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 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 formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is halogenated alkyl; 
         R 2 , R 3 , R 4  and R 5  are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl; 
         R 6  and R 7  are each independently hydrogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 8  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 9  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         X is —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O)—, or —C(O)NR 16 —, where R 16  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         Y is —C(O)—, —S(O) 2 —, or —S(O)—; 
         wherein, when present, any aryl, heteroaryl, or heterocycle group may optionally be substituted by halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylalkyl-C(O)—, —C(O)O-alkyl, benzodioxol, benzo[d]oxazol-2(3H)-one, cycloalkyl-NH—C(O)—, and combinations thereof; 
         or pharmaceutically acceptable salts thereof; 
         with the proviso that said compound is not 4-chloro-N-[2-oxo-2-[4-[[2-(trifluoromethyl)phenyl]sulfonyl]-1-piperazinyl]ethyl]benzamide or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the condition is obesity or diabetes. 
     
     
         3 . 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 formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 11  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 12  and R 13  are each independently hydrogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 15  is hydrogen or alkyl; 
         A is —C(O)—, —S(O) 2 —, or —S(O)—; 
         B is a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O)—, or —C(O)NR 15 —, where R 15  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 14  is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         wherein, when present, any aryl, heteroaryl, or heterocycle group may optionally be substituted by halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl and combinations thereof; 
         or pharmaceutically acceptable salts thereof; 
         with the proviso that when B is a bond, R 14  is arylalkyl; and 
         said compound is not 
         N-[2-[4-(2-furanylcarbonyl)-1-piperazinyl]-2-oxoethyl]-[1,1′-biphenyl]-4-carboxamide, 
         N-[2oxo-2-[4-(2-thienylcarbonyl)-1-piperazinyl]ethyl]-[1,1′-biphenyl]-4-carboxamide, or 
         N-[1-methyl-2-oxo-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-[1,1′-biphenyl]-4-carboxamide, 
         N-[2-[4-[(4-cyanophenyl)methyl]-1-piperazinyl]-2-oxoethyl]-[1,1′-biphenyl]-4-carboxamide, 
         2-[([1,1′-biphenyl]-4-ylmethyl)amino]3-phenyl-1-[4-(phenylmethyl)-1-piperazinyl]-1-propanone, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method according to  claim 3 , wherein the condition is obesity or diabetes. 
     
     
         5 . 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 formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R 16  is hydrogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 17  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 18  and R 19  are each independently hydrogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 20  is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         J is —C(O)—, —S(O) 2 —, or —S(O)—; 
         G is a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O)—, or —C(O)NR 21 —, where R 21  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         T is —O—, —S—, —NH—, —C(O)—, —S(O)— or —S(O) 2 —; 
         wherein, when present, any aryl, heteroaryl, or heterocycle group may optionally be substituted by halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl and combinations thereof; 
         or pharmaceutically acceptable salts thereof; 
         with the proviso that when J is —C(O)—, R 17 -R 19  are hydrogen and G is a bond, then R 20  is not thienylmethyl, thiazolylmethyl, pyridinyl, thiazolylmethyl, pyrrolidinylethyl or pyridinylmethyl; 
         and said compound is not 
         N-[2-[4-(2-furanylcarbonyl)-1-piperazinyl]2-oxoethyl]-4-phenoxy-benzamide, 
         N-[2-[4-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1-piperazinyl]-2-oxoethyl]-4-phenoxy-benzamide, 
         N-[(3,5-dimethyl-4-isoxazolyl)methoxy]-N-methyl-N-[2-oxo-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-benzamide, 
         N-2-oxo-2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethyl]-4-phenoxy-benzamide, 
         N-[2-oxo-2-[4-(2-thienylcarbonyl)-1-piperazinyl]ethyl]-4-phenoxy-benzamide, or 
         N-methyl-N-[2-[4-[(3-methylphenyl)methyl]-1-piperazinyl]-2-oxoethyl]-4-(1-pyrrolidinylsulfonyl)-benzamide, 
         N-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl]-4-phenoxy-benzamide, 
         N-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-2-oxoethyl]-4-phenoxy-benzamide, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The method according to  claim 5 , wherein the condition is obesity or diabetes. 
     
     
         7 . 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 formula (IV): 
       
         
           
           
               
               
           
         
         wherein 
         R 21  is halogen; 
         R 24  is halogen or alkoxy; 
         R 22 , R 23  and R 25  are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl; 
         R 26  and R 27  are each independently hydrogen, hydroxyl, cyano, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 28  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         R 29  is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         D is —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O)—, or —C(O)NR 30 —, where R 30  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         M is —C(O)—, —S(O) 2 —, or —S(O)—; 
         wherein, when present, any aryl, heteroaryl, or heterocycle group may optionally be substituted by halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl and combinations thereof; 
         or pharmaceutically acceptable salts thereof; 
         with the proviso that said compound is not 
         N-[2-[4-[(2,5-difluorophenyl)sulfonyl]1-piperazinyl]2-oxoethyl]-3-fluoro-benzamide, 
         N-[2-[4-[(2,5-difluorophenyl)sulfonyl]1-piperazinyl]2-oxoethyl]-3,4-dimethoxy-benzamide, 
         N-[2-[4-(2-bromo-5-methoxybenzoyl)-1-piperazinyl]-2-oxoethyl]-4-methoxy-2-quinolinecarboxamide, 
         N-[2-[4-(2,5-dibromophenyl)sulfonyl)-1-piperazinyl]-2-oxoethyl]-4-methoxy-2-quinolinecarboxamide, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method according to  claim 7 , wherein the condition is obesity or diabetes. 
     
     
         9 . 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 formula (V): 
       
         
           
           
               
               
           
         
         Wherein 
         R 31  is halogenated alkyl; 
         R 32 , R 33 , R 34  and R 35  are each independently hydrogen or halogen; 
         R 36  and R 37  are each independently hydrogen or alkyl; 
         R 38  is hydrogen or alkyl; 
         R 39  is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl; 
         X 1  is —C(O)—, —S(O) 2 —, or —S(O)—; 
         Y 1  is —C(R 40 )(R 41 )—, where R 40  and R 41  are each independently hydrogen or alkyl; 
         wherein, when present, any aryl, heteroaryl, or heterocycle group may optionally be substituted by halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl and combinations thereof; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         10 . The method according to  claim 9 , wherein the condition is obesity or diabetes.