Phenoxypyridinylamide derivatives and their use in the treatment of PDE4 mediated disease states
A phenyl, alkoxy technology, applied in the field of phenoxy pyridyl amide derivatives, can solve problems such as limitation
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Embodiment 1
[0294] N-((1S,4S)-4-(5-fluoro-2-(4'-(piperazin-1-ylmethyl)biphenyl-3-yloxy)pyridine-3-carboxamido)ring Hexyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide
[0295]
[0296] Step (a) (1S,4S)-tert-butyl 4-(5-fluoro-2-(3-iodophenoxy)pyridine-3-carboxamido)cyclohexylcarbamate
[0297] 2-chloro-5-fluoropyridine-3-carboxylic acid (4.5g, 25.63mmol), cesium carbonate (16.70g, 51.27mmol) and 3-iodophenol (5.64g, 25.63mmol) in the solvent DMF (50mL) The mixture was heated at 60°C for 48 hours. The mixture was poured into water (200 mL) and the product was extracted into EtOAc. The organic layer was dried over sodium sulfate. Filtration and evaporation gave a brown foam (7.5g). This solid was dissolved in DMF (50 mL), DIPEA (13.43 mL, 76.90 mmol) was added to the solution, followed by HATU (9.75 g, 25.63 mmol), and the mixture was stirred at room temperature for 10 minutes. To this solution was added tert-butyl (1S,4S)-4-aminocyclohexylcarbamate (5.49 g, 25.63 mmol), an...
Embodiment 2
[0306] N-((1S,4S)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(4'-hydroxyl-2'- (Morpholinomethyl)biphenyl-3-yloxy)pyridine-3-carboxamide
[0307]
[0308] Step (a) N-((1S,4S)-4-(1,5-Dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoro-2-(3-iodobenzene Oxy)pyridine-3-carboxamide
[0309] To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.123 g, 0.88 mmol) in dry DMF (10 mL) was added DIPEA (0.460 mL, 2.64 mmol) followed by HATU (0.334 g, 0.88 mmol). The mixture was stirred at room temperature for 10 minutes. To this mixture was added N-((1S,4S)-4-aminocyclohexyl)-5-fluoro-2-(3-iodophenoxy)pyridine-3-carboxamide (0.400 g, 0.88 mmol), and The mixture was stirred overnight, poured onto water and the crude product was collected by filtration, dried and used in step (c) without purification.
[0310] [M+H] + = 577 (multimode+).
[0311] Step (b) 4-Hydroxy-2-(morpholinomethyl)phenylboronic acid
[0312] Morpholine (1.19 mL, 13.7 mmol) wa...
Embodiment 3
[0316] N-((1S,4S)-4-((1,5-Dimethyl-1H-pyrazol-3-yl)methylamino)cyclohexyl)-5-fluoro-2-(4'-hydroxyl- 2'-(morpholinomethyl)biphenyl-3-yloxy)pyridine-3-carboxamide trifluoroacetate
[0317]
[0318] Step (a) (1S,4S)-4-(5-fluoro-2-(4'-hydroxy-2'-(morpholinomethyl)biphenyl-3-yloxy)pyridine-3-formyl Amino) tert-butyl cyclohexylcarbamate
[0319] To a solution of dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.177 g, 0.43 mmol) in acetonitrile (60.0 mL) was added palladium(II) diacetate (0.049 g , 0.22 mmol), and the mixture was stirred at room temperature for 10 minutes. To this solution was added potassium carbonate (0.896 g, 6.48 mmol) in water (20 mL) followed by (1S,4S)-4-(5-fluoro-2-(3-iodophenoxy)pyridine-3- Formamido)cyclohexylcarbamate tert-butyl ester (1.2g) (from Example 1, step a) and 4-hydroxy-2-(morpholinomethyl)phenylboronic acid (0.512g, 2.16mmol) (from Example 1 Example 2 step b). The mixture was then heated at 70°C for 3 hours. The mixture was poured...
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