Table 6.
Inhibitory Activity at the Plk1 PBD of Triazoloquinazolinones Modified in Zones 3 and 4 with a Preferred 7-Fluoro Substitution, Except for 69 with 9-Fluoro (IC50 Values Are n = 3 Unless Noted in Parentheses) and Microsomal Half-Life, PAMPA Assays, and Aqueous Solubility
| Cmpd | R2 = | IC50 (μM, ELISA) | t1/2 (min, RLM) | PAMPA (1e-6 cm/s) | Solub. (μg/ml) |
|---|---|---|---|---|---|
| 63 | Et | 1.98 ± 0.07 | >30 | 39.5 | >39 |
| 64 | Pr | 1.16 ± 0.06 (12) | >30 | 195 | >28 |
| 65 |  |
0.75 ± 0.06 (5) | >30 | 117 | 17.3 |
| 66 |  |
1.44 ± 0.10 (9) | >30 | 222 | >43 |
| 67 |  |
4.33 ± 0.18 | >30 | 8.2 | >41 |
| 68 |  |
2.26 ± 0.07 (4) | >30c >30d |
<lc 16.8d |
>43c 27d |
| 69 |  |
5.07 ± 0.16 | >30 | 4.2 | 15.9 |
| 70 |  |
2.45 ± 0.25 | >30 | 177 | >45 |
| 71a |  |
6.12 ± 0.17 | >30 | 186 | >47 |
| 72 |  |
2.48 ± 0.20 | >30 | 12.9 | >47 |
| 73 |  |
2.48 ± 0.08 (6) | >30 | 18.0 | >50 |
| 74 |  |
1.60 ± 0.19 (4) | >30 | 267 | 21.9 |
| 75 |  |
2.77 ± 0.31 | >30 | 8.9 | >53 |
| 76 |  |
1.87 ± 0.06 | >30 | 10.8 | 34 |
| 77 |  |
21.70 ± 1.73 | ND | 9.3 | >51 |
| 78 |  |
13.89 ± 0.59 | >30 | 16.7 | >59 |
| 79 |  |
0.77 ± 0.08 (8) | >30 | 46.0 | 16.2 |
| 80b |  |
1.19 ± 0.05 (4) | >30 | 188 | 13.2 |
| 81 |  |
14.37 ± 0.33 | 22.8 | 56.3 | 3.0 |
| 82 |  |
5.71 ± 0.44 | >30 | <1 | 1.2 |
| 83 |  |
0.87 ± 0.07 (4) | >30 | 355 | 13.0 |
| 84 |  |
1.07 ± 0.13 (9) | >30 | <1 | 25.1 |
| 85 |  |
0.89 ± 0.05 (4) | >30 | 32.7 | 10.9 |
| 86 |  |
5.67 ± 0.30 | ND | 229 | 15 |
| 87a |  |
5.67 ± 0.42 | >30 | 53.8 | 17.8 |
| 88 |  |
1.51 ± 0.19 (4) | >30 | 358 | 2.4 |
| 89 |  |
1.37 ± 0.08 (5) | >30 | 234 | 20.2 |
| 90 |  |
1.63 ± 0.22 (5) | >30 | 67.0 | >52 |
| 91 |  |
6.72 ± 0.17 | >30 | 12.7 | >54 |
| 92 |  |
1.84 ± 0.01 | 26.3 | 33.1 | 20.5 |
| 93 |  |
2.83 ± 0.36 | >30 | 201 | <1 |
a
Racemic.
b
Relative stereochemistry, trans.
c
TFA salt.
d
Free base. ND, not determined.