Claims for Patent: 9,682,080

Summary for Patent: 9,682,080

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 Michael (Boston, MA)
Assignee:	AGIOS PHARMACEUTICALS, INC (Cambridge, MA)
Application Number:	14/886,750
Patent Claims:	1. A method of activating pyruvate kinase R in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 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 h is 1 and g is 1. 3. The method of claim 2, wherein W, X, Y and Z are CH. 4. The method of claim 3, wherein D is NR.sup.b and D.sup.1 is a bond. 5. The method of claim 4, wherein R.sup.b is H, methyl or ethyl. 6. The method of claim 5, 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)--. 7. The method of claim 6, wherein L is --(CR.sup.cR.sup.c).sub.m--. 8. The method of claim 7, wherein R.sup.1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 9. The method of claim 8, wherein L is --CH.sub.2-- and n is 0. 10. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: ##STR00020## ##STR00021## ##STR00022## 11. A method of treating beta-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, 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 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. 12. The method of claim 11, wherein h is 1 and g is 1. 13. The method of claim 12, wherein W, X, Y and Z are CH. 14. The method of claim 13, wherein D is NR.sup.b and D.sup.1 is a bond. 15. The method of claim 14, wherein R.sup.b is H, methyl or ethyl. 16. The method of claim 15, 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)--. 17. The method of claim 16, wherein L is --(CR.sup.cR.sup.c).sub.m--. 18. The method of claim 17, wherein R.sup.1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 19. The method of claim 18, wherein L is --CH.sub.2-- and n is 0. 20. The method of claim 11, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: ##STR00024## ##STR00025## ##STR00026## 21. A method of treating sickle cell anemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein: ##STR00027## Y and Z are each independently selected from CH or N; 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; m is 1, 2 or 3; h is 0, 1, 2; and g is 0, 1 or 2. 22. The method of claim 21, wherein h is 1 and g is 1. 23. The method of claim 22, wherein Y and Z are CH. 24. The method of claim 23, wherein R.sup.b is H, methyl or ethyl. 25. The method of claim 24, 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)--. 26. The method of claim 25, wherein L is --(CR.sup.cR.sup.c).sub.m--. 27. The method of claim 26, wherein R.sup.1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 28. The method of claim 27, wherein L is --CH.sub.2-- and n is 0. 29. The method of claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: ##STR00028## ##STR00029## ##STR00030## 30. A method of treating a disorder selected from thalassemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia or Bassen-Kornzweig syndrome, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, and anemia of chronic diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: ##STR00031## 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.