Journal of Medicinal Chemistry
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NMR (DMSO-d6, 125 MHz): δ = 150.5, 134.5 × 2, 114.6, 110.9 × 2,
48.1, 19.5 × 2 ppm. MS (ESI): m/z 300.1 [M + H]+. CHN calculated
for C13H15Cl2N3O: C, 52.01; H, 5.04; N, 14.00. Found: C, 52.10; H,
5.19; N, 13.87.
13C NMR (DMSO-d6, 125 MHz): δ = 151.7, 129.8, 127.0, 124.3,
117.5, 107.5, 89.0, 52.6, 44.0, 27.9 ppm. MS (ESI): m/z 216.1 [M +
H]+. CHN calculated for C12H13N3O: C, 66.96; H, 6.09; N, 19.52.
Found: C, 66.85; H, 6.11; N, 19.44.
5-((tert-Butyl(3,5-dichlorophenyl)amino)methyl)-1H-pyra-
zol-3(2H)-one (18). The title compound was prepared according to
general procedures B, C, and E. 1H NMR (DMSO-d6, 500 MHz): δ =
6.68−6.67 (m, 3H), 5.22 (s, 1H), 4.25 (s, 2H), 4.17−4.15 (m, 1H),
1.13 (d, J = 7.0 Hz, 6H). 13C NMR (DMSO-d6, 125 MHz): δ = 151.4,
133.0 × 2, 127.4, 123.9, 55.7, 17.8 × 3 ppm. MS (ESI): m/z 314.1 [M
+ H]+. CHN calculated for C14H17Cl2N3O: C, 53.52; H, 5.45; N,
13.37. Found: C, 53.45; H, 5.45; N, 13.40.
5-((Cyclopropyl(3,5-dichlorophenyl)amino)methyl)-1H-pyra-
zol-3(2H)-one (19). The title compound was prepared according to
general procedures B, C, and E. 1H NMR (DMSO-d6, 500 MHz): δ =
9.42 (br s, 1H), 6.86 (s, 2H), 6.74 (s, 1H), 5.10 (s, 1H), 4.37 (s, 2H),
2.43 (s, 1H), 0.83−0.82 (m, 2H), 0.55 (s, 2H). 13C NMR (DMSO-d6,
125 MHz): δ = 151.3, 134.2 × 2, 116.1, 112.3 × 2, 88.4, 46.7, 32.2, 9.1
× 2 ppm. MS (ESI): m/z 298.0 [M + H]+. CHN calculated for
C13H13Cl2N3O: C, 52.37; H, 4.39; N, 14.09. Found: C, 52.33; H, 4.37;
N, 14.89.
5-((Benzyl(3,5-dichlorophenyl)amino)methyl)-1H-pyrazol-
3(2H)-one (20). The title compound was prepared according to
general procedures B, C, and E. 1H NMR (DMSO-d6, 500 MHz): δ =
7.34 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz,
2H), 6.70 (s, 1H), 6.68 (s, 2H), 5.32 (s, 1H), 4.66 (s, 2H), 4.52 (s,
2H). 13C NMR (DMSO-d6, 125 MHz): δ = 150.0, 137.8, 134.4 × 2,
128.6 × 2, 127.0, 126.4 × 2, 115.0, 110.8 × 2, 53.8 ppm. MS (ESI): m/
z 298.0 [M + H]+. CHN calculated for C17H15Cl2N3O: C, 58.63; H,
4.34; N, 12.07. Found: C, 59.01; H, 4.63; N, 11.83.
5-(((3,5-Dichlorophenyl)(phenyl)amino)methyl)-1H-pyrazol-
3(2H)-one (21). The title compound was prepared according to
general procedures B, C,33 and E. 1H NMR (DMSO-d6, 500 MHz): δ
= 11.59 (br s, 1H), 9.65 (br s, 1H), 7.43 (t, J = 7.0 Hz, 2H), 7.28−7.22
(m, 3H), 6.88 (s, 1H), 6.72 (s, 2H), 5.24 (s, 1H), 4.77 (s, 2H). 13C
NMR (DMSO-d6, 125 MHz): δ = 150.0, 145.6, 134.4 × 2, 130.0 × 2,
125.8 × 2, 125.6, 117.2, 113.8 × 2 ppm. MS (ESI): m/z 334.0 [M +
H]+. CHN calculated for C16H13Cl2N3O: C, 57.50; H, 3.92; N, 12.57.
Found: C, 57.70; H, 4.27; N, 12.94.
5-((3,4-Dihydroquinolin-1(2H)-yl)methyl)-1H-pyrazol-3(2H)-
one (26). The title compound was prepared according to general
procedures D and E. 1H NMR (DMSO-d6, 500 MHz): δ = 6.91 (t, J =
7.0 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.47 (t,
J = 7.5 Hz, 1H), 5.26 (s, 1H), 4.28 (s, 2H), 3.28 (t, J = 5.5 Hz, 2H),
2.66 (t, J = 5.5 Hz, 2H), 1.87 (p, J = 6.0 Hz, 2H). 13C NMR (DMSO-
d6, 125 MHz): δ = 144.9, 128.8, 126.7, 122.2, 115.8, 111.2, 88.4, 49.1,
46.5, 39.0, 27.5, 21.8 ppm. MS (ESI): m/z 216.1 [M + H]+. CHN
calculated for C13H15N3O: C, 68.10; H, 6.59; N, 18.33. Found: C,
68.02; H, 6.60; N, 18.29.
5-(3,5-Dichlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
c]pyridin-3(2H)-one (27). The title compound was prepared
according to the literature procedure34 and general procedure E. H
1
NMR (DMSO-d6, 500 MHz): δ = 6.95 (s, 2H), 6.82 (d, J = 1.5 Hz,
1H), 4.06 (s, 2H), 3.59 (t, J = 6.0 Hz, 1H), 2.63−2.62 (m, 2H). 13C
NMR (DMSO-d6, 125 MHz): δ = 152.1, 134.7 × 2, 116.4, 112.9 × 2,
45.0, 43.0 ppm. MS (ESI): m/z 284.0 [M + H]+. CHN calculated for
C12H11Cl2N3O: C, 50.72; H, 3.90; N, 14.79. Found: C, 50.53; H, 4.03;
N, 14.83.
6-(3,5-Dichlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-
c]pyridin-3(2H)-one (28). The title compound was prepared
according to the literature procedure34 and general procedure E. H
1
NMR (DMSO-d6, 500 MHz): δ = 6.96 (d, J = 1.5 Hz, 2H), 6.83 (d, J
= 1.5 Hz, 1H), 4.26 (s, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.16 (d, J = 5.0
Hz, 1H), 2.41−2.39 (m, 2H). 13C NMR (DMSO-d6, 125 MHz): δ =
152.0, 134.7 × 2, 116.6, 113.1 × 2, 46.2, 29.5, 18.6 ppm. MS (ESI): m/
z 284.0 [M + H]+. CHN calculated for C12H11Cl2N3O: C, 50.72; H,
3.90; N, 14.79. Found: C, 50.51; H, 3.78; N, 14.57.
2-Benzyl-5-(((3,5-dichlorophenyl)(methyl)amino)methyl)-
1H-pyrazol-3(2H)-one (29). To a solution of ethyl 4-((3,5-
dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol)
and benzylhydrazine dihydrochloride (388 mg, 2.0 mmol) in EtOH (5
mL) was added anhydrous triethylamine (570 uL, 4.0 mmol). The
resulting solution was stirred at room temperature overnight. After
evaporation of the volatiles, the residue was purified on a silica gel
column, eluting with a mixture of MeOH and dichloromethane (1−2%
MeOH) to afford the product as a pale yellow solid (320 mg, 88%).
The solid was then recrystallized in dichloromethane/hexane to give
5-(((3,5-Dichlorophenyl)(prop-2-ynyl)amino)methyl)-1H-
pyrazol-3(2H)-one (22). The title compound was prepared
1
according to general procedures B, C, and E. H NMR (DMSO-d6,
500 MHz): δ = 6.82 (s, 3H), 5.35 (s, 1H), 4.41 (s, 2H), 4.21 (d, J =
2.0 Hz, 2H), 3.26 (d, J = 2.0 Hz, 1H). 13C NMR (DMSO-d6, 125
MHz): δ = 149.4, 134.4 × 2, 116.1, 111.8 × 2, 89.1, 79.6, 75.2 ppm.
MS (ESI): m/z 296.1 [M + H]+. CHN calculated for C13H11Cl2N3O:
C, 52.72; H, 3.74; N, 14.19. Found: C, 52.63; H, 3.91; N, 13.92.
5-(2-((3,5-Dichlorophenyl)(methyl)amino)ethyl)-1H-pyrazol-
3(2H)-one (23). The title compound was prepared according to
general procedures A, C, and E. 1H NMR (DMSO-d6, 500 MHz): δ =
11.35 (br s, 1H), 9.41 (br s, 1H), 6.69 (d, J = 1.5 Hz, 1H), 6.66 (d, J =
2.0 Hz, 2H), 5.33 (s, 1H), 3.54 (t, J = 7.5 Hz, 2H), 2.85 (s, 3H), 2.64
(t, J = 7.5 Hz, 2H). 13C NMR (DMSO-d6, 125 MHz): δ = 150.4, 134.7
× 2, 114.3, 110.0 × 2, 88.7, 51.1, 37.9 ppm. MS (ESI): m/z 286.0 [M
+ H]+. CHN calculated for C12H13Cl2N3O: C, 50.37; H, 4.58; N,
14.68. Found: C, 50.66; H, 4.80; N, 14.58.
5-(3-((3,5-Dichlorophenyl)(methyl)amino)propyl)-1H-pyra-
zol-3(2H)-one (24). The title compound was prepared according to
general procedures B, C, and E. 1H NMR (DMSO-d6, 500 MHz): δ =
11.27 (br s, 1H), 9.30 (br s, 1H), 6.66 (d, J = 1.5 Hz, 1H), 6.61 (d, J =
1.5 Hz, 2H), 5.26 (s, 1H), 3.32 (t, J = 7.5 Hz, 2H), 2.88 (s, 3H), 2.45
(t, J = 7.5 Hz, 2H), 1.76−1.73 (m, 2H). 13C NMR (DMSO-d6, 125
MHz): δ = 150.7, 134.7 × 2, 114.0, 109.8 × 2, 50.9, 38.0, 25.4 ppm.
MS (ESI): m/z 300.1 [M + H]+. CHN calculated for C13H15Cl2N3O:
C, 52.01; H, 5.04; N, 14.00. Found: C, 52.23; H, 5.14; N, 14.94.
5-(Indolin-1-ylmethyl)-1H-pyrazol-3(2H)-one (25). The title
compound was prepared according to general procedures D and E. 1H
NMR (DMSO-d6, 500 MHz): δ = 7.02 (d, J = 7.0 Hz, 1H), 6.98 (t, J =
7.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.58 (t, J = 7.5 Hz, 1H), 5.31 (s,
1H), 4.12 (s, 2H), 3.24 (t, J = 8.0 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H).
1
the product as a white solid. H NMR (DMSO-d6, 500 MHz): δ =
11.00 (br s, 1H), 7.28 (t, J = 7.0 Hz, 2H), 7.23 (d, J = 7.0 Hz, 1H),
7.11 (d, J = 7.0 Hz, 2H), 6.74 (d, J = 1.5 Hz, 2H), 6.69 (s, 1H), 5.12
(s, 1H), 5.01 (s, 2H), 4.33 (s, 2H), 2.98 (s, 2H). 13C NMR (DMSO-
d6, 125 MHz): δ = 152.7, 151.0, 146.8, 138.0, 134.4 × 2, 128.4 × 2,
127.1, 127.0 × 2, 114.4, 110.6 × 2, 84.6, 50.3, 49.2, 38.9 ppm. MS
(ESI): m/z 284.0 [M + H]+. CHN calculated for C18H17Cl2N3O: C,
59.68; H, 4.73; N, 11.60. Found: C, 59.79; H, 4.68; N, 11.48.
5-(((3,5-Dichlorophenyl)(methyl)amino)methyl)-2-methyl-
1H-pyrazol-3(2H)-one (30). To a solution of ethyl 4-((3,5-
dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol)
in EtOH (5 mL) was added anhydrous methylhydrazine (105 μL, 2.0
mmol). The resulting solution was stirred at room temperature
overnight. After evaporation of the volatiles, the residue was purified
on a silica gel column, eluting with a mixture of MeOH and
dichloromethane (2−10% MeOH) to afford the product as a pale
yellow solid (231 mg, 81%). The solid was then recrystallized in
dichloromethane/hexane to give the product as a white solid. 1H
NMR (DMSO-d6, 500 MHz): δ = 6.72 (d, J = 1.5 Hz, 2H), 6.68 (t, J =
1.5 Hz, 1H), 5.13 (s, 1H), 4.29 (s, 2H), 3.43 (s, 3H), 2.95 (s, 3H). 13C
NMR (DMSO-d6, 125 MHz): δ = 152.5, 151.0, 146.0, 134.4 × 2,
114.3, 110.4 × 2, 84.5, 49.9, 38.5, 33.0 ppm. MS (ESI): m/z 286.1 [M
+ H]+. CHN calculated for C12H13Cl2N3O: C, 50.37; H, 4.58; N,
14.68. Found: C, 50.60; H, 4.65; N, 14.62. FTIR (solid), ν 1591, 1552,
1495, 1445, 1309, 1272, 1094, 1012, 980, 950, 813, 756, 662 cm−1;
(DMSO), ν 1591, 1552, 1436, 1309, 1042 (bw), 950, 806, 756, 697,
663 cm−1.
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dx.doi.org/10.1021/jm400079a | J. Med. Chem. 2013, 56, 2665−2675