Compositions and Methods of Using the Same for Treatment of Neurodegenerative and Mitochondrial Disease

Abstract

The disclosure is directed to compounds and pharmaceutically acceptable salts thereof for the treatment and/or prevention of neurodegenerative and/or mitochondrial diseases, such as Parkinson's disease and Leigh's disease. The compounds and pharmaceutically acceptable salts thereof are of the class of nitrogenous bases, for example, pyrimidines, purines, pteridines, and pharmaceutically acceptable salts thereof.

1 - 27 . (canceled) 
     
     
         28 . A method of treating cardiomyopathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein X is selected from C—H, C—CH 3 , C—CH 2 CH 3 , C—CH 2 CH 2 CH 3 , and CR 3 ; 
         wherein R 3  is selected from a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; 
         wherein L 1  is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 
         wherein R 1  is hydrogen, oxo, halogen, —CY 3 , —CN, —SO 2 C1, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O)m, —NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —N(R 7 )C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 COR 9 , —OCY 3 , —OCHY 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         wherein R 2  is N; 
         wherein R 4  is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         wherein R 5  is CH, CCH 3 , CCF 3 , or CC 6 H 5 ; and 
         wherein R 6  is N, CH, CD, or C-L 1 -R 6 ;
 wherein R 6′  is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 C1, —SO 3 H, —SO 4 H, —SO 2 NH 2 , SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —N(R 7 )C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCY 3 , —OCHY 2 , —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 wherein R 7 , R 8 , R 9 , and R 10  are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 C1, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 wherein m and v are independently 1 or 2; and 
 wherein n is independently an integer from 0 to 4, and Y is independently —Cl, —Br, —I, or —F, 
 
         or a pharmaceutically acceptable salt thereof, provided that the compound is not kinetin or cytokinin, thereby treating cardiomyopathy in the subject. 
       
     
     
         29 . The method of  claim 28 , wherein X is C—H or C—CH 3 . 
     
     
         30 . The method of  claim 28 , wherein L 1  is N—H. 
     
     
         31 . The method of  claim 28 , wherein L 1  is N—H, R 2  is N; R 4  is hydrogen, R 6  is N; and wherein R 1  is a substituted or unsubstituted alkyl group or heteroalkyl group. 
     
     
         32 . The method of  claim 28 , wherein L 1  is N—H, R 2  is N; R 4  is hydrogen, R 6  is N; and wherein R 1  is a substituted carbon, propyl, butyl, propylene, or butylene group. 
     
     
         33 . The method of  claim 28 , wherein R 1  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         34 . The method of  claim 28 , wherein R 1  is the substituted or unsubstituted heteroaryl. 
     
     
         35 . The method of  claim 28 , wherein R 1  is the substituted or unsubstituted alkyl, and wherein the substituted or unsubstituted alkyl is a substituted or unsubstituted alkenyl. 
     
     
         36 . The method of  claim 28 , wherein R 4  is hydrogen. 
     
     
         37 . The method of  claim 28 , wherein R 5  is CH, CCH 3 , or CC 6 H 5 . 
     
     
         38 . The method of  claim 28 , wherein R 5  is CCF 3 . 
     
     
         39 . The method of  claim 28 , wherein R 6  is N. 
     
     
         40 . The method of  claim 28 , wherein X is C—H or C—CH 3 , wherein R 4  is hydrogen, and wherein R 6  is N. 
     
     
         41 . The method of  claim 28 , wherein X is CR 3 , wherein R 3  is selected from the group consisting of hydrogen, CH 3 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted 2,5-dihydrofuranyl, substituted or unsubstituted tetrahydrothienyl, substituted or unsubstituted 2,5-dihydrothienyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 2,5-dihydro-1H-pyrrolyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclopentenyl, or substituted or unsubstituted 1,3-oxathiolanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted 2,5-dihydrofuranyl, substituted or unsubstituted tetrahydrothienyl, substituted or unsubstituted 2,5-dihydrothienyl, unsubstituted pyrrolidinyl, substituted or unsubstituted 2,5-dihydro-1H-pyrrolyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclopentenyl, and substituted or unsubstituted 1,3-oxathiolanyl; and wherein L 1  is a bond or an amine. 
     
     
         42 . The method of  claim 28 , wherein R 1  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein R 6  is N. 
     
     
         43 . The method of  claim 28 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The method of  claim 28 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         45 . The method of  claim 28 , wherein the compound has a structure represented by a formula selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         46 . The method of  claim 28 , wherein the effective amount is a therapeutically effective amount. 
     
     
         47 . The method of  claim 28 , wherein the effective amount is a prophylactically effective amount.