Heterocyclic glp-1 agonists

Abstract

This disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein: 
            indicates an optional single or double bond, as allowed by valence; 
         each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  is independently selected from the group consisting of C, CH, and N, provided that at least two and no more than four of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8  are N; 
         T 1  is C(═O)OH; 
         T 2  is hydrogen or (C 1 -C 6 )alkyl which is optionally substituted with (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, (C 1 -C 6 )haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of the (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 R T ; 
         each R T  is independently selected from the group consisting of OH, SH, CN, NO 2 , halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, amino, (C 1 -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino; 
         L 1  is a bond or (C 1 -C 3 )alkylene which is optionally substituted with 1-3 R L ; 
         L 2  is a bond, —O—, —S(O) 0-2 —, or —NH—; 
         each R L  is independently selected from the group consisting of: halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl; or a pair of R L  on the same or on adjacent carbon atoms, taken together with the atom(s) to which each is attached, forms a (C 3 -C 6 )cycloalkyl ring; 
         Ring A is selected from the group consisting of: (A-1), (A-2), and (A-3): 
       
       
         
           
           
               
               
           
         
         wherein mm represents the point of attachment to L 2 , and nn represents the point of attachment to L 3 ; 
         n1 is 0, 1, or 2; m1 and m2 are independently 0 or 1; 
         W 1  is CR Y1  or N, provided that when L 2  is —O—, —S—, or —N(H)—, then W 1  is CR Y1 ; 
         W 2  is CR Y2 ; 
         L w  is (C 1 -C 3 )alkylene; 
         each occurrence of R Y  is independently selected from the group consisting of halogen, CN, —OH, oxo, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; 
         R Y1  and R Y2  are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or 
         when W 1  is CR Y1 , the R Y1  and R Y2  groups taken together form (C 1 -C 4 )alkylene, wherein one of the CH 2  units of the (C 1 -C 4 )alkylene is optionally replaced by a heteroatom selected from the group consisting of O, S, NH, and N(C 1 -3)alkyl; 
         L 3  is —O—; 
         each occurrence of R a  is independently selected from the group consisting of: hydrogen, halogen, CN, —OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or 
         a pair of R a  taken together with the carbon atom to which each is attached forms a (C 3 -C5)cycloalkyl ring; 
         Ring B is selected from the group consisting of: (B-I), (B-II), and (B-III): 
       
       
         
           
           
               
               
           
         
         wherein aa represents the point of attachment to L 3 ; 
         each of B 1 , B 2 , B 3 , and B 4  is independently selected from the group consisting of CR 1  and N; 
         each of B 5  and B 8  is independently selected from the group consisting of: C and N, provided that: 
         when Ring B is (B-III), then B 5  is C, and when L 4  is —O—, —S—, —N(H)—, or —N(C 1-3  alkyl)-, and Ring B is (B-III), then B 8  is C; 
         each of B 6 , B 7 , and B 9  is independently selected from the group consisting of: O, S, CR 1 , NR N , and N, 
         each   in (B-III) is independently a single bond or a double bond, 
         provided that at least one of B 5 , B 6 , B 7 , B 8 , and B 9  is an independently selected heteroatom, at least one of B 5 , B 6 , B 7 , B 8 , and B 9  is C or CR 1 , and the ring including B 5 , B 6 , B 7 , B 8 , and B 9  is heteroaryl; 
         each R 1  is selected from the group consisting of hydrogen, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl; (C 1 -C 3 )alkyl(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl(3- to 5-membered heterocycloalkyl), and —C(O)NR 2 R 3 ; 
         each R 2  and R 3  is independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl; 
         each R N  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, C(═O)(C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )alkyl, and C(═O)O(C 1 -C 6 )alkyl; 
         L 4  is selected from the group consisting of: —C(R c R c )—; —O—; —S—; —N(H)—; —N(C 1-3  alkyl)-; —C(═O)—; and —S(O) 1-2 —; 
         L 5  is selected from the group consisting of: a bond; —C(R c R c )—; —O—; —S—; —N(H)—; —N(C 1-3  alkyl)-; —C(═O)—; and —S(O) 1-2 —; 
         provided that when L 4  is —O—, —S—, —N(H)—, or —N(C 1-3  alkyl)-, then L 5  is a bond, —C(R c R c )—, —C(═O), or —S(O) 1-2 —, and 
         provided that when L 5  is —O—, —S—, —N(H)—, or —N(C 1-3  alkyl)-, then L 4  is —C(R c R c )—, —C(═O), or —S(O) 1-2 —, 
         each occurrence of R c  is independently selected from the group consisting of: hydrogen, halogen, CN, —OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or 
         a pair of R c  taken together with the carbon atom to which each is attached forms a (C 3 -C 8 )cycloalkyl ring; 
         Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 10 )bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; 
         each R b  is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 3 -C 6 )cycloalkyl, and CN; and 
         b is an integer selected from 0-3. 
       
     
     
         2 - 256 . (canceled) 
     
     
         257 . The compound of  claim 1 , wherein X 8 , X 5 , and X 3  are C; X 2  and X 4  are N; X 7  is CH; and X 1  and X 6  are independently CH or N. 
     
     
         258 . The compound of  claim 257 , wherein X 1  and X 6  are CH. 
     
     
         259 . The compound of  claim 257 , wherein X 1  is N and X 6  is CH. 
     
     
         260 . The compound of  claim 1 , wherein T 2  is (C 1 -C 3 )alkyl which is substituted with 4- to 6-membered heterocycloalkyl. 
     
     
         261 . The compound of  claim 1 , wherein T is 
       
         
           
           
               
               
           
         
       
     
     
         262 . The compound of  claim 1 , wherein L 1  is CH 2 ; and L 2  is a bond. 
     
     
         263 . The compound of  claim 1 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
     
     
         264 . The compound of  claim 263 , wherein n1 is 0. 
     
     
         265 . The compound of  claim 1 , wherein Ring B is 
       
         
           
           
               
               
           
         
       
     
     
         266 . The compound of  claim 1 , wherein B 2  is N. 
     
     
         267 . The compound of  claim 1 , wherein L 4  is —CH 2 —. 
     
     
         268 . The compound of  claim 1 , wherein L 4  is —CF 2 —, —CH(Me)-, or 
       
         
           
           
               
               
           
         
       
     
     
         269 . The compound of  claim 1 , wherein L 4  is —O—; and L 5  is a bond. 
     
     
         270 . The compound of  claim 1 , wherein L 4  is —C(R c R c )—; and L 5  is —O—. 
     
     
         271 . The compound of  claim 1 , wherein Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl. 
     
     
         272 . The compound of  claim 1 , wherein Ring C is phenyl. 
     
     
         273 . The compound of  claim 1 , wherein b is 1-3. 
     
     
         274 . The compound of  claim 1 , wherein b is 2. 
     
     
         275 . The compound of  claim 1 , wherein b is 1. 
     
     
         276 . The compound of  claim 1 , wherein b is 0. 
     
     
         277 . The compound of  claim 1 , wherein Ring C is phenyl; and b is 2. 
     
     
         278 . The compound of claim  22 , wherein each occurrence of R b  is independently selected from the group consisting of —F, —Cl, —CH 3 , —CF 3 , and CN. 
     
     
         279 . The compound of  claim 1 , wherein the compound of Formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         280 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 
     
     
         281 . A method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         282 . The method of  claim 281 , the method comprising administering to the patient a therapeutically effective amount of an additional therapy or therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or any combinations thereof. 
     
     
         283 . A method for modulating insulin levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.