# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
** Yield = 60%; mp = 191-193 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.31 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 1.43 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.78 (s, 3H, NCH\({}_{3}\)), 2.99 (s, 3H, NCH\({}_{3}\)), 4.21 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.27 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.27 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.34 (s, 2H, CH\({}_{2}\)Ph), 4.72 (s, 2H, CH\({}_{2}\)Ph), 6.55 (m, 1H, pyrazole), 6.65 (m, 1H, pyrazole), 7.10 (exch br s, 4H, NH\({}_{2}\)), 7.30-7.45 (m, 10H, Ar), 7.58 (m, 1H, pyrazole), 7.69 (m, 1H, pyrazole). Anal. Calcd for C\({}_{18}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 61.35; H, 5.72; N, 23.85. Found C, 61.15; H, 5.71; N, 23.91. **4-Amino-2-ethyl-6-(morpholine-4-carbonyl)-5-(2H-pyrazol-3-yl)pyridazin-3(2H)-one, 9d. ** Yield = 92%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.41 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.28 (m, 2H, morpholine), 3.44 (m, 2H, morpholine), 3.71 (m, 2H, morpholine), 3.77 (m, 2H, morpholine), 4.26 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.63 (m, 1H, pyrazole), 7.69 (m, 1H, pyrazole). Anal. Calcd for C\({}_{14}\)H\({}_{18}\)N\({}_{6}\)O\({}_{3}\): C, 52.82; H, 5.70; N, 26.40. Found C, 52.70; H, 5.70; N, 26.47. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid methyl-propylamide, 9e. ** Yield = 47%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 0.76 (t, 1.5H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N), 0.94 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N), 1.30-1.68 (m, 5H, 3H CH\({}_{3}\)CH\({}_{2}\)N and 2H CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)C\({}_{2}\)N), 2.80 (s, 3H, NCH\({}_{3}\)), 3.08 (s, 1.5H, NCH\({}_{3}\)), 2.92 (m, 1H, NCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\)), 3.50 (m, 1H, NCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\)), 4.26 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.58 (m, 1H, pyrazole), 7.64 (m, 1H, pyrazole). Anal. Calcd for C\({}_{14}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 55.25; H, 6.62; N, 27.61. Found C, 55.10; H, 6.62; N, 27.69. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydro-pyridazine-3-carboxylic acid butyl-methylamide, 9f. ** Yield = 73%; mp = 197-198 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 0.83 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 0.97 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 1.60 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)\({}_{4}\)N), \(J\) = 7.2 Hz), 1.10-1.38 (m, 8H, CH\({}_{3}\)(CH\({}_{2}\CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz) 3.45 (t, 2H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 4.25 (q, 4H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 6.8 Hz), 6.60 (m, 1H, pyrazole), 6.85 (m, 1H, pyrazole), 7.70 (m, 2H, pyrazole), 8.21 (exch br s, 2H, NH). Calcd for C\({}_{16}\)H\({}_{24}\)N\({}_{6}\)O\({}_{2}\): C, 57.81; H, 7.28; N, 25.28. Found C, 57.95; H, 7.28; N, 25.34. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid ethylmethylamide, 9h. ** Yield = 55%; mp = 178-180 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.06 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 7.2 Hz), 1.22 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.42 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 2.81 (s, 3H, NCH\({}_{3}\)), 3.10 (s, 3H, NCH\({}_{3}\)), 3.21 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 7.2 Hz), 3.60 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 7.2 Hz), 4.27 (q, 4H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.60 (m, 2H, pyrazole), 6.9-7.1 (exch br s, 4H, NH\({}_{2}\)), 7.60 (m, 2H, pyrazole). Anal. Calcd for C\({}_{13}\)H\({}_{18}\)N\({}_{6}\)O\({}_{2}\): C, 53.78; H, 6.25; N, 28.95. Found C, 53.65; H, 6.24; N, 29.05. **4-Amino-2-ethyl-6-(4-phenylpiperazine-1-carbonyl)-5-(2H-pyrazol-3-yl)pyridazin-3(2H)-one, 9i.