(R)-2-四氢糠胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 0° C. solution of (R)-(tetrahydrofuran-2-yl)methanamine (5.0 g, 49.5 mmol) and triethylamine (690 uL, 4.95 mmol) in tetrahydrofuran (100 mL) was added carbon disulfide (5.65 g, 74.3 mmol). Stirring was continued for 0.5 hour followed by the dropwise addition of 30% hydrogen peroxide (5.6 g, 49.5 mmol) so that the temperature was maintained below 40° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated to afford an oil. The residue was dissolved in tetrahydrofuran, and treated with 7 N ammonia in methanol (14.3 mL, 100 mmol). The precipitate was collected by filtration and washed with water to afford the title compound. was maintained below 40° C extracted with ethyl acetate The organic extract was dried (Na2SO4) filtered concentrated to afford an oil The precipitate was collected by filtration washed with water

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from the product of Example 45A and commercially available (R)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from the product of Example 45A and commercially available (R)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 98 mg, 0.51 mmol, 1.5 equiv) and 4-(dimethylamino)pyridine (DMAP; 70 mg, 0.57 mmol, 1.7 equiv) to a solution of 4-(3-cyclopentylindole-1-sulfonyl)benzoic acid (126 mg, 0.341 mmol, 1 equiv) and (R)-(−)-tetrahydrofurfurylamine (Aldrich; 140 μL, 140 mg, 1.4 mmol, 4.0 equiv) in anhydr CH2Cl2 (1 mL). After stirring 16 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (10-45% EtOAc/hex) to give 24 mg (16%) of 4-(3-cyclopentylindole-1-sulfonyl)-N—[(R)-1-(tetrahydrofuran-2-yl)methyl]benzamide as a white foam. MS (m/e): 452.96 (M+1); 451.14 (M−1). elute (10-45% EtOAc/hex)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 98 mg, 0.51 mmol, 1.5 equiv) and 4-(dimethylamino)pyridine (DMAP; 70 mg, 0.57 mmol, 1.7 equiv) to a solution of 4-(3-cyclopentylindole-1-sulfonyl)benzoic acid (126 mg, 0.341 mmol, 1 equiv) and (R)-(−)-tetrahydrofurfurylamine (Aldrich; 140 μL, 140 mg, 1.4 mmol, 4.0 equiv) in anhydr CH2Cl2 (1 mL). After stirring 16 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (10-45% EtOAc/hex) to give 24 mg (16%) of 4-(3-cyclopentylindole-1-sulfonyl)-N—[(R)-1-(tetrahydrofuran-2-yl)methyl]benzamide as a white foam. MS (m/e): 452.96 (M+1); 451.14 (M−1). elute (10-45% EtOAc/hex)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (R)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (35 mg, 96%). The product was obtained after purification by preparative HPLC

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (R)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (35 mg, 96%). The product was obtained after purification by preparative HPLC

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to example 7, using 4-methoxy-3-oxo-butanoic acid methyl ester as compound of formula R, 2-bromo-1-[2-chloro-5-(trifluoromethyl)phenyl]-ethanone as compound of formula S, (R)-tetrahydro-furfurylamine as R3—(CH2)m—NH2 and cyclohexylamine as R1R2NH, MS (ISP) 499.4 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to example 7, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-[2-chloro-5-(trifluoromethyl)-phenyl]-ethanone as compound of formula S, (R)-tetrahydrofurfurylamine as R3—(CH2)m—NH2 and cyclohexylamine as R1R2NH, MS (ISP) 469.4 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to example 7, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-[2-chloro-5-(trifluoromethyl)-phenyl]-ethanone as compound of formula S, (R)-tetrahydrofurfurylamine as R3—(CH2)m—NH2 and (1R,2R)-2-aminocyclohexanol as R1R2NH, MS (ISP) 485.5 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 7, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-[2-fluoro-5-(trifluoromethyl)-phenyl]-ethanone as compound of formula S, (R)-tetrahydrofurfurylamine as R3—(CH2)m—NH2 and (1R,2R)-2-aminocyclohexanol as R1R2NH, MS (ISP) 469.5 (M+H)+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to example 7, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-[2-fluoro-5-(trifluoromethyl)-phenyl]-ethanone as compound of formula S, (R)-tetrahydrofurfurylamine as R3—(CH2)m—NH2 and cyclohexylamine as R1R2NH, MS (ISP) 453.6 (M+H)+.