Pyruvate kinase activators for use in therapy

Patent metadata

Field	Value
Publication number	US-12377093-B2
Application number	US-202318368709-A
Country	US
Kind code	B2
Filing date	Sep 15, 2023
Priority date	May 3, 2011
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

Described herein are methods for using compounds that activate pyruvate kinase.

First claim

What is claimed is:

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 D 1 are each independently selected from a bond and NR b ;
A is optionally substituted aryl or optionally substituted heteroaryl;
L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)— (wherein the point of the attachment to R 1 is on the left-hand side);
R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ;
each R 3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a , or two adjacent R 3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
each R a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each R b is independently selected from hydrogen and alkyl;
each R c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl;
each R d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b and —OR a , or two R 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; and
his 1 and g is 2, or g is 1 and his 2.

2. The method of claim 1 , wherein W, X, Y and Z are CH.

3. The method of claim 1 , wherein D is NR b and D 1 is a bond.

4. The method of claim 1 , wherein R b is H, methyl or ethyl.

5. The method of claim 1 , wherein n is 0.

6. The method of claim 1 , wherein n is 1 and R 3 is CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OH, F, Cl, or CF 3 .

7. The method of claim 1 , wherein L is a bond, —(CR c R c ) m —, —NR b C(O)—, —(CR c R c ) m —C(O)—, —(CR c R c ) m —OC(O)—, —C(O)—, or —O(CO)—.

8. The method of claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from:

9. A method of activating a mutant 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 D 1 are each independently selected from a bond and NR b ;
A is optionally substituted aryl or optionally substituted heteroaryl;
L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)— (wherein the point of the attachment to R 1 is on the left-hand side);
R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ;
each R 3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a , or two adjacent R 3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
each R a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each R b is independently selected from hydrogen and alkyl;
each R c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl;
each R d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b and —OR a , or two R 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; and
his 1 and g is 2, or g is 1 and h is 2.

10. The method of claim 9 , wherein W, X, Y and Z are CH.

11. The method of claim 9 , wherein D is NR b and D 1 is a bond.

12. The method of claim 9 , wherein R b is H, methyl or ethyl.

13. The method of claim 9 , wherein n is 0.

14. The method of claim 9 , wherein n is 1 and R 3 is CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OH, F, Cl, or CF 3 .

15. The method of claim 9 , wherein L is a bond, —(CR c R c ) m —, —NR b C(O)—, —(CR c R c ) m —C(O)—, —(CR c R c ) m —OC(O)—, —C(O)—, or —O(CO)—.

16. The method of claim 9 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from:

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Su Shin-San Michael
• Dang Lenny

Classifications

• C07D307/14

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D241/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07C307/10

  having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C13/04

  with a three-membered ring · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title