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1. WO2020117759 - AGENTS DE DÉGRADATIONS DE PETITES MOLÉCULES DE HELIOS ET PROCÉDÉS D'UTILISATION

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

What is claimed is:

1. A compound represented by a structure of formula I:


wherein:

Q represents CH2 or C=O;

X represents NR, O, or S, wherein R is H or Me;

Y is absent or represents optionally substituted C1– C5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;


, or


wherein n is 2 or 3; wherein n’ is 0 or 1; wherein R’ is halo, optionally substituted C1-C2 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; wherein R’’ represents

optionally substituted C1-C2 alkyl; wherein Z represents

W1 and W2 are independently absent or independently represent CH, CH2, O, O-CH2, NH-CH2 or optionally substituted amino;

M represents a 5- or 6-membered cyclic group;

and

Ar represents optionally substituted phenyl or benzyl;

wherein
or Y is absent;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1, wherein Q is C=O.

3. The compound of claim 1, wherein Q is CH2.

4. The compound of any one of claims 1-3, wherein X is NH.

5. The compound of any one of claims 1-3, wherein X is NMe.

6. The compound of any one of claims 1-3, wherein X is O.

7. The compound of any one of claims 1-3, wherein X is S.

8. The compound of any one of claims 1-2, wherein
is absent and Q is C O, and the compound has a structure of formula la,


9. The compound of claim 8, wherein Y represents an optionally substituted /V-aryl group.

10. The compound of claim 9, wherein the /V-aryl group is optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, optionally substituted tetrazolyl, optionally substituted thiazolyl, optionally substituted quinolinyl, optionally substituted indolyl, or optionally substituted indazolyl.

11. The compound of claim 8, where Y represents optionally substituted C1 - C5 alkyl.

12. The compound of claim 8, wherein Y represents optionally substituted phenyl or optionally substituted benzyl.

13. The compound of claim 8, wherein Y represents phenyl, benzyl,

wherein R1 represents alkyl, aryl, or heteroaryl.

14. The compound of claim 13, where R1 represents ethyl, isopropyl, tert-butyl, phenyl, benzyl, pyrazolyl, imidazolyl, tetrazolyl, pyridinyl, or pyrimidinyl.

15. The compound of claim 1, wherein Y is absent and the compound has a structure of formula lb:


or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The compound of claim 15, wherein


17. The compound of claim 15, wherein
represents an optionally substituted fused-5,6 or -6,6 ring system.

18. The compound of claim 17, wherein


19. The compound of claim 18, wherein Z represents



20. The compound of claim 19, wherein Ar represents
, wherein R3 represents alkyl, halo, aryl, or heteroaryl, and n is 0, 1, or 2.

21. The compound of claim 20, where R3 independently represents methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, chloro, or fluoro.

22. The compound of claim 20, wherein Ar represents
or


23. The compound of any one of claims 8 and 15, where the optional substituent is independently

methyl, chloro. fluoro, phenyl, benzyl,

24. The compound of claim 1, which is:


pharmaceutically acceptable salt or stereoisomer thereof.

25. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of any one of claims 1-24, or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

26. A method of treating a disease or disorder that is characterized or mediated by dysfunctional activity of a protein that is a substrate for a complex between CRBN and a compound of any one of claims 1-24, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any of claims 1-24.

27. The method of claim 26, wherein the disease or disorder is characterized or mediated by dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1a, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1, or ZKSC5.

28. The method of claim 27, wherein the disease or disorder is mediated by dysfunctional IKZF2 (Helios) activity.

29. The method of claim 27 or 28, wherein the disease or disorder is coronary heart disease.

30. The method of claim 27 or 28, wherein the disease is cancer.

31. The method of claim 30, wherein the disease or disorder is leukemia.

32. The method of claim 30, wherein the disease or disorder is carcinoma.

33. The method of claim 30, wherein the cancer is T cell leukemia or T cell lymphoma.

34. The method of claim 30, wherein the cancer is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

35. The method of claim 30, wherein the cancer is myeloid leukemia.

36. The method of claim 30, wherein the cancer is non-small cell lung cancer (NSCLC).

37. The method of claim 30, wherein the cancer is melanoma.

38. The method of claim 30, wherein the cancer is triple-negative breast cancer (TNBC).

39. The method of claim 30, wherein the cancer is nasopharyngeal cancer (NPC).

40. A method of treating a disease or disorder that is affected by a reduction of TXNIP protein levels, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 1-24.

41. The method of claim 40, wherein the disease or disorder is gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, nonalcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy, or diabetic cardiomyopathy.

42. A compound represented by a structure of formula II:


wherein R4 is H or a substituent;

R5 represents H, -Me, -Et,

W3 and W4 are independently absent or independently represent CH2, NH, or NH-CH2; and Ar1 is optionally substituted aryl or heteroaryl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

43. The compound of claim 42, wherein


; wherein R5’ is H, Me, or Et.

44. The compound of claim 42, wherein R.4 is alkyl, halo, hydroxyl, amino, amido, substituted carbamate, or substituted carbamide.

45. The compound of claim 42, wherein Ari is optionally substituted phenyl.

46. The compound of claim 42, which is:


or a pharmaceutically acceptable salt or stereoisomer thereof.

47. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 42-46, and a pharmaceutically acceptable carrier.

48. A method of treating a disease or disorder that is characterized or mediated by dysfunctional activity of activity of a protein that is a substrate for a complex between CRBN and the compound of any one of claims 42-46, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 42-46.

49. The method of claim 48, wherein the disease or disorder is characterized or mediated by dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1a, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1, or ZKSC5.

50. The method of claim 49, wherein the disease or disorder is mediated by dysfunctional IKZF2 (Helios) activity.

51. The method of claim 49 or 50, wherein the disease or disorder is coronary heart disease.

52. The method of claim 49 or 50, wherein the disease or disorder is cancer.

53. The method of claim 52, wherein the disease or disorder is leukemia.

54. The method of claim 52, wherein the disease or disorder is a carcinoma.

55. The method of claim 52, wherein the cancer is T cell leukemia or T cell lymphoma.

56. The method of claim 52, wherein the cancer is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

57. The method of claim 52, wherein the cancer is myeloid leukemia.

58. The method of claim 52, wherein the cancer is non-small cell lung cancer (NSCLC).

59. The method of claim 52, wherein the cancer is melanoma.

60. The method of claim 52, wherein the cancer is triple-negative breast cancer (TNBC).

61. The method of claim 52, wherein the cancer is nasopharyngeal cancer (NPC).

62. A method of treating a disease or disorder that is affected by a reduction of TXNIP protein levels, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 42-46.

63. The method of claim 62, wherein the disease or disorder is selected from gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, nonalcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy.

64. A compound represented by a structure of formula III:

wherein

W5 and W6 each independently represents -CH2- or -NH-, provided that one of W5 and W6 is -NH-; and

Ar2 is optionally substituted aryl or heteroaryl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

65. The compound of claim 64, wherein W5 and W6 are both -NH-.

66. The compound of claim 64, wherein Ar2 is phenyl substituted with one or more groups selected from alkyl, halo, and haloalkyl.

67. The compound of claim 64, which is selected from the group consisting of:


r a pharmaceutically acceptable salt or stereoisomer thereof.

68. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 64-67, and a pharmaceutically acceptable carrier.

69. A method of treating a disease or disorder that is characterized or mediated by dysfunctional activity of activity of a protein that is a substrate for a complex between CRBN and a compound of any one of claims 64-67, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any of claims 64-67.

70. The method of claim 69, wherein the disease or disorder is characterized or mediated by dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1a, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1, or ZKSC5,

71. The method of claim 70, wherein the disease or disorder is mediated by dysfunctional IKZF2 (Helios) activity.

72. The method of claim 70 or 71, wherein the disease or disorder is coronary heart disease.

73. The method of claim 70 or 71, wherein the disease or disorder is cancer.

74. The method of claim 73, wherein the disease or disorder is leukemia.

75. The method of claim 73, wherein the disease or disorder is carcinoma.

76. The method of claim 73, wherein the cancer is T cell leukemia or T cell lymphoma.

77. The method of claim 73, wherein the cancer is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

78. The method of claim 73, wherein the cancer is myeloid leukemia.

79. The method of claim 73, wherein the cancer is non-small cell lung cancer (NSCLC).

80. The method of claim 73, wherein the cancer is melanoma.

81. The method of claim 73, wherein the cancer is triple-negative breast cancer (TNBC).

82. The method of claim 73, wherein the cancer is nasopharyngeal cancer (NPC).

83. A method of treating a disease or disorder that is affected by the reduction of TXNIP protein levels, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer of any one of claims 64-67.

84. The method of claim 83, wherein the disease or disorder is gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, nonalcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy, or diabetic cardiomyopathy.