IRE-1α 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. A compound having a structural formula (1c):
or a pharmaceutically acceptable salt thereof,
wherein R6 is:
wherein R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered or a 6-membered saturated heterocycle containing 1 or 2 N, substituted with C1-C6 alkyl or
(b) furyl substituted with
wherein (a) R9 and R10 independently are C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle having 2 nitrogen atoms;
(c) pyrimidinyl substituted with
in which R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle having 2 nitrogen atoms;
(d) thiazolyl substituted with C1-C6 alkyl or
wherein (a) R9 and R10 independently are hydrogen or C1-C6 alkoxyl C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered saturated ring containing one nitrogen atom or a 6-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen;
(e) oxazolyl substituted with
wherein (a) R9 and R10 independently are hydrogen or C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered heterocycle containing two nitrogen atoms;
(f) triazolyl substituted with C1-C6 alkoxyl C1-C6 alkyl or
wherein R10 is C1-C6 alkyl; or
wherein (a) R9 and R10 independently are C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle containing the nitrogen atom and one oxygen atom.
2. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable vehicle.
3. A method of inhibiting IRE-1α, comprising contacting IRE-1α with a compound of claim 1 or pharmaceutically acceptable salt of the compound thereby inhibiting the IRE-1α.
4. A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or pharmaceutically acceptable salt of the compound.
5. A compound having structural formula (1a):
or a pharmaceutically acceptable salt thereof, wherein R7 is phenyl substituted with
wherein R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle containing 2 nitrogen atoms, substituted with C1-C6 alkyl.
6. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable vehicle.
7. A method of inhibiting IRE-1α, comprising contacting IRE-1α with a compound of claim 5 or pharmaceutically acceptable salt of the compound thereby inhibiting the IRE-1α.
8. A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of a compound of claim 5 or pharmaceutically acceptable salt of the compound.
9. The compound of claim 5 , wherein the C1-C6 alkyl is selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, and C1-C3 alkyl.
10. The compound of claim 5 , wherein the C1-C6 alkyl is selected from the group consisting of isopropyl, sec-butyl, tert-butyl, n-butyl, and 2-butyl.
11. The compound of claim 1 , wherein R6 is
wherein R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered or a 6-membered saturated heterocycle containing 1 or 2 N, substituted with C1-C6 alkyl or
12. The compound of claim 1 , wherein R6 is furyl substituted with
wherein (a) R9 and R10 independently are C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle having 2 nitrogen atoms.
13. The compound of claim 1 , wherein R6 is pyrimidinyl substituted with
in which R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle having 2 nitrogen atoms.
14. The compound of claim 1 , wherein R6 is thiazolyl substituted with C1-C6 alkyl or
wherein (a) R9 and R10 independently are hydrogen or C1-C6 alkoxyl C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered saturated ring containing one nitrogen atom or a 6-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen.
15. The compound of claim 1 , wherein R6 is oxazolyl substituted with
wherein (a) R9 and R10 independently are hydrogen or C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered heterocycle containing two nitrogen atoms.
16. The compound of claim 1 , wherein R6 is triazolyl substituted with C1-C6 alkoxyl C1-C6 alkyl or
wherein R10 is C1-C6 alkyl.
17. The compound of claim 1 , wherein R6 is
wherein (a) R9 and R10 independently are C1-C6 alkyl or (b) R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle containing the nitrogen atom and one oxygen atom.