# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
The crude final compounds **5a-d** were purified by column chromatography using dichloromethane/methanol 9:1 (for **5b,5c,5d**) or cyclohexane/ethyl acetate 1:3 (for **5a**) as eluents. **4-[(3-(Heptylcarbamoyl)]-5-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide, 5a. ** Yield = 24%; mp = 178-181 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 0.86 (t, 3H, NH(CH\({}_{2}\))\({}_{6}\)CH\({}_{3}\), \(J\) = 6.4 Hz), 1.20-1.30 (m, 8H, 4 \(\times\) CH\({}_{2}\)), 1.45-150 (m, 2H, CH\({}_{2}\)), 2.72 (s, 3H, CH\({}_{3}\)), 3.18 (q, 2H, NHCH\({}_{2}\)(CH\({}_{2}\))\({}_{5}\)CH\({}_{3}\), \(J\) = 6.4 Hz), 3.72 (s, 3H, OCH\({}_{3}\)), 6.62 (s, 1H, Ar), 6.98 (s, 1H, Ar), 7.04 (s, 1H, Ar), 7.28 (t, 1H, Ar, \(J\) = 7.6 Hz), 7.59 (d, 1H, Ar, \(J\) = 6.8 Hz), 7.67 (d, 1H, Ar, \(J\) = 8.4 Hz), 7.73 (exch br s, 1H, NH), 8.29 (exch br s, 2H, NH\({}_{2}\)), 9.05 (s, 1H, Ar), 10.40 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 14.40, 18.58, 22.52, 26.88, 28.89, 29.49, 31.69, 55.78, 107.18, 108.13, 111.54, 114.53, 121.21, 123.67, 125.32, 131.18, 137.10, 137.24, 145.40, 148.69, 149.00, 160.27, 165.95, 170.07. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{26}\)H\({}_{33}\)N\({}_{4}\)O\({}_{3}\) 449.2547; found 449.2549. Anal. Calcd for C\({}_{26}\)H\({}_{32}\)N\({}_{4}\)O\({}_{3}\): C, 69.62; H, 7.19; N, 12.49. Found C, 69.34; H, 7.16; N, 12.44. **4-[(3-Methoxy-5(undecylcarbamoyl)phenylamino)-8-methylquinoline-3-carboxamide, 5b. ** Yield = 14%; mp = 177-179 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 0.85 (t, 3H, NH(CH\({}_{2}\))\({}_{10}\)CH\({}_{3}\), \(J145.47, 148.57, 148.87, 149.11, 160.26, 165.95, 170.13. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{30}\)H\({}_{41}\)N\({}_{4}\)O\({}_{3}\) 505.3173; found 505.3165. Anal. Calcd for C\({}_{30}\)H\({}_{40}\)N\({}_{4}\)O\({}_{3}\): C, 71.40; H, 7.99; N, 11.10. Found C, 71.68; H, 8.02; N, 11.14. **4-[3-[(2-(2-Hydroxyethoxy)ethyl)carbamoyl]-5-(methoxy)amino)-8-methylquinoline-3-carboxamide, Sc. ** Yield = 16%; mp = 155-157 \({}^{\circ}\)C (EtOH). 1\({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8.272 (s, 3H, CH\({}_{3}\)), 3.30-3.40 (m, 4H, 2 \(\times\) CH\({}_{2}\)), 3.45-3.50 (m, 4H, 2 \(\times\) CH\({}_{2}\)), 3.72 (s, 3H, OCH\({}_{3}\)), 4.58 (exch br s, 1H, OH), 6.65 (s, 1H, Ar), 7.00 (s, 1H, Ar), 7.05 (s, 1H, Ar), 7.31 (t, 1H, Ar, \(J\) = 7.6 Hz), 7.61 (d, 1H, Ar, \(J\) = 6.8 Hz), 7.73 (d, 1H, Ar), \(J\) = 8.4 Hz), 7.74 (exch br s, 1H, NH), 8.26 (exch br s, 1H, NH), 8.39 (exch br t, 1H, CONhCH\({}_{2}\), \(J\) = 5.4 Hz), 9.01 (s, 1H, Ar), 10.32 (exch br s, 1H, NH). 13C-NMR (100 MHz, DMSO-d\({}_{6}\)) 8 16.90, 40.65, 55.85, 61.03, 70.10, 107.20, 108.54, 111.70, 114.65, 121.86, 123.65, 125.40, 131.15, 137.01, 137.36, 145.50, 148.71, 149.15, 160.30, 166.25, 170.15. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{23}\)H\({}_{27}\)N\({}_{4}\)O\({}_{5}\) 439.1976; found 439.1980. Anal. Calcd for C\({}_{23}\)H\({}_{26}\)N\({}_{4}\)O\({}_{5}\): C, 63.00; H, 5.98; N, 12.78. Found C, 63.25; H, 6.00; N, 12.83. **4-[(2-Hydroxy)carbamoyl-5-methoxyphenyl]amino)-8-methylquinoline-3-carboxamide, Sd. ** Yield = 54%; mp = 233-234 \({}^{\circ}\)C (EtOH). 1\({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8 2.72 (s, 3H, CH\({}_{3}\)), 3.25-3.32 (m, 2H, CH\({}_{2}\)), 3.45-3.50 (m, 2H, CH\({}_{2}\)), 3.72 (s, 3H, OCH\({}_{3}\)), 4.68 (exch br s, 1H, OH), 6.61 (s, 1H, Ar), 7.01 (s, 1H, Ar), 7.06 (s, 1H, Ar), 7.29 (t, 1H, Ar, \(J\) = 7.6 Hz), 7.60 (d, 1H, Ar, \(J\) = 6.8 Hz), 7.66 (d, 1H, Ar, \(J\) = 8.4 Hz), 7.72 (exch br s, 1H, NH), 8.25 (exch br s, 1H, NH), 8.32 (exch br t, 1H, CONhCH\({}_{2}\), \(J\) = 5.4 Hz), 9.04 (s, 1H, Ar), 10.35 (exch br s, 1H, NH). 13C-NMR (100 MHz, DMSO-d\({}_{6}\)) 8 18.58, 42.64, 55.79, 60.14, 107.17, 108.24, 111.67, 114.62, 121.26, 123.63, 125.38, 131.16, 136.93, 137.31, 145.46, 148.61, 149.05, 160.26, 166.20, 170.05. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{21}\)H\({}_{23}\)N\({}_{4}\)O\({}_{4}\) 395.1714; found 395.1718. Anal.