Claims for Patent: 11,793,806

Summary for Patent: 11,793,806

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, Lenny Dang
Assignee:	Agios Pharmaceuticals Inc
Application Number:	US17/221,423
Patent Claims:	1. A method for increasing the lifetime of red blood cells (RBCs) in a subject in need thereof comprising administering to the subject an 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 independently selected from a bond or 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, and wherein the subject has pyruvate kinase deficiency (PKD). 2. 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 independently selected from a bond or 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 cyclyl; 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. 3. The method of claim 2, wherein h is 1 and g is 1. 4. The method of claim 3, wherein W, X, Y and Z are CH. 5. The method of claim 4, wherein D is NRb and D1 is a bond. 6. The method of claim 5, wherein Rb is H, methyl or ethyl. 7. The method of claim 1, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—C(O)—, —C(O)—, or —O(CO)—. 8. The method of claim 7, wherein L is —(CRcRc)m—. 9. The method of claim 8, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd. 10. The method of claim 8, wherein R1 is cycloalkyl. 11. The method of claim 10, wherein L is —CH2— and n is 0. 12. The method of claim 1, wherein A is quinolinyl. 13. The method of claim 1, wherein A is 14. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the structural formula: 15. A method for increasing the lifetime of red blood cells (RBCs) in a subject in need thereof comprising administering to the subject an effective amount of the compound N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the subject has pyruvate kinase deficiency (PKD).