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.
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1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (E): wherein: R1 is hydrogen or —OCH3; andR2 is 2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (X): wherei
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by structural formula (E): wherein: R1 is hydrogen or —OCH3; andR2 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;Rx, Ry, and Rz can be present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″Ra, —OH, —OA″Ra, —NO2, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, —COOH, —COOA″Ra, —CONH2, —CONHA″Ra, —CON(A″Ra)(A′″Rb), and Ra and Rb are hydrogen, —COOH, —COOA, —CONH2, —CONHA, —CONAA′, —NH2, —NHA, —NAA′, —NCOA, —NCOOA, —OH, or —OA;Y is C1-C10 alkylene or C2-C8 alkenylene, in which (a) one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, or NRc and/or (b) 1-7H atoms may be independently replaced by F or Cl;A and A′ are: (a) independently C1-C10 alkyl or C2-C8 alkenyl, in which (i) one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, or NRc 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 C2-C7 alkylene, in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, NRc, NCORc or NCOORc, to form, for example, an alkylenedioxy group;A″, A′″ are independently (a) absent, (b) C1-C10 alkylene, C2-C8 alkenylene, or C3-C7 cycloalkyl in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH or NRc and/or 1-7H atoms may be replaced by F and/or Cl; or (c) together are C2-C7 alkyl in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, NRc, NCORc or NCOORc,Rc is C1-C10 alkyl, C3-C7 cycloalkyl, C4-C8 alkylenecycloalkyl, or C2-C8 alkenyl, in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, 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 Ra;aryl is phenyl, benzyl, naphthyl, fluorenyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, —CF3, —Rf, —ORd, —N(Rd)2, —NO2, —CN, —COORd, CON(Rd)2, —NRdCORe, —NRdCON(Re)2, —NRdSO2A, —CORd, —SO2N(Rd)2, —S(O)mRf, AA′ together, or —O(aryl),Rd and Re are independently H or C1-C6 alkyl;Rf is C1-C6 alkyl;Rg is hydrogen, —NH2, —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, Rf, —ORd, —N(Rd)2, —NO2, —CN, —COORd, —CON(Rd)2, —NRdCORe, —NRdCON(Re)2, —NRfSO2Re, —CORd, —SO2NRd and/or —S(O)mRf; andm 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: R1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 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 C1-C3 linear or branched alkyl, C1-C3 phenylalkyl, C1-C3 alkoxyphenylalkyl, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkoxy, C1-C3 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: R1 and R2 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 —CH2OH, —CHO, —OCH3, halogen, —OH, —CH3, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, and R4 is hydrogen. 5. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula: wherein R1 and R2 are independently hydrogen, —CH3, or —OH. 6. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the compound is represented by the structural formula: wherein R1 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl. 7. A pharmaceutical composition comprising: a compound of claim 1 or a pharmaceutically acceptable salt thereof; anda 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: R1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 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 C1-C3 linear or branched alkyl, C1-C3 phenylalkyl, C1-C3 alkoxyphenylalkyl, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkoxy, C1-C3 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: R1 and R2 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 —CH2OH —CHO, —OCH3, halogen, —OH, —CH3, R3 is hydrogen, halogen, —NO2 C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, and R4 is hydrogen, 12. The method of claim 8, wherein the compound is represented by the structural formula: wherein R1 and R2 are independently hydrogen, —CH3 or —OH. 13. The method of claim 8, wherein the compound is represented by the structural formula: wherein R1 is hydrogen, halogen, —NO2 C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 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 R1, R3 and R4 are hydrogen, R2 is a five-membered heterocycle substituted with and Rg is substituted aryl. 20. The compound of claim 19 or the pharmaceutically acceptable salt thereof, wherein R2 is thiophene. 21. The compound of claim 20 or the pharmaceutically acceptable salt thereof, wherein the substituted aryl is phenyl, substituted with —ORd, wherein Rd is C1-C6 alkyl. 22. The compound of claim 21 or the pharmaceutically acceptable salt thereof, wherein Rd is methyl. 23. The compound of claim 2, wherein Rx, Ry, and Rz are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″Ra, —OH, —OA″Ra, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, and 24. The compound of claim 2, wherein Rg is hydrogen, —NH2, —NHA, —NAA′, —NCOA, or optionally substituted aryl. 25. The compound of claim 23, wherein Rg is hydrogen, —NH2, —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, Rf, —ORd, —N(Rd)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(Rd)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(Rd)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 29. A pharmaceutical composition, comprising: a compound of claim 1 or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier. 30. The pharmaceutical composition of claim 7, wherein the compound is represented by the structural formula: wherein: R1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 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 C1-C3 linear or branched alkyl, C1-C3 phenylalkyl, C1-C3 alkoxyphenylalkyl, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkoxy, C1-C3 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: R1 and R2 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 —CH2OH, —CHO, —OCH3, halogen, —OH, —CH3, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, and R4 is hydrogen, 32. The pharmaceutical composition of claim 7, wherein the compound is represented by the structural formula: wherein R1 and R2 are independently hydrogen, —CH3, or —OH. 33. The pharmaceutical composition of claim 7, wherein the compound is represented by the structural formula: wherein R1 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl. 34. The pharmaceutical composition of claim 31, wherein R1, R3 and R4 are hydrogen, R2 is a five-membered heterocycle substituted with and Rg is substituted aryl. 35. The pharmaceutical composition of claim 34 or the pharmaceutically acceptable salt thereof, wherein R2 is thiophene. 36. The pharmaceutical composition of claim 35 or the pharmaceutically acceptable salt thereof, wherein the substituted aryl is phenyl, substituted with —ORd, wherein Rd is C1-C6 alkyl. 37. The pharmaceutical composition of claim 36 or the pharmaceutically acceptable salt thereof, wherein Rd is methyl. 38. The pharmaceutical composition of claim 7, wherein Rx, Ry, and Rz are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″Ra, —OH, —OA″Ra, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, and 39. The pharmaceutical composition of claim 7, wherein Rg is hydrogen, —NH2, —NHA, —NAA′, —NCOA, or optionally substituted aryl. 40. The pharmaceutical composition of claim 38, wherein Rg is hydrogen, —NH2, —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, Rf, —ORd, —N(Rd)2, NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(Rd)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(Rd)2, NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 44. The method of claim 11, wherein R1, R3 and R4 are hydrogen, R2 is a five-membered heterocycle substituted with and Rg is substituted aryl. 45. The method of claim 44, wherein R2 is thiophene. 46. The method of claim 45, wherein the substituted aryl is phenyl, substituted with —ORd, wherein Rd is C1-C6 alkyl. 47. The method of claim 46, wherein Rd is methyl. 48. The method of claim 8, wherein Rx, Ry, and Rz are present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″Ra, —OH, —OA″Ra, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, and 49. The method of claim 8, wherein Rg is hydrogen, —NH2, —NHA, —NAA′, —NCOA, or optionally substituted aryl. 50. The method of claim 48, wherein Rg is hydrogen, —NH2, —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, Rf, —ORd, —N(Rd)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(R)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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, Rf, —ORd, —N(R)2, —NRdCORe, —NRdCON(Re)2, or —NRfSO2Re. 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.
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