Orally bioavailable caffeic acid related anticancer drugs
The present invention concerns compounds and their use to treat cell proliferative diseases such as cancer. Compounds of the present invention display significant potency as inhibitors of Jak2/STAT3 pathways and downstream targets and inhibit the growth and survival of cancerous cell lines.
1. A compound selected from the group consisting of:
wherein R 1 is —H or cyano and R 2 is heteroatom-unsubstituted C 3 -C 7 -cycloalkyl;
wherein X 1 is halo and R 3 is heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl;
wherein X 2 is halo and R 4 is hydroxy or heteroatom-unsubstituted C 1 -C 10 -acyloxy;
wherein:
X 3 is halo or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy,
R 5 is —H or cyano, and
R 6 is heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl;
wherein:
X 4 is halo or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy,
R 7 is —H or cyano, and
R 8 is a heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl;
wherein:
X 5 is heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy,
R 9 is —H or cyano, and
R 10 is a heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl; and
wherein:
A is —C(O)—, and
X 6 is halo or heteroatom-unsubstituted C 1 -C 10 -alkyl or C 1 -C 10 -alkoxy,
R 11 is heteroatom-unsubstituted C 3 -C 7 -cycloalkyl, C 1 -C 10 -acyloxy, C 6 -C 10 -aryl, or C 7 -C 10 -aralkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
3. The compound of claim 1 , wherein R 3 is selected from the group consisting of phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
4. The compound of claim 1 , wherein X 1 or X 2 is selected from the group consisting of —F, —Cl, —Br and —I.
5. The compound of claim 1 , wherein R 4 is selected from a group consisting of hydroxy, acetoxy and 2,2-dimethylpropionyloxy.
6. The compound of claim 1 , wherein X 3 or X 4 is selected from the group consisting of methoxy, —F, —Cl, —Br and —I.
7. The compound of claim 1 , wherein R 6 or R 8 is cyclopropyl.
8. The compound of claim 1 , wherein X 5 is methyl.
9. The compound of claim 1 , having the formula:
10. The compound of claim 1 , having the formula:
11. The compound of claim 1 , having the formula:
12. The compound of claim 1 , having the formula:
13. The compound of claim 1 , having the formula:
14. The compound of claim 1 , having the formula:
15. The compound of claim 1 , having the formula:
16. The compound of claim 1 , having the formula:
17. The compound of claim 1 , having the formula:
18. The compound of claim 1 , having the formula:
19. The compound of claim 1 , having the formula:
20. The compound of claim 1 , having the formula:
21. The compound of claim 1 , further defined as a compound of formula(I).
22. The compound of claim 1 , further defined as a compound of formula (II).
23. The compound of claim 1 , further defined as a compound of formula (III).
24. The compound of claim 1 , further defined as a compound of formula (IV).
25. The compound of claim 1 , further defined as a compound of formula (V).
26. The compound of claim 1 , further defined as a compound of formula (VI).
27. The compound of claim 1 , further defined as a compound of formula (VII).