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US 9,193,701 B2Granted
Pyruvate kinase activators for use in therapy
AssigneeAgios Pharmaceuticals, Inc.
InventorShin-San M. Su
Life of this patent
Estimating the term…
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Claims83
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.
14 more elements
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.
15 more elements
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.
15 more elements
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.
15 more elements
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.
14 more elements
Dependencies are inferred from the claim text.