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.

We claim: 
     
         1 . A compound of Formula (I):
   R 1 —W—P-Q-R 2   (I)
   wherein P is   
       
         
           
           
               
               
           
         
         Q is 
       
       
         
           
           
               
               
           
         
         W is —N(R 8 )C(O)—, —C(O)N(R 8 )— or a direct bond; 
         n is 1, 2, or 3; 
         p is 0, 1, 2, to 2n; 
         q is 0, 1, 2, or 3; 
         R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
         R 2  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, aralkyloxy, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; 
         R 3  is alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, trifluoromethoxyl, cyano, hydroxy, or —N(R 8 ) 2 ; 
         R 5  and R 5a  are independently selected from hydrogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cycloalkylalkyl or aralkyl; 
         or R 5  and R 5a  are together to form an oxo (═O) group, or to form a cycloaklyl; 
         R 6  is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, haloalkyl, alkoxy, cycloalkylalkyl, or aralkyl; 
         or R 5  and R 6  on adjacent carbons are together to form a cycloaklyl, or to form an aryl; 
         R 7  is hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, cycloalkylalkyl or aralkyl; and 
         R 8  is hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl or aralkyl;
 a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein P is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein W is —N(R 8 )C(O)—, and R 1  is hydrogen, alkyl, aryl, aralkyl or heteroarylalkyl. 
     
     
         4 . The compound according to  claim 1 , wherein W is a direct bond and R 1  is aryl or heteroaryl. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  is hydroxy, C 1 -C 4 alkyl, cycloalkylalkyl, haloalkyl, aralkyl, aralkyloxy or heteroarylalkyl. 
     
     
         6 . The compound according to  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , wherein
 P is   
       
         
           
           
               
               
           
         
         Q is 
       
       
         
           
           
               
               
           
         
         W is —N(R 8 )C(O)—; 
         R 1  is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 
         R 2  is hydroxy, C 1 -C 4  alkyl, cycloalkylalkyl, aryl, aralkyl, aralkyloxy, heteroaryl or heteroarylalkyl; and 
         R 8  is hydrogen or C 1 -C 4 alkyl. 
       
     
     
         8 . The compound according to  claim 1 , wherein
 R 2  is hydroxy, C 1 -C 4  alkyl, cycloalkylalkyl, aralkyl, aralkyloxy or heteroarylalkyl, wherein the cycloalkylalkyl is   
       
         
           
           
               
               
           
         
       
       aralkyl is 
       
         
           
           
               
               
           
         
       
       C 1 -C 4  alkyl is 
       
         
           
           
               
               
           
         
       
       aralkyloxy is 
       
         
           
           
               
               
           
         
       
       and 
       heteroarylalkyl is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according  claim 1 , wherein
 R 2  is C 1 -C 4 alkyl, cycloalkylalkyl, or aralkyl,   
       wherein the cycloalkylalkyl is 
       
         
           
           
               
               
           
         
       
       aralkyl is 
       
         
           
           
               
               
           
         
       
       C 1 -C 4  alkyl is 
       
         
           
           
               
               
           
         
       
       and heteroarylalkyl is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound according to  claim 4 , wherein
 W is a direct bond and   R 1  is   
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , wherein the compound is
 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-methylisonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(oxazol-4-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-5-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylpyrazin-2-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-2-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(oxazol-2-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-imidazol-4-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)isonicotinamide,   N-((1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylisoxazol-3-yl)methyl)isonicotinamide,   N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   (R)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((2-methylthiazol-4-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(isoxazol-3-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((2-(trifluoromethyl)thiazol-4-yl)methyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((4-methyl-2-phenylthiazol-5-yl)methyl)isonicotinamide,   N-benzyl-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-2-ylmethyl)isonicotinamide,   N-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   N-(cyclopropylmethyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide,   N-(2-cyclopropylethyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   N-benzyl-2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide,   2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-2-ylmethyl)isonicotinamide,   2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide,   2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(3,4-difluorobenzyl)isonicotinamide,   N-benzyl-2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide,   N-(3,4-difluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   N-(4-fluorobenzyl)-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinamide,   N-(4-fluorobenzyl)-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide,   N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinamide,   N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinamide,   N-benzyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide,   2-(3-((4-(difluoromethyl)phenyl)difluoromethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide,   2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide,   N-benzyl-2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide,   N-benzyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)isonicotinamide,   2-oxo-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide,   4-benzyloxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide,   4-hydroxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide,   N-benzyl-2-(3-benzyl-2-oxopiperidin-1-yl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)isonicotinamide,   N-(4-fluorobenzyl)-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)isonicotinamide,   2-(3-(benzo[c][1,2,5]-thiadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-N-benzylisonicotinamide,   N-((1,3,4-oxadiazol-2-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(benzo[c][1,2,5]-oxadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-N-benzylisonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(1-phenylethyl)-isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-2-ylmethyl)quinoline-4-carboxamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-2-ylmethyl)-isonicotinamide,   N-((3-bromoisoxazol-5-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-phenylisoxazol-3-yl)methyl)-isonicotinamide,   N-((2-chlorothiazol-5-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(pyridin-2-ylmethyl)-isonicotinamide,   N-((5-methylisoxazol-3-yl)methyl)-2-(2-oxo-3-(4-(trifluoromethoxy)-benzyl)imidazolidin-1-yl)isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(thiazol-5-ylmethyl)-isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(pyridin-2-ylmethyl)-isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)-isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(thiazol-2-ylmethyl)-isonicotinamide,   N-((5-methylisoxazol-3-yl)methyl)-2-(2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(thiazol-2-ylmethyl)-isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(thiazol-5-ylmethyl)-isonicotinamide,   N-((2-chlorothiazol-5-yl)methyl)-2-(2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)isonicotinamide,   2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(thiazol-2-ylmethyl)-isonicotinamide,   2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-((5-methylisoxazol-3-yl)methyl)-isonicotinamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylisoxazol-3-yl)methyl)-isonicotinamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-5-ylmethyl)-isonicotinamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-2-ylmethyl)-isonicotinamide,   2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(thiazol-5-ylmethyl)-isonicotinamide,   2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-2-ylmethyl)-isonicotinamide,   2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-((5-methylisoxazol-3-yl)methyl)-isonicotinamide,   2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(thiazol-2-ylmethyl)-isonicotinamide,   2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-2-ylmethyl)-isonicotinamide,   2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)isonicotinamide,   2-(2-oxo-3-(4-(trifluoromethoxy)-benzyl)imidazolidin-1-yl)isonicotinamide,   N-((2-chlorothiazol-5-yl)methyl)-2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide, and   N-((2-chlorothiazol-5-yl)methyl)-2-(2-oxo-3-(4-(trifluoromethoxy)-benzyl)imidazolidin-1-yl)isonicotinamide.   
     
     
         12 . A pharmaceutical composition, comprising:
 the compound of Formula (I) according to  claim 1  and   a pharmaceutically acceptable excipient or carrier.   
     
     
         13 . 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) or (II) according to any one of  claims 1 - 16  and  18 .   
     
     
         14 . The method according to  claim 13 , wherein the disease or condition is metabolic syndrome, Syndrome X, diabetes, insulin resistance, hyperinsulinanemia, reperfusion injury, angiplastic restenosis, thrombosis, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders, weight loss, body mass index or leptin related diseases. 
     
     
         15 . The method according to  claim 13 , where the disease or condition is a skin disorder.