Cyclic bridgehead ether dgat1 inhibitors

Abstract

The invention relates to compounds of formula (I): useful for treating disorders mediated by acyl coA-diacylglycerol acyl transferase 1 (DGAT1), e.g. metabolic disorders. The invention also provides methods of treating such disorders, and compounds and compositions etc. for their treatment.

We claim: 
     
         1 . A compound according to formula (I) or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
         Wherein 
         p is 1, 2 or 3; 
         X is O or CH 2 ; 
         Y is O, CH 2  or absent, wherein exactly one of X and Y is O; 
         Z 1 , Z 2 , Z 3  and Z 4  are each, independently, N or CH; 
         L is C(O) or absent; and 
         A is a substituted oxazole, thiazole, oxadiazole or thiadiazole substituted with at least one C 1-6 alkyl, C 3-7 cycloalkyl or C 1-6 haloalkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is of formula (II) or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein the compound is of formula (III) or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein the compound is of formula (IV) or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , or a salt or solvate thereof, wherein p is 1. 
     
     
         6 . The compound according to  claim 1 , or a salt or solvate thereof, wherein p is 2. 
     
     
         7 . The compound according to  claim 1  or a salt or solvate thereof, wherein Z 1 , Z 2 , Z 3  and Z 4  are all CH. 
     
     
         8 . The compound according to  claim 1 , or a salt or solvate thereof, wherein Z 1  is N and Z 2 , Z 3  and Z 4  are each CH. 
     
     
         9 . The compound according to  claim 1 , or a salt or solvate thereof, wherein Z 2  is N and Z 1 , Z 3  and Z 4  are each CH. 
     
     
         10 . The compound according to  claim 1 , or a salt or solvate thereof, wherein Z 1  and Z 2  are both N and Z 3  and Z 4  are both CH. 
     
     
         11 . The compound according to  claim 1 , or a salt or solvate thereof, wherein L is C(O). 
     
     
         12 . The compound according to  claim 1 , or a salt or solvate thereof, wherein L is absent. 
     
     
         13 . The compound according to  claim 1 , or a salt or solvate thereof, wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound according to  claim 1 , or a salt or solvate thereof, wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 1 , or a salt or solvate thereof, wherein A is selected from 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , or a salt or solvate thereof, which compound is selected from:
 2-(4-(4′-((5-cyclobutyl-1,3,4-thiadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(4-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(4-(4-(5-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(4-(4-(5-(2-ethyl-4-methyloxazole-5-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(4-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   2-(1-(4′-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;   2-(1-(4′-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;   2-(1-(4-(5-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;   2-(1-(4-(5-(2-methyl-5-(trifluoromethyl)oxazole-4-carboxamido)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid;   2-(4-(4′-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetic acid;   3-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)propanoic acid;   2-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)acetic acid; or a salt or solvate thereof.   
     
     
         17 . A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         18 . A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to  claim 1  and a second therapeutically active agent. 
     
     
         19 . A method for the treatment of a disease or condition mediated by DGAT1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to  claim 1 . 
     
     
         20 . The method of  claim 19 , in which the disease or condition is selected from the group consisting of HCV, impaired glucose tolerance, Type II diabetes or obesity. 
     
     
         21 . A method of treating HCV, impaired glucose tolerance, Type II diabetes or obesity comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of  claim 1 .