7
4
Chem. Pharm. Bull.
Vol. 65, No. 1 (2017)
mixture of dichloromethane–methanol (100:1, v/v) as the elu- (1H, t, D O exchang., COCH NH, J=5.2Hz), 5.31 (2H, s,
2
2
1
ent to provide pure 13g as a yellow oil. Yield: 57%. H-NMR CH –pyrazole), 6.70 (2H, d, H-2″′, H-6″′, J=7.7Hz), 6.76 (1H,
400MHz, CDCl ) δ: 1.18 (3H, m, cyclohexyl H), 1.36 (2H, s, H-4), 6.78 (2H, d, H-3′, H-5′, J=8.5Hz), 6.84 (1H, t, H-4″′,
2
(
3
m, cyclohexyl H), 1.57 (1H, m, cyclohexyl H), 1.69 (2H, J=7.2Hz), 7.11 (2H, d, H-2′, H-6′, J=8.5Hz), 7.23 (2H, t, H-3″′,
m, cyclohexyl H), 2.01 (2H, m, cyclohexyl H), 2.36 (6H, s, H-5″′, J=7.5Hz), 8.30 (1H, s, H-7), 9.05 (1H, s, D O exchang.,
2
13
N(CH ) ), 3.11 (2H, s, NHCOCH ), 3.42 (1H, m, cyclohexyl NHCO). C-NMR (50MHz, CDCl ) δ: 24.8 (cyclohexyl C-3″,
3
2
2
3
H-1″), 3.70 (3H, s, OCH ), 4.30 (1H, brs, D O exchang., NH– C-5″), 25.9 (cyclohexyl C-4″), 33.0 (cyclohexyl C-2″, C-6″),
3
2
cyclohexylamine), 5.32 (2H, s, CH –pyrazole), 6.77 (2H, d, 49.3 (NHCOCH ), 51.2 (cyclohexyl C-1″), 53.2 (CH –pyrazole),
2
2
2
H-3′, H-5′, J=8.6Hz), 6.84 (1H, s, H-4), 7.11 (2H, d, H-2′, 55.3 (OCH ), 94.1 (C-4), 113.5 (C-2″′, C-6‴), 114.3 (C-3′, C-5′),
3
H-6′, J=8.6Hz), 8.28 (1H, s, H-7), 9.55 (1H, s, D O exchang., 119.7 (C-4‴), 125.0 (C-3a), 127.9 (C-1′), 128.8 (C-2′, C-6′),
2
13
NHCO). C-NMR (50MHz, CDCl ) δ: 24.6 (cyclohexyl C-3″, 129.6 (C-3″′, C-5‴), 130.9 (C-7), 133.3 (C-7a), 136.9 (C-3),
3
C-5″), 25.7 (cyclohexyl C-4″), 33.0 (cyclohexyl C-2″, C-6″), 146.9 (C-1‴), 151.6 (C-5), 159.5 (C-4′), 169.0 (CO). HR-MS
+
4
5
1
1
5.9 (N(CH ) ), 50.9 (cyclohexyl C-1″), 52.7 (CH –pyrazole), (ESI) m/z: Calcd for C H N O : [M1+H] =485.2660. Found
3
2
2
28 33
6
2
5.0 (OCH ), 62.9 (NHCOCH ), 93.9 (C-4), 114.0 (C-3′, C-5′), 485.2663. Anal. Calcd for C H N O : C, 69.40; H, 6.66; N,
3
2
2
8
3
2
6
2
24.2 (C-3a), 128.1 (C-1′), 128.5 (C-2′, C-6′), 131.6 (C-7), 17.34. Found: C, 69.63; H, 6.80; N, 17.12.
33.5 (C-7a), 137.3 (C-3), 151.8 (C-5), 159.2 (C-4′), 168.5 (CO). 2-(Dimethylamino)-N-(1-(4-methoxybenzyl)-5-phenyl-
HR-MS (ESI) m/z: Calcd for C H N O : [M1+H] =437.2660. amino-1H-pyrazolo[3,4-c]pyridin-3-yl)acetamide (13j)
Found 437.2666. Anal. Calcd for C H N O : C, 66.03; H, This compound was prepared according to the general pro-
+
2
4
33
6
2
2
4
32
6
2
7.39; N, 19.25. Found: C, 66.21; H, 7.52; N, 19.01.
cedure described above, upon reaction of the chloride 12d
N-(5-(Cyclohexylamino)-1-(4-methoxybenzyl)-1H- with dimethylamine (5.6M solution in ethanol). The product
pyrazolo[3,4-c]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)- was purified by column chromatography (silica gel) using a
acetamide (13h) This compound was prepared according mixture of dichloromethane–ethyl acetate (6:4, v/v) as the
to the general procedure described above, upon reaction eluent to provide pure 13j as a pale green solid. Yield: 70%,
1
of the chloride 12c with 1-methylpiperazine. The product mp: 143°C (Et O). H-NMR (400MHz, CDCl ) δ: 2.36 (6H, s,
2
3
was purified by column chromatography (silica gel) using N(CH ) ), 3.12 (2H, s, NHCOCH ), 3.72 (3H, s, OCH ), 5.36
3
2
2
3
a mixture of dichloromethane–methanol (96:4, v/v) as the (2H, s, CH –pyrazole), 6.82 (2H, d, H-3″, H-5″, J=8.7Hz), 6.90
2
eluent to provide pure 13h as a yellow solid. Yield: 98%, (2H, m, H-4′, NH–aniline), 7.17 (2H, d, H-2″, H-6″, J=8.7Hz),
1
mp: 157–158°C (CHCl /Et O). H-NMR (400MHz, CDCl3) 7.26 (4H, m, H-2′, H-3′, H-5′, H-6′), 7.59 (1H, d, H-4,
3
2
δ: 1.21 (3H, m, cyclohexyl H), 1.40 (2H, m, cyclohexyl H), J=1.0Hz), 8.45 (1H, d, H-7, J=1.0Hz), 9.69 (1H, brs, D O
2
13
1
.62 (1H, m, cyclohexyl H), 1.74 (2H, m, cyclohexyl H), 2.04 exch., NHCO). C-NMR (50MHz, CDCl ) δ: 46.0 (N(CH ) ),
3 3 2
(
2H, m, cyclohexyl H), 2.47 (3H, s, CH –piperazine), 2.74 53.0 (CH –pyrazole), 55.3 (OCH ), 63.0 (NHCOCH ), 99.1
3
2
3
2
(4H, brs, piperazine H-3″′, H-5‴), 2.84 (4H, brs, piperazine (C-4), 114.3 (C-3″, C-5″), 117.9 (C-2′, C-6′), 121.1 (C-4′), 123.8
H-2″′, H-6‴), 3.26 (2H, s, NHCOCH ), 3.44 (1H, m, cyclo- (C-3a), 128.1 (C-1″), 128.9 (C-2″, C-6″), 129.2 (C-3′, C-5′),
2
hexyl H-1″), 3.77 (3H, s, OCH ), 4.29 (1H, brs, D O exchang., 131.9 (C-7), 134.5 (C-7a), 138.1 (C-3), 142.2 (C-1′), 148.1
3
2
NH–cyclohexylamine), 5.37 (2H, s, CH –pyrazole), 6.80 (1H, (C-5), 159.5 (C-4″), 168.9 (CO). HR-MS (ESI) m/z: Calcd for
2
+
d, H-4, J=1.0Hz), 6.83 (2H, d, H-3′, H-5′, J=8.7Hz), 7.16 (2H, C H N O : [M1+H] =431.2190. Found 431.2191. Anal. Calcd
2
4
27
6
2
d, H-2′, H-6′, J=8.7Hz), 8.31 (1H, d, H-7, J=1.0Hz), 9.34 (1H, for C H N O : C, 66.96; H, 6.09; N, 19.52. Found: C, 67.11;
2
4
26
6
2
13
s, D O exchang., NHCO). C-NMR (50MHz, CDCl ) δ: 24.9 H, 6.24; N, 19.39.
2
3
(cyclohexyl C-3″, C-5″), 26.0 (cyclohexyl C-4″), 33.3 (cyclo-
N-(1-(4-Methoxybenzyl)-5-(phenylamino)-1H-pyrazolo-
hexyl C-2″, C-6″), 45.4 (CH –piperazine), 51.2 (cyclohexyl [3,4-c]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide
3
C-1″), 52.7 (piperazine C-2″′, C-6‴), 53.1 (CH –pyrazole), (13k) This compound was prepared according to the general
2
5
9
4.8 (piperazine C-3″′, C-5‴), 55.4 (OCH ), 61.5 (NHCOCH ), procedure described above, upon reaction of the chloride 12d
4.0 (C-4), 114.4 (C-3′, C-5′), 124.6 (C-3a), 128.4 (C-1′), 128.9 with 1-methylpiperazine. The product was purified by column
3
2
(
C-2″, C-6″), 132.1 (C-7), 133.8 (C-7a), 137.3 (C-3), 152.2 chromatography (silica gel) using a mixture of dichlorometh-
(C-5), 159.6 (C-4″), 168.0 (CO). HR-MS (ESI) m/z: Calcd for ane–methanol (98:2, v/v) as the eluent to provide pure 13k
+
C H N O : [M1+H] =492.3081. Found 492.3085. Anal. as a pale green solid. Yield: 70%, mp: 134°C (CH Cl /Et O).
2
7
38
7
2
2
2
2
1
Calcd for C H N O : C, 65.96; H, 7.59; N, 19.94. Found: C,
H-NMR (400MHz, CDCl ) δ: 2.31 (3H, s, CH –piperazine),
2
7
37
7
2
3
3
65.78; H, 7.51; N, 20.20.
2.52 (4H, brs, piperazine H-3″′, H-5‴), 2.68 (4H, brs, pi-
N-(5-(Cyclohexylamino)-1-(4-methoxybenzyl)-1H- perazine H-2″′, H-6‴), 3.18 (2H, s, NHCOCH ), 3.74 (3H, s,
2
pyrazolo[3,4-c]pyridin-3-yl)-2-(phenylamino)acetamide OCH ), 5.40 (2H, s, CH –pyrazole), 6.74 (1H, brs, NH), 6.82
3
2
(13i) This compound was prepared according to the general (2H, d, H-3″, H-5″, J=8.7Hz), 6.92 (1H, m, H-4′), 7.17 (2H,
procedure described above, upon reaction of the chloride 12c d, H-2″, H-6″, J=8.7Hz), 7.26 (4H, m, H-2′, H-3′, H-5′, H-6′),
with aniline. The product was purified by column chroma- 7.51 (1H, d, H-4, J=1.0Hz), 8.42 (1H, d, H-7, J=1.0Hz), 9.51
13
tography (silica gel) using a mixture of dichloromethane– (1H, brs, D O exch., NHCO). C-NMR (50MHz, CDCl ) δ:
2
3
methanol (100:1, v/v) as the eluent to provide pure 13i as a 45.8 (CH –piperazine), 53.1 (CH –pyrazole), 53.3 (piperazine
3
2
1
yellow solid. Yield: 46%, mp: 152°C (CHCl /Et O). H-NMR C-2″′, C-6‴), 54.9 (piperazine C-3″′, C-5‴), 55.3 (OCH3),
3
2
(
400MHz, CDCl ) δ: 1.24 (3H, m, cyclohexyl H), 1.40 (2H, m, 61.4 (NHCOCH ), 98.7 (C-4), 114.3 (C-3″, C-5″), 118.0 (C-2′,
3
2
cyclohexyl H), 1.64 (1H, m, cyclohexyl H), 1.75 (2H, m, cyclo- C-6′), 121.2 (C-4′), 123.9 (C-3a), 128.0 (C-1″), 128.8 (C-2″,
hexyl H), 2.05 (2H, m, cyclohexyl H), 3.44 (1H, m, cyclohexyl C-6″), 129.2 (C-3′, C-5′), 132.0 (C-7), 134.5 (C-7a), 137.8 (C-3),
H-1″), 3.74 (3H, s, OCH ), 3.97 (2H, d, COCH NH, J=5.2Hz), 142.1 (C-1′), 148.1 (C-5), 159.5 (C-4″), 168.4 (CO). HR-MS
3
2
+
4
.32 (1H, brs, D O exchang., NH–cyclohexylamine), 4.45 (ESI) m/z: Calcd for C H N O : [M1+H] =486.2612. Found
2
2
7
3
2
7
2