# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
** Yield = 21%; mp = 224-226 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.40 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.94 (m, 2H, piperazine), 3.24 (m, 2H, piperazine), 3.45 (m, 2H, piperazine), 3.97 (m, 2H, piperazine), 4.26 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.60 (m, 1H, pyrazole), 6.94 (m, 3H, Ar), 7.29 (m, 2H, Ar), 7.57 (m, 1H, pyrazole), 11.21 (exch br s, 1H, NH). Anal. Calcd for C\({}_{20}\)H\({}_{23}\)N\({}_{7}\)O\({}_{2}\): C, 61.05; H, 5.89; N, 24.92. Found C, 61.22; H, 5.88; N, 24.98. **4-Amino-6-(4-benzyl-piperazine-1-carbonyl)-2-ethyl-5-(2H-pyrazol-3-yl)-2H-pyridazin-3-one, 9j. ** Yield = 53%; mp = 118-120 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.39 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.28 (m, 2H, piperazine), 2.55 (m, 2H, piperazine), 3.31 (m, 2H, piperazine), 3.55 (s, 2H, NCH\({}_{2}\)Ph), 3.83 (m, 2H, piperazine), 4.24 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.53 (d, 1H, pyrazole, \(J\) = 2.4 Hz), 7.28-7.35 (m, 5H, Ar), 7.53 (d, 1H, pyrazole, \(J\) = 2.4 Hz). Anal. Calcd for C\({}_{21}\)H\({}_{25}\)N\({}_{7}\)O\({}_{2}\): C, 61.90; H, 6.18; N, 24.06. Found C, 61.73; H, 6.20; N, 24.13. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid (3-methoxyphenyl)amide, 9k. ** Yield = 15%; mp = 250-251 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8 1.32 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 3.74 (s, 3H, OCH\({}_{3}\)), 4.13 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 6.31 (d, 1H, pyrazole, \(J\) = 1.6 Hz), 6.70 (m, 1H, Ar), 7.21-7.28 (m, 2H, Ar), 7.36 (s, 1H, Ar), 7.81 (d, 1H, pyrazole, \(J\) = 1.6 Hz), 10.66 (exch br s, 1H, NH), 13.21 (exch br s, 2H, NH\({}_{2}\)). Anal. Calcd for C\({}_{17}\)H\({}_{18}\)N\({}_{6}\)O\({}_{3}\): C, 57.62; H, 5.12; N, 23.72. Found C, 57.46; H, 5.11; N, 23.78. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid [2-(3,4-dimethoxyyphenyl)ethyl]amide, 9h. ** Yield = 38%; mp = 177-19 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, (400 MHz, CDCl\({}_{3}\)) 8 1.38 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.83 (t, 2H, NHCH\({}_{2}\)CH\({}_{2}\), \(J\) = 6.4 Hz), 3.59 (m, 2H, NHCH\({}_{2}\)CH\({}_{2}\)), 3.87 (s, 3H, OCH\({}_{3}\)), 3.88 (s, 3H, OCH\({}_{3}\)), 4.19 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.41 (m, 1H, pyrazole), 6.69-6.77 (m, 3H, Ar), 6.96 (exch br s, 1H, NH), 7.72 (m, 1H, pyrazole). Anal. Calcd for C\({}_{20}\)H\({}_{24}\)N\({}_{6}\)O\({}_{4}\): C, 58.24; H, 5.87; N, 20.38. Found C, 58.07; H, 5.86; N, 20.32. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid (3-methoxybenzyl)methylamide, 9m. ** Yield = 26%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.31 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 1.40 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.79 (s, 6H, NCH\({}_{3}\)), 2.99 (s, 6H, NCH\({}_{3}\)), 3.76 (s, 6H, OCH\({}_{3}\)), 3.81 (s, 6H, OCH\({}_{3}\)), 4.19-4.30 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)), 4.69 (s, 4H, NCH\({}_{2}\)), 6.47 (m, 1H, pyrazole), 6.57 (m, 1H, pyrazole), 6.57-6.90 (m, 6H, Ar), 7.19-7.28 (m, 2H, Ar), 7.55 (m, 1H, pyrazole), 7.65 (m, 1H, pyrazole). Anal. Calcd for C\({}_{19}\)(exch br s, 2H, NH\({}_{2}\)), 13.22 (exch br s, 1H, NH). Anal. Calcd for C\({}_{19}\)H\({}_{20}\)N\({}_{6}\)O\({}_{4}\): C, 57.57; H, 5.09; N, 21.20. Found C, 57.44; H, 5.09; N, 21.24. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyropyridazine-3-carboxylic acid benzylamide, 9o. ** Yield = 37%; mp = 195-197 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) 8. 1.45 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.34 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.65 (m, 2H, NHCH\({}_{2}\)Ph), 6.34 (m, 1H, pyrazole), 7.41-7.60 (m, 5H, Ar), 7.72 (m, 1H, pyrazole), 8.86 (exch br s, 1H, NH), 10.87 (exch br s, 2H, NH\({}_{2}\)), 13.02 (exch br s, 1H, NH). Anal. Calcd for C\({}_{17}\)H\({}_{18}\)N\({}_{6}\)O\({}_{2}\): C, 60.34; H, 5.36; N, 24.84.