VMAT2 INHIBITOR COMPOUNDS AND COMPOSITIONS THEREOF

• US 20200131173A1
• Filed: 04/17/2018
• Published: 04/30/2020
• Est. Priority Date: 04/19/2017
• Status: Active Grant

• Current Assignee: Neurocrine Biosciences Inc.
• Original Assignee: Neurocrine Biosciences Inc.
• Inventors: Harriott, Nicole, Hettinger, Donald, Branum, Shawn, Culhane, Jeffrey C.
• Granted Patent: US 11,040,970 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided is a compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof: (I) wherein R¹, R², R³ and R⁴ are as defined herein. Such compounds are inhibitors of the vesicular monoamine transporter 2 (VMAT2) and have utility for treating, for example, neurological and psychiatric diseases and disorders. Also disclosed are compositions containing such compounds in combination with a pharmaceutically acceptable carrier, as well as methods relating to their use in subjects in need thereof.

Claims

1. A compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

2. The compound of claim 1, selected from compounds of Formula (II) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

3. The compound of claim 1 or 2, wherein R² is lower alkyl.

4. The compound of claim 3, wherein R² is C_1-4 saturated alkyl.

5. The compound of claim 4, wherein R² is methyl.

6. The compound of any one of claims 1 to 5, wherein R² is deuterated.

7. The compound of claim 6, wherein R² is —

CD₃ or —

CD₂CD₃.

8. The compound of claim 1, selected from compounds of Formula (III) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

9. The compound of any one of claims 1 to 8, wherein R³ is C_1-6 saturated alkyl.

10. The compound of claim 9, wherein R³ is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, or neo-pentyl.

11. The compound of claim 10, wherein R³ is methyl.

12. The compound of any one of claims 1 to 11, wherein R⁴ is lower alkyl.

13. The compound of claim 12, wherein R⁴ is C_1-6 saturated alkyl.

14. The compound of claim 13, wherein R⁴ is iso-butyl or neo-pentyl.

15. The compound of claim 1, selected from compounds of Formula (IV) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

16. The compound of any one of claims 1 to 11, wherein R⁴ is lower cycloalkyl or lower cycloalkylalkyl.

17. The compound of claim 16, wherein R⁴ is cyclopropyl, cyclobutyl, or —

CH₂-cyclobutyl.

18. The compound of any one of claims 1 to 11, wherein R⁴ is lower cycloalkylalkyl wherein the lower alkyl portion of the lower cycloalkylalkyl is C_1-4 saturated alkyl and the cycloalkyl portion of the lower cycloalkylalkyl is cyclopropyl or cyclobutyl.

19. The compound of claim 1, selected from compounds of Formula (V) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

20. The compound of claim 1, selected from compounds of Formula (VI) and pharmaceutically acceptable salts, solvates, and hydrates thereof:

21. The compound of any one of claims 1 to 20, wherein R¹ is lower alkyl.

22. The compound of claim 21, wherein R¹ is C_1-6 saturated alkyl.

23. The compound of claim 22, wherein R¹ is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, neo-pentyl.

24. The compound of any one of claims 1 to 20, wherein R¹ is fluoroalkyl.

25. The compound of any one of claims 1 to 20, wherein R¹ is lower alkyl substituted with halo.

26. The compound of claim 25, wherein R¹ is C_1-4 saturated alkyl substituted with one, two, or three halo groups.

27. The compound of claim 26, wherein each of the one, two, or three halo groups is fluoro.

28. The compound of claim 27, wherein R¹ is —

(CH₂)₃CH₂F, —

(CH₂)₂CH₂F, —

CH₂CH₂F, —

(CH₂)₄CF₃, —

(CH₂)₃CF₃, —

(CH₂)₂CF₃, or —

CH₂CF₃.

29. The compound of any one of claims 1 to 20, wherein R¹ is lower alkyl substituted with lower alkoxy.

30. The compound of claim 29, wherein R¹ is C_1-4 saturated alkyl substituted with C_1-4 saturated alkoxy.

31. The compound of claim 30, wherein R¹ is —

CH₂CH₂OCH₃.

32. The compound of any one of claims 1 to 20, wherein R¹ is lower alkyl substituted with cyano.

33. The compound of claim 32, wherein R¹ is C_1-4 saturated alkyl substituted with a cyano group.

34. The compound of claim 33, wherein R¹ is —

CH₂CH₂CH₂CN.

35. The compound of any one of claims 1 to 20, wherein R¹ is cycloalkyl.

36. The compound of claim 35, wherein R¹ is cyclopropyl or cyclobutyl.

37. The compound of any one of claims 1 to 20, wherein R¹ is cycloalkylalkyl.

38. The compound of claim 37, wherein R¹ is lower cycloalkylalkyl wherein the lower alkyl portion of the lower cycloalkylalkyl is C_1-4 saturated alkyl and the cycloalkyl portion of the lower cycloalkylalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.

39. The compound of claim 38, wherein R¹ is —

CH₂-cyclopropyl, —

CH₂-cyclobutyl, or —

CH₂-cyclopentyl.

40. The compound of any one of claims 1 to 20, wherein R¹ is cycloalkylalkyl substituted with halo.

41. The compound of claim 40, wherein R¹ is lower cycloalkylalkyl substituted with halo wherein the lower alkyl portion of the lower cycloalkylalkyl is C_1-4 saturated alkyl and the cycloalkyl portion of the lower cycloalkylalkyl is cyclopropyl, cyclobutyl, or cyclopentyl and wherein either portion of the lower cycloalkylalkyl group is substituted with halo.

42. The compound of claim 41, wherein R¹ is:

43. The compound of any one of claims 1 to 42, wherein R¹ is deuterated.

44. The compound of claim 43, wherein R¹ is —

CD₃ or —

CD₂CD₃.

45. The compound of claim 1, selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:

64. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 63 in combination with one or more pharmaceutically acceptable excipients and/or diluents.

65. A method of treating a neurological or psychiatric disease or disorder comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1 to 63, or a pharmaceutical composition of claim 64.

66. Use of a compound according to any one of claims 1 to 63, for production of a medication for use in the treatment of a neurological or psychiatric disease or disorder.

67. A compound according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64, for use in a method of treatment of the human or animal body by therapy.

68. A compound according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64, for use in a method for the treatment of a neurological or psychiatric disease or disorder in the human or animal body by therapy.

69. The method of claim 65, the use of claim 66, the compound of claim 68, or the pharmaceutical composition according to claim 68, wherein the neurological or psychiatric disease or disorder is hyperkinetic movement disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, mania in mood disorders, depression in mood disorder, treatment-refractory obsessive compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer'"'"'s disease, Fragile X syndrome or Fragile X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett syndrome, or chorea-acanthocytosis.

70. The method of claim 65, the use of claim 66, the compound of claim 68, or the pharmaceutical composition according to claim 68, wherein the neurological or psychiatric disease or disorder is a hyperkinetic movement disorder.

71. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is tardive dyskinesia.

72. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is Tourette'"'"'s syndrome.

73. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is Huntington'"'"'s disease.

74. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is tics.

75. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is chorea associated with Huntington'"'"'s disease.

76. The method of claim 70, the use of claim 70, the compound of claim 70, or the pharmaceutical composition according to claim 70, wherein the hyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacial spasm, ton'"'"'s disease, myoclonus, restless leg syndrome, or tremors.

77. The method of claim 65, the use of claim 66, the compound of claim 68, or the pharmaceutical composition according to claim 68, wherein the neurological or psychiatric disease or disorder is restricted and repetitive behaviors associated with Autism spectrum disorder (ASD).

78. The method of claim 65, the use of claim 66, the compound of claim 68, or the pharmaceutical composition according to claim 68, wherein the neurological or psychiatric disease or disorder is obsessions and compulsions in partial and non-responders (or completely refractory) with Obsessive-Compulsive Disorder (OCD).

79. The method of claim 78, the use of claim 78, the compound of claim 78, or the pharmaceutical composition of claim 78, wherein the compound of any one of claims 1 to 63, or a pharmaceutical composition of claim 64 is administered as adjunctive therapy with an antidepressant.

80. The method of claim 65, the use of claim 66, the compound of claim 68, or the pharmaceutical composition according to claim 68, wherein the neurological or psychiatric disease or disorder is Bipolar I Disorder.

81. The method of claim 80, the use of claim 80, the compound of claim 80, or the pharmaceutical composition of claim 80, wherein the compound of any one of claims 1 to 63, or a pharmaceutical composition of claim 64 is administered as monotherapy.

82. The method of claim 80 or 81, the use of claim 80 or 81, the compound of claim 80 or 81, or the pharmaceutical composition of claim 80 or 81, wherein the compound of any one of claims 1 to 63, or a pharmaceutical composition of claim 64 is administered as maintenance therapy.

83. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 63 and one or more pharmaceutically acceptable excipients and/or diluents.

46. A compound selected from 3-(2,2-dimethylpropyl)-9,10-dimethoxy-2-methyl-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

47. The compound of claim 46, selected from (3R,11bS)-3-(2,2-dimethylpropyl)-9,10-dimethoxy-2-methyl-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

48. A compound selected from 9-cyclopropoxy-10-methoxy-2-methyl-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

49. The compound of claim 48, selected from (3R,11bS)-9-cyclopropoxy-10-methoxy-2-methyl-3-(2-methylpropyl)-1H,2H, 3H,4H, 6H, 7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

50. A compound selected from 3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(2,2,2-trifluoroethoxy)-1H,2H2H, 3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

51. The compound of claim 50, selected from (3R,1 bS)-3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

52. A compound selected from 3-(2,2-dimethylpropyl)-9-ethoxy-10-methoxy-2-methyl-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

53. The compound of claim 52, selected from (3R,1 bS)-3-(2,2-dimethylpropyl)-9-ethoxy-10-methoxy-2-methyl-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

54. A compound selected from 3-(2,2-dimethylpropyl)-9,10-bis(methoxy-d₃)-2-methyl-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

55. The compound of claim 54, selected from (3R,11bS)-3-(2,2-dimethylpropyl)-9,10-bis(methoxy-d₃)-2-methyl-1H,2H,3H,34H,6H,7H, 1 bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

56. A compound selected from 10-methoxy-2-methyl-3-(2-methylpropyl)-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

57. The compound of claim 56, selected from (3R,11bS)-10-methoxy-2-methyl-3-(2-methylpropyl)-9-(2,2,2-trifluoroethoxy)-1H, 2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

58. A compound selected from 10-methoxy-2-methyl-3-(2-methylpropyl)-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

59. The compound of claim 58, selected from (3R,11bS)-10-methoxy-2-methyl-3-(2-methylpropyl)-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H, 6H,7H,1 bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

60. A compound selected from 3-(2,2-dimethylpropyl)-9-(3-fluoropropoxy)-10-methoxy-2-methyl-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

61. The compound of claim 60, selected from (3R,11bS)-3-(2,2-dimethylpropyl)-9-(3-fluoropropoxy)-10-methoxy-2-methyl-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

63. The compound of claim 60, selected from (3R,1 bS)-3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.

62. A compound selected from 3-(2,2-dimethylpropyl)-10-methoxy-2-methyl-9-(3,3,3-trifluoropropoxy)-1H,2H,3H,4H,6H,7H, 11bH-piperazino[2,1-a]isoquinoline and pharmaceutically acceptable salts, solvates, and hydrates thereof.