# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
** Yield = 98%; mp = 164-166 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.35 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 1.48 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.99 (s, 3H, NCH\({}_{3}\)), 3.25 (s, 3H, NCH\({}_{3}\)), 4.32 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.42 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)), \(J\) = 7.2 Hz), 4.55 (s, 2H, CH\({}_{2}\)Ph), 4.90 (s, 2H, CH\({}_{2}\)Ph), 6.87 (m, 1H, Ar), 7.00 (m, 1H, Ar), 7.20-7.31 (m, 6H, Ar), 7.42-7.50 (m, 4H, Ar), 8.19 (d, 1H, Ar, \(J\) = 2.4), 8.27 (d, 1H, Ar, \(J\) = 2.4), 9.43 (s, 2H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 11.98, 35.61, 36.53, 54.49, 96.60, 123.01, 127.10, 127.91, 128.62, 133.82, 136.43, 141.71, 142.26, 146.43, 152.98, 156.99, 159.44. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{19}\)H\({}_{19}\)N\({}_{6}\)O\({}_{2}\): C, 62.97; H, 5.01; N, 23.19. Found C, 62.79; H, 5.00; N, 23.25. **3-Ethly-4-oxo-3,4-dihydropyrazolo [1/5\({}^{\prime}\):1,6]pyrimido [4,5-]pyridazine-1-(\(N\)-ethyl-\(N\)-methylcarboxamide, 10j. ** Yield = 28%; mp = 213-214 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.20 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 6.8 Hz), 1.40 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 6.8 Hz), 1.47 (t, 6H, CH\({}_{3}\)CH  
**3-Ethyl-1-[(4-phenylpiperazin-1-yl)carbonyl]pyrazolo [1/5/5/:1,6]pyrimidine [4,5-d] pyridazin-4(3H)-one, 10k. ** Yield = 57%; mp = 244-246 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.48 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.20 (m, 2H, piparazine), 3.43 (m, 2H, piperazine), 3.70 (m, 2H, piperazine), 4.18 (m, 2H, piperazine), 4.41 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.90-7.10 (m, 4H, Ar), 7.30-7.40 (m, 2H, Ar), 8.30 (m, 1H, Ar), 9.47 (s, 1H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 12.15, 36.45, 49.51, 53.34, 96.62, 114.32, 122.01, 122.91, 129.62, 133.78, 141.68, 142.23, 146.38, 149.64, 153.04, 157.15, 158.82. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{21}\)H\({}_{22}\)N\({}_{7}\)O\({}_{2}\) 404.1829; found 404.1821. Anal. Calcd for C\({}_{21}\)H\({}_{21}\)N\({}_{7}\)O\({}_{2}\): C, 62.52; H, 5.25; N, 24.30. Found C, 62.73; H, 5.26; N, 24.35. **  
**3-Ethyl-1-[(4-benzylpiperazin-1-yl)carbonyl]pyrazolo [1/5/:1,6]pyrimidine [4,5-d] pyridazin-4(3H)-one, 10l. ** Yield = 18%; mp = 178-180 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.45 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.44 (m, 2H, piparazine), 2.69 (m, 2H, piperazine), 3.49-3.60 (m, 4H, 2H piperazine; 2H NCH\({}_{2}\)Ph), 3.99 (m, 2H, piperazine), 4.38 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 7.00 (d, 1H, Ar, \(J\) = 2.0 Hz), 7.20-7.50 (m, 5H, Ar), 8.30 (d, 1H, Ar), \(J\) = 2.0 Hz), 9.45 (s, 1H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 12.24, 36.51, 50.03, 54.56, 64.38, 96.78, 122.91, 127.26, 128.43, 128.90, 133.78, 138.64, 141.72, 142.24, 146.38, 153.02, 157.12, 158.91. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{22}\)H\({}_{24}\)N\({}_{7}\)O\({}_{2}\) 418.1986; found 418.1979. Anal. Calcd for C\({}_{22}\)H\({}_{23}\)N\({}_{7}\)O\({}_{2}\): C, 63.30; H, 5.55; N, 23.49. Found C, 63.43; H, 5.54; N, 23.43. **  
**3-Ethyl-4-oxo-3,4-dihydropyrazolo [1/5/:1,6]pyrimidine [4,5-d]pyridazine-1-N-(3-methoxymenylcarboxamide), 10m. ** Yield = 98%; mp = 240-243 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 1.36 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.76 (s, 3H, OCH\({}_{3}\)), 4.25 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.80 (d, 1H, Ar, \(J\) = 6.4 Hz), 6.99 (s, 1H, Ar), 7.30-7.40 (m, 2H, Ar), 8.40 (d, 1H, Ar, \(J\) = 1.6 Hz), 9.75 (s, 1H, Ar), 10.93 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 12.18, 36.52, 55.82, 96.58, 110.21, 114.02, 116.38. 123.01, 129.78, 133.83, 137.03, 141.69, 142.18, 146.45, 153.02, 157.12, 161.03, 160.90.