Heterocyclic Carboxamides For Use As Thrombin Inhibitors

Abstract

This invention relates to novel pharmaceutically useful compounds of formula (I), in particular compounds that are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production. Formula (I)

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X is N, O or NH; 
 Y is CH 2  when X is O or NH, with X and Y connected via a single bond, or, alternatively, 
 Y is CH when X is N, with X and Y connected via a double bond; 
 R 1  is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S, wherein said 5-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1 or 2 substituents independently selected from C 1-6  alkyl and a 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, wherein said 6-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1, 2 or 3 substituents independently selected from C 1-6  alkyl; 
 R 2  is H, halogen, cyano, C 1-6  alkyl and C 1-6  alkoxy, wherein said C 1-6  alkyl or C 1-6  alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen; 
 G represents 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 3  is H, R 5 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or C 3-6  cycloalkyl, wherein each of said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl and C 3-6  cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5 substituents selected from halogen and 0, 1 or 2 substituents selected from OH, oxo, cyano, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , C 1-4  alkyl, C 3-6  cycloalkyl, C 4-7  cycloalkenyl, cycloheteroalkyl, R 5  and R 6 ; 
 R 5  is phenyl, 
 a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, S and N, 
 a 4-, 5- or 6-membered cycloheteroalkyl ring containing 1 or 2 heteroatoms independently selected from O, S and N or 
 a phenyl-fused 5- or 6-membered cycloheteroalkyl ring containing 1 or 2 heteroatoms independently selected from O, S and N, wherein said phenyl, said heteroaromatic ring, said cycloheteroalkyl ring and said phenyl-fused cycloheteroalkyl ring are substituted, at any carbon ring atom, by 0, 1, 2, 3, 4 or 5 substituents independently selected from COOH, OH, halogen, CF 3 , CHF 2 , CH 2 F, cyano, C 1-6  alkyl, R 6  and SO 2 R 7 ; 
 R 6  is C 1-6  alkoxy, wherein said C 1-6  alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen; 
 R 7  is C 1-6  alkyl; 
 R 4  is OH, OC(O)R 7 , OC(O)R 8  or NHR 9 ; 
 R 8  is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4  alkyl, C 1-4  alkoxy, cyano, F, CF 3 , CHF 2  and CH 2 F or C 1-4  alkyl, wherein said C 1-4  alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from methyl and ethyl and 0 or 1 substituents selected from phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4  alkyl, C 1-4  alkoxy, cyano, F, CF 3 , CHF 2 , CH 2 F and OC(O)R 7 ; 
 R 9  is H, COOR 7  or SO 2 R 7  wherein said R 7  is substituted by 0, 1, 2 or 3 substituents independently selected from OH, halogen, cyano, R 6  and C 3-7  cycloalkyl; 
 Q is O, CH 2  or S(O) n ; 
 W is C or N; 
 n is independently 0, 1 or 2; 
 each t is independently 0, 1 or 2; 
 u is independently 0 or 1; 
 R 10  is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo, cyano, C 1-4  alkyl, C 3-6  cycloalkyl, R 5  and R 6 , wherein said C 1-4  alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4  alkyl) or N(C 1-4  alkyl) 2 ; and 
 R 11  is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, cyano, C 1-4  alkyl, C 3-6  cycloalkyl, R 5  and R 6 , wherein said C 1-4  alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4  alkyl) or N(C 1-4  alkyl) 2 ; 
 or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer. 
 
     
     
         2 . A compound according to  claim 1 , wherein G is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer. 
     
     
         3 . A compound according to  claim 2 , wherein
 R 1  is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S;   R 2  is H or halogen;   R 3  is C 1-6  alkyl, C 3-6  cycloalkyl, a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, S and N,   a 4-, 5- or 6-membered cycloheteroalkyl ring containing 1 or 2 heteroatoms independently selected from O, S and N, or R 12 , wherein said C 1-6  alkyl, said C 3-6  cycloalkyl, said heteroaromatic ring and said cycloheteroalkyl ring are substituted by 0 or 1 substituents selected from NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , C 3  cycloalkyl, R 6  or R 12 ;   R 12  is phenyl, wherein said phenyl is substituted by 0, 1 or 2 substituents selected from halogen and R 6 ; and   R 4  is OH, OC(O)R 7 , OC(O)R 8  or NH 2 ;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         4 . A compound according to  claim 3 , wherein
 R 1  is tetrazole;   R 2  is H, Cl or F;   R 3  is C 3-6  cycloalkyl, R 12  or C 1-6  alkyl, wherein said C 1-6  alkyl is substituted by 0 or 1 substituents selected from C 3  cycloalkyl, N(C 1-4  alkyl) 2 , R 6  or R 12 ; and   R 4  is OH or OC(O)R 7 ;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         5 . A compound according to  claim 3 , wherein the stereochemical configuration around the carbon in the pyrazolidine, dihydropyrazole or isoxazolidine, i.e. the ring containing X and Y, which is covalently bound to the carbonyl is (S) and the stereochemical configuration around the carbon substituted by R 3  and R 4  in G is (R);
 or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         6 . A compound according to  claim 1 , wherein G is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer. 
       
     
     
         7 . A compound according to  claim 6 , wherein
 R 1  is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S;   R 2  is H or halogen;   Q is O or CH 2 ;   each t is independently 0 or 1;   R 10  is 0, 1 or  2  substituents selected from oxo, C 1-4  alkyl, R 5  and R 6 ; and   R 5  is phenyl, which is substituted, by 0, 1, 2, 3, 4 or 5 substituents independently selected from COOH, OH, halogen, CF 3 , cyano, C 1-6  alkyl, R 6  and SO 2 R 7 ;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         8 . A compound according to  claim 7 , wherein
 R 1  is tetrazole;   R 2  is H, Cl or F; and   R 10  is 0, 1 or 2 substituents selected from oxo and C 1-4  alkyl;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         9 . A compound according to  claim 1 , wherein G is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer. 
     
     
         10 . A compound according to  claim 9 , wherein
 R 1  is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S;   R 2  is H or halogen;   R 4  is OH, OC(O)R 7 , OC(O)R 8  or NH 2 ;   Q is O or CH 2 ;   u is independently 0 or 1;   R 10  is 0, 1 or 2 substituents selected from C 1-4  alkyl, halogen and R 6 ; and   R 11  is 0, 1 or 2 substituents selected from C 1-4  alkyl, halogen and R 6 ;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         11 . A compound according to  claim 10 , wherein
 R 1  is tetrazole;   R 2  is Cl;   R 4  is OH or OC(O)R 7 ;   R 10  is 0, 1 or 2 substituents selected from C 1-4  alkyl, F, Cl, OCH 3 , OCF 3 , OCHF 2  and OCH 2 F; and   R 11  is 0, 1 or 2 substituents selected from C 1-4  alkyl, F, Cl, OCH 3 , OCF 3 , OCHF 2  and OCH 2 F;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         12 . A compound according to  claim 7 , wherein
 the stereochemical configuration around the carbon in the pyrazolidine, dihydropyrazole or isoxazolidine, i.e. the ring containing X and Y, which is covalently bound to the carbonyl is (S);   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         13 . A compound according to  claim 3 , wherein
 X is NH and Y is CH 2 , with X and Y connected via a single bond;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         14 . A compound according to  claim 3 , wherein
 X is O and Y is CH 2 , with X and Y connected via a single bond;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         15 . A compound according to  claim 3 , wherein
 X is N and Y is CH, with X and Y connected via a double bond;   or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer.   
     
     
         16 . A compound according to  claim 1  which is selected from
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,3-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)-1-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3,5-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclopentyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,4-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-5-methylhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2-fluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxyhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-phenylacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-methoxy-3-methylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-phenylpropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-(4-methyl-D-leucyl)-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-3-cyclopropyl-2-hydroxypropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3-cyanophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 (5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2S)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide, 
 [(1R)-2-[(5S)-5-[[5-Chloro-2-(tetrazol-1-yl)phenyl]methylcarbamoyl]-4,5-dihydropyrazol-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]acetate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl 3-methylbutanoate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl butanoate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl 2-methylpropanoate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl pentanoate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl propanoate, 
 (1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl benzoate, 
 (R)-2-((S)-5-(5-Chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl 3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide, 
 (3S)-2-(O-tert-Butyl-D-seryl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,3-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3,5-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[hydroxy(3-methylphenyl)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxyhexanoyl]isoxazolidine-3-carboxamide, 
 3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-5-methylhexanoyl]isoxazolidine-3-carboxamide, 
 (3S)-2-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclopentyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3-cyanophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]pyrazolidine-3-carboxamide, 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]pyrazolidine-3-carboxamide or 
 (3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]pyrazolidine-3-carboxamide; 
 or a pharmaceutically acceptable salt or an enantiomer or a pharmaceutically acceptable salt of said enantiomer. 
 
     
     
         17 . A pharmaceutical formulation comprising a compound of formula (I) according to  claim 1  in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         18 - 23 . (canceled) 
     
     
         24 . A method of treatment of a condition where inhibition of thrombin is beneficial, which method comprises administration of a therapeutically effective amount of a compound as defined in  claim 1  to a person suffering from, or susceptible to, such a condition. 
     
     
         25 . A method of treatment and prevention of thromboembolic disorders, which method comprises administration of a therapeutically effective amount of a compound as defined in  claim 1  to a person suffering from, or susceptible to, thrombophilia conditions.