IRE-1α inhibitors
Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response and can be used as single agents or in combination therapies.
1. A compound which directly inhibits IRE-1α activity in vitro and is represented by structural formula (B):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
R 2 is phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl,
and
R 4 is hydrogen,
2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.
3. A method of inhibiting the activity of IRE1-α comprising contacting the IRE1-α enzyme with a compound of claim 1 .
4. The method of claim 3 wherein the compound is the compound of claim 21 .
5. The method of claim 3 wherein the compound is the compound of claim 22 .
6. The compound of claim 1 wherein R 1 , R 3 , and R 4 are hydrogen.
7. The compound of claim 6 wherein R 2 is a five-membered heterocycle.
8. The compound of claim 7 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
9. The compound of claim 1 wherein R 2 is a five-membered heterocycle.
10. The compound of claim 9 wherein R 2 is
11. The compound of claim 9 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
12. A compound which has the structural formula:
13. The pharmaceutical composition of claim 2 wherein R 1 , R 3 , and R 4 are hydrogen.
14. The pharmaceutical composition of claim 13 wherein R 2 is a five-membered heterocycle.
15. The pharmaceutical composition of claim 14 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
16. The pharmaceutical composition of claim 2 wherein R 2 is a five-membered heterocycle.
17. The pharmaceutical composition of claim 16 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
18. A pharmaceutical composition comprising:
a compound which has the structural formula
or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable vehicle.
19. The method of claim 3 wherein R 1 , R 3 , and R 4 are hydrogen.
20. The method of claim 19 wherein R 2 is a five-membered heterocycle.
21. The method of claim 19 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
22. The method of claim 3 wherein R 2 is a five-membered heterocycle.
23. The method of claim 22 wherein the five-membered heterocycle is substituted with
—CH 3 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,
24. A method of inhibiting the activity of IRE1-α comprising contacting the IRE1-α enzyme with a compound having the structural formula
or a pharmaceutically acceptable salt thereof.