Compounds and their methods of use

Patent metadata

Field	Value
Publication number	US-9303002-B2
Application number	US-201314085947-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Nov 21, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

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 a bond, —S—, —S(O)—, —SO 2 —, —CH═CH—, 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 3a )—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 7 )—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 bond, the sum of m and n is from 3 to 6 and when X is —S—, —S(O)—, —SO 2 —, —CH═CH—, 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;
with the proviso that:
(1) when X is —S—, m and n are both 2, each R 6 is H, then (i) R 1 and R 2 are not both —NHC(O)—R 4 , wherein R 4 is C 1-6 alkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic aralkyl, monocyclic heteroaralkyl and each member of R 4 is substituted with 0-3 occurrences of R 5 ; and (ii) R 1 and R 2 are not both —NHC(O)O-methyl, —NHC(O)O-ethyl, —NHC(O)-6-pyrimidine-2,4(1H,3H)-dionyl, or —NHC(O)NH-phenyl wherein said phenyl of the —NHC(O)NH-phenyl moiety is optionally substituted with 1 or 2 groups selected from methyl, nitro, and halo;
(2) when X is —S—, m and n are both 1, each R 6 is H, then (i) R 1 and R 2 are not both —NH-phenyl or —NH-4-methoxy-phenyl;
(3) when X is a bond, the sum of m and n is 3, each R 6 is H, then R 1 and R 2 are not both NHC(O)-phenyl;
(4) when X is a bond, m and n are both 2, each R 6 is H, then R 1 and R 2 are not both —NHC(O)-furanyl, —NHC(O)-phenyl, —NHC(O)-o-methoxy-phenyl, —NHC(O)—C 1-6 alkyl, —NH-benzyl, or —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is substituted with 0-3 occurrences of R 5 ;
(5) when X is a bond, the sum of m and n is 5, each R 6 is H, then R 1 and R 2 are not both —NHC(O)—C 1-6 alkyl, —NHC(O)-cyclohexyl, or —NH-phenyl wherein said phenyl of the —NH-phenyl moiety is optionally substituted with methyl; and
(6) when X is a bond, m and n are both 3, each R 6 is H, then R 1 and R 2 are not both NH-phenyl.

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 each W is —CH═, each Z is —O— and each Y is —N═.

4. The compound of claim 1 , wherein o is 1 and p is 1.

5. The compound 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 compound of claim 5 , wherein R 1 and R 2 are the same.

7. The compound of claim 1 , wherein the compound is a compound of Formula (II):

8. The compound of claim 6 , wherein R 1 and R 2 are the same.

9. The compound of claim 1 , wherein the compound is a compound of Formula (III):

10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:

14. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, 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-

Assignees

• Lemieux Rene M
• Popovici-Muller Janeta
• Salituro Francesco G
• Saunders Jeffrey O
• Travins Jeremy
• Yan Shunqi
• Agios Pharmaceuticals Inc

Inventors

• Lemieux Rene M
• Popovici-Muller Janeta
• Salituro Francesco G
• Saunders Jeffrey O
• Travins Jeremy
• Yan Shunqi

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/12

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

• C07D285/12

  1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title