Amide-substituted thiazoles as modulators of RORγt
A thiazolyl-based and pyrazolyl-based technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problem of impaired differentiation of Th17 cells in vitro, decreased number of Th17 cell populations, and sensitivity to EAE Sexual decline and other issues
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[0268] The preparation of the triazoles of the present invention is depicted in Scheme IV. A-V through a series of NaBH 4 Reduction, IBX oxidation, and treatment with dimethyl (1-diazo-2-oxopropyl)phosphonate are converted to intermediate D-I. D-I can be treated with sodium azide at elevated temperature to give [1,2,3]-triazole compounds of structure D-II. [1,2,4]-Triazoles can be prepared starting from A-II with the primary amine RxNH at elevated temperature after deprotection with HCl 2 Work up to give intermediate D-III. Alternatively, A-II was first treated with the primary amine RxNH at elevated temperature 2 After work-up, deprotection with HCl affords compounds of structure D-III. A series of Pd-catalyzed couplings, oxidations, and amide couplings afford compounds of structure D-IV. For unsubstituted [1,2,4]triazoles at the 4-position, a deprotection step follows. Alternatively, D-III is first oxidized, followed by amide bond formation and Pd-catalyzed coupling to...
Embodiment 1
[0736] Embodiment 1: step a
[0737] 5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl)thiazole-2-carboxy Acid (S)-ethyl ester
[0738]
[0739] Ethyl 4-(hydroxymethyl)thiazole-2-carboxylate (470 mg, intermediate 1, step a), (S)-4-bromo-2,3-dichloro-N-(1,1,1 -Trifluoropropan-2-yl)benzenesulfonamide (1.0 g, 2.5 mmol, intermediate 12 / 3), Pd(OAc) 2 (200mg, 0.89mmol), P(Cy) 3 ·HBF 4 (200mg, 0.54mmol), pivalic acid (200mg, 2.0mmol) and Na 2 CO 3 (530 mg, 5.0 mmol) in DMA (20 mL) was stirred at 90 °C overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, washed with anhydrous Na 2 SO 4 Dried and concentrated to dryness. The residue was purified by FCC on silica gel (PE / EtOAc = 2:1) to give the title compound as a tan solid.
[0740] Embodiment 1: Step b
[0741] (S)-5-(2,3-dichloro-4-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)phenyl)-2-(eth...
Embodiment 2
[0783] Embodiment 2: step a
[0784] 3-(5-(5-(2,3-dichloro-4-(N-(1,1,1-trifluorobut-2-yl)sulfamoyl)phenyl)-4-(hydroxymethyl ) thiophene (Azol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoic acid (S)-methyl ester
[0785]
[0786] in N 2 Under atmosphere, to (S)-4-bromo-2,3-dichloro-N-(1,1,1-trifluorobut-2-yl)benzenesulfonamide (620mg, 1.6mmol, intermediate 12 / 4) and 3-(5-(4-(hydroxymethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropanoic acid methyl ester ( To a solution of 480 mg, 1.6 mmol, intermediate 1, step f) in DMA (30 mL) was added P(Cy) 3 ·HBF 4 (200mg, 0.54mmol), pivalic acid (200mg, 2.0mmol), Pd(OAc) 2 (200mg, 0.89mmol) and K 2 CO 3 (440 g, 3.2 mmol). The mixture was heated to 110°C and stirred overnight. The mixture was cooled to room temperature, and H was added 2 O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with DCM (50 mL x 3), and the combined organic layers were washed with anhydrous MgSO 4 Dry, filter and concen...
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