Journal of Medicinal Chemistry
Article
132.73, 130.09, 128.96, 128.81, 128.68, 128.42, 126.53, 125.81,
123.79, 123.02, 120.33, 114.04, 113.91, 111.57, 109.79, 106.82, 60.30,
59.64, 55.37, 55.22, 55.04, 50.56, 40.25, 39.97, 39.69, 39.41, 39.13,
38.86, 38.58, 32.42, 32.24, 28.28, 18.21.
pale yellow solid. Purity: 98.57%. mp: 138−140 °C; ESI-MS m/z:
617.1 ([M + H]+).
1H NMR (400 MHz, DMSO) δ 10.16 (d, J = 7.8 Hz, 1H, ArOH),
9.77 (s, 1H, ArNHCO-), 9.02 (d, J = 8.1 Hz, 1H, ArNHAr), 8.44 (s,
1H, ArH), 8.20 (d, J = 7.2 Hz, 1H, ArH), 7.71 (d, J = 8.4 Hz, 3H,
ArH), 7.60−7.46 (m, 2H, ArH), 7.41 (s, 1H, ArH), 7.30−7.19 (m,
3H, ArH), 6.93 (s, 1H, ArH), 6.66 (d, J = 6.7 Hz, 2H, ArH), 5.77 (d, J
= 2.0 Hz, 1H, ArH), 3.69 (d, J = 7.7 Hz, 6H, -OCH3), 3.58 (s, 2H,
-NCH2Ar), 3.41 (s, 2H, ArCH2CH2-), 2.76 (d, J = 35.1 Hz, 6H,
-CH2-), 2.32 (d, J = 7.5 Hz, 3H, ArCH3).
IR (KBr, cm−1) ν: 3435.22, 3282.84, 2927.94, 1653, 1558.48,
1516.05, 1251.8, 1128.36, 1099.43, 806.25.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-4-methyl-3-((4-(p-tolyl)pyrimidin-2-yl)-
amino)benzamide (9). Referring to the preparation method of 6,
compound 9 was obtained from g4 and c to give a pale yellow solid.
Purity: 99.67%. mp: 118−120 °C; ESI-MS m/z: 615.2 ([M + H]+).
1H NMR (300 MHz, DMSO) δ 10.16 (s, 1H, ArNHCO-), 8.97 (s,
1H, ArNHAr), 8.46 (d, J = 5.0 Hz, 1H, ArH), 8.35 (s, 1H, ArH), 8.03
(d, J = 7.8 Hz, 1H, ArH), 7.72 (d, J = 7.9 Hz, 2H, ArH), 7.36 (dd, J =
16.1, 6.5 Hz, 1H, ArH), 7.25 (t, J = 8.4 Hz, 2H, ArH), 6.90 (d, J = 7.8
Hz, 2H, ArH), 6.64 (d, J = 5.2 Hz, 3H, ArH), 6.51 (d, J = 7.8 Hz, 2H,
ArH), 3.70 (s, 6H, -OCH3), 3.54 (d, J = 4.8 Hz, 2H, ArCH2N-), 2.69
(d, J = 5.7 Hz, 8H, -CH2-), 2.61 (s, 3H, ArCH3), 2.35 (s, 3H,
ArCH3).
13C NMR (75 MHz, DMSO) δ 165.00, 163.73, 160.98, 158.94,
157.73, 147.07, 146.80, 138.13, 137.98, 137.15, 136.26, 135.37,
132.71, 130.12, 129.67, 128.66, 125.66, 124.33, 123.41, 120.40,
117.75, 117.66, 117.55, 113.51, 111.57, 109.78, 107.57, 59.41, 55.36,
54.90, 50.45, 45.22, 40.25, 39.97, 39.69, 39.41, 39.14, 38.86, 38.58,
32.21, 29.02, 28.99, 28.05, 18.23.
IR (KBr, cm−1) ν: 3734.19, 3334.92, 2929.87, 2357.01, 2322.29,
1506.41, 1317.38, 1257.59, 1224.80, 999.13, 821.68, 783.10.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-3-((4-(4-fluorophenyl)pyrimidin-2-yl)-
amino)-4-methylbenzamide (13). Referring to the preparation
method of 6, compound 13 was obtained from g8 and c to give a
pale yellow solid. Purity: 99.52%. mp: 109−111 °C; ESI-MS m/z:
619.1 ([M + H]+).
13C NMR (75 MHz, DMSO) δ 165.13, 163.08, 161.40, 160.81,
158.74, 147.00, 146.76, 138.20, 137.15, 135.57, 135.51, 132.73,
130.09, 128.96, 128.80, 128.68, 128.42, 126.53, 125.81, 123.79,
123.03, 120.33, 114.04, 113.91, 111.56, 109.79, 106.82, 60.30, 59.64,
55.36, 55.33, 55.22, 55.05, 50.56, 40.24, 39.96, 39.69, 39.41, 39.13,
38.85, 38.58, 32.42, 32.23, 28.28, 18.21.
1H NMR (400 MHz, DMSO) δ 10.18 (s, 1H, ArNHCO-), 9.13 (s,
1H, ArNHAr), 8.72 (d, J = 4.1 Hz, 1H, ArH), 8.59 (d, J = 5.0 Hz, 1H,
ArH), 8.37−8.31 (m, 2H, ArH), 7.90 (t, J = 7.7 Hz, 1H, ArH), 7.76−
7.70 (m, 4H, ArH), 7.52−7.48 (m, 1H, ArH), 7.41 (d, J = 8.1 Hz, 1H,
ArH), 7.23 (d, J = 8.4 Hz, 2H, ArH), 6.64 (d, J = 6.7 Hz, 2H, ArH),
3.70 (s, 6H, -OCH3), 3.54 (s, 2H, ArCH2N-), 2.73−2.62 (m, 8H,
-CH2-), 2.36 (s, 3H, ArCH3).
IR (KBr, cm−1) ν: 3334.92, 2927.94, 1647.21, 1517.98, 1508.33,
1456.26, 1224.8, 1126.43, 1097.5, 1012.63, 798.53, 750.31.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)-
amino)benzamide (10). Referring to the preparation method of 6,
compound 10 was obtained from g5 and c to give a pale yellow solid.
Purity: 99.84%. mp: 126−128 °C; ESI-MS m/z: 602.1 ([M + H]+).
1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H, ArNHCO-), 9.28 (s,
1H, ArNHAr), 9.16 (s, 1H, ArH), 8.68 (d, J = 4.5 Hz, 1H, ArH), 8.54
(d, J = 5.0 Hz, 1H, ArH), 8.44 (d, J = 7.9 Hz, 1H, ArH), 8.28 (s, 1H,
ArH), 7.75−7.66 (m, 3H, ArH), 7.52−7.44 (m, 2H, ArH), 7.40 (d, J
= 7.9 Hz, 1H, ArH), 7.22 (d, J = 8.1 Hz, 2H, ArH), 6.64 (d, J = 6.8
Hz, 2H, ArH), 3.70 (s, 6H, -OCH3), 3.55 (s, 2H, ArCH2N-), 2.81−
2.67 (m, 8H, -CH2-), 2.33 (d, J = 7.9 Hz, 3H, ArCH3).
13C NMR (75 MHz, DMSO) δ 165.03, 163.47, 160.94, 159.15,
146.98, 146.74, 138.07, 137.12, 136.53, 135.79, 135.57, 132.67,
130.77, 130.09, 128.93, 128.73, 128.66, 126.79, 126.55, 125.80,
124.15, 124.06, 123.24, 120.35, 113.88, 111.59, 109.81, 107.57, 79.25,
59.65, 55.38, 55.35, 55.05, 50.57, 40.25, 39.98, 39.70, 39.42, 39.14,
38.86, 38.58, 32.42, 28.28, 18.20; ESI-MS m/z: 619.1 ([M + H]+).
IR (KBr, cm−1) ν: 3414.00, 3334.92, 2918.30, 2791.00, 2357.01,
1635.64, 1517.98, 1456.26, 1253.73, 1224.80, 1130.29, 1006.84,
856.39, 817.82, 524.64.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-4-methyl-3-((4-(pyridin-2-yl)pyrimidin-2-yl)-
amino)benzamide (14). Referring to the preparation method of 6,
compound 14 was obtained from g9 and c to give a pale yellow solid.
Purity: 97.82%. mp: 133−135 °C; ESI-MS m/z: 602.1 ([M + H]+).
1H NMR (400 MHz, DMSO) δ 10.18 (s, 1H, ArNHCO-), 9.13 (s,
1H, ArNHAr), 8.71 (d, J = 4.5 Hz, 1H, ArH), 8.58 (d, J = 2.4 Hz, 1H,
ArH), 8.42−8.30 (m, 2H, ArH), 7.90 (t, J = 7.7 Hz, 1H, ArH), 7.72
(q, J = 7.9, 5.0 Hz, 4H, ArH), 7.51 (s, 1H, ArH), 7.40 (d, J = 8.1 Hz,
1H, ArH), 7.22 (d, J = 8.4 Hz, 2H, ArH), 6.63 (d, J = 6.5 Hz, 2H,
ArH), 3.69 (s, 6H, -OCH3), 3.54 (s, 2H, -NCH2Ar), 2.81−2.65 (m,
8H, -CH2-), 2.36 (s, 3H, ArCH3).
13C NMR (75 MHz, CDCl3) δ 165.48, 163.33, 159.55, 158.69,
153.54, 148.94, 146.95, 146.63, 137.35, 136.75, 135.93, 135.80,
132.99, 131.10, 130.22, 128.99, 128.69, 125.91, 125.56, 124.80,
121.33, 121.24, 119.95, 118.92, 114.80, 110.75, 108.88, 108.72, 77.05,
76.63, 76.21, 59.73, 55.36, 55.18, 50.53, 32.91, 29.21, 28.15, 17.69.
IR (KBr, cm−1) ν: 3334.92, 2914.44, 2355.08, 2320.37, 1653.00,
1575.84, 1516.05, 1456.26, 1317.38, 1255.66, 1224.80, 1126.43,
798.53.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-3-((4-(furan-2-yl)pyrimidin-2-yl)amino)-4-
methylbenzamide (11). Referring to the preparation method of 6,
compound 11 was obtained from g6 and c to give a pale yellow solid.
Purity: 98.77%. mp: 145−147 °C; ESI-MS m/z: 591.1 ([M + H]+).
1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H, ArNHCO-), 9.01 (s,
1H, ArNHAr), 8.44 (d, J = 5.1 Hz, 1H, ArH), 8.24 (s, 1H, ArH), 7.92
(s, 1H, ArH), 7.69 (d, J = 8.2 Hz, 3H, ArH), 7.37 (d, J = 8.0 Hz, 1H,
ArH), 7.23 (d, J = 8.4 Hz, 3H, ArH), 7.09 (d, J = 5.1 Hz, 1H, ArH),
6.70 (s, 1H, ArH), 6.65 (d, J = 5.6 Hz, 2H, ArH), 3.70 (s, 6H,
-OCH3), 3.55 (s, 2H, ArCH2N-), 2.75 (d, J = 32.0 Hz, 8H, -CH2-),
2.33 (s, 3H, ArCH3).
13C NMR (75 MHz, CDCl3) δ 165.41, 163.40, 159.60, 158.73,
153.61, 148.97, 147.04, 146.73, 137.44, 136.75, 135.90, 133.04,
131.05, 130.26, 128.99, 128.71, 125.99, 125.64, 124.79, 121.29,
121.24, 119.93, 118.87, 114.81, 110.88, 109.01, 108.80, 77.01, 76.58,
76.16, 60.10, 59.69, 55.39, 55.19, 50.53, 32.92, 32.57, 28.16, 17.66.
IR (KBr, cm−1) ν: 3334.92, 2916.37, 1651.07, 1516.05, 1404.18,
1319.31, 1253.73, 1224.80, 1126.43, 1004.91, 823.60, 781.17, 746.45.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-4-methyl-3-((4-phenylpyrimidin-2-yl)-
amino)benzamide (15). Referring to the preparation method of 6,
compound 15 was obtained from g10 and c to give a pale yellow
solid. Purity: 96.91%. mp: 115−117 °C; ESI-MS m/z: 601.1 ([M +
H]+).
13C NMR (101 MHz, DMSO) δ 165.58, 161.26, 159.54, 155.76,
151.96, 147.55, 147.31, 146.25, 138.53, 137.60, 136.29, 136.13,
133.27, 130.58, 129.20, 127.09, 126.35, 124.54, 124.31, 123.66,
120.84, 113.07, 113.00, 112.58, 112.17, 110.38, 106.10, 60.12, 55.92,
55.89, 55.56, 51.08, 40.60, 40.39, 40.18, 39.98, 39.77, 39.56, 39.35,
32.93, 28.80, 18.70.
IR (KBr, cm−1) ν: 3290.56, 2916.37, 1570.06, 1541.12, 1516.05,
1506.41, 1253.73, 1224.8, 1126.43, 1099.43, 1004.91, 815.89, 750.31.
Synthesis of N-(4-(2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)phenyl)-3-((4-(3-hydroxyphenyl)pyrimidin-2-yl)-
amino)-4-methylbenzamide (12). Referring to the preparation
method of 6, compound 12 was obtained from g7 and c to give a
1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H, ArNHCO-), 9.04 (s,
1H, ArNHAr), 8.49 (d, J = 5.2 Hz, 1H, ArH), 8.30 (s, 1H, ArH), 8.12
(d, J = 9.2 Hz, 2H, ArH), 7.75−7.67 (m, 3H, ArH), 7.47 (d, J = 7.7
Hz, 3H, ArH), 7.38 (d, J = 5.4 Hz, 2H, ArH), 7.22 (d, J = 8.4 Hz, 2H,
ArH), 6.64 (d, J = 7.2 Hz, 2H, ArH), 3.69 (d, J = 1.5 Hz, 6H,
6192
J. Med. Chem. 2021, 64, 6179−6197