IP Library › Granted Patent US 11,760,747

Granted Patent B2

US 11,760,747 · App. 17/556,295 · Granted Sep 19, 2023

Substituted piperidino compounds and related methods of treatment

Inventors: Lewis D. Pennington (Arlington, MA); Younggi Choi (Stow, MA); Hoan Huynh (Waltham, MA); Brian M. Aquila (Marlborough, MA); Ingo Andreas Mugge (Waltham, MA); Yuan Hu (Waltham, MA); James R. Woods (Waltham, MA); Brian Kenneth Raymer (Holliston, MA); Jörg Martin Bentzien (White Plains, NY); Jonathan Ward Lehmann (Burlington, MA); Srinivasa Karra (Pembroke, MA); Roman A. Valiulin (Cambridge, MA); Daljit Matharu (Lexington, MA)

Assignee: Alkermes, Inc.

C07D401/14 A61P25/26 C07D211/98 C07D401/04 C07D471/04 C07D487/04

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Quick Facts

Patent No.: US 11,760,747
App. No.: 17/556,295
Granted: Sep 19, 2023
Kind: B2

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Abstract

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Claims (213)

1. A compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein:

T is CR 6 or N;

U is CR 5 or N;

V is CR 4 or N;

W is CR 3 or N;

X is CR 2 or N;

and provided that

includes no more than 3 nitrogen atoms in the ring;

E is selected from the group consisting of NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, and C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) wherein the C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;

R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;

R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

R c and R d are each, independently, H, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

n is 0 or 1;

each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, halogen, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

or, alternatively, R 8 and R 11 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

or, alternatively, R 9 and R 10 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

p is 0, 1, 2, 3, or 4; and

each R 14 is, independently, selected from the group consisting of deuterium, halogen, hydroxyl, and cyano.

2. The compound of claim 1 , wherein

is selected from the group consisting of:

3. The compound of claim 1 , wherein

is selected from the group consisting of:

4. The compound of claim 1 , wherein

is selected from the group consisting of:

5. The compound of claim 1 , wherein

6. The compound of claim 1 , wherein p is 0.

7. The compound of claim 1 , wherein p is 1 or 2.

8. The compound of claim 1 , wherein E is NR a R b .

9. The compound of claim 1 , wherein E is C 1 -C 3 alkylene-NR a R b .

10. The compound of claim 1 , wherein E is unsubstituted C 1 -C 3 alkyl, unsubstituted C 2 -C 4 alkenyl, or unsubstituted C 2 -C 4 alkynyl.

11. The compound of claim 1 , wherein E is C 1 -C 3 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

12. The compound of claim 1 , wherein E is unsubstituted C 1 -C 3 alkyl.

13. The compound of claim 1 , wherein E is C 1 -C 3 alkyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

14. The compound of claim 1 , wherein E is unsubstituted C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, unsubstituted C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), substituted C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), unsubstituted 4- to 10-membered heterocyclyl, substituted 4- to 10-membered heterocyclyl, unsubstituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), or substituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl).

15. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted.

16. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

17. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 0.

18. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

19. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 1.

20. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.

21. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) wherein the aryl is unsubstituted.

22. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

23. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) wherein the aryl is unsubstituted and further wherein n is 0.

24. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

25. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted, (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium, (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted and further wherein n is 0, or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

26. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.

27. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

28. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.

29. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

30. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.

31. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

32. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.

33. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.

34. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

35. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

36. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

37. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

38. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

39. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

40. The compound of claim 1 , wherein R 1 is (CR c R d ) n -(5- to 7-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is independently H, unsubstituted C 1 -C 3 alkyl, or fluorine.

41. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.

42. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.

43. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 -C 10 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.

44. The compound of claim 1 , wherein R 1 is (CR c R d ) n —(C 6 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , Ru, Ria, and R 13 is independently H, unsubstituted C 1 -C 3 alkyl, or fluorine.

45. The compound of claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

46. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

47. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 46 .

48. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 46 .

49. A pharmaceutical composition comprising a compound of claim 45 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

50. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 45 or a pharmaceutically acceptable salt thereof, or a composition according to claim 49 .

51. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 49 .

52. The compound of claim 1 , wherein the compound is: