Modulators of g-protein coupled receptors

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) glucagon-like peptide-1 receptor (“GLP-1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP-1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, the modulation results in an enhancement of (e.g., an increase in) existing levels (e.g., normal or below normal levels) of GLP-1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.

1 . A compound having formula (IAA), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is: 
 a saturated or unsaturated monocyclic ring that includes from 3-8 ring atoms (inclusive of G and the nitrogen atom labelled N*), wherein:
 G is C(O); and 
 the dotted, circular line connecting G and N* is a divalent group that includes from 1-6 ring atoms; wherein: 
 
 (a) from 0-2 of the divalent group's ring atoms are ring heteroatoms, which are each independently selected from the group consisting of N, O, and S; and 
 (b) from 1-6 of the divalent group's ring atoms are ring carbon atoms, which are each independently selected from the group consisting of C, CH, CH 2 , CR b , C(R b ) 2 , and CHR b ; 
 wherein: 
 each of the divalent group's 1-6 ring carbon atoms is independently selected from the group consisting of CH, CH 2 , CR b , C(R b ) 2 , and CHR b ; and 
 L is: 
 (i) —(CH 2 ) m —X 1 —(CH 2 ) n —X 2 —(CH 2 ) p — (formula VIII), wherein m is from 1-6; n is from 0-2; 
 and p is from 0-8; or 
 (ii) —(CH 2 ) m —X 1 —(CH 2 ) p — (formula VIII), wherein m is from 1-6; and p is from 0-8; 
 X 1  is —N(R′)C(O)— or —C(O)N(R′)—; wherein each occurrence of R′ is H; 
 X 2  is: 
 —S—; 
 each of R 1 , R 2 , and R 4  is H; 
 R 2′  is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 3  is —C(O)OH; 
 a is 0-5; 
 a′ is 0 or 1; and 
 each of R 3a  and R 3b  is H; 
 each occurrence of R b  is independently selected from the group consisting of: C 1-6  alkyl; C 1-4  haloalkyl; —OH; oxo; —F; —N(R a )(R″); C 1-4  alkoxy; C 1-4  haloalkoxy; —C(═O)(C 1-4  alkyl); —C(═O)O(C 1-6  alkyl); —C(═O)OH, —C(═O)N(R′″)(R″″), —S(O) 1-2 (C 1-6  alkyl); and cyano; and 
 —N(R 4 )W is a peptide having formula (XIV): 
 
       
         
           
                 
                 
               
                     
                   
                     GTFTSDYSIYLDKQAA(Aib)EFVNWLLAGGPSSGAPPPS-R 5 ; 
                   
                 
             
                
               
            
           
         
         wherein 
         R 5  is a C-terminal amino acid or amino acid amide that is optionally substituted with from 1-2 modifying groups selected from an acyl group and a PEG group). 
       
     
     
         2 - 169 . (canceled) 
     
     
         170 . The compound of  claim 1 , wherein R 5  has formula (XI-OH): 
       
         
           
           
               
               
           
         
       
       wherein R* is 
       
         
           
           
               
               
           
         
       
     
     
         171 - 218 . (canceled) 
     
     
         219 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         220 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         221 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         222 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         223 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         224 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         225 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         226 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the structure 
       
         
           
           
               
               
           
         
       
     
     
         227 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         228 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         229 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         230 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         231 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         232 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         233 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         234 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         235 . The compound or pharmaceutically acceptable salt thereof of  claim 227 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         236 . A method for treating type 2 diabetes mellitus in a human subject, the method comprising administering to the human subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt thereof of  claim 1  or  227 . 
     
     
         237 . A method for treating obesity in a human subject, the method comprising administering to the human subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt thereof of  claim 1  or  227 , optionally wherein the method comprises administering the compound to the subject in combination with a diet therapy or an exercise therapy. 
     
     
         238 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of  claim 1  or  227  and one or more pharmaceutically acceptable excipients.