Diacylglycerol Acyltransferase Inhibitors

Abstract

Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

1 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl; 
 R 2  is C or N; 
 R 3  is C, N, S or O; 
 R 4  is C, O, S or N; 
 R 5  is C, N or S; 
 R 6  is H, alkyl, halogen, haloalkyl, thioalkyl or hydrogen; 
 R 7  is 
 
     
       
         
         
             
             
         
       
       at least one of R 8  or R 9  is N; and the other is carbon; 
       R 10  is —NR 11 R 12 , O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —N(CH 3 )C(O)CH 3 , cyclopropanecarbonyl-methyl, —OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , OCH 2 C(O)OH, —CH 2 OH, —CH 2 OCH 3  and —OH; 
       R 11  is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH 2 CH 2 CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , —OCH 2 C(O)OH and —OH; 
       R 12  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The compound according to  claim 1 , wherein:
 R 1  is unsubstituted aryl or aryl substituted with a group selected from the group consisting of alkyl and halogen;   R 2  is C;   R 3  is N;   R 4  is O;   R 5  is C;   R 6  is alkyl;   R 7  is   
     
       
         
         
             
             
         
       
     
     at least one of R 8  or R 9  is N; and the other is carbon;
 R 10  is —NR 11 R 12 , O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —N(CH 3 )C(O)CH 3 , cyclopropanecarbonyl-methyl, —OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , OCH 2 C(O)OH, —CH 2 OH, —CH 2 OCH 3  and —OH; 
 R 11  is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH 2 CH 2 CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , —OCH 2 C(O)OH and —OH; 
 R 12  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
 
   
   
       3 . The compound according to  claim 1 , wherein:
 R 1  is unsubstituted aryl or aryl substituted with a group selected from the group consisting of alkyl and halogen;   R 2  is C;   R 3  is O;   R 4  is N;   R 5  is C;   R 6  is H, alkyl, halogen, haloalkyl, thioalkyl or hydrogen;   R 7  is   
     
       
         
         
             
             
         
       
     
     at least one of R 8  or R 9  is N; and the other is carbon;
 R 10  is —NR 11 R 12 , O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —N(CH 3 )C(O)CH 3 , cyclopropanecarbonyl-methyl, —OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , OCH 2 C(O)OH, —CH 2 OH, —CH 2 OCH 3  and —OH; 
 R 11  is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH 2 CH 2 CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , —OCH 2 C(O)OH and —OH; 
 R 12  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
 
   
   
       4 . The compound according to  claim 1 , wherein:
 R 1  is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;   R 2  is C or N;   R 3  is C, N, S or O;   R 4  is C, O, S or N;   R 5  is C, N or S;   R 6  is H, alkyl, halogen, haloalkyl, thioalkyl or absent hydrogen;   R 7  is   
     
       
         
         
             
             
         
       
     
     at least one of R 8  or R 9  is N; and the other is carbon;
 R 10  is —NR 11 R 12 ; 
 R 11  is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of −OCH 3 , —CH 2 OH, —CH 2 OCH 3  and —OH; 
 R 12  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
 
   
   
       5 . The compound according to  claim 1 , wherein:
 R 1  is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;   R 2  is C or N;   R 3  is C, N, S or O;   R 4  is C, O, S or N;   R 5  is C, N or S;   R 6  is H, alkyl, halogen, haloalkyl, thioalkyl or hydrogen;   R 7  is   
     
       
         
         
             
             
         
       
     
     at least one of R 8  or R 9  is N; and the other is carbon;
 R 10  is —NR 11 R 12 , O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —N(CH 3 )C(O)CH 3 , cyclopropanecarbonyl-methyl, —OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , OCH 2 C(O)OH, —CH 2 OH, —CH 2 OCH 3  and —OH; 
 R 11  is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH 2 CH 2 CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , —OCH 2 C(O)OH and —OH; 
 R 12  is H or lower alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The compound according to  claim 1 , wherein:
 R 1  is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;   R 2  is C or N;   R 3  is C, N, S or O;   R 4  is C, O, S or N;   R 5  is C, N or S;   R 6  is H, alkyl, halogen, haloalkyl, thioalkyl or hydrogen;   R 7  is   
     
       
         
         
             
             
         
       
     
     at least one of R 8  or R 9  is N; and the other is carbon;
 R 10  is —NR 11 R 12 , O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —N(CH 3 )C(O)CH 3 , cyclopropanecarbonyl-methyl, —OCH 3 , —OCH 2 C(O)OC(CH 3 ) 3 , OCH 2 C(O)OH, —CH 2 OH, —CH 2 OCH 3  and —OH; 
 R 11  is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH 2 CH 2 CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , CH 2 C(O)OC(CH 3 ) 3 , —OCH 2 C(O)OH and —OH; 
 R 12  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
 
   
   
       7 . The compound according to  claim 1 , wherein R 6  is —CF 3 . 
   
   
       8 . The compound according to  claim 1 , wherein R 10  is —(CH 3 )(CH 2 ) n OCH 3 , —N(CH 3 )CH 2 C(O)OCH 3 , —N(CH 3 )CH 2 C(O)NHCH 3 , —N(CH 3 )C(O)CH 3 , —N(CH 3 )(CH 2 ) n CH 3 , —NH(CH 2 ) n CH 3 , —N(CH 2 CH 3 )(CH 2 ) n OCH 3 , diethylamino, —N(CH 3 )C(O)CH 2 OCH 3 , —N(CH 3 )CH(CH 3 )CH 2 OCH 3 , —N(CH 3 )(CH 2 ) n O, —N(CH 2 ) n O, —NCH 2 (CH 3 )CH 2 O or —N-tetrahydropyran; wherein n is 1, 2 or 3. 
   
   
       9 . The compound according to  claim 1 , wherein said compound is 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 
   
   
       10 - 13 . (canceled) 
   
   
       14 . The compound according to  claim 1 , wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. 
   
   
       15 - 20 . (canceled) 
   
   
       21 . The compound of  claim 1  wherein said compound has the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 6  and R 10  are as above. 
   
   
       22 . The compound of  claim 1  wherein said compound has the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 6  and R 10  are as above. 
   
   
       23 . The compound of  claim 1  wherein said compound has the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 6  and R 10  are as above.