# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
** Yield = 96%; mp = 153-156 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8 1.22 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 1.45 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.45 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.89 (s, 3H, NCH\({}_{3}\)), 3.02 (s, 6H, \(\overline{\rm C6}\)-CH\({}_{3}\)), 3.10 (s, 3H, NCH\({}_{CH\({}_{2}\)Ph), 6.74 (m, 1H, Ar), 6.89 (m, 1H, Ar), 7.22-7.46 (m, 10H, Ar), 8.36 (m, 1H, Ar), 8.45 (m, 1H, Ar), 13C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 12.21, 18.63, 35.61, 36.53, 54.53, 96.64, 119.91, 127.05, 127.91, 128.53, 134.01, 136.42, 142.01, 146.43. 153.03, 157.23, 159.42, 167.72. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{20}\)H\({}_{21}\)N\({}_{6}\)O\({}_{2}\) 377.1721; found 377.1715. Anal. Calcd for C\({}_{20}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 63.82; H, 5.36; N, 22.33. Found C, 63.65; H, 5.35; N, 22.39. **3-Ethly-6-methyl-1-(morpholin-4-ylcarbonyl)pyrazolo [1/5/5/1,6]pyrimido [4,5-\(d\)] pyridazin-4(3H)-one, 10f. ** Yield = 73%; mp = 278-280 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.46 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.18 (s, 3H, C6-CH\({}_{3}\)), 3.48 (m, 2H, morpholine), 3.67 (m, 2H, morpholine), 3.90 (m, 2H, morpholine), 3.99 (m, 2H, morpholine), 4.39 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 7.03 (d, 1H, Ar, \(J\) = 2.0 Hz), 8.26 (d, 1H, Ar, \(J\) = 2.0 Hz), 146.43, 153.01, 157.18, 158.81, 167.67. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{16}\)H\({}_{18}\)N\({}_{6}\)O\({}_{3}\) 343.1513; found 343.1516. Anal. Calcd for C\({}_{16}\)H\({}_{18}\)N\({}_{6}\)O\({}_{3}\) C, 56.29; H, 5.31; N, 24.50. **3-Ethly-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5/5/1,6]pyrimido [4,5-\(d\)]pyridazine-1-(N-ethyl-N-methylcarboxamide), 10g. ** Yield = 39%; mp = 182-185 \({}^{\circ}\)C (Cyclohexane); 1H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 0.78 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.08 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.44 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.60 (m, 2H, CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)N), 1.81 (m, 2H, CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)N), 2.97 (s, 3H, C6-CH\({}_{3}\)), 3.15 (s, 3H, C6-CH\({}_{3}\)), 3.22 (t, 2H, NCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.6 Hz), 3.25 (s, 6H, NCH\({}_{3}\)), 3.65 (t, 2H, NCH\({}_{2}\)CH\({}_{2}\)CH\({}_{2}\)N), \(J\) = 7.6 Hz), 4.34-4.40 (q, 4H, CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 6.92 (d, 1H, Ar, \(J\) = 2.0 Hz), 7.01 (d, 1H, Ar, \(J\) = 2.0 Hz), 8.21 (d, 2H, Ar, \(J\) = 2 Hz). 13C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 11.54. 12.20, 18.62, 20.61, 36.06, 36.59, 54.06, 96.61, 120.01, 133.85, 141.72, 146.43, 153.02, 157.21, 159.10, 167.72. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{16}\)H\({}_{21}\)N\({}_{6}\)O\({}_{2}\) 329.1721; found 339.1726. Anal. Calcd for C\({}_{16}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 58.52; H, 6.14; N, 25.59. Found C, 58.67; H, 6.13; N, 25.52. **3-Ethly-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5/5/1,6]pyrimido [4,5-\(d\)]pyridazine-1-(N-butyl-N-methylcarboxamide), 10h. ** Yield = 58%; mp = 199-200 \({}^{\circ}\)C (Cyclohexane); 1H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 0.81 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 1.06 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 1.21 (m, 2H, CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)CH\({}_{2}\)N) 1.44 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.6 Hz), 1.55-1.80 (m, SH, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)CH\({}_{2}\)N), 2.98 (s, 3H, C6-CH\({}_{3}\)), 3.12 (s, 3H, C6-CH\({}_{3}\)), 3.23 (t, 2H, NCH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 3.28 (s, 6H, NCH\({}_{3}\)), 3.70 (t, 2H, NCH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 4.40 (q, 4H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.6 Hz), 6.93 (d, 1H, Ar, \(J\) = 2.0 Hz), 7.01 (d, 1H, Ar, \(J\) = 2.0 Hz), 8.25 (d, 2H, Ar, \(J\) = 2.0 Hz).