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 an optionally substituted C 3 -C 7 cycloalkylene;
W is independently —S—, —CH═CH—, —CH═CR 1 —, or —CR 1 ═CR 1 —;
W′ is independently —S—, —CH═CH—, —CH═CR 2 —, or —CR 2 ═CR 2 —; provided that at least one of W and W′ is —CH═CH—, —CH═CR 1 —, or —CR 1 ═CR 1 —;
Y, Z, Y′ and Z′ are each —N═;
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 is1,2or3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is —CH═CH—, Y is —N═, Z is —N═, W′ is —S—, Y′ is —N═and Z′ is —N═.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein o is 1 and p is 1.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 0.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1 and m is 1.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein each R 6 is hydrogen.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are different.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II):
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIa):
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIb):
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV) and q is 0, 1, 2, 3, or 4:
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IVa) and q is 0, 1, 2, 3, or 4:
15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IVb) and q is 0, 1, 2, 3, or 4:
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IVc) and q is 0, 1, 2, 3, or 4:
17. A method of making a compound of claim 1 or a pharmaceutically acceptable salt thereof,
comprising reacting
wherein each G is a leaving group, with
18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.
19. A method of treating a cancer associated with aberrant or elevated function of glutaminase, the method comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
20. The method of claim 19 , 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.
21. A compound of claim 1 or pharmaceutically acceptable salt thereof selected from:
Cmpd #
Structure
1
2
10
14
20
37
41
75
98
99
152
175
176
180
291
22. A method of treating a cancer associated with aberrant or elevated function of glutaminase, the method comprising administering a composition of claim 18 to a subject in need thereof.
23. The method of claim 22 , 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.
24. The method of claim 19 wherein the cancer is selected from non-small cell lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma, lipoma, chondrosarcoma, mesothelioma, colon cancer, renal cell carcinoma, acute myeloid leukemia (AML), melanoma and multiple myeloma.
25. The method of claim 22 wherein the cancer is selected from non-small cell lung cancer, breast cancer, hepatocellular carcinoma, osteosarcoma, lipoma, chondrosarcoma, mesothelioma, colon cancer, renal cell carcinoma, acute myeloid leukemia (AML), melanoma and multiple myeloma.