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1. WO2021061204 - NOUVEAUX DÉRIVÉS DE QUINOLÉINE-8-CARBONITRILE SUBSTITUÉS AYANT UNE ACTIVITÉ DE DÉGRADATION DU RÉCEPTEUR DES ANDROGÈNES ET LEURS UTILISATIONS

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 of Formula (1) or a pharmaceutically acceptable salt thereof:

wherein:

X1 is CR1 or N;

X2 is CR2 or N;

X3 is CR3 or N;

X4 is CR4 or N;

each of R1, R2, R3, and R4 is independently selected from hydrogen, halogen, C1-C3alkoxy, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS;

each R5 is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, -N(R9)2, and -CN, each of which is substituted with 0, 1, 2, or 3 RS;

each R6 is independently selected from hydrogen, halogen, C1-C3alkyl, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS, or two R6 groups are taken together to form an oxo;

each R7 is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, -N(R9)2, and -CN, each of which is substituted with 0, 1, 2, or 3 RS;

each R8 is independently selected from hydrogen, hydroxyl, C1-C3alkyl, and C1-C3haloalkyl, each of which is substituted with 0, 1, 2, or 3 RS, or two R8 groups are taken together to form an oxo;

each R9 is independently selected from hydrogen, C1-C3alkyl, -C(=O)-(C1-C3alkyl), -C(=O)-O-(C1-C3alkyl), and -C(=O)-NH-(C1-C3alkyl), each of which is substituted with 0, 1, 2, or 3 RS, or two R9 groups are taken together to form a 3- to 6-membered heterocycle or heteroaryl;

each RS is independently selected from halogen, hydroxyl, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, -N(R9)2, and -CN;

L is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS;

m is 0, 1, or 2;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, or 3,

wherein each hydrogen atom is independently and optionally replaced by a deuterium atom. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is N.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X2 is N.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 and X2 are each N.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X2 is CR2, X3 is CR3, and X4 is CR4.

6. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R2, R3, and R4 are each independently selected from H and F.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is CR1, X2 is CR2, X3 is CR3, and X4 is CR4.

8. The compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R1, R2, R3, and R4 are each independently selected from H and F.

9. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R1 is F.

10. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R2 is F.

11. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R3 is F.

12. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R4 is F.

13. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R1 and R3 are each F.

14. The compound or pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R3 and R4 are each F.

15. The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein R2, R3, and R4 are each H.

16. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein R1, R3, and R4 are each H.

17. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R1, R2, and R4 are each H.

18. The compound or pharmaceutically acceptable salt thereof according to claim 12, wherein R1, R2, and R3 are each H.

19. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R2 and R4 are each H.

20. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein R1 and R2 are each H.

21. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein each R5 is independently selected from halogen, C1-C3alkoxy, and C1-C3haloalkyl.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein each R5 is independently selected from -Cl, -OCH3, and -CF3.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein m is 0 or 1.

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein m is 0.

26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein m is 1.

27. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 26, wherein o is 0.

28. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 26, wherein o is 1.

29. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 23, wherein m and o are each 0.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein each R6 is independently selected from H and C1-C3alkyl.

31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein each R6 is independently selected from H and -CH3.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein the two R6 groups attached to the same carbon are identical.

33. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein each R6 is identical.

34. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein each R6 is different.

35. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to

34, wherein the group is selected from , ,

36. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to

. 37. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 36, wherein each R7 is independently selected from halogen, hydroxyl, C1-C3alkyl, and C1-C3haloalkyl.

38. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein each R7 is independently selected from halogen, hydroxyl, -CH3, and -CF3.

39. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, wherein each R7 is independently selected from F, hydroxyl, -CH3, and -CF3.

40. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein each R7 is independently F.

41. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein n is 0.

42. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein n is 1.

43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein each R8 is hydrogen or two R8 groups are taken together to form an oxo.

44. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein each R8 is hydrogen.

45. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein two R8 groups are taken together to form an oxo.

46. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, wherein each R9 is independently selected from hydrogen, C1-C3alkyl, and -C(=O)-C1-C3alkyl.

47. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 46, wherein each R9 is independently selected from hydrogen and C1-C3alkyl.

48. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, wherein each R9 is independently selected from hydrogen, -CH3, -CH2CH3, and -CH(CH3)2.

49. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to

50. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 49, wherein L is a linker of 1 to 12 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(=O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS.

51. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 50, wherein L is a linker of 1 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(=O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS.

52. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 51, wherein L is a linker of 1 to 8 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(=O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS.

53. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 52, wherein L is a linker of 1 to 6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(=O), O, N(R9), S, C2-alkenyl, C2-alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS.

54. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 53, wherein one or more carbon atoms of linker L are optionally replaced by C(=O), O, N(R9), S, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R9, C2-alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 RS.

55. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 54, wherein one or more carbon atoms of linker L are optionally replaced by O, N(R9), cycloalkyl, or heterocycle, wherein the R9, cycloalkyl, and heterocycle are each independently substituted with 0, 1, 2, or 3 RS.

56. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 55, wherein at least one carbon atom of linker L is replaced by a heterocycle, which is substituted with 0, 1, 2, or 3 RS.

57. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 55, wherein at least two carbon atoms of linker L are replaced by a heterocycle, each of which is substituted with 0, 1, 2, or 3 RS.

58. The compound or pharmaceutically acceptable salt thereof according to claim 56 or 57, wherein the heterocycle is selected from piperidine and piperazine, each of which is substituted with 0, 1, 2, or 3 RS.

59. The compound or pharmaceutically acceptable salt thereof according to claim 56 or 57, wherein

the heterocycle is selected from

60. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to

61. The compound according to claim 1, wherein the compound is chosen from:

or a pharmaceutically acceptable salt thereof, wherein each hydrogen is independently and optionally replaced by a deuterium.

62. A pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 and a pharmaceutically acceptable carrier.

63. The pharmaceutical composition according to claim 62, wherein the compound or pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.

64. A method of treating cancer in a subject in need thereof, comprising administering to said subject a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63.

65. The method according to claim 64, wherein the cancer is selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer.

66. The method according to claim 64 or 65, wherein the cancer is prostate cancer.

67. The method according to any one of claims 64 to 66, wherein the cancer is androgen receptor positive.

68. The method according to any one of claims 64 to 67, wherein the subject has been previously treated with an anti-cancer agent.

69. The method according to claim 68, wherein the anti-cancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiraterone, or a combination of any of the foregoing.

70. The method according to claim 69, wherein the anti-cancer agent is enzalutamide.

71. A use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 for treating cancer.

72. The use according to claim 71, wherein the cancer is selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer. 73. The method according to claim 71 or 72, wherein the cancer is prostate cancer.

74. The method according to any one of claims 71 to 73, wherein the cancer is androgen receptor positive.

75. A use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63 in the manufacture of a medicament.

76. The use according to claim 75, wherein the medicament is for the treatment of a cancer selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer.

77. The use according to claim 76, wherein the cancer is prostate cancer.

78. The use according to claim 76 or 77, wherein the cancer is androgen receptor positive.

79. A method of inhibiting cell growth, comprising contacting a cell with a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 or 63.

80. The method according to claim 79, wherein the cell is a cancer cell.

81. The method according to claim 80, wherein the cancer cell is a prostate cancer cell.

82. The method according to any one of claims 79 to 81, wherein the cell is androgen receptor positive.

83. The compound of Formula (1) according to claim 1, wherein the compound is a compound of Formula (1A)