AKT1 regulator

JP2025532245APending Publication Date: 2025-09-29ALTEROME THERAPEUTICS INC
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Patent Information

Application Number
JP2025517985
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-09-14
Filing Date
2023-09-25
Publication Date
2025-09-29

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Abstract

Provided herein are inhibitors of AKT1, pharmaceutical compositions containing the inhibitory compounds, and methods of using the AKT1 inhibitory compounds for the treatment of diseases. One embodiment provides a compound having the structure of Formula (I) below, or a pharmaceutically acceptable salt or solvate thereof. One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides a method wherein the disease or disorder is cancer.
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Claims

1. One embodiment provides a compound having the structure of formula (I) below, or a pharmaceutically acceptable salt or solvate thereof: 【Chemical 1】 During the ceremony, Z １ is N, C—H, or C—R ３ and Z ２ is N, C—H, or C—R ４ and Z ３ is N, C—OH, or C—R ９ and Ar is selected from: 【Chemistry 2】 X １ is N or C-R ７ and X ２ is N or C-R ７ and X ３ is N or C-R ７ and X ４ is N or C-R ７ and Y is O, S, or N-R ９ and R １ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, halogen, —OH, —CN, —N(R ９ ) ２ , -OR ９ , -SR ９ , -SO ２ R ９ , -CO ２ R ９ , -CON(R ９ ) ２ , -SR ９ , -S(O)R ９ , -S(O) ２ R ９ , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, aryl substituted with an optionally substituted 4- to 6-membered heterocyclyl, optionally substituted heteroaryl, or heteroaryl substituted with an optionally substituted 3- to 6-membered carbocyclyl; R ３ is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ４ is selected from halogen, —CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ５ and R ６ are each independently hydrogen, deuterium, halogen, —OH, or optionally substituted C1-C6 alkyl, or R ５ and R ６ together form an oxo, or R ５ and R ６ are joined together to form a carbocyclic or heterocyclic ring, Each R ７ are independently selected from hydrogen, deuterium, halogen, —OH, —SH, optionally substituted C1-C6 alkoxy, —S—(optionally substituted C1-C6 alkyl), —CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; L is -N(R ８ )—or a divalent radical selected from: 【Chemistry 3-1】 【Chemistry 3-2】 where the asterisk (*) indicates the bond to the —CO—Ar group; R ８ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; Each R ９ is hydrogen or optionally substituted C1-C6 alkyl; R １０ is an optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3, and A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0 or 1.

2. A compound having the structure of formula (Ia) below, or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 4】 During the ceremony, Z １ is N, C—H, or C—R ３ and Z ２ is N, C—H, or C—R ４ and Z ３ is N, C—H, Ar is selected from: 【Chemistry 5】 X １ is N or C-R ７ and X ２ is N or C-R ７ and X ３ is N or C-R ７ and X ４ is N or C-R ７ and Y is O, S, or N-R ９ and R １ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is hydrogen, halogen, —OH, —CN, —N(R ９ ) ２ , -OR ９ , -SR ９ , -SO ２ R ９ , -CO ２ R ９ , -CON(R ９ ) ２ , optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ４ is selected from halogen, —CN, optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ５ and R ６ are each independently hydrogen, deuterium, halogen, —OH, or optionally substituted C1-C6 alkyl, or R ５ and R ６ together form an oxo, or R ５ and R ６ are joined together to form a carbocyclic or heterocyclic ring, Each R ７ are independently selected from hydrogen, deuterium, halogen, —OH, —SH, optionally substituted C1-C6 alkoxy, —S—(optionally substituted C1-C6 alkyl), —CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; L is -N(R ８ )—or a divalent radical selected from: 【Chemistry 6-1】 【Chemistry 6-2】 where the asterisk (*) indicates the bond to the —CO—Ar group; R ８ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; Each R ９ is hydrogen or optionally substituted C1-C6 alkyl; R １０ is an optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3, and A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0 or 1.

3. A compound having the structure of formula (Ib) below, or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 7】 During the ceremony, Z １ is N, C—H, or C—R ３ and Z ２ is N, C—H, or C—R ４ and Ar is selected from: 【Chemistry 8】 X １ is N or C-R ７ and X ２ is N or C-R ７ and X ３ is N or C-R ７ and X ４ is N or C-R ７ and Y is O, S, or N-R ９ and R １ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ２ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ３ is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ４ is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R ５ and R ６ are each independently hydrogen, deuterium, halogen, —OH, or optionally substituted C1-C6 alkyl, or R ５ and R ６ together form an oxo, or R ５ and R ６ are joined together to form a carbocyclic or heterocyclic ring, Each R ７ are independently selected from hydrogen, deuterium, halogen, —OH, —SH, optionally substituted C1-C6 alkoxy, —S—(optionally substituted C1-C6 alkyl), —CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; L is -N(R ８ )—or a divalent radical selected from: 【Chemistry 9-1】 【Chemistry 9-2】 where the asterisk (*) indicates the bond to the —CO—Ar group; R ８ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; R ９ is hydrogen or optionally substituted C1-C6 alkyl; m is 0, 1, or 2; n is 1, 2, or 3, and A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0 or 1.

4. Z １ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein

5. Z ２ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

6. Z ２ is C-R ４ 5. The compound of claim 1, wherein:

7. R １ The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted heteroaryl.

8. 8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein said optionally substituted heteroaryl is optionally substituted pyridyl.

9. R ２ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted aryl.

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein said optionally substituted aryl is optionally substituted phenyl.

11. R ５ The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

12. R ６ The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

13. R ５ and R ６ The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein together form oxo.

14. R ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted C1-C6 alkyl.

15. R ５ and R ６ The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein: are linked together to form a carbocyclic or heterocyclic ring.

16. L is -N(R ８ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein:

17. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 10】

18. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 11】

19. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 12】

20. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 13】

21. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 14】

22. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the following: 【Chemistry 15】

23. R ８ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen or optionally substituted C1-C6 alkyl.

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

25. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

26. Ar is 【Chemistry 16】 26. The compound of any one of claims 1 to 25, wherein:

27. Ar is 【Chemistry 17】 26. The compound of any one of claims 1 to 25, wherein:

28. Ar is 【Chemistry 18】 26. The compound of any one of claims 1 to 25, wherein:

29. X １ , X ２ , and X ３ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

30. X １ is N and X ２ and X ３ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

31. X ２ is N and X １ and X ３ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

32. X ３ is N and X １ and X ２ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

33. X １ is N and X ２ and X ３ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein is C-H.

34. 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

35. 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S.

36. Y is N-R ９ 34. The compound of any one of claims 1 to 33, wherein:

37. R ９ 37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein: is hydrogen.

38. R ９ 37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted C1-C6 alkyl.

39. Ar is 【Chemistry 19】 26. The compound of any one of claims 1 to 25, wherein:

40. X １ 40. The compound of any one of claims 1 to 25 or 39, or a pharmaceutically acceptable salt or solvate thereof, wherein:

41. X ２ is N, or a pharmaceutically acceptable salt or solvate thereof.

42. X ３ is N, or a pharmaceutically acceptable salt or solvate thereof.

43. X ４ is N, or a pharmaceutically acceptable salt or solvate thereof.

44. X １ 44. The compound of any one of claims 1 to 25 or 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein:

45. X ２ 45. The compound of any one of claims 1 to 25 or 39 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein:

46. X ３ 46. ​​The compound of any one of claims 1 to 25 or 39 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein:

47. X ４ 47. The compound of any one of claims 1 to 25 or 39 to 46, or a pharmaceutically acceptable salt or solvate thereof, wherein:

48. R ３ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted C1-C6 alkyl.

49. R ３ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted aryl.

50. R ４ 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted C1-C6 alkyl.

51. R ４ 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein: is optionally substituted aryl.

52. A compound set forth in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

53. A compound set forth in Table 2, or a pharmaceutically acceptable salt or solvate thereof.

54. 54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

55. 54. A method of making a pharmaceutical composition, comprising mixing a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

56. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

57. 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, for use in a method for treating cancer or a neoplastic disease.

58. 54. Use of a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer or a neoplastic disease.

59. 54. A method of treating cancer in a patient in need thereof, comprising administering to said patient a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof.

60. 54. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising the compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

61. 54. A method of inhibiting the AKT1 enzyme, comprising contacting said enzyme with a compound of any one of claims 1 to 53, wherein said AKT1 enzyme is contacted under in vitro conditions.

62. 54. A method of inhibiting the AKT1 enzyme, comprising contacting said enzyme with a compound of any one of claims 1 to 53, wherein said AKT1 enzyme is contacted in an in vivo setting.