Compounds and their methods 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 compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
X is C 3 -C 7 cycloalkylene;
each W, Y and Z is independently —S—, —CH═, —O—, —N═, or —NH—, provided that at least one of W, Y and Z is not —CH═;
each R 1 and R 2 is independently —NH 2 , —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 or —N(R 3 )—C(O)—SR 4 ;
each R 3 is independently hydrogen, C 1-6 alkyl or aryl;
each R 4 is independently C 1-6 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, or heterocyclyl, each of which is substituted with 0-3 occurrences of R 5 ;
each R 5 is independently C 1-6 alkyl, C 1-6 alkoxy, —O—C 1-6 alkyleneC 1-6 alkoxy, C 1-6 thioalkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cyano, halo, oxo, —OH, —OCF 3 , —OCHF 2 , —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —C(O)N(R 7 ) 2 , —N(R 7 )S(O) 1-2 —C 1-6 alkyl, —S(O) 2 N(R 7 ) 2 , —N(R 7 ) 2 , —C 1-6 alkylene-N(R 7 ) 2 , wherein said alkyl, C 1-6 alkoxy, —O—C 1-6 alkyleneC 1-6 alkoxy, C 1-6 thioalkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, —SO 2 —C 1-6 alkyl, —NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —C(O)N(R 7 ) 2 , —N(R 7 )S(O) 1-2 —C 1-6 alkyl, —S(O) 2 N(R 7 ) 2 , —N(R 7 ) 2 , or —C 1-6 alkylene-N(R 7 ) 2 is optionally substituted with 0-3 occurrences of R 8 ; or two adjacent R 5 moieties, taken together with the atoms to which they are attached form a cycloalkyl or heterocyclyl;
each R 6 is independently hydrogen, fluoro, C 1-6 alkyl, —OH, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , or C 1-6 alkoxy;
each R 7 is independently hydrogen or C 1-6 alkyl;
each R 8 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, —OH, —N(R 7 ) 2 , or C 1-6 alkoxy, —O—C 1-6 alkyleneC 1-6 alkoxy, CN, NO 2 , —N(R 7 )—C(O)—C 1-6 alkyl, —C(O)N(R 7 ) 2 , —N(R 7 )S(O) 1-2 C 1-6 alkyl, or —S(O) 2 N(R 7 ) 2 ;
m is 0, 1, or 2;
n is 0, 1, or 2;
o is 1, 2 or 3; and
p is 1, 2 or 3; provided that (1) when X is unsubstituted cyclopropyl, R 1 and R 2 are not both NH-phenyl; and (2) X is other than substituted cyclobutyl or substituted cyclopentyl.
2. The compound of claim 1 , wherein each W is —S—, each Y is —N═and each Z is —N═.
3. The compound of claim 1 , wherein o is 1 and p is 1.
4. The compound of claim 1 , wherein m is 0 and n is 0.
5. The compound of claim 1 , wherein n is 1 and m is 1.
6. The compound of claim 5 , wherein each R 6 is hydrogen.
7. The compound of claim 1 , wherein R 1 and R 2 are the same.
8. The compound of claim 1 , wherein R 1 and R 2 are different.
9. The compound of claim 1 , wherein R 1 and R 2 are each —N(R 3 )—C(O)—R 4 wherein each R 3 is hydrogen and each R 4 is aralkyl or heteroaralkyl, each of which is substituted with 0-3 occurrences of R 5 .
10. The compound of claim 1 , wherein the compound is a compound of Formula (II):
11. The compound of claim 10 , wherein the compound is a compound of Formula (IIa):
12. The compound of claim 1 , wherein the compound is a compound of Formula (III):
13. The compound of claim 1 , wherein the compound is a compound of Formula (IV) and q is 0, 1, 2, 3, or 4 :
14. The compound of claim 1 , wherein the compound is a compound of Formula (IVa) and q is 0, 1, 2, 3, or 4:
15. The compound of claim 1 , wherein the compound is a compound of Formula (IVb) and q is 0, 1, 2, 3, or 4:
16. The compound of claim 1 , wherein the compound is a compound of Formula (IVc) and q is 0, 1, 2, 3, or 4:
17. A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
18. A method of treating cancer, the method comprising administering a compound of claim 1 or a composition of claim 17 to a subject in need thereof, wherein the cancer is selected from: lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma, chondrosarcoma, and mesothelioma.
19. The method of claim 18 , wherein the cancer is lung cancer.
20. The method of claim 19 , wherein the lung cancer is non-small cell lung cancer.