at room temperature under a nitrogen
atmosphere for 3 h. After this time the reaction mixture was concentrated
under vacuum and the resulting residue was diluted with DMF (2 mL)
and added dropwise to a stirred solution of N-[4-(piperazine-1-sulfonyl)-
phenyl]acrylamide (15, 0.2 g, 0.68 mmol) and diisopropylethylamine
(0.35 mL, 2.04 mmol) in DMF (4 mL). The resulting mixture was
stirred at room temperature under a nitrogen atmosphere for 18 h.
After this time the reaction mixture was concentrated under vacuum
and the residue was purified using preparative HPLC to give the title
compound (0.029 g, 12% yield) as a white powder. MS (ES+) m/z
(M + 1) 466; δH (500 MHz, DMSO-d6) 10.58 (1H, s), 7.92 (d, J =
8.35 Hz, 2H), 7.70 (d, J = 8.20 Hz, 2H), 7.35−7.45 (1H, m), 7.14−
7.27 (2H, m), 6.43−6.53 (1H, m), 6.30−6.40 (1H, m), 5.85 (d, J =
10.09 Hz, 1H), 5.11 (2H, s), 3.47 (4H, br s), 2.87 (4H, br s).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 4-Fluorobenzyl Ester (16p). MS (ES+) m/z (M + 1) 448; δH
(500 MHz, DMSO-d6) 10.61 (1H, br s), 7.93 (d, J = 8.32 Hz, 2H),
7.69 (d, J = 8.32 Hz, 2H), 7.38−7.31 (2H, m), 7.16−7.11 (2H, m),
6.50−6.27 (2H, m), 5.83 (d, J = 10.12 Hz, 1H), 4.98 (2H, s), 3.51−
3.42 (4H, m), 2.89−2.81 (4H, m).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 3,5-Difluorobenzyl Ester (16q). MS (ES+) m/z (M + 1) 466;
HRMS (ES+) m/z 466.1233 (466.1248 calcd for C21H21F2N3O5S,
M + H); 1H NMR (500 MHz, DMSO) 10.57 (s, 1H), 7.91 (d, J = 8.83
Hz, 2H), 7.70 (d, J = 8.67 Hz, 2H), 7.12−7.19 (m, 1H), 7.05 (d, J =
6.46 Hz, 2H), 6.41−6.51 (m, 1H), 6.27−6.38 (m, 1H), 5.83 (dd, J =
10.17, 1.66 Hz, 1H), 5.03 (s, 2H), 3.49 (br s, 4H), 2.89 (t, J = 4.81 Hz,
4H); 13C NMR (126 MHz, DMSO-d6) δ 163.7, 162.3 (dd, J = 247, 14
Hz), 153.8, 143.4, 141.2 (t, J = 10 Hz), 131.4, 128.9, 128.6, 128.2,
119.2, 110.4 (dd, J = 20, 6 Hz), 103.2 (t, J = 26 Hz), 65.1, 45.6, 42.7
(br).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid Naphthalen-1-ylmethyl Ester (16v). MS (ES+) m/z (M + 23)
502; δH (500 MHz, DMSO-d6) 10.61 (1H, br s), 7.80−7.99 (5H, m),
7.67 (d, J = 8.67 Hz, 2H), 7.29−7.59 (4H, m), 6.42−6.53 (1H, m),
6.27−6.39 (1H, m), 5.85 (dd, J = 10.09, 1.73 Hz, 1H), 5.48 (2H, s),
3.45 (4H, br s), 2.69−2.96 (4H, m).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid Naphthalen-2-ylmethyl Ester (16w). MS (ES+) m/z (M + 23)
502; HRMS (ES+) m/z 480.1577 (480.1593 calcd for C25H25N3O5S,
1
M + H); H NMR (500 MHz, DMSO) 10.61 (br s, 1H), 7.64−7.97
(m, 11H), 7.38−7.59 (m, 4H), 6.26−6.53 (m, 2H), 5.80−5.91
(m, 1H), 5.19 (s, 2H), 3.51 (br s, 4H), 2.89 (t, J = 4.89 Hz, 4H); 13C
NMR (126 MHz, DMSO-d6) δ 163.8, 154.2, 143.4, 134.2, 132.7,
132.5, 131.4, 128.9, 128.6, 128.2, 128.1, 127.8, 127.6, 126.4, 126.3,
126.2, 125.6, 119.7, 66.6, 45.7, 42.8.
N-(4-{4-[2-(3-Phenoxyphenyl)acetyl]piperazine-1-sulfonyl}-
phenyl)acrylamide (16x). MS (ES+) m/z (M + 1) 506; δH (500
MHz, DMSO-d6) 10.59 (1H, s), 7.91 (d, J = 8.67 Hz, 2H), 7.67 (d, J =
8.83 Hz, 2H), 7.35 (t, J = 7.88 Hz, 2H), 7.22 (t, J = 7.88 Hz, 1H), 7.11
(t, J = 7.33 Hz, 1H), 6.75−7.01 (5H, m), 6.26−6.51 (2H, m), 5.83
(dd, J = 10.09, 1.73 Hz, 1H), 3.65 (2H, s), 3.53 (d, J = 3.78 Hz, 4H),
2.72−2.90 (4H, m).
N-(4-{4-[2-(4-Phenoxyphenyl)acetyl]piperazine-1-sulfonyl}-
phenyl)acrylamide (16y). MS (ES+) m/z (M + 1) 506; δH (500 MHz,
DMSO-d6) 10.59 (1H, s), 7.91 (d, J = 8.67 Hz, 2H), 7.69 (d, J =
8.83 Hz, 2H), 7.36 (t, J = 7.88 Hz, 2H), 7.06−7.20 (3H, m), 6.79−
7.00 (4H, m), 6.40−6.50 (1H, m), 6.25−6.37 (1H, m), 5.83 (dd, J =
10.17, 1.81 Hz, 1H), 3.50−3.68 (6H, m), 2.75−2.88 (4H, m).
N-{4-[4-(Octahydroisoquinoline-2-carbonyl)piperazine-1-
sulfonyl]phenyl}acrylamide (17a). MS (ES+) m/z (M + 1) 461; δH
(500 MHz, DMSO-d6) 10.59 (1H, s), 7.92 (d, J = 8.83 Hz, 2H), 7.70
(d, J = 8.83 Hz, 2H), 6.39−6.53 (1H, m), 6.25−6.36 (1H, m), 5.71−
5.89 (1H, m), 3.06−3.28 (5H, m), 2.72−2.95 (6H, m), 1.05−1.80
(12H, m).
4-(4-Acryloylaminobenzenesulfonyl)piperazine-1-carboxylic
Acid 2-Chlorobenzyl Ester (16r). MS (ES+) m/z (M + 1) 464;
HRMS (ES+) m/z 464.1058 (464.1047 calcd for C21H22ClN3O5S,
M + H); 1H NMR (500 MHz, DMSO) 10.60 (br s, 1H), 7.91 (d, J = 8.67
Hz, 2H), 7.69 (d, J = 8.67 Hz, 2H), 7.27−7.50 (m, 3H), 6.41−6.51
(m, 1H), 6.26−6.37 (m, 1H), 5.80−5.89 (m, 1H), 5.09 (s, 2H), 3.48
(br s, 3H), 2.87 (d, J = 4.26 Hz, 3H); 13C NMR (126 MHz, DMSO-d6)
δ 163.7, 153.9, 143.4, 133.9, 132.9, 132.4, 131.3, 129.9, 129.9, 129.3, 128.9,
128.5, 128.2, 127.3, 119.2, 64.0, 45.6, 42.8.
N-{4-[4-(Octahydroquinoline-1-carbonyl)piperazine-1-
sulfonyl]phenyl}acrylamide (17b). MS (ES+) m/z (M + 1) 461;
HRMS (ES+) m/z 461.2210 (461.2223 calcd for C23H32N4O4S,
M + H); 1H NMR (500 MHz, DMSO) 10.59 (s, 1H), 7.92 (d, J = 8.67
Hz, 2H), 7.70 (d, J = 8.67 Hz, 2H), 6.41−6.52 (m, 1H), 6.25−6.37
(m, 1H), 5.83 (dd, J = 10.17, 1.66 Hz, 1H), 3.59 (d, J = 12.14 Hz, 1H),
3.04−3.28 (m, 5H), 2.74−2.93 (m, 5H), 1.06−1.81 (m, 13H); 13C
1041
dx.doi.org/10.1021/jm201310y | J. Med. Chem. 2012, 55, 1021−1046