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):	Shin-San Michael Su
Assignee:	Agios Pharmaceuticals Inc
Application Number:	US14/886,750
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: 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 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 NRb and D1 is a bond. 5. The method of claim 4, wherein Rb is H, methyl or ethyl. 6. The method of claim 5, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—C(O)—, —C(O)—, or —O(CO)—. 7. The method of claim 6, wherein L is —(CRcRc)m—. 8. The method of claim 7, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd. 9. The method of claim 8, wherein L is —CH2— and n is 0. 10. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: 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: 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. 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 NRb and D1 is a bond. 15. The method of claim 14, wherein Rb is H, methyl or ethyl. 16. The method of claim 15, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—, —C(O)—, —C(O)—, or —O(CO)—. 17. The method of claim 16, wherein L is —(CRcRc)m—. 18. The method of claim 17, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd. 19. The method of claim 18, wherein L is —CH2— and n is 0. 20. The method of claim 11, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: 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: 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)—, —(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; 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 Rb is H, methyl or ethyl. 25. The method of claim 24, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—, —C(O)—, —C(O)—, or —O(CO)—. 26. The method of claim 25, wherein L is —(CRcRc)m—. 27. The method of claim 26, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd. 28. The method of claim 27, wherein L is —CH2— and n is 0. 29. The method of claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: 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: 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.