Glutaminase inhibitors and method of use
Compounds and compositions comprising compounds that inhibit glutaminase are described herein. Also described herein are methods of using the compounds that inhibit glutaminase in the treatment of cancer.
1. A method for treating a cancer associated with the aberrant function of glutaminase or elevated activity of glutaminase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof or (b) a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein:
X is —S(O)—, —SO 2 —, or —C(O)—;
each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—, provided that (1) at least one of W, Y and Z is not —CH═ and (2) when one of W is —S— and the Y in the same ring is N, then the Z in the same ring is not —CH═;
each R 1 and R 2 is independently C 1-6 alkylene-R 4 , N(R 3 )—C(O)—R 4 , —C(O)—N(R 3 )—R 4 , —N(R 3 )—C(O)—O—R 4 , —N(R 3 )—C(O)—N(R 3 )—R 4 , —O—C(O)—N(R 3 )—R 4 , —N(R 3 )—C(O)—C 1-6 alkylene-C(O)—R 4 , —N(R 3 )—C(O)—C 1-6 alkylene-N(R 3 )—C(O)—R 4 or —N(R 3 )—C(O)—CH 2 —N(R 3 )—C(O)—R 4 ;
each R 3 is independently hydrogen, C 1-6 alkyl or aryl;
each R 4 is independently C 1-6 alkyl, C 1-6 alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cycloalkyl or cycloalkylalkyl, each of which is substituted with 0-3 occurrences of R 5 , or two adjacent R 5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl;
each R 5 is independently oxo (═O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, cyano, halo, —OH, —SH, —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —N(R 6 ) 2 , —O—C(O)—C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)alkyl, aryl, aryloxy, —C(O)-aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl or heterocyclyl, wherein each aryl, heteroaryl or heterocyclyl is further substituted with 0-3 occurrences of R 7 ;
each R 6 is independently hydrogen, OH or C 1-6 alkyl;
each R 7 is independently hydrogen, C 1-6 alkyl, —OH, —SH, cyano, halo, —CF 3 , —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 6 )—C(O)—C 1-6 alkyl, N(R 6 ) 2 or C 1-6 alkoxy;
m is 1, 2 or 3;
n is 1, 2 or 3; provided that when X is, —S(O)—, —SO 2 —, or —C(O)—, the sum of m and n is from 2 to 4;
o is 1, 2 or 3; and
p is 1, 2 or 3.
2. The method of claim 1 , wherein each W is —S—, each Y is —N═ and each Z is —N═.
3. The method of claim 1 , wherein each W is —CH═, each Z is —O— and each Y is —N═.
4. The method of claim 1 , wherein o is 1 and p is 1.
5. The method of claim 1 , wherein R 1 and R 2 are each —N(R 3 )—C(O)—O—R 4 , wherein R 3 is hydrogen.
6. The method of claim 5 , wherein R 1 and R 2 are the same.
7. The method of claim 1 , wherein the compound is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein R 1 and R 2 are the same.
9. A method for treating a cancer associated with the aberrant function of glutaminase or elevated activity of glutaminase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof or (b) a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein:
X is —S(O)— or —SO 2 —;
each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—, provided that (1) at least one of W, Y and Z is not —CH═ and (2) when one of W is —S— and the Y in the same ring is N, then the Z in the same ring is not —CH═;
each R 1 and R 2 is independently C 1-6 alkylene-R 4 , N(R 3 )—C(O)—R 4 , —C(O)—N(R 3 )—R 4 , —N(R 3 )—C(O)—O—R 4 , —N(R 3 )—C(O)—N(R 3 )—R 4 , —O—C(O)—N(R 3 )—R 4 , —N(R 3 )—C(O)—C 1-6 alkylene-C(O)—R 4 , —N(R 3 )—C(O)—C 1-6 alkylene-N(R 3 )—C(O)—R 4 or —N(R 3 )—C(O)—CH 2 —N(R 3 )—C(O)—R 4 ;
each R 3 is independently hydrogen, C 1-6 alkyl or aryl;
each R 4 is independently C 1-6 alkyl, C 1-6 alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cycloalkyl or cycloalkylalkyl, each of which is substituted with 0-3 occurrences of R 5 , or two adjacent R 5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl;
each R 5 is independently oxo (═O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, cyano, halo, —OH, —SH, —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —N(R 6 ) 2 , —O—C(O)—C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)alkyl, aryl, aryloxy, —C(O)-aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl or heterocyclyl, wherein each aryl, heteroaryl or heterocyclyl is further substituted with 0-3 occurrences of R 7 ;
each R 6 is independently hydrogen, fluoro, —OH or C 1-6 alkyl;
each R 7 is independently hydrogen, C 1-6 alkyl, —OH, —SH, cyano, halo, —CF 3 , —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 6 )—C(O)—C 1-6 alkyl, N(R 6 ) 2 or C 1-6 alkoxy;
m is 1, 2 or 3;
n is 1, 2 or 3;
o is 1, 2 or 3; and
p is 1, 2 or 3.
10. The method of claim 9 , wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof wherein:
X is —SO 2 —;
each R 4 is independently aralkyl, heteroaralkyl, or heterocyclylalkyl, each of which is substituted with 0-3 occurrences of R 5 , or two adjacent R 5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl;
each R 5 is independently oxo (═O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, cyano, halo, —OH, —SH, —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —N(R 6 ) 2 , —O—C(O)—C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)alkyl, aryl, aryloxy, —C(O)-aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl or heterocyclyl, wherein each aryl, heteroaryl or heterocyclyl is further substituted with 0-3 occurrences of R 7 ;
each R 6 is independently hydrogen, fluoro, OH or C 1-6 alkyl;
each R 7 is independently hydrogen, C 1-6 alkyl, —OH, —SH, cyano, halo, —CF 3 , —OCF 3 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 6 )—C(O)—C 1-6 alkyl, N(R 6 ) 2 or C 1-6 alkoxy;
m is 1, 2 or 3; and
n is 1, 2 or 3; provided that the sum of m and n is from 2 to 4.
11. The method of claim 10 , wherein m and n are both 2.
12. The method of claim 10 , wherein each R 4 is independently aralkyl or heteroaralkyl, each of which is substituted with 0-3 occurrences of R 5 , or two adjacent R 5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl.
13. The method of claim 12 , wherein each R 4 is heteroaralkyl.
14. The method of claim 12 , wherein each R 4 is aralkyl.
15. The method of claim 10 , wherein each R 6 is hydrogen.
16. A method for treating a cancer associated with the aberrant function of glutaminase or elevated activity of glutaminase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound selected from:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the cancer is lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma, lipomas, or mesothelioma.
18. The method of claim 17 , wherein the lung cancer is non-small cell lung cancer.
19. The method of claim 1 , wherein the cancer is chondrosarcoma.