PKM2 modulators and methods for their use
Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
1. A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof,
wherein:
R 1 is haloalkyl, halo, nitrile or amino;
R 2 is H or halo;
R 3 is alkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or aralkyl;
R 4 has one of the following structures:
R 5 and R 6 are each independently H or alkyl;
R 7 and R 8 are each independently H, alkyl, alkoxy, halo, hydroxyl, hydroxylalkyl, amino, aminoalkyl, alkylaminoalkyl, nitrile, nitro, —O(CH 2 ) m P(═O)(OH) 2 or amino acid ester; and
m is 0 or 1,
wherein each occurrence of cycloalkyl, haloalkyl, alkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aralkyl and aryl is optionally substituted.
2. The compound of claim 1 , wherein R 4 has one of the following structures:
3. The compound of claim 1 , wherein R 7 and R 8 are each H.
4. The compound of claim 1 , wherein R 7 or R 8 is halo or alkylaminoalkyl.
5. The compound of claim 1 , wherein R 3 has one of the following structures (D), (E) or (F):
wherein:
Q is CH 2 , O, NR 13 , CF 2 , or S(O) w ;
B is CH 2 , O, NR 14 , C(═O) or
R 9 , R 11 and R 13 are each independently H or alkyl;
R 10 is H, hydroxyl, halo, alkoxy or alkyl;
R 12 is H, amino or alkoxy;
R 14 is H, alkyl or alkyl sulfone;
q, v and w are each independently 0, 1 or 2;
r and s are each independently 1 or 2;
t is 1, 2 or 3; and
u is 0, 1, 2 or 3.
6. The compound of claim 5 , wherein R 3 has structure (D).
7. The compound of claim 6 , wherein s is 1.
8. The compound of claim 6 , wherein s is 2.
9. The compound of claim 6 , wherein r is 1.
10. The compound of claim 6 , wherein r is 2.
11. The compound of claim 6 , wherein q is 0.
12. The compound of claim 6 , wherein q is 1.
13. The compound of claim 6 , wherein q is 2.
14. The compound of claim 1 , wherein R 3 has one of the following structures:
15. The compound of claim 5 , wherein R 3 has structure (E).
16. The compound of claim 15 , wherein Q is CH 2 .
17. The compound of claim 15 , wherein Q is SO 2 .
18. The compound of claim 15 , wherein Q is O.
19. The compound of claim 15 , wherein Q is CF 2 .
20. The compound of claim 15 , wherein Q is NR 13 .
21. The compound of claim 19 , wherein R H is methyl or ethyl.
22. The compound of claim 15 , wherein R 10 and R 11 are each H.
23. The compound of claim 15 , wherein R 10 is methyl, fluoro, hydroxyl or methoxy.
24. The compound of claim 5 , wherein R 3 has structure (F).
25. The compound of claim 24 , wherein B is CH 2 .
26. The compound of claim 24 , wherein R 12 is H or alkoxy.
27. The compound of claim 24 , wherein R 12 is methoxy, ethoxy or isopropoxy.
28. The compound of claim 1 , wherein R 3 is alkyl or alkoxyalkyl.
29. The compound of claim 28 , wherein R 3 is alkyl substituted with one or more substituents selected from hydroxyl, halo, amino, alkylamino, alkoxy and alkylsulfone.
30. The compound of claim 1 , wherein R 3 is heteroaryl, cycloalkoxyalkyl or aralkyl.
31. The compound of claim 1 , wherein R 5 and R 6 are each H.
32. The compound of claim 1 , wherein R 2 is H or F.
33. The compound of any of claim 1 , wherein R 1 is CF 3 , Cl, Br, nitrile or amino.
34. The compound of claim 1 , wherein the compound has one of the following structures:
35. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
36. A method of activating PKM2 in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound of claim 1 .
37. A method for therapeutically treating PKM2-mediated cancer in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound of claim 1 wherein treatment is effected by activating PKM2.