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. A compound of formula (1d):
or a pharmaceutically acceptable salt thereof,
wherein
R3, R4, and R8 independently are hydrogen; perfluoroalkoxy; or alkoxy;
R5 and R7 are hydrogen, provided that R3, R4, R5, R7, and R8 are not simultaneously hydrogen;
R6 is:
(a)
wherein
R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered or a 6-membered saturated heterocycle having 1 or 2 nitrogen atoms, substituted with alkyl or
R13 is alkyl; and
R14 is hydrogen;
(b) furyl substituted with
wherein
R9 is alkyl;
R10 is alkyl;
or 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
wherein
R9 is alkyl;
R10 is alkyl;
or 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 alkyl or
wherein
R9 is alkoxylalkyl;
R10 is hydrogen or alkoxylalkyl;
or R9 and R10, together with the nitrogen atom to which they are attached, form a 5-membered saturated ring containing the nitrogen atom or a 6-membered saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen;
(e) oxazolyl substituted with
wherein
R9 is alkyl;
R10 is hydrogen or alkyl;
or R9 and R10, together with the nitrogen atom to which they are attached, form a 6-membered saturated heterocycle having 2 nitrogen atoms;
(f) triazolyl substituted with alkoxylalkyl or
wherein
R10 is alkyl; or
(g)
wherein
n is 0, 1, or 2;
R9 is alkyl;
R10 is alkyl;
or 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 compound of formula (3g):
or a pharmaceutically acceptable salt thereof,
wherein
R6 is
R32 is —OH, or
R12 is hydrogen;
R11 is benzyl, optionally substituted with C1-C3 alkoxy; cyclohexane; a 6-membered saturated heterocycle with 1 or 2 heteroatoms selected from O, N, and S; or phenyl, optionally substituted with 1-methyl-piperazine or dimethyl-piperazine;
or R11 and R12, together with the nitrogen atom to which they are attached, form a six-membered heterocycle containing 2 heteroatoms selected from N, O, and S, optionally substituted with C1-C3 alkyl or phenyl; and
n is 1, 2, or 3.
3. A pharmaceutical composition comprising:
the compound or pharmaceutically acceptable salt of claim 1 ; and
a pharmaceutically acceptable vehicle.
4. A method of inhibiting IRE-1α, comprising contacting IRE-1α with the compound or pharmaceutically acceptable salt of claim 1 , thereby inhibiting IRE-1α.
5. 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 or pharmaceutically acceptable salt of claim 1 .
6. A pharmaceutical composition comprising:
the compound or pharmaceutically acceptable salt of claim 2 ; and
a pharmaceutically acceptable vehicle.
7. A method of inhibiting IRE-1α, comprising contacting IRE-1α with the compound or pharmaceutically acceptable salt of claim 2 , thereby inhibiting 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 the compound or pharmaceutically acceptable salt of claim 2 .
9. The compound of claim 2 , wherein
R32 is
and
R11 and R12, together with the nitrogen atom to which they are attached, form a six-membered heterocycle containing the nitrogen atom and one oxygen atom.
10. The compound of claim 1 , wherein
R3 and R8 are hydrogen; and
R4 is alkoxy.
11. The compound of claim 1 , wherein
R4 and R8 are hydrogen; and
R3 is alkoxy.
12. The compound of claim 1 , wherein
R3 and R4 are alkoxy; and
R8 is hydrogen.
13. A compound of formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein
R3, R4, and R8 independently are hydrogen, perfluoroalkoxy, or alkoxy;
R5 is hydrogen;
R6 is hydrogen;
R7 is phenyl substituted with
and
R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O and S, optionally substituted with alkyl.
14. A pharmaceutical composition comprising:
the compound or pharmaceutically acceptable salt of claim 13 ; and
a pharmaceutically acceptable vehicle.
15. A method of inhibiting IRE-1α, comprising contacting IRE-1α with the compound or pharmaceutically acceptable salt of claim 13 , thereby inhibiting IRE-1α.
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 or pharmaceutically acceptable salt of claim 13 .
17. A compound of formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein
R5 is hydrogen;
R6 is hydrogen;
R7 is phenyl substituted with
R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O and S, optionally substituted with alkyl; and
(1) R3 and R8 are hydrogen and R4 is alkoxy;
(2) R4 and R8 are hydrogen and R3 is alkoxy; or
(3) R3 and R4 are alkoxy and R8 is hydrogen.