Enzyme inhibitors
A CH2, selected technology, applied in the direction of anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as unknown causes
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Embodiment 342
[0457] (2S)-N-[(1-aminoisoquinolin-6-yl)methyl]-3-(3,4-difluorophenyl)-2-{2-[(2R,6S)-2, 6-Dimethylpiperidin-1-yl]acetamido}propionamide
[0458]
[0459] (2S)-3-(3,4-Difluoro, dissolved in DCM (30 mL), HBTU (128 mg, 0.34 mmol) and N,N-diisopropylethylamine (55 mg, 0.42 mmol) was added at room temperature Phenyl)-2-{2-[(2R,6S)-2,6-dimethylpiperidin-1-yl]acetamido}propanoic acid (100 mg, 0.28 mmol). After 20 minutes, 6-aminomethyl-isoquinolin-1-ylamine (54 mg, 0.31 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (50 mL) and successively washed with saturated NaHCO 3 Washed with aqueous solution (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo. By flash chromatography (0-12% MeOH in CHCl 3 Middle) Purification of the crude product gave the title compound which was lyophilized from MeCN / water to give a white solid (36 mg, 25% yield)...
Embodiment 064
[0757] (S)-N-(1-(((1-aminoisoquinolin-6-yl)methyl)amino)-3-(3,4-difluorophenyl)-1-oxopropane-2- base)-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-5-carboxamide
[0758]
[0759] N-tert-butoxycarbonyl-N-[6-[[[(2S)-3-(3,4-difluorophenyl)-2-(2-trimethylsilylethoxycarbonylamino)propane Acyl]amino]methyl]-1-isoquinolinyl]carbamate tert-butyl ester
[0760]
[0761] Following General Procedure C(i), (2S)-3-(3,4-difluorophenyl)-2-(2-trimethylsilylethoxycarbonylamino)propanoic acid (20.8 g, 60.1 mmol ) was reacted with tert-butyl N-[6-(aminomethyl)-1-isoquinolinyl]-N-tert-butoxycarbonylcarbamate (22.5 g, 60.1 mmol). Flash chromatography (0-35% EtOAc in isohexane) gave the title compound (36.06 g, 75% yield) as an off-white powder.
[0762] [M+H]+=701.3
[0763] N-tert-butoxycarbonyl-N-[6-[[[(2S)-2-amino-3-(3,4-difluorophenyl)propionyl]amino]methyl]-1-isoquinolinyl ] tert-butyl carbamate
[0764]
[0765] N-tert-butoxycarbonyl-N-[6-[[[(2S)-3-(3,4-difluorophenyl)-2-(2-tr...
Embodiment 3104
[0776] (2S)-N-[(3-Amino-1H-indazol-6-yl)methyl]-3-(3,4-difluorophenyl)-2-{2-[(2R,6S)- 2,6-Dimethylpiperidin-1-yl]acetamido}propionamide
[0777]
[0778] (2S)-N-[(4-cyano-3-fluorophenyl)methyl]-3-(3,4-difluorophenyl)-2-{2-[(2R,6S)-2, 6-Dimethylpiperidin-1-yl]acetamido}propionamide
[0779]
[0780] Following general condition C(ii), (2S)-3-(3,4-difluorophenyl)-2-{2-[(2R,6S)-2,6-dimethylpiperidine-1- Acetyl}propionic acid (250 mg, 0.71 mmol) was reacted with 4-(aminomethyl)-2-fluorobenzonitrile (145 mg, 0.78 mmol) to give the title compound (320 mg, 93% yield) as a white solid. Rate).
[0781] [M+H] + =487.4
[0782] (2S)-N-[(3-Amino-1H-indazol-6-yl)methyl]-3-(3,4-difluorophenyl)-2-{2-[(2R,6S)- 2,6-Dimethylpiperidin-1-yl]acetamido}propionamide
[0783]
[0784] Under nitrogen, (2S)-N-[(4-cyano-3-fluorophenyl)methyl]-3-(3,4-difluorophenyl)-2-{2-[(2R, 6S)-2,6-Dimethylpiperidin-1-yl]acetamido}propionamide (120 mg, 0.25 mmol) was dissolved in n-butanol (25 mL). Hy...
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