Compounds and their methods of use

1. A method for treating a cancer characterized by aberrant function of glutaminase or elevated activity of glutaminase in a subject in need thereof that has been diagnosed with said cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein

X is an optionally substituted C 3 -C 7 cycloalkylene;

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, —O— heterocyclyl, 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 or —C 1-6 alkylene-N(R 7 ) 2 , wherein said alkyl, C 1-6 alkoxy, —O—C 1-6 alkyleneC 1-6 alkoxy, —O-heterocyclyl, 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;

n is 0;

o is 1; and

p is 1; provided that (1) when X is unsubstituted cyclopropyl, R 1 and R 2 are not both —NH 2 or —NH—C(O)-phenyl and (2) X is other than substituted cyclobutyl or substituted cyclopentyl.

2. The method of claim 1 , wherein R 1 and R 2 are the same.

3. The method of claim 1 , wherein R 1 and R 2 are each independently —N(R 3 )—C(O)—R 4 and 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 .

4. The method of claim 1 , wherein the compound is a compound of Formula (IV) or a pharmaceutically acceptable salt thereof and q is 0, 1, 2, 3, or 4:

5. The method of claim 1 , wherein the compound is a compound of Formula (IVa) or a pharmaceutically acceptable salt thereof, and q is 0, 1, 2, 3, or 4:

6. The method of claim 1 , wherein the compound is a compound of Formula (IVb) or a pharmaceutically acceptable salt thereof and q is 0, 1, 2, 3, or 4:

7. The method of claim 1 , wherein the compound is a compound of Formula (IVc) or a pharmaceutically acceptable salt thereof and q is 0, 1, 2, 3, or 4:

8. The method of claim 1 wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is incorporated into a pharmaceutical composition.

13. The method of claim 1 , wherein the cancer is selected from a cancer characterized by i) a low level of E-cadherin expression compared to a reference standard, ii) a high level of vimentin expression compared to a reference standard, or iii) a low or decreased level of pyruvate carboxylase expression.

14. The method of claim 1 , wherein said cancer is selected from non-small cell lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma, lipomas, chondrosarcoma, mesothelioma, colon cancer, renal cell carcinoma, acute myeloid leukemia (AML), melanoma and multiple myeloma.