5230 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
Nugiel et al.
d6): δ 13.6 (bs, 1 H), 11.3 (s, 1 H), 8.35 (d, J ) 8.4 Hz, 1 H),
8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H), 7.2 (d, J ) 7.0
Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 3.8 (s, 3 H), 3.2 (bs, 2 H), 2.8
(bs, 8 H). HRMS m/e calcd for C23H23N4O3S (M + H), 435.1491;
found, 435.1477. Anal. (C23H22N4O3S) C, H, N.
reaction mixture was diluted with water (120 mL) and
extracted with ethyl acetate (2 × 100 mL). The organic layer
was separated, washed with brine (50 mL), and dried (Na2-
SO4), and the solvent was removed at reduced pressure to give
a gummy orange residue. Cold ethyl ether (100 mL) was added
to this residue to give a precipitate. The precipitate was
collected and washed with ethyl ether (2 × 10 mL) to give
desired product as a yellow solid (1.65 g, 78%); mp 256-58
°C. 1H NMR (DMSO-d6): δ 10.8 (s, 1H), 8.1 (d, J ) 8.0 Hz,
1H), 7.6 (d, J ) 2.9 Hz, 2H), 7.5 (m, 3H), 7.3 (m, 3H), 7.1 (t,
1H), 6.9 (d, J ) 10.8 Hz, 2H), 3.8 (s, 3H). HRMS calcd for
3-(4-Meth oxyph en yl)-5-(m or ph olin oacetam ido)in den o-
[1,2-c]p yr a zol-4-on e (6h ). mp 295 °C. NMR (DMSO-d6): δ
13.6 (bs, 1 H), 11.3 (s, 1 H), 8.35 (d, J ) 8.4 Hz, 1 H), 8.1 (d,
J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H), 7.2 (d, J ) 7.0 Hz, 1
H), 7.1 (d, J ) 8.8 Hz, 2 H), 3.8 (s, 3 H), 3.7 (m, 4 H), 3.2 (s, 2
H), 2.6 (m, 4 H). HRMS m/e calcd for C23H23N4O4 (M + H),
419.1719; found, 419.1709. Anal. (C23H22N4O4) C, H, N.
3-(4-Meth oxyp h en yl)-5-(4-m eth ylp ip er a zin yla ceta m i-
d o)in d en o[1,2-c]p yr a zol-4-on e (6i). mp >300 °C. NMR
(DMSO-d6): δ 13.6 (bs, 1 H), 11.3 (s, 1 H), 8.35 (d, J ) 8.4 Hz,
1 H), 8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H), 7.2 (d,
J ) 7.0 Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 3.8 (s, 3 H), 3.3 (bs,
4 H), 3.1 (s, 2 H), 2.8 (bs, 4 H), 2.2 (s, 3 H). HRMS m/e calcd
for C24H26N5O3 (M + H), 432.2036; found, 432.2030. Anal.
(C24H25N5O3) C, H, N.
3-(4-Met h oxyp h en yl)-5-(4-a m in om et h ylp ip er id in yl-
a ceta m id o)in d en o[1,2-c]p yr a zol-4-on e (6j). mp >300 °C.
NMR (DMSO-d6): δ 13.6 (bs, 1 H), 11.3 (s, 1 H), 8.35 (d, J )
8.4 Hz, 1 H), 8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H),
7.2 (d, J ) 7.0 Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 3.8 (s, 3 H),
3.2 (bs, 2 H), 2.9(bs, 2 H), 2.5 (d, J ) 8.0 Hz, 2 H), 2.2 (t, J )
8.0 Hz, 2 H), 1.6 (m, 5 H). HRMS m/e calcd for C25H28N5O3 (M
+ H), 446.2192; found, 446.2169. Anal. (C25H27N5O3) C, H, N.
3-(4-Meth oxyph en yl)-5-(4-am idopiper idin ylacetam ido)-
in den o[1,2-c]pyr azol-4-on e (6k). mp >300 °C. NMR (DMSO-
d6): δ 13.6 (bs, 1 H), 11.7 (s, 1 H), 8.35 (d, J ) 8.4 Hz, 1 H),
8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H), 7.2 (d, J ) 7.0
Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 6.8 (bs, 2 H), 3.8 (s, 3 H), 3.2
(s, 2 H), 2.9 (m, 2 H), 2.2 (m, 2 H), 1.7 (m, 2 H). HRMS m/e
calcd for C25H26N5O4 (M + H), 460.1984; found, 460.1997. Anal.
(C25H25N5O4) C, H, N.
3-(4-Meth oxyp h en yl)-5-(4-h yd r oxym eth ylp ip er id in yl-
a ceta m id o)in d en o[1,2-c]p yr a zol-4-on e (6m ). mp >300 °C.
NMR (DMSO-d6): δ 13.6 (bs, 1 H), 11.7 (s, 1 H), 8.35 (d, J )
8.4 Hz, 1 H), 8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H),
7.2 (d, J ) 7.0 Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 4.5 (t, J ) 5.5
Hz, 1 H), 3.8 (s, 3 H), 3.4 (m, 2 H), 3.2 (s, 2 H), 2.9 (m, 2 H),
2.2 (m, 2 H), 1.6 (m, 5 H). HRMS m/e calcd for C25H27N4O4 (M
+ H), 447.2032; found, 447.2012. Anal. (C25H26N4O4) C, H, N.
3-(4-Met h oxyp h en yl)-5-(4-a m id op ip er izin yla cet a m i-
d o)in d en o[1,2-c]p yr a zol-4-on e (6n ). mp >300 °C. NMR
(DMSO-d6): δ 13.6 (bs, 1 H), 11.4 (s, 1 H), 8.35 (d, J ) 8.4 Hz,
1 H), 8.1 (d, J ) 8.8 Hz, 2 H), 7.5 (t, J ) 7.7 Hz 1 H), 7.2 (d,
J ) 7.0 Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 6.0 (bs, 2 H), 3.8 (s,
3 H), 3.4 (m, 2 H), 3.2 (s, 2 H). HRMS m/e calcd for C24H25N6O4
(M + H), 461.1937; found, 461.1945. Anal. (C24H24N6O4) C, H,
N.
3-(4-Me t h oxyp h e n yl)-5-(4-ca r b a m id oylp ip e r izin yl-
a ceta m id o)in d en o[1,2-c]p yr a zol-4-on e (6p ). mp >300 °C.
NMR (DMSO-d6): δ 13.6 (bs, 1 H), 11.5 (s, 1 H), 8.35 (d, J )
8.4 Hz, 1 H), 8.1 (d, J ) 8.8 Hz, 2 H), 7.6 (bs, 3 H), 7.2 (d, J )
7.0 Hz, 1 H), 7.1 (d, J ) 8.8 Hz, 2 H), 3.8 (s, 3 H), 3.6 (bs, 4 H),
3.2 (s, 2 H), 2.6 (bs, 4 H). HRMS m/e calcd for C24H26N7O3 (M
+ H), 460.2097; found, 460.2089. Anal. (C24H25N7O3) C, H, N.
4-Am in o-2-(4-m eth oxy-ben zoyl)in dan -1,3-dion e (8). Com-
pound 7 (2.0 g, 5.93 mmol) was dissolved in 20% HCl in
methanol (50 mL). This solution was stirred at reflux for a
period of 3 h. It was then allowed to cool to room temperature
and stirred overnight. The product was filtered off, washed
with ethanol (20 mL), and air-dried to give the product as a
yellow solid (1.5 g, 86%); mp 268-269 °C. 1H NMR (DMSO-
d6): δ 8.2 (d, J ) 8.8 Hz, 2H), 7.5 (t, 1H), 7.1 (d, J ) 8.7 Hz,
2H), 7.0 (m, 2H), 3.9 (s, 1H). HRMS calcd for C17H14N1O4 (M
+ H+), 296.0923; found, 296.0899.
C
24H18N1O6 (M + H+), 416.1134; found, 416.1105.
3-(4-Meth oxyph en yl)-5-(bu tylcar bam oyl)am in oin den o-
[1,2-c]p yr a zol-4-on e (11h ). Carbamate 9 (0.03 g, 0.072 mmol)
in anhydrous DMSO (2 mL) was treated with butylamine (0.01
g, 0.082 mmol) and 4-(dimethylamino)pyridine (0.005 g, 0.04
mmol) and heated to 80 °C for 3 h. The solvent was removed
under reduced pressure, and the residue was triturated with
ethanol to give a dark solid. The solid was collected and
washed with ethanol (5 mL) to give urea 10 (0.03 g, 100%).
The tricarbonyl urea intermediate 10 (0.03 g, 0.078 mmol) was
treated with hydrazine hydrate (0.1 mL, 3.21 mmol) and
p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) in
refluxing ethanol (4 mL) for a period of 3 h. The reaction
mixture was cooled to room temperature, and the solid was
collected, washed with cold ethanol (2 × 2 mL), and air-dried
to give the product as a yellowish solid (0.01 g, 30.6%); mp
1
255-256 °C. H NMR (DMSO-d6): δ 9.41 (s, 1 H),_8.16 (d, J
) 8.0 Hz, 2 H),7.4 (d, J ) 6.0 Hz, 1 H), 7.06 (d, J ) 9.2 Hz, 2
H), 6.95 (d, J ) 7.1 Hz, 1 H), 3.79 (s, 3 H), 2.99 (m, 2 H), 1.43
(m, 2 H), 0.86 (m, 3 H). HRMS calcd for C21H21N4O3 (M + H+),
377.1614; found, 377.1588. Anal. (C21H20N4O3) C, H, N.
3-(4-Meth oxyp h en yl)-5-(ca r ba m oyl)a m in oin d en o[1,2-
c]p yr a zol-4-on e (11a ). mp 267-269 °C. 1H NMR (DMSO-
d6): δ 9.35 (s, 1 H), 8.2 (m, 3 H), 7.4 (m, 1 H), 7.1 (d, J ) 8.8
Hz, 2 H), 7.0 (d, J ) 7 Hz, 1 H), 3.8 (s, 3 H). HRMS calcd for
C
18H145N4O3 (M - H-), 335.1144; found, 335.1162. Anal.
(C18H14N4O3) C, H, N.
3-(4-Meth oxyp h en yl)-5-(d ieth ylca r ba m oyl)a m in oin d e-
n o[1,2-c]p yr a zol-4-on e (11b). mp 261-262 °C. 1H NMR
(DMSO-d6): δ 8.2 (d, J ) 8.5 Hz, 1 H),_8.15 (d, J ) 9.0 Hz, 1
H), 7.4 (d, J ) 8.1 Hz, 2 H), 7.1 (m, 3 H), 3.8 (s, 3 H), 2.9 (m,
4 H), 1.1 (m, 6 H). HRMS calcd for C22H23N4O3 (M + H+),
391.1770; found, 391.1764. Anal. (C22H22N4O3) C, H, N.
3-(4-Meth oxyph en yl)-5-(ben zylcar bam oyl)am in oin den o-
[1,2-c]pyr azol-4-on e (11c). mp 279-280 °C. 1H NMR (DMSO-
d6): δ 9.5 (s, 1 H), 8.2 (m, 3 H), 7.3 (m, 6 H), 7.1 (m, 3 H), 4.3
(d, J ) 5.9 Hz, 2 H), 3.8 (s, 3 H). HRMS calcd for C25H21N4O3
(M + H+), 425.1614; found, 425.1639. Anal. (C25H20N4O3) C,
H, N.
3-(4-Meth oxyp h en yl)-5-(1-ben zyl-1-m eth ylca r ba m oyl)-
a m in oin d en o[1,2-c]p yr a zol-4-on e (11d ). mp 259-260 °C.
1H NMR (DMSO-d6): δ 9.7 (s, 1 H), 8.3 (d, J ) 8.4 Hz, 1 H),
8.1 (d, J ) 8.8 Hz, 2 H), 7.4 (m, 1 H), 7.3 (m, 5 H), 7.1 (m, 3
H), 4.6 (s, 2 H), 3.8 (s, 3 H), 3.0 (s, 3 H). HRMS calcd for
C
26H23N4O3 (M + H+), 439.1770; found, 439.1762. Anal.
(C26H22N4O3) C, H, N.
3-(4-Meth oxyp h en yl)-5-(4-p icolylca r ba m oyl)a m in oin -
d en o[1,2-c]p yr a zol-4-on e (11e). mp >300 °C. 1H NMR
(DMSO-d6): δ 13.6 (s, 1 H), 9.6 (s, 1 H), 8.5 (d, J ) 5.9 Hz, 2
H), 8.3 (m, 1 H), 8.2 (m, 3 H), 7.4 (m, 1 H), 7.3 (d, J ) 5.5 Hz,
2 H), 7.10 (m, 3 H), 4.3 (d, J ) 5.9 Hz, 2 H), 3.8 (s, 3 H). HRMS
calcd for C24H20N5O3 (M + H+), 426.1566; found, 426.1572.
Anal. (C24H19N5O3) C, H, N.
3-(4-Meth oxyp h en yl)-5-(4-m eth oxyben zylca r ba m oyl)-
a m in oin d en o[1,2-c]p yr a zol-4-on e (11f). mp 259-262 °C. 1H
NMR (DMSO-d6): δ 9.4 (s, 1 H), 8.2 (m, 3 H), 7.4 (m, 1 H), 7.2
(m, 2 H), 7.1 (m, 3 H), 6.9 (m, 3 H), 4.2 (d, J ) 5.1 Hz, 2 H),
3.8 (s, 3 H), 3.7 (s, 3 H). HRMS calcd for C26H23N4O4 (M +
H+), 455.1719; found, 455.1719. Anal. (C26H22N4O4) C, H, N.
3-(4-Meth oxyp h en yl)-5-(p h en ylca r ba m oyl)a m in oin d e-
n o[1,2-c]p yr a zol-4-on e (11g). mp >300 °C. 1H NMR (DMSO-
d6): δ 10.0 (s, 1 H), 9.7 (s, 1 H), 8.2 (m, 3 H), 7.5 (d, J ) 7.7
Hz, 2 H), 7.4 (t, 1 H), 7.3 (t, 2 H), 7.1 (m, 3 H), 7.0 (t, 1H), 3.8
[2-(4-Met h oxyb en zoyl)-1,3-d ioxo-in d a n -4-yl]ca r b a m -
ic Acid P h en yl Ester (9). Aniline 8 (1.5 g, 5.08 mmol) was
dissolved in acetone (40 mL) and treated with sodium carbon-
ate (1.26 g, 15.24 mmol) and phenyl chloroformate (1.19 g, 7.62
mmol). The suspension was stirred at 50 °C for 3 h. The