Methods for treating polycystic kidney disease and polycystic liver disease

Abstract

The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and/or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and/or killing a cyst cell.

1 - 36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising:
 a compound of Formula (I) or (II):   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and
 optionally a pharmaceutically acceptable excipient, wherein: 
 Ring A is substituted or unsubstituted phenyl or naphthyl, or substituted or unsubstituted, monocyclic or bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur; 
 each instance of R A  is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —SCN, —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )N(R A1 ) 2 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or optionally two R A  groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; 
 each instance of R A1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or optionally two R A1  groups are joined to form a substituted or unsubstituted heterocyclic ring; 
 k is 0, 1, 2, 3, 4, or 5; 
 L is a linker stable under intracellular conditions; 
 one instance of   is a double bond; 
 the other instance of   is a single or double bond; 
 each instance of R B  is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR B1 , —N(R B1 ) 2 , —SR B1 , —CN, —SCN, —C(═NR B1 )R B1 , —C(═NR B1 )OR B1 , —C(═NR B1 )N(R B1 ) 2 , —C(═O)R B1 , —C(═O)OR B1 , —C(═O)N(R B1 ) 2 , —NO 2 , —NR B1 C(═O)R B1 , —NR B1 C(═O)OR B1 , —NR B1 C(═O)N(R B1 ) 2 , —OC(═O)R B1 , —OC(═O)OR B1 , —OC(═O)N(R B1 ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or optionally two R B  groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; 
 each instance of R B1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or optionally two R B1  groups are joined to form a substituted or unsubstituted heterocyclic ring; 
 each instance of R C , R D , and R E  is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR  C1 , —N(R C1 ) 2 , —SR  C1 , —CN, —SCN, —C(═NR C1 )R C1 , —C(═NR C1 )OR C1 , —C(═NR C1 )N(R C1 ) 2 , —C(═O)R C1 , —C(═O)OR C1 , —C(═O)N(R C1 ) 2 , —NO 2 , —NR C1 C(═O)R C1 , —NR C1 C(═O)OR C1 , —NR C1 C(═O)N(R C1 ) 2 , —OC(═O)R C1 , —OC(═O)OR C1 , —OC(═O)N(R C1 ) 2 , or a nitrogen protecting group when attached to a nitrogen atom; 
 each instance of R C1  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or optionally two R C1  groups are joined to form a substituted or unsubstituted heterocyclic ring; 
 optionally R C  and R D  are joined to form a substituted or unsubstituted, monocyclic carbocyclic ring; and 
 optionally R D  and R E  are joined to form a substituted or unsubstituted, monocyclic or bicyclic carbocyclic ring; 
 provided the compound is not a compound of the formula: 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each instance of R A1  is independently unsubstituted C 1-6  alkyl or C 1-6  alkyl substituted with one or more substituents independently selected from the group consisting of halogen and —O(unsubstituted C 1-6  alkyl); 
 L 1 , L 3 , and L 5  are independently an unsubstituted C 1-8  hydrocarbon chain or a C 1-8  hydrocarbon chain substituted with one or more substituents independently selected from the group consisting of halogen and O(unsubstituted C 1-6  alkyl); 
 L 2  and L 4  are independently —NR L —, —NR L C(═O)O—, or —OC(═O)NR L —; and 
 each instance of R L  is independently hydrogen, unsubstituted C 1-6  alkyl, or C 1-6  alkyl substituted with one or more substituents independently selected from the group consisting of halogen and O(unsubstituted C 1-6  alkyl). 
 
     
     
         44 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The pharmaceutical composition of  claim 37 , wherein Ring A is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein each instance of R A1  is independently substituted or unsubstituted C 1-6  alkyl. 
     
     
         50 . The pharmaceutical composition of  claim 37 , wherein at least one R A  is —N(R A1 ) 2 , wherein each instance of R A1  is independently unsubstituted C 1-6  alkyl or substituted C 1-6  alkyl substituted with one or more substituents independently selected from the group consisting of halogen and —O(unsubstituted C 1-6  alkyl). 
     
     
         51 . The pharmaceutical composition of  claim 37 , wherein the molecular weight of L is less than 300. 
     
     
         52 . The pharmaceutical composition of  claim 37 , wherein L is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 L 1 , L 3 , and L 5  are independently an unsubstituted C 1-8  hydrocarbon chain or a C 1-8  hydrocarbon chain substituted with one or more substituents independently selected from the group consisting of halogen and O(unsubstituted C 1-6  alkyl); 
 L 2  and L 4  are independently —NR L —, —NR L C(═O)O—, or —OC(═O)NR L —; and 
 each instance of R L  is independently hydrogen, unsubstituted C 1-6  alkyl, or C 1-6  alkyl substituted with one or more substituents independently selected from the group consisting of halogen and —O(unsubstituted C 1-6  alkyl). 
 
     
     
         53 . The pharmaceutical composition of  claim 37 , wherein R C  and R D  are joined to form a substituted or unsubstituted, 6-membered, monocyclic carbocyclic ring. 
     
     
         54 . The pharmaceutical composition of  claim 37 , wherein R D  and R E  are joined to form a substituted or unsubstituted, 6-membered, monocyclic carbocyclic ring. 
     
     
         55 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         56 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.