(1R)-1-(4-fluorophenyl)ethanamine

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

実験手順: DBU (4.50 equiv.) was added to a stirred, capped mixture of methyl 5-(2-benzyl-6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (1 eq), Pd(OAc)2 (0.05 equiv.), molybdenum hexacarbonyl (1.0 equiv.) and (R)-1-(4-fluorophenyl)ethylamine (1.20 equiv.) in THF (0.2 M) and the mixture was stirred at 150° C. for 30 min. in a microwave. The mixture was purified by preparative TLC [1 mm] eluting with 50% EtOAc/hexanes to afford (R)-methyl 5-(2-benzyl-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate. capped The mixture was purified by preparative TLC [1 mm] eluting with 50% EtOAc/hexanes

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-fluoro-phenyl)ethylamine (3.9 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water to give 9.0 g (98%) of 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. the mixture was stirred at 25° C. overnight the solid which precipitated was filtered off washed with a small amount of water

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

実験手順: A solution of 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid (10.25 mg, 0.021 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.0085 mL, 0.063 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (12 mg, 0.025 mmol) and diisopropylethylamine (0.012 mL, 0.07 mmol) in 0.2 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide which was subsequently dissolved in 0.2 mL CH2Cl2 and 0.5 mL TFA. The reaction mixture was stirred for 1 h and concentrated. Lyophilization gave 3-((2-amino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide as the TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=8.0 Hz, 1H), 7.92 (app d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.18 (m, 2H), 7.05 (m, 2H), 5.25 (m, 1H), 4.70 (m, 2H), 3.44 (A of AB, d, J=10.1 Hz, 1H), 3.38 (B of AB, d, J=10.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.4 Hz, 1H), 2.50 (m, 2H), 2.18 (m, 2H), 2.03 (m, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.25 (s, 3H). Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA

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

実験手順: A solution of 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid (10.25 mg, 0.021 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.0085 mL, 0.063 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (12 mg, 0.025 mmol) and diisopropylethylamine (0.012 mL, 0.07 mmol) in 0.2 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide which was subsequently dissolved in 0.2 mL CH2Cl2 and 0.5 mL TFA. The reaction mixture was stirred for 1 h and concentrated. Lyophilization gave 3-((2-amino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide as the TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=8.0 Hz, 1H), 7.92 (app d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.18 (m, 2H), 7.05 (m, 2H), 5.25 (m, 1H), 4.70 (m, 2H), 3.44 (A of AB, d, J=10.1 Hz, 1H), 3.38 (B of AB, d, J=10.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.4 Hz, 1H), 2.50 (m, 2H), 2.18 (m, 2H), 2.03 (m, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.25 (s, 3H). Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183. Upon cooling to room temperature a precipitate formed which was collected by filtration washed with water The solid was partitioned between water and EtOAc the aqueous phase extracted once more with EtOAc The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea), without further purification. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183. Upon cooling to room temperature a precipitate formed which was collected by filtration washed with water The solid was partitioned between water and EtOAc the aqueous phase extracted once more with EtOAc The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (301 mg, 0.8 mmol), CDI (519 mg, 3.2 mmol), DIEA (0.5 ml, 2.87 mmol and 1,4-dioxane (5 mL) were charged in a microwave vial. The mixture was stirred at 50° C. for 4.5 h. Additional CDI (519 mg, 3.2 mmol) and imidazole (218 mg, 3.20 mmol) were added, the mixture was stirred at 50° C. for 16 h and then treated with (R)-1-(4-fluorophenyl)ethanamine (536 mg, 3.85 mmol). The mixture was stirred at 50° C. for 2 h and then diluted with EtOAc washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (0-40% EtOAc in hexane, 25 CV; 40-100% EtOAc in hexane, 20 CV) to afford (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (154 mg, 0.229 mmol, 28%) as a yellow solid. MS ESI calc'd. for C34H29FN5O [M+H]+ 542, found 542. the mixture was stirred at 50° C. for 16 h The mixture was stirred at 50° C. for 2 h washed with water, brine dried (Na2SO4) concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (0-40% EtOAc in hexane, 25 CV; 40-100% EtOAc in hexane, 20 CV)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (301 mg, 0.8 mmol), CDI (519 mg, 3.2 mmol), DIEA (0.5 ml, 2.87 mmol and 1,4-dioxane (5 mL) were charged in a microwave vial. The mixture was stirred at 50° C. for 4.5 h. Additional CDI (519 mg, 3.2 mmol) and imidazole (218 mg, 3.20 mmol) were added, the mixture was stirred at 50° C. for 16 h and then treated with (R)-1-(4-fluorophenyl)ethanamine (536 mg, 3.85 mmol). The mixture was stirred at 50° C. for 2 h and then diluted with EtOAc washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (0-40% EtOAc in hexane, 25 CV; 40-100% EtOAc in hexane, 20 CV) to afford (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (154 mg, 0.229 mmol, 28%) as a yellow solid. MS ESI calc'd. for C34H29FN5O [M+H]+ 542, found 542. the mixture was stirred at 50° C. for 16 h The mixture was stirred at 50° C. for 2 h washed with water, brine dried (Na2SO4) concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (0-40% EtOAc in hexane, 25 CV; 40-100% EtOAc in hexane, 20 CV)

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

実験手順: A solution of 3-(5-((2R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid (20 mg, 0.039 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.017 mL, 0.13 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (24 mg, 0.05 mmol) and diisopropylethylamine (0.024 mL, 0.14 mmol) in 0.4 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.16 (m, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.06 (m, 4H), 6.56 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 5.07 (bs, 1H), 3.59 (d, J=13.6 Hz, 1H), 3.40 (d, J=13.6 Hz, 1H), 2.55 (m, 2H), 2.16-1.98 (m, 6H), 1.72 (s, 3H), 1.64 (d, J=7.0 Hz, 3H), 1.41 (s, 9H). Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (110 mg, 0.18 mmol) was suspended in THF (2 ml), cooled to 0° C., then 4-methylmorpholine (55.3 mg, 0.55 mmol) and ethylchloroformate (27.7 mg, 0.26 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h, then (R)-1-(4-fluorophenyl)ethylamine was added. The reaction was warmed to RT and stirred for 1 h, then concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-5% MeOH/DCM) to provide (R)-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-(1-(4-fluorophenyl)ethyl)picolinamide (100 mg, yield: 76%). MS (M+H)+: 724. The reaction was warmed to RT stirred for 1 h concentrated in vacuo The resulting residue was purified column chromatography (eluted with 0-5% MeOH/DCM)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro nicotinonitrile (Method 1, 0.3 g, 1.0 mmol) and (R)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.1 mmol) was added to n-BuOH (2 ml) and DIEA (0.18 g, 1.4 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hours, then cooled to room temperature and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.11 g, 26%). 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]+ 381. cooled to room temperature concentrated The resulting residue was purified by column chromatography (DCM-MeOH=80:1)

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

実験手順: 1-(tert-Butoxycarbonylamino)-4-oxocyclohexanecarboxylic acid (750 mg) was coupled with (R)-1-(4-fluorophenyl)ethanamine using the HATU procedure as described in Example 1. The crude was chromatographed with gradient elution 15-80% ethyl acetate in heptane to yield the title compound (900 mg). MS MH+ 379.3 The crude was chromatographed with gradient elution 15-80% ethyl acetate in heptane