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 method of inhibiting IRE-1a activity, comprising contacting IRE-1a with a compound of formula (A-1k):
or a prodrug or pharmaceutically acceptable salt thereof;
wherein
R3 is hydrogen, optionally substituted alkoxyl, or optionally substituted alkylamino;
R4 is hydrogen or alkoxyl;
R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF 3 , or, together with R6 and the carbon atoms to which they are attached, forms a five-membered cycloalkyl;
R6 is
(a) alkenyl, optionally substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
or
(b) alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
or
(c) phenyl, substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
R9 and R10 are independently hydrogen; alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n 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, 3, or 4 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
R11 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
R12 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R11; 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 substitutents selected independently from R11; or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substitutents selected independently from R11;
R13 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n is 0, 1, 2, or 3; and R14 is hydrogen or R13; or
R13 and R14, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, or 3 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substitutents selected independently from R16;
R15 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21; 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 substitutents selected from R21; or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substitutents selected from R21;
R16 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
R17 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n is 0, 1, 2, or 3; and R18 is hydrogen or R17; or
R17 and R18, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R20;
R19 is alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
R20 is a 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected independently from R21; or R21; and
R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH 2 , —CON(CH 3 ) 2 , alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
wherein the compound directly inhibits IRE-1a activity in vitro.
2. The method of claim 1 , wherein the IRE-1a activity is selected from the group consisting of cleavage of RNA, cleavage of mRNA, RNA splicing, and mRNA splicing.
3. The method of claim 2 , wherein the IRE-1a activity is cleavage of mRNA and wherein the mRNA is selected from the group consisting of Blos1 mRNA, DGAT2 mRNA, CD59 mRNA, and IRE-1α mRNA.
4. The method of claim 2 , which comprises administering the compound or the prodrug or pharmaceutically acceptable salt thereof to a patient in need thereof to treat a disorder associated with the unfolded protein response or a disorder associated with a target of regulated IRE1-dependent decay (RIDD).
5. The method of claim 4 , wherein the disorder is associated with the unfolded protein response, further comprising administering to the patient a therapeutic agent that induces or up-regulates IRE-1α expression.
6. The method of claim 4 , wherein the disorder is associated with the unfolded protein response, further comprising administering to the patient a therapeutic agent which is less effective when IRE-1a is expressed.
7. The method of claim 4 , wherein the disorder is associated with the unfolded protein response, further comprising administering a proteasome inhibitor.
8. The method of claim 4 , wherein the disorder is associated with a target of RIDD.
9. The method of claim 1 , wherein R3 is optionally substituted alkoxyl.
10. The method of claim 1 , wherein R4 is hydrogen.
11. The method of claim 1 , wherein R5 is alkyl.
12. The method of claim 1 , wherein R6 is alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
13. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. A method of inhibiting IRE-1a activity, comprising contacting IRE-1a with a pharmaceutical composition comprising:
1) a compound of formula (A-1k):
or a prodrug or pharmaceutically acceptable salt thereof;
wherein
R3 is hydrogen, optionally substituted alkoxyl, or optionally substituted alkylamino;
R4 is hydrogen or alkoxyl;
R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF 3 , or, together with R6 and the carbon atoms to which they are attached, forms a five-membered cycloalkyl;
R6 is
(a) alkenyl, optionally substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
or
(b) alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
or
(c) phenyl, substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
R9 and R10 are independently hydrogen; alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n 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, 3, or 4 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
R11 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
R12 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R11; 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 substitutents selected independently from R11; or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substitutents selected independently from R11;
R13 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n is 0, 1, 2, or 3; and R14 is hydrogen or R13; or
R13 and R14, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, or 3 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substitutents selected independently from R16;
R15 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21; 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 substitutents selected from R21; or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substitutents selected from R21;
R16 is hydrogen; alkyl; aryl; heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; arylalkyl; heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
R17 is alkyl; alkoxylalkyl; perfluoroalkoxylalkyl; aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or
wherein n is 0, 1, 2, or 3; and R18 is hydrogen or R17; or
R17 and R18, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R20;
R19 is alkoxy; aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21; a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21; or a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
R20 is a 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R21; a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected independently from R21; or R21; and
R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH 2 , —CON(CH 3 ) 2 , alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
wherein the compound directly inhibits IRE-1a activity in vitro; and
2) a pharmaceutically acceptable vehicle.
16. The method of claim 15 , wherein the IRE-1a activity is selected from the group consisting of cleavage of RNA, cleavage of mRNA, RNA splicing, and mRNA splicing.
17. The method of claim 16 , wherein the IRE-1a activity is cleavage of mRNA and wherein the mRNA is selected from the group consisting of Blos1 mRNA, DGAT2 mRNA, CD59 mRNA, and IRE-1α mRNA.
18. The method of claim 16 , which comprises administering the compound or the prodrug or pharmaceutically acceptable salt thereof to a patient in need thereof to treat a disorder associated with the unfolded protein response or a disorder associated with a target of regulated IRE1-dependent decay (RIDD).
19. The method of claim 18 , wherein the disorder is associated with the unfolded protein response, further comprising administering to the patient a therapeutic agent that induces or up-regulates IRE-1α expression.
20. The method of claim 18 , wherein the disorder is associated with the unfolded protein response, further comprising administering to the patient a therapeutic agent which is less effective when IRE-1α is expressed.
21. The method of claim 18 , wherein the disorder is associated with the unfolded protein response, further comprising administering a proteasome inhibitor.
22. The method of claim 18 , wherein the disorder is associated with a target of RIDD.
23. The method of claim 15 , wherein R3 is optionally substituted alkoxyl.
24. The method of claim 15 , wherein R4 is hydrogen.
25. The method of claim 15 , wherein R5 is alkyl.
26. The method of claim 15 , wherein R6 is alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
27. The method of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
28. The method of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.