Deuterated OTX-015
This invention relates to novel thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines, 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 an inhibitor of binding between an acetylated histone and a bromodomain-containing protein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein R 1 and R 2 are each CD 3 and R 3 is CH 3 ; or
R 2 and R 3 are each CD 3 and R 1 is CH 3 ; or
R 1 , R 2 , and R 3 are each CD 3 ; and
each of Y 1 , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , and Y 6b is independently selected from hydrogen and deuterium;
wherein each position designated specifically as deuterium has at least 50.1% incorporation of deuterium.
2. The compound of claim 1 , wherein Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; and Y 6a and Y 6b are the same.
3. The compound of claim 2 , wherein R 1 , R 2 , and R 3 are each CD 3 .
4. The compound of claim 2 , wherein R 2 and R 3 are each CD 3 and R 1 is CH 3 .
5. The compound of claim 2 , wherein R 1 and R 2 are each CD 3 and R 3 is CH 3 .
6. The compound of claim 2 , wherein Y 1 is deuterium.
7. The compound of claim 2 , wherein Y 1 is hydrogen.
8. The compound of claim 2 , wherein Y 2a and Y 2b are each deuterium.
9. The compound of claim 2 , wherein Y 2a and Y 2b are each hydrogen.
10. The compound of claim 2 , wherein Y 3a , Y 3b , Y 4a , and Y 4b are each hydrogen.
11. The compound of claim 2 , wherein Y 5a , Y 5b , Y 6a , and Y 6b are each hydrogen.
12. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. The compound of claim 2 , wherein the compound is selected from any one of the compounds (Cmpd) set forth in table below:
Y 3a /
Y 4a /
Y 5a /
Y 6a /
Cmpd
R 1
R 2
R 3
Y 1
Y 2a /Y 2b
Y 3b
Y 4b
Y 5b
Y 6b
201
CD 3
CD 3
CD 3
D
D
D
D
D
D
202
CD 3
CD 3
CD 3
H
D
D
D
D
D
203
CD 3
CD 3
CD 3
D
H
D
D
D
D
204
CD 3
CD 3
CD 3
H
H
D
D
D
D
205
CD 3
CD 3
CD 3
D
D
H
D
D
D
206
CD 3
CD 3
CD 3
D
D
D
D
H
D
207
CD 3
CD 3
CD 3
D
D
H
H
D
D
208
CD 3
CD 3
CD 3
D
D
D
D
H
H
209
CD 3
CD 3
CD 3
D
D
H
H
H
H
210
CD 3
CD 3
CD 3
H
H
H
H
H
H
221
CH 3
CD 3
CD 3
D
D
D
D
D
D
222
CH 3
CD 3
CD 3
H
D
D
D
D
D
223
CH 3
CD 3
CD 3
D
H
D
D
D
D
224
CH 3
CD 3
CD 3
H
H
D
D
D
D
225
CH 3
CD 3
CD 3
D
D
H
D
D
D
226
CH 3
CD 3
CD 3
D
D
D
D
H
D
227
CH 3
CD 3
CD 3
D
D
H
H
D
D
228
CH 3
CD 3
CD 3
D
D
D
D
H
H
229
CH 3
CD 3
CD 3
D
D
H
H
H
H
230
CH 3
CD 3
CD 3
H
H
H
H
H
H
251
CD 3
CD 3
CH 3
D
D
D
D
D
D
252
CD 3
CD 3
CH 3
H
D
D
D
D
D
253
CD 3
CD 3
CH 3
D
H
D
D
D
D
254
CD 3
CD 3
CH 3
H
H
D
D
D
D
255
CD 3
CD 3
CH 3
D
D
H
D
D
D
256
CD 3
CD 3
CH 3
D
D
D
D
H
D
257
CD 3
CD 3
CH 3
D
D
H
H
D
D
258
CD 3
CD 3
CH 3
D
D
D
D
H
H
259
CD 3
CD 3
CH 3
D
D
H
H
H
H
260
CD 3
CD 3
CH 3
H
H
H
H
H
H,
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method of inhibiting binding between an acetylated histone and a bromodomain-containing protein in a cell, comprising contacting the cell with a compound of claim 1 or a composition of claim 14 .
16. A method of treating a disease or condition selected from recurrent glioblastoma multiforme (GBM), hematological malignancies, acute leukemia, acute myeloid leukemia (AML), non-small cell lung cancer with rearranged ALK gene/fusion protein or KRAS Mutation, castrate-resistant prostate cancer (CRPC), and pancreatic ductal adenocarcinoma, comprising the step of administering to a subject in need thereof a compound of claim 1 or a composition of claim 14 .
17. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 90% incorporation of deuterium.
18. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 95% incorporation of deuterium.
19. The compound of claim 1 , wherein each position designated specifically as deuterium has at least 97% incorporation of deuterium.
20. The compound of claim 1 , wherein
R 1 and R 2 are each CD 3 and R 3 is CH 3;
Y 1 is deuterium; and
each of Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , and Y 6b is hydrogen,
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
22. The compound of claim 20 , wherein each position designated specifically as deuterium has at least 90% incorporation of deuterium.
23. The compound of claim 20 , wherein each position designated specifically as deuterium has at least 95% incorporation of deuterium.
24. The compound of claim 20 , wherein each position designated specifically as deuterium has at least 97% incorporation of deuterium.