Organic compounds

Abstract

The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         V is selected from —N(R 5 )C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, —N(R 5 )C(O)N(R 5 )—, —O—, —N(R 5 )—, —S—, —S(O) t —, —N(R 5 )S(O) t —, —S(O) t N(R 5 )—, —OS(O) 2 —, —OS(O) 2 N(R 5 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 5 )C(═N(R 5a ))NR 5 —, —N(R 5 )C(═S)NR 5 —, —N(R 5 )((R 5a )N═)C—, —C(═N(R 5a ))N(R 5 )—, alkylene, alkenylene, alkynylene, aryl, heteroaryl, cycloalkyl, heterocyclyl or a direct bond; 
         W is selected from —N(R 5 )C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, —N(R 5 )C(O)N(R 5 )—, —O—, —N(R 5 )—, —S—, —S(O) t —, —N(R 5 )S(O) t —, —S(O) t N(R 5 )—, —OS(O) 2 N(R 5 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 5 )C(═N(R 5a ))NR 5 —, —N(R 5 )((R 5a )N═)C—, —C(═N(R 5a ))N(R 5 )—, aryl, heteroaryl, heterocyclyl, alkynylene, alkenylene, alkylene or a direct bond; 
         X is selected from C(H) or N; 
         Y is selected from S, O, N(H) or N(CH 3 ); 
         p is 0, 1, 2, or 3; 
         t is 1 or 2; 
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 1  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; 
         or R 2  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         R 3  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano and —N(R 5 ) 2 ; 
         R 4  is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, —OCF 3 , —OC(H)F 2 , and cyano; 
         or two adjacent R 4  groups, together with the carbon atoms to which they are attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R 4  groups, if present, are as described above; 
         R 5  is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; 
         R 5a  is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. 
       
     
     
         2 . A pharmaceutical composition, comprising the compound of formula (I) according to  claim 1  and a pharmaceutically acceptable excipient or carrier. 
     
     
         3 . A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         V is selected from —N(R 5 )C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, N(R 5 )C(O)N(R 5 )—, —O—, —N(R 5 )—, —S—, —S(O) t —, —N(R 5 )S(O) t —, —S(O) t N(R 5 )—, —OS(O) 2 —, —O—S(O) 2 N(R 5 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 5 )C(═N(R 5a ))NR 5 —, —N(R 5 )C(═S)NR 5 —, —N(R 5 )((R 5a )N═)C—, —C(═N(R 5a ))N(R 5 )—, alkylene, alkenylene, alkynylene, aryl, heteroaryl, cycloalkyl, heterocyclyl or a direct bond; 
         W is selected from —N(R 5 )C(O)—, —C(O)N(R 5 )—, —OC(O)N(R 5 )—, —N(R 5 )C(O)O—, —N(R 5 )C(O)N(R 5 )—, —O—, —N(R 5 )—, —S—, —S(O) t —, —N(R 5 )S(O) t —, —S(O) t N(R 5 )—, —O—S(O) 2 N(R 5 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 5 )C(═N(R 5a ))NR 5 —, —N(R 5 )((R 5a )N═)C—, —C(═N(R 5a ))N(R 5 )—, aryl, heteroaryl, heterocyclyl, alkynylene, alkenylene, alkylene or a direct bond; 
         X is selected from C(H) or N; 
         Y is selected from S, O, N(H) or N(CH 3 ); 
         p is 0, 1, 2, or 3; 
         t is 1 or 2; 
         R 1  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; 
         or R 1  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; 
         or R 2  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         R 3  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano and —N(R 5 ) 2 ; 
         R 4  is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, —OCF 3 , —OC(H)F 2 , and cyano; 
         or two adjacent R 4  groups, together with the carbon atoms to which they attached, may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R 4  groups, if present, are as described above; 
         R 5  is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; 
         R 5a  is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. 
       
     
     
         4 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, comprising:
 administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) according to  claim 1 .   
     
     
         5 . A pharmaceutical composition, comprising:
 a therapeutically effective amount of a compound of  claim 1  in combination with a therapeutically effective amount of insulin, insulin derivative or mimetic; insulin secretagogue; insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulin sensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid; or aspirin.