# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
\({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 2.28 (s, 3H, CH\({}_{3}\) piperazine), 2.75-2.85 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 2.81 (s, 3H, CH\({}_{3}\)), 3.50-3.60 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 3.74 (s, 3H, OCH\({}_{3}\)), 6.48 (s, 2H, Ar), 6.56 (d, 1H, Ar, \(J\) = 9.2 Hz), 7.13 (t, 1H, Ar, \(J\) = 8.0 Hz), 7.55 (d, 1H, Ar, \(J\) = 6.8 Hz), 7.67 (s, 1H, Ar), 7.74 (d, 1H, Ar, \(J\) = 8.0 Hz), 8.72 (s, 1H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 16.50, 46.75, 54.79, 55.85, 59.57, 107.20, 110.98, 111.80, 116.53, 123.42, 125.56, 125.70, 130.08, 131.70, 137.13, 142.70, 146.01, 152.87, 161.91, 164.08. ESI-HRMS (\(m/z\)) [M+H]\({}^{*}\): calculated for C\({}_{23}\)H\({}_{27}\)N\({}_{4}\)O\({}_{2}\) 391.2129; found 391.2132. Anal. Calcd for C\({}_{23}\)H\({}_{26}\)N\({}_{4}\)O\({}_{2}\): C, 70.75; H, 6.71; N, 14.35. Found C, 70.47; H, 6.68; N, 14.29. **  
**N-Hetyl-4(3-methoxyphenyl)aminoESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{25}\)H\({}_{32}\)N\({}_{3}\)O\({}_{2}\) 406.2489; found 406.2485. Anal. Calcd for C\({}_{25}\)H\({}_{31}\)N\({}_{3}\)O\({}_{2}\): C, 74.04; H, 7.71; N, 10.36. Found C, 74.34; H, 7.74; N, 10.40. **4-[(3-Methoxyphenyl)amino]-8-methyl-N-undecylquinoline-3-carboxamide, 3f. ** Yield = 54%; mp = 182-184 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 0.86 (t, 3H, NH-CH\({}_{2}\)-(CH\({}_{2}\))\({}_{9}\)CH\({}_{3}\), \(J\) = 6.8 Hz), 1.15-135 (m, 18H, NH-CH\({}_{2}\)-(CH\({}_{2}\))\({}_{9}\)CH\({}_{3}\)), 2.74 (s, 3H, CH\({}_{3}\)), 2.81-2.86 (m, 2H, NH-CH\({}_{2}\)-(CH\({}_{2}\))\({}_{9}\)CH\({}_{3}\)), 3.74 (s, 3H, OCH\({}_{3}\)), 6.80-6.90 (m, 3H, Ar), 7.28 (t, 1H, Ar, \(J\) = 8.4 Hz), 7.61 (t, 1H, Ar, \(J\) = 7.6 Hz), 7.87 (d, 1H, Ar, \(J\) = 7.2 Hz), 8.39 (s, 1H, Ar), 8.63 (s, 1H, Ar), 8.71 (exch br s, 1H, NH), 11.26 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 14.41, 18.40, 22.56, 27.02, 28.73, 29.17, 29.41, 29.48, 31.77, 55.62, 108.88, 112.58, 115.77, 119.69, 123.11, 127.21, 130.34, 135.17, 160.20, 164.39. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{29}\)H\({}_{40}\)N\({}_{3}\)O\({}_{2}\) 462.3115; found 462.3111. Anal. Calcd for C\({}_{29}\)H\({}_{39}\)N\({}_{3}\)O\({}_{2}\): C, 75.45; H, 8.52; N, 9.10. Found C, 75.75; H, 8.55; N, 9.13. **N-[2-(2-Hydroxyethoxy)ethyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide, 3g. ** Yield = 57%; mp = 92-95 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 2.75 (s, 3H, CH\({}_{3}\)), 3.01 (q, 2H, CH\({}_{2}\), \(J\) = 6.0 Hz), 3.30 (t, 2H, CH\({}_{2}\), \(J\) = 6.0 Hz), 3.41 (t, 2H, CH\({}_{2}\), \(J\) = 6.0 Hz), 3.51 (t, 2H, CH\({}_{2}\), \(J\) = 6.0 Hz), 3.75 (s, 3H, OCH\({}_{3}\)), 6.80-6.85 (m, 3H, Ar), 7.30 (t, 1H, Ar, \(J\) = 8.4 Hz), 7.62 (t, 1H, Ar, \(J\) = 7.8 Hz), 7.87 (d, 1H, Ar, \(J\) = 6.8 Hz), 8.46 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.62 (s, 1H, Ar), 8.84 (exch br t, 1H, NH, \(J\) = 5.4 Hz), 11.27 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 18.48, 55.66, 60.60, 68.64, 72.57, 108.92, 112.03, 112.77, 115.88, 119.70, 123.13, 127.27, 130.10, 130.35, 135.26, 141.08, 144.04, 153.25, 160.16, 164.59. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{22}\)H\({}_{26}\)N\({}_{3}\)O\({}_{4}\) 396.1918; found 396.1914. Anal. Calcd for C\({}_{22}\)H\({}_{25}\)N\({}_{3}\)O\({}_{4}\): C, 66.82; H, 6.37; N, 10.63. Found C, 66.55; H, 6.34; N, 10.59. **General procedure for 5a-d.** To a cooled (\(-\)5 \({}^{\circ}\)C) and stirred solution of intermediate **4**[20] (0.28 mmol) in anhydrous tetrahydrofuran (10 mL), Et\({}_{3}\)N (0.99 mmol) was added. After 30 min, the mixture was allowed to warm up to 0 \({}^{\circ}\)C, and ethyl chloroformate (0.31 mmol) was added. After 1 h, a suitable commercially available alkyl amine (0.34 mmol) was added. The reaction was carried out at room temperature overnight. After evaporation of the solvent, ice-cold water (20-30 mL) was added, and the solid formed was recovered by vacuum filtration.