Bicyclic PKM2 activators

Patent metadata

Field	Value
Publication number	US-10087169-B2
Application number	US-201715645621-A
Country	US
Kind code	B2
Filing date	Jul 10, 2017
Priority date	Dec 21, 2010
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

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

First claim

What is claimed is:

1. A pharmaceutically acceptable salt of a compound of formula (Ia) wherein:

X and Y are each independently selected from O and N(-L-R 1 ), wherein X is O and Y is N(-L-R 1 ) or X is N(-L-R 1 ) and Y is O;
each L is independently selected from a bond, —C(O)—, —(CR a R b ) m —, —C(O)N(R c )— or —C(O)O—;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R d ;
each R 1 is independently selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, alkyl-O-alkylene, C 3-10 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ;
each R a and each R b are independently selected from hydrogen, C 1-4 alkyl, or R a and R b bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl;
each R c is independently selected from hydrogen and C 1-4 alkyl;
each R d is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, nitro, cyano, —OH and —O(C 1-4 alkyl), or two R d , attached to the same or adjacent carbon atoms, taken together with the atom(s) to which they are attached form an optionally substituted heterocyclyl;
each R f is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, nitro, cyano, —OH and —O(C 1-4 alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R g is independently selected from nitro, cyano, —OH, —O(C 1-4 alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R 2 is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and hydroxyl;
each m is independently 1, 2 or 3; and
each n is independently 0, 1, 2 or 3.

2. The pharmaceutically acceptable salt of a compound of claim 1 , wherein the compound has the structure:

3. A pharmaceutically acceptable salt of a compound of formula (IIa), wherein:

X and Y are each independently selected from O and N-L-R 1 , wherein X is O and Y is N(-L-R 1 ) or X is N(-L-R 1 ) and Y is O;
each L is independently selected from a bond, —C(O)—, —C(O)NR c — or —C(O)O—;
A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R d ;
each R 1 is independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ;
each R a and each R b are independently selected from hydrogen, C 1-4 alkyl, or R a and R b bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl;
each R c is independently selected from hydrogen and C 1-4 alkyl;
each R d is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, nitro, cyano, —OH and —O(C 1-4 alkyl), or two R d , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R f is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, nitro, cyano, —OH and —O(C 1-4 alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R g is independently selected from nitro, cyano, —OH, —O(C 1-4 alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl;
each R 2 is independently selected from halo, halo C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and hydroxyl;
each m is independently 1, 2 or 3; and
each n is independently 0, 1, 2 or 3.

4. The pharmaceutically acceptable salt of a compound of claim 3 , wherein the compound is:

5. The pharmaceutically acceptable salt of a compound selected from any one of the compounds below:

6. The pharmaceutically acceptable salt of a compound of claim 3 wherein the compound is:

7. The pharmaceutically acceptable salt of a compound of claim 3 wherein the compound is:

8. The pharmaceutically acceptable salt of a compound of claim 3 wherein the compound is:

9. The pharmaceutically acceptable salt of a compound of claim 3 wherein the compound is:

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Salituro Francesco G
• Saunders Jeffrey O

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D265/18

  with hetero atoms directly attached in position 2 · CPC title

• C07D265/36

  condensed with one six-membered ring · CPC title

• C07D413/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title