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D.B. Khadka et al. / European Journal of Medicinal Chemistry 92 (2015) 583e607
1H, NH), 7.37e7.29 (m, 4H, AreH), 7.11 (s, 1H, AreH), 6.97e6.85 (m,
4H, AreH), 6.80e6.68 (m, 4H, AreH), 4.71 (d, J ¼ 5.4 Hz, 2H, NCH2),
3.70 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.38 (s,
z3H, OCH3, partially overlapped with the DMSO peak), 2.32 (s, 3H,
6.1.59. 3-(2,6-Dimethylphenyl)-4-(3-methoxyphenyl)-6-methyl-1-
(piperazin-1-yl)isoquinoline (6da)
The procedures described for compound 6ac were used with
compound 7d (200 mg, 0.51 mmol), anhydrous piperazine (177 mg,
2.06 mmol), K2CO3 (641 mg, 4.64 mmol), and DMF (7 mL), followed
by column chromatography (n-hexane:EtOAc ¼ 3:1, EtOAc, MeOH)
to obtain compound 6da as an off-white semi-solid (180 mg, 79%).
Rf ¼ 0.65 (EtOAc). IR (cmꢀ1): 3496 (NeH). 1H NMR (300 MHz,
AreCH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 159.7, 158.8, 153.4,
147.8, 147.4, 147.3, 140.6, 139.7, 137.7, 134.1, 132.1, 129.3, 127.2, 125.3,
124.5, 122.8, 121.0, 120.1, 117.3, 114.6, 113.9, 113.7, 112.3, 110.1, 55.7,
55.38, 55.31, 55.2, 45.3, 21.9. MS (ESI): m/z 521 (MþH)þ, 559
(MþK)þ.
DMSO-d6)
d
(ppm): 8.08 (d, J ¼ 8.4 Hz, 1H, AreH), 7.46e7.43 (m, 1H,
AreH), 7.26 (s, 1H, AreH), 7.19 (t, J ¼ 7.9 Hz, 1H, AreH), 7.03e6.86
(m, 3H, AreH), 6.80e6.74 (m, 2H, AreH), 6.60 (m, 1H, AreH), 3.59
(s, 3H, OCH3), 3.22 (m, z4H, 100-N(CH2)2, partially overlapped with
the DMSO peak), 2.93 (m, 4H, 400-N(CH2)2), 2.37 (s, 3H, AreCH3),
1.97 (s, 3H, AreCH3), 1.86 (s, 3H, AreCH3). 13C NMR (125 MHz,
6.1.56. 1-(4-Ethylpiperazin-1-yl)-4-(3-methoxyphenyl)-6-methyl-
3-(m-tolyl)isoquinoline (6cc)
The procedures described for compound 6ac were used with
compound 7c (200 mg, 0.53 mmol), 1-ethylpiperazine (244 mg,
2.139 mmol), K2CO3 (665 mg, 4.81 mmol), and DMF (5 mL), fol-
lowed by column chromatography (n-hexane:EtOAc ¼ 3:1, 1:1,
EtOAc) to obtain compound 6cc as a brown semi-solid (141 mg,
CDCl3)
d (ppm):159.7, 158.7, 148.5, 140.5, 139.6, 138.3, 138.1, 135.77,
135.7,128.4,127.9,127.1,126.9,126.8,126.2,125.1,124.9,122.9,118.4,
115.4, 113.0, 55.0, 51.0, 44.7, 22.0, 20.4, 20.2.
58%). 1H NMR (300 MHz, CDCl3)
d
(ppm): 8.05 (d, J ¼ 8.4 Hz, 1H,
6.1.60. 3-(2,6-Dimethylphenyl)-N-(4-methoxybenzyl)-4-(3-
methoxyphenyl)-6-methylisoquinolin-1-amine (6dm)
The procedures described for compound 6ac were used with
compound 7d (400 mg, 1.03 mmol), 98% 4-methoxybenzylamine
(577 mg, 4.12 mmol), K2CO3 (1.28 g, 9.28 mmol), and DMF (7 mL),
AreH), 7.38 (s, 1H, AreH), 7.32e7.24 (m, z3H, AreH, partially
overlapped with the CHCl3 peak), 7.15 (d, J ¼ 7.5 Hz, 1H, AreH), 7.03
(t, J ¼ 7.5 Hz,1H, AreH), 6.96 (d, J ¼ 7.2 Hz,1H, AreH), 6.89e6.85 (m,
1H, AreH), 6.84e6.80 (m, 1H, AreH), 6.76e6.74 (m, 1H, AreH), 3.71
(s, 3H, OCH3), 3.56 (M, 4H, 100-N(CH2)2), 2.76 (m, 4H, 400-N(CH2)2),
2.56 (q, J ¼ 7.2 Hz, 2H, NCH2CH3), 2.40 (s, 3H, AreCH3), 2.22 (s, 3H,
AreCH3), 1.17 (t, J ¼ 7.2 Hz, 3H, NCH2CH3). 13C NMR (125 MHz,
followed
by
column
chromatography
(CH2Cl2,
n-
hexane:EtOAc ¼ 5:1) to obtain compound 6dm as a transparent
semi-solid (208 mg, 41%). Rf ¼ 0.67 (n-hexane:EtOAc ¼ 5:1). 1H
CDCl3)
d (ppm): 159.4, 147.6, 141.0, 139.6, 138.5, 136.6, 132.0, 131.0,
NMR (300 MHz, DMSO-d6)
d
(ppm): 8.26 (d, J ¼ 8.7 Hz, 1H, AreH),
129.1, 128.5, 128.4, 127.5, 127.2, 127.1, 125.2, 125.0, 124.8, 124.2, 55.2,
52.9, 52.4, 51.0, 22.0, 21.4, 11.8. MS (ESI): m/z 452 (MþH)þ.
7.97 (t, J ¼ 5.7 Hz, 1H, NH), 7.37e7.34 (m, 1H, AreH), 7.24e7.21 (m,
2H, 200-H and 600-H), 7.18e7.12 (m, 2H, AreH), 6.97e6.87 (m, 2H,
AreH), 6.83e6.79 (m, 3H, AreH, 300-H and 500-H), 6.74e6.69 (m, 2H,
AreH), 6.55e6.54 (m, 1H, AreH), 4.61e4.59 (m, 2H, NCH2), 3.69 (s,
3H, OCH3), 3.57 (s, 3H, OCH3), 2.33 (s, 3H, AreCH3), 1.94 (s, 3H,
AreCH3), 1.84 (s, 3H, AreCH3).
6.1.57. N-(3-methoxyphenethyl)-4-(3-methoxyphenyl)-6-methyl-
3-(m-tolyl)isoquinolin-1-amine (6cl)
The procedures described for compound 6ac were used with
compound 7c (200 mg, 0.53 mmol), 2-(3-methoxyphenyl)ethyl-
amine (324 mg, 2.14 mmol), K2CO3 (665 mg, 4.81 mmol), and DMF
6.1.61. 3-(2-Methoxyphenyl)-4-(3-methoxyphenyl)-1-(piperazin-1-
yl)isoquinoline (6ea)
(5
mL),
followed
by
column
chromatography
(n-
hexane:CH2Cl2 ¼ 5:1, 3:2, n-hexane:EtOAc ¼ 7:1) to obtain com-
The procedures described for compound 6ac were used with
compound 7e (200 mg, 0.53 mmol), anhydrous piperazine (183 mg,
2.12 mmol), K2CO3 (662 mg, 4.79 mmol), and DMF (7 mL), followed
by column chromatography (n-hexane:EtOAc ¼ 4:1, EtOAc, MeOH)
to obtain compound 6ea as a transparent semi-solid (184 mg, 81%).
Rf ¼ 0.16 (MeOH). IR (cmꢀ1): 3454 (NeH). 1H NMR (300 MHz,
pound 6cl as a transparent semi-solid (238 mg, 91%). 1H NMR
(300 MHz, CDCl3)
d
(ppm): 7.57 (d, J ¼ 8.4 Hz, 1H, AreH), 7.35e7.18
(m, 6H, AreH), 7.04 (t, J ¼ 7.6 Hz, 1H, AreH), 6.97e6.74 (m, 7H,
AreH), 5.31 (t, J ¼ 5.4 Hz, 1H, NH), 3.97 (q, J ¼ 6.5 Hz, 2H, NCH2),
3.77 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.07 (t, J ¼ 6.9 Hz, 2H,
NCH2CH2), 2.38 (s, 3H, AreCH3), 2.23 (3H, AreCH3). 13C NMR
CD3OD)
d (ppm): 8.26e8.21 (m, 1H, AreH), 7.58e7.54 (m, 3H,
(125 MHz, CDCl3)
d (ppm): 159.7, 159.3, 153.6, 148.4, 141.5, 140.2,
AreH), 7.22e7.13 (m, 3H, AreH), 6.87e6.74 (m, 4H, AreH), 6.66 (s,
1H, AreH), 3.63 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 3.42e3.38 (m, 4H,
100-N(CH2)2), 3.13e3.09 (M, 4H, 400-N(CH2)2). 13C NMR (125 MHz,
139.5,137.5,136.5,131.0,129.5,129.0,127.4,127.2,127.0,121.3,120.9,
120.4, 117.4, 114.8, 114.4, 112.3, 111.7, 55.2, 55.1, 42.8, 35.9, 21.9, 21.4.
MS (ESI): m/z 489 (MþH)þ.
CDCl3)
d (ppm): 159.2, 158.7, 156.3, 146.5, 138.8, 137.7, 131.5, 130.6,
129.6, 128.7, 128.4, 127.6, 126.2, 125.8, 124.8, 123.7, 120.1, 120.0,
6.1.58. 4-(3-Methoxyphenyl)-6-methyl-N-phenyl-3-(m-tolyl)
isoquinolin-1-amine (6co)
116.1, 112.7, 110.6, 55.08, 55.0, 50.1, 44.1. MS (ESI): m/z 426 (MþH)þ.
The procedures described for compound 6ac were used with
compound 7c (211 mg, 0.56 mmol), aniline (210 mg, 2.25 mmol),
K2CO3 (702 mg, 5.08 mmol), and DMF (5 mL), followed by column
6.1.62. 2-(4-(3-(2-Methoxyphenyl)-4-(3-methoxyphenyl)
isoquinolin-1-yl)piperazin-1-yl)-N,N-dimethylethanamine (6ed)
The procedures described for compound 6ac were used with
compound 7e (200 mg, 0.53 mmol), 1-[2-(dimethylamino)ethyl]
piperazine (335 mg, 2.12 mmol), K2CO3 (662 mg, 4.79 mmol), and
DMF (5 mL), followed by column chromatography (n-
hexane:EtOAc ¼ 3:1, EtOAc, MeOH) to obtain compound 6ed as a
yellow semi-solid (229 mg, 86%). Rf ¼ 0.14 (MeOH). 1H NMR
chromatography (n-hexane:CH2Cl2
¼
5:1, 3:1, 1:1, n-
hexane:EtOAc ¼ 5:1) to obtain compound 6co as a yellow semi-
solid (114 mg, 46%). IR (cmꢀ1): 3426 (NeH). 1H NMR (300 MHz,
DMSO-d6)
d
(ppm): 9.24 (s, 1H, NH), 8.53 (d, J ¼ 8.4 Hz, 1H, AreH),
8.00e7.96 (m, 2H, AreH), 7.49e7.46 (m, 1H, AreH), 7.34e7.27 (m,
3H, AreH), 7.24e7.23 (m, 2H, AreH), 7.09e6.90 (m, 5H, AreH), 6.79
(d, J ¼ 7.8 Hz, 1H, AreH), 6.73e6.71 (m, 1H, AreH), 3.67 (s, 3H,
OCH3), 2.38 (s, 3H, AreCH3), 2.18 (s, 3H, AreCH3). 13C NMR
(300 MHz, CDCl3)
d (ppm): 8.18e8.15 (m, 1H, AreH), 7.71e7.68 (m,
1H, AreH), 7.34e7.45 (m, 2H, AreH), 7.28e7.27 (m, z2H, AreH,
partially overlapped with the CHCl3 peak), 7.21e7.13 (m, 2H, AreH),
6.92e6.87 (m, 1H, AreH), 6.82e6.66 (m, 3H, AreH), 3.62 (s, 3H,
OCH3), 3.54e3.50 (m, 4H, 100-N(CH2)2), 3.45 (s, 3H, OCH3), 2.77 (t,
J ¼ 4.5 Hz, 4H, 300,500-(CH2)2), 2.65e2.60 (m, 2H, CH2CH2 N(CH3)2),
2.54e2.49 (m, 2H, CH2CH2 N(CH3)2), 2.29 (s, 6H, N(CH3)2). 13C NMR
(125 MHz, CDCl3)
d (ppm): 159.4, 150.6, 148.0, 141.0, 140.9, 140.0,
139.7, 137.9, 136.7, 131.0, 129.1, 128.8, 128.0, 127.5, 127.2, 127.1, 125.6,
124.4,123.0,121.9,121.2,119.3,117.3,115.6,112.5, 55.2, 21.9, 21.4. MS
(ESI): m/z 431 (MþH)þ.