Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto

Abstract

The present invention relates to certain substituted pyridinyl and pyrimidinyl derivatives of Fomula (Ia) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the treatment of metabolic-related disorders and complications thereof, such as, diabetes and obesity.

1 . A compound of Formula (Ia):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         X is N or CR 8  wherein R 8  is H or halogen;  
         Y is NH or O;  
         Z is CH or N;  
         R 1  is carbo-C 1-6 -alkoxy, oxadiazolyl or pyrimidinyl wherein said carbo-C 1-6 -alkoxy, oxadiazolyl and pyrimidinyl are each optionally substituted with 1 or 2 substituents selected independently from the group consisting of C 1-4  alkyl, C 1-4  alkoxy and C 3-5  cycloalkyl;  
         R 2  is H or C 1-4  alkyl;  
         R 3  is C 1-4  alkoxy, O—C 2-4 -alkynyl or hydroxyl;  
         R 4  is selected from the group consisting of H, C 1-4  alkoxy, C 1-4  alkyl, C 2-4  alkynyl and halogen;  
         R 5  is selected from the group consisting of C 1-4  acylsulfonamide, C 1-4  alkoxy, C 1-4  alkyl, C 1-4  alkylamino, C 1-4  alkylsulfonyl, C 1-4  alkylthio, cyano, heterocyclyl, di-C 1-4 -dialkylamino and sulfonamide, wherein said C 1-4  alkoxy, C 1-4  alkyl, C 1-4  alkylamino, C 1-4  alkylsulfonyl, C 1-4  alkylthio, di-C 1-4 -dialkylamino and heterocyclyl are each optionally substituted with 1 or 2 substituents selected independently from the group consisting of C 2-4  alkynyl, C 1-4  alkoxy, C 1-4  alkylcarboxamide, C 1-4  alkylsulfonyl, C 3-5  cycloalkyl, C 3-5  cycloalkyloxy, di-C 1-4 -alkylcarboxamide, hydroxyl and phosphonooxy, wherein said C 1-4  alkylcarboxamide is optionally substituted with hydroxyl; or  
         R 5  is a group of Formula (A):  
         
           
             
             
                 
                 
             
           
         
         wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0, 1 or 2; and “t” is 0 or 1;  
         R 6  is H or halogen; and  
         R 7  is H or C 1-4  alkyl.  
       
     
     
         2 . The compound according to  claim 1  wherein X is N.  
     
     
         3 . The compound according to  claim 1  wherein X is CR 8 .  
     
     
         4 . The compound according to  claim 1  wherein R 8  is H or F.  
     
     
         5 . The compound according to  claim 1  wherein Y is NH.  
     
     
         6 . The compound according to  claim 1  wherein Y is O.  
     
     
         7 . The compound according to  claim 1  wherein Z is CH.  
     
     
         8 . The compound according to  claim 1  wherein Z is N.  
     
     
         9 . The compound according to  claim 1  wherein R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl.  
     
     
         10 . The compound according to  claim 1  wherein R 1  is selected form the group consisting of C(O)OCH 2 CH 3 , C(O)OCH(CH 3 ) 2 , C(O)OCH(CH 3 )(CH 2 CH 3 ), C(O)OCH 2 -cyclopropyl, C(O)OCH(CH 3 )(cyclopropyl), and C(O)OCH(CH 2 CH 3 ) 2 .  
     
     
         11 . The compound according to  claim 1  wherein R 1  is selected form the group consisting of C(O)OCH 2 CH 3 , C(O)OCH(CH 3 ) 2 , C(O)OCH(CH 3 )(CH 2 CH 3 ), C(O)OCH 2 -cyclopropyl and C(O)OCH(CH 3 )(cyclopropyl).  
     
     
         12 . The compound according to  claim 1  wherein R 1  is oxadiazolyl optionally substituted with one C 1-4  alkyl group.  
     
     
         13 . The compound according to  claim 1  wherein R 1  is 5-isopropyl-[1,2,4]oxadiazol-3-yl.  
     
     
         14 . The compound according to  claim 1  wherein R 1  is pyrimidinyl optionally substituted with one C 1-4  alkoxy group.  
     
     
         15 . The compound according to  claim 1  wherein R 1  is 5-methoxy-pyrimidin-2-yl.  
     
     
         16 . The compound according to  claim 1  wherein R 2  is H.  
     
     
         17 . The compound according to  claim 1  wherein R 2  is CH 3 .  
     
     
         18 . The compound according to  claim 1  wherein R 3  is C 1-4  alkoxy.  
     
     
         19 . The compound according to  claim 1  wherein R 3  is OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , and OCH 2 CH 2 CH 3 .  
     
     
         20 . The compound according to  claim 1  wherein R 3  is OCH 3  or OCH 2 CH 3 .  
     
     
         21 . The compound according to  claim 1  wherein R 3  is OH or O—C≡CH.  
     
     
         22 . The compound according to  claim 1  wherein R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F, Cl and C≡CH.  
     
     
         23 . The compound according to  claim 1  wherein R 4  is CH 3 .  
     
     
         24 . The compound according to  claim 1  wherein R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NH 2 , CH 3 , SCH 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , SCH 2 CH 3 , SCH(CH 3 ) 2 , S(O) 2 CH(CH 3 ) 2 , and CH 2 OH.  
     
     
         25 . The compound according to  claim 1  wherein R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2  and S(O) 2 NH 2 .  
     
     
         26 . The compound according to  claim 1  wherein R 5  is selected from the group consisting of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, amino, NHCH 2 CH 3 , NHCH(CH 3 ) 2  and NHCH(CH 3 )CH 2 CH 3 .  
     
     
         27 . The compound according to  claim 1  wherein R 5  is a group of Formula (A):  
       
         
           
           
               
               
           
         
         wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0, 1 or 2; and “t” is 0 or 1.  
       
     
     
         28 . The compound according to  claim 1  wherein “m” and “n” are each independently 0 or 1.  
     
     
         29 . The compound according to  claim 1  wherein “q” is 0 or 1 and “r” is 1 or 2.  
     
     
         30 . The compound according to  claim 1  wherein R 6  is H.  
     
     
         31 . The compound according to  claim 1  wherein R 6  is F.  
     
     
         32 . The compound according to  claim 1  wherein R 7  is H.  
     
     
         33 . The compound according to  claim 1  wherein R 7  is CH 3 .  
     
     
         34 . The compound according to  claim 1  having Formula (IIa):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         Y is NH or O;  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2  and S(O) 2 NH 2 ;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         35 . The compound according to  claim 1  having Formula (IIc):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2  and S(O) 2 NH 2 ;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         36 . The compound according to  claim 1  having Formula (IIe):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2  and S(O) 2 NH 2 ;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         37 . The compound according to  claim 1  having Formula (IIe):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 5  is selected from the group consisting of OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 CH 2 OH, S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH and S(O) 2 NH 2 ;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         38 . The compound according to  claim 1  having Formula (IIg):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 5  is selected from the group consisting of OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 OH, S(O) 2 CH 3 , CH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH 2 OH, cyano, CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(CH 3 )OH, CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 NHC(O)CH 2 CH 3 , CH 2 CH 2 O-cyclopropyl, NHCH 2 CH 2 OCH 3 , OCH 2 CH 2 S(O) 2 CH 3 , NHCH 2 CH(CH 3 )OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OP(O)(OH) 2 , NHCH 2 CH(CH 3 )S(O) 2 CH 3 , N(CH 3 )CH 2 CH(CH 3 )S(O) 2 CH 3 , 3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl, CH 2 C(O)N(CH 3 ) 2 , 3-methanesulfonyl-azetidin-1-yl, CH 2 C(O)NHCH 2 CH 2 OH, SCH 2 CH 2 OH, S(O) 2 CH 2 CH 2 OP(O)(OH) 2 , S(O) 2 CH 2 CH 3 , NHCH 2 CH(OH)CH 2 OH, S(O) 2 CH 2 CH 2 OH, OCH 2 CH 2 OP(O)(OH) 2 , OCH 2 CH 2 CH 2 OP(O)(OH) 2  and S(O) 2 NH 2 ;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         39 . The compound according to  claim 1  having Formula (IIi):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or hydrate thereof;  
         wherein:  
         “m” and “n” are each independently 0 or 1;  
         “q” is 0 or 1;  
         “r” is 1 or 2;  
         X is N or O;  
         R 1  is carbo-C 1-6 -alkoxy optionally substituted with C 3-5  cycloalkyl;  
         R 2  is H or CH 3 ;  
         R 3  is C 1-4  alkoxy;  
         R 4  is selected from the group consisting of H, OCH 3 , CH 3 , CH 2 CH 3 , F and Cl;  
         R 6  is H or F; and  
         R 7  is H or CH 3 .  
       
     
     
         40 . The compound according to  claim 1  selected from the group consisting of: 
 4-[6-(4-Methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[6-(2-methoxy-ethyl)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid 1-cyclopropyl-ethyl ester;    4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Hydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methoxy-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenylamino}-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Methanesulfonyl-ethylamino)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[2-Fluoro-4-(2-hydroxy-ethylsulfanyl)-phenylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester; and    4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester; 
 or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
     
     
         41 . The compound according to  claim 1  selected from the group consisting of: 
 4-[2-(2-Fluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(2-hydroxy-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[5-Fluoro-2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Ethyl-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-2-methyl-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Fluoro-2-[6-(2-hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(4-Cyano-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(2-Chloro-4-cyano-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(3-Hydroxy-butyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{3-Ethoxy-2-[2-fluoro-4-(2-phosphonooxy-ethyl)-phenylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[3-Methoxy-2-(2-methoxy-4-propionylsulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    (2-Fluoro-4-methanesulfonyl-phenyl)-{4-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yloxy]-3-methoxy-pyridin-2-yl}-amine;    (2-Fluoro-4-methanesulfonyl-phenyl)-{3-methoxy-4-[1-(5-methoxy-pyrimidin-2-yl)-piperidin-4-yloxy]-pyridin-2-yl}-amine;    4-{2-[6-(2-Cyclopropoxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(2-Chloro-4-methanesulfonyl-phenylamino)-5-fluoro-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[3-Ethoxy-2-(4-methanesulfonyl-2-methoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(5-Fluoro-2-methyl-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-hydroxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(2-Chloro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-(2-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-ylamino}-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(3-Methanesulfonyl-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(3-Methanesulfonyl-azetidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[3-Ethynyloxy-2-(2-fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(2-phosphonooxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[2-(4-Ethanesulfonyl-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid sec-butyl ester;    4-{2-[6-(2,3-Dihydroxy-propylamino)-4-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(2-hydroxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[3-Methoxy-2-(2-methoxy-4-sulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[2-Fluoro-4-(3-phosphonooxy-propyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{2-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester; and    4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester; 
 or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
     
     
         42 . The compound according to  claim 1  selected from the group consisting of: 
 4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[5-Methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[2-methyl-6-(propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Ethanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-{5-Methoxy-6-[2-methyl-6-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;    4-[5-Hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[5-Ethoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[5-Isopropoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid 1-ethyl-propyl ester;    4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid sec-butyl ester;    4-[6-(6-Cyano-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester; and    4-[6-(6-Hydroxymethyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;    {6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine;    4-[6-(6-Methanesulfonyl-2,4-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester; and    4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl; 
 or a pharmaceutically acceptable salt, solvate or hydrate thereof.  
   
     
     
         43 . A pharmaceutical composition comprising at least one compound according to  claim 1 ,  40 ,  41 , or  42 , and a pharmaceutically acceptable carrier.  
     
     
         44 . A method for treatment of a metabolic-related disorder in an individual comprising administering to said individual in need of such treatment a therapeutically effective amount of a compound according to  claim 1 ,  40 ,  41 , or  42 .  
     
     
         45 . The method according to  claim 44  wherein said metabolic-related disorder is selected from the group consisting of type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.  
     
     
         46 . The method according to  claim 44  wherein said metabolic-related disorder is type II diabetes.  
     
     
         47 . A method of decreasing food intake of an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         48 . A method of inducing satiety in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         49 . A method of controlling or decreasing weight gain of an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         50 . A method of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound according to  claim 1 ,  40 ,  41 , or  42 .  
     
     
         51 . The method of modulating the RUP3 receptor according to  claim 50  wherein said compound is an agonist.  
     
     
         52 . The method of modulating the RUP3 receptor according to  claim 50  wherein said modulation of the RUP3 receptor is for treatment of a metabolic-related disorder.  
     
     
         53 . The method of modulating the RUP3 receptor according to  claim 52  wherein said metabolic-related disorder is selected from the group consisting of type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.  
     
     
         54 . The method of modulating the RUP3 receptor according to  claim 52  wherein said metabolic-related disorder is type II diabetes.  
     
     
         55 . The method of modulating the RUP3 receptor according to  claim 50  wherein said modulation of the RUP3 receptor reduces food intake of said individual.  
     
     
         56 . The method of modulating the RUP3 receptor according to  claim 50  wherein said modulation of the RUP3 receptor induces satiety in said individual.  
     
     
         57 . The method of modulating the RUP3 receptor according to  claim 50  wherein said modulation of the RUP3 receptor controls or reduces weight gain of said individual.  
     
     
         58 . A method of producing a pharmaceutical composition comprising admixing a compound of  claim 1 ,  40 ,  41 , or  42  and a pharmaceutically acceptable carrier.