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):	Shin-San M. Su
Assignee:	Agios Pharmaceuticals Inc
Application Number:	US14/115,289
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: W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted aryl or optionally substituted heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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 W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted aryl or optionally substituted heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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 W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted aryl or optionally substituted heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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 W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted aryl or optionally substituted heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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: W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted bicyclic heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)—; R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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 NRb and D1 is a bond. 11. The method of claim 10, wherein Rb is H, methyl or ethyl. 12. The method of claim 7, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)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 R1 is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of Rd. 15. The method of claim 12, wherein L is —(CRcRc)m—. 16. The method of claim 15, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd. 17. The method of claim 12, wherein L is —NRbC(O)— and Rb is hydrogen. 18. The method of claim 17, wherein R1 is aryl substituted with 0-5 occurrences of Rd. 19. The method of claim 12, wherein L is —(CRcRc)m—C(O)—. 20. The method of claim 19, wherein R1 is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrences of Rd. 21. The method of claim 12, wherein L is —C(O)—. 22. The method of claim 21, wherein R1 is aryl, alkyl, or heteroaryl substituted with 0-5 occurrences of Rd. 23. The method of claim 12, wherein L is —OC(O)—. 24. The method of claim 23, wherein R1 is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of Rd. 25. The method of claim 12, wherein L is —(CRcRc)m—OC(O)—. 26. The method of claim 25, wherein R1 is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of Rd. 27. The method of claim 12, wherein n is 0. 28. The method of claim 12, wherein n is 1 and R3 is CH3, CH2CH3, OCH3, OCH2CH3, OH, F, Cl, or CF3. 29. The method of claim 1, wherein the compound is represented by formula (Id): 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: W, X, Y and Z are each independently selected from CH or N; D and D1 are each independently selected from a bond and NRb; A is optionally substituted aryl or optionally substituted heteroaryl; L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd 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 36. The method of claim 32, wherein A is 37. The method of claim 5, wherein the compound of formula I is selected from: 38. The method of claim 5, wherein the compound of formula I is selected from: 39. The method of claim 5, wherein the compound of formula I is selected from: 40. The method of claim 5, wherein the compound of formula I is selected from: 41. The method of claim 5, wherein the compound of formula I is selected from: 42. The method of claim 5, wherein the compound of formula I is selected from: 43. The method of claim 5. wherein the compound of formula I is selected from: 44. The method of claim 5, wherein the compound of formula I is selected from: 45. The method of claim 5, wherein the compound of formula I is selected from: 46. The method of claim 5, wherein the compound of formula I is selected from: 47. The method of claim 5, wherein the compound of formula I is selected from: 48. The method of claim 5, wherein the compound of formula I is selected from: 49. The method of claim 5, wherein the compound of formula I is selected from: 50. The method of claim 5, wherein the compound of formula I is selected from: 51. The method of claim 5, wherein the compound of formula I is selected from: 52. The method of claim 5, wherein the compound of formula I is selected from: 53. The method of claim 31, wherein the compound of formula I is selected from: 54. The method of claim 31, wherein the compound of formula I is selected from: 55. The method of claim 31, wherein the compound of formula I is selected from: 56. The method of claim 31, wherein the compound of formula I is selected from: 57. The method of claim 31, wherein the compound of formula I is selected from: 58. The method of claim 31, wherein the compound of formula I is selected from: 59. The method of claim 31, wherein the compound of formula I is selected from: 60. The method of claim 31, wherein the compound of formula I is selected from: 61. The method of claim 31, wherein the compound of formula I is selected from: 62. The method of claim 31, wherein the compound of formula I is selected from: 63. The method of claim 31, wherein the compound of formula I is selected from: 64. The method of claim 31, wherein the compound of formula I is selected from: 65. The method of claim 31. wherein the compound of formula I is selected from: 66. The method of claim 31, wherein the compound of formula I is selected from: 67. The method of claim 31, wherein the compound of formula I is selected from: 68. The method of claim 32, wherein the compound of formula I is selected from: 69. The method of claim 32, wherein the compound of formula I is selected from: 70. The method of claim 32, wherein the compound of formula I is selected from: 71. The method of claim 32, wherein the compound of formula I is selected from: 72. The method of claim 32, wherein the compound of formula I is selected from: 73. The method of claim 32, wherein the compound of formula I is selected from: 74. The method of claim 32, wherein the compound of formula I is selected from: 75. The method of claim 32, wherein the compound of formula I is selected from: 76. The method of claim 32, wherein the compound of formula I is selected from: 77. The method of claim 32, wherein the compound of formula I is selected from: 78. The method of claim 32, wherein the compound of formula I is selected from: 79. The method of claim 32, wherein the compound of formula I is selected from: 80. The method of claim 32, wherein the compound of formula I is selected from: 81. The method of claim 32, wherein the compound of formula I is selected from: 82. The method of claim 32, wherein the compound of formula I is selected from: 83. The method of claim 32, wherein the compound of formula I is selected from: