Phenyl linked quinolinyl modulators of ror-gamma-t
An alkyl and pyridyl-based technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as weakened Th17 cell differentiation, decreased susceptibility, and decreased Th17 cell population
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[0236] The compounds of the present invention can be prepared by methods known to those skilled in the art. The following examples are intended to represent examples of the invention only and are by no means intended to limit the invention.
[0237] Intermediate 1: Step a
[0238] Methyl 5-bromo-2-(2-phenylacetamido)benzoate
[0239]
[0240] Methyl 2-amino-5-bromobenzoate (9.00 g, 39.1 mmol) and Et 3 CH of mixture of N (7.6 mL, 54.8 mmol) 2 Cl 2 (90mL) solution, 2-phenylacetyl chloride (7.26g, 46.9mmol) was added dropwise. After the addition was complete, the cooling bath was removed, and the mixture was stirred for 27 hours. TLC showed some starting methyl 2-amino-5-bromobenzoate still present. More 2-phenylacetyl chloride (1.88 g, 12.2 mmol) and Et3N (2.2 mL, 15.9 mmol) were added, and the mixture was stirred overnight. Join K 2 CO 3 (aqueous), the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 extraction. The combined organic la...
example 1
[0739] Example 1: (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1 H -Imidazol-5-yl)(pyridin-2-yl)methanol
[0740]
[0741] via syringe at -78°C n -BuLi solution (2.5M in hexane, 0.34mL, 0.85mmol) was added dropwise to 6-bromo-2,4-dichloro-3-phenylquinoline (305.4mg, 0.865mmol, intermediate 1, step c ) in anhydrous THF (4.4 mL). After 1.5 minutes, (1-methyl-1 H -Imidazol-5-yl)(pyridin-2-yl)methanone (0.175 g, 0.936 mmol, intermediate 11, step b) in anhydrous THF (1.8 mL). The reaction mixture was stirred at -78°C for 5 minutes, then the reaction flask was placed in an ice-water bath. After 10 minutes, the mixture was warmed to room temperature, and the reaction was quenched with methanol and water. The mixture was partitioned between water and DCM. The separated aqueous phase was further extracted with DCM. Dry the organic phase (Na 2 SO 4 ), filtered and concentrated. The crude product was purified via flash column chromatography (silica gel, 0-10% MeOH-DCM) to a...
example 2
[0742] Example 2: (2,4-Dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-3-yl)methanol
[0743]
[0744] N 2 (g) A solution of 6-bromo-2,4-dichloro-3-phenylquinoline (353 mg, 1.0 mmol, Intermediate 1, step c) in THF (15 mL) was stirred at -70 °C for 15 min, then join n - BuLi (1.6M in hexane, 0.81 mL, 1.3 mmol). After the addition, the reaction mixture was allowed to stir at -70°C for 15 minutes. A solution of phenyl(pyridin-3-yl)methanone (183 mg, 1.00 mmol) in THF (20 mL) was added and stirring of the resulting reaction mixture was continued at low temperature for 30 minutes. The cooling bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was quenched with water and washed with CH 2 Cl 2 extraction. The organic phase was dried, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, 1:40CH 3 OH / CH 2 Cl 2 ), to obtain the title compound. 1 HNMR (300MH...
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