# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
13C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 12.23, 13.80, 18.67, 20.03, 30.01, 36.05, 36.57, 51.54, 96.68, 120.02, 133.81, 141.74, 146.43, 153.00, 157.21, 159.18, 167.71. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{17}\)H\({}_{23}\)N\({}_{6}\)O\({}_{2}\) 343.1877; found 343.1878. Anal. Calcd for C\({}_{17}\)H\({}_{22}\)N\({}_{6}\)O\({}_{2}\): C, 59.63; H, 6.48; N, 24.54. Found C, 59.79; H, 6.47; N, 24.62. **3-Ethly-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5/1,6]pyrimido [4,5-\(d\)]pyridazine-1-(N-methyl-\(N\)-methyl-carboxamide), 10i. ** Yield = 56%; mp = 177-178 \({}^{\circ}\)C (Cyclohexane); 1H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 0.78 (t, 34.26 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 7.03 (m, 1H, Ar), 7.56 (m, 1H, Ar), 7.77 (m, 1H, Ar), 8.03 (m, 1H, Ar), 8.42 (m, 1H, Ar), 11.10 (exch br s, 1H, NH). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 12.19, 18.62, 36.49, 96.70, 119.89, 121.08, 126.01, 127.02, 128.31, 129.04, 133.79, 135.81, 141.68, 146.38, 153.02, 157.18, 160.88, 166.29, 167.72. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{19}\)H\({}_{17}\)N\({}_{6}\)O\({}_{4}\) 393.1306; found 393.1310. Anal. Calcd for C\({}_{19}\)H\({}_{16}\)N\({}_{6}\)O\({}_{4}\): C, 58.16; H, 4.11; N, 21.42. Found C, 58.30; H, 4.10; N, 21.48. **3-Ethly-6-methyl-4-oxo-3-4-dihydropyrazolo [1/5\({}^{\prime}\):1,6]pyrimido [4,5-]pyridazine-1-(N-benzyl)carboxamide, 10q. ** Yield = 38%; mp = 212-214 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 1.37 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.00 (s, 3H, C6-CH\({}_{3}\)), 4.24 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.57 (exch br \(\overline{d}\), \(\overline{2}\)H, NHCH\({}_{2}\)Ph, \(J\) = 6.0 Hz), 6.97 (d, 1H, Ar, \(J\) = 2.0 Hz), 7.29-7.42 (m, 5H, Ar), 8.36 (d, 1H, Ar, \(J\) = 2.0 Hz), 9.43 (exch br t, 1H, NH, \(J\) = 6.0 Hz). \({}^{13}\)C-NMR (100 MHz, DMSO-d\({}_{6}\)) \(\delta\) 12.23, 18.61, 36.49, 43.58, 96.58, 120.03, 126.72, 127.02, 128.54, 133.83, 138.05, 141.67, 146.42, 152.89, 157.18, 164.02, 167.69. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{19}\)H\({}_{19}\)N\({}_{6}\)O\({}_{2}\) 363.1564; found 363.1566. Anal. Calcd for C\({}_{19}\)H\({}_{18}\)N\({}_{6}\)O\({}_{2}\): C, 62.97; H, 5.01; N, 23.19. Found C, 62.83; H, 5.02; N, 23.13. **General procedure for 10b, 10e, and 10j-o. ** A mixture of compounds **9a, 9c, 9h-m** (0.24 mmol), triethylorthoformate (12-20 mmol), and a catalytic amount of concentrated sulfuric acid in anhydrous DMF (0.5-1 mL) was stirred at room temperature for 10-30 min. Cold water was added, and the mixture was neutralized with NaHCO\({}_{3}\) and extracted with CH\({}_{2}\)Cl\({}_{2}\). Evaporation of the solvent afforded the desired final compounds, which were purified by crystallization with ethanol. **3-Ethly-4-oxo-3,4-dihydropyrazolo [1/5\({}^{\prime}\):1,6]pyrimido [4,5-]pyridazine-1-(\(N\),N-diethylcarboxamide), 10b. ** Yield = 48%; mp = 213-15 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.20 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.41-1.49 (m, 6H, 3H (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N), 3.33 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.72 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 4.40 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 7.00 (d, 1H, Ar, \(J\) = 1.5 Hz), 8.27 (s, 1H, Ar, \(J\) = 1.5 Hz), 9.45 (s, 1H, Ar), 13C-NMR (100 MHz, CDCl\({}_{3}\)) \(\delta\) 12.23, 12.85, 36.52, 43.58, 96.61, 122.88, 133.84, 141.74, 142.22, 146.46, 152.86, 157.05, 158.76. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{15}\)H\({}_{19}\)N\({}_{6}\)O\({}_{2}\) 315.1564; found 315.1570. Calcd for C\({}_{15}\)H\({}_{18}\)N\({}_{6}\)O\({}_{2}\): C, 57.31; H, 5.77; N, 26.74. Found C, 57.44; H, 5.76; N, 26.67. **3-Ethly-4-oxo-3,4-dihydropyrazolo [1/5\({}^{\prime}\):1,6]pyrimido [4,5-]pyridazine-1-(N-benzyl-\(N\)-methylcarboxamide), 10e.