4H-Pyrrolo[3,2-c]pyridin-4-one,1,5,6,7-tetrahydro-(9CI)

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

実験手順: A suspension of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 26.0 mg, 0.065 mmol), bis(2-chloroethyl) ether (Aldrich; 0.015 mL, 0.130 mmol), and DIPEA (0.068 mL, 0.391 mmol) in DMF (1.0 mL) was stirred in a sealed flask at 150° C. for 70 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-10% (2M NH3 in MeOH)/DCM). Product-containing fractions were combined and diluted with DCM (20 mL), and the resulting mixture was sequentially washed with half-saturated brine (30 mL) and water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(2-methyl-3-((1s,3s)-3-morpholinocyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (5.8 mg, 0.013 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.63 (1H, br. s.), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.68 (1H, dd, J=8.1, 1.3 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.0 Hz), 5.25-5.33 (1H, m), 5.09 (1H, d, J=4.1 Hz), 4.22-4.32 (1H, m), 3.75 (4H, t, J=4.5 Hz), 3.70 (2H, m, J=6.8, 6.8, 2.5 Hz), 3.61-3.67 (1H, m), 3.00 (2H, t, J=6.8 Hz), 2.82-2.92 (2H, m), 2.57 (3H, s), 2.42 (4H, br. s.), 1.90-2.01 (2H, m). m/z (ESI, +ve) 433.1 (M+H)+. The reaction mixture was then concentrated onto silica gel chromatographically purified (silica gel, 0-10% (2M NH3 in MeOH)/DCM) diluted with DCM (20 mL) the resulting mixture was sequentially washed with half-saturated brine (30 mL) and water (30 mL) dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 27.4 mg, 0.069 mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (Oakwood Products, Inc., West Columbia, S.C.; 0.073 mL, 0.446 mmol), and DIPEA (0.120 mL, 0.686 mmol) in a mixture of THF (1.0 mL) and DMF (1.0 mL) was heated in a sealed flask at 110° C. for 30 min. The reaction mixture was then cooled to RT, concentrated onto silica gel, and chromatographically purified (silica gel, 10-100% (3:1 EtOAc-EtOH)/hexanes). The product-containing fractions were concentrated in vacuo, and the residue was taken up in 5% MeOH/DCM (40 mL), sequentially washed with half-saturated aqueous NaHCO3 (30 mL) and water (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(2-methyl-3-(1s,3s)-3-((2,2,2-trifluoroethyl)amino)cyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (11.8 mg, 0.027 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.57 (1H, br. s.), 7.94 (1H, dd, J=7.5, 1.1 Hz), 7.68 (1H, dd, J=8.1, 1.1 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.2 Hz), 5.31 (1H, br. s.), 5.16 (1H, d, J=4.7 Hz), 4.13-4.27 (1H, m), 3.68 (2H, td, J=6.9, 2.4 Hz), 3.32-3.43 (1H, m), 3.23 (2H, q, J=9.4 Hz), 3.01-3.08 (2H, m), 2.99 (2H, t, J=6.8 Hz), 2.59 (3H, s), 1.80-1.94 (2H, m). 19F NMR (376 MHz, CDCl3) δ ppm −71.65 (3F, br. s.). m/z (ESI, +ve) 445.0 (M+H)+. The reaction mixture was then cooled to RT concentrated onto silica gel chromatographically purified (silica gel, 10-100% (3:1 EtOAc-EtOH)/hexanes) The product-containing fractions were concentrated in vacuo sequentially washed with half-saturated aqueous NaHCO3 (30 mL) and water (30 mL) dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 72 mg, 0.255 mmol), 1-methylcyclopropanamine hydrochloride (54.9 mg, 0.510 mmol, ChemBridge, San Diego, Calif.), and DIPEA (223 μl, 1.275 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2434(1-methylcyclopropyl)amino)-quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (s, 4H) 1.54 (s, 3H) 2.93 (t, J=6.85 Hz, 2H) 3.46 (td, J=6.85, 2.35 Hz, 2H) 6.99 (br. s., 1H) 7.15 (d, J=1.56 Hz, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.63 (dd, J=8.02, 0.98 Hz, 1H) 8.05 (dd, J=7.63, 1.17 Hz, 1H) 8.33 (s, 2H) 12.89 (br. s., 1H). MS (ESI, pos. ion) m/z: 334.1 (M+1). Prepared similarly to that Purification by silica gel (100% DCM to 4% MeOH/DCM)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 2-aminocyclohexanol (37.0 mg, 0.324 mmol, TCI America, Portland, Oreg.; mixture of racemic cis- and trans-isomers) and heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2434(2-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (24% yield; mixture of racemic cis- and trans-isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.50 (m, 2H) 1.54-1.86 (m, 6H) 2.56 (s, 3H) 2.88 (t, J=6.85 Hz, 2H) 3.44 (td, J=6.75, 2.15 Hz, 2H) 4.08 (br. s., 2H) 4.84 (br. s., 1H) 6.23 (d, J=7.04 Hz, 1H) 6.89 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.32 (t, J=7.82 Hz, 1H) 7.56 (d, J=6.85 Hz, 1H) 7.86 (d, J=6.26 Hz, 1H) 11.86 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.3 (M+1). Prepared similarly to that Purification by silica gel (100% DCM to 8% MeOH/DCM)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 2-aminocyclohexanol (37.0 mg, 0.324 mmol, TCI America, Portland, Oreg.; mixture of racemic cis- and trans-isomers) and heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2434(2-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (24% yield; mixture of racemic cis- and trans-isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.50 (m, 2H) 1.54-1.86 (m, 6H) 2.56 (s, 3H) 2.88 (t, J=6.85 Hz, 2H) 3.44 (td, J=6.75, 2.15 Hz, 2H) 4.08 (br. s., 2H) 4.84 (br. s., 1H) 6.23 (d, J=7.04 Hz, 1H) 6.89 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.32 (t, J=7.82 Hz, 1H) 7.56 (d, J=6.85 Hz, 1H) 7.86 (d, J=6.26 Hz, 1H) 11.86 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.3 (M+1). Prepared similarly to that Purification by silica gel (100% DCM to 8% MeOH/DCM)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 3-aminocyclohexanol (37.0 mg, 0.324 mmol, AB Chem, Inc., Dorval, Canada; mixture of racemic cis- and trans-isomers) and heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2434(3-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (17% yield; mixture of racemic cis- and trans-isomers). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 1H) 1.32-1.51 (m, 3H) 1.55-1.69 (m, 1H) 1.70-1.83 (m, 1H) 1.87 (d, J=12.72 Hz, 1H) 2.00 (br. s., 2H) 2.27 (d, J=11.93 Hz, 1H) 2.55 (d, J=4.11 Hz, 3H) 2.86-3.05 (m, 3H) 3.41-3.72 (m, 4H) 4.02-4.48 (m, 2H) 4.69-4.83 (m, 1H) 6.73-7.02 (m, 2H) 7.07-7.18 (m, 1H) 7.32 (td, J=7.82, 2.15 Hz, 1H) 7.53-7.60 (m, 1H) 7.85-7.96 (m, 1H) 11.86-12.16 (m, 1H). MS (ESI, pos. ion) m/z: 392 (M+1). Prepared similarly to that Purification by silica gel (100% DCM to 8% MeOH/DCM)

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

実験手順: Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 46.7 mg, 0.106 mmol), 3,3-difluorocyclobutanamine hydrochloride (PharmaStone, Lexington, Mass.; 45.5 mg, 0.317 mmol), and DIPEA (0.110 mL, 0.634 mmol) in DMSO (0.8 mL), heating at 80° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2434(3,3-difluorocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26.5 mg, 0.069 mmol, 66% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s.), 7.88 (1H, dd, J=7.6, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.0 Hz), 7.51 (1H, d, J=5.5 Hz), 7.37 (1H, t, J=7.8 Hz), 7.06 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 4.39-4.51 (1H, m), 3.45 (2H, td, J=6.7, 2.5 Hz), 3.04-3.15 (2H, m), 2.88 (2H, t, J=6.7 Hz), 2.86-2.92 (2H, m), 2.57 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −82.16 to −81.43 (1F, m), −95.87 to −95.05 (1F, m). m/z (ESI, +ve) 384.2 (M+H)+. Prepared similar to Chromatographic purification (silica gel, 0-100% EtOAc/hexanes

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

実験手順: Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 2-methylpropane-1,2-diamine (35.7 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(34(2-amino-2-methylpropyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.79-12.88 (m, 1H), 7.82-7.88 (m, 1H), 7.52-7.57 (m, 1H), 7.25-7.32 (m, 1H), 7.11-7.23 (m, 1H), 6.96-7.01 (m, 1H), 6.89-6.95 (m, 1H), 4.31-4.37 (m, 1H), 3.44-3.48 (m, 5H), 2.91-2.97 (m, 2H), 2.54-2.60 (m, 3H), 1.20 (s, 6H). m/z (ESI, +ve) 365.1 (M+H)+. Prepared Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.)

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

実験手順: Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 1-methylcyclopentanamine (40.2 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-(1-methylcyclopentyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.21 (s, 1H), 7.83-7.91 (m, 1H), 7.53-7.61 (m, 1H), 7.30-7.39 (m, 1H), 7.07 (s, 1H), 6.95 (s, 1H), 6.18 (s, 1H), 3.40-3.48 (m, 2H), 2.85-2.94 (m, 2H), 2.55 (s, 3H), 2.37-2.48 (m, 2H), 1.67-1.85 (m, 6H), 1.64 (s, 3H). m/z (ESI, +ve) 376.1 (M+H)+. Prepared Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-(2-methyl-3-(piperidin-4-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 53, 55 mg, 0.146 mmol) and DIPEA (76 μl, 0.438 mmol, EMD Biosciences, Rockland, Mass.) in DCM (5.8 mL) was set stirring at 25° C. before adding Ac2O (15.16 μl, 0.161 mmol, Sigma Aldrich) dropwise. The reaction was stirred for 30 min before concentrating under reduced pressure. The residue was taken up in DMSO, and purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 75%). Product-containing fractions were concentrated under reduced pressure and the residue was loaded onto a pre-washed (MeOH, 1 volume) functionalized Si-carbonate column (Silicyle) and allowed to percolate through to provide 2-(34(1-acetylpiperidin-4-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12.2 mg, 20.0%). 1H NMR (MeOH-d4) δ: 7.84-7.88 (m, 1H), 7.60-7.65 (m, 1H), 7.34-7.40 (m, 1H), 7.23 (s, 1H), 4.55-4.63 (m, 1H), 4.34-4.45 (m, 1H), 3.99-4.07 (m, 1H), 3.58-3.66 (m, 2H), 3.39-3.50 (m, 2H), 2.98-3.04 (m, 1H), 2.58 (s, 3H), 2.27-2.36 (m, 2H), 2.18-2.24 (m, 1H), 2.15 (s, 3H), 1.58-1.69 (m, 2H). m/z (ESI, −ve) 417.1 (M−H)−. The reaction was stirred for 30 min before concentrating under reduced pressure purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 75%) Product-containing fractions were concentrated under reduced pressure a pre-washed (MeOH, 1 volume) functionalized Si-carbonate column (Silicyle)

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

実験手順: Prepared according to Example 102, using 3-fluoroaniline (230 μl, 2.069 mmol, Sigma Aldrich), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 77 mg, 0.259 mmol), and 1.0 M LHMDS, in THF (2069 μl, 2.069 mmol, Sigma Aldrich) and stirring at 25° C. for 30 min. Purification by column chromatography (silica gel: 0 to 100% EtOAc/hexanes) provided 2424(3-fluorophenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (43 mg, 44.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-12.00 (m, 1H) 9.69-9.77 (1H, m) 8.14-8.21 (1H, m) 7.87-7.93 (2H, m) 7.62-7.77 (3H, m) 7.31-7.54 (2H, m) 7.08-7.16 (2H, m) 6.78-6.89 (1H, m) 3.38-3.50 (2H, m) 2.67-2.76 (2H, m). m/z (ESI, +ve) 373.1 (M+H)+. Prepared Purification by column chromatography (silica gel: 0 to 100% EtOAc/hexanes)

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

実験手順: Prepared according to Example 102, using 3-fluoroaniline (230 μl, 2.069 mmol, Sigma Aldrich), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 77 mg, 0.259 mmol), and 1.0 M LHMDS, in THF (2069 μl, 2.069 mmol, Sigma Aldrich) and stirring at 25° C. for 30 min. Purification by column chromatography (silica gel: 0 to 100% EtOAc/hexanes) provided 2424(3-fluorophenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (43 mg, 44.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-12.00 (m, 1H) 9.69-9.77 (1H, m) 8.14-8.21 (1H, m) 7.87-7.93 (2H, m) 7.62-7.77 (3H, m) 7.31-7.54 (2H, m) 7.08-7.16 (2H, m) 6.78-6.89 (1H, m) 3.38-3.50 (2H, m) 2.67-2.76 (2H, m). m/z (ESI, +ve) 373.1 (M+H)+. Prepared Purification by column chromatography (silica gel: 0 to 100% EtOAc/hexanes)