THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE

1 . 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 formula (I) or a pharmaceutically acceptable salt thereof, wherein:

wherein:

W, X, Y and Z are each independently selected from CH or N;

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;

Q is C═O or SO 2 ;

D and D 1 are independently selected from a bond, oxygen or NR c ;

A is aryl or heteroaryl each substituted with 0-3 occurrences of R 2 ;

R 1 is independently selected from alkyl, acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;

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 , —C(O)NR c R c′ , cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, or heteroaralkyl;

each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and —OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms they are attached to form an optionally substituted heterocyclyl;

each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(O)OR b , alkyl-C(O)OR b , and haloalkyl;

each R b is independently alkyl;

each R c and R c′ is independently selected from hydrogen, alkyl, alkyl-C(O)OR b and alkenyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, 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;

h is 0, 1, 2; and

g is 0, 1 or 2.

2 . The method of claim 1 , wherein the compound is selected from any one of the compounds set forth in the table below:

Compound

3 . The method of claim 1 or 2 , wherein the compound or pharmaceutically acceptable salt thereof is formulated into a pharmaceutical together with a pharmaceutically acceptable carrier.

4 . The method of any one of claims 1 to 3 , wherein the subject is evaluated for the presence of an IDH1 R132X mutant allele prior to administration of the compound.

5 . The method of any one of claims 1 to 3 , wherein the subject is evaluated for the presence of an elevated level of 2HG prior to administration of the compound.

6 . The method of any one of claims 1 to 3 , wherein efficacy of treatment of cancer comprises monitoring the level of 2HG in a subject during treatment.

7 . The method of any one of claims 1 to 3 , wherein efficacy of treatment of cancer comprises monitoring the level of 2HG in a subject following termination of treatment.

8 . (canceled)

9 . A compound of formula (Ic):

W, X, Y and Z are each independently selected from CH or N;

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 aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;

R 1 is independently selected from acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;

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′ ;

each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and —OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;

each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(O)OR b , alkyl-C(O)OR b , and haloalkyl;

each R b is independently alkyl;

each R c and R c′ is independently selected from hydrogen, alkyl, alkyl-C(O)OR b and alkenyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, 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;

h is 0, 1, 2; and

g is 0, 1 or 2;

provided that:

(1) when W, X, Y and Z are each independently selected from CH;

B and B 1 taken together with the carbon to which they are attached form a carbonyl group;

each R 3 is independently selected from halo, alkyl and —OR a ;

(i) h and g are each 1; one of D and D 1 is a bond and the other is NH; R 1 is phenyl or monocyclic heteroaryl, each of which may be optionally substituted with 0-3 occurrences of R d ;

then A is not phenyl optionally substituted with unsubstituted alkyl, unsubstituted alkoxy, halo, CF 3 , CH 2 CH 2 NH 2 , NO 2 , or acyl;

(ii) h and g are each 1; of D and D 1 is a bond and the other is NH; R 1 is acyl;

then n is 1, R 3 is alkyl and R 3 is connected to W, and A is not phenyl substituted by methyl, F, methoxy or ethoxy; and

(iii) the sum of h and g is 3, D is a bond and D 1 is NH; R 1 is o-methoxyphenyl;

then A is not phenyl substituted with unsubstituted alkyl, methoxy, ethoxy or halo;

(2) the compound is not N-(4-butylphenyl)-N′-[3-[[4-2-(methoxyphenyl)-1-piperazinyl]carbonyl]-4-methylphenyl]-sulfamide.

10 . The compound of claim 9 , wherein the compound is a compound of formula (II):

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 aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;

R 1 is independently selected from cycloalkyl, aryl, heteroaryl or heterocyclyl; each of which may be optionally substituted with 0-3 occurrences of R d ;

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′ ;

each R 3 is independently selected from halo, haloalkyl, alkyl and —OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;

each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(O)OR b , alkyl-C(O)OR b , and haloalkyl; each R c and R c′ is independently selected from hydrogen, alkyl, alkyl-C(O)OR b and alkenyl;

each R b is independently alkyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, 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; and

provided that when B and B 1 taken together with the carbon to which they are attached form a carbonyl group;

each R 3 is independently selected from halo, alkyl and —OR a ;

one of D and D 1 is a bond and the other is NH; and

R 1 is phenyl or monocyclic heteroaryl, each of which may be optionally substituted with 0-3 occurrences of R d ;

then A is not phenyl optionally substituted with unsubstituted alkyl, unsubstituted alkoxy, halo, CF 3 , CH 2 CH 2 NH 2 , NO 2 , or acyl.

11 . The compound of claim 9 , wherein the compound is a compound of formula (III):

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 aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;

R 1 is independently selected from acyl, optionally substituted with 0-3 occurrences of R d ;

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 alkyl and haloalkyl;each R c and R c′ is independently selected from hydrogen, alkyl, and alkenyl;

each R b is independently alkyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and —OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; and

provided that when B and B 1 taken together with the carbon to which they are attached form a carbonyl group; D and D 1 is a bond and the other is NH;

then A is not phenyl substituted by methyl, fluorine, methoxy or ethoxy.

12 . The compound of claim 11 , wherein B and B 1 are taken together with the carbon atoms to which they are attached to form a carbonyl group.

13 . The compound of claim 11 , wherein D is a bond and D 1 is NR c .

14 . The compound of claim 9 , wherein the compound is a compound of formula (IV):

wherein:

D and D 1 are independently selected from a bond or NR c ;

A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;

R 1 is independently selected from heterocyclylalkyl, cycloalkylalkyl, aralkyl and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;

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 alkyl and haloalkyl; each R c and R c′ is independently selected from hydrogen, alkyl, and alkenyl;

each R b is independently alkyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and —OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; and

provided that when D is a bond and D 1 is NH, then A is not phenyl substituted with methyl or methoxy.

15 . The compound of claim 14 , wherein D is a bond and D 1 is NR c .

16 . The compound of claim 15 , wherein R c is hydrogen.

17 . The compound of claim 14 , wherein R 1 is aralkyl or heteroaralkyl substituted with 0-3 occurrences of R d .

18 . The compound of claim 14 , wherein A is phenyl substituted with 0-3 occurrences of R 2 .