Claims for Patent: 9,980,961

Summary for Patent: 9,980,961

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), Dang; Lenny (Boston, MA)
Assignee:	AGIOS PHARMACEUTICALS, INC. (Cambridge, MA)
Application Number:	15/583,412
Patent Claims:	1. A method of activating a mutant pyruvate kinase R in a subject in need thereof, the method 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 an optionally substituted aryl or an 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 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R.sup.d. 9. The method of claim 7, wherein R.sup.1 is cycloalkyl. 10. The method of claim 9, wherein L is --CH.sub.2-- and n is 0. 11. The method of claim 1, wherein A is quinolinyl. 12. The method of claim 1, wherein A is ##STR00020## 13. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: ##STR00021## ##STR00022## ##STR00023## 14. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00024## 15. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00025## 16. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00026## 17. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00027## 18. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00028## 19. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00029## 20. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00030## 21. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00031## 22. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00032## 23. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: ##STR00033## 24. The method of claim 1, wherein the mutant PKR is selected from G332S, G364D, T384M, R479H, R479K, R486W, R532W, R510Q, and R490W.