Heteroaryl-isochroman compounds and uses thereof
Compounds of Formula I are described as are pharmaceutical compositions containing such compounds. Methods of treating neurological or psychiatric diseases and disorders in a subject in need are also disclosed.
1. A method for treating a neurological or psychiatric disorder in a subject, comprising administering to said subject in need thereof an effective amount of a compound of formula
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 3 and R 4 are chosen independently from H and aliphatic (C 1 -C 8 )hydrocarbon, wherein the aliphatic (C 1 -C 8 )hydrocarbon is optionally substituted with one or more substituents selected from halogen, hydroxyl, (C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino;
or, taken together, R 1 and R 2 form (C 3 -C 6 )cycloalkyl;
R 5 and R 6 are chosen independently from H, halogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
R 9 and R 10 are chosen independently from H, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl and (C 1 -C 6 )alkoxy;
one of R 11 , R 12 , R 13 , and R 14 is optionally substituted benzyl, optionally substituted aryl, or optionally substituted heteroaryl; and the remaining three are H; and
wherein said benzyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from halogen, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, aminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 4 )acyl, (C 1 -C 4 )haloalkoxy, hydroxy(C 1 -C 4 )alkyl, carboxy, (C 1 -C 4 )alkoxycarbonyl, acetoxy, nitro, amino, (C 1 -C 4 )alkylamino, and di(C 1 -C 4 )alkylamino,
wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive compulsive disorder, social disorder, attention deficit hyperactivity disorder, an anxiety disorder, or epilepsy.
2. The method according to claim 1 , wherein the neurological or psychiatric disorder is depression.
3. The method according to claim 2 , wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.
4. The method according to claim 1 , wherein the neurological or psychiatric disorder is epilepsy.
5. A method for treating a neurological or psychiatric disorder in a subject, comprising administering to said subject in need thereof an effective amount of a compound which is:
wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive compulsive disorder, social disorder, attention deficit hyperactivity disorder, an anxiety disorder, or epilepsy.
6. The method according to claim 5 , wherein the neurological or psychiatric disorder is epilepsy.
7. A method for treating a neurological or psychiatric disorder in a subject, comprising administering to said subject in need thereof an effective amount of a compound which is:
wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive compulsive disorder, social disorder, attention deficit hyperactivity disorder, an anxiety disorder, or epilepsy.
8. The method according to claim 7 , wherein the neurological or psychiatric disorder is epilepsy.
9. The method according to claim 1 wherein R 1 is hydrogen and R 2 is hydrogen or methyl.
10. The method according to claim 1 wherein R 1 and R 2 are both hydrogen.
11. The method according to claim 1 wherein R 3 is hydrogen and R 4 is hydrogen, methyl or ethyl.
12. The method according to claim 1 wherein R 3 and R 4 are both hydrogen.
13. The method according to claim 1 wherein R 5 and R 6 are both hydrogen.
14. The method according to claim 1 wherein R 9 and R 10 are chosen independently from H, fluoro, and methyl.
15. The method according to claim 1 wherein R 9 is chosen from H, fluoro, and methyl and R 10 is H.
16. The method according to claim 1 wherein R 11 is optionally substituted benzyl, optionally substituted aryl, or optionally substituted heteroaryl.
17. The method according to claim 1 wherein R 12 is optionally substituted benzyl, optionally substituted aryl, or optionally substituted heteroaryl.
18. The method according to claim 1 wherein R 13 is optionally substituted benzyl, optionally substituted aryl, or optionally substituted heteroaryl.
19. The method according to claim 1 wherein R 11 is optionally substituted benzyl, optionally substituted aryl, or optionally substituted heteroaryl.
20. The method according to claim 1 wherein said benzyl, aryl or heteroaryl is unsubstituted.
21. The method according to claim 1 wherein said optionally substituted aryl is phenyl, and said optionally substituted heteroaryl is nitrogen-containing heteroaryl.
22. The method according to claim 21 wherein said nitrogen-containing heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and pyrrolyl.
23. The method according to claim 21 wherein said nitrogen-containing heteroaryl is pyridinyl.
24. The method according to claim 23 wherein said pyridinyl is at the R 11 , R 12 or R 13 position.
25. The method according to claim 1 , wherein the compound has Formula IIa:
26. The method according to claim 1 , wherein the compound has Formula IIb:
27. The method according to claim 1 wherein R 1 is hydrogen; R 2 is hydrogen or methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 5 is hydrogen; and R 6 is hydrogen.
28. The method according to claim 27 wherein R 9 and R 10 are each independently hydrogen, fluoro, or methyl.
29. The method according to claim 28 wherein all of R 1 , R 2 , R 3 , R 5 , R 6 , R 9 and R 1- ° are hydrogen, and R 4 is hydrogen or methyl.
30. The method according to claim 29 wherein all of R 1 , R 2 , R 3 , R 5 , R 6 , R 9 , R 10 and R 14 are hydrogen; R 4 is hydrogen or methyl; and one of R 11 , R 12 , or R 13 is pyridinyl, and the remaining two are H.
31. The method according to claim 30 , wherein R 11 is pyridinyl.
32. The method according to claim 30 , wherein R 12 is pyridinyl.
33. The method according to claim 30 , wherein R 12 is 3-pyridinyl.
34. The method according to claim 30 , wherein R 13 is pyridinyl.
35. The method according to claim 30 , wherein R 13 is 3-pyridinyl or 4-pyridinyl.
36. The method according to claim 25 wherein all of R 1 , R 2 , R 3 , R 5 , R 6 , R 9 and R 10 are hydrogen, and R 4 is hydrogen or methyl.
37. The method according to claim 36 wherein one of R 11 , R 12 , or R 13 is pyridinyl, and the remaining two are H.
38. The method according to claim 26 wherein all of R 1 , R 2 , R 3 , R 5 , R 6 , R 9 and R 10 are hydrogen; and R 4 is hydrogen or methyl.
39. The method according to claim 38 wherein R 4 is hydrogen.
40. The method according to claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
41. The method according to claim 40 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
42. The method according to claim 40 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
43. The method according to claim 40 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
44. The method according to claim 40 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
45. The method according to claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
46. The method according to claim 45 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
47. The method according to claim 45 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
48. The method according to claim 45 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
49. The method according to claim 45 wherein the compound is:
or a pharmaceutically acceptable salt thereof.
50. The method according to claim 1 , wherein the compound is selected from:
Compound
Structure
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
or a pharmaceutically acceptable salt thereof.
51. The method according to claim 1 , wherein the compound is selected from:
Compound No
Chemical name
1
(R)-N-Methyl-1-(8-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
2
(S)-N-Methyl-1-(8-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
3
(R)-N-Methyl-1-(7-(pyridin-3-yl)isochroman-1-yl)methanamine dihydrochloride
4
(S)-N-methyl-1-(7-(pyridin-3-yl)isochroman-1-yl)methanamine dihydrochloride
5
(R)-N-Methyl(6-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
6
(S)-N-methyl(6-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
7
(R)-N-Methyl(5-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
8
(S)-N-Methyl(5-(pyridin-3-yl)isochroman-1-yl)methanamine bis-hydrochloride
9
(R)-(8-(Pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
10
(S)-(8-(Pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
11
(R)-(7-(pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
12
(S)-(7-(pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
13
(R)-tert-Butyl (6-(pyridin-3-yl)isochroman-1-yl)methylcarbamate hydrochloride
14
(S)-tert-Butyl (6-(pyridin-3-yl)isochroman-1-yl)methylcarbamate hydrochloride
15
(R)-(5-(Pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
16
(S)-(5-(Pyridin-3-yl)isochroman-1-yl)methanamine hydrochloride
17
(R)-N-Methyl(5-(pyridin-4-yl)isochroman-1-yl)methanamine dihydrochloride
18
(S)-N-Methyl(5-(pyridin-4-yl)isochroman-1-yl)methanamine dihydrochloride
19
(R)-(5-(Pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
20
(S)-(5-(Pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
21
(R)-N-Methyl-1-(6-(pyrimidin-2-yl)isochroman-1-yl)methanamine hydrochloride
22
(S)-N-Methyl-1-(6-(pyrimidin-2-yl)isochroman-1-yl)methanamine hydrochloride
23
(S)-N-Methyl-1-(5-(pyrimidin-2-yl)isochroman-1-yl)methanamine hydrochloride
24
(R)-N-Methyl-1-(5-(pyrimidin-2-yl)isochroman-1-yl)methanamine hydrochloride
25
(S)-N-Methyl-1-(7-(pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
26
(R)-N-Methyl-1-(7-(pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
27
(R)-(5-(Pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
28
(S)-(5-(Pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
29
(R)-N-Methyl-1-(5-(pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
30
(S)-N-Methyl-1-(5-(pyrimidin-5-yl)isochroman-1-yl)methanamine hydrochloride
31
(R)-N-Methyl-1-(6-(pyridazin-3-yl)isochroman-1-yl)methanamine hydrochloride
32
(S)-N-Methyl-1-(6-(pyridazin-3-yl)isochroman-1-yl)methanamine hydrochloride
43
(R)-N-Methyl-1-(5-(pyridin-2-yl)isochroman-1-yl)methanamine hydrochloride
44
(S)-N-Methyl-1-(5-(pyridin-2-yl)isochroman-1-yl)methanamine hydrochloride
45
(R)-(5-(pyridin-2-yl)isochroman-1-yl)methanamine hydrochloride
46
(S)-(5-(pyridin-2-yl)isochroman-1-yl)methanamine hydrochloride
47
(R)-(7-(pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
48
(S)-(7-(pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
49
(R)-N-Methyl-1-(7-(pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
50
(S)-N-Methyl-1-(7-(pyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
51
N-((5-(pyridin-4-yl)isochroman-1-yl)methyl)ethanamine
52
N-Methyl-1-(5-(thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
53
N-Methyl-1-(5-(pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
54
N-Methyl-1-(5-(pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
55
N-Methyl-1-(5-(pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
56
N-Methyl-1-(5-(pyrazin-2-yl)isochroman-1-yl)methanamine hydrochloride
57
7-(Pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
58
N-Methyl-1-(7-(pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
59
(5-(Thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
60
(5-(Pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
61
(5-(Pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
62
(5-(Pyridazin-3-yl)isochroman-1-yl)methanaminehydrochloride
63
(5-(Pyrazin-2-yl)isochroman-1-yl)methanamine hydrochloride
64
(5-(Isoxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
65
1-(5-(Isoxazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
66
(R)-N-((5-(Pyridin-4-yl) isochroman-1-yl)methyl)ethanamine hydrochloride
67
(S)-N-((5-(Pyridin-4-yl) isochroman-1-yl)methyl)ethanamine hydrochloride
68
(R)-N-Methyl-1-(5-(thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
69
(S)-N-Methyl-1-(5-(thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
70
(R)-(5-(Thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
71
(S)-(5-(Thiazol-5-yl)isochroman-1-yl)methanamine hydrochloride
72
(R)-N-Methyl-1-(5-(pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
73
(S)-N-Methyl-1-(5-(pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
74
(R)-(5-(Pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
75
(S)-(5-(Pyrimidin-4-yl)isochroman-1-yl)methanamine hydrochloride
76
(R)-N-Methyl-1-(5-(pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
77
(S)-N-Methyl-1-(5-(pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
78
(R)-(5-(Pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
79
(S)-(5-(Pyridazin-4-yl)isochroman-1-yl)methanamine hydrochloride
80
(R)-N-Methyl-1-(5-(pyrazine-2-yl)isochroman-1-yl)methanamine
81
(S)-N-Methyl-1-(5-(pyrazine-2-yl)isochroman-1-yl)methanamine
82
(R)-(5-(Pyrazin-2-yl)isochroman-1-yl)methanamine hydrochloride
83
(S)-(5-(Pyrazin-2-yl)isochroman-1-yl)methanamine hydrochloride
84
(R)-1-(5-(Isoxazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
85
(S)-1-(5-(Isoxazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
86
(R)-(5-(Isoxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
87
(S)-(5-(Isoxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
88
(R)-(5-(Isoxazol-3-yl)isochroman-1-yl)methanamine hydrochloride
89
(S)-(5-(Isoxazol-3-yl)isochroman-1-yl)methanamine hydrochloride
90
(R)-1-(5-(Isoxazol-3-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
91
(S)-1-(5-(Isoxazol-3-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
92
(R)-(5-(Isoxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
93
(S)-(5-(Isoxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
94
(R)-1-(5-(Isoxazol-5-yl)isochroman-1-yl)-N-methylmethanamine
95
(S)-1-(5-(Isoxazol-5-yl)isochroman-1-yl)-N-methylmethanamine
96
(R)-N-Methyl-1-(5-(oxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
97
(S)-N-Methyl-1-(5-(oxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
98
(R)-(5-(Oxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
99
(S)-(5-(Oxazol-5-yl)isochroman-1-yl)methanamine hydrochloride
100
(R)-(5-(oxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
101
(S)-(5-(oxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
102
(R)-N-methyl-1-(5-(oxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
103
(S)-N-methyl-1-(5-(oxazol-4-yl)isochroman-1-yl)methanamine hydrochloride
104
(R)-N-Methyl-1-(5-(oxazol-2-yl)isochroman-1-yl)methanamine hydrochloride
105
(S)-N-methyl-1-(5-(oxazol-2-yl)isochroman-1-yl)methanamine dihydrochloride
106
(R)-(5-(Oxazol-2-yl)isochroman-1-yl)methanamine hydrochloride
107
(S)-(5-(Oxazol-2-yl)isochroman-1-yl)methanamine hydrochloride
108
(R)-(5-(1H-Imidazol-2-yl)isochroman-1-yl)methanamine hydrochloride
109
(S)-(5-(1H-Imidazol-2-yl)isochroman-1-yl)methanamine hydrochloride
110
(R)-1-(5-(1H-Imidazol-2-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
111
(S)-1-(5-(1H-Imidazol-2-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
112
(R)-(5-(1H-Imidazol-4-yl)isochroman-1-yl)methanamine hydrochloride
113
(S)-(5-(1H-Imidazol-4-yl)isochroman-1-yl)methanamine hydrochloride
114
(R)-1-(5-(1H-imidazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
115
(S)-1-(5-(1H-imidazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
116
(R)-(5-(1H-pyrazol-4-yl)isochroman-1-yl)methanamine hydrochloride
117
(S)-(5-(1H-pyrazol-4-yl)isochroman-1-yl)methanamine hydrochloride
118
(R)-1-(5-(1H-pyrazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
119
(S)-1-(5-(1H-pyrazol-4-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
120
(R)-N-Methyl-1-(5-(2-methylpyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
121
(S)-N-Methyl-1-(5-(2-methylpyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
122
(R)-(5-(2-Methylpyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
123
(S)-(5-(2-Methylpyridin-4-yl)isochroman-1-yl)methanamine hydrochloride
124
(R)-1-(5-(2,6-dimethylpyridin-4-yl)isochroman-1-yl)-N-methylmethanamine dihydrochloride
125
(S)-1-(5-(2,6-dimethylpyridin-4-yl)isochroman-1-yl)-N-methylmethanamine dihydrochloride
126
(R)-1-(5-(2,6-dimethylpyridin-4-yl)isochroman-1-yl)-N-methylmethanamine dihydrochloride
127
(S)-1-(5-(2,6-dimethylpyridin-4-yl)isochroman-1-yl)-N-methylmethanamine dihydrochloride
128
(R)-N-Methyl-1-(5-phenylisochroman-1-yl)methanamine hydrochloride
129
(S)-N-Methyl-1-(5-phenylisochroman-1-yl)methanamine hydrochloride
130
(R)-(5-Phenylisochroman-1-yl)methanamine hydrochloride
131
(S)-(5-Phenylisochroman-1-yl)methanamine hydrochloride
180
(R)-N-((5-(Pyridin-4-yl)isochroman-1-yl)methyl)cyclopropanamine hydrochloride
181
(S)-N-((5-(Pyridin-4-yl)isochroman-1-yl)methyl)cyclopropanamine hydrochloride
182
(R)-1-(5-(1H-Imidazol-1-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
183
(S)-1-(5-(1H-Imidazol-1-yl)isochroman-1-yl)-N-methylmethanamine hydrochloride
184
(R)-(5-(1H-Imidazol-1-yl)isochroman-1-yl)methanamine hydrochloride
185
(S)-(5-(1H-Imidazol-1-yl)isochroman-1-yl)methanamine hydrochloride
186
(R)-1-(5-(1H-pyrazol-1-yl)isochroman-1-yL)-N-methylmethanamine
187
(S)-1-(5-(1H-pyrazol-1-yl)isochroman-1-yl)-N-methylmethanamine
188
(R)-(5-(1H-pyrazol-1-yl)isochroman-1-yl)methanamine hydrochloride
189
(S)-(5-(1H-pyrazol-1-yl)isochroman-1-yl)methanamine hydrochloride
190
(R)-1-(5-(4H-1,2,4-triazol-4-yl)isochroman-1-yl)-N-methylmethanamine
191
(S)-1-(5-(4H-1,2,4-triazol-4-yl)isochroman-1-yl)-N-methylmethanamine
192
(R)-(5-(4H-1,2,4-triazol-4-yl)isochroman-1-yl)methanamine
193
(S)-(5-(4H-1,2,4-triazol-4-yl)isochroman-1-yl)methanamine
194
(R)-N,N-dimethyl-1-(5-(pyridin-4-yl)isochroman-1-yl)methanamine, and
195
(S)-N,N-dimethyl-1-(5-(pyridin-4-yl)isochroman-1-yl)methanamine,
or a pharmaceutically acceptable salt thereof.
52. The method according to claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
53. The method according to claim 52 , wherein the compound is greater than 95% enantiomerically pure.
54. The method according to claim 52 , wherein the compound is greater than 99% enantiomerically pure.
55. The method according to claim 46 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
56. The method according to claim 55 , wherein the compound is greater than 95% enantiomerically pure.
57. The method according to claim 55 , wherein the compound is greater than 99% enantiomerically pure.