PKM2 modulators and methods for their use
View Patent ↗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 R1, R2, R3, R4, R5 and R6 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 cycloalkyl or haloalkyl;
R 2 is H;
R 3 is alkyl optionally substituted with one or more substituents selected from hydroxyl, halo, amino, alkylamino, alkoxy and alkysulfone or heterocyclylalkyl;
R 4 is aryl;
R 5 and R 6 are each H.
2. The compound of claim 1 , wherein R 4 has the following structure (A):
wherein:
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.
3. The compound of claim 2 , wherein R 7 and R 8 are each independently H, halo or amino.
4. The compound of claim 2 , wherein R 4 has the following structure:
5. The compound of claim 4 , wherein R 7 is H or amino.
6. The compound of claim 4 , wherein R 8 is chloro or fluoro.
7. The compound of claim 1 , wherein R 4 has one of the following structures:
8. 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 O, NR 14 or
R 9 , R 11 and R 13 are each independently H or alkyl;
R 10 is H, H hydroxyl, halo, alkoxy or alkyl;
R 12 is H, amino or alkoxy;
R 14 is H, H alkyl or alkyl sulfone;
q and w are each independently 0, 1 or 2;
r, s and v are each independently 1 or 2;
t is 1, 2 or 3; and
u is 0, 1, 2 or 3.
9. The compound of claim 8 , wherein R 3 has structure (D).
10. The compound of claim 9 , wherein s is 1.
11. The compound of claim 9 , wherein s is 2.
12. The compound of claim 10 , wherein r is 1.
13. The compound of claim 10 , wherein r is 2.
14. The compound of claim 10 , wherein q is 0.
15. The compound of claim 10 , wherein q is 1.
16. The compound of claim 10 , wherein q is 2.
17. The compound of claim 1 , wherein R 3 has one of the following structures:
18. The compound of claim 8 , wherein R 3 has structure (E).
19. The compound of claim 18 , wherein Q is CH 2 .
20. The compound of claim 18 , wherein Q is SO 2 .
21. The compound of claim 18 , wherein Q is O.
22. The compound of claim 18 , wherein Q is CF 2 .
23. The compound of claim 18 , wherein Q is NR 13 .
24. The compound of claim 22 , wherein R 13 is methyl or ethyl.
25. The compound of claim 18 , wherein R 10 and R 11 are each H.
26. The compound of claim 18 , wherein R 10 is methyl, fluoro, hydroxyl or methoxy.
27. The compound of claim 1 , wherein R 3 has one of the following structures:
28. The compound of claim 8 , wherein R 3 has structure (F).
29. The compound of claim 28 , wherein R 12 is H.
30. The compound of claim 28 , wherein R 12 is alkoxy.
31. The compound of claim 28 , wherein R 12 is methoxy, ethoxy or isopropoxy.
32. The compound of claim 1 , wherein R 3 has one of the following structures:
33. The compound of claim 1 , wherein R 3 is alkyl.
34. The compound of claim 1 , wherein R 1 is CF 3 .
35. The compound of claim 1 , wherein R 1 is cyclopropyl.
36. The compound of claim 1 , wherein the compound has the following structure (Ia):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof,
wherein:
R 15 is halo;
R 16 is H or NH 2 ; and
w is 1 or 2.
37. The compound of claim 36 , wherein R 15 is chloro.
38. The compound of claim 36 , wherein R 15 is fluoro.
39. The compound of claim 36 , wherein R 16 is H.
40. The compound of claim 36 , wherein R 16 is NH 2 .
41. The compound of claim 36 , wherein w is 1.
42. The compound of claim 36 , wherein w is 2.
43. The compound of claim 1 , wherein the compound has the following structure (Ib):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof,
wherein:
R 17 is halo;
R 18 is H or NH 2 ;
Z is CH 2 , O, NH, NR 19 , CHR 20 or CF 2 ;
R 19 is alkyl;
R 20 is alkoxy, hydroxyl or halo; and
x is 0, 1, 2 or 3.
44. The compound of claim 43 , wherein R 17 is chloro.
45. The compound of claim 43 , wherein R 18 is NH 2 .
46. The compound of claim 43 , wherein Z is CHOH.
47. The compound of claim 43 , wherein Z is CHOCH 3 .
48. The compound of claim 43 , wherein Z is CHF.
49. The compound of claim 43 , wherein Z is O.
50. The compound of claim 43 , wherein x is 1.
51. The compound of claim 43 , wherein x is 2.
52. The compound of claim 1 , wherein the compound has one of the following structures: