Journal of Medicinal Chemistry
Article
NMR (DMSO-d6) δ 1.39 (t, 3H, CH2CH3, J = 7.2 Hz), 2.12 (s, 3H,
COCH3), 2.43 (s, 3H, Ph-CH3), 4.44 (q, 2H, CH2, J = 7.2 Hz), 7.49−
7.57 (m, 2H, Ar), 7.80−7.86 (m, 3H, Ar), 8.38 (d, 1H, Ar, J = 9.2 Hz),
8.65 (s, 1H, Ar), 10.32 (exch br s, 1H, NH).
chlorosulfonic acid was slowly added. The mixture was stirred at 80−
90 °C for 4−5 h. After cooling, ice-cold water (15 mL) and 33%
aqueous ammonia (5 mL) were added, resulting in a precipitate, which
was recovered by suction. Yield = 10%; mp = 257 °C dec (EtOH). 1H
NMR (DMSO-d6) δ 6.50 (exch br s, 1H, OH), 7.24 (t, 1H, Ar, J = 8.4
Hz), 7.73 (d, 1H, Ar, J = 6.8 Hz), 8.10 (exch br s, 2h, NH2), 8.45 (d,
1H, Ar, J = 7.6 Hz).
1-(3-Methylbenzoyl)-5-propionylamino-1H-indazole-3-carboxylic
1
Acid Ethyl Ester (20b). Yield = 95%; mp = 116−119 °C (EtOH). H
NMR (CDCl3) δ 1.32 (t, 3H, COCH2CH3, J = 7.2 Hz), 1.51 (t, 3H,
OCH2CH3, J = 7.2 Hz), 2.47 (s, 3H, Ph-CH3), 2.51 (q, 2H,
COCH2CH3, J = 7.2 Hz), 4.55 (q, 2H, OCH2CH3, J = 7.2 Hz), 7.42−
7.48 (m, 3H, Ar), 7.83 (d, 1H, Ar, J = 9.2 Hz), 7.95 (s, 2H, Ar), 8.46
(exch br s, 1H, NH), 8.51 (d, 1H, Ar, J = 9.2 Hz).
7-Sulfamoyl-1H-indazole-3-carboxylic Acid Ethyl Ester (23).
A mixture of 22 (0.62 mmol) and a catalytic amount of conc H2SO4 in
anhydrous ethanol (7.5 mL) was heated at 100 °C for 5 h. After
cooling, ice-cold water was added and the precipitate was recovered by
suction and recrystallized from ethanol. Yield = 48%; mp = 244 °C dec
5-Butyrylamino-1-(3-methylbenzoyl)-1H-indazole-3-carboxylic
1
1
Acid Ethyl Ester (20c). Yield = 72%; mp = 122−125 °C (EtOH). H
(EtOH). H NMR (DMSO-d6) δ 1.40 (t, 3H, CH3, J = 7.2 Hz), 4.43
NMR (CDCl3) δ 1.07 (t, 3H, CH2CH2CH3, J = 7.2 Hz), 1.51 (t, 3H,
OCH2CH3, J = 7.2 Hz), 1.84 (m, 2H, CH2CH2CH3, J = 7.2 Hz), 2.43
(t, 2H, COCH2, J = 7.2 Hz), 2.47 (s, 3H, Ph-CH3), 4.54 (q, 2H,
OCH2CH3, J = 7.2 Hz), 7.37 (s, 1H, Ar), 7.42−7.48 (m, 2H, Ar), 7.82
(d, 1H, Ar, J = 8.8 Hz), 7.96 (s, 2H, Ar), 8.46 (exch br s, 1H, NH),
8.51 (d, 1H, Ar, J = 8.8 Hz).
(q, 2H, CH2, J = 7.2 Hz), 7.50 (t, 1H, Ar, J = 8.0 Hz), 7.71 (exch br s,
2H, SO2NH2), 7.90 (d, 1H, Ar, J = 7.2 Hz), 8.34 (d, 1H, Ar, J = 8.0
Hz), 13.91 (exch br s, 1H, NH). 13C NMR (DMSO-d6) δ 14.4 (q),
60.9 (t), 122.7 (d), 124.0 (s), 125.7 (2d), 127.5 (s), 135.2 (s), 136.0
(s), 162.0 (s).
General Procedures for 24a,b. Compounds 24a,b were obtained
starting from 23 following the general procedure described for 5a−c,e.
After dilution with water and neutralization with 0.5 NaOH, the
mixture was extracted with ethyl acetate (3 × 15 mL). Evaporation of
the solvent resulted in the final compounds, which were purified by
flash chromatography using as eluents cyclohexane/ethyl acetate 2:1
for 24a and 1:2 for 24b.
5-Benzoylamino-1-(3-methylbenzoyl)-1H-indazole-3-carboxylic
1
Acid Ethyl Ester (20d). Yield = 78%; mp = 196−198 °C (EtOH). H
NMR (CDCl3) δ 1.52 (t, 3H, CH2CH3, J = 7.2 Hz), 2.48 (s, 3H, Ph-
CH3), 4.55 (q, 2H, CH2, J = 7.2 Hz), 7.42−7.47 (m, 2H, Ar), 7.55−
7.60 (m, 3H, Ar), 7.94−8.00 (m, 5H, Ar), 8.04 (exch br s, 1H, NH),
8.58 (d, 2H, Ar, J = 9.2).
5-(Cyclohexanecarbonylamino)-1-(3-methylbenzoyl)-1H-inda-
zole-3-carboxylic Acid Ethyl Ester (20e). Yield = 64%; mp = 189−191
°C (EtOH). 1H NMR (CDCl3) δ 1.29−1.39 (m, 3H, cC6H11), 1.51 (t,
3H, CH2CH3, J = 7.2 Hz), 1.63 (t, 2H, cC6H11, J = 5.6 Hz), 1.70−1.80
(m, 1H, cC6H11), 1.85−1.95 (m, 2H, cC6H11), 2.00−2.2.05 (m, 2H,
cC6H11), 2.28−2.38 (m, 1H, cC6H11), 2.48 (s, 3H, Ph-CH3), 4.55 (q,
2H, CH2CH3, J = 7.2 Hz), 7.32−7.40 (m, 1H, Ar), 7.40−7.46 (m, 2H,
Ar), 7.84 (d, 1H, Ar, J = 9.6 Hz), 7.96 (s, 2H, Ar), 8.45 (exch br s, 1H,
NH), 8.51 (d, 1H, Ar, J = 8.4 Hz).
5-(Cyclopropanecarbonylamino)-1-(3-methylbenzoyl)-1H-inda-
zole-3-carboxylic Acid Ethyl Ester (20f). Yield = 82%; mp = 204−205
°C (EtOH). 1H NMR (CDCl3) δ 0.92 (m, 2H, cC3H11), 1.17 (m, 2H,
cC3H11), 1.50 (t, 3H, CH2CH3, J = 7.2 Hz), 1.58 (m, 1H, cC3H11),
2.47 (s, 3H, Ph-CH3), 4.53 (q, 2H, CH2CH3, J = 7.2 Hz), 7.42−7.47
(m, 2H, Ar), 7.60 (exch br s, 1H, NH), 7.,85 (d, 1H, Ar), 7.95 (s, 2H,
Ar), 8.44 (s, 1H, Ar), 8.50 (d, 1H, Ar, J = 9.2 Hz).
5-(Cyclopentanecarbonylamino)-1-(3-methylbenzoyl)-1H-
indazole-3-carboxylic Acid Ethyl Ester (20g). Compound 20g was
obtained starting from 17 following the same procedure described for
14c,d,g,h. After dilution with cold water, the mixture was neutralized
with 0.5 N NaOH and extracted with ethyl acetate (3 × 15 mL).
Evaporation of the solvent resulted in a residue, which was purified by
crystallization from ethanol. Yield = 20%; mp = 157−160 °C (EtOH).
1H NMR (CDCl3) δ 1.50 (t, 3H, CH2CH3, J = 7.2 Hz), 1.65−1.70 (m,
1-Benzoyl-7-sulfamoyl-1H-indazole-3-carboxylic Acid Ethyl Ester
1
(24a). Yield = 29%; mp = 139−140 °C (EtOH). H NMR (DMSO-
d6) δ 1.38−1.42 (m, 3H, CH3), 4.45−4.60 (m, 2H, CH2), 7.61−7.70
(m, 2H, Ar), 7.72−7.80 (m, 1H, Ar), 7.90−8.05 (m, 1H, Ar), 8.15 (d,
2H, Ar, J = 6.8 Hz), 8.45 (d, 1H, Ar, J = 7.2 Hz), 8.52 (d, 1H, Ar, J =
7.2 Hz).
1-(3-Methylbenzoyl)-7-sulfamoyl-1H-indazole-3-carboxylic Acid
Ethyl Ester (24b). Yield = 17%; mp = 176−178 °C (EtOH). 1H
NMR (CDCl3) δ 1.50−1.60 (m, 3H, CH3), 2.51 (s, 3H, Ph-CH3),
4.58−4.65 (m, 2H, CH2), 7.52 (s, 2H, Ar), 7.80−7.90 (m, 1H, Ar),
8.17 (s, 1H, Ar), 8.22−8.27 (m, 2H, Ar), 8.51 (d, 1H, Ar).
General Procedures for 26a,b and 26f. Compounds 26a,b and
26f were obtained starting from 25a,b32 following the same general
procedure described for 5a−c,e. For compound 26a, after dilution
with water and neutralization with NaOH, the crude precipitate was
recovered by suction and crystallized by ethanol. The suspension of
26b and 26f was extracted with CH2Cl2 (3 × 15 mL), and evaporation
of the solvent resulted in the final compounds, which were
recrystallized from ethanol.
1-Benzoyl-5-bromo-1H-indazole-3-carboxylic Acid Methyl Ester
(26a). Yield = 82%; mp = 143−146 °C (EtOH). 1H NMR (CDCl3) δ
4.08 (s, 3H, CH3), 7.55−7.60 (m, 2H, Ar), 7.65−7.71 (m, 1H, Ar),
7.77 (d, 1H, Ar, J = 7.2 Hz), 8.12−8.17 (m, 2H, Ar), 8.47 (d, 1H, Ar, J
= 6.4 Hz), 8.49 (s, 1H, Ar).
2H, cC5H9), 1.85−1.88 (m, 2H, cC5H9), 1.95−2.01 (m, 4H, cC5H9),
2.47 (s, 3H, Ph-CH3), 2.73−2.80 (m, 1H, cC5H9), 4.55 (q, 2H,
CH2CH3, J = 7.2 Hz), 7.38−7.47 (m, 3H, 1H NH e 2H Ar), 7.85 (d,
1H, Ar, J = 9.2 Hz), 7.95 (s, 2H, Ar), 8.46 (s, 1H, Ar), 8.50 (d, 1H, Ar,
J = 9.2 Hz).
5-Bromo-1-(3-methylbenzoyl)-1H-indazole-3-carboxylic Acid
1
Methyl Ester (26b). Yield = 58%; mp = 121−123 °C (EtOH). H
NMR (CDCl3) δ 2.48 (s, 3H, Ph-CH3), 4.07 (s, 3H, OCH3), 7.43−
7.49 (m, 2H, Ar), 7.77 (d, 1H, Ar, J = 9.2 Hz), 7.93 (d, 2H, Ar, J = 7.2
Hz), 8.46 (d, 1H, Ar, J = 9.2 Hz), 8.48 (s, 1H, Ar).
1-(3-Methylbenzoyl)-5-phenylamino-1H-indazole-3-carbox-
ylic Acid Ethyl Ester (20h). A mixture of activated powdered 4A
molecular sieves (500 mg), 0.30 mmol of 17, 5 mL of anhydrous
CH2Cl2, 0.60 mmol of phenylboronic acid, 0.45 mol of Cu(Ac)2, and
0.60 mol of Et3N was stirred for 24 h at room temperature. Molecular
sieves were removed by suction filtration, and the organic layer was
washed with 33% aqueous ammonia (3 × 5 mL). Evaporation of the
solvent resulted in the final compound, which was purified by flash
chromatography using toluene/ethyl acetate 7:3 as eluent. Yield =
5-Bromo-1-(3-methylbenzoyl)-1H-indazole-3-carboxylic Acid
Ethyl Ester (26f). Yield = 50%; mp = 116−117 °C (EtOH). 1H
NMR (CDCl3) δ 1.50 (t, 3H, CH2CH3, J = 7.2 Hz), 2.48 (s, 3H, Ph-
CH3), 4.55 (q, 2H, CH2, J = 7.2 Hz), 7.43−7.49 (m, 2H, Ar), 7.76 (d,
1H, Ar, J = 8.0 Hz), 7.95 (s, 2H, Ar), 8.45 (s, 2H, Ar).
General Procedures for 26c,d, and 26g,h. These compounds
were obtained starting from compounds 25a32 or 25b32 following the
general procedure described for 14c,d,g,h. For 26d and 26h, the
precipitate was recovered by suction and recrystallized from ethanol;
for compounds 26c and 26g, after dilution and neutralization with 0.5
N NaOH, the suspension was extracted with CH2Cl2 (3 × 15 mL),
and evaporation of the solvent resulted in the final compounds, which
were purified by crystallization from ethanol.
1
71%; mp = 123−125 °C (EtOH). H NMR (CDCl3) δ 1.45 (t, 3H,
CH2CH3, J = 7.2 Hz), 2.46 (s, 3H, Ph-CH3), 4.50 (q, 2H, CH2, J = 7.2
Hz), 7.03 (t, 1H, Ar, J = 7.2 Hz), 7.19 (d, 2H, Ar, J = 8.0 Hz), 7.34 (t,
2H, Ar, J = 8.0 Hz), 7.39−7.44 (m, 3H, Ar), 7.94 (s, 3H, Ar), 8.44 (d,
1H, Ar, J = 9.2 Hz), 8.95 (exch br s, 1H, NH).
5-Bromo-1-(3-methoxybenzoyl)-1H-indazole-3-carboxylic Acid
1
7-Sulfamoyl-1H-indazole-3-carboxylic Acid (22). To 0.43
mmol of 21 (commercially available) cooled at 0 °C, 1 mL of
Methyl Ester (26c). Yield = 26%; mp = 105−108 °C (EtOH). H
NMR (CDCl3) δ 3.91 (s, 3H, OCH3), 4.07 (s, 3H, COOCH3), 7.21
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dx.doi.org/10.1021/jm400742j | J. Med. Chem. 2013, 56, 6259−6272