Heteroaryl-ureas and their use as glucokinase activators

Abstract

This invention relates to compounds of formula (I) which are activators of glucokinase and thus may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

The invention claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is 
       
       
         
           
           
               
               
           
         
         R 2  is 
       
       
         
           
           
               
               
           
         
       
       and
 R 5  and R 31  are independently selected from the group consisting of 
  halogen, nitro, cyano, hydroxy, oxo, carboxy, —CF 3 ; or —NR 10 R 11 ; or
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6  cycloalkyl-C 1-6 -alkoxy, aryl-C 1-6 -alkoxy, heteroaryl, heteroaryl-C 1-6 -alkoxy, aryloxy, heteroaryloxy, C 1-6 -alkylthio, arylthio, heteroarylthio, C 3-8 -cycloalkylthio, aryl-C 1-6 -alkylthio, heteroaryl-C 1-6 -alkylthio, C 1-6 -alkylsulfenyl, C 3-6 -cycloalkyl-C 1-6 -alkylthio, C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkylthio-C 1-6 -alkyl, carboxy-C 1-6 -alkyloxy, amino-C 1-6 -alkyl, C 1-6 -alkylamino-C 1-6 -alkyl, di-(C 1-6 -alkyl)amino-C 1-6 -alkyl, C 1-6 -alkylsulfamoyl, di (C 1-6 -alkyl)sulfamoyl, C 1-6 -alkylsulfinamoyl or di(C 1-6 -alkyl)sulfinamoyl each of which is optionally substituted with one or more substituents independently selected from R 12 ; or 
 —C(O)—R 27 , —S(O) 2 —R 27 , —C(O)—NR 13 R 14 , —S(O) 2 —NR 13 R 14 , —C 1-6 -alkyl-C(O)—NR 13 R 14 ; 
 
 R 10  and R 11  independently represent hydrogen, C 1-6 -alkyl, —C(O)—C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C(O)—C 1-6 -alkyl-C(O)OH, —S(O) 2 —C 1-6 -alkyl, or aryl; 
 R 27  is C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 cycloalkyl-C 1-6 -alkyl, C 3-8 cycloalkyl-C 2-6 -alkenyl, aryl, aryl-C 1-6 -alkyl, aryloxy-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl, C 3-8 -heterocyclyl, heteroaryl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, heteroaryloxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, carboxy-C 2-6 -alkenyl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 2-6 -alkenyl, C 1-6 -alkylthio-C 1-6 -alkyl, R 10 HN—C 1-6 -alkyl, R 10 R 11 —N—C 1-6 -alkyl, R 10 R 11 —N—C 2-6 -alkenyl, R 10 R 11 —N—S(O) 2 —C 1-6 -alkyl, R 10 R 11 —N—C(O)—C 1-6 -alkyl, C 1-6 -alkyl-C(O)—NH—C 1-6 -alkyl, aryl-C(O)—NH—C 1-6 -alkyl, heteroaryl-C(O)—NH—C 1-6 -alkyl, C 3-8 -cycloalkyl-C(O)—NH—C 1-6 -alkyl, C 1-6 -alkyl-S(O) 2 —NH—C 1-6 -alkyl, aryl-S(O) 2 —NH—C 1-6 -alkyl, heteroaryl-S(O) 2 —NH—C 1-6 -alkyl, or C 3-8 -cycloalkyl-S(O) 2 —NH C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 12 ; 
 R 12  is halogen, cyano, hydroxy, —C(O)—O—C 1-6 -alkyl, carboxy, —CF 3 , C 1-6 -alkyl, C 1-6 -alkoxy, —NR 10 R 11 , —S(O) 2 CH 3 , or —S(O) 2 NH 2 ; 
 R 13  and R 14  are independently selected from the group consisting of hydrogen, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from R 15 ; or R 13  and R 14  together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur; 
 R 15  is halogen, cyano, hydroxy, carboxy, —CF 3 , C 1-6 -alkyl, —S(O) 2 CH 3 , or —S(O) 2 NH 2 ; 
 A is 
 
       
         
           
           
               
               
           
         
         R 8  is selected from
 halogen, carboxy, cyano, nitro, hydroxy, —CF 3 , —SCN; or 
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 1-6 -alkylthio, C 2-6 -alkenylthio, C 1-6 -alkylamino, C 1-6 -alkylsulfenyl, C(O) O C 1-6 -alkyl, formyl, —C(O)—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-O—C(O)—C 1-6 -alkyl, —NH—C(O)—C 1-6 -alkyl, —C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 alkyl-S C 1-6 -alkyl, carboxy-C 1-6 -alkyl, or hydroxy-C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or 
 aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, aryl-C 1-6 -alkoxy, heteroaryl-C 1-6 -alkoxy, aryl-C 1-6 -alkylthio, heteroaryl-C 1-6 -alkylthio, heteroaryl-thio-C 1-6 -alkyl, heteroaryl-oxy-C 1-6 -alkyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-C 1-6 -alkylamino, —C(O)-aryl, or —C(O)-heteroaryl, each of which is optionally substituted on the aryl or heteroaryl part with one or more substituents independently selected from R 17 ; or 
 C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, C 3-8 -cycloalkylthio, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkenyl-C 1-6 -alkyl, C 3-6 -cycloalkyl-C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkylthio, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from R 18 ; or 
 C 3-8 -heterocyclyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkylthio, C 3-8 -heterocyclylthio, C 3-8 -heterocyclyl-amino-C 1-6 -alkyl, or C(O) C 3-8 -heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or 
 —NR 19 R 20 , —C 1-6 -alkyl-NR 19 R 20 , —C 2-6 -alkenyl-NR 19 R 20 , —C 1-6 -alkyl-S—R 21 , —C 1-6 -alkyl-S (O) R 21 , C 1-6 -alkyl-S(O) 2  R 21 , S(O) 2  R 21  or —S(O) 2 —NR 19 R 20 , wherein each alkyl part may be substituted with one or more substituents independently selected from R 25 ; or 
 —C(O)NR 22 R 23 , —C 1-6 -alkyl-C(O)NR 22 R 23 —C 1-6 -alkyl-NH—NR 22 R 23  —C 1-6 -alkyl-NH—C(O)—C 1-6 -alkyl-NR 22 R 23 , each optionally substituted with one or more substituents independently selected from R 26 ; or 
 
         R 16 , R 17 , and R 18  are independently C 1-6 -alkyl, halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF 3 , carboxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkyl-C(O) O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—NR 19 R 20 , —C(O)—O—C 1-6 -alkyl, —C(O)—C 1-6 -alkyl-C(O)—C 1-6 -alkyl, —NR 19 NR 20 , —NHS(O) 2 C 1-6 -alkyl, —C(O) NR 19 R 20 , S(O) 2 C 1-6 -alkyl, or S(O) 2 NR 19 R 20 ; 
         R 19  and R 20  independently represent hydrogen, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, aryl, heteroaryl C 3-8 -heterocyclyl, aryl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-NR 22 R 23 , or —S(O) 2 —C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 24 , or R 19  and R 20  together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 ; 
         R 21  is selected from
 C 1-56 -alkyl C 2-6 -alkenyl, carboxy-C 1-6 -alkyl, C 1-6 -alkylamino-C 1-6 -alkyl or hydroxy-C 1-6 -alkyl, —C 1-6 -alkyl-NR 22 R 23 ; or 
 aryl, heteroaryl, aryl-C 1-6 -alkyl, or heteroaryl-C 1-6 -alkyl, wherein the aryl or heteroaryl part is optionally substituted with one or more substituents independently selected from R 24 ; or 
 C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkenyl-C 1-6 -alkyl; 
 
         R 22  and R 23  are independently selected from hydrogen, C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-6 -alkyl-C(O) O—C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-S(O) 2 —C 1-6 -alkyl, C 3-8 -cycloalkyl, aryl, or heteroaryl; or R 22  and R 23  together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 ; 
         R 24  is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF 3 , C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C(O)—C 1-6 -alkyl, —C(O)—C 3-8 -cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)—C 3-8 -heterocyclyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 3-8 -cycloalkyl-C 1-6- alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—C 3-8 -heterocyclyl, —C(O)—O—C 1-6 -alkyl-aryl, —NH—S(O) 2 R 28 , or —S(O) 2 R 28 , wherein each cyclic moiety is optionally substituted with one or more substituents independently selected from R 29 ; 
         R 25  and R 26  are independently C 1-6 -alkyl, halogen, nitro, cyano, hydroxy, —C(O)—O—C 1-6 -alkyl, carboxy, C 1-6 -alkyl-C(O) O C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —CF 3 , —S(O) 2 CH 3 , or —S(O) 2 NH 2 ; 
         R 28  is C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C 1-6 -alkyl-C (O)—O—C 1-6 -alkyl, C 3-8 -cycloalkyl, aryl, aryl-C 1-6 -alkyl, heteroaryl optionally substituted with C 1-6 -alkyl, NH 2 , or N(CH 3 ) 2 ; 
         R 29  is halogen, nitro, cyano, hydroxy, carboxy, oxo, —CF 3 , C 1-6 -alkyl, or C 1-6 -alkoxy; 
         as well as any salt hereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, racemic mixture, or tautomeric form thereof. 
       
     
     
       2. A compound according to  claim 1 , wherein R 5  and R 31  are independently selected from the group consisting of
 halogen, oxo, cyano, hydroxy, carboxy, —CF 3 ; or   —NR 10 R 11 ; or   C 1-6 -alkyl, C 2-6 -alkenyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkoxy, aryl-C 1-6 -alkoxy, C 1-6 -alkylthio, arylthio, —C(O)—O—C 1-6 -alkyl, or C 1-6 -alkyl-C (O)—O—C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 12 ; or   —C(O)—R 27 , —S(O) 2 —R 27 , —C(O)—NR 13 R 14 , —S(O) 2 —NR 13 R 14 , —C 1-6 -alkyl-C(O)—NR 13 R 14 ; or   two substituents selected from R 3 , R 4 , R 5  and R 6  or R 30 , R 31 , R 32  and R 33  attached to the same or adjacent atoms together form a radical —O—(CH 2 ) 1-3 —O—.   
     
     
       3. A compound according to  claim 2 , wherein R 5  and R 31  are independently selected from the group consisting of
 halogen, oxo, —CF 3 ; or   NR 10 R 11 ; or   C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, aryl, aryl-C 1-6 -alkyl, arylthio, —C(O)—O—C 1-6 -alkyl, or C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 12 ; or   —C(O)—R 27 , —S(O) 2 —NR 13 R 14  or —S(O) 2 —R 27 ; or   two substituents selected from R 3 , R 4 , R 5  and R 6  or R 30 , R 31 , R 32  and R 33  attached to the same or adjacent atoms together form a radical O (CH 2 ) 1-3  O.   
     
     
       4. A compound according to  claim 3 , wherein R 5  and R 31  are independently selected from the group consisting of
 halogen, —CF 3 ; or   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy. propoxy, phenylthio, —C(O)—O—CH 3 , or —C(O)—O—CH 2 CH 3 , each of which is optionally substituted with one or more substituents independently selected from R 12 ; or   —C(O)—R 27 , —S(O) 2 —NR 13 R 14  or —S(O) 2 —R 27 ; or   two substituents selected from R 3 , R 4 , R 5  and R 6  or R 30 , R 31 , R 32  and R 33  attached to the same or adjacent atoms together form a radical —O—(CH 2 ) 1-3 —O—.   
     
     
       5. A compound according to  claim 4 , wherein R 5  and R 31  are independently selected from the group consisting of
 halogen, —CF 3 ; or   methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphtyl, benzyl, phenyl-ethyl, methoxy, ethoxy, propoxy, phenylthio, —C(O)—O—CH 3 , or —C(O)—O—CH 2 CH 3 , each of which is optionally substituted with one or more substituents independently selected from R 12 ; or   —C(O)—R 27 , -—S(O) 2 —NR 13 R 14  or —S(O) 2 —R 27 .   
     
     
       6. A compound according to  claim 5 , wherein R 5  and R 31  are independently selected from the group consisting of F, Cl, —CF 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, —C(O)—R 27 , —S(O) 2 —NR 13 R 14  or —S(O) 2 —R 27 . 
     
     
       7. A compound according to  claim 3 , wherein R 5  and R 31  are independently selected from C 1-6 -alkyl, C 1-6 -alkoxy, —S(O) 2 —R 27  or —C(O)—R 27 . 
     
     
       8. A compound according to  claim 1 , wherein R 10  and R 11  independently represent hydrogen, methyl, ethyl, propyl, —C(O)—CH 3 , —C(O)—CH 2 CH 3 , —CH 2 —C(O)OH, —CH 2 CH 2 C(O)OH, —C(O)—CH 2 C(O)OH, —C(O)—CH 2 CH 2 —C(O)OH, S(O) 2 CH 3 , or phenyl. 
     
     
       9. A compound according to  claim 8 , wherein R 10  and R 11  independently represent hydrogen, methyl, ethyl, —C(O)—CH 3 , —CH 2 C(O)OH, —C(O)—CH 2 —C(O)OH, —S(O) 2 CH 3 , or phenyl. 
     
     
       10. A compound according to  claim 9 , wherein R 10  and R 11  independently represent hydrogen, methyl, ethyl, or phenyl. 
     
     
       11. A compound according to  claim 1 , wherein R 27  is C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl, heteroaryl-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, C 1-6 -alkthio-C 1-6 -alkyl, R 10 HN—C 1-6 -alkyl, R 10 R 11 N—C 1-6 -alkyl, R 10 R 11 N—S(O) 2 —C 1-6 -alkyl, or R 10 R 11 N—C(O)—C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 12 . 
     
     
       12. A compound according to  claim 11 , wherein R 27  is C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 3-8 cycloalkyl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl, heteroaryl, heteroaryl-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, R 10 HN—C 1-6 -alkyl, R 10 R 11 N—C 1-6 -alkyl, R 10 R 11 N(O) 2 —C 1-6 -alkyl, or R 10 R 11 N(O)—C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 12 . 
     
     
       13. A compound according to  claim 12 , wherein R 27  is C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 alkyl, aryl, heteroaryl-C 1-6 -alkyl, aryl-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from R 12 . 
     
     
       14. A compound according to  claim 13 , wherein R 27  is methyl, ethyl, propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole, or thiazole, each of which is optionally substituted with one or more substituents independently selected from R 12 . 
     
     
       15. A compound according to  claim 14 , wherein R 27  is methyl, ethyl, propyl, n-butyl, isobutyl, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, phenyl, or pyridyl, thiophene, imidazole, or thiazole. 
     
     
       16. A compound according to  claim 1 , wherein R 12  is halogen, cyano, hydroxy, carboxy, —CF 3 , or C 1-6 -alkyl. 
     
     
       17. A compound according to  claim 16 , wherein R 12  is halogen, cyano, hydroxy, carboxy, —CF 3 , methoxy, methyl, ethyl or propyl. 
     
     
       18. A compound according to  claim 17 , wherein R 12  is halogen, carboxy, methyl, ethyl or propyl. 
     
     
       19. A compound according to  claim 1 , wherein R 13  and R 14  are independently selected from the group consisting of hydrogen, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, phenyl, or naphtyl, each of which is optionally substituted with one or more substituents independently selected from R 15 ; or R 13 3  and R 14  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur. 
     
     
       20. A compound according to  claim 19 , wherein R 13  and R 14  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, hydroxy-methyl, hydroxy-ethyl, carboxy-methyl, carboxy-ethyl, phenyl, or naphtyl, each of which is optionally substituted with one or more substituents independently selected from R 15 ; or R 13  and R 14  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur. 
     
     
       21. A compound according to  claim 20 , wherein R 13  and R 14  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, or phenyl, each of which is optionally substituted with one or more substituents independently selected from R 15 . 
     
     
       22. A compound according to  claim 1 , wherein R 15  is halogen, cyano, hydroxy, carboxy, —CF 3 , methyl, ethyl, or propyl. 
     
     
       23. A compound according to  claim 22 , wherein R 15  is halogen, hydroxy, carboxy, —CF 3 , methyl, or ethyl. 
     
     
       24. A compound according to  claim 1 , wherein R 8  is selected from
 halogen, carboxy, cyano, nitro, hydroxy, —CF 3 , —SCN; or   C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylamino, C 1-6 -alkylsulfenyl, —C(O)—O—C 1-6 -alkyl, NH C(O) C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, —C 1-6 -alkyl-S—C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-6 -cycloalkyl-C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkylthio each of which is optionally substituted with one or more substituents independently selected from R 16 ; or   aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, aryl-C 1-6 -alkoxy, heteroaryl-C 1-6 -alkoxy, heteroaryl-thio-C 1-6 -alkyl, aryloxy, heteroaryloxy, heteroarylthio, each of which is optionally substituted on the aryl or heteroaryl part with one or more substituents independently selected from R 17 ; or   C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, C 3-8 -cycloalkenyl-C 1-6 -alkyl, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from R 18 ; or   C 3-8 -heterocyclyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, C 3-8 -heterocyclylthio, or —C(O)—C 3-8 -heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or NR 19 R 20 , C 1-6 -alkyl-NR 19 R 20 , C 1-6 -alkyl-S R 21 , —C 1-6 -alkyl-S(O)—R 21 , —C 1-6 -alkyl-S(O) 2 —R 21 , S(O) 2  R 21  or S(O) 2  NR 19 R 20 , wherein each alkyl part may be substituted with one or more substituents independently selected from R 25 ; or   —C(O)NR 22 R 23 , —C 1-6 -alkyl-C(O)NR 22 R 23  optionally substituted with one or more substituents independently selected from R 26 .   
     
     
       25. A compound according to  claim 24 , wherein R 8  is selected from
 halogen, carboxy, cyano, or —CF 3 ; or   C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, C 1-6 -alkylthio, —C(O)—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkoxy-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or   aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, each of which is optionally substituted on the aryl or heteroaryl part with one or more substituents independently selected from R 17 ; or   C 3-8 -cycloalkyl, C 3-8 cycloalkyl-C 1-6 -alkyl, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from R 18 ; or   C 3-8 -heterocyclyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, or —C(O)—C 3-8 -heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or   NR 19 R 20 , —C 1-6 -alkyl-NR 19 R 20 , —S(O) 2 —R 21  or —S(O) 2 —NR 19 R 20 , wherein each alkyl part may be substituted with one or more substituents independently selected from R 25 ; or   —C(O)NR 22 R 23 , —C 1-6 -alkyl-C(O)NR 22 R 23  optionally substituted with one or more substituents independently selected from R 26 .   
     
     
       26. A compound according to  claim 25 , wherein R 8  is selected from
 halogen, carboxy or —CF 3 ; or   C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, —C 1-6 -alkyl-C (O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-O—C(O)—C 1-6 -alkyl or —C(O)—O—C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or   phenyl, benzyl, or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, and wherein each aryl or heteroaryl is optionally substituted on the aryl or heteroaryl part with one or more substituents independently selected from R 17 ; or   cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from R 18 ; or   pyrrolidinyl, piperidyl, piperazinyl, or morpholinyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or   —C(O)NR 22 R 23 , —S(O) 2 —R 21  or —S(O) 2 —NR 19 R 20 .   
     
     
       27. A compound according to  claim 26 , wherein R 8  is selected from halogen, carboxy, —CF 3 , —S—CH 3 , —S—CH 2 CH 3 , —S—CH 2 CH 2 CH 3 , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, CH 2  C (O)—O—CH 3 , —CH 2 —C(O)—O—CH 2 CH 3 , —CH 2 CH 2 —C(O)—O—CH 3 , —CH 2 CH 2 —C(O)—O—CH 2 CH 3 , —CH 2 —O—C(O)—CH 3 , —CH 2 —O—C(O)—CH 2 CH 3 , —CH 2 CH 2 —O—C(O)—CH 3 , —CH 2 CH 2 —O—C(O)—CH 2 CH 3 , —C(O)—O—CH 3 , —C(O)—O—CH 2 CH 3 , each of which is optionally substituted with one or more substituents independently selected from R 16 ; or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, each optionally substituted on the heteroaryl part with one or more substituents independently selected from R 17 , or pyrrolidinyl, piperidyl, piperazinyl, or morpholinyl, each of which is optionally substituted with one or more substituents independently selected from R 16 , or —S(O) 2 —R 21 . 
     
     
       28. A compound according to  claim 27 , wherein R 8  is selected from Cl, F, Br, —CF 3 , —S—CH 3 , —S—CH 2 CH 3 , —S—CH 2 CH 2 CH 3 , methyl, ethyl, methoxy, ethoxy, —CH 2 —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 3 , or —C(O)—O—CH 2 CH 3 , each of which is optionally substituted with one or more substituents independently selected from R 16 ; or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, each optionally substituted on the heteroaryl part with one or more substituents independently selected from R 17 , or pyrrolidinyl, piperidyl, piperazinyl, or morpholinyl, each of which is optionally substituted with one or more substituents independently selected from R 16 . 
     
     
       29. A compound according to  claim 1 , wherein R 16 , R 17 , and R 18  are independently C 1-6 -alkyl, halogen, hydroxy, oxo, carboxy, —CF 3 , carboxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —NR 19 R 20 , —C(O)NR 19 R 20  or —S(O) 2 —C 1-6 -alkyl. 
     
     
       30. A compound according to  claim 29 , wherein R 16 , R 17 , and R 18  are independently methyl, ethyl, propyl, halogen, hydroxy, oxo, carboxy, CF 3 , carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, —CH 2 —C(O)—O—CH 3 , —CH 2 —C (O)—O—CH 2 CH 3 , —CH 2 CH 2 —C(O)—O—CH 3 , —CH 2 CH 2 —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 3 , —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 2 CH 2 CH 3 , or —S(O) 2 CH 3 . 
     
     
       31. A compound according to  claim 30 , wherein R 16 , R 17 , and R 18  are independently methyl, ethyl, propyl, halogen, oxo, carboxy, carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, CH 2  C(O) O CH 3 , CH 2  C(O) O CH 2 CH 3 , —CH 2 CH 2 —C(O)—O—CH 3 , —CH 2 CH 2 —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 3 , —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 2 CH 2 CH 3 , or —S(O) 2 CH 3 . 
     
     
       32. A compound according to  claim 29 , wherein R 16 , R 17 , and R 18  are independently C 1-6 -alkyl, carboxy, —NR 19 R 20 , —C(O)—O—C 1-6 -alkyl or —C(O)NR 19 R 20 . 
     
     
       33. A compound according to  claim 1 , wherein R 19  and R 20  independently represent hydrogen, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, phenyl, naphtyl, C 3-8 -heterocyclyl, phenyl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-NR 22 R 23  or —S(O) 2 —C 1-6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 24 ; or R 19  and R 20  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       34. A compound according to  claim 33 , wherein R 19  and R 20  independently represent hydrogen, methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, phenyl, phenyl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-NR 22 R 23 , or naphtyl, or R 19  and R 2 ° together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       35. A compound according to  claim 33 , wherein R 19  and R 20  independently represent hydrogen, C 1-6 -alkyl, or R 19  and R 20  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       36. A compound according to  claim 35 , wherein R 19  and R 20  independently represent hydrogen, methyl, ethyl, or propyl, or R 19  and R 20  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, wherein the heterocyclic ring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, or morpholinyl, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       37. A compound according to  claim 1 , wherein R 21  is selected from
 C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C 1-6 -alkyl-NR 22 R 23  or hydroxy-C 1-6 -alkyl; or   phenyl, naphtyl, or pheny-C 1-6 -alkyl, wherein the aryl part is optionally substituted with one or more substituents independently selected from R 24 ; or   C 3-8 -cycloalkyl, or C 3-8 -cycloalkyl-C 1-6 -alkyl.   
     
     
       38. A compound according to  claim 37 , wherein R 21  is selected from
 methyl, ethyl, propyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl; or   phenyl, naphtyl, or phenyl-C 1-6 -alkyl, wherein the aryl part is optionally substituted with one or more substituents independently selected from R 24 ; or   C 3-8 -cycloalkyl, or C 3-8 -cycloalkyl-C 1-6 -alkyl.   
     
     
       39. A compound according to  claim 38 , wherein R 21  is selected from
 methyl, ethyl, carboxy-methyl, carboxy-ethyl, carboxy-propyl; or   phenyl, naphtyl, or phenyl-C 1-6 -alkyl, wherein the aryl part is optionally substituted with one or more substituents independently selected from R 24 .   
     
     
       40. A compound according to  claim 1 , wherein R 22  and R 23  are independently selected from hydrogen, C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, C 3-8 -cycloalkyl, phenyl, naphtyl, or R 22  and R 23  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       41. A compound according to  claim 40 , wherein R 22  and R 23  are independently selected from hydrogen, methyl, ethyl, propyl, butyl, carboxymethyl, carboxyethyl, carboxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphtyl, or R 22  and R 23  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, wherein the heterocyclic ring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, or morpholinyl, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       42. A compound according to  claim 41 , wherein R 22  and R 23  together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring with the said nitrogen atom, wherein the heterocyclic ring is pyrrolidyl, piperidyl, piperazinyl, homopiperazinyl, or morpholinyl, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 
     
     
       43. A compound according to  claim 1 , wherein R 24  is halogen, hydroxy, carboxy, oxo, —CF 3 , C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C(O) C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl-aryl, or —S(O) 2 R 28 , wherein aryl is phenyl or naphtyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each cyclic moiety is optionally substituted with one or more substituents independently selected from R 29 . 
     
     
       44. A compound according to  claim 43 , wherein R 24  is halogen, hydroxy, carboxy, oxo, —CF 3 , C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C(O) C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, or —S(O) 2 R 28 , wherein aryl is phenyl or naphtyl, or heteroaryl is pyridyl or pyrimidyl, and wherein each cyclic moiety is optionally substituted with one or more substituents independently selected from R 29 . 
     
     
       45. A compound according to  claim 44 , wherein R 24  is halogen, carboxy, oxo, —CF 3 , C 1-6 -alkyl, carboxy-C 1-6 -alkyl, —C(O)—C 1-6 -alkyl, —C(O)—O—C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, or —S(O) 2 R 28 , wherein aryl is phenyl or naphtyl, and wherein each cyclic moiety is optionally substituted with one or more substituents independently selected from R 29 . 
     
     
       46. A compound according to  claim 45 , wherein R 24  is carboxy, oxo, C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C(O) O C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, or —S(O) 2 R 28 , wherein aryl is phenyl or naphtyl, and wherein each cyclic moiety is optionally substituted with one or more substituents independently selected from R 29 . 
     
     
       47. A compound according to  claim 1 , wherein R 25  and R 26  are independently C 1-6 -alkyl, halogen, hydroxy, carboxy, or —CF 3 . 
     
     
       48. A compound according to  claim 47 , wherein R 25  and R 26  are independently methyl, ethyl, propyl, halogen, hydroxy, carboxy, or —CF 3 . 
     
     
       49. A compound according to  claim 1 , wherein R 28  is C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, phenyl, phenyl-C 1-6 -alkyl, heteroaryl optionally substituted with C 1-6 -alkyl or —N(CH 3 ) 2 , wherein heteroaryl is imidazolyl, pyridyl or pyrimidyl. 
     
     
       50. A compound according to  claim 49 , wherein R 28  is C 1-6 -alkyl, —C 1-6 -alkyl-C(O)—O—C 1-6 -alkyl, or N(CH 3 ) 2 . 
     
     
       51. A compound according to  claim 1 , wherein R 29  is halogen, carboxy, —CF 3 , C 1-6 -alkyl, or C 1-6 -alkoxy. 
     
     
       52. 1-(1-Acetyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea or a pharmaceutically acceptable salt thereof.