Claims for Patent: 9,193,701

Summary for Patent: 9,193,701

Title:	Pyruvate kinase activators for use in therapy
Abstract:	Described herein are methods for using compounds that activate pyruvate kinase.
Inventor(s):	Su; Shin-San M. (Newton, MA)
Assignee:	AGIOS PHARMACEUTICALS, INC (Cambridge, MA)
Application Number:	14/115,289
Patent Claims:	1. A method for increasing the lifetime of red blood cells (RBCs) in need thereof comprising contacting blood with an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: ##STR00019## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted aryl or optionally substituted heteroaryl; 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 0, 1, 2; and g is 0, 1 or 2. 2. The method of claim 1, wherein the compound is added directly to whole blood or packed cells extracorporeally. 3. The method of claim 1, wherein the pharmaceutical composition is administered to a subject in need thereof. 4. A method for regulating 2,3-diphosphoglycerate levels in blood in need thereof comprising contacting blood with an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein ##STR00020## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted aryl or optionally substituted heteroaryl; 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 0, 1, 2; and g is 0, 1 or 2. 5. A method for treating hemolytic anemia comprising administering to a subject in need thereof a therapeutically effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein ##STR00021## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted aryl or optionally substituted heteroaryl; 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 0, 1, 2; and g is 0, 1 or 2. 6. A method for treating sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein ##STR00022## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted aryl or optionally substituted heteroaryl; 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 0, 1, 2; and g is 0, 1 or 2. 7. The method of claim 1, wherein the compound is represented by formula (I), wherein: ##STR00023## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted bicyclic heteroaryl; 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)--; 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 0, 1, 2; and g is 0, 1 or 2. 8. The method of claim 7, wherein h is 1 and g is 1. 9. The method of claim 8, wherein W, X, Y and Z are CH. 10. The method of claim 9, wherein D is NR.sup.b and D.sup.1 is a bond. 11. The method of claim 10, wherein R.sup.b is H, methyl or ethyl. 12. The method of claim 7, 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)--. 13. The method of claim 12, wherein L is a bond. 14. The method of claim 13, wherein R.sup.1 is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of R.sup.d. 15. The method of claim 12, wherein L is --(CR.sup.cR.sup.c).sub.m--. 16. The method of claim 15, wherein R.sup.1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 17. The method of claim 12, wherein L is --NR.sup.bC(O)-- and R.sup.b is hydrogen. 18. The method of claim 17, wherein R.sup.1 is aryl substituted with 0-5 occurrences of R.sup.d. 19. The method of claim 12, wherein L is --(CR.sup.cR.sup.c).sub.m--C(O)--. 20. The method of claim 19, wherein R.sup.1 is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrences of R.sup.d. 21. The method of claim 12, wherein L is --C(O)--. 22. The method of claim 21, wherein R.sup.1 is aryl, alkyl, or heteroaryl substituted with 0-5 occurrences of R.sup.d. 23. The method of claim 12, wherein L is --OC(O)--. 24. The method of claim 23, wherein R.sup.1 is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 25. The method of claim 12, wherein L is --(CR.sup.cR.sup.c).sub.m--OC(O)--. 26. The method of claim 25, wherein R.sup.1 is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of R.sup.d. 27. The method of claim 12, wherein n is 0. 28. The method of claim 12, 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. 29. The method of claim 1, wherein the compound is represented by formula (Id): ##STR00024## 30. The method of claim 1, wherein the compound is selected from FIG. 1. 31. The method of claim 5, wherein the hemolytic anemia is hereditary non-spherocytic hemolytic anemia. 32. A method of treating pyruvate kinase deficiency (PKD) in a subject comprising (1) a compound of formula I or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: ##STR00025## W, X, Y and Z are each independently selected from CH or N; D and D.sup.1 are each independently selected from a bond and NR.sup.b; A is optionally substituted aryl or optionally substituted heteroaryl; 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 0, 1, 2; and g is 0, 1 or 2. 33. The method of claim 5, wherein A is optionally substituted quinolinyl. 34. The method of claim 32, wherein A is optionally substituted quinolinyl. 35. The method of claim 5, wherein A is ##STR00026## 36. The method of claim 32, wherein A is ##STR00027## 37. The method of claim 5, wherein the compound of formula I is selected from: ##STR00028## ##STR00029## ##STR00030## 38. The method of claim 5, wherein the compound of formula I is selected from: ##STR00031## 39. The method of claim 5, wherein the compound of formula I is selected from: ##STR00032## 40. The method of claim 5, wherein the compound of formula I is selected from: ##STR00033## 41. The method of claim 5, wherein the compound of formula I is selected from: ##STR00034## 42. The method of claim 5, wherein the compound of formula I is selected from: ##STR00035## 43. The method of claim 5. wherein the compound of formula I is selected from: ##STR00036## 44. The method of claim 5, wherein the compound of formula I is selected from: ##STR00037## 45. The method of claim 5, wherein the compound of formula I is selected from: ##STR00038## 46. The method of claim 5, wherein the compound of formula I is selected from: ##STR00039## 47. The method of claim 5, wherein the compound of formula I is selected from: ##STR00040## 48. The method of claim 5, wherein the compound of formula I is selected from: ##STR00041## 49. The method of claim 5, wherein the compound of formula I is selected from: ##STR00042## 50. The method of claim 5, wherein the compound of formula I is selected from: ##STR00043## 51. The method of claim 5, wherein the compound of formula I is selected from: ##STR00044## 52. The method of claim 5, wherein the compound of formula I is selected from: ##STR00045## 53. The method of claim 31, wherein the compound of formula I is selected from: ##STR00046## 54. The method of claim 31, wherein the compound of formula I is selected from: ##STR00047## 55. The method of claim 31, wherein the compound of formula I is selected from: ##STR00048## 56. The method of claim 31, wherein the compound of formula I is selected from: ##STR00049## 57. The method of claim 31, wherein the compound of formula I is selected from: ##STR00050## 58. The method of claim 31, wherein the compound of formula I is selected from: ##STR00051## 59. The method of claim 31, wherein the compound of formula I is selected from: ##STR00052## 60. The method of claim 31, wherein the compound of formula I is selected from: ##STR00053## 61. The method of claim 31, wherein the compound of formula I is selected from: ##STR00054## 62. The method of claim 31, wherein the compound of formula I is selected from: ##STR00055## 63. The method of claim 31, wherein the compound of formula I is selected from: ##STR00056## 64. The method of claim 31, wherein the compound of formula I is selected from: ##STR00057## 65. The method of claim 31. wherein the compound of formula I is selected from: ##STR00058## 66. The method of claim 31, wherein the compound of formula I is selected from: ##STR00059## 67. The method of claim 31, wherein the compound of formula I is selected from: ##STR00060## 68. The method of claim 32, wherein the compound of formula I is selected from: ##STR00061## 69. The method of claim 32, wherein the compound of formula I is selected from: ##STR00062## 70. The method of claim 32, wherein the compound of formula I is selected from: ##STR00063## 71. The method of claim 32, wherein the compound of formula I is selected from: ##STR00064## 72. The method of claim 32, wherein the compound of formula I is selected from: ##STR00065## 73. The method of claim 32, wherein the compound of formula I is selected from: ##STR00066## 74. The method of claim 32, wherein the compound of formula I is selected from: ##STR00067## 75. The method of claim 32, wherein the compound of formula I is selected from: ##STR00068## 76. The method of claim 32, wherein the compound of formula I is selected from: ##STR00069## 77. The method of claim 32, wherein the compound of formula I is selected from: ##STR00070## 78. The method of claim 32, wherein the compound of formula I is selected from: ##STR00071## 79. The method of claim 32, wherein the compound of formula I is selected from: ##STR00072## 80. The method of claim 32, wherein the compound of formula I is selected from: ##STR00073## 81. The method of claim 32, wherein the compound of formula I is selected from: ##STR00074## 82. The method of claim 32, wherein the compound of formula I is selected from: ##STR00075## 83. The method of claim 32, wherein the compound of formula I is selected from: ##STR00076##