Fatty acid cysteamine conjugates and their use as activators of autophagy

Abstract

The invention relates to fatty acid cysteamine conjugates, compositions comprising a fatty acid cysteamine conjugate, and methods for using such conjugates and compositions to treat disease, such as a disease caused by dysregulation of autophagy.

1 . A method of treating a disease selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis (IPF), a neurodegenerative disease, inflammatory disease, liver disease, muscle disease, infection, Duchenne's Muscular Dystrophy and immune disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I to treat the disease, wherein Formula I is represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; wherein: 
         R I-1 , R I-2 , R I-3 , R I-4 , R I-5 , and R I-6  each represent independently for each occurrence hydrogen or C 1 -C 3  alkyl; 
         Y I-1  a 6-membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, hydroxyl, alkoxyl, halogen, and acyl;
 n* and m* are independently 1, 2, or 3; 
 
         Z* is 
       
       
         
           
           
               
               
           
         
          wherein:
 R 1  and R 2  independently are hydrogen, C1-C4 alkyl, or halogen; 
 r is 2, 3, or 7; 
 s is 3, 5, or 6; 
 t is 0 or 1; and 
 v is 1, 2, or 6. 
 
       
     
     
         2 . The method of  claim 1 , wherein the disease is cystic fibrosis. 
     
     
         3 . The method of  claim 1 , wherein the disease is idiopathic pulmonary fibrosis (IPF) 
     
     
         4 . The method of  claim 1 , wherein the disease is Duchenne's Muscular Dystrophy. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the subject is a human. 
     
     
         7 . A method of activating autophagy in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I-A to activate autophagy in the subject, wherein Formula I-A is represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; wherein: 
         R I-1 , R I-2 , R I-3 , R I-4 , R I-5 , and R I-6  each represent independently for each occurrence hydrogen or C 1 -C 3  alkyl; 
         Y I-1  is a 6-membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, hydroxyl, alkoxyl, halogen, and acyl;
 n* and m* are independently 2 or 3; 
 
         Z* is 
       
       
         
           
           
               
               
           
         
          wherein:
 R 1  and R 2  independently are hydrogen, C1-C4 alkyl, or halogen; 
 r is 2, 3, or 7; 
 s is 3, 5, or 6; 
 t is 0 or 1; and 
 v is 1, 2, or 6; 
 
         provided that, when Z is 
       
       
         
           
           
               
               
           
         
       
       then at least one of R I-1 , R I-2 , R I-3 , R I-4 , R I-5 , or R I-6  is C 1 -C 3  alkyl, at least one of n* or m* is 1 or 3, or Y I-1  is other than 3-pyridinyl. 
     
     
         8 . The method of  claim 7 , wherein the administering increases the ratio of light chain 3-II (LC3-II) to light chain 3-I (LC3-I) in the subject by at least 10%. 
     
     
         9 . The method of  claim 7 , wherein the administering decreases the amount of p62 protein in the subject by at least 1% w/w. 
     
     
         10 . The method of  claim 7 , wherein the subject has been diagnosed as having cystic fibrosis or idiopathic pulmonary fibrosis or Duchenne's Muscular Dystrophy. 
     
     
         11 . The method of  claim 7 , wherein the subject is a human. 
     
     
         12 . The method of  claim 1 , wherein the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 7 , wherein the compound is a compound of Formula I-A or a pharmaceutically acceptable salt thereof. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein n* is 2. 
     
     
         17 . The method of  claim 1 , wherein m* is 2. 
     
     
         18 . The method of  claim 1 , wherein Y I-1  is a 6-membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, hydroxyl, and alkoxyl. 
     
     
         19 . The method of  claim 1 , wherein Y I-1  is pyridinyl or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, hydroxyl, and alkoxyl. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein Y I-1  is 
       
         
           
           
               
               
           
         
       
       optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, hydroxyl, and alkoxyl. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein Z* is 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are hydrogen or methyl. 
     
     
         25 . (canceled) 
     
     
         26 . The method  claim 1 , wherein Z* is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 1 , wherein at least one pair of R I-2  and R I-3  bonded to the same carbon atom independently are C 1 -C 3  alkyl. 
     
     
         28 . The method of  claim 27 , wherein each C 1 -C 3  alkyl is a methyl. 
     
     
         29 . The method of  claim 1 , wherein at least one pair of R I-4  and R I-5  bonded to the same carbon atom independently are C 1 -C 3  alkyl. 
     
     
         30 . The method of  claim 29 , wherein each C 1 -C 3  alkyl is a methyl. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . The method of  claim 27 , wherein R I-1  and R I-6  are hydrogen, and Y I-1  is 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method of treating a disease selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis (IPF), a neurodegenerative disease, inflammatory disease, liver disease, muscle disease, infection, Duchenne's Muscular Dystrophy and immune disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III to treat the disease, wherein Formula III is represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; wherein 
         W 1  and W 2  independently is NR; 
         each R is independently H, —C 1 -C 3  alkyl, phenyl, benzyl, —CH 2 CO 2 R 3 , —CH 2 CONR 3 R 3  or straight or branched C 1 -C 4  alkyl optionally substituted with OH or halogen; 
         R 5  independently is selected from the group consisting of —H, -D, —Cl, —F, —CN, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —C(O)H, —C(O)C 1 -C 3  alkyl, —C(O)OC 1 -C 3  alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 3  alkyl), —C(O)N(C 1 -C 3  alkyl) 2 , —C 1 -C 3  alkyl, —O—C 1 -C 3  alkyl, —S(O)C 1 -C 3  alkyl and —S(O) 2 C 1 -C 3  alkyl; 
         each a, b, c, and d independently is H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
         each n, o, p, and q is independently 0 or 1; 
         each Z independently is 
       
       
         
           
           
               
               
           
         
         each r independently is 2, 3, or 7; 
         each s independently is 3, 5, or 6; 
         each t independently is 0 or 1; 
         each v independently is 1, 2, or 6; 
         R 1  and R 2  independently are each H, D, —C 1 -C 4  alkyl, -halogen, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 2 -C 3  alkenyl, —C 2 -C 3  alkynyl, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each R 3  is independently H or C 1 -C 6  alkyl, or two R 3  groups, when taken together with the nitrogen to which they are attached, can form a heterocycle. 
       
     
     
         36 . The method of  claim 35 , wherein the disease is cystic fibrosis. 
     
     
         37 . The method of  claim 35 , wherein the disease is idiopathic pulmonary fibrosis (IPF) 
     
     
         38 . The method of  claim 35 , wherein the disease is Duchenne's Muscular Dystrophy. 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 35 , wherein the subject is a human. 
     
     
         41 . The method of  claim 35 , wherein at least one pair of a and a, b and b, c and c, d and d, when bonded to the same carbon atom is a C 1 -C 3  alkyl. 
     
     
         42 . The method of  claim 41 , wherein the C 1 -C 3  alkyl is a methyl. 
     
     
         43 . The method of  claim 1 , wherein the compound is one of the following or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         44 - 45 . (canceled) 
     
     
         46 . The method of  claim 1 , wherein the compound is the following or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         47 . The method of  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         48 - 83 . (canceled) 
     
     
         84 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         85 . The method of  claim 7 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         86 . The method of  claim 35 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         87 . The method of  claim 35 , wherein the compound is