3.9. General Procedure for the Synthesis of 5a–v
To a solution of
4a–
p (0.2 mmol) in isopropanol (3 mL) was added various primary amines or secondary amines (0.4 mmol) and TFA (0.6 mmol, 68 mg). The resulting solution was stirred in a sealed vessel inside a microwave apparatus at 160 °C for 20 min. After cooling, TLC indicated the completion of the reaction. After removal of the solvent by rotary evaporation, the residue was redissolved in DCM, and washed with saturated NaHCO
3 solution. The organic layer was dried, concentrated and purified by column chromatography (1% DCM-methanol) to give the desired compound [
11].
N-(1-Benzylpiperidin-4-yl)-5-methoxy-2-(4-methylpiperazin-1-yl)quinolin-4-amine (5a): Yellow solid, Mp: 268–269 °C. 80% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.38–7.29 (m, 4H), 7.21 (t, J = 6.9 Hz, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.32 (s, 4H), 3.07 (dd, J = 12.5Hz, 8.0 Hz, 6H), 2.79(s, 3H), 2.52 (s, 3H), 2.08 (s, 2H), 1.73 (d, J = 12.5 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 138.6, 131.5, 128.8 (2C), 128.4 (2C), 127.2, 120.2, 105.7, 102.0, 94.6, 64.7, 57.2 (2C), 56.8, 56.2, 51.9 (2C), 47.6 (2C), 46.6, 30.3 (2C). ESI-MS: m/z 446.2875 [M+H]+.
N-(1-Benzylpiperidin-4-yl)-5-methoxy-2-morpholinoquinolin-4-amine (5b): Yellow solid, Mp: 248–249 °C. 82% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.34–7.29 (m, 4H), 7.25 (t, J = 6.9 Hz, 2H), 6.91 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 3.95 (s, 3H), 3.71(d, J = 4.1 Hz, 4H), 3.61(s, 4H), 3.06–2.88 (m, 2H), 2.01 (s, 2H), 1.64 (s, 2H), 1.20 (q, J = 8.0 Hz, 5H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 138.6, 131.5, 128.8 (2C), 128.4 (2C), 127.2, 120.2, 105.7, 102.0, 94.6, 66.3 (2C), 64.7, 56.8, 56.2, 51.9 (2C), 48.7 (2C), 30.3 (2C). ESI-MS: m/z 433.2559 [M+H]+.
N-(1-Benzylpiperidin-4-yl)-5-methoxy-2-(piperidin-1-yl)quinolin-4-amine (5c): Yellow solid, Mp: 244–246 °C. 85% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.39–7.30 (m, 4H), 7.25 (t, J = 6.9 Hz, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.79–3.43 (m, 6H), 2.70 (s, 2H), 2.33 (s, 2H), 1.98 (s, 2H), 1.68 (s, 7H), 1.25(d, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 138.6, 131.5, 128.8 (2C), 128.4 (2C), 127.2, 120.2, 105.7, 102.0, 94.6, 64.7, 56.8, 56.2, 51.9 (2C), 47.2 (2C), 30.3 (2C), 25.5 (2C), 24.5. ESI-MS: m/z 431.2766 [M+H]+.
N4-(1-Benzylpiperidin-4-yl)-5-methoxy-N2-(pyrimidin-2-yl)quinoline-2,4-diamine (5d): Yellow solid, Mp: 224–226 °C. 84% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 7.58–7.29 (m, 10H), 6.86 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.29 (s, 1H), 4.44 (br s, 1H), 3.90 (s, 3H), 3.61 (s, 2H), 3.12–3.05 (m, 3H), 2.26 (d, J = 8.0 Hz, 2H), 2.09 (s, 2H), 1.73 (d, J = 8.0 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 169.3, 157.9 (2C), 155.5, 148.4, 148.0, 146.0, 138.6, 129.9, 128.8 (2C), 128.4 (2C), 127.2, 117.8, 115.3, 104.6, 100.6, 94.5, 64.7, 56.8, 56.2, 51.9 (2C), 30.3 (2C). ESI-MS: m/z 441.2358 [M+H]+.
N4-(1-Benzylpiperidin-4-yl)-5-methoxy-N2-(4-nitrophenyl)quinoline-2,4-diamine (5e): Yellow solid, Mp: 226–228 °C. 88% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 8.36 (d, J = 8.1 Hz, 2H), 8.19 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 4.2 Hz, 1H), 7.35 (s, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.0 Hz, 1H), 6.13 (s, 1H), 3.96 (s, 3H), 3.54 (s, 2H), 2.25 (br s, 4H), 2.05 (br s, 4H). 13C-NMR (100 MHz, DMSO-d6): δ 155.5, 148.4, 148.0, 147.0, 146.0, 138.6, 137.9, 129.9, 128.8 (2C), 128.4 (2C), 127.2, 124.7 (2C), 119.2 (2C), 117.8, 104.6, 100.6, 94.5, 64.7, 56.8, 56.2, 51.9 (2C), 30.3 (2C). ESI-MS: m/z 484.2304 [M+H]+.
N4-(1-Benzylpiperidin-4-yl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-methoxyquinoline-2,4-diamine (5f): Yellow solid, Mp: 221–223 °C. 88% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 10.79 (s, 2H), 7.54–7.29 (m, 6H), 7.40–7.20 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.34 (s, 1H) , 4.33 (s, 1H), 3.91 (s, 3H), 3.59 (s, 2H), 3.21–2.94 (m, 3H), 2.27 (d, J = 12.2 Hz, 2H), 2.08 (s, 2H), 1.68 (d, J = 12.2 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.5, 148.4, 148.0, 146.0, 140.7, 138.6, 132.1 (2C), 129.9, 128.8 (2C), 128.4 (2C), 127.2, 124.2 (2C), 119.3 (2C), 117.8, 113.1, 104.6, 100.6, 94.5, 64.7, 56.8, 56.2, 51.9 (2C), 30.3 (2C). ESI-MS: m/z 575.2201 [M+H]+.
N-(1-Benzylpiperidin-4-yl)-5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5g): Yellow solid, Mp: 235–237 °C. 95% yield from 4a. 1H-NMR (400 MHz, DMSO-d6): δ 7.34–7.04 (m, 9H), 6.42 (d, J = 7.4 Hz, 1H), 5.51 (s, 1H), 3.89 (s, 2H), 3.83 (s, 3H), 3.76–3.60 (m, 3H), 3.43 (br s, 1H), 2.70 (s, 4H), 2.53 (t, J = 4.0 Hz, 2H), 2.24 (t, J = 4.0 Hz , 2H), 2.09–1.89 (m, 5H), 1.82–1.46 (m, 4H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 138.6, 131.5, 128.8 (2C), 128.4 (2C), 127.2, 120.2, 105.7, 102.0, 94.6, 64.7, 61.8, 59.0, 57.6, 56.8, 56.2, 51.9 (3C), 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 460.3032 [M+H]+.
N-Isopentyl-5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5h): Yellow solid, Mp: 215–217 °C. 80% yield from 4b. 1H-NMR (400 MHz, DMSO-d6): δ 7.51 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 6.74 (dd, J = 8.1, 2.2 Hz, 1H), 5.51 (s, 1H), 4.00 (s, 2H), 3.90 (s, 3H), 3.84 (t, J = 4.0 Hz, 2H), 3.74 (s, 1H), 3.29 (q, J = 8.0 Hz, 2H), 2.82 (t, J = 4.1 Hz, 2H), 2.62 (t, J = 4.0 Hz, 2H), 2.41(s, 3H), 2.10 (t, J = 8.1 Hz, 2H), 1.80–1.63 (m, 1H), 1.66 (q, J = 8.2 Hz, 2H), 1.22 (s, 3H), 1.00 (d, J = 8.1 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2 150.5, 149.8, 147.6, 131.5, 120.2, 105.7, 102.0, 94.6, 61.8, 59.0, 57.6, 56.2, 51.9, 46.9, 42.6, 26.4, 25.5, 22.9 (2C). ESI-MS: m/z 357.2610 [M+H]+.
N-(1-Isopropylpiperidin-4-yl)-5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5i): Yellow solid, Mp: 213–215 °C. 87% yield from 4c. 1H-NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 4.0 Hz, 1H), 7.21 (t, J = 8.1 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.9 Hz, 1H), 5.63 (s, 1H), 3.91 (s, 3H), 3.79 (s, 1H), 3.64 (t, J = 7.9 Hz, 2H), 3.51–3.22 (m, 1H), 2.61 (s, 4H), 2.32–2.07 (m, 4H), 2.07–1.76 (m, 3H), 1.55 (d, J = 8.0 Hz, 2H), 1.35–1.13 (m, 4H), 1.07–0.89 (m, 6H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 131.5, 120.2, 105.7, 102.0, 94.6, 61.8, 59.0, 58.3, 57.6, 56.8, 56.2, 51.9, 49.5 (2C), 46.9, 30.6 (2C), 26.4, 18.1. ESI-MS: m/z 412.3032 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)quinolin-4-amine (5j): Yellow solid, Mp: 210–212 °C. 86% yield from 4d. 1H-NMR (400 MHz, DMSO-d6): δ 7.39 (d, J = 4.2 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 1H), 3.64 (t, J = 8.1 Hz, 2H), 3.51 (s, 3H), 3.45–3.21 (m, 2H), 2.61 (s, 4H), 2.53–2.07 (m, 6H), 2.03–1.65 (m, 3H), 1.47 (d, J = 7.8 Hz, 2H), 1.35–0.98 (m, 4H), 0.78 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 131.5, 120.2, 105.7, 102.0, 94.6, 61.8, 59.0, 57.6 (5C), 56.2, 55.5, 51.9, 47.6, 47.6, 46.9, 46.6, 26.4. ESI-MS: m/z 413.2984 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k): Yellow solid, Mp: 212–220 °C. 86% yield from 4e. 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (d, J = 4.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 5.69 (s, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 3.64 (t, J = 8.5 Hz, 2H), 3.54 (s, 1H), 3.44 (q, J = 7.0 Hz, 1H), 2.71–2.55 (m, 4H), 2.29 (t, J = 3.4 Hz, 5H), 2.25–2.18 (m, 3H), 1.98 (d, J = 10.2 Hz, 2H), 1.94–1.85 (m, 2H), 1.56 (dd, J = 18.3, 9.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6): δ 157.3, 157.2, 151.2,150.6, 128.5, 119.6, 105.6, 100.7, 83.1, 57.8, 56.5, 56.0(2C), 53.1, 45.9(4C), 45.3, 30.5, 27.0, 18. ESI-MS: m/z 384.2719 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine (5l): Yellow solid, Mp: 213–215 °C. 86% yield from 4f. 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.04 (s, 1H), 5.77 (s, 1H), 4.32 (s, 1H), 4.03 (s, 4H), 3.94–3.65 (m, 3H), 3.56 (t, J = 10.4 Hz, 3H), 3.37 (d, J = 7.4 Hz, 1H), 3.37 (d, J = 7.4 Hz, 1H), 3.07 (s, 1H), 2.80 (s, 2H), 2.22 (s, 1H), 1.99 (d, J = 12.3 Hz, 2H), 1.64 (d, J = 9.1 Hz, 2H), 1.20 (dd, J = 16.0, 8.6 Hz, 3H), 0.85 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 149.8, 147.6, 131.5, 120.2, 105.7, 102.0, 94.6, 65.5 (2C), 61.8, 59.0, 57.6, 56.2, 55.5, 51.9, 46.9, 36.8 (2C), 26.4. ESI-MS: m/z 371.2402 [M+H]+.
5-Methoxy-N-(4-methoxyphenyl)-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5m): Yellow solid, Mp: 268–270 °C. 81% yield from 4g. 1H-NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 7.70 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.3, 153.1, 150.1, 149.5, 133.2, 130.6, 121.7 (2C), 118.5, 115.1 (2C), 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 55.8, 52.3, 46.9, 26.4. ESI-MS: m/z 393.2246 [M+H]+.
N-(4-Isopropylphenyl)-5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5n): Yellow solid, Mp: 278–280 °C. 81% yield from 4h. 1H-NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H),7.62 (d, J = 9.0 Hz, 2H), 7.35 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.88 (s, 1H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.20 (d, J = 8.5 Hz, 6H), 1.08–0.97 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.1, 150.1, 149.5, 138.4, 138.1, 130.6, 126.9 (2C), 120.1 (2C), 118.5, 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 52.3, 46.9, 33.2, 26.4, 23.3 (2C). ESI-MS: m/z 405.2610 [M+H]+.
5-Methoxy-N-(2-methoxyphenyl)-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5o): Yellow solid, Mp: 265–267 °C. 81% yield from 4i. 1H-NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.93 (s, 2H), 6.73 (s, 1H), 3.87 (s, 6H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.1, 150.1, 149.5, 147.4, 132.6, 130.6, 122.6, 121.8, 118.5, 113.4, 112.0, 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 55.8, 52.3, 46.9, 26.4. ESI-MS: m/z 393.2246 [M+H]+.
N1-(5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-yl)-N4,N4-dimethylbenzene-1,4-diamine (5p): Yellow solid, Mp: 268–270 °C. 81% yield from 4l. 1H-NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H),7.62 (d, J = 9.0 Hz, 2H), 7.35 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 3.02 (s, 6H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.08–0.97 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.1, 150.1, 149.5, 138.4, 138.1, 130.6, 126.9 (2C), 120.1 (2C), 118.5, 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 52.3, 46.9, 26.4, 23.3 (2C). ESI-MS: m/z 406.2562 [M+H]+.
5-Methoxy-N-(4-methoxy-2-methylphenyl)-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5q): Yellow solid, Mp: 258–260 °C. 88% yield from 4j. 1H-NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 7.70 (s, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 2.12 (s, 3H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.1, 151.1, 150.1, 149.5, 134.3, 130.6, 130.0, 121.4, 118.5, 117.2, 112.1, 110.9, 101.6, 99.8, 66.3 (2C), 56.2, 55.8, 53.7 (2C), 17.9. ESI-MS: m/z 407.2402 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(p-tolyl)quinolin-4-amine (5r): Yellow solid, Mp: 246–248 °C. 88% yield from 4m. 1H-NMR (400 MHz, DMSO-d6): δ 7.23 (d, J = 9.0 Hz, 4H), 7.35 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 3.51 (s, 2H), 3.45 (br s, 2H), 3.03–2.88 (m, 2H), 2.84 (s, 6H), 2.58 (s, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.3, 153.1, 150.1, 149.5, 133.2, 131.2, 129.8 (2C), 118.5, 116.3 (2C), 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 52.3, 46.9, 26.4, 21.3. ESI-MS: m/z 377.2297 [M+H]+.
5-Methoxy-N-(3-methoxyphenyl)-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5s): Yellow solid, Mp: 244–246 °C. 86% yield from 4k. 1H-NMR (400 MHz, DMSO-d6): δ7.73–7.45 (m, 2H), 7.25 (dd, J = 14.5 HZ, 8.0 HZ, 3H), 6.85 (d, J =7.5 HZ, 1H), 6.62 (s, 1H), 6.58 (s, 1H), 6.47 (s, 1H), 3.90 (s, 3H), 3.51 (s, 2H), 3.45 (br s, 2H), 3.03–2.88 (m, 2H), 2.84 (s, 6H), 2.58 (s, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 155.8, 153.1, 150.1, 149.5, 147.4, 132.6, 130.6, 122.6, 121.8, 118.5, 113.4, 112.0, 110.9, 101.6, 99.8, 61.8, 59.0, 58.0, 56.2, 55.8, 52.3, 46.9, 26.4. ESI-MS: m/z 393.2246 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(pyrimidin-5-yl)quinolin-4-amine (5t): Yellow solid, Mp: 254–256 °C. 88% yield from 4n. 1H-NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.47 (d, J = 8.5 Hz, 2H), 7.19–7.17 (m, 2H), 6.91 (s, 1H), 6.87 (t, J = 8.5 Hz, 1H), 6.19 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 147.6, 147.4, 144.8, 143.7 (2C), 142.9, 131.5, 120.2, 105.7, 102.0, 94.6, 61.8, 59.0, 57.6, 56.2, 51.9, 46.9, 26.4. ESI-MS: m/z 365.2045 [M+H]+.
5-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(4-nitrophenyl)quinolin-4-amine (5u): Yellow solid, Mp: 283–285 °C. 88% yield from 4o. 1H-NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.70 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 3.90 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 152.0, 150.5, 147.6, 144.8, 137.9, 131.5, 124.7 (2C), 120.2, 119.2 (2C), 105.7, 102.0, 94.6, 61.8, 59.0, 57.6, 56.2, 51.9, 46.9, 26.4. ESI-MS: m/z 408.1991 [M+H]+.
N-(3,5-Bis(trifluoromethyl)phenyl)-5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine (5v): Yellow solid, Mp: 297–299 °C. 78% yield from 4p. 1H-NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.56 (s, 2H), 7.49 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 6.33 (s, 1H), 3.90 (s, 3H), 3.49 (br s, 4H), 3.16 (t, J = 8.5 Hz, 2H), 2.85 (s, 3H), 2.59 (t, J = 8.5 Hz, 2H), 1.23–1.08 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.2, 150.5, 147.6, 144.8, 143.0, 132.1 (2C), 131.5, 124.4 (2C), 120.2, 119.3 (2C), 113.1, 105.7, 102.0, 94.6, 61.8, 59.0, 57.6, 56.2, 51.9, 46.9, 26.4. ESI-MS: m/z 499.1888 [M+H]+.
3.12. General Procedure for the Synthesis of 9a–i
The general procedure for the synthesis of 9a–i was the same as that described for 5a–v.
6-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9a): Yellow solid, Mp: 266–268 °C. 75% yield from 8a. 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 8 Hz, 1H), 7.26 (s, 1H), 6.97 (d, J = 8 Hz, 1H), 6.36 (s, 1H), 5.65 (s, 1H), 3.81 (s, 3H), 3.79 (s, 1H), 3.66 (t, J = 8 Hz, 2H), 3.48 (s, 3H), 2.61 (s, 4H), 2.25–2.05 (m, 4H), 2.05–1.76 (m, 3H), 1.58 (d, J = 8 Hz, 2H), 1.35–0.98 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 171.7, 154.7, 152.5, 145.4, 129.6 122.7, 116.7, 101.6, 96.0, 61.8, 59.0, 57.6, 56.8, 56.2, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 384.2719 [M+H]+.
7-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9b): Yellow solid, Mp: 261–263 °C. 65% yield from 8b. 1H-NMR (400 MHz, DMSO-d6): δ 7.42 (d, J = 8 Hz, 1H), 7.09 (s, 1H), 6.85 (d, J = 8 Hz, 1H), 6.40 (s, 1H), 5.65 (s, 1H), 3.87 (s, 3H), 3.79 (s, 1H), 3.62 (t, J = 8 Hz, 2H), 3.48 (s, 3H), 2.65 (s, 4H), 2.15–2.05 (m, 4H), 2.05–1.66 (m, 3H), 1.45 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.4, 155.6, 150.7, 147.8, 122.5, 112.9, 109.2, 106.4, 93.3, 61.8, 59.0, 57.6, 56.8, 56.2, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 384.2719 [M+H]+.
8-Methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9c): Yellow solid, Mp: 251–253 °C. 69% yield from 8c. 1H-NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8 Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 8 Hz, 1H), 6.38 (s, 1H), 5.65 (s, 1H), 4.07 (s, 3H), 3.79 (s, 1H), 3.68 (t, J = 8 Hz, 2H), 3.56 (s, 3H), 2.45 (s, 4H), 2.18–2.05 (m, 4H), 2.05–1.66 (m, 3H), 1.45 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 173.0, 155.8, 155.2, 141.6, 117.4, 116.5, 116.3, 107.5, 95.8, 61.8, 59.0, 57.6, 56.8, 56.2, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 384.2717 [M+H]+.
5,6-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9d): Yellow solid, Mp: 272–274 °C. 73% yield from 8d. 1H-NMR (400 MHz, DMSO-d6): δ 7.00 (d, J = 8 Hz, 1H), 6.81 (s, 1H), 6.23 (d, J = 8 Hz, 1H), 5.65 (s, 1H), 3.83 (s, 6H), 3.79 (s, 1H), 3.68 (t, J = 8 Hz, 2H), 3.56 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 172.0, 151.1, 148.6, 146.2, 133.8, 122.5, 121.7, 106.7, 95.1, 61.8, 59.0, 57.6, 56.8, 56.2, 55.8, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2824 [M+H]+.
5,7-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9e): Yellow solid, Mp: 272–274 °C. 73% yield from 8e. 1H-NMR (400 MHz, DMSO-d6): δ 6.54 (s, 1H), 6.27 (s, 1H), 6.22 (s, 1H), 5.65 (s, 1H), 3.81 (s, 6H), 3.77 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.57 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 174.4, 155.8, 154.7, 151.5, 149.5, 101.4, 98.5, 94.6, 92.4, 61.8, 59.0, 57.6, 56.8, 56.2, 55.8, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2822 [M+H]+.
5,8-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9f): Yellow solid, Mp: 276–278 °C. 69% yield from 8f. 1H-NMR (400 MHz, DMSO-d6): δ 6.25 (s, 1H), 5.97 (d, J = 8 Hz, 1H), 5.88 (d, J = 8 Hz, 1H), 5.65 (s, 1H), 3.80 (s, 6H), 3.77 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.57 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 173.3, 149.1, 147.9, 142.4, 139.7, 107.3, 106.5, 99.3, 94.9, 61.8, 59.0, 57.6, 56.8, 56.2, 55.8, 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2824 [M+H]+.
6,7-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9g): Yellow solid, Mp: 253–255 °C. 69% yield from 8g. 1H-NMR (400 MHz, DMSO-d6): δ 6.73 (s, 1H), 6.54 (s, 1H), 6.26 (s, 1H), 5.65 (s, 1H), 3.80 (s, 6H), 3.77 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.57 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 172.2, 154.4, 151.2, 146.4, 145.6, 112.4, 105.8, 100.0, 93.8, 61.8, 59.0, 57.6, 56.8, 56.1 (2C), 54.5 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2820 [M+H]+.
6,8-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9h): Yellow solid, Mp: 258–260 °C. 73% yield from 8h. 1H-NMR (400 MHz, DMSO-d6): δ 6.71 (s, 1H), 6.33 (s, 1H), 6.24 (s, 1H), 5.65 (s, 1H), 3.93 (s, 6H), 3.77 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.57 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 170.8, 156.1, 154.8, 154.0, 137.3, 117.5, 96.3, 93.7, 93.0, 61.8, 59.0, 57.6, 56.8, 56.1 (2C), 55.8 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2824 [M+H]+.
7,8-Dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (9i): Yellow solid, Mp: 258–260 °C. 73% yield from 8i. 1H-NMR (400 MHz, DMSO-d6): δ 6.87 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 6.28 (s, 1H), 5.65 (s, 1H), 3.83 (s, 6H), 3.77 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.57 (s, 3H), 2.45 (s, 4H), 2.19–2.09 (m, 4H), 2.09–1.66 (m, 3H), 1.43 (d, J = 8 Hz, 2H), 1.35–0.88 (m, 4H), 0.84 (d, J = 7.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 173.5, 154.9, 142.6, 141.8 (2C), 114.6, 112.2, 108.4, 93.6, 93.0, 61.8, 60.9, 59.0, 57.6, 56.1, 55.8 (2C), 51.9, 46.9, 30.3 (2C), 26.4. ESI-MS: m/z 414.2824 [M+H]+.