3-Pyridinecarboxamide derivatives as HDL-cholesterol raising agents

Abstract

The present invention relates to a method of raising HDL cholesterol comprising administering to a patient in need thereof a compound of the formula wherein A, G, R 1 to R 8 and R 17 are as defined in the description.

1 . A method of raising HDL cholesterol comprising administering to a patient in need thereof a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A is CH or N;  
 R 2  is hydrogen and R 1  is selected from the group consisting of: 
 (a) cycloalkyl, which is optionally substituted by hydroxy, lower hydroxyalkyl or lower alkoxy,  
 (b) 1-hydroxy-2-indanyl,  
 (c) lower hydroxyalkyl,  
 (d) lower hydroxyhalogenalkyl,  
 (e) lower hydroxyalkoxyalkyl,  
 (f) —CH 2 —CR 9 R 10 -cycloalkyl, wherein R 9  is hydrogen or lower alkyl; and wherein R 10  is hydrogen, hydroxy or lower alkoxy; and  
 (g) —CR 11 R 12 —COOR 13 ; wherein R 11  and R 12  independently from each other are hydrogen or lower alkyl; and wherein R 13  is lower alkyl;  
 
 or alternatively, R 1  and R 2  together with the nitrogen atom to which they are attached form a morpholinyl ring;  
 G is a group selected from the group consisting of: 
 (a) —X—R 3 , wherein X is O or NR 14 , wherein R 14  is selected from the group consisting of hydrogen, lower alkyl and lower hydroxyalkyl; and R 3  is selected from the group consisting of:  
 (1) lower alkyl,  
 (2) cycloalkyl,  
 (3) lower cycloalkylalkyl,  
 (4) lower hydroxyalkyl,  
 (5) lower alkoxyalkyl,  
 (6) lower halogenalkyl,  
 (7) lower carbamoylalkyl,  
 (8) lower alkylcarbonylaminoalkyl,  
 (9) lower phenylalkyl,  
 (10) lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,  
 (11) lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and  
 (12) phenyl which is unsubstituted or mono- or di-substituted by halogen;  
 
 or alternatively R 3  and R 14  together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing a further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being optionally substituted by one or two groups independently selected from the group consisting of hydroxy, lower alkoxy and halogen;  
 (b) —C≡C—R 15 , wherein R 15  is selected from the group consisting of lower alkoxyalkyl, cycloalkyl and furanyl substituted by halogen; and  
 (c) —CH 2 —CH 2 —R 16 , wherein R 16  is selected from the group consisting of: 
 (1) a cycloalkyl which is optionally substituted by hydroxy or lower alkoxy,  
 (2) a heteroaryl which is pyridyl or imidazolyl, which is optionally substituted by lower alkyl or halogen, and  
 (3) lower alkylaminocarbonyl;  
 
 R 4  and R 8  independently from each other are hydrogen or halogen;  
 R 5  and R 7  independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;  
 R 6  is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano; and  
 R 17  is selected from the group consisting of hydrogen, lower alkyl and lower halogenalkyl.  
 
     
     
         2 . The method of  claim 1 , comprising administering a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A is CH or N;  
 R 2  is hydrogen and R 1  is selected from the group consisting of: 
 (a) cycloalkyl, which is optionally substituted by hydroxy, lower hydroxyalkyl or lower alkoxy,  
 (b) 1-hydroxy-2-indanyl,  
 (c) lower hydroxyalkyl,  
 (d) lower hydroxyhalogenalkyl,  
 (e) lower hydroxyalkoxyalkyl,  
 (f) —CH 2 —CR 9 R 10 -cycloalkyl, wherein R 9  is hydrogen or lower alkyl; and wherein R 10  is hydrogen, hydroxy or lower alkoxy; and  
 (g) —CR 11 R 12 —COOR 13 ; wherein R 11  and R 12  independently from each other are hydrogen or lower alkyl; and wherein R 13  is lower alkyl;  
 or alternatively, R 1  and R 2  together with the nitrogen atom to which they are attached form a morpholinyl ring;  
 
 X is O or NR 14 , wherein R 14  is selected from the group consisting of hydrogen, lower alkyl and lower hydroxyalkyl; and R 3  is selected from the group consisting of: 
 (a) cycloalkyl,  
 (b) lower cycloalkylalkyl,  
 (c) lower hydroxyalkyl,  
 (d) lower alkoxyalkyl,  
 (e) lower halogenalkyl,  
 (f) lower carbamoylalkyl,  
 (g) lower alkylcarbonylaminoalkyl,  
 (h) lower phenylalkyl,  
 (i) lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,  
 (j) lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and  
 (h) phenyl which is unsubstituted or mono- or di-substituted by halogen;  
 
 or alternatively R 3  and R 14  together with the nitrogen atom to which they are attached to form a 4-, 5-, 6- or 7-membered heterocyclic ring optionally containing a further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being optionally substituted by one or two groups independently selected from the group consisting of hydroxy, lower alkoxy and halogen;  
 R 4  and R 8  independently from each other are hydrogen or halogen;  
 R 5  and R 7  independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;  
 R 6  is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano; and  
 R 17  is selected from the group consisting of hydrogen, lower alkyl and lower halogenalkyl.  
 
     
     
         3 . The method of  claim 1 , comprising administering a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein A, R 1  to R 8 , R 15  and R 17  are as defined in  claim 1 .  
     
     
         4 . The method of  claim 1 , comprising administering a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein A, R 1  to R 8 , R 16  and R 17  are as defined in  claim 1 .  
     
     
         5 . The method of  claim 1 , wherein A is CH.  
     
     
         6 . The method of  claim 1 , wherein A is N.  
     
     
         7 . The method of  claim 1 , comprising administering a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 2  is hydrogen and R 1  is selected from the group consisting of: 
 (a) cycloalkyl, which is optionally substituted by hydroxy or lower alkoxy,  
 (b) lower hydroxyalkyl,  
 (c) lower hydroxyhalogenalkyl,  
 (d) —CH 2 —CR 9 R 10 -cycloalkyl, wherein R 9  is hydrogen or lower alkyl; and wherein R 10  is hydrogen, hydroxy or lower alkoxy; and  
 (e) —CR 11 R 12 —COOR 13 ; wherein R 11  and R 12  independently from each other are hydrogen or lower alkyl; and wherein R 13  is lower alkyl;  
 
 X is O or NR 14 , wherein R 14  is hydrogen or lower alkyl  
 R 3  is selected from the group consisting of: 
 (a) lower alkyl,  
 (b) cycloalkyl,  
 (c) lower cycloalkylalkyl,  
 (d) lower alkoxyalkyl,  
 (e) lower halogenalkyl,  
 (f) lower carbamoylalkyl,  
 (g) lower phenylalkyl,  
 (h) lower heterocyclylalkyl  
 (i) lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and  
 (j) phenyl which is unsubstituted or mono- or di-substituted by halogen;  
 or alternatively R 3  and R 14  together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring  
 
 R 4  and R 8  independently from each other are hydrogen or halogen;  
 R 5  and R 7  independently from each other are selected from the group consisting of hydrogen, halogen, lower halogenalkyl, lower halogenalkoxy and cyano; and  
 R 6  is selected from the group consisting of hydrogen, halogen, lower halogenalkyl, lower halogenalkoxy and cyano.  
 
     
     
         8 . The method of  claim 1 , wherein X is O.  
     
     
         9 . The method of  claim 1 , wherein R 1  is cycloalkyl substituted by hydroxy.  
     
     
         10 . The method of  claim 1 , wherein R 1  is —CH 2 —CR 9 R 10 -cycloalkyl and wherein R 9  is hydrogen and R 10  is hydroxy.  
     
     
         11 . The method of  claim 1 , wherein R 3  is selected from the group consisting of lower cycloalkylalkyl, lower alkoxyalkyl and lower halogenalkyl.  
     
     
         12 . The method of  claim 1 , wherein R 6  is halogen or lower halogenalkyl and R 4 , R 5 , R 7  and R 8  are hydrogen.  
     
     
         13 . The method of  claim 1 , wherein: 
 R 1  is cycloalkyl which is substituted by hydroxy, or —CH 2 —CR 9 R 10 -cycloalkyl;    R 9  is hydrogen or lower alkyl;    R 10  is hydrogen, hydroxy or lower alkoxy;    R 2  is hydrogen;    X is O;    R 3  is selected from the group consisting of lower cycloalkylalkyl, lower alkoxyalkyl and lower halogenalkyl;    R 4 , R 5 , R 7  and R 8  are hydrogen; and    R 6  is halogen.    
     
     
         14 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide,    N—((R)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         15 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,    N—((R)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-nicotinamide,    6-butoxy-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    6-cyclopentyloxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(2-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         16 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 6-(2-chloro-phenyl)-5-cyclopentylamino-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-(4-chloro-phenyl)-6-cyclopentyloxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(2-chloro-5-trifluoromethyl-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    6-(4-chloro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (1-hydroxy-indan-2-yl)-amide,    6-(3,4-dichloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N—((R)-1-hydroxymethyl-pentyl)-6-(2-methoxy-ethoxy)-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N-((trans)-2-hydroxy-cyclohexyl)-nicotinamide,    6-cyclopropylmethoxy-5-(3,4-dichloro-phenyl)-N-((trans)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         17 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 6-(4-fluoro-phenyl)-5-(3-methoxy-propoxy)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    5-cyclopropylmethoxy-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    6-((R)-sec-butoxy)-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-1-methyl-ethoxy)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-methoxymethyl-propoxy)-nicotinamide,    6-(4-fluoro-phenyl)-5-((R)-2-methoxy-propoxy)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-[(R)-1-(tetrahydro-furan-2-yl)methoxy]-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-((S)-2-methoxy-propoxy)-nicotinamide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         18 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 6-sec-butoxy-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(4-chloro-phenyl)-5-(3-methyl-butylamino)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-(cyclopropylmethyl-amino)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-Chloro-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide    5,6-bis-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-6-(cyclopropylmethyl-methyl-amino)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(cyclopropylmethyl-methyl-amino)-5-(4-fluoro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    N-(2-cyclopropyl-2-hydroxy-propyl)-6-(cyclopropylmethyl-methyl-amino)-5-(4-fluoro-phenyl)-nicotinamide,    N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-5-(4-trifluoromethyl-phenyl)-nicotinamide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         19 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 5-butoxy-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(methyl-propyl-amino)-nicotinamide,    5-(4-chloro-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(methyl-propyl-amino)-nicotinamide,    5-cyclopropylmethoxy-6-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(2-methoxy-ethoxy)-5-(4-trifluoromethyl-phenyl)-nicotinamide,    5-(4-fluoro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(methyl-propyl-amino)-nicotinamide,    N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-5-(4-trifluoromethoxy-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(pyridin-4-ylmethoxy)-nicotinamide,    6-(4-fluoro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-2-hydroxy-propyl)-amide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         20 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 6-(4-fluoro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    6-(4-fluoro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-cyclopropylmethoxy-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-(4-chloro-phenyl)-N—((R)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    5-(4-chloro-phenyl)-N—((R)-2-cyclopropyl-2-hydroxy-propyl)-6-(3-methyl-isoxazol-5-ylmethoxy)-nicotinamide,    5-cyclopropylmethoxy-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-(cyclopropylmethyl-methyl-amino)-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-cyclopropylmethoxy-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         21 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-methyl-nicotinamide,    N—((R)-2-cyclopropyl-2-hydroxy-propyl)-5-(4-fluoro-phenyl)-6-(pyridin-2-ylmethoxy)-nicotinamide,    6-(4-chloro-phenyl)-5-thiomorpholin-4-yl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-cyclopropylmethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-5-(4-trifluoromethyl-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(pyridin-2-ylmethoxy)-nicotinamide,    5-(4-cyano-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N—((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-nicotinamide,    5-(4-chloro-3-methyl-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-5-(3-methoxy-phenyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-5-(4-trifluoromethoxy-phenyl)-nicotinamide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         22 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-pyridin-2-yl-ethyl)-nicotinamide    5-(4-chloro-phenyl)-6-[2-(5-fluoro-pyridin-2-yl)-ethyl]-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(4-butylcarbamoyl-butoxy)-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-[4-(2-butylcarbamoyl-ethyl)-phenyl]-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(2-fluoro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-fluoro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(3-chloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-chloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(3,4-dichloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    3′-(3-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide, 
 and any pharmaceutically acceptable salt thereof.  
   
     
     
         23 . A compound of formula I as defined in  claim 1 , selected from the group consisting of: 
 6-cyclohexyloxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-butoxy-N-(2-cyclopropyl-2-hydroxy-propyl)-5-(2-fluoro-5-trifluoromethyl-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-6-cyclohexyloxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-cyclopentyloxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    6-cyclopentyloxy-N-(2-cyclopropyl-2-hydroxy-propyl)-5-(2-fluoro-5-trifluoromethyl-phenyl)-nicotinamide,    6-(2-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    6-(2-chloro-phenyl)-5-cyclopentylamino-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-(4-chloro-phenyl)-6-cyclopentyloxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(2-chloro-5-trifluoromethyl-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-phenoxy-nicotinamide,    6-(4-chloro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid (1-hydroxy-indan-2-yl)-amide,    6-(3,4-dichloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    [5-(4-chloro-phenyl)-6-(2-methoxy-ethoxy)-pyridin-3-yl]-morpholin-4-yl-methanone,    5-(4-chloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-(2-propionylamino-ethoxy)-nicotinamide,    5-(4-chloro-phenyl)-N—((R)-1-hydroxymethyl-pentyl)-6-(2-methoxy-ethoxy)-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-6-(2-methoxy-ethoxy)-nicotinamide,    6-cyclopropylmethoxy-5-(3,4-dichloro-phenyl)-N-((trans)-2-hydroxy-cyclohexyl)-nicotinamide,    6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide,    5-(4-chloro-phenyl)-N-(2-hydroxy-3-methoxy-propyl)-6-(2-methoxy-ethoxy)-nicotinamide,    5-(2-chloro-phenoxy)-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    6-(4-fluoro-phenyl)-5-(3-methoxy-propoxy)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    6-((R)-sec-butoxy)-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-isopropoxy-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-1-methyl-ethoxy)-nicotinamide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-methoxymethyl-propoxy)-nicotinamide,    6-(4-fluoro-phenyl)-5-((R)-2-methoxy-propoxy)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-((S)-2-methoxy-propoxy)-nicotinamide,    6-sec-butoxy-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-cyclopropylmethoxy-6-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-(3-methyl-butylamino)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-cyclopropylamino-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-(3-methoxy-azetidin-1-yl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-[3-(2-oxo-pyrrolidin-1-yl)-propoxy]-nicotinamide,    5-(4-fluoro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(3-methoxy-propoxy)-nicotinamide,    6-(4-chloro-phenyl)-5-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-2-hydroxy-propyl)-amide,    N-(2-cyclopropyl-2-hydroxy-propyl)-6-(cyclopropylmethyl-methyl-amino)-5-(4-fluoro-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(methyl-propyl-amino)-nicotinamide,    5-cyclopropylmethoxy-6-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(2-methoxy-ethoxy)-5-(4-trifluoromethyl-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N-(2-cyclopropyl-2-hydroxy-propyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide,    3′-(4-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide,    N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-5-(4-trifluoromethoxy-phenyl)-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(pyridin-4-ylmethoxy)-nicotinamide,    6-(4-fluoro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-cyclopropylmethoxy-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide,    5-(4-cyano-phenyl)-N—((R)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-cyclopropylmethoxy-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N-(1-hydroxymethyl-cyclopentyl)-nicotinamide,    5-[bis-(2-hydroxy-ethyl)-amino]-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(5-bromo-furan-2-ylethynyl)-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(3-methoxy-prop-1-ynyl)-nicotinamide,    5-(4-chloro-phenyl)-6-cyclopropylethynyl-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-methyl-nicotinamide,    5-(2-pyridin-3-yl-ethyl)-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-methyl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide,    6-(4-chloro-phenyl)-5-thiomorpholin-4-yl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-(4,4-difluoro-piperidin-1-yl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-chloro-phenyl)-5-(2-cyclopropyl-ethyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(2-pyridin-2-yl-ethyl)-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide,    5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-[2-(1-hydroxy-cyclopentyl)-ethyl]-nicotinamide,    6-cyclopropylmethoxy-5-(4-fluoro-phenyl)-N—((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-nicotinamide,    5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-trifluoromethyl-nicotinamide    N—((S)-1-hydroxymethyl-3-methyl-butyl)-5-(3-methoxy-phenyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((S)-1-hydroxymethyl-3-methyl-butyl)-5-(4-methoxy-phenyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-chloro-3-methyl-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-5-(3-methoxy-phenyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-5-(4-methoxy-phenyl)-6-pyrrolidin-1-yl-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-5-(4-trifluoromethyl-phenyl)-nicotinamide,    N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-5-(4-trifluoromethoxy-phenyl)-nicotinamide,    5-(4-cyano-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    N-((1R,2R)-2-hydroxy-cyclohexyl)-6-[2-(3-methyl-3H-imidazol-4-yl)-ethyl]-5-(4-trifluoromethyl-phenyl)-nicotinamide,    (R)-2-{[6-(4-fluoro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester    6-(4-butylcarbamoyl-butoxy)-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-[4-(2-butylcarbamoyl-ethyl)-phenyl]-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide,    5-(2,4-dichloro-phenyl)-N-(2-hydroxy-ethyl)-6-propoxy-nicotinamide,    6-cyclopentylmethoxy-5-(2,4-dichloro-phenyl)-N-(2-hydroxy-ethyl)-nicotinamide,    5-(4-chloro-phenyl)-N—((S)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(3,4-dichloro-phenyl)-N—((S)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-chloro-3-methyl-phenyl)-N—((S)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(2-fluoro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-fluoro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(3-chloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(4-chloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    5-(3,4-dichloro-phenyl)-N—((R)-1-hydroxymethyl-3-methyl-butyl)-6-pyrrolidin-1-yl-nicotinamide,    3′-(3-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide, 
 and any pharmaceutically acceptable salt thereof.