NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE

Abstract

The present invention relates to piperazine derivatives that act as inhibitors of stearoyl-CoA desaturase. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is 1 or 2; 
         R 1  is aryl, heterocycloalkyl, heteroaryl or heterocycle; 
         R 2  is aryl, hcteroaryl or heterocycle; 
         R 3  and R 4  are each independently hydrogen, halogen or alkyl; or 
         R 3  and R 4 , together with the carbon atom to which they are attached, form a cycloalkyl group; 
         R 5  is hydrogen or alkyl; 
         X is —C(O)—, or —S(O) 2 —; 
         wherein, when present, an aryl, heteroaryl or heterocycle group may optionally be substituted by one or more halogen, hydroxy, cyano, arylamino, amido, alkylamido, alkyl, halogenated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkoxy, aryloxy, arysulfonyl, and combinations thereof; 
         and pharmaceutically acceptable salts, solvates, hydrates, or solvates of pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein n is 1 and R 1  is aryl, heteroaryl or heterocycle. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein R2 is substituted by one or more alkyl, halogen, halogenated alkyl, or cyano groups. 
     
     
         6 . The compound of  claim 1 , wherein R1 is aryl. 
     
     
         7 . The compound of  claim 6 , wherein R1 is substituted by one or more aryl, heteroaryl, or heterocycle. 
     
     
         8 . The compound of  claim 1 , wherein X is —C(O)—, and wherein R2 is aryl. 
     
     
         9 . The compound of  claim 8 , wherein R2 is substituted by one or more halogen. 
     
     
         10 . The compound of  claim 1 , wherein the compound is selected from:
 N-Biphenyl-4-yl-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   N-Biphenyl-4-yl-3-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-methyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide,   N-Biphenyl-4-yl-3-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvates of pharmaceutically acceptable salts thereof.   
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from:
 N-Biphenyl-4-yl-3-[4-(2,4-dichloro-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N Biphenyl-4-yl-3-[4-(3-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-4-yl-344-(2-chloro-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propionamide,   N-Biphenyl-3 y1-3-oxo-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   3-Oxo-N-(5-phenyl-pyridin-2-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   N-(4-[1,2,4]Oxadiazol-3-yl-phenyl)-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   N-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-3-oxo-344-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvates of pharmaceutically acceptable salts thereof.   
     
     
         12 . The compound of  claim 1 , wherein the compound is selected from:
 N-(6-Benzyloxy-pyridin-3-yl)-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   3-Oxo-N-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   N-Methyl-4-{3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionylamino}-benzamide,   3-Oxo-N-(4-piperidin-1-yl-phenyl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide   3-Oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   3-Oxo-N-(4-phenyl-thiazol-2-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide,   3-Oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide,   N-(4-[1, 2, and 4]Oxadiazol-3-yl-phenyl)-3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide,   3-Oxo-N-(4-phenylamino-phenyl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide:   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide:   and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvates of pharmaceutically acceptable salts thereof.   
     
     
         13 . The compound of  claim 1 , wherein the compound is selected from:
 3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-N-(4-[1,2, and 4]oxadiazol-3-yl-phenyl)-3-oxo-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-N-(4-morpholin-4-yl-phenyl)-3-oxo-propionamide, and   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-propionamide,   1-[4-(2-Bromo-benzoyl)-piperazine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-2-fluoro-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(3-cyano-benzoyl)-piperazin-1-yl]-2-fluoro-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(3-Fluoro-benzoyl)-piperazin-1-yl]-2-fluoro-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-2-methyl-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-N-methyl-3-oxo-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(3-phenyl-isoxazol-5-yl)-propionamide,   and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvates of pharmaceutically acceptable salts thereof.   
     
     
         14 . The compound of  claim 1 , wherein the compound is selected from:
 N-Biphenyl-4-yl-3-(4-cyclohexanecarbonyl-piperazin-1-yl)-3-oxo-propionamide,   N-Biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-[1,4]diazepan-1-yl]-3 -oxo-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-3-oxo-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-pyridin-3-yl-phenyl)-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(1-phenyl-1H-pyrazol-4-yl)-propionamide,   N-Biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-benzyl)-piperazin-1-yl]-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(4-thiophen-3-yl-phenyl)-propionamide,   3-[4-(2-Bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(5-phenyl-pyridin-2-yl)-propionamide,   3-Oxo-N-(5-phenyl-pyridin-2-yl)-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide,   and pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvates of pharmaceutically acceptable salts thereof.   
     
     
         15 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is 1 or 2; 
         R 1  is selected from the group consisting of phenyl, napthyl, pyridnyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, benzoxazolyl, piperidinyl, piperazinyl and pyrrolidinyl; 
         R 2  is substituted or unsubstituted phenyl; 
         R 3  and R 4  are each independently hydrogen, halogen or alkyl; or 
         R 3  and R 4 , together with the carbon atom to which they are attached, form a cycloalkyl group; 
         R 5  is hydrogen or alkyl; 
         X is —C(O)—, or —S(O) 2 ; 
         wherein, R 1  may optionally be substituted by one or more halogen, hydroxyl, cyano, alkylamino, arlyamino, amido, alklylamido, alkyl, halogenated alkyl, aryl, arylalkyl, heteroaryl, heterocycle, alkoxy, aryloxy, or arylalkyloxy, and combinations thereof; 
         wherein, when present, an aryl group is a substituted or unsubstituted phenyl; 
         wherein, when present, a heteroaryl group is oxadiazolyl, oxo-pyridinyl, pyridinyl or thio phenyl; 
         wherein when present, a heterocycle group is piperazinyl or morpholinyl; 
         and pharmaceutically acceptable salts thereof; 
       
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method for treating a condition that responds to a stearoyl-CoA desaturase inhibitor comprising administering to a patient in need thereof an effective amount of a compound of  claim 1  . 
     
     
         19 . The method of  claim 18 , wherein the stearoyl-CoA desaturase inhibitor is a stearoyl-CoA desaturase I (SCD1) inhibitor. 
     
     
         20 . The method according to  claim 18 , wherein the condition is obesity. 
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 15  and a pharmaceutically acceptable carrier. 
     
     
         22 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is 1 or 2; 
         R 1  is selected from the group consisting of phenyl, pyridnyl, thiazolyl, pyrazolyl, isoxazolyl; 
         R 2  is phenyl or cyclohexyl; 
         R 3  and R 4  are each independently hydrogen, halogen or alkyl; or 
         R 3  and R 4 , together with the carbon atom to which they are attached, form a cycloalkyl group; 
         R 5  is hydrogen or alkyl; 
         X is —C(O)— or —S(O) 2 —; 
         wherein, R 1  may optionally be substituted by phenyl, halogenated phenyl, oxadiazole, benzyloxy, oxo-benzooxazole, amide, piperidine, phenylamino, morpholine, pyridine, oxopyridine, thiophene and combinations thereof; 
         wherein, when R 2  is phenyl, it may optionally be substituted by one or more halogen, alkyl, halogenated alkyl, cyano, and combinations thereof; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 22  and a pharmaceutically acceptable carrier.