Example 2
To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 393.9.
Example 5
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (21 mg, 88%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.74 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 6
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(p-tolyl)ethanamine to give the title compound as a white solid (39.3 mg, 83%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.28 (s, 3H), 4.86-4.95 (m, 1H), 5.01-5.11 (m, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.74 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 7
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (14 mg, 58%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.01-5.10 (m, 2H), 6.85-6.92 (m, 2H), 7.23-7.29 (m, 2H), 7.92-8.00 (m, 1H), 8.07-8.16 (m, 1H), 8.21-8.28 (m, 2H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 339.0.
Example 8
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chlorophenyl)ethanamine to give the title compound as a white solid (10 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.93 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.33-7.42 (m, 4H), 7.92-7.98 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 342.9, 345.0.
Example 9
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (16.3 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.98-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.92-7.96 (m, 1H), 8.08-8.14 (m, 1H), 8.20-8.27 (m, 2H), 8.74 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 337.0.
Example 10
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(o-tolyl)ethanamine to give the title compound as a white solid (1 mg, 4%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05 (d, J=2.4 Hz, 2H), 5.09 (t, J=7.3 Hz, 1H), 7.11-7.16 (m, 2H), 7.19-7.24 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.80 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 11
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-ethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (19.4 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29-1.33 (m, 3H), 1.37 (d, J=6.8 Hz, 3H), 3.96-4.04 (m, 2H), 4.84-4.93 (m, 1H), 5.01-5.10 (m, 2H), 6.85-6.90 (m, 2H), 7.21-7.28 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.16 (m, 1H), 8.21-8.29 (m, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 12
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethoxyphenyl)ethanamine, HCl to give the title compound as a white solid (17.2 mg, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.8 Hz, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 5.06 (s, 2H), 5.14 (quin, J=7.3 Hz, 1H), 6.49-6.53 (m, 2H), 6.49-6.52 (m, 1H), 6.52 (s, 2H), 7.22 (d, J=7.8 Hz, 1H), 7.95 (td, J=7.6, 1.5 Hz, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.62 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]+ 390.9.
Example 13
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (81 mg, 88%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40-1.43 (m, 3H), 5.01 (quin, J=7.2 Hz, 1H), 5.10 (s, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.10-8.14 (m, 1H), 8.21-8.28 (m, 2H), 8.91 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+Na]+ 399.3.
Example 14
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.4 mg, 77%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.10-7.24 (m, 4H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 341.0.
Example 15
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (18.6 mg, 58%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.29 (m, 2H), 7.96-8.03 (m, 2H), 8.33-8.39 (m, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 357.0.
Example 16
The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (13.0 mg, 43%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.1 Hz, 1H), 5.06-5.09 (m, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 7.91-8.03 (m, 2H), 8.04-8.09 (m, 1H), 8.73 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 341.0.
Example 17
The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (22.4 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.92-8.03 (m, 2H), 8.06 (dd, J=7.8, 1.5 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 357.0.
Example 18
The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.1 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.97 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.5 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.58 (d, J=2.4 Hz, 1H), 7.63-7.68 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 19
The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (15.6 mg, 52%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=7.3 Hz, 3H), 2.25-2.28 (m, 3H), 4.86-4.94 (m, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 357.0, 358.9.
Example 20
The title compound was prepared in a manner similar to Example 2 using 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (20.4 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 372.4, 374.9.
Example 21
The title compound was prepared in a manner similar to Example 2 using 2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an white solid (15.3 mg, 51%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.98 (dd, J=8.5, 2.2 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 357.0, 358.9.
Example 22
The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as an off-white solid (18.6 mg, 63%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.29 (m, 3H), 4.91 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.24 (m, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.17-8.26 (m, 2H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 357.0, 358.9.
Example 23
The title compound was prepared in a manner similar to Example 2 using 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (14.2 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.87-7.94 (m, 1H), 8.22 (ddd, J=18.4, 7.9, 1.5 Hz, 2H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 372.9, 374.9.
Example 24
The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.0 mg, 26%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.27 (s, 3H), 2.77 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.05 (d, J=1.5 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.19-7.24 (m, 2H), 7.78-7.85 (m, 1H), 7.91-7.96 (m, 1H), 8.04-8.10 (m, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 337.0.
Example 25
The title compound was prepared in a manner similar to Example 2 using 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (6.0 mg, 19%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.77 (s, 3H), 3.71-3.75 (m, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.04 (d, J=2.4 Hz, 2H), 6.86-6.92 (m, 2H), 7.21-7.28 (m, 2H), 7.78-7.85 (m, 1H), 7.94 (dt, J=7.1, 1.3 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 26
The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.1 mg, 42%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 4.86-4.94 (m, 1H), 5.07 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.44-8.47 (m, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 390.8, 392.9.
Example 27
The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.2 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.86-4.93 (m, 1H), 5.07 (d, J=1.0 Hz, 2H), 6.87-6.91 (m, 2H), 7.22-7.28 (m, 2H), 8.18-8.22 (m, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 406.8, 408.8.
Example 28
The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (9.1 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (t, J=7.6 Hz, 1H), 5.04 (d, J=1.5 Hz, 2H), 7.11-7.16 (m, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.92 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 337.1.
Example 29
The title compound was prepared in a manner similar to Example 2 using 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as an off-white solid (7.0 mg, 22%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.54-2.57 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.93 (dd, J=8.3, 1.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 30
The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (12.3 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.04 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.03 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.72-7.76 (m, 1H), 7.85-7.90 (m, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 31
The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (11.8 mg, 38%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.72-3.74 (m, 3H), 4.04 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 4.99-5.05 (m, 2H), 6.86-6.91 (m, 2H), 7.21-7.27 (m, 2H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.71-7.77 (m, 1H), 7.84-7.90 (m, 1H), 8.68 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 369.0.
Example 32
The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (11.3 mg, 37%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.24-2.29 (m, 4H), 4.87-4.95 (m, 1H), 5.02 (s, 2H), 7.11-7.15 (m, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.71-7.78 (m, 1H), 8.03-8.14 (m, 2H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 341.0.
Example 33
The title compound was prepared in a manner similar to Example 2 using 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (8.4 mg, 26%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.71-3.75 (m, 3H), 4.84-4.95 (m, 1H), 5.01 (s, 2H), 6.86-6.92 (m, 2H), 7.22-7.28 (m, 2H), 7.71-7.79 (m, 1H), 8.04-8.08 (m, 1H), 8.08-8.15 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 356.9.
Example 34
The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (28.2 mg, 92%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.57 (s, 3H), 4.90 (t, J=7.3 Hz, 1H), 5.04 (d, J=1.0 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.23 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.72 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]+ 359.0.
Example 35
The title compound was prepared in a manner similar to Example 2 using 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (24.1 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.00-0.00 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 2.56-2.59 (m, 3H), 3.73 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.03 (d, J=2.0 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.80 (m, 1H), 8.04 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.66-8.73 (m, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 36
The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (23.3 mg, 78%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.3 Hz, 1H), 5.03 (d, J=1.0 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 353.0.
Example 37
The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.6 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=7.3 Hz, 3H), 3.71-3.74 (m, 3H), 3.99 (s, 3H), 4.89 (quin, J=7.2 Hz, 1H), 5.02 (d, J=1.5 Hz, 2H), 6.86-6.91 (m, 2H), 7.22-7.27 (m, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 8.11-8.18 (m, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 369.0.
Example 38
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (4.2 mg, 13%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 3.70-3.74 (m, 3H), 3.92 (s, 3H), 4.83-4.92 (m, 1H), 4.95 (d, J=2.0 Hz, 2H), 6.85-6.91 (m, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.67-7.71 (m, 1H), 7.96-8.04 (m, 1H), 8.65 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 369.0.
Example 39
The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (1.2 mg, 4%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.34-1.39 (m, 3H), 2.26-2.29 (m, 4H), 2.81 (s, 3H), 4.85-4.94 (m, 1H), 5.00 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.25 (m, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+Na]+ 359.0.
Example 40
The title compound was prepared in a manner similar to Example 2 using 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (0.5 mg, 2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.81 (s, 3H), 3.72-3.75 (m, 3H), 4.86-4.94 (m, 1H), 4.99 (s, 2H), 6.85-6.93 (m, 2H), 7.23-7.29 (m, 2H), 7.68-7.74 (m, 1H), 7.91-7.97 (m, 1H), 7.99-8.05 (m, 1H), 8.68 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]+ 375.0.
Example 41
The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (10.7 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 2.73 (s, 3H), 4.90 (quin, J=7.3 Hz, 1H), 5.03 (d, J=2.4 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20-7.23 (m, 2H), 7.77 (s, 1H), 7.87 (s, 1H), 8.71 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 351.1.
Example 42
The title compound was prepared in a manner similar to Example 2 using 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (9.0 mg, 29%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (d, J=2.4 Hz, 1H), 2.73 (s, 3H), 3.73 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.02 (d, J=2.9 Hz, 2H), 6.86-6.91 (m, 2H), 7.23-7.27 (m, 2H), 7.75-7.79 (m, 1H), 7.88 (d, J=1.0 Hz, 1H), 8.69 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 367.0.
Example 43
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (16.8 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.26-2.28 (m, 3H), 4.91 (t, J=7.6 Hz, 1H), 5.11 (s, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.20-7.25 (m, 2H), 8.41-8.53 (m, 3H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 391.0.
Example 44
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a white solid (20.3 mg, 68%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 3.73 (s, 3H), 4.86-4.95 (m, 1H), 5.10 (d, J=1.0 Hz, 2H), 6.84-6.93 (m, 2H), 7.23-7.27 (m, 2H), 8.41-8.54 (m, 3H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+Na]+ 429.0.
Example 45
The title compound was prepared in a manner similar to Example 2 using 2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(p-tolyl)ethanamine to give the title compound as a white solid (25.5 mg, 57%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.27 (s, 3H), 2.55 (s, 3H), 4.90 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.83-7.90 (m, 2H), 8.72 (d, J=8.3 Hz, 1H); ESI-MS m/z [M+H]+ 355.4.
Example 46
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-methoxy-4-methylphenyl)ethanamine, HCl to give the title compound as a tan solid (38.8 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.8 Hz, 3H), 2.28 (s, 3H), 3.77 (s, 3H), 5.03-5.08 (m, 2H), 5.16 (quin, J=7.2 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.78 (s, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.92-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.28 (m, 2H), 8.66 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 353.2.
Example 47
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (30.1 mg, 57%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.19 (quin, J=7.1 Hz, 1H), 7.27 (td, J=8.5, 2.9 Hz, 1H), 7.39 (dd, J=8.8, 2.9 Hz, 1H), 7.54 (dd, J=8.8, 6.3 Hz, 1H), 7.90-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M, M+2]+ 360.1, 362.1.
Example 48
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-bromo-4-fluorophenyl)ethanamine, HCl to give the title compound as a white solid (37.4 mg, 63%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (d, J=7.3 Hz, 3H), 5.09 (s, 2H), 5.11-5.19 (m, 1H), 7.32 (td, J=8.5, 2.4 Hz, 1H), 7.49-7.56 (m, 2H), 7.92-7.98 (m, 1H), 8.11 (td, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 9.00 (d, J=7.8 Hz, 1H); ESI-MS m/z [M, M+2]+ 405.1, 407.1.
Example 49
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-fluorophenyl)ethanamine to give the title compound as a white solid (27.9 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.41 (m, 3H), 4.95 (quin, J=7.2 Hz, 1H), 5.07 (s, 2H), 7.12-7.21 (m, 2H), 7.35-7.41 (m, 2H), 7.92-7.99 (m, 1H), 8.08-8.15 (m, 1H), 8.20-8.29 (m, 2H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 327.2.
Example 52
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound as a white solid (23.6 mg, 74%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (d, J=6.8 Hz, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 4.99-5.08 (m, 3H), 6.94 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.97-8.03 (m, 2H), 8.35 (dd, J=8.8, 4.9 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 355.3.
Example 53
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (23.4 mg, 71%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.29 (s, 3H), 5.05-5.16 (m, 3H), 6.93-7.03 (m, 2H), 7.31 (t, J=8.1 Hz, 1H), 7.91-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.20-8.28 (m, 2H), 8.83 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 341.2.
Example 54
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the title compound as a white solid (13.6 mg, 42%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.8 Hz, 3H), 2.29 (s, 3H), 5.05-5.14 (m, 3H), 6.91-7.04 (m, 2H), 7.30 (t, J=8.1 Hz, 1H), 7.97-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 359.2.
Example 55
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (13.2 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-1.42 (m, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.08 (s, 2H), 7.30-7.35 (m, 2H), 7.42-7.47 (m, 2H), 7.97-8.03 (m, 2H), 8.33-8.40 (m, 1H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 411.2.
Example 56
The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (21.8 mg, 81%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 4.97 (quin, J=7.2 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.44-7.52 (m, 3H), 7.67 (d, J=2.4 Hz, 1H), 8.15 (d, J=9.3 Hz, 1H), 8.84 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 423.4.
Example 57
The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (17.3 mg, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 3.98 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.58 (d, J=2.9 Hz, 1H), 7.64-7.69 (m, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 423.3.
Example 58
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (16.2 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.93-5.00 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.48 (m, 3H), 7.65-7.72 (m, 1H), 8.00 (t, J=8.3 Hz, 1H), 8.79 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 423.3.
Example 59
The title compound was prepared in a manner similar to Example 2 using 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (22.5 mg, 87%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.8 Hz, 3H), 3.99 (s, 3H), 5.00 (quin, J=7.1 Hz, 1H), 5.07 (s, 2H), 7.49 (dd, J=8.8, 2.9 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 8.91 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 407.4.
Example 60
The title compound was prepared in a manner similar to Example 2 using 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (19.9 mg, 77%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.97 (s, 3H), 4.97-5.03 (m, 1H), 5.07 (s, 2H), 7.54-7.58 (m, 3H), 7.65 (dd, J=9.0, 2.7 Hz, 1H), 7.70 (d, J=7.8 Hz, 2H), 8.17 (d, J=9.3 Hz, 1H), 8.90 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 407.4.
Example 61
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (12.9 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=7.3 Hz, 3H), 3.93 (s, 3H), 4.96-5.04 (m, 3H), 7.41-7.47 (m, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.66-7.73 (m, 3H), 7.99 (t, J=8.3 Hz, 1H), 8.86 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 407.4.
Example 62
The title compound was prepared in a manner similar to Example 2 using 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compound as a white solid (4.8 mg, 18%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.39 (d, J=7.3 Hz, 3H), 4.04 (s, 3H), 4.97 (quin, J=7.1 Hz, 1H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.43-7.49 (m, 2H), 7.62-7.67 (m, 1H), 7.74 (dd, J=7.8, 1.0 Hz, 1H), 7.84-7.91 (m, 1H), 8.82 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 423.3.
Example 64
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (10.6 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=7.3 Hz, 3H), 4.97-5.05 (m, 1H), 5.10 (s, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.97-8.02 (m, 2H), 8.36 (ddq, J=8.2, 4.9, 1.5, 1.5, 1.5 Hz, 1H), 8.92 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 395.3.
Example 65
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (11.3 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.8 Hz, 3H), 5.10 (s, 2H), 5.14-5.21 (m, 1H), 7.59-7.70 (m, 3H), 7.92-7.98 (m, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.27 (m, 2H), 9.02 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 395.6.
Example 66
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (19.2 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35-1.40 (m, 3H), 4.88-4.99 (m, 1H), 5.03-5.09 (m, 2H), 7.03-7.36 (m, 3H), 7.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.95-7.98 (m, 1H), 8.08-8.15 (m, 1H), 8.21-8.28 (m, 2H), 8.81 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 375.7.
Example 67
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the title compound as a white solid (15.0 mg, 73%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.8 Hz, 3H), 3.92 (s, 3H), 4.97-5.02 (m, 2H), 5.16 (quin, J=7.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.57-7.72 (m, 4H), 7.99 (t, J=8.1 Hz, 1H), 8.97 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 425.4.
Example 68
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (12.1 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.89-4.99 (m, 1H), 5.07 (s, 2H), 7.03-7.41 (m, 5H), 7.95-8.05 (m, 2H), 8.33-8.40 (m, 1H), 8.77-8.84 (m, 1H); ESI-MS m/z [M+H]+ 393.4.
Example 69
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (17.5 mg, 78%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.8 Hz, 3H), 3.93 (s, 3H), 4.89-5.00 (m, 3H), 7.01-7.41 (m, 2H), 7.11-7.16 (m, 1H), 7.42-7.47 (m, 1H), 7.67-7.72 (m, 1H), 7.99 (t, J=8.3 Hz, 1H), 8.75 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 405.4.
Example 70
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (6.0 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.13 (quin, J=7.1 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.36 (dd, J=10.5, 1.7 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.92-7.99 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.95 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 411.3.
Example 71
The title compound was prepared in a manner similar to Example 2 using 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (7.8 mg, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 5.09 (s, 2H), 5.10-5.17 (m, 1H), 7.27 (d, J=9.8 Hz, 1H), 7.36 (d, J=10.7 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.95-8.04 (m, 2H), 8.36 (dd, J=8.5, 5.1 Hz, 1H), 8.95 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 429.2.
Example 72
The title compound was prepared in a manner similar to Example 2 using 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give the title compound as a white solid (11.8 mg, 49%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-1.42 (m, 3H), 3.92 (s, 3H), 4.99 (s, 2H), 5.13 (quin, J=7.2 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.33-7.39 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.5 Hz, 1H), 7.69 (dd, J=7.8, 1.0 Hz, 1H), 7.97-8.03 (m, 1H), 8.90 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]+ 441.2.
Example 73
To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was allowed to stir at RT for 45 min, and was then added to a solution of 2-phenylethanamine (15 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by HPLC Method A provided the title compound as a white solid (11.1 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.73 (t, J=7.6 Hz, 2H), 3.29-3.34 (m, 2H), 5.00 (s, 2H), 7.20-7.33 (m, 5H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M+H]+ 309.9.
Example 74
To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25 mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride (21 μL, 0.244 mmol). The mixture was stirred at RT for 45 min, then added to a solution of 2-(4-chlorophenyl)ethanamine (17 μL, 0.122 mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reaction mixture was stirred at RT for 18 h. Purification by flash silica gel chromatography, eluting with 0-70% EtOAc in heptanes provided the title compound as a white solid (5.2 mg, 13%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.73 (t, J=7.1 Hz, 2H), 3.28-3.32 (m, 2H), 4.99 (s, 2H), 7.24-7.29 (m, 2H), 7.33-7.37 (m, 2H), 7.93-8.00 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.39 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]+ 342.9, 344.9.
Example 75
The title compound was prepared in a manner similar to Example 74 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(3-chlorophenyl)ethanamine to give the title compound as a white solid (8.4 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.75 (t, J=7.1 Hz, 2H), 3.32-3.36 (m, 2H), 4.99 (s, 2H), 7.18-7.35 (m, 4H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.41 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]+ 342.9, 344.9.
Example 76
The title compound was prepared in a manner similar to Example 73 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(p-tolyl)ethanamine to give the title compound as a white solid (5.5 mg, 14%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 3.25-3.31 (m, 2H), 4.99 (s, 2H), 7.10 (s, 4H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.37-8.42 (m, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 79
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-2-phenylpropan-1-amine to give the title compound as a white solid (12.5 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.89 (sxt, J=7.1 Hz, 1H), 3.24 (dd, J=7.1, 6.1 Hz, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.92-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 80
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-2-phenylpropan-1-amine to give the title compound as a white solid (13.1 mg, 56%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.8 Hz, 3H), 2.86-2.93 (m, 1H), 3.22-3.26 (m, 2H), 4.99 (s, 2H), 7.17-7.34 (m, 5H), 7.96 (td, J=7.6, 1.5 Hz, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2H), 8.36 (t, J=5.9 Hz, 1H); ESI-MS m/z [M+H]+ 323.0.
Example 81
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and 2-(2-chloro-4-methoxyphenyl)ethanamine to give the title compound as a white solid (16.6 mg, 61%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.3 Hz, 2H), 3.25-3.30 (m, 2H), 3.31 (s, 2H), 3.75 (s, 3H), 4.99 (s, 2H), 6.87 (dd, J=8.5, 2.7 Hz, 1H), 7.01 (d, J=2.9 Hz, 1H), 7.21-7.27 (m, 1H), 7.93-8.00 (m, 1H), 8.09-8.16 (m, 1H), 8.22-8.30 (m, 2H), 8.42 (t, J=5.6 Hz, 1H); ESI-MS m/z [M, M+2]+ 373.0, 374.9.
Example 82
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (R)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (17.9 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.72 (m, 2H), 3.70-3.74 (m, 3H), 3.91 (spt, J=6.8 Hz, 1H), 4.92-5.02 (m, 2H), 4.97 (d, J=4.9 Hz, 2H), 6.79-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.92-8.00 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]+ 354.0.
Example 83
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as a white solid (14.1 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.53-2.74 (m, 2H), 3.70-3.74 (m, 3H), 3.88-3.96 (m, 1H), 4.92-5.02 (m, 2H), 6.81-6.88 (m, 2H), 7.08-7.16 (m, 2H), 7.96 (ddd, J=8.1, 7.1, 1.5 Hz, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.22-8.30 (m, 3H); ESI-MS m/z [M+H]+ 353.9.
Example 84
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine to give the title compound as a white solid (19.7 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.8 Hz, 3H), 2.67 (d, J=6.8 Hz, 2H), 3.78-3.82 (m, 3H), 3.97-4.07 (m, 1H), 4.89-4.99 (m, 2H), 6.92 (dd, J=7.8, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.22-8.28 (m, 2H); ESI-MS m/z [M, M+2]+ 386.9, 389.0.
Example 85
The title compound was prepared in a manner similar to Example 2 using 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and (S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine, HCl to give the title compound as a tan solid (32.5 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.8 Hz, 3H), 2.75-2.78 (m, 2H), 3.75 (s, 3H), 3.99-4.09 (m, 1H), 4.89-5.02 (m, 2H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.22-7.27 (m, 1H), 7.96-7.99 (m, 1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.31 (m, 3H); ESI-MS m/z [M, M+2]+ 386.9, 388.9.
Example 87
The title compound was prepared in a manner similar to Example 87 using (S)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride to give the title compound as an off-white solid (19 mg, 56%). 1H NMR (500 MHz, chloroform-d) δ ppm 0.92 (t, J=7.1 Hz, 3H) 1.86 (t, J=7.3 Hz, 2H) 4.95 (d, J=7.3 Hz, 1H) 5.13 (s, 2H) 6.31 (d, J=7.8 Hz, 1H) 7.40 (d, J=7.8 Hz, 2H) 7.59 (d, J=7.8 Hz, 2H) 7.86 (d, J=8.3 Hz, 1H) 8.00 (s, 1H) 8.21 (d, J=8.3 Hz, 1H) 8.38 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 391.
The compounds of the invention can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of invention and at least one pharmaceutically acceptable excipient.
In effecting treatment of a patient in need of such treatment, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The compounds of the invention can be administered by parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.
The pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form. The term “pharmaceutically acceptable excipient” refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
The present pharmaceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention. The term “unit dose form” refers to a physically discrete unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regimen to produce the desired therapeutic effect. One or more “unit dose form” may be taken to affect the treatment dosage, typically on a daily schedule.
In one particular variation, the composition is a pharmaceutical composition adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration. In still another particular variation, the pharmaceutical composition is a liquid formulation adapted for parenteral administration.
In another embodiment, the invention provides a method of treating a disease, disorder or condition associated with GPR139, comprising: administering to a patient in need thereof an effective amount of a compound of the invention. In another embodiment, a compound of the invention is provided for use as a medicament. The invention also provides the use of a compound of the invention, including the use for the manufacture of a medicament, to treat a disease, disorder or condition associated with GPR139 described herein. The compounds of the invention are GPR139 agonists for treating a variety of subjects (e.g., humans, non-human mammals and non-mammals).
As used herein terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state. The compounds of the invention are GPR139 agonists and may be useful for treating a variety of conditions. The term “disease, disorder or condition associated with GPR139” includes conditions, disorders, and diseases in which an agonist of GPR139 may provide a therapeutic benefit, such as CNS disorders, disorders of the pancreas, such as pancreatitis, phenylketonuria, and pituitary disorders.
The term “disease, disorder or condition associated with GPR139” includes specifically, but is not limited to, CNS disorders such as schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, including mild cognitive impairment, Alzheimer's Disease, disorders affecting short term memory, disorders affecting long term memory, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, including generalized anxiety disorder and social anxiety disorder, pain, fibromyalgia and other disorders mentioned herein, among others.
Schizophrenia is a chronic, severe, and disabling disorder characterized, in part, by negative symptoms, such as blunted affect, deficits in social functioning, anhedonia, avolition and poverty of speech, and by congnitive impairment associated with schizophrenia (CIAS), such as impairment in attention, working memory, executive function and social cognition. Autism spectrum disorder is a group of developmental disabilities that can cause significant social, communication and behavioral challenges (repetitive and stereotyped behavior). Because of the pro-social effects expected from GPR139 agonists, the present compounds may treat schizophrenia and autism spectrum disorder.
In particular, the term “disease, disorder or condition associated with GPR139” includes schizophrenia.
In particular, the term “disease, disorder or condition associated with GPR139” includes autism spectrum disorder.
In particular, the term “disease, disorder or condition associated with GPR139” includes addiction. Examples include addiction to nicotine, alcohol, and/or cocaine.
In particular, the term “disease, disorder or condition associated with GPR139” includes attention deficit hyperactivity disorder.
In particular, the term “disease, disorder or condition associated with GPR139” includes bipolar disorder.
In particular, the term “disease, disorder or condition associated with GPR139” includes depression, such as major depressive disorder.
The terms “treat,” “treatment,” and “treating” include improvement of the conditions described herein. The terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms “treat,” “treatment,” and “treating” are intended to include therapeutic treatment of such disorders. The terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.
As used herein the terms “patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.
As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 1 mg to 100 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient having a mass that falls outside of this weight range.
The compounds of the invention may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more disorders, diseases or conditions for which GPR139 is indicated may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating a particular disease, disorder or condition associated with GPR139.
For example, in the treatment of schizophrenia the compounds of the invention may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists, GlyT1 inhibitors, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazopam, thioridazine, thiothixene, tracazolate, kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and the like.
Also for example, in the treatment of depression the compounds of the invention may be administered in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide, venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and the like.
In yet another example, in the treatment of Alzheimer's disease or mild cognitive impairment the compounds of the invention may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, anti-amyloid antibodies, also sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, and tranquilizers, and such other medications as are used in the treatment of Alzheimer's disease or mild cognitive impairment.
The activity of compounds as GPR139 agonists may be determined by a variety of methods, including in vitro and in vivo methods.
