Pyruvate kinase activators for use in therapy

Patent metadata

Field	Value
Publication number	US-9682080-B2
Application number	US-201514886750-A
Country	US
Kind code	B2
Filing date	Oct 19, 2015
Priority date	May 3, 2011
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

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;
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 NR b and D 1 is a bond.

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

6. The method of claim 5 , wherein L is a bond, —(CR c R c ) m —, —NR b C(O)—, —(CR c R c ) m —C(O)—, —C(O)—, or —O(CO)—.

7. The method of claim 6 , wherein L is —(CR c R c ) m —.

8. The method of claim 7 , wherein R 1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R d .

9. The method of claim 8 , wherein L is —CH 2 — 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 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;
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 NR b and D 1 is a bond.

15. The method of claim 14 , wherein R b is H, methyl or ethyl.

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

17. The method of claim 16 , wherein L is —(CR c R c ) m —.

18. The method of claim 17 , wherein R 1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R d .

19. The method of claim 18 , wherein L is —CH 2 — 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)—, —(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 ca

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Su Shin-San Michael

Classifications

• C07D307/14

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

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D241/04

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

• A61P7/06

  Antianaemics · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title