Compounds and their methods of use

Patent metadata

Field	Value
Publication number	US-10000479-B2
Application number	US-201515127742-A
Country	US
Kind code	B2
Filing date	Mar 20, 2015
Priority date	Mar 21, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Cianchetta Giovanni
• Lemieux Rene M
• Cao Sheldon
• Ding Yue
• Ye Zhixiong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D237/20

  Nitrogen atoms (nitro radicals C07D237/12) · CPC title