Derivatives of pyrazole-substituted amino-heteroaryl compounds
This invention relates to novel pyrazole-substituted amino-heteroaryl 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 an inhibitor of anaplastic lymphoma kinase (ALK).
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each Cl;
R 3 is CH 3 or CD 3 ;
X 1a , X 1b , X 2a and X 2b are the same and are hydrogen or deuterium;
X 3a , X 3b , X 4a and X 4b are the same and are hydrogen or deuterium;
X 5 is hydrogen or deuterium;
Y 1 is hydrogen or deuterium; and
Y 2 is hydrogen or deuterium;
provided that X 1a , X 1b , X 2a and X 2b are each deuterium, or X 3a , X 3b , X 4a and X 4b are each deuterium, or X 1a , X 1b , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b are each deuterium.
2. The compound of claim 1 , wherein each X 1 , each X 2 , each X 3 and each X 4 is deuterium.
3. The compound of claim 1 , wherein each X 1 and each X 2 are hydrogen; and each X 3 and each X 4 are deuterium.
4. The compound of claim 1 , wherein each X 1 and each X 2 are deuterium; and each X 3 and each X 4 are hydrogen.
5. The compound of claim 1 wherein:
X 5 is hydrogen, Y 1 is hydrogen and Y 2 is hydrogen; or
X 5 is hydrogen, Y 1 is deuterium and Y 2 is hydrogen; or
X 5 is hydrogen, Y 1 is hydrogen and Y 2 is deuterium; or
X 5 is hydrogen, Y 1 is deuterium and Y 2 is deuterium; or
X 5 is deuterium, Y 1 is hydrogen and Y 2 is hydrogen; or
X 5 is deuterium, Y 1 is deuterium and Y 2 is hydrogen; or
X 5 is deuterium, Y 1 is hydrogen and Y 2 is deuterium; or
X 5 is deuterium, Y 1 is deuterium and Y 2 is deuterium.
6. The compound of claim 5 wherein R 3 is CH 3 .
7. The compound of claim 5 wherein R 3 is CD 3 .
8. The compound of claim 1 selected from any one of the compounds in the table below:
X 1a /
X 2a /
X 3a /
X 4a /
Cmpd
X 1b
X 2b
X 3b
X 4b
X 5
Y 1
Y 2
R 1 and R 2
R 3
100
D
D
D
D
D
D
D
Cl
CD 3
101
D
D
D
D
D
H
D
Cl
CD 3
102
D
D
D
D
H
D
H
Cl
CH 3
103
D
D
H
H
D
H
D
Cl
CD 3
104
D
D
H
H
D
H
H
Cl
CH 3
105
D
D
H
H
D
D
H
Cl
CH 3
106
D
D
H
H
H
D
H
Cl
CH 3
107
D
D
H
H
H
D
D
Cl
CD 3
108
H
H
D
D
D
D
H
Cl
CD 3
109
H
H
D
D
D
H
H
Cl
CH 3
110
H
H
D
D
D
H
D
Cl
CD 3
111
H
H
D
D
D
D
H
Cl
CH 3
wherein any atom not designated as deuterium is present at its natural isotopic abundance, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 selected from any one of the compounds in the table below:
X 1a /
X 2a /
X 3a /
X 4a /
Cmpd
X 1b
X 2b
X 3b
X 4b
X 5
Y 1
Y 2
R 1
R 2
R 3
200
D
D
D
D
D
H
H
Cl
Cl
CD 3
201
D
D
D
D
D
H
D
Cl
Cl
CH 3
wherein any atom not designated as deuterium is present at its natural isotopic abundance, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 selected from any one of the compounds in the table below:
X 1a /
X 2a /
X 3a /
X 4a /
Cmpd
X 1b
X 2b
X 3b
X 4b
X 5
Y 1
Y 2
R 1
R 2
R 3
210
D
D
D
D
H
H
H
Cl
Cl
CH 3
211
H
H
D
D
H
H
H
Cl
Cl
CH 3
212
D
D
H
H
H
H
H
Cl
Cl
CH 3
213
D
D
D
D
H
H
H
Cl
Cl
CD 3
214
H
H
D
D
H
H
H
Cl
Cl
CD 3
215
D
D
H
H
H
H
H
Cl
Cl
CD 3
216
D
D
D
D
H
H
D
Cl
Cl
CD 3
217
H
H
D
D
H
H
D
Cl
Cl
CD 3
218
D
D
H
H
H
H
D
Cl
Cl
CD 3
219
D
D
D
D
D
H
H
Cl
Cl
CH 3
220
H
H
D
D
D
H
H
Cl
Cl
CD 3
221
D
D
H
H
D
H
H
Cl
Cl
CD 3
wherein any atom not designated as deuterium is present at its natural isotopic abundance, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 wherein any atom not designated as deuterium is present at its natural isotopic abundance.
12. A pyrogen-free pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.