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US 2016/0106742 A1Published application
Pyruvate kinase activators for use in therapy
AssigneeAgios Pharmaceuticals, Inc.
InventorShin-San Michael Su
Life of this patent
Estimating the term…
Abstract
Described herein are methods for using compounds that activate pyruvate kinase.
Claims31
1-30. (canceled)
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.
13 more elements
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.
13 more elements
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.
11 more elements
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.
13 more elements
Dependencies are inferred from the claim text.