Claims for Patent: 8,785,450

Summary for Patent: 8,785,450

Title:	Therapeutic compounds and compositions
Abstract:	Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.
Inventor(s):	Salituro; Francesco G. (Marlborough, MA), Saunders; Jeffrey O. (Concord, MA), Yan; Shunqi (Irvine, CA)
Assignee:	Agios Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	12/826,630
Patent Claims:	1. A compound of formula II or a pharmaceutically acceptable salt thereof, wherein: ##STR00764## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are independently selected from a bond or NR.sup.b; L is a bond, --C(O)--, --(CR.sup.cR.sup.c).sub.m--, --OC(O)--, --(CR.sup.cR.sup.c).sub.m--OC(O)--, --(CR.sup.cR.sup.c).sub.m--C(O)--, --NR.sup.bC(S)--, or --NR.sup.bC(O)-- (wherein the point of the attachment to R.sup.1 is on the left-hand side); R.sup.1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R.sup.d; each R.sup.3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and --OR.sup.a or two adjacent R.sup.3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each R.sup.a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each R.sup.b is independently selected from hydrogen and alkyl; each R.sup.c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R.sup.c taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each R.sup.d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, --C(O)R.sup.a, --OC(O)R.sup.a, --C(O)OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b and --OR.sup.a, or two R.sup.d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 1; and g is 1. 2. The compound of claim 1, wherein W, X, Y and Z are CH. 3. The compound of claim 2, wherein D is NR.sup.b and D.sup.1 is a bond. 4. The compound of claim 3, wherein R.sup.b is H, methyl or ethyl. 5. The compound of claim 1, wherein L is a bond, --(CR.sup.cR.sup.c).sub.m--, --NR.sup.bC(O)--, --(CR.sup.cR.sup.c).sub.m--C(O)--, --C(O)--, or --O(CO)--. 6. The compound of claim 5, wherein L is a bond. 7. The compound of claim 6, wherein R.sup.1 is alkyl, aryl or heteroaryl, each substituted with 0-5 occurrences of R.sup.d. 8. The compound of claim 5, wherein L is --(CR.sup.cR.sup.c).sub.m--. 9. The compound of claim 8, wherein R.sup.1 is cycloalkyl, aryl, heteroaryl or heterocyclyl, each substituted with 0-5 occurrences of R.sup.d. 10. The compound of claim 5, wherein L is --NR.sup.bC(O)-- and R.sup.b is hydrogen. 11. The compound of claim 10, wherein R.sup.1 is aryl substituted with 0-5 occurrences of R.sup.d. 12. The compound of claim 5, wherein L is --(CR.sup.cR.sup.c).sub.m--C(O)--. 13. The compound of claim 12, wherein R.sup.1 is cycloalkyl, aryl or heteroaryl, each substituted with 0-5 occurrences of R.sup.d. 14. The compound of claim 5, wherein L is --C(O)--. 15. The compound of claim 14, wherein R.sup.1 is aryl, alkyl, or heteroaryl, each substituted with 0-5 occurrences of R.sup.d. 16. The compound of claim 5, wherein L is --OC(O)--. 17. The compound of claim 16, wherein R.sup.1 is alkyl, aryl or heterocyclyl, each substituted with 0-5 occurrences of R.sup.d. 18. The compound of claim 1, wherein L is --(CR.sup.cR.sup.c).sub.m--OC(O)--. 19. The compound of claim 18, wherein R.sup.1 is heterocyclyl or cycloalkyl, each substituted with 0-5 occurrences of R.sup.d. 20. The compound of claim 5, wherein n is 0. 21. The compound of claim 5, wherein n is 1 and R.sup.3 is CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OH, F, Cl, or CF.sub.3. 22. A pharmaceutical composition comprising a compound formula II or a pharmaceutically acceptable salt thereof, wherein: ##STR00765## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are independently selected from a bond or NR.sup.b; L is a bond, --C(O)--, --(CR.sup.cR.sup.c).sub.m--, --OC(O)--, --(CR.sup.cR.sup.c).sub.m--OC(O)--, --(CR.sup.cR.sup.c).sub.m--C(O)--, --NR.sup.bC(S)--, or --NR.sup.bC(O)-- (wherein the point of the attachment to R.sup.1 is on the left-hand side); R.sup.1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R.sup.d; each R.sup.3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and --OR.sup.a, or two adjacent R.sup.3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each R.sup.a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each R.sup.b is independently selected from hydrogen and alkyl; each R.sup.c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R.sup.c taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each R.sup.d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, --C(O)R.sup.a, --OC(O)R.sup.a, --C(O)OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b and --OR.sup.a, or two R.sup.d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 1; and g is 1. 23. The pharmaceutical composition of claim 22, wherein the compound is a compound of formula: ##STR00766## 24. The compound of claim 1, wherein the compound is selected from the following: ##STR00767## ##STR00768## ##STR00769## ##STR00770## ##STR00771## ##STR00772## ##STR00773## ##STR00774## ##STR00775## ##STR00776## ##STR00777## ##STR00778## ##STR00779## ##STR00780## ##STR00781## ##STR00782## ##STR00783## ##STR00784## ##STR00785## ##STR00786## ##STR00787## ##STR00788## ##STR00789## ##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794## ##STR00795## ##STR00796## ##STR00797## ##STR00798## ##STR00799## ##STR00800## ##STR00801## ##STR00802## ##STR00803## ##STR00804## ##STR00805## ##STR00806## ##STR00807## ##STR00808## ##STR00809## ##STR00810## ##STR00811## ##STR00812## ##STR00813## ##STR00814## ##STR00815## ##STR00816## ##STR00817## ##STR00818## ##STR00819## ##STR00820## ##STR00821## ##STR00822## ##STR00823## ##STR00824## ##STR00825## ##STR00826## ##STR00827## ##STR00828## ##STR00829## ##STR00830## ##STR00831## ##STR00832## ##STR00833## ##STR00834## ##STR00835## ##STR00836## ##STR00837## ##STR00838## ##STR00839## ##STR00840## ##STR00841## 25. The compound of claim 1 selected from the following: ##STR00842## ##STR00843## ##STR00844## ##STR00845## ##STR00846## ##STR00847## ##STR00848## ##STR00849## ##STR00850## ##STR00851## ##STR00852## ##STR00853## ##STR00854## ##STR00855## ##STR00856## ##STR00857## ##STR00858## ##STR00859## ##STR00860## ##STR00861## ##STR00862## ##STR00863## ##STR00864## ##STR00865## ##STR00866## 26. The compound of claim 1 selected from: ##STR00867## 27. The compound of claim 1 selected from: ##STR00868## 28. The compound of claim 1 selected from: ##STR00869## 29. The compound of claim 1 selected from: ##STR00870## 30. The compound of claim 1 selected from: ##STR00871## 31. The compound of claim 1 selected from: ##STR00872## 32. The compound of claim 1 selected from: ##STR00873## 33. The compound of claim 1 selected from: ##STR00874## 34. The compound of claim 1 selected from: ##STR00875## 35. The compound of claim 1 selected from: ##STR00876## 36. The compound of claim 1 selected from: ##STR00877## 37. The compound of claim 1 selected from: ##STR00878## 38. The compound of claim 1 selected from: ##STR00879## 39. The compound of claim 1 selected from: ##STR00880## 40. The compound of claim 1 selected from: ##STR00881## 41. The compound of claim 1 selected from: ##STR00882## 42. The compound of claim 1 selected from: ##STR00883## 43. The compound of claim 1 selected from: ##STR00884## 44. The compound of claim 1 selected from: ##STR00885## 45. The compound of claim 1 selected from: ##STR00886## 46. The compound of claim 1 selected from: ##STR00887## 47. The compound of claim 1 selected from: ##STR00888## 48. The compound of claim 1 selected from: ##STR00889## 49. A compound selected from one of the following: ##STR00890## 50. A pharmaceutical composition comprising a compound of any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, or a compound of claim 49. 51. A pharmaceutical composition comprising a compound of claim 24, or a pharmaceutically acceptable salt thereof.