Journal of Medicinal Chemistry
Article
obtained after purification by TLC (dichloromethane/methanol) as a
2-[(R)-3-((6R,12aR)-6-Benzo[1,3]dioxol-5-yl-1,4-dioxo-
3,4,6,7,12,12a-hexahydro-1H-pyrazino[1′,2′:1,6]pyrido[3,4-b]-
indol-2-yl)pyrrolidin-1-yl]-N,N-dimethylacetamide (14). The
intermediate 4 (50 mg), N,N′-dimethylchloroacetamide (1 equiv),
and triethylamine (1.1 equiv) were dissolved in dioxane (1 mL) and
stirred at room temperature for 6 days. The reaction mixture was then
heated to 70 °C for 15 h. The dioxane was removed by evaporation.
The residue was dissolved in ethyl acetate, washed with saturated
NaHCO3 aqueous solution, dried over MgSO4, and evaporated to
dryness, Purification by TLC (dichloromethane/methanol) gave 26
mg of a white powder (44%). LC: tR = 4.0 min. MS (ESI+): m/z = 530
[M + H]+. 1H NMR (MeOD): δ 7.54 (d, J = 7.2 Hz, 1H), 7.29 (d, J =
7.2 Hz, 1H), 7.01−7.12 (m, 2H), 6.67−6.81 (m, 3H), 6.26 (s, 1H),
5.86 (s, 2H), 5.14 (m, 1H), 4.40 (dd, J = 11.4 Hz and J = 4.8 Hz, 1H),
4.32 (d, J = 17.1 Hz, 1H), 4.18 (d, J = 16.5 Hz, 1H), 3.61 (dd, J = 15.9
Hz and J = 5.1 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.30 (m, 1H),
2.98−3.18 (m, 3H), 3.12 (s, 3H), 2.94 (s, 3H), 2.55 (dd, J = 10.5 Hz
and J = 7.8 Hz, 1H), 2.23−2.41 (m, 2H), 1.70 (m, 1H). 13C NMR
(MeOD): δ 24.35, 30.64, 36.19, 37.80, 46.80, 52.92, 54.36, 57.13,
57.24, 57.57, 58.30, 102.38, 103.86, 107.37, 108.25, 109.03, 112.19,
119.38, 120.88, 121.34, 123.25, 125.60, 126.52, 127.32, 134.29, 137.22,
137.62, 167.52, 169.17.
white powder (20 mg, 31%). LC: tR = 5.0 min. MS (ESI+): m/z = 565
1
[M + H]+. H NMR (CD2Cl2): δ 8.06 (s, 1H), 7.55 (d, J = 6.8 Hz,
1H), 7.21−7.32 (m, 3H), 7.11 (m, 2H), 6.83 (m, 3H), 6.72 (d, J = 1.7
Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 5.85 (d, J = 1.2 Hz,
1H), 5.83 (d, J = 1.2 Hz, 1H), 5.12 (m, 1H), 4.38 (d, J = 9.8 Hz, 1H),
4.21 (dd, J = 11.5 Hz and J = 4.3 Hz, 1H), 3.93 (d, J = 17.6 Hz, 1H),
3.74 (s, 3H), 3.57−3.66 (m, 2H), 3.44 (d, J = 12.7 Hz, 1H), 3.14 (dd, J
= 16.0 Hz and J = 11.5 Hz, 1H), 2.94 (m, 1H), 2.70 (d, J = 9.7 Hz,
1H), 2.41 (m, 1H), 2.25 (m, 2H), 1.67 (m, 1H). 13C NMR (CD2Cl2):
δ 24.34, 30.56, 34.44, 46.94, 53.25, 54.85, 56.22, 57.12, 57.25, 57.30,
97.20, 102.38, 107.46, 108.23, 109.03, 112.14, 114.65, 119.55, 120.94,
121.40, 123.32, 127.50, 130.79, 132.25, 149.00, 149.50, 134.18, 137.07,
137.58, 154.00, 161.00, 167.50, 186.56.
(6R, 12aR)-6-Benzo[1, 3]dioxol-5-yl-2-[(R)-1-(4-
dimethylaminobenzyl)pyrrolidin-3-yl]-2,3,6,7,12,12a-
hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione
(11). 11 was prepared according to protocol “a” starting from
intermediate 4 (45 mg) and p-dimethylaminobenzaldehyde (1.5
equiv) and obtained after purification by TLC (dichloromethane/
methanol) as a white powder (16 mg, 27%). LC: tR = 5.14 min. MS
1
(ESI+): m/z = 578 [M + H]+. H NMR (MeOD): δ 7.52 (d, J = 6.9
Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.06 (m,
2H), 6.66−6.79 (m, 5H), 6.24 (s, 1H), 5.85 (s, 2H), 5.04 (brs, 1H),
4.34 (dd, J = 11.7 Hz and J = 5.4 Hz, 1H), 4.31 (d, J = 17.1 Hz, 1H),
4.09 (dd, J = 17.1 Hz and J = 1.2 Hz, 1H), 3.66 (d, J = 12.3 Hz, 1H),
3.58 (dd, J = 15.6 Hz and J = 4.8 Hz, 1H), 3.46 (d, J = 12.6 Hz, 1H),
3.12 (dd, J = 15.9 Hz and J = 11.7 Hz, 1H), 2.97 (m, 1H), 2.90 (s,
6H), 2.75 (dd, J = 10.8 Hz and J = 4.2 Hz, 1H), 2.54 (dd, J = 10.5 Hz
and J = 7.8 Hz, 1H), 2.25−2.38 (m, 2H), 1.19−1.72 (m, 1H). 13C
NMR (MeOD): δ 24.50, 30.50, 41.50, 47.02, 52.77, 54.50, 57.12,
57.22, 60.05, 102.37, 107.48, 108.22, 109.03, 112.14, 113.41, 119.55,
120.93, 121.39, 123.31, 127.32, 130.47, 134.20, 137.11, 137.58, 148.94,
151.06, 167.46, 169.19.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-((R)-1-pyridin-2-ylme-
thylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino-
[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (12). 12 was prepared
according to protocol “a” starting from intermediate 4 (45 mg) and
pyridine-2-carboxaldehyde (1.5 equiv) and obtained after purification
by TLC (dichloromethane/methanol) as a white powder (27 mg,
50%). LC: tR =4.58 min. MS (ESI+): m/z = 536 [M + H]+. 1H NMR
(MeOD): δ 8.53 (d, J = 4.8 Hz, 1H), 7.86 (td, J = 7.8 Hz and J = 1.8
Hz, 1H), 7.55 (m, 2H), 7.36 (dd, J = 6.6 Hz and J = 5.1 Hz, 1H), 7.29
(d, J = 7.5 Hz, 1H), 7.06 (m, 2H), 6.78−6.81 (m, 2H), 6.68 (d, J = 8.7
Hz, 1H), 6.25 (s, 1H), 5.85 (s, 2H), 5.01 (brs, 1H), 4.39 (dd, J = 11.7
Hz and J = 5.1 Hz, 1H), 4.3 (d, J = 17.1 Hz, 1H), 4.19 (d, J = 17.7 Hz,
1H), 3.92−4.03 (m, 2H), 3.61 (dd, J = 15.6 Hz and J = 4.8 Hz, 1H),
3.07−3.25 (m, 3H), 2.78−2.84 (m, 1H), 2.54−2.62 (m, 1H), 2.32−
2.43 (m, 1H), 1.89−1.84 (m, 1H). 13C NMR (MeOD): δ 24.37, 30.09,
44.55, 53.55, 54.14, 56.93, 57.21, 57.31, 102.38, 105.21, 107.31,
108.24, 109.04, 110.38, 112.91, 119.52, 120.92, 121.44, 123.31, 123.65,
124.33, 125.46, 127.30, 134.21, 137.02, 137.60, 137.83, 149.66, 150.14,
167.76, 168.76
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-[(R)-1-(1-methyl-1H-imi-
dazol-2-ylmethyl)pyrrolidin-3-yl]-2,3,6,7,12,12a-
hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione
(13). 13 was prepared according to protocol “a” starting from
intermediate 4 (45 mg) and 1-methyl-2-imidazolecarboxaldehyde (1.5
equiv) and obtained after purification by TLC (dichloromethane/
methanol) as a white powder (26 mg, 48%). LC: tR =4.2 min. MS (ESI
+): m/z = 539 [M + H]+. 1H NMR (CD2Cl2): δ 8.38 (s, 1H), 7.55 (d,
J = 6.9 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.05−7.14 (m, 2H), 6.90 (d,
J = 4.0 Hz, 2H), 6.79 (dd, J = 8.0 Hz and J = 1.7 Hz, 2H), 6.71 (d, J =
1.7 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 5.85 (d, J = 7.2 Hz,
1H), 5.82 (d, J = 1.2 Hz, 1H), 5.15 (brs, 1H), 4.18 (m, 2H), 3.86 (d, J
= 17.1 Hz, 1H), 3.64 (m, 5H), 3.14 (dd, J = 15.6 Hz and J = 5.1 Hz,
1H), 2.83 (t, J = 7.76 Hz, 1H), 2.67−2.22 (m, 3H), 2.00 (s, 1H), 1.60
(m, 1H). 13C NMR (CD2Cl2): δ 24.35, 30.59, 34.00, 46.67, 52.62,
52.90, 54.14, 57.14, 57.32, 57.60, 102.37, 107.34, 108.24, 109.02,
112.17, 119.54, 120.89, 121.39, 122.71, 123.28, 126.87, 127.28, 127.77,
134.17,137.09, 127.77, 146.50, 148.90, 167.42, 168.92.
2-[(R)-3-((6R,12aR)-6-Benzo[1,3]dioxol-5-yl-1,4-dioxo-
3,4,6,7,12,12a-hexahydro-1H-pyrazino[1′,2′:1,6]pyrido[3,4-b]-
indol-2-yl)pyrrolidin-1-yl]ethylcarbamic Acid tert-Butyl Ester
(15). The intermediate 4 (50 mg), 2-(Boc-amino)ethyl bromide (25
mg, 1 equiv), and triethylamine (1.1 equiv) were dissolved in dioxane
(1 mL) and stirred at room temperature. After 46 h, 0.5 equiv of 2-
(Boc-amino)ethyl bromide, 0.5 equiv of TEA, and 0.5 mL of dioxane
were added. After 96 h, the reaction mixture was heated to 70 °C for
20 h. The dioxane was removed by evaporation. The residue was
dissolved in ethyl acetate, washed with saturated NaHCO3 aqueous
solution, dried over MgSO4, and evaporated to dryness, It was purified
by TLC (dichloromethane/methanol) to give 29 mg of a white
powder (44%). LC: tR = 5.20 min. MS (ESI+): m/z = 604 [M + H]+.
1H NMR (MeOD): δ 7.53 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.2 Hz,
1H), 7.07 (m, 2H), 6.68−6.80 (m, 3H), 6.27 (s, 1H), 5.86 (s, 2H),
5.10 (m, 1H), 4.41 (dd, J = 11.4 Hz and J = 4.5 Hz, 1H), 4.31 (d, J =
17.4 Hz, 1H), 4.18 (d, J = 17.1 Hz, 1H), 3.61 (dd, J = 15.6 Hz and J =
4.8 Hz, 1H), 2.87−3.23 (m, 5H), 2.50−2.63 (m, 3H), 2.23−2.32 (m,
2H), 1.65−1.71 (m, 1H), 1.44 (s, 9H). 13C NMR (MeOD): 23.44,
28.37, 29.79, 39.50, 46.73, 53.22, 54.01, 55.72, 56.80, 56.90, 56.96,
63.02, 102.00, 105.66, 107.82, 108.56, 111.88, 118.54, 119.92, 120.69,
122.37, 126.95, 134.21, 137.05, 138.05, 147.75, 168.86, 169.70.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-((R)-1-cyclopentylme-
thylpyrrolidin-3-yl)-2,3,6,7,12,12a-hexahydropyrazino-
[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (16). Compound 16 was
prepared according to protocol “b” starting from intermediate 18 (100
mg), amine 16b (2 equiv), and triethylamine (6 equiv) in methanol
(32 h) and obtained after purification by HPLC as a white powder (15
1
mg, 12%). LC: tR = 4.85 min. MS (ESI+): m/z = 527 [M + H]+. H
NMR (CD2Cl2): δ 8.65 (s, 1H), 7.59 (dd, J = 7.0 Hz and J = 1.7 Hz,
1H), 7.32 (dd, J = 6.4 Hz an J = 1.86 Hz, 1H), 7.14 (m, 2H), 6.84 (dd,
J = 8.0 Hz and J = 1.7 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 6.69 (d, J =
8.0 Hz, 1H), 6.25 (s, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.86 (d, J = 1.3 Hz,
1H), 5.10 (m, 1H), 4.36 (d, J = 17.1 Hz, 1H), 4.28 (dd, J = 11.7 Hz
and J = 4.8 Hz, 1H), 4.03 (d, J = 17.5 Hz, 1H), 3.68 (dd, J = 15.9 Hz
and J = 4.8 Hz, 1H), 3.19 (ddd, J = 15.9 Hz, J = 11.5 Hz and J = 0.9
Hz, 1H), 3.10 (dd, J = 8.7 Hz and J = 6.1 Hz, 1H), 2.95 (dd, J = 10.7
Hz and J = 3.2 Hz, 1H), 2.58 (dd, J = 11.1 Hz and J = 8.0 Hz, 1H),
2.46 (m, 2H), 2.31 (m, 2H), 2.07 (hept, J = 7.6 Hz, 1H), 1.8 (m, 3H),
1.6 (m, 4H), 1.25 (m, 2H). 13C NMR (CD2Cl2): δ 23.27, 25.23, 25.27,
29.21, 31.24, 31.26, 38.45, 46.37, 52.24, 56.11, 56.22, 56.25, 61.18,
101.36, 106.20, 107.23, 107.02, 111.25, 118.48, 119.82, 120.26, 122.20,
126.26, 133.33, 136.02, 136.60, 147.05, 147.89, 166.71, 168.09.
((R)-1-Cyclopentylmethylpyrrolidin-3-yl)carbamic Acid tert-
Butyl Ester (16a). (R)-(+)-3-(Boc-amino)pyrrolidine (300 mg),
cyclopentanecarbaldehyde (1.1 equiv), and acetic acid (5 mol %) were
dissolved in DCM (10 mL). NaBH3CN (1.1 equiv) was added, and
the reaction mixture was stirred at room temperature over a weekend.
The reaction mixture was diluted with EtOAc. The product was
1280
dx.doi.org/10.1021/jm201422e | J. Med. Chem. 2012, 55, 1274−1286