10
X. Tong et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
residue was purified by chromatography on a silica gel column
(petroleum/EtOAc, 1:1 ? 1:3) to give title compounds 11ꢂ12.
(CH2C@O), 113.2 (30-C), 113.9 (50-C), 128.7 (60-C), 130.2 (10-C),
134.7 (40-C), 150.5 (3-C), 158.5 (20-C), 168.0 (C@O), 208.9 (C@O).
TOF-HRMS: m/z [M+H]+ calcd for C17H20Br2N3O3: 471.9866; found:
471.9862.
4.3.1. Compound 11a
1-(5-(5-Chloro-2-hydroxy-phenyl)-3-methyl-4,5-dihydro-pyra-
zol-1-yl)ethanone-2-piperidine, yellow powder, yield, 66%; mp
151–152 °C; 1H (300 MHz, CDCl3) d (ppm): 1.33–1.69 (m, 6H),
2.16 (s, 3H, CH3), 2.45–2.60 (m, 4H), 2.92 (dd, 1H, J1 = 3.7 Hz,
J2 = 18.6 Hz, 4-Ha), 3.33 (dd, 1H, J1 = 11.4 Hz, J2 = 18.6 Hz, 4-Hb),
3.52 (s, 2H, Ha, Hb), 5.60 (dd, 1H, J1 = 3.7 Hz, J2 = 11.4 Hz, 5-H),
6.77 (d, 1H, J = 8.6 Hz, 30-H), 6.83 (d, 1H, J = 2.5 Hz, 40-H), 7.06
(dd, 1H, J1 = 2.5 Hz, J2 = 8.6 Hz, 60-H). TOF-HRMS: m/z [M+H]+ calcd
for C17H23N3O2: 336.1473; found: 336.1474.
4.3.6. Compound 12c
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
pyrazol-1-yl)ethanone-2-piperazidine, colorless crystals, yield,
63%; mp 162–165 °C; IR (KBr,
2822 ( sCAH), 2720 ( sCAH), 1647 (
702 (
@CAH); 1H (300 MHz, CDCl3) d (ppm): 1.05 (t, 3H, J = 7.0 Hz,
m
/cmꢁ1): 3425 (
C@O), 1457 (
m
m
OAH), 2949 (
ArC@C), 861 (
m
asCAH),
m
m
m
c@CAH),
c
CH3CH2OH), 1.96 (s, 3H, CH3C), 2.54–2.59 (m, 5H, overlap, pyrazole
4-Ha, 2ꢃ CH2), 2.80–2.84 (m, 4H, 2ꢃ CH2), 3.32 (m, 1H, overlap,
pyrazole 4-Hb), 3.36 (d, 1H, J = 15.6 Hz, Ha), 3.44 (q, 2H,
J = 7.0 Hz, CH3CH2OH), 3.61 (d, 1H, J = 15.8 Hz, Hb), 5.43 (dd, 1H,
J1 = 4.6 Hz, J2 = 11.5 Hz, pyrazole 5-H), 6.76 (d, 1H, J = 2.4 Hz, 60-
H), 7.43 (d, 1H, J = 2.4 Hz, 40-H); 13C NMR (75 MHz, CDCl3) d
(ppm): 15.6 (CH3), 18.4, 44.1 (4-C), 44.2, 51.7, 55.8 (5-C), 56.0,
58.6 (CH2C@O), 105.1 (30-C), 113.6 (50-C), 127.1 (60-C), 132.2 (10-
C), 132.7 (40-C), 155.4 (3-C), 157.4 (20-C), 165.8 (C@O). TOF-HRMS:
m/z [M+H]+ calcd for C16H21Br2N4O2: 459.0026; found: 459.0023.
4.3.2. Compound 11b
1-(5-(5-Chloro-2-hydroxy-phenyl)-3-methyl-4,5-dihydro-pyra-
zol-1-yl)ethanone-2-morpholin white powder, yield, 58%; mp
183–184 °C; 1H (300 MHz, CDCl3) d (ppm): 2.16 (s, 3H, CH3), 2.63
(d, 4H, J = 2.9 Hz), 2.89 (dd, 1H, J1 = 3.6 Hz, J2 = 18.7 Hz, 4-Ha),
3.35 (dd, 1H, J1 = 11.4 Hz, J2 = 18.6 Hz, 4-Hb), 3.54 (d, 1H,
J = 16.7 Hz, Ha), 3.61 (d, 1H, J = 16.7 Hz, Hb), 3.77 (t, 4H,
J = 4.5 Hz), 5.63 (dd, 1H, J1 = 3.6 Hz, J2 = 11.3 Hz, 5-H), 6.70 (d, 1H,
J = 8.6 Hz, 30-H), 6.81 (d, 1H, J = 2.5 Hz, 40-H), 7.04 (dd, 1H,
J1 = 2.4 Hz, J2 = 8.6 Hz, 60-H); 13C NMR (75 MHz, CDCl3) d (ppm):
16.1(CH3), 44.2 (4-C), 54.0 (5-C, 2C), 59.5, 66.8 (2C), 119.2 (30-C),
124.8 (50-C), 124.9 (40-C), 128.1(60-C), 129.0 (10-C), 153.3 (3-C),
158.9 (20-C), 167.9. TOF-HRMS: m/z [M+H]+ calcd for C16H21ClN3O3:
338.1266; found: 338.1263.
4.3.7. Compound 12d
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
pyrazol-1-yl)ethanone-2-(4-hydroxyethyl)piperazidine,
white
powder, yield, 72%; mp 236–238 °C; 1H (300 MHz, C5D5N) d
(ppm): 1.96 (s, 3H, CH3), 2.64–2.85 (m, 11H, 5ꢃ CH2, pyrazole 4-
Ha), 3.37 (dd, 1H, J1 = 11.6 Hz, J2 = 18.1 Hz, pyrazole 4-Hb), 3.68
(d, 1H, J = 15.2 Hz, Ha), 3.92 (d, 2H, J = 6.3 Hz, CH2OH), 3.92 (d,
1H, J = 14.8 Hz, Hb), 5.99 (dd, 1H, J1 = 4.8 Hz, J2 = 11.5 Hz, pyrazole
5-H), 7.47 (s, 1H, 60-H), 7.72 (s, 1H, 40-H); 13C NMR (75 MHz,
C5D5N) d (ppm): 16.0 (CH3), 44.9 (4-C), 54.2, 54.3, 56.5 (5-C),
59.8, 60.0 (CH2C@O), 61.7 (CH2OH), 112.7 (30-C), 114.1 (50-C),
129.1 (60-C), 134.4 (10-C), 134.8 (40-C), 152.3 (3-C), 157.3 (20-C),
167.9 (C@O). TOF-HRMS: m/z [M+H]+ calcd for C18H25Br2N4O3:
503.0288; found: 503.0287.
4.3.3. Compound 11c
1-(5-(5-Chloro-2-hydroxy-phenyl)-3-methyl-4,5-dihydro-pyra-
zol-1-yl)ethanone-2-imidazole, white powder, yield, 62%; mp 165–
166 °C; IR (KBr,
asCAH), 1678 (
869 ( @CAH), 820 (
m
/cmꢁ1): 3418 (
C@O), 1460 (
@CAH); 1H (300 MHz, CDCl3) d (ppm): 2.16 (s,
m
OAH), 3136 (
mas@CAH), 2917
(m
m
m
ArC@C), 1431 ( ArC@C), 1276, 1108,
m
c
c
3H, CH3), 2.91 (dd, 1H, J1 = 4.4 Hz, J2 = 18.7 Hz, 4-Ha), 3.37 (dd,
1H, J1 = 11.2 Hz, J2 = 18.4 Hz, 4-Hb), 5.06 (s, 2H, Ha, Hb), 5.59 (dd,
1H, J1 = 4.5 Hz, J2 = 11.5 Hz, 5-H), 6.74 (d, 1H, J = 8.6 Hz, 30-H),
6.85 (d, 1H, J = 2.5 Hz, 40-H), 6.94–7.13 (m, 3H, 60-H, iminazole 5-
H, iminazole 4-H), 7.56 (s, 1H, iminazole 2-H). TOF-HRMS: m/z
[M+H]+ calcd for C15H16ClN4O2: 319.0956; found: 319.0957.
4.3.8. Compound 12e
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
pyrazol-1-yl)ethanone-2-(4-hydroxyl)piperidine, colorless crys-
tals, yield, 48%; mp 89–92 °C; 1H (300 MHz, CDCl3) d (ppm):
1.61–1.74 (m, 2H), 1.90–1.99 (m, 2H), 2.15 (s, 3H, CH3), 2.39–
2.50 (m, 2H), 2.87 (dd, 1H, J1 = 4.2 Hz, J2 = 15.8 Hz, pyrazole
4-Ha), 2.88–3.00 (m, 2H), 3.35 (dd, 1H, J1 = 11.6 Hz, J2 = 15.8 Hz,
pyrazole 4-Hb), 3.56 (d, 1H, J = 16.7 Hz, Ha), 3.64 (d, 1H,
J = 16.7 Hz, Hb), 3.69–3.79 (m, 1H), 5.59 (dd, 1H, J1 = 4.2 Hz,
J2 = 11.5 Hz, pyrazole 5-H), 6.99 (d, 1H, J = 2.3 Hz, 60-H), 7.57 (d,
1H, J = 2.3 Hz, 40-H); 13C NMR (75 MHz, CDCl3) d (ppm): 16.2
(CH3), 34.2, 44.1 (4-C), 51.5, 54.6 (5-C), 58.8 (CH2C@O), 67.4 (CH2-
OH), 113.0 (30-C), 114.1 (50-C), 128.7 (60-C), 130.6 (10-C), 134.7
(40-C), 150.8 (3-C), 158.3 (20-C), 168.0 (C@O). TOF-HRMS: m/z
[M+H]+ calcd for C17H22Br2N3O3: 474.0022; found: 474.0019.
4.3.4. Compound 12a
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
pyrazol-1-yl)ethanone-2-piperidine, white powder, yield, 66%; mp
186–189 °C; 1H (300 MHz, CDCl3) d (ppm): 1.43–1.65 (m, 6H), 2.15
(s, 3H, CH3), 2.51–2.64 (m, 4H), 2.88 (dd, 1H, J1 = 3.0 Hz,
J2 = 18.8 Hz, pyrazole 4-Ha), 3.34 (dd, 1H, J1 = 11.5 Hz,
J2 = 18.8 Hz, pyrazole 4-Hb), 3.51 (d, 1H, J = 17.0 Hz, Ha), 3.58 (d,
1H, J = 17.0 Hz, Hb), 5.58 (dd, 1H, J1 = 3.2 Hz, J2 = 11.2 Hz, pyrazole
5-H), 6.99 (s, 1H, 60-H), 7.57 (s, 1H, 40-H); 13C NMR (75 MHz, CDCl3)
d (ppm): 16.2 (CH3), 24.1, 25.9, 43.9 (4-C), 54.4 (5-C), 55.1, 59.8
(CH2C@O), 112.9 (30-C), 114.3 (50-C), 128.6 (60-C), 130.6 (10-C),
134.8 (40-C), 151.1 (3-C), 158.1 (20-C), 168.5 (C@O). TOF-HRMS:
m/z [M+H]+ calcd for C17H22Br2N3O2: 458.0073; found: 458.0073.
4.3.9. Compound 12f
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
pyrazol-1-yl)ethanone-2-(4-hydroxymethyl)piperidine, colorless
4.3.5. Compound 12b
crystals, yield, 65%; mp 215–217 °C; IR (KBr,
m
/cmꢁ1): 3416 (
ArC@C), 866 ( @CAH);
mOAH),
1-(5-(3,5-Dibromo-2-hydroxyphenyl)-3-methyl-4,5-dihydro-
2929 ( asCH2), 2850 ( sCH2), 1635 ( C@O), 1461 (
m
m
m
m
c
pyrazol-1-yl)ethanone-2-piperidin-4-one, Oil, yield, 31%; 1H
1H (300 MHz, DMSO-d6) d (ppm): 1.15–1.34 (m, 3H), 1.57–1.61 (m,
2H), 1.98 (s, 3H, CH3), 2.02–2.16 (m, 2H), 2.58 (dd, 1H, J1 = 4.7 Hz,
J2 = 18.5 Hz, pyrazole 4-Ha), 2.84–2.93 (m, 2H), 3.22 (d, 2H,
J = 6.2 Hz, CH2OH), 3.31 (d, 1H, J = 15.5 Hz, Ha), 3.40 (dd, 1H,
J1 = 11.7 Hz, J2 = 18.6 Hz, pyrazole 4-Hb), 3.62 (d, 1H, J = 15.5 Hz,
Hb), 5.49 (dd, 1H, J1 = 4.7 Hz, J2 = 11.6 Hz, pyrazole 5-H), 6.90 (d,
1H, J = 2.3 Hz, 60-H), 7.62 (d, 1H, J = 2.4 Hz, 40-H); 13C NMR
(75 MHz, DMSO-d6) d (ppm): 15.5 (CH3), 28.5 (CH2), 28.6 (CH2),
(300 MHz, CDCl3)
d (ppm): 2.16 (s, 3H, CH3), 2.52 (d, 4H,
J = 6.0 Hz, CH2CO), 2.84–3.02 (m, 5H, overlap, pyrazole 4-Ha, 2ꢃ
CH2), 3.37 (ddd, 1H, J1 = 0.9 Hz, J2 = 11.6 Hz, J3 = 15.2 Hz, pyrazole
4-Hb), 3.65 (d, 1H, J = 16.8 Hz, Ha), 3.75 (d, 1H, J = 16.8 Hz, Hb),
5.61 (dd, 1H, J1 = 4.2 Hz, J2 = 11.5 Hz, pyrazole 5-H), 7.01 (d, 1H,
J = 2.3 Hz, 60-H), 7.58 (d, 1H, J = 2.3 Hz, 40-H); 13C NMR (75 MHz,
CDCl3) d (ppm): 16.2 (CH3), 41.4, 44.1 (4-C), 53.7, 54.5 (5-C), 58.2