N-甲基-1-(四氢呋喃-2-基)甲胺

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+). subsequently extracted with 1N HCl, saturated NaHCO3, brine dried with Na2SO4 concentrated to dryness The crude was purified by silica chromatography The resulting material was dissolved in 3 ml of methanol aqueous NaOH (1 ml, 2 N in H2O) was added the mixture stirred overnight at room temperature The solvent was removed under reduced pressure The resulting crude was directly purified by mass-triggered reverse phase HPLC

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+). subsequently extracted with 1N HCl, saturated NaHCO3, brine dried with Na2SO4 concentrated to dryness The crude was purified by silica chromatography The resulting material was dissolved in 3 ml of methanol aqueous NaOH (1 ml, 2 N in H2O) was added the mixture stirred overnight at room temperature The solvent was removed under reduced pressure The resulting crude was directly purified by mass-triggered reverse phase HPLC

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

实验步骤: N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below), N-methyltetrahydrofurfurylamine (81 mg, 0.7 mmol) and acetic acid (26 μl, 0.45 mmol) were dissolved in tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (144 mg, 0.7 mmol) was then added and the mixture stirred for a further 3 hours. The mixture was concentrated and the residue purified by flash chromatography eluting with 100% ethyl acetate. Concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) was added and the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam/gum (43 mg, 22%). NMR Spectrum: (DMSO-d6, 373K) 1H NMR 1.53 (m, 1H), 1.82 (m, 2H), 1.98 (m, 1H), 2.37 (s, 3H), 2.64 (m, 2H), 3.00 (br s, 2H), 3.66 (q, 1H), 3.77 (q, 1H), 3.84 (m, 2H), 4.04 (m, 1H), 6.63 (m, 1H), 6.82 (d, 1H), 6.98 (m, 1H), 7.27 (d, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.29 (s, 1H), 8.89 (s, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H+ 442. the mixture stirred for a further 3 hours The mixture was concentrated the residue purified by flash chromatography eluting with 100% ethyl acetate Concentration of the solvent gave product as a gum the solution then stirred at ambient temperature for 2 hours The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated

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

实验步骤: 4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-1-(tetrahydrofuran-2-yl)methanamine via General Procedure E to give 10.7 mg of 290 following reverse phase purification. MS (Q1) 477.2 (M)+ to give 10.7 mg of 290 following reverse phase purification

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

实验步骤: 4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-1-(tetrahydrofuran-2-yl)methanamine via General Procedure E to give 10.7 mg of 290 following reverse phase purification. MS (Q1) 477.2 (M)+ to give 10.7 mg of 290 following reverse phase purification

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+). subsequently extracted with 1N HCl, saturated NaHCO3, brine dried with Na2SO4 concentrated to dryness The crude was purified by silica chromatography The resulting material was dissolved in 3 ml of methanol aqueous NaOH (1 ml, 2 N in H2O) was added the mixture stirred overnight at room temperature The solvent was removed under reduced pressure The resulting crude was directly purified by mass-triggered reverse phase HPLC

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

实验步骤: N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below), N-methyltetrahydrofurfurylamine (81 mg, 0.7 mmol) and acetic acid (26 μl, 0.45 mmol) were dissolved in tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (144 mg, 0.7 mmol) was then added and the mixture stirred for a further 3 hours. The mixture was concentrated and the residue purified by flash chromatography eluting with 100% ethyl acetate. Concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) was added and the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam/gum (43 mg, 22%). NMR Spectrum: (DMSO-d6, 373K) 1H NMR 1.53 (m, 1H), 1.82 (m, 2H), 1.98 (m, 1H), 2.37 (s, 3H), 2.64 (m, 2H), 3.00 (br s, 2H), 3.66 (q, 1H), 3.77 (q, 1H), 3.84 (m, 2H), 4.04 (m, 1H), 6.63 (m, 1H), 6.82 (d, 1H), 6.98 (m, 1H), 7.27 (d, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.29 (s, 1H), 8.89 (s, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H+ 442. the mixture stirred for a further 3 hours The mixture was concentrated the residue purified by flash chromatography eluting with 100% ethyl acetate Concentration of the solvent gave product as a gum the solution then stirred at ambient temperature for 2 hours The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated