Substituted purines for the treatment of neurodegenerative and mitochondrial diseases
The present disclosure is directed, in part, to substituted purines, or pharmaceutically acceptable salts thereof, represented by formula (VIII): for the treatment and/or prevention of neurodegenerative disease, mitochondrial disease, fibrosis, and/or cardiomyopathy.
1. A compound represented by formula VIII:
or a pharmaceutically acceptable salt thereof,
wherein:
L 1 is —NHCH 2 —, wherein —NH— is attached to the purine ring and —CH 2 — is attached to R 1 ;
R 1 is CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH═CHCH 3 , or C(CH 3 )═CH 2 ;
R 2 is N;
R 3 is C 1-8 alkyl;
R 4 is H;
R 5 is C 1-8 alkyl;
R 6 is N; and
R 7 is N.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is C 1-4 alkyl; and
R 5 is C 1-4 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ; and
R 5 is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 .
4. The compound of claim 1 , wherein the compound is represented by formula X:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is CH 2 CH 2 CH 3 , CH═CHCH 3 , or C(CH 3 )═CH 2 ;
R 3 is CH 3 ; and
R 5 is CH 3 .
6. The compound of claim 1 , wherein the compound is formula Villa or formula VIIIb:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8. A method for modulating PTEN induced kinase 1 activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the subject has a disease selected from the group consisting of cardiomyopathy, fibrosis, a mitochondrial disease, and a neurodegenerative disease.
10. The method of claim 9 , wherein the subject has cardiomyopathy.
11. The method of claim 9 , wherein the subject has fibrosis.
12. The method of claim 9 , wherein the subject has a mitochondrial disease.
13. The method of claim 9 , wherein the subject has a neurodegenerative disease.
14. The method of claim 13 , wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease.
15. The method of claim 8 , wherein the compound is formula Villa or formula VIIIb:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 9 , wherein the compound is formula Villa or formula VIIIb:
or a pharmaceutically acceptable salt thereof.