DEUTERATED CFTR POTENTIATORS
This invention relates to compounds of Formula I: 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 a CFTR potentiator.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is independently hydrogen or deuterium;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is independently CH 3 or CD 3 ;
provided that if each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is CH 3 , then at least one of X′, X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is deuterium.
2 . The compound of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are the same.
3 . The compound of claim 2 , wherein X 6 and X 7 are the same.
4 . The compound of claim 2 , wherein Y 1 , Y 2 , and Y 3 are the same.
5 . The compound of claim 2 , wherein Y 4 , Y 5 , and Y 6 are the same.
6 . The compound of claim 2 , wherein X 6 and X 7 are the same.
7 . The compound of claim 1 , wherein X 5 is deuterium.
8 . The compound claim 1 , wherein at least one of C(Y 1 )(Y 2 )(Y 3 ) and C(Y 4 )(Y 5 )(Y 6 ) is C(CD 3 ) 3 .
9 . The compound of claim 1 , wherein Y 1 , Y 2 , and Y 3 are CD 3 .
10 . The compound of claim 1 , wherein Y 4 , Y 5 , and Y 6 are CD 3 .
11 . 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.
12 . The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
100
D
D
D
D
D
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
101
H
H
H
H
D
H
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
102
H
H
H
H
D
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
103
H
H
H
H
D
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
104
H
H
H
H
D
H
H
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
105
H
H
H
H
H
H
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
106
H
H
H
H
H
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
107
H
H
H
H
H
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13 . The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
110
H
H
H
H
H
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
111
H
H
H
H
D
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
112
H
H
H
H
D
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
113
H
H
H
H
D
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
114
H
H
H
H
D
D
D
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
115
H
H
H
H
H
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
116
H
H
H
H
H
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
117
D
D
D
D
D
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
118
D
D
D
D
D
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
119
D
D
D
D
D
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
120
D
D
D
D
D
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
121
H
H
H
H
H
H
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
122
H
H
H
H
H
H
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
123
H
H
H
H
H
H
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
14 . The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
124
H
H
H
H
H
D
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
125
H
H
H
H
H
D
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
126
H
H
H
H
H
D
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
15 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
16 . A method of treating cystic fibrosis in a subject comprising administering to the subject the compound of claim 1 .
17 . A method of treating COPD or Parkinson's disease in a subject comprising administering to the subject the compound of claim 1 .
18 . A method of treating a bile duct disorder or a kidney ion channel disorder in a subject comprising administering to the subject the compound of claim 1 .
19 . The method of claim 18 , wherein the kidney ion channel disorder is Bartter's syndrome or Dent's disease.