Substituted triazolobenzodiazepines
This invention relates to novel substituted triazolobenzodiazepines of the Formula I: wherein each of the variables are defined herein and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering I-BET762.
1. A method of treating a subject suffering from a chronic autoimmune or inflammatory condition selected from rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, Crohn's disease ulcerative colitis, asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs, the method comprising a step of administering to the subject in need thereof a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
Y 1a and Y 1b are the same and are hydrogen or deuterium;
Y 2 is hydrogen or deuterium;
R 1 and R 2 are each independently selected from CH 3 and CD 3 ;
R 3 is selected from CH 2 CH 3 , CH 2 CD 3 , CD 2 CH 3 , and CD 2 CD 3 ; and
if R 1 and R 2 are each CH 3 , R 3 is CH 2 CH 3 , and Y 2 is hydrogen, then Y 1a and Y 1b are each deuterium; and wherein any atom not designated as deuterium is present at its natural isotopic abundance.
2. The method of claim 1 , wherein the inflammatory condition is dermatitis.
3. The method of claim 1 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
4. The method of claim 1 , wherein for the compound of Formula I, Y 1a and Y 1b are hydrogen.
5. The method of claim 1 , wherein for the compound of Formula I, Y 1a and Y 1b are deuterium.
6. The method of claim 1 , wherein for the compound of Formula I, R 3 is selected from CH 2 CH 3 and CD 2 CD 3 .
7. The method of claim 4 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:
Compound
Y 2
R 1
R 2
R 3
101
H
—CH 3
—CH 3
—CD 2 CD 3
102
H
—CH 3
—CH 3
—CD 2 CH 3
103
H
—CH 3
—CH 3
—CH 2 CD 3
104
H
—CD 3
—CH 3
—CH 2 CH 3
105
H
—CH 3
—CD 3
—CH 2 CH 3
106
D
—CH 3
—CH 3
—CH 2 CH 3
107
D
—CD 3
—CH 3
—CH 2 CH 3
108
D
—CH 3
—CD 3
—CH 2 CH 3
109
D
—CH 3
—CH 3
—CD 2 CD 3
110
D
—CH 3
—CH 3
—CD 2 CH 3
111
D
—CH 3
—CH 3
—CH 2 CD 3
112
H
—CD 3
—CD 3
—CH 2 CH 3
113
H
—CD 3
—CH 3
—CD 2 CD 3
114
H
—CD 3
—CH 3
—CD 2 CH 3
115
H
—CD 3
—CH 3
—CH 2 CD 3
116
H
—CH 3
—CD 3
—CD 2 CD 3
117
H
—CH 3
—CD 3
—CD 2 CH 3
118
H
—CH 3
—CD 3
—CH 2 CD 3
119
D
—CD 3
—CD 3
—CH 2 CH 3
120
D
—CD 3
—CH 3
—CD 2 CD 3
121
D
—CD 3
—CH 3
—CD 2 CH 3
122
D
—CD 3
—CH 3
—CH 2 CD 3
123
D
—CH 3
—CD 3
—CD 2 CD 3
124
D
—CH 3
—CD 3
—CD 2 CH 3
125
D
—CH 3
—CD 3
—CH 2 CD 3
126
H
—CD 3
—CD 3
—CD 2 CD 3
127
H
—CD 3
—CD 3
—CD 2 CH 3
128
H
—CD 3
—CD 3
—CH 2 CD 3
129
D
—CD 3
—CD 3
—CD 2 CD 3
130
D
—CD 3
—CD 3
—CD 2 CH 3
131
D
—CD 3
—CD 3
—CH 2 CD 3
or a pharmaceutically acceptable salt thereof.
8. The method of claim 5 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:
Compound
Y 2
R 1
R 2
R 3
200
H
—CH 3
—CH 3
—CH 2 CH 3
201
H
—CH 3
—CH 3
—CD 2 CD 3
202
H
—CH 3
—CH 3
—CD 2 CH 3
203
H
—CH 3
—CH 3
—CH 2 CD 3
204
H
—CD 3
—CH 3
—CH 2 CH 3
205
H
—CH 3
—CD 3
—CH 2 CH 3
206
D
—CH 3
—CH 3
—CH 2 CH 3
207
D
—CD 3
—CH 3
—CH 2 CH 3
208
D
—CH 3
—CD 3
—CH 2 CH 3
209
D
—CH 3
—CH 3
—CD 2 CD 3
210
D
—CH 3
—CH 3
—CD 2 CH 3
211
D
—CH 3
—CH 3
—CH 2 CD 3
212
H
—CD 3
—CD 3
—CH 2 CH 3
213
H
—CD 3
—CH 3
—CD 2 CD 3
214
H
—CD 3
—CH 3
—CD 2 CH 3
215
H
—CD 3
—CH 3
—CH 2 CD 3
216
H
—CH 3
—CD 3
—CD 2 CD 3
217
H
—CH 3
—CD 3
—CD 2 CH 3
218
H
—CH 3
—CD 3
—CH 2 CD 3
219
D
—CD 3
—CD 3
—CH 2 CH 3
220
D
—CD 3
—CH 3
—CD 2 CD 3
221
D
—CD 3
—CH 3
—CD 2 CH 3
222
D
—CD 3
—CH 3
—CH 2 CD 3
223
D
—CH 3
—CD 3
—CD 2 CD 3
224
D
—CH 3
—CD 3
—CD 2 CH 3
225
D
—CH 3
—CD 3
—CH 2 CD 3
226
H
—CD 3
—CD 3
—CD 2 CD 3
227
H
—CD 3
—CD 3
—CD 2 CH 3
228
H
—CD 3
—CD 3
—CH 2 CD 3
229
D
—CD 3
—CD 3
—CD 2 CD 3
230
D
—CD 3
—CD 3
—CD 2 CH 3
231
D
—CD 3
—CD 3
—CH 2 CD 3
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).
10. The method of claim 1 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).
11. The method of claim 7 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:
Compound
Y 2
R 1
R 2
R 3
101
H
—CH 3
—CH 3
—CD 2 CD 3
105
H
—CH 3
—CD 3
—CH 2 CH 3
108
D
—CH 3
—CD 3
—CH 2 CH 3
109
D
—CH 3
—CH 3
—CD 2 CD 3
112
H
—CD 3
—CD 3
—CH 2 CH 3
113
H
—CD 3
—CH 3
—CD 2 CD 3
116
H
—CH 3
—CD 3
—CD 2 CD 3
117
H
—CH 3
—CD 3
—CD 2 CH 3
118
H
—CH 3
—CD 3
—CH 2 CD 3
119
D
—CD 3
—CD 3
—CH 2 CH 3
120
D
—CD 3
—CH 3
—CD 2 CD 3
123
D
—CH 3
—CD 3
—CD 2 CD 3
124
D
—CH 3
—CD 3
—CD 2 CH 3
125
D
—CH 3
—CD 3
—CH 2 CD 3
126
H
—CD 3
—CD 3
—CD 2 CD 3
127
H
—CD 3
—CD 3
—CD 2 CH 3
128
H
—CD 3
—CD 3
—CH 2 CD 3
129
D
—CD 3
—CD 3
—CD 2 CD 3
130
D
—CD 3
—CD 3
—CD 2 CH 3
131
D
—CD 3
—CD 3
—CH 2 CD 3
or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).
12. The method of claim 8 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:
Compound
Y 2
R 1
R 2
R 3
201
H
—CH 3
—CH 3
—CD 2 CD 3
205
H
—CH 3
—CD 3
—CH 2 CH 3
208
D
—CH 3
—CD 3
—CH 2 CH 3
209
D
—CH 3
—CH 3
—CD 2 CD 3
212
H
—CD 3
—CD 3
—CH 2 CH 3
213
H
—CD 3
—CH 3
—CD 2 CD 3
216
H
—CH 3
—CD 3
—CD 2 CD 3
217
H
—CH 3
—CD 3
—CD 2 CH 3
218
H
—CH 3
—CD 3
—CH 2 CD 3
219
D
—CD 3
—CD 3
—CH 2 CH 3
220
D
—CD 3
—CH 3
—CD 2 CD 3
223
D
—CH 3
—CD 3
—CD 2 CD 3
224
D
—CH 3
—CD 3
—CD 2 CH 3
225
D
—CH 3
—CD 3
—CH 2 CD 3
226
H
—CD 3
—CD 3
—CD 2 CD 3
227
H
—CD 3
—CD 3
—CD 2 CH 3
228
H
—CD 3
—CD 3
—CH 2 CD 3
229
D
—CD 3
—CD 3
—CD 2 CD 3
230
D
—CD 3
—CD 3
—CD 2 CH 3
231
D
—CD 3
—CD 3
—CH 2 CD 3
or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).
13. The method of claim 11 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).
14. The method of claim 12 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).