Quinolines that modulate serca and their use for treating disease

Abstract

Provided herein are compounds of Formula I, pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of a neurological disease, neurodegenerative disorder, or diabetes.

What is claimed: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each as defined herein.
 R 1  is (a) hydrogen or (b) C 1-3  alkyl; 
 R 2  is phenyl, 2-thienyl, 2-furyl, 2-benzothienyl, or 2-benzofuryl, wherein R 2  is optionally substituted with one to two substituents independently selected from halo, cyano, —O—(C 1 -C 4  alkyl or haloalkyl), C 1 -C 4  alkyl or haloalkyl, —N(CH 3 ) 2 , and —NH—(C 1 -C 4  alkyl) with the exception of F and NO 2 ; 
 R 3  is CH 3  or H; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  are each independently (a) hydrogen, cyano, or halo; (b) C 1-4  alkyl, —O—(C 1 -C 4  alkyl), or —N(CH 3 ) 2 . 
 
     
     
         2 . The compound according to  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A method for treating Alzheimer's or Parkinson's disease in a subject comprising administering to the subject an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each as defined herein.
 R 1  is (a) hydrogen or (b) C 1-3  alkyl; 
 R 2  is phenyl, 2-thienyl, 2-furyl, 2-benzothienyl, or 2-benzofuryl, wherein R 2  is optionally substituted with one to two substituents independently selected from halo, cyano, —O—(C 1 -C 4  alkyl or haloalkyl), C 1 -C 4  alkyl or haloalkyl, —N(CH 3 ) 2 , and —NH—(C 1 -C 4  alkyl) with the exception of F and NO 2 ; 
 R 3  is CH 3  or H; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  are each independently (a) hydrogen, cyano, or halo; (b) C 1-4  alkyl, —O—(C 1 -C 4  alkyl), or —N(CH 3 ) 2 . 
 
     
     
         4 . The compound according to  claim 3  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A method for treating one or more symptoms of diabetes in a subject in need thereof comprising administering to the subject an effective amount of A compound of Formula I 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are each as defined herein.
 R 1  is (a) hydrogen or (b) C 1-3  alkyl; 
 R 2  is phenyl, 2-thienyl, 2-furyl, 2-benzothienyl, or 2-benzofuryl, wherein R 2  is optionally substituted with one to two substituents independently selected from halo, cyano, —O—(C 1 -C 4  alkyl or haloalkyl), C 1 -C 4  alkyl or haloalkyl, —N(CH 3 ) 2 , and —NH—(C 1 -C 4  alkyl) with the exception of F and NO 2 ; 
 R 3  is CH 3  or H; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  are each independently (a) hydrogen, cyano, or halo; (b) C 1-4  alkyl, —O—(C 1 -C 4  alkyl), or —N(CH 3 ) 2 . 
 
     
     
         6 . The compound according to  claim 5  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 5  wherein the diabetes is type 1. 
     
     
         8 . The method of  claim 5  wherein the diabetes is type 2.