IRE-1α inhibitors

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (E):

wherein:

R 1 is hydrogen or —OCH 3 ; and

R 2 is

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (X):

wherein:

the OH substituent is located ortho to

Q′ is selected from benzene, naphthalene, pyridine, pyridine N-oxide, thiophene, benzo[b]thiophene, benzo[c]thiophene, furan, pyrrole, pyridazine, pyrimidine, pyrazine, triazine, isoxazoline, oxazoline, thiazoline, pyrazoline, imidazoline, fluorenyl, biphenyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, benzofuran, indole, isoindole, isobenzofuran, benzimidazole, 1,2-benzisoxazole, and carbazole;

R x , R y , and R z can be present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″R a , —OH, —OA″R a , —NO 2 , —NH 2 , —NHA″R a , —N(A″R a )(A′″R b ), —NHCOA″R a , —NHCOOA″R a , —NHCONH 2 , —NHCONHA″R a , —NHCON(A″R a )(A′″R b ), halogen, —COOH, —COOA″R a , —CONH 2 , —CONHA″R a , —CON(A″R a )(A′″R b ), and

R a and R b are hydrogen, —COOH, —COOA, —CONH 2 , —CONHA, —CONAA′, —NH 2 , —NHA, —NAA′, —NCOA, —NCOOA, —OH, or —OA;

Y is C 1 -C 10 alkylene or C 2 -C 8 alkenylene, in which (a) one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH, or NR c and/or (b) 1-7H atoms may be independently replaced by F or Cl;

A and A′ are:

(a) independently C 1 -C 10 alkyl or C 2 -C 8 alkenyl, in which (i) one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH, or NR c and/or (ii) 1-7H atoms may be independently replaced by F or Cl, aryl or heterocyclic; or

(b) A and A′ together are alternatively C 2 -C 7 alkylene, in which one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH, NR c , NCOR c or NCOOR c , to form, for example, an alkylenedioxy group;

A″, A′″ are independently (a) absent, (b) C 1 -C 10 alkylene, C 2 -C 8 alkenylene, or C 3 -C 7 cycloalkyl in which one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH or NR c and/or 1-7H atoms may be replaced by F and/or Cl; or (c) together are C 2 -C 7 alkyl in which one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH, NR c , NCOR c or NCOOR c ,

R c is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 8 alkylenecycloalkyl, or C 2 -C 8 alkenyl, in which one, two or three CH 2 groups may be replaced by O, S, SO, SO 2 , NH, NMe, NEt and/or by —CH═CH— groups, 1-7H atoms may be replaced by F and/or Cl, and/or 1 H atom may be replaced by R a ;

aryl is phenyl, benzyl, naphthyl, fluorenyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, —CF 3 , —R f , —OR d , —N(R d ) 2 , —NO 2 , —CN, —COOR d , CON(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , —NR d SO 2 A, —COR d , —SO 2 N(R d ) 2 , —S(O) m R f , AA′ together, or —O(aryl),

R d and R e are independently H or C 1 -C 6 alkyl;

R f is C 1 -C 6 alkyl;

R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or —OA, or optionally substituted aryl;

heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by carbonyl, oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NO 2 , —CN, —COOR d , —CON(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , —NR f SO 2 R e , —COR d , —SO 2 NR d and/or —S(O) m R f ; and

m is 0, 1 or 2.

3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula:

wherein:

R 1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 2 is hydrogen,

phenyl, or a 5- or 6-membered heterocyclic containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic is optionally benzofused and wherein the heterocyclic is optionally substituted by 1, 2, or 3 substituents independently selected from

C 1 -C 3 linear or branched alkyl,

C 1 -C 3 phenylalkyl, C 1 -C 3 alkoxyphenylalkyl,

R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl,

and

Q is a five- or six-membered heterocycle.

4. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula:

wherein:

R 1 and R 2 independently are hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with

—CH 2 OH, —CHO, —OCH 3 , halogen, —OH, —CH 3 ,

R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl,

and

R 4 is hydrogen.

5. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula:

wherein R 1 and R 2 are independently hydrogen, —CH 3 , or —OH.

6. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula:

wherein R 1 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl.

7. A pharmaceutical composition comprising:

a compound of claim 1 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

8. A method of inhibiting IRE-1α activity, comprising administering to a subject a compound of claim 2 or a pharmaceutically acceptable salt of the compound.

9. A method of inhibiting IRE-1α activity, comprising administering to a subject a compound of claim 1 .

10. The method of claim 8 , wherein the compound is represented by the structural formula:

wherein:

R 1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 2 is hydrogen,

phenyl, or a 5- or 6-membered heterocyclic containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic is optionally benzofused and wherein the heterocyclic is optionally substituted by 1, 2, or 3 substituents independently selected from

C 1 -C 3 linear or branched alkyl,

C 1 -C 3 phenylalkyl, C 1 -C 3 alkoxyphenylalkyl,

R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl

and

Q is a five- or six-membered heterocycle.

11. The method of claim 8 , wherein the compound is represented by the structural formula:

wherein:

R 1 and R 2 independently are hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with

—CH 2 OH —CHO, —OCH 3 , halogen, —OH, —CH 3 ,

R 3 is hydrogen, halogen, —NO 2 C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl,

and

R 4 is hydrogen,

12. The method of claim 8 , wherein the compound is represented by the structural formula:

wherein R 1 and R 2 are independently hydrogen, —CH 3 or —OH.

13. The method of claim 8 , wherein the compound is represented by the structural formula:

wherein R 1 is hydrogen, halogen, —NO 2 C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl

14. The method of claim 8 wherein cells of the subject have an activated unfolded protein response.

15. The method of claim 8 , wherein the subject has cancer.

16. The method of claim 15 , wherein the cancer is myeloma.

17. The method of claim 8 , further comprising administering to the subject an agent that induces or up-regulates IRE-1α expression.

18. The method of claim 8 , further comprising administering to the subject a biotherapeutic agent, a chemotherapeutic agent, radiation, or a proteasome inhibitor.

19. The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein R 1 , R 3 and R 4 are hydrogen, R 2 is a five-membered heterocycle substituted with

and R g is substituted aryl.

20. The compound of claim 19 or the pharmaceutically acceptable salt thereof, wherein R 2 is thiophene.

21. The compound of claim 20 or the pharmaceutically acceptable salt thereof, wherein the substituted aryl is phenyl, substituted with —OR d , wherein R d is C 1 -C 6 alkyl.

22. The compound of claim 21 or the pharmaceutically acceptable salt thereof, wherein R d is methyl.

23. The compound of claim 2 , wherein R x , R y , and R z are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″R a , —OH, —OA″R a , —NH 2 , —NHA″R a , —N(A″R a )(A′″R b ), —NHCOA″R a , —NHCOOA″R a , —NHCONH 2 , —NHCONHA″R a , —NHCON(A″R a )(A′″R b ), halogen, and

24. The compound of claim 2 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

25. The compound of claim 23 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

26. The compound of claim 2 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

27. The compound of claim 23 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

28. The compound of claim 24 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

29. A pharmaceutical composition, comprising:

a compound of claim 1 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 7 , wherein the compound is represented by the structural formula:

wherein:

R 1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 2 is hydrogen,

phenyl, or a 5- or 6-membered heterocyclic containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic is optionally benzofused and wherein the heterocyclic is optionally substituted by 1, 2, or 3 substituents independently selected from

C 1 -C 3 linear or branched alkyl,

C 1 -C 3 phenylalkyl, C 1 -C 3 alkoxyphenylalkyl,

R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl

and

Q is a five- or six-membered heterocycle.

31. The pharmaceutical composition of claim 7 , wherein the compound is represented by the structural formula:

wherein:

R 1 and R 2 independently are hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with —CH 2 OH,

—CHO, —OCH 3 , halogen, —OH, —CH 3 ,

R 3 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl,

and

R 4 is hydrogen,

32. The pharmaceutical composition of claim 7 , wherein the compound is represented by the structural formula:

wherein R 1 and R 2 are independently hydrogen, —CH 3 , or —OH.

33. The pharmaceutical composition of claim 7 , wherein the compound is represented by the structural formula:

wherein R 1 is hydrogen, halogen, —NO 2 , C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched alkoxy, C 1 -C 3 linear or branched hydroxyl alkyl.

34. The pharmaceutical composition of claim 31 , wherein R 1 , R 3 and R 4 are hydrogen, R 2 is a five-membered heterocycle substituted with

and R g is substituted aryl.

35. The pharmaceutical composition of claim 34 or the pharmaceutically acceptable salt thereof, wherein R 2 is thiophene.

36. The pharmaceutical composition of claim 35 or the pharmaceutically acceptable salt thereof, wherein the substituted aryl is phenyl, substituted with —OR d , wherein R d is C 1 -C 6 alkyl.

37. The pharmaceutical composition of claim 36 or the pharmaceutically acceptable salt thereof, wherein R d is methyl.

38. The pharmaceutical composition of claim 7 , wherein R x , R y , and R z are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″R a , —OH, —OA″R a , —NH 2 , —NHA″R a , —N(A″R a )(A′″R b ), —NHCOA″R a , —NHCOOA″R a , —NHCONH 2 , —NHCONHA″R a , —NHCON(A″R a )(A′″R b ), halogen, and

39. The pharmaceutical composition of claim 7 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

40. The pharmaceutical composition of claim 38 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

41. The pharmaceutical composition of claim 7 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

42. The compound of claim 38 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

43. The pharmaceutical composition of claim 39 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

44. The method of claim 11 , wherein R 1 , R 3 and R 4 are hydrogen, R 2 is a five-membered heterocycle substituted with

and R g is substituted aryl.

45. The method of claim 44 , wherein R 2 is thiophene.

46. The method of claim 45 , wherein the substituted aryl is phenyl, substituted with —OR d , wherein R d is C 1 -C 6 alkyl.

47. The method of claim 46 , wherein R d is methyl.

48. The method of claim 8 , wherein R x , R y , and R z are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″R a , —OH, —OA″R a , —NH 2 , —NHA″R a , —N(A″R a )(A′″R b ), —NHCOA″R a , —NHCOOA″R a , —NHCONH 2 , —NHCONHA″R a , —NHCON(A″R a )(A′″R b ), halogen, and

49. The method of claim 8 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

50. The method of claim 48 , wherein R g is hydrogen, —NH 2 , —NHA, —NAA′, —NCOA, or optionally substituted aryl.

51. The method of claim 8 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R d ) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

52. The method of claim 48 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

53. The method of claim 49 , wherein the heterocyclic is a monocyclic or bicyclic saturated or unsaturated heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by oxygen, halogen, R f , —OR d , —N(R) 2 , —NR d COR e , —NR d CON(R e ) 2 , or —NR f SO 2 R e .

54. The method of claim 9 , wherein cells of the subject have an activated unfolded protein response.

55. The method of claim 9 , wherein the subject has cancer.

56. The method of claim 55 , wherein the cancer is myeloma.

57. The method of claim 9 , further comprising administering to the subject an agent that induces or up-regulates IRE-1α expression.