IRE-1alpha INHIBITORS
The invention provides 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 - 9 . (canceled)
10 . A compound of formula (2b):
or a pharmaceutically acceptable salt thereof,
wherein
R3 is hydrogen or —CN;
R6 is
Het is a five-membered heteroaryl containing 1, 2, or 3 heteroatoms atoms selected from N, S, and O and optionally substituted with alkyl, provided that Het is not unsubstituted
R24 is —OH or
R9 and R10 independently are alkyl; or
R9 and R10, together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycle containing 1 or 2 heteroatoms selected from N, O and S, optionally substituted with alkyl;
or R9 is hydrogen and R10 is
wherein n is 0, 1, 2, or 3; and
R25 is C1-C3 alkoxy or a 5- or 6-membered heteroaryl or heterocycle having one or two heteroatoms selected from N, O, and S and optionally substituted with alkyl, with the proviso that when Het is
then R24 is not —OH,
11 . The compound of claim 10 , wherein Het is thienyl optionally substituted with alkyl.
12 . A pharmaceutical composition, comprising the compound of claim 10 , and a pharmaceutically acceptable vehicle.
13 . A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of the compound of claim 10 .
14 . A compound of formula (3f):
or a pharmaceutically acceptable salt thereof,
wherein
R6 is
in which R30 is hydrogen or halogen; one of R28 and R29 is hydrogen and the other is
R31 is —OH or
R9 and R10 independently are hydrogen, methyl, benzyl, or
or R9 and R10, together with the nitrogen to which they are attached, form a 6-membered saturated heterocycle, optionally substituted with C1-C3 alkyl, provided that either (1) R30 and R28 are not both hydrogen; or (2) R30 and R29 are not both hydrogen.
15 . A pharmaceutical composition, comprising the compound of claim 14 , and a pharmaceutically acceptable vehicle.
16 . A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of the compound of claim 15 .