1-bromo-3-methylsulfonylpropane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of methyl 3-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 12-c (1000 mg, 3.92 mmol), 1-bromo-3-(methylsulfonyl)propane 12-b (804 mg, 3.92 mmol) and cesium carbonate (1277 mg, 3.92 mmol) in dry DMF (8 ml) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and poured into iced water. The product was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by column chromatography using a gradient starting from 0% to 10% MeOH/DCM. After evaporation and drying in vacuo, 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.23 (m, 2H) 2.97 (s, 3H) 3.13-3.22 (m, 2H) 3.95 (s, 3H) 4.65 (t, J=7.28 Hz, 2H) 7.75 (dd, J=6.02, 1.00 Hz, 1H) 8.47 (d, J=6.02 Hz, 1H) 8.88 (d, J=1.00 Hz, 1H); m/z=375 (M+H)+, Br pattern. The reaction mixture was then cooled to room temperature The product was extracted three times with DCM The combined organic layers were dried over Na2SO4 filtered evaporated to dryness The crude was purified by column chromatography After evaporation drying in vacuo 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Bromo-3-methanesulfonylpropane (500 mg, 2.5 mmol) was suspended in a dimethylamine solution (2 M in THF; 10 mL, 20 mmol) and stirred at RT, resulting in a crystalline solid. The reaction was left to stand overnight and the reaction mixture was then diluted with Et2O (10 mL) and filtered. The filtrate was concentrated in vacuo resulting in an orange oily solid which was redissolved in Et2O (10 mL), filtered and concentrated in vacuo to give the title compound as an orange oil (420 mg). resulting in a crystalline solid The reaction was left filtered The filtrate was concentrated in vacuo resulting in an orange oily solid which filtered concentrated in vacuo

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Example 12 (150 mg, 0.28 mmol) in MeCN (2 mL) was added 1-bromo-3-methanesulfonyl-propane (225 mg, 1.12 mmol). The resulting mixture was heated at 90° C. for 40 minutes using microwave irradiation. The solvent was removed in vacuo and the resultant residue was purified by reverse phase chromatography (MDAP), giving the title compound as an off-white solid (65 mg) microwave irradiation The solvent was removed in vacuo the resultant residue was purified by reverse phase chromatography (MDAP)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Example 12 (150 mg, 0.28 mmol) in MeCN (2 mL) was added 1-bromo-3-methanesulfonyl-propane (225 mg, 1.12 mmol). The resulting mixture was heated at 90° C. for 40 minutes using microwave irradiation. The solvent was removed in vacuo and the resultant residue was purified by reverse phase chromatography (MDAP), giving the title compound as an off-white solid (65 mg) microwave irradiation The solvent was removed in vacuo the resultant residue was purified by reverse phase chromatography (MDAP)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of methyl 3-bromo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 12-c (1000 mg, 3.92 mmol), 1-bromo-3-(methylsulfonyl)propane 12-b (804 mg, 3.92 mmol) and cesium carbonate (1277 mg, 3.92 mmol) in dry DMF (8 ml) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and poured into iced water. The product was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by column chromatography using a gradient starting from 0% to 10% MeOH/DCM. After evaporation and drying in vacuo, 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.23 (m, 2H) 2.97 (s, 3H) 3.13-3.22 (m, 2H) 3.95 (s, 3H) 4.65 (t, J=7.28 Hz, 2H) 7.75 (dd, J=6.02, 1.00 Hz, 1H) 8.47 (d, J=6.02 Hz, 1H) 8.88 (d, J=1.00 Hz, 1H); m/z=375 (M+H)+, Br pattern. The reaction mixture was then cooled to room temperature The product was extracted three times with DCM The combined organic layers were dried over Na2SO4 filtered evaporated to dryness The crude was purified by column chromatography After evaporation drying in vacuo 750 mg (2.0 mmol, 51.0%) of the target product 12-d was obtained as a white solid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared from 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 70 mg. 0.152 mmol) and 1-bromo-3-methanesulfonyl-propane (53 mg, 0.264 mmol) using a similar method to that employed for Example 11 (27 mg).

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-(5-{2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (intermediate 5) (66 mg, 0.15 mmol) and 1-bromo-3-methanesulfonyl propane (201 mg, 1.0 mmol) in acetonitrile (0.20 mL) was heated at 120° C. for 6 h. The mix was cooled to RT and diluted with acetonitrile (2 mL) and water (1 mL) then treated with 1M sodium hydroxide (0.20 ml). The mixture was heated at 50° C. for 2 h. The cold mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by MDAP to afford the title compound (10 mg). The mix was cooled to RT The mixture was heated at 50° C. for 2 h extracted with EtOAc (2×10 mL) The combined organic phase was dried (sodium sulfate) concentrated in vacuo The residue was purified by MDAP

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (30 mg, 0.2 mmol) and sodium bicarbonate (110 mg, 1.3 mmol) in DMF (2 ml) was treated with a solution of mixture of 3-bromopropyl methyl sulfone and 3-chloropropyl methyl sulfone (for example, as prepared for Intermediate 19) (124 mg) in DMF (0.5 ml) and the mixture was heated at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue (126 mg) was purified by MDAP. Appropriate fractions were combined and concentrated in vacuo and the residue (30 mg) was applied to an SCX-2 cartridge (5 g), pre-conditioned with methanol and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo to give the free base of the title compound (21 mg, 18%): This was treated with 1.25 M hydrogen chloride solution in methanol (0.15 ml) and the solution was evaporated in vacuo to give the title compound (22 mg, 89%): LCMS RT=2.49 min, ES+ve m/z 405 (M+H)+. eluted with methanol followed by 10% aqueous 0.88 s concentrated in vacuo the residue (126 mg) was purified by MDAP concentrated in vacuo eluted with methanol followed by 10% aqueous 0.88 s concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.