Bridged and fused antidiabetic compounds

Abstract

This invention provides for certain bridged and fused compounds of the formula G-L-A I or a pharmaceutically acceptable salt, ester of solvate thereof wherein: A is: (I) and the other variables are defined herein; the inventive compounds are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR). This invention further relates to pharmaceutical compositions containing these compounds, and the use of these compounds to regulate insulin levels in a mammal. The compounds may be used, for example in the prevention and treatment of Type 2 diabetes mellitus and in the prevention and treatment of conditions related to Type 2 diabetes mellitus, such as insulin resistance, obesity and lipid disorders.

1 . A compound of the formula:
   G-L-A  I
   
       or a pharmaceutically acceptable salt thereof 
       wherein
 G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which are optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 A is 
 
       
         
           
           
               
               
           
         
         W is —C— or —N—; 
         X is a bond, —O—, —C(O)—, —S(O) q , —C(R a )(R b )— or —N(R 8 )—; 
         Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
         Z is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
         R is a group selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  is independently selected from the group consisting of H, alkyl and haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; 
         R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituents selected from the group consisting of halo and —OR 5 ; 
         R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
         wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6  and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
         R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —N(R 5 )(R 6 ), —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups where 
         R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
         m is independently 1, 2, or 3; 
         n is independently 0, 1 or 2; 
         q is independently 0, 1, or 2; and 
         p is 0, 1, 2, or 3, 
       
       provided that Y and Z cannot be a bond at the same time. 
     
     
         2 . A compound according to  claim 1  which is represented by the structural formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 W is —C— or —N—; 
 X is a bond, —O—, —C(O)—, —S(O) q , —C(R a )(R b )— or —N(R 8 )—; 
 Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 Z is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 R is a group selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  is independently selected from the group consisting of H, alkyl and haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; 
         R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ; 
         R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
         wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6  and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
         R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —N(R 5 )(R 6 ), —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups where 
         R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
         m is independently 1, 2, or 3; 
         n is independently 0, 1 or 2; 
         q is independently 0, 1, or 2; and 
         p is 0, 1, 2, or 3, 
       
       provided that Y and Z cannot both be a bond at the same time. 
     
     
         3 . A compound according to  claim 1  which represented by the structural Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 W is —C— or —N—; 
 X is a bond, —O—, —C(O)—, —S(O) q , —C(R a )(R b )— or —N(R 8 )—; 
 Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 Z is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 R is a group selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  is independently selected from the group consisting of H, alkyl and haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; 
         R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ; 
         R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
         wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6  and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
         R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —N(R 5 )(R 6 ), —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups where 
         R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
         m is independently 1, 2, or 3; 
         n is independently 0, 1 or 2; 
         q is independently 0, 1, or 2; and 
         p is 0, 1, 2, or 3, 
       
       provided that Y and Z cannot both be a bond at the same time. 
     
     
         4 . The compound according to  claim 2  which is represented by the structural formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 W is —C— or —N—; 
 Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 R is a group selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —S(O) q -alkyl, —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O) q -alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of 
       
       H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;
 R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
 R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ; 
 R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
 wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6 , and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
 R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, —N(R 6 )(R 7 ) and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups, where 
 R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
 m is independently 1, 2, or 3; 
 n is independently 0, 1 or 2; 
 q is independently 0, 1, or 2; and 
 p is 0, 1, 2, or 3. 
 
     
     
         5 . The compound according to  claim 4  wherein W is —CH—. 
     
     
         6 . The compound according to  claim 5  wherein R is 
       
         
           
           
               
               
           
         
       
       and R 8  is H or —(C 1 -C 4 )alkyl. 
     
     
         7 . The compound according to  claim 6 , wherein Y is —CH 2 —. 
     
     
         8 . The compound according to  claim 2  which is represented by the structural formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 W is —C— or —N—; 
 X is a bond, —O—, —C(O)—, —S(O) q , —C(R a )(R b )— or —N(R 8 )—; 
 Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 R is a group selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —S(O) q -alkyl, —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O) q -alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of 
       
       H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;
 R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
 R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ; 
 R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
 wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6 , and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
 R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, —N(R 6 )(R 7 ) and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups, where 
 R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
 m is independently 1, 2, or 3; 
 n is independently 0, 1 or 2; 
 q is independently 0, 1, or 2; and 
 p is 0, 1, 2, or 3. 
 
     
     
         9 . The compound of  claim 8  wherein W is —CH—. 
     
     
         10 . The compound of  claim 9  wherein R is 
       
         
           
           
               
               
           
         
       
       and R 8  is H or —(C 1 -C 4 )alkyl. 
     
     
         11 . The compound according to  claim 10 , wherein X is —O— and Y is —CH 2 —. 
     
     
         12 . The compound according to  claim 3  which is represented by the structural formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ; 
 L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—; 
 W is —C— or —N—; 
 X is a bond, —O—, —C(O)—, —S(O) q , —C(R a )(R b )— or —N(R 8 )—; 
 Y is a bond, —[C(R a )(R b )] n —O—[C(R a )(R b )] n , —[C(R a )(R b )] n —C(O)—[C(R a )(R b )] n , —[C(R a )(R b )] n —S(O) q —[C(R a )(R b )] n , —[C(R a )(R b )] m — or —N(R 8 )—; 
 R is a group selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         and
 (v) tetrazolyl,
 wherein
 Q is —CH— or —N—, and 
 J is —S—, —CH 2 —, —O— or —N(R 8 )—; 
 
 
 
         R a  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R b  is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; 
         R 1  is independently selected from the group consisting of H, halogen, —SF 5 , —S(O) q -alkyl, —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O) q -alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 2  is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; 
         R 3  independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 4  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 5  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         R 6  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; 
         R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 6  and R 7  together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12  moieties; 
         R 8  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)-alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; 
         R 9  is independently selected from the group consisting of H, alkyl, haloalkyl; 
         R 10  is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ; 
         R 11  is independently selected from the group consisting of H, alkyl, and haloalkyl; 
         wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6 , and R 7  are independently unsubstituted or substituted by one or more R 12  groups, where 
         R 12  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, —N(R 6 )(R 7 ) and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12  is independently unsubstituted or substituted by one or more R 13  groups, where 
         R 13  is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo; 
         m is independently 1, 2, or 3; 
         n is independently 0, 1 or 2; 
         q is independently 0, 1, or 2; and 
         p is 0, 1, 2, or 3. 
       
     
     
         13 . The compound according to  12 , wherein W is —CH—. 
     
     
         14 . The compound according to  claim 13 , wherein R is 
       
         
           
           
               
               
           
         
       
       and R 8  is H or —(C 1 -C 4 )alkyl. 
     
     
         15 . The compound according to  claim 14 , wherein X is —O— and Y is —CH 2 —. 
     
     
         16 . The compound according to  claim 1  which is a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         18 . A method for controlling insulin levels in a mammal in need thereof which comprises administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to said mammal. 
     
     
         19 . A method for the prevention or treatment of Type-2 diabetis mellitus in a mammal in need thereof which comprises administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to said mammal. 
     
     
         20 . A method for the prevention or treatment of conditions related to Type-2 diabetis mellitus in a mammal in need there of which comprises administering an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof to said mammal. 
     
     
         21 . (canceled)