DEUTERATED DERIVATIVES OF RUXOLITINIB
The present invention in one embodiment provides a compound of Formula A: or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising the compound; and methods of treating the indications disclosed herein.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y 6 , Y 7 and Y 8 are each hydrogen, and the compound is selected from any one of the compounds set forth in the table below:
Cmpd
Y 1
Each Y 2
Each Y 3
Y 4
each Y 5
100
H
H
H
D
H
101
H
H
H
H
D
102
H
H
H
D
D
103
H
H
D
H
H
104
H
H
D
D
H
105
H
H
D
H
D
106
H
H
D
D
D
107
H
D
H
H
H
108
H
D
H
D
H
109
H
D
H
H
D
110
H
D
H
D
D
111
H
D
D
H
H
112
H
D
D
D
H
113
H
D
D
H
D
114
H
D
D
D
D
115
D
H
H
H
H
116
D
H
H
D
H
117
D
H
H
H
D
118
D
H
H
D
D
119
D
H
D
H
H
120
D
H
D
D
H
121
D
H
D
H
D
122
D
H
D
D
D
123
D
D
H
H
H
124
D
D
H
D
H
125
D
D
H
H
D
126
D
D
H
D
D
128
D
D
D
D
H
129
D
D
D
H
D
130
D
D
D
D
D
wherein any atom not designated as deuterium is present at its natural isotopic abundance.
2 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y 6 , Y 7 and Y 8 are each deuterium, and the compound is selected from any one of the compounds set forth in the table below:
Cmpd
Y 1
Each Y 2
Each Y 3
Y 4
each Y 5
200
H
H
H
D
H
201
H
H
H
H
D
202
H
H
H
D
D
203
H
H
D
H
H
204
H
H
D
D
H
205
H
H
D
H
D
206
H
H
D
D
D
207
H
D
H
H
H
208
H
D
H
D
H
209
H
D
H
H
D
210
H
D
H
D
D
211
H
D
D
H
H
212
H
D
D
D
H
213
H
D
D
H
D
214
H
D
D
D
D
215
D
H
H
H
H
216
D
H
H
D
H
217
D
H
H
H
D
218
D
H
H
D
D
219
D
H
D
H
H
220
D
H
D
D
H
221
D
H
D
H
D
222
D
H
D
D
D
223
D
D
H
H
H
224
D
D
H
D
H
225
D
D
H
H
D
226
D
D
H
D
D
227
D
D
D
H
H
228
D
D
D
D
H
229
D
D
D
H
D
230
D
D
D
D
D
231
H
H
H
H
H
wherein any atom not designated as deuterium is present at its natural isotopic abundance.
3 . A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.
4 . A pharmaceutical composition comprising the compound of claim 2 , and a pharmaceutically acceptable carrier.
5 . A pharmaceutical composition comprising Compound 127,
and a pharmaceutically acceptable carrier.
6 . The composition of claim 3 further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.
7 . A method of inhibiting the activity of one or more of JAK1 or JAK2, in a cell, comprising contacting such a cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8 . A method of inhibiting the activity of one or more of JAK1 or JAK2, in a cell, comprising contacting such a cell with Compound 127,
or a pharmaceutically acceptable salt thereof.
9 . A method of treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma, psoriasis, or a combination thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 3 .
10 . The method of claim 9 , wherein the myelofibrosis is primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, essential thrombocythemia or a combination thereof.
11 . The method of claim 9 , further comprising administering to the subject in need thereof, a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.
12 . The composition of claim 4 further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.
13 . The composition of claim 5 further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.
14 . A method of inhibiting the activity of one or more of JAK1 or JAK2, in a cell, comprising contacting such a cell with a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
15 . A method of treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma, psoriasis, or a combination thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 4 .
16 . A method of treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma, psoriasis, or a combination thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 5 .