Gpr120 receptor agonists and uses thereof

Abstract

GPR120 agonists are provided. These compounds are useful for the treatment of metabolic diseases, including Type II diabetes and diseases associated with poor glycemic control.

1 . A compound of Formula (A) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         the group J is absent or selected from the group consisting 
       
       
         
           
           
               
               
           
         
         the ring Q is selected from the group consisting of aryl, heteroaryl, 
       
       
         
           
           
               
               
           
         
         wherein Q is optionally substituted with (R 6 ) k ; 
         A 1 , A 2 , A 3  and A 4  are independently selected from the group consisting of N and C, with the proviso that only 0, 1 or 2 of A 1 , A 2 , A 3  and A 4  is N; 
         T 1 , T 2 , T 3  and T are independently selected from the group consisting of N, O, CR 1  and CR 1 R 2 , with the proviso that only 0, 1 or 2 of T 1 , T 2 , T 3  and T 4  is selected from N and O; 
         W 1 , W 2 , W 3  and W 4  are independently selected from the group consisting of N, NRa, CR 1 , CR 1 R 2 , O, S, S(O) and S(O) 2 , with the proviso that ring J is not 1,3-dioxolane; 
         E 1 , E 2  and E 3  are independently selected from the group consisting of C and N; 
         one of X and Y is a bond, —CH 2 —, —CHD-, or —CD 2 -, and the other of X and Y is selected from the group consisting of —CH 2 —, —CHD-, —CD 2 -, —C(O), —C(O)NR a —, —NR a —, —O—, —S—, —S(O)— and —S(O) 2 —; 
         L is —(CR 4 R 5 ) q  wherein optionally one —(CR 4 R 5 )— is replaced with —N—, —O—, —S—, —CR 4 ═CR 5 —, or -phenyl-; 
         G is selected from the group consisting of —C(O)OZ and —C(O)NZ 2 ; 
         each Z is independently selected from the group consisting of H, alkyl and substituted alkyl; 
         each R 1  and R 2  is independently selected from the group consisting of H, deuterium, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, alkoxy, substituted alkoxy, CN, —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —SR a , —S(O)R a  and —S(O) 2 R a , and optionally R 1  and R 2  can cyclize to form a C 3-7 heterocyclyl, substituted C 3-7 heterocyclyl, spiro C 3-7 heterocyclyl, substituted spiro C 3-7 heterocyclyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, spiroC 3-7 cycloalkyl or spiro substituted C 3-7 cycloalkyl; 
         each R 3  is independently selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, —C(O)NR a R b , —NR a C(O)R b , —NR a R b , aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy and —CN; 
         each R 4  and R 5  is independently selected from the group consisting H, deuterium, fluoro, alkyl, substituted alkyl, alkoxy and substituted alkoxy, and optionally R 4  and R 5  can cyclize to form a C 3-7 heterocyclyl, substituted C 3-7 heterocyclyl, spiro C 3-7 heterocyclyl, substituted spiro C 3-7 heterocyclyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, spiroC 3-7 cycloalkyl or spiro substituted C 3-7 cycloalkyl; 
         each R 6  is independently selected from the group consisting of H, halo, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CN, —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —SR a , —S(O)R a  and —S(O) 2 R a ; 
         each of R a  and R b  is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         the subscript k is 0, 1, 2 or 3; 
         the subscript m is 0, 1, 2 or 3; and 
         the subscript q is 0, 1, 2, 3 or 4. 
       
     
     
         2 . A compound of  claim 1  of Formula (B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, provided that W 1  and W 3  are not both O. 
       
     
     
         3 . The compound of  claim 2  wherein W 1  and W 3  are independently selected from the group consisting of CR 1 R 2  and O. 
     
     
         4 . The compound of  claim 3  of Formula (C): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 4 , wherein E 1 , E 2  and E 3  are all C. 
     
     
         6 . The compound of  claim 5 , wherein X is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -, and Y is O. 
     
     
         7 . The compound of  claim 6 , wherein in L the subscript q is 2 or 3. 
     
     
         8 . The compound of  claim 7 , wherein the subscript q is 2. 
     
     
         9 . The compound of  claim 8 , wherein G is —C(O)OZ. 
     
     
         10 . The compound of  claim 9 , wherein Z is H. 
     
     
         11 . The compound of  claim 10 , wherein the subscript m is 1 or 2, and each R 3  is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy and substituted alkoxy. 
     
     
         12 . The compound of  claim 11 , wherein, each R 3  is independently selected from the group consisting of F, Cl, —CH 3 , —CF 3  and —OCH 3 . 
     
     
         13 . The compound of  claim 12 , wherein R 1  and R 2  are independently selected from the group consisting of C 1-3 alkyl and —CF 3 . 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein the subscript k is 0, 1 or 2. 
     
     
         16 . The compound of  claim 15 , wherein each R 6  is independently selected from the group consisting of fluoro, chloro, —CH 3 , —C 2 H 5  and —CF 3 . 
     
     
         17 . The compound of  claim 1 , wherein, the ring Q is 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound of  claim 17 , wherein ring J is absent and each R 3  is independently selected from the group consisting of alkoxy, substituted alkoxy and halo. 
     
     
         19 . (canceled) 
     
     
         20 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein said disease is Type II diabetes. 
     
     
         23 . A method of lowering blood glucose in a mammal, said method comprising administering a therapeutically effective amount of a compound of  claim 1  to a mammal in need of such treatment. 
     
     
         24 . The method of  claim 23 , wherein said mammal is a human. 
     
     
         25 . A method of modulating GPR120 activity in a cell, said method comprising contacting said cell with a therapeutically effective amount of a compound of  claim 1 .