Pteridines useful as HCV inhibitors and methods for the preparation thereof

Abstract

The present invention relates to the use of pteridines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.

1 - 21 . (canceled) 
   
   
       22 . A method of inhibiting HCV replication in a mammal infected with HCV, wherein said method comprises the administration of an effective amount of a HCV inhibitory compound, said compound having the formula (I) 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein 
       R 1  is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-6 alkyl, C 2-6 alkenyl,
 C 2-6 alkynyl, C 1-14 alkoxyC 1-4 alkyl, diC 1-14 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkyl, or C 1-4 alkoxy; 
 
       L is —NR 8 —, —NR 8 —C 1-6 alkanediyl-, —NR 8 —CO—C 1-6 alkanediyl-, —NR 8 —SO 2 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-, or 
     
     
       
         
         
             
             
         
       
       
         wherein the dotted ring together with N and Z form a Het 1  cycle having 5 to 8 members including ring members N and Z, and wherein said L ring is attached to the pteridine ring by the nitrogen atom; 
       
       Z represents N or CH; 
       R 2  represents hydrogen, hydroxyC 1-6 alkyl, C 3-7 cycloalkyl, aryl, Het 1 , or Het 2 , wherein said C 3-7 cycloalkyl, aryl, Het 1 , and Het 2  are each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl,
 C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b . —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 7 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; 
 
       R 3  represents a C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, Het 1 , Het 2  or Het 2 -C 1-6 alkyl, each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 —OCOR 6 —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b ; and wherein R 4a  and R 4b  may optionally form, together with the nitrogen atom to which they are bound, a 5 to 8 membered saturated, unsaturated or partially unsaturated ring, optionally comprising one or two additional heteroatoms; 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, Het 1 -C 1-4 alkyl, polyhaloC 1-4 alkyl, cyano, or nitro; 
       each R 5  is independently hydrogen, or C 1-4 alkyl; 
       each R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       R 8  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylcarbonyl, aminoC 1-10 alkyl, aryl, arylcarbonyl, arylC 1-10 alkyl, Het 1 , Het 1 C 1-6 alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, phenyl,
 C 1-4 alkylphenyl, phenylcarbonyl, aminophenyl, aminoC 1-4 alkylphenyl, aminophenylcarbonyl, halo, —OR 6 , —NR 4a R 4b , —SR 5 , —SOR 5 , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SO 2 R 5 , —OCOR 6 , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a COOR 6 , —OCONR 4a R 4b , —COOR 6 , —SO 3 R 6 , —CONR 4a R 4b , —SO 2 NR 4a R 4b , cyano, polyhalo-C 1-4 alkyl, and nitro; 
 
       Het 1  as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxy-carbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; 
       Het 2  as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur, and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, optionally mono- or disubstituted aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1  and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; and 
       aryl as a group or part of a group is phenyl. 
     
   
   
       23 . The method of inhibiting HCV replication according to  claim 22 , wherein the compound has the formula (II) 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein 
       R 9  represents C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b . —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 7 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, or aminophenyl-carbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; and 
       n is 0, 1, 2, 3, or 4. 
     
   
   
       24 . The method of inhibiting HCV replication according to  claim 22 , wherein the compound has the formula (III): 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein 
       R 10  represents C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , and —SO 2 NR 4a R 4b ; and 
       m is 0, 1, 2, 3, or 4. 
     
   
   
       25 . The method of inhibiting HCV replication according to  claim 22 , wherein the compound has the formula (IV): 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, and further wherein 
       R 9  represents C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, or aminophenyl-carbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; 
       R 10  represents C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , and —SO 2 NR 4a R 4b ; 
       n is 0, 1, 2, 3, or 4; and 
       m is 0, 1, 2, 3, or 4. 
     
   
   
       26 . The method of inhibiting HCV replication according to  claim 22 , wherein the compound has the formula (V): 
     
       
         
         
             
             
         
       
     
     or a salt, stereoisomeric form, or racemic mixture thereof, wherein
 R 1  is hydrogen or amino; 
 R 8  is hydrogen, C 1-6 alkyl, aminoC 1-4 alkyl, phenylC 1-4 alkyl, pyrrolidin-1-ylC 1-4 alkyl, or C 1-6 alkoxycarbonyl; 
 each R 9  represents, independently, hydrogen, C 1-4 alkyl, —COR 6 , —COOR 7 , or —CONR 4a R 4b ; 
 n is 0, 1, 2, 3, or 4; 
 R 11  represents hydrogen, halo, or —NR 4a R 4b , wherein R 4a  and R 4b  may optionally form, together with the nitrogen atom to which they are bound, a 5 to 8 membered saturated, unsaturated or partially unsaturated ring, optionally comprising one or two additional heteroatoms; 
 R 12  represents hydrogen, halo, C 1-4 alkyl, or polyhaloC 1-4 alkyl; 
 R 6  is hydrogen, or C 1-4 alkyl; 
 R 7  is hydrogen, or C 1-4 alkyl; and 
 R 4a  and R 4b , independently, are hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl. 
 
   
   
       27 . The method of inhibiting HCV replication according to  claim 26 , wherein the compound has the formula (VI): 
     
       
         
         
             
             
         
       
       or a salt, stereoisomeric form, or racemic mixture thereof. 
     
   
   
       28 . A compound of the formula (VII): 
     
       
         
         
             
             
         
       
       or a salt, stereoisomeric form, or racemic mixture thereof, wherein 
       R 1  is hydrogen or amino; 
       R 8  is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl; 
       R 9  represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ; 
       R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; 
       with the proviso that when R 8  is hydrogen, R 9  is not hydrogen. 
     
   
   
       29 . A compound according to  claim 28 , wherein
 R 8  is C 1-6 alkyl, phenylC 1-4 alkyl.   
   
   
       30 . A compound according to  claim 28 , wherein
 R 9  represents C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b .   
   
   
       31 . A compound of the formula (VIII): 
     
       
         
         
             
             
         
       
       or a salt, stereoisomeric form, or racemic mixture thereof, wherein 
       R 1  is independently hydrogen or amino; 
       R 8  is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl; 
       R 9  represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ; 
       R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; 
       with the proviso that when R 8  is hydrogen, R 9  is not hydrogen. 
     
   
   
       32 . A compound according to  claim 31 , wherein
 R 9  represents C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b .   
   
   
       33 . A compound according to  claim 31 , wherein
 R 8  represents C 1-6 alkyl or phenylC 1-4 alkyl.   
   
   
       34 . A compound according to  claim 28 , wherein
 R 1  is hydrogen;   R 8  is hydrogen; and   R 9  represents C 1-4 alkyl.   
   
   
       35 . A compound according to  claim 28 , wherein
 R 1  is hydrogen;   R 8  is C 1-6 alkyl; and   R 9  represents hydrogen.   
   
   
       36 . A compound according to  claim 31 , wherein
 R 1  is hydrogen;   R 8  is hydrogen; and   R 9  represents C 1-4 alkyl.   
   
   
       37 . A compound according to  claim 31 , wherein
 R 1  is hydrogen;   R 8  is C 1-6 alkyl; and   R 9  represents hydrogen.   
   
   
       38 . A pharmaceutical composition comprising a compound of the formula (VII): 
     
       
         
         
             
             
         
       
       or a salt, stereoisomeric form, or racemic mixture thereof, wherein 
       R 1  is hydrogen or amino; 
       R 8  is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl; 
       R 9  represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ; 
       R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; 
       with the proviso that when R 8  is hydrogen, R 9  is not hydrogen. 
     
   
   
       39 . A pharmaceutical composition comprising a compound of the formula (VII): 
     
       
         
         
             
             
         
       
       or a salt, stereoisomeric form, or racemic mixture thereof, wherein 
       R 1  is hydrogen or amino; 
       R 8  is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl; 
       R 9  represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ; 
       R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; 
       with the proviso that when R 8  is hydrogen, R 9  is not hydrogen, and further comprising one or more other anti-HCV agents. 
     
   
   
       40 . A method of treating a mammal infected with HCV, wherein said method comprises the administration of an effective amount of a HCV inhibitory compound, said compound having the formula (I) 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein 
       R 1  is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-6 alkyl, C 2-6 alkenyl,
 C 2-6 alkynyl, C 1-14 alkoxyC 1-4 alkyl, diC 1-4 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkyl, or C 1-4 alkoxy; 
 
       L is —NR 8 —, —NR 8 —C 1-6 alkanediyl-, —NR 8 —CO—C 1-6 alkanediyl-, —NR 8 —SO 2 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-, or 
     
     
       
         
         
             
             
         
       
       
         wherein the dotted ring together with N and Z form a Het 1  cycle having 5 to 8 members including ring members N and Z, and wherein said L ring is attached to the pteridine ring by the nitrogen atom; 
       
       Z represents N or CH; 
       R 2  represents hydrogen, hydroxyC 1-6 alkyl, C 3-7 cycloalkyl, aryl, Het 1 , or Het 2 , wherein said C 3-7 cycloalkyl, aryl, Het 1 , and Het 2  are each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl,
 C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b . —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 4a , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; 
 
       R 3  represents a C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, Het 1 , Het 2  or Het 2 -C 1-6 alkyl, each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CON 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 4b , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b ; and wherein R 4a  and R 4b  may optionally form, together with the nitrogen atom to which they are bound, a 5 to 8 membered saturated, unsaturated or partially unsaturated ring, optionally comprising one or two additional heteroatoms; 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, Het 1 -C 1-4 alkyl, polyhaloC 1-4 alkyl, cyano, or nitro; 
       each R 5  is independently hydrogen, or C 1-4 alkyl; 
       each R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       R 8  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylcarbonyl, aminoC 1-10 alkyl, aryl, arylcarbonyl, arylC 1-10 alkyl, Het 1 , Het 1 C 1-6 alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, phenyl,
 C 1-4 alkylphenyl, phenylcarbonyl, aminophenyl, aminoC 1-4 alkylphenyl, aminophenylcarbonyl, halo, —OR 6 , —NR 4a R 4b , —SR 5 , —SOR 5 , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SO 2 R 5 , —OCOR 6 , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a COOR 6 , —OCONR 4a R 4b , —COOR 6 , —SO 3 R 6 , —CONR 4a R 4b , —SO 2 NR 4a R 4b , cyano, polyhalo-C 1-4 alkyl, and nitro; 
 
       Het 1  as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxy-carbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; 
       Het 2  as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur, and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, optionally mono- or disubstituted aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1  and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; and 
       aryl as a group or part of a group is phenyl. 
     
   
   
       41 . A method of treating clinical conditions relating to HCV infection in a mammal, wherein said method comprises the administration of an effective amount of a HCV inhibitory compound, said compound having the formula (I) 
     
       
         
         
             
             
         
       
       or an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein 
       R 1  is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-6 alkyl, C 2-6 alkenyl,
 C 2-6 alkynyl, C 1-4 alkoxyC 1-4 alkyl, diC 1-4 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkyl, or C 1-4 alkoxy; 
 
       L is —NR 8 —, —NR 8 —C 1-6 alkanediyl-, —NR 8 —CO—C 1-6 alkanediyl-, —NR 8 —SO 2 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-, or 
     
     
       
         
         
             
             
         
       
       
         wherein the dotted ring together with N and Z form a Het 1  cycle having 5 to 8 members including ring members N and Z, and wherein said L ring is attached to the pteridine ring by the nitrogen atom; 
       
       Z represents N or CH; 
       R 2  represents hydrogen, hydroxyC 1-6 alkyl, C 3-7 cycloalkyl, aryl, Het 1 , or Het 2 , wherein said C 3-7 cycloalkyl, aryl, Het 1 , and Het 2  are each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl,
 C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b , morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 ; 
 
       R 3  represents a C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, Het 1 , Het 2  or Het 2 -C 1-6 alkyl, each independently optionally substituted with one or more substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, polyhaloC 1-4 alkyl, halo, cyano, nitro, —COR 6 , —COOR 7 , —CONR 4a R 4b , —OR 7 , —OCOR 6 , —OCONR 4a R 4b , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a COOR 7 , —NR 4a CONR 4a R 4b , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SR 5 , —SOR 7 , —SO 2 R 5 , —SO 3 R 7 , —SO 2 NR 4a R 4b ; and wherein R 4a  and R 4b  may optionally form, together with the nitrogen atom to which they are bound, a 5 to 8 membered saturated, unsaturated or partially unsaturated ring, optionally comprising one or two additional heteroatoms; 
       each R 4a  and R 4b  is independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, Het 1 -C 1-4 alkyl, polyhaloC 1-4 alkyl, cyano, or nitro; 
       each R 5  is independently hydrogen, or C 1-4 alkyl; 
       each R 6  is independently hydrogen, or C 1-4 alkyl; 
       each R 7  is independently hydrogen, or C 1-4 alkyl; and 
       R 8  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylcarbonyl, aminoC 1-10 alkyl, aryl, arylcarbonyl, arylC 1-10 alkyl, Het 1 , Het 1 C 1-6 alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-10 alkylcarbonyl, phenyl,
 C 1-10 alkylphenyl, phenylcarbonyl, aminophenyl, aminoC 1-4 alkylphenyl, aminophenylcarbonyl, halo, —OR 6 , —NR 4a R 4b , —SR 5 , —SOR 5 , —NR 4a SOR 5 , —NR 4a SO 2 R 5 , —SO 2 R 5 , —OCOR 6 , —NR 4a COR 6 , —NR 4a CONR 4a R 4b , —NR 4a COOR 6 , —OCONR 4a R 4b , —COOR 6 , —SO 3 R 6 , —CONR 4a R 4b , —SO 2 NR 4a R 4b , cyano, polyhalo-C 1-4 alkyl, and nitro; 
 
       Het 1  as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxy-carbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; 
       Het 2  as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members, preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur, and which is optionally substituted on one or more carbon atoms by C 1-6 alkyl, optionally mono- or disubstituted aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC 1-4 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1  and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are hydrogen, or C 1-4 alkyl; and 
       aryl as a group or part of a group is phenyl. 
     
   
   
       42 . The method of treating clinical conditions relating to HCV infection according to  claim 41 , wherein the clinical conditions are other than liver fibrosis.