Table 1. R Exploration.
| Entry | R | mTOR enz Ki nMa | mTORC1/2 IC50 nMa | PI3Kα Ki nMa | S35 @ 10 μMb | ChromlogD6.5d | Solubility μMd |
|---|---|---|---|---|---|---|---|
| 1 | n/a | 1 | 1/5 | 28 | 0.20 | 0.4 | 82 |
| 3a | -Me | 62 | 40/200 | 990 | -c | 0.8 | 74 |
| 4a | -Me | 33 | 30/90 | 2200 | 0.02 | 1.4 | 5.2 |
| 3b | -Et | 50 | 60/140 | 85 | 0.02 | 1.2 | 62 |
| 3c | -CH2OH | 4000 | -c/-c | >10000 | -c | 0.2 | 82 |
| 3d | -OMe | 370 | 420/680 | 250 | -c | 1.6 | <1 |
| 3e | -Cl | 10 | 8/20 | 920 | 0.02 | 1.7 | 2 |
| 4b | -Cl | 11 | 7/20 | 4600 | 0.02 | 2.3 | <1 |
| 3f | -F | 13 | 40/80 | 2600 | -c | 1.8 | <1 |
| 3g | -Br | 21 | 35/60 | 1000 | -c | 1.8 | 4 |
| 3h | -CF3 | 2300 | -c/-c | >10000 | -c | 2.4 | <1 |
| 3i | -CN | 2200 | -c/-c | >10000 | -c | 1.8 | <1 |
| 3j | -NH2 | 4 | 4/11 | 150 | 0.10 | –0.1 | 88 |
| 3k | -H | 6 | 7/15 | 780 | 0.26 | 1.1 | 1.6 |
a
Geomean of at least 2 determinations. See Supporting Information for assay details.
b
S35 is defined as the ratio of the number kinases with less than 35% residual activity over the total number of kinases. The test was performed at DiscoverX.21
c
Not tested.
d
See Supporting Information for assay details.