# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
Calcd for C\({}_{15}\)H\({}_{17}\)ClN\({}_{2}\)O: C, 58.35; H, 5.55; N, 9.07. Found C, 58.58; H, 5.57; N, 9.10. **General procedure for 3a-g.** To a solution of intermediates **2a-g** (0.53 mmol) in 2 mL of anhydrous acetonitrile, 0.58 mmol of 3-methoxyaniline was added. The mixture was stirred at reflux for 3-4 h. After cooling, the precipitate was recovered by vacuum filtration, and the crude product was purified by crystallization from ethanol (for **3b,3c,3e,3f,3g**) or by flash column chromatography using dichloromethane/methanol 9:1 as eluent (for **3a** and **3d**). **4-[(3-Methoxyphenyl)amino]-8-methyl-N-(4-methylpiperazine-1-yl)quinoline-3-carboxamide, 3a. ** Yield = 56%; yellow oil. \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 2.32 (s, 3H, CH\({}_{3}\) piperazine), 2.60-2.70 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 2.74 (s, 3H, CH\({}_{3}\)), 2.90-3.05 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 3.69 (s, 3H, OCH\({}_{3}\)), 6.47 (s, 2H, Ar), 6.57 (d, 1H, Ar, \(J\) = 6.0 Hz), 7.08-7.15 (m, 2H, Ar), 7.48 (s, 1H, Ar), 7.64 (d, 1H, Ar, \(J\) = 7.2 Hz), 7.98 (exch br s, 1H, NH), 8.90 (s, 1H, Ar), 10.65 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 16.69, 46.65, 54.70, 55.84, 59.47, 107.20, 110.98, 111.80, 116.53, 123.42, 125.56, 125.70, 130.08, 131.70, 137.13, 146.01, 151.87, 160.91, 164.08. ESI-HRMS (\(m/J\) [M+H]\({}^{*}\): calculated for C\({}_{23}\)H\({}_{28}\)N\({}_{5}\)O\({}_{2}\) 406.2238; found 406.2243. Anal. Calcd for C\({}_{23}\)H\({}_{27}\)N\({}_{5}\)O\({}_{2}\): C, 68.13; H, 6.71; N, 17.27. Found C, 68.40; H, 6.74; N, 17.33. **  
**N-(2-Hydroxyethyl)-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide, 3b. ** Yield = 59%; mp = 180-183 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 2.86 (s, 3H, CH\({}_{3}\)), 3.72 (t, 2H, NHCH\({}_{2}\)CH\({}_{2}\)OH, \(J\) = 4.4 Hz), 3.80 (s, 3H, OCH\({}_{3}\)), 3.99 (t, 2H, NHCH\({}_{2}\)CH\({}_{2}\)OH, \(J\) = 4.4 Hz), 6.78-6.83 (m, 2H, Ar), 6.92 (d, 1H, Ar, \(J\) = 8.4 Hz), 7.15 (t, 1H, Ar, \(J\) = 8.0 Hz), 7.34 (t, 1H, Ar, \(J\) = 8.0 Hz), 7.54 (d, 1H, Ar, \(J\) = 8.4 Hz), 7.60 (d, 1H, Ar, \(J\) = 6.8 Hz), 9.74 (s, 1H, Ar), 10.08 (exch br s, 1H, NH), 12.95 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 18.52, 43.61, 55.54, 61.07, 107.10, 109.88, 113.81, 116.60, 117.53, 125.32, 125.46, 129.60, 130.78, 135.07, 138.13, 140.71, 143.79, 156.87, 160.91, 167.03. ESI-HRMS (\(m/z\)) [M+H]\({}^{*}\): calculated for C\({}_{20}\)H\({}_{22}\)N\({}_{3}\)O\({}_{3}\) 352.1656; found 352.1650. Anal. Calcd for C\({}_{20}\)H\({}_{21}\)N\({}_{3}\)O\({}_{3}\): C, 68.36; H, 6.02; N, 11.96. Found C, 68.63; H, 6.04; N, 11.91. **  
**4-[(3-Methoxyphenyl)amino]-8-methyl-N-propylquinoline-3-carboxamide, 3c. ** Yield = 95%; mp = 161-164 \({}^{\circ}\)C (EtOH). \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.02 (t, 3H, NHCH\({}_{2}\)CH\({}_{2}\)H\({}_{3}\), \(J\) = 7.2 Hz), 1.78 (sex, 2H, NHCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 2.90 (s, 3H, CH\({}_{3}\)), 3.46 (q, 2H, NHCH\({}_{2}\)CH\({}_{3}\), \(J\) = 6.8 Hz), 3.80 (s, 3H, OCH\({}_{3}\)), 6.77-6.82 (m, 2H, Ar), 6.92 (d, 1H, Ar, \(J\) = 8.4 Hz), 7.15 (t, 1H, Ar, \(J\) = 8.4 Hz), 7.34 (t, 1H, Ar, \(J\) = 8.2 Hz), 7.54 (d, 1H, Ar, \(J\) = 8.8 Hz), 7.59 (d, 1H, Ar, \(J\) = 7.2 Hz), 9.28 (s, 1H, Ar), 9.73 (exch br s, 1H, NH), 13.02 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 11.64, 18.87, 22.47, 42.10, 55.52, 107.14, 109.85, 113.63, 116.48, 117.57, 125.19, 125.51, 130.10, 130.75, 135.03, 138.25, 140.77, 142.69, 156.79, 160.90, 166.67. ESI-HRMS (\(m/z\)) [M+H]\({}^{*}\): calculated for C\({}_{21}\)H\({}_{24}\)N\({}_{3}\)O\({}_{2}\) 350.1863; found 350.1857. Anal. Calcd for C\({}_{21}\)H\({}_{23}\)N\({}_{3}\)O\({}_{2}\): C, 72.18; H, 6.63; N, 12.03. Found C, 72.47; H, 6.65; N, 12.08. **  
**4-[(3-Methoxyphenyl)amino]-8-methylquinoline-3-yl](4-methylpiperazine-1-yl)methananone, 3d. ** Yield = 89%; yellow oil.