Substrate selective inhibitors of insulin-degrading enzyme (ide) and uses thereof

Abstract

Provided herein are compounds of Formulae (RL), (I), (II), (HI), (IV), and (V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and isotopically labeled derivatives thereof. Also provided are pharmaceutical compositions, kits, and methods involving the inventive compounds for the treatment of metabolic disorders (e.g., diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, obesity). The compound are useful as substrate selective inhibitors of insulin-degrading enzyme (IDE).

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof, 
         wherein:
 G 1  is of formula: 
 
       
       
         
           
           
               
               
           
         
         
           Ring A is carbocyclylene, heterocyclylene, arylene, or heteroarylene; 
           R 1  is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —CH 2 -halo, —CH 2 OR 1a , —CH 2 SR 1a , or —CH 2 N(R 1a ) 2 , wherein each R 1a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, or an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 1a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring 
           R 2  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —OR 2a , —N(R 2a ) 2 , wherein each R 2a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 2a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
           each R 3  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 3a , —N(R 3a ) 2 , wherein each R 3a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 3a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
           each R 4  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —OR 4a , or —N(R 4a ) 2 , wherein each R 4a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 4a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
         
         R 5  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —C(═O)R 5a , —C(═O)OR 5a , —C(═O)N(R 5a ) 2 , —S(═O) 2 R 5a , —S(═O) 2 OR 5a , —S(═O) 2 N(R 5a ) 2 , or a nitrogen protecting group, wherein each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 5a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring;
 m is 0, 1, 2, 3, or 4; and 
 p is 0, 1, 2, 3, or 4. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  is of formula: 
       
         
           
           
               
               
           
         
         wherein:
 L′ is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, —O—, —S—, —NR L —, —C(═O)—, —C(═O)NR L —, or —NR L C(═O)—, wherein R L  is hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group; 
 Ring B is a carbocyclic, heterocyclic, aryl or heteroaryl ring; 
 each R 9  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 9a , —N(R 9a ) 2 , —S(═O) 2 R 9a , —S(═O) 2 OR 9a , or —S(═O) 2 N(R 9a ) 2 , wherein each R 9a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 9a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; and 
 k is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         3 . The compound of  claim 1 , wherein the compound is of Formula (I-d): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof. 
       
     
     
         4 . The compound of  claim 1 , wherein the compound is of Formula (I-f): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof. 
       
     
     
         5 . The compound of  claim 1 , wherein the compound is of Formula (I-k): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof. 
       
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein R 1  is optionally substituted alkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 1  is —(CH 2 ) n OR 1a , and n is 0, 1, 2, 3, or 4. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein R 2  is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 - 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein k is 0 or 1. 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 15 , wherein R 9  is halogen, optionally substituted C 1-6  alkyl, or —OR 9a . 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein R 5  is hydrogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, —S(═O) 2 OR 5a , or —S(═O) 2 N(R 5a ) 2 . 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein R 5  is optionally substituted C 2-6  alkyl. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , wherein R 5  is optionally substituted acyl. 
     
     
         31 - 36 . (canceled) 
     
     
         37 . The compound of  claim 1 , wherein m is 0 or 1. 
     
     
         38 . The compound of  claim 1 , wherein p is 0 or 1. 
     
     
         39 . (canceled) 
     
     
         40 . The compound of  claim 1 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and isotopically labeled derivatives thereof. 
       
     
     
         41 - 64 . (canceled) 
     
     
         65 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof, 
         wherein:
 R 31  is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —CH 2 OR 31a , or —CH 2 N(R 31a ) 2 , wherein each R 31a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 36a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring 
 R 35  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —S(═O) 2 R 35a , —S(═O) 2 OR 35a , —S(═O) 2 N(R 35a ) 2 , or a nitrogen protecting group, wherein each R 35a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 35a  joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
 R 36  is —CN or —CH 2 N(R 36a ) 2 , wherein each R 36a  is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group, or two R 36a  are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; 
 Ring A 3  is carbocyclylene, heterocyclylene, arylene, or heteroarylene;
 each R 33  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 33a , —N(R 33a ) 2 , or two R 33  are joined to form an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each R 33a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 33a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
 
 Ring B 3  is a carbocyclic, heterocyclic, aryl or heteroaryl ring; 
 
         each R 39  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 39a , —N(R 39a ) 2 , —S(═O) 2 R 39a , —S(═O) 2 OR 39a , or —S(═O) 2 N(R 39a ) 2 , or two R 39  are joined to form an optionally substituted carbocyclic, heterocyclic, aryl or heteroaryl ring, wherein each R 39a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 39a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; and
 m3 is 0, 1, 2, 3, or 4; and 
 k3 is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         66 - 87 . (canceled) 
     
     
         88 . A compound of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, prodrug, or isotopically labeled derivative thereof, 
         wherein:
 R 45  is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —OR 45a , —N(R 45a ) 2 , —S(═O) 2 R 45a , —S(═O) 2 OR 45a , or —S(═O) 2 N(R 45a ) 2  wherein each R 45a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 45a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
 Ring C 4  is carbocyclylene, heterocyclylene, arylene, or heteroarylene; 
 L 4  is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, —O—, —NR L —, —C(═O)—, —C(═O)NR L —, or —NR L C(═O)—, wherein R L  is hydrogen, optionally substituted C 1-6  alkyl, or a nitrogen protecting group; 
 
         each R 44  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 44a , —N(R 44a ) 2 , or two R 44  are joined to form an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each R 44a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 44a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring;
 Ring A 4  is 6-membered arylene or 5-7 membered heteroarylene, 
 Ring B 4  is 6 membered aryl or 5-7 membered heteroaryl; 
 each R 43  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 43a , or —N(R 43a ) 2 , or two R 43  are joined to form an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each R 43a  a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 43a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
 each R 49  is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, —NO 2 , —CN, —OR 49a , —N(R 49a ) 2 , —S(═O) 2 R 49a , —S(═O) 2 OR 49a , or —S(═O) 2 N(R 49a ) 2 , or two R 49  are joined to form an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl ring, wherein each R 49a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R 49a  are joined to form an optionally substituted heteroaryl or optionally substituted heterocyclic ring; 
 m4 is 0, 1, 2, 3, or 4; 
 p4 is 0, 1, 2, 3, or 4; and 
 k4 is 0, 1, 2, 3, 4, or 5; 
 
         wherein the sum of m4 and k4 is at least one, and at least one R 43  or R 49  is attached ortho to the bond between Rings A 4  and B 4 . 
       
     
     
         89 - 148 . (canceled) 
     
     
         149 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. 
     
     
         150 . A method of treating a metabolic disorder comprising administering a therapeutically effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to a subject in need thereof. 
     
     
         151 - 186 . (canceled)