IRE-1α inhibitors

1. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (I):

wherein:

the OH substituent is located ortho to the aldehyde substituent;

Q is an aromatic isocyclic or heterocyclic ring system selected from benzene, naphthalene, pyridine, pyridine N-oxide, thiophene, benzo[b]thiophene, benzo[c]thiophene, furan, pyrrole, pyridazine, pyrmidine, 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 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 y can be present or absent and is selected from hydrogen, aryl, heterocyclic, -A″R a , —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 is hydrogen, —COOH, —COOA, —CONH 2 , —CONHA, —CONAA′, —NH 2 , —NHA, —NAA′, —NCOA, —NCOOA, or —OA;

R b is 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) 1-7 H 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) 1-7 H 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 1-7 H 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, 1-7 H 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;

heterocyclic is a monocyclic or bicyclic saturated, unsaturated or aromatic 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,

provided that the compound is not salicylaldehyde.

2. The method of claim 1 wherein the IRE-1α is in a cell.

3. The method of claim 1 wherein the cell has an activated unfolded protein response.

4. The method of claim 2 wherein the cell is a cancer cell.

5. The method of claim 2 wherein the cell is a myeloma cell.

6. The method of claim 2 wherein inhibition of the IRE-1α activity inhibits cell proliferation.

7. The method of claim 2 wherein inhibition of the IRE-1α activity induces apoptosis.

8. The method of claim 2 further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression.

9. The method of claim 2 further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation.

10. The method of claim 2 further comprising contacting the cell with a proteasome inhibitor.

11. The method of claim 1 wherein the compound is provided in the form of a pharmaceutically acceptable salt.

12. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (B):

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 ,

 and either:

(1) 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

 or

(2) R 3 is 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,

wherein the IRE-1α is in a cell.

13. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (A):

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, provided that structural formula (A) does not encompass salicylaldehyde.

14. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (C):

wherein:

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

the hydroxy substitutent in ring A is located ortho to the aldehyde substituent.

15. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (D):

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,

16. The method of claim 12 , wherein the cell has an activated unfolded protein response.

17. The method of claim 12 , wherein the cell is a cancer cell.

18. The method of claim 12 , wherein the cell is a myeloma cell.

19. The method of claim 12 , wherein inhibition of the IRE-1α activity inhibits cell proliferation.

20. The method of claim 12 , wherein inhibition of the IRE-1α activity induces apoptosis.

21. The method of claim 13 , further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression.

22. The method of claim 12 , further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation.

23. The method of claim 12 further comprising contacting the cell with a proteasome inhibitor.

24. The method of claim 12 wherein the compound is provided in the form of a pharmaceutically acceptable salt.

25. The method of claim 13 , wherein the IRE-1α is in a cell.

26. The method of claim 25 , wherein the cell has an activated unfolded protein response.

27. The method of claim 25 , wherein the cell is a cancer cell.

28. The method of claim 25 , wherein the cell is a myeloma cell.

29. The method of claim 25 , wherein inhibition of the IRE-1α activity inhibits cell proliferation.

30. The method of claim 25 , wherein inhibition of the IRE-1α activity induces apoptosis.

31. The method of claim 25 , further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression.

32. The method of claim 25 , further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation.

33. The method of claim 25 , further comprising contacting the cell with a proteasome inhibitor.

34. The method of claim 25 wherein the compound is provided in the form of a pharmaceutically acceptable salt.

35. The method of claim 14 , wherein the IRE-1α is in a cell.

36. The method of claim 35 , wherein the cell has an activated unfolded protein response.

37. The method of claim 35 , wherein the cell is a cancer cell.

38. The method of claim 35 , wherein the cell is a myeloma cell.

39. The method of claim 35 , wherein inhibition of the IRE-1α activity inhibits cell proliferation.

40. The method of claim 35 , wherein inhibition of the IRE-1α activity induces apoptosis.

41. The method of claim 35 , further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression.

42. The method of claim 35 , further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation.

43. The method of claim 35 , further comprising contacting the cell with a proteasome inhibitor.

44. The method of claim 35 , wherein the compound is provided in the form of a pharmaceutically acceptable salt.

45. The method of claim 15 , wherein the IRE-1α is in a cell.

46. The method of claim 45 , wherein the cell has an activated unfolded protein response.

47. The method of claim 45 , wherein the cell is a cancer cell.

48. The method of claim 45 , wherein the cell is a myeloma cell.

49. The method of claim 45 , wherein inhibition of the IRE-1α activity inhibits cell proliferation.

50. The method of claim 45 , wherein inhibition of the IRE-1α activity induces apoptosis.

51. The method of claim 45 , further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression.

52. The method of claim 45 , further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation.

53. The method of claim 45 , further comprising contacting the cell with a proteasome inhibitor.

54. The method of claim 45 , wherein the compound is provided in the form of a pharmaceutically acceptable salt.

55. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (B):

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

 and

R 4 is hydrogen,

56. The method of claim 55 , wherein R 3 is C3 alkyl or C3 alkoxy.