Substituted triazolo-pyridazine derivatives
This invention relates to novel substituted triazolo-pyridazines 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 α1-GABA A receptor antagonist or an α2- and/or an α3-GABA A receptor partial agonist.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —CH 3 , or —CH 2 CH 3 , wherein R 1 is optionally substituted with deuterium;
R 2 is —CZ(R 3 ) 2 ;
Z is —OH or —CH 3 , wherein the —CH 3 of Z is optionally substituted with deuterium;
each R 3 is —CH 3 wherein each R 3 is optionally substituted with deuterium;
each Y 1 is independently hydrogen or deuterium; and
Y 2 is hydrogen or deuterium;
with the proviso that when R 1 is unsubstituted —CH 3 or unsubstituted —CH 2 CH 3 Z is unsubstituted —CH 3 ; and R 2 is not substituted with deuterium; then at least one of Y 1 and Y 2 is deuterium.
2. The compound of claim 1 , wherein R 1 is —CH 3 , —CD 3 , —CH 2 CH 3 , CD 2 CH 3 , —CH 2 CD 3 , or —CD 2 CD 3 .
3. The compound of claim 2 , wherein R 1 is —CH 2 CH 3 , —CD 2 CH 3 , —CH 2 CD 3 , or —CD 2 CD 3 .
4. The compound of claim 1 , wherein Y 1a and Y 1b are hydrogen.
5. The compound of claim 1 , wherein Y 1a and Y 1b are deuterium.
6. The compound of claim 1 wherein Y 2 is hydrogen.
7. The compound of claim 1 wherein —CZ(R 3 ) 2 is —C(CH 3 ) 3 or —C(CD 3 ) 3 .
8. The compound of claim 7 , wherein —CZ(R 3 ) 2 is —C(CD 3 ) 3 .
9. The compound of claim 1 wherein —CZ(R 3 ) 2 is —C(CD 3 ) 2 OH.
10. The compound of claim 1 wherein —CZ(R 3 ) 2 is —C(CH 3 ) 2 OH.
11. The compound of claim 2 , wherein Y 1a and Y 1b are the same; Y 2 is hydrogen; and —CZ(R 3 ) 2 is —C(CH 3 ) 3 or —C(CD 3 ) 3 .
12. The compound of claim 1 wherein Y 2 is hydrogen; —CZ(R 3 ) 2 is —C(CD 3 ) 3 ; and the compound is selected from any one of the compounds set forth in the table below
Compound
R 1
Y 1a
Y 1b
101
CH 2 CH 3
D
D
102
CH 2 CH 3
H
H
103
CH 2 CD 3
H
H
104
CH 2 CD 3
D
D
105
CD 2 CD 3
H
H
106
CD 2 CD 3
D
D
107
CD 2 CH 3
H
H
108
CD 2 CH 3
D
D
or a pharmaceutically acceptable salt of any of the foregoing.
13. The compound of claim 1 wherein Y 2 is hydrogen; —CZ(R 3 ) 2 is
and the compound is selected from any one of the compounds set forth in the table below
Compound
R 1
R 3
Y 1a
Y 1b
201
CH 2 CH 3
CD 3
D
D
202
CH 2 CH 3
CD 3
H
H
203
CH 2 CD 3
CD 3
H
H
204
CH 2 CD 3
CD 3
D
D
205
CD 2 CD 3
CD 3
H
H
206
CD 2 CD 3
CD 3
D
D
207
CD 2 CH 3
CD 3
H
H
208
CD 2 CH 3
CD 3
D
D
209
CH 2 CH 3
CH 3
D
D
210
CH 2 CH 3
CH 3
H
H
211
CH 2 CD 3
CH 3
H
H
212
CH 2 CD 3
CH 3
D
D
213
CD 2 CD 3
CH 3
H
H
214
CD 2 CD 3
CH 3
D
D
215
CD 2 CH 3
CH 3
H
H
216
CD 2 CH 3
CH 3
D
D
or a pharmaceutically acceptable salt of any of the foregoing.
14. A compound of claim 1 selected from 109 and 110:
or a pharmaceutically acceptable salt of the foregoing.
15. The compound of claim 1 wherein any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
16. A pyrogen-free pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.