Therapeutic compounds and compositions

Patent metadata

Field	Value
Publication number	US-9365545-B2
Application number	US-201514814862-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Mar 15, 2013
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Compounds of general formula I:

and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.

First claim

What is claimed is:

1. A compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted bicyclic heteroaryl;
X is selected from —NH—S(O) 2 —, —NH—S(O) 2 —CH 2 —, —CH 2 —S(O)—NH— or —CH 2 —S(O) 2 —NH—;
R 1b is selected from C 1-8 alkyl optionally substituted with one to four R 5 groups; C 1-8 alkenyl optionally substituted with one to four R 5 groups; cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl; cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl; aralkenyl; heteroaralkyl; and heteroaralkenyl; wherein each cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl is optionally substituted;
each R 2 is independently selected from halo, alkyl, CN, OH, and alkoxy, wherein said alkyl or alkoxy is optionally substituted with one to four R 5 groups; or two adjacent R 2 groups are taken together with the ring atoms they are attached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic or heteroaryl ring;
each R 5 is independently selected from halo, OH, C 1-6 alkoxy, CN, NH 2 , —SO 2 —C 1-6 alkyl, —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; and
n is 0, 1, 2 or 3.

2. The compound of claim 1 , wherein A is an optionally substituted quinolin-8-yl.

3. The compound of claim 1 , wherein A is an optionally substituted quinoxalin-8-yl.

4. The compound of claim 1 , wherein A is

5. The compound of claim 1 , wherein A is

6. The compound of claim 1 , wherein X is —NH—S(O) 2 —.

7. The compound of claim 1 , wherein R 1b is C 1-8 alkyl optionally substituted with one to four R 5 groups; aryl; heteroaryl; aralkyl; or heteroaralkyl; wherein each aryl; heteroaryl; aralkyl; or heteroaralkyl; is optionally substituted.

8. The compound of claim 6 , wherein each aryl; heteroaryl; aralkyl; or heteroaralkyl is optionally substituted with halo, C 1-6 alkyl, —OH, C 1-6 alkoxy, —CN, —NH 2 , —SO 2 —C 1-6 alkyl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , aryl, haloalkyl, or haloalkoxy.

9. The compound of claim 1 , wherein R 1b is C 1-8 alkyl optionally substituted with one to four R 5 groups.

10. The compound of claim 1 , wherein R 1b is selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, t-pentyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 3,3-difluoropropyl, ethoxymethyl, N,N-dimethylmethyl, pyrrollomethyl and 2-hydroxypropyl.

11. The compound of claim 1 , wherein R 1b is selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, and t-pentyl.

12. The compound of claim 1 , wherein n is 0.

13. The compound of claim 1 , wherein the compound is selected from:

14. The compound of claim 1 having the following structure:

15. The compound of claim 1 having the following structure:

16. The compound of claim 1 having the following structure:

17. The compound of claim 1 having the following structure:

18. The compound of claim 1 having the following structure:

19. The compound of claim 1 having the following structure:

20. The compound of claim 1 having the following structure:

21. The compound of claim 1 hav

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Cianchetta Giovanni
• Popovici-Muller Janeta
• Zahler Robert
• Cao Sheldon
• Wang Xiaolei
• Ye Zhixiong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title