THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
Compounds and compositions comprising compounds useful in the treatment of cancer are described herein.
1 . A compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:
B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
D and D 1 are independently selected from a bond or NR c ;
A is phenyl substituted with 0-3 occurrences of R 2 ;
R 1 is represented by the following structure:
wherein p is 0, 1 or 2; and each R d is independently selected from the group consisting of halo, haloalkyl, alkyl, aryl, and —OR a ;
each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, —NR c R c′ alkyl-NR c R c′ , —OR a , —C(O)OH, —C(O)OR b , or —C(O)NR c R c′ ;
R 3 is halo, haloalkyl, alkyl, or —OR a ;
each R a is independently selected from optionally substituted alkyl and haloalkyl;
each R c and R c′ is independently selected from hydrogen, alkyl, and alkenyl;
each R b is independently alkyl;
provided that when B and B 1 taken together with the carbon to which they are attached form a carbonyl group; and one of D and D 1 is a bond and the other is NH;
then A is not phenyl substituted by methyl, fluorine, methoxy or ethoxy.
2 . The compound of claim 1 , wherein B and B 1 are taken together with the carbon atoms to which they are attached to form a carbonyl group.
3 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein D is a bond and D 1 is NR c .
4 . A compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein:
D and D 1 are independently selected from a bond or NR c ;
A is phenyl substituted with 0-3 occurrences of R 2 ;
R 1 is represented by the following structure:
wherein p is 0, 1 or 2; and each R d is independently selected from the group consisting of halo, haloalkyl, alkyl, aryl, and −0R a ;
each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, —NR c R c′ alkyl-NR c R c′ , —OR a , —C(O)OH, —C(O)OR b , or —C(O)NR c R c′ ;
R 3 is alkyl;
each R a is independently selected from optionally substituted alkyl and haloalkyl; each R c and R c′ is independently selected from hydrogen, alkyl, and alkenyl;
each R b is independently alkyl; and
provided that when D is a bond and D 1 is NH, then A is not phenyl substituted with methyl or methoxy.
5 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein D is a bond and D 1 is NR c .
6 . The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R c is hydrogen.
7 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaralkyl substituted with 0-3 occurrences of R d .
8 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with 1 or 2 occurrences of R 2 .
9 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is —OR a and R a is alkyl.
10 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is —OR a and R a is alkyl.
11 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl.
12 . The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is alkyl.
13 . The compound of claim 1 or a pharmaceutically acceptable salt thereof having the following structure:
14 . The compound of claim 1 or a pharmaceutically acceptable salt thereof having the following structure:
15 . The compound of claim 1 or a pharmaceutically acceptable salt thereof having the following structure:
16 . The compound of claim 1 or a pharmaceutically acceptable salt thereof having the following structure:
17 . A method of treating a cancer characterized as having an IDH mutation, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
18 . A method of treating a cancer characterized as having an IDH mutation, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.
19 . The method of claim 17 , wherein the IDH1 mutation is IDH1 R132X.
20 . The method of claim 18 , wherein the IDH1 mutation is IDH1 R132X.