Therapeutic compounds and compositions

Patent metadata

Field	Value
Publication number	US-10029987-B2
Application number	US-201715412976-A
Country	US
Kind code	B2
Filing date	Jan 23, 2017
Priority date	Jun 29, 2009
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

First claim

What is claimed is:

1. 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 independently selected from a bond or NR b ;
A is optionally substituted bicyclic 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)—;
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 cyclyl;
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
h is 1 and g is 2, or g is 1 and h is 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W, X, Y and Z are CH.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein D is NR b and D 1 is a bond.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R b is H, methyl or ethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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)—.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is a bond.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of R d .

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —(CR c R c ) m —.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R d .

10. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —NR b C(O)— and R b is hydrogen.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl substituted with 0-5 occurrences of R d .

12. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —(CR c R c ) m —C(O)—.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrences of R d .

14. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —C(O)—.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl, alkyl, or heteroaryl substituted with 0-5 occurrences of R d .

16. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —OC(O)—.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of R d .

18. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is —(CR c R c ) m—OC(O)—.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of R d .

20. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein n is 0.

21. The compound of claim 5 or a pharmaceutically acceptable salt thereof, 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 .

22. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 22 , wherein the compound is a compound of Formula (Id):

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

Assignees

• Agios Pharmaceuticals Inc
• Agios Pharmaceuticals Inc

Inventors

• Salituro Francesco G
• Saunders Jeffrey O
• Yan Shunqi

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D215/40

  attached in position 8 · CPC title

• C07D215/36 Primary

  Sulfur atoms (C07D215/24 takes precedence) · CPC title

• A61K31/497 Primary

  containing further heterocyclic rings · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title