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 or with regulated IRE1-dependent decay (RIDD) and can be used as single agents or in combination therapies.
1. A compound or pharmaceutically acceptable salt thereof, where the compound is represented by structural formula (A-3):
wherein:
R3 and R4 independently are hydrogen; alkyl or alkoxy, each optionally substituted with (1) a C1-C6 hydrocarbon chain containing an N or O atom, or (2) a cycloalkyl which optionally contains 1 or 2 heteroatoms selected from N, O, and S;
R6 is alkynyl or phenyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, and
a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkoxy, and
wherein n1 is 0, 1, or 2;
R7 is H or methyl;
R9 and R10 are independently hydrogen; alkyl; alkoxylalkyl; or
wherein n2 is 0, 1, 2, or 3; or,
R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
R11 is hydrogen or alkyl;
R12 is amino; alkoxy; or a 5- or 6-membered heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R11;
with the exception of compounds of structural formula (A-3) in which:
R3 and R4 are hydrogen and R6 is optionally substituted phenyl.
2. The compound or pharmaceutically acceptable salt thereof according to structural formula (A-3) of claim 1 ,
wherein R3 and R4 independently are hydrogen; ethyl or methoxy.
3. The compound or pharmaceutically acceptable salt thereof according to structural formula (A-3) of claim 1 ,
wherein R6 is
wherein n1 is 1, or 2.
4. The compound or pharmaceutically acceptable salt thereof according to structural formula (A-3) of claim 1 ,
wherein R9 and R10 are independent hydrogen; alkyl; or
wherein n2 is 2; or,
R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle selected from morpholinyl and piperazinyl, optionally substituted with alkyl.
5. The compound or pharmaceutically acceptable salt thereof according to structural formula (A-3) of claim 1 ,
wherein R12 is methoxy; or morpholinyl.
6. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
7. The compound or pharmaceutically acceptable salt thereof according to claim 6 , wherein the compound is selected from:
8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.
9. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable vehicle.