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.

Claims

1-21. (canceled)

22. A compound of the formula (VII): ##STR00097## or a salt, stereoisomeric form, or racemic mixture thereof, wherein R.sup.1 is hydrogen; R.sup.8 is hydrogen and R.sup.9 is C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b; or R.sup.8 is C.sub.1-6alkyl or phenylC.sub.1-4alkyl and R.sup.9 is hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b; R.sup.6 is independently hydrogen, or C.sub.1-4alkyl; each R.sup.7 is independently hydrogen, or C.sub.1-4alkyl; and each R.sup.4a and R.sup.4b is independently hydrogen, C.sub.1-4alkyl,

23. The compound according to claim 22, wherein R.sup.8 is hydrogen and R.sup.9 is C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b.

24. The compound according to claim 23, wherein R.sup.9 is CONR.sup.4aR.sup.4b.

25. The compound according to claim 22, wherein R.sup.8 is C.sub.1-6alkyl or phenylC.sub.1-4alkyl and R.sup.9 is hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b.

26. The compound according to claim 25, wherein R.sup.8 is C.sub.1-6alkyl and R.sup.9 is hydrogen.

27. The compound according to claim 25, wherein R.sup.8 is phenylC.sub.1-4alkyl and R.sup.9 is hydrogen.

28. The compound according to claim 22 of the formula (VIII): ##STR00098##

29. The compound according to claim 28, wherein R.sup.8 is hydrogen and R.sup.9 is C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b.

30. The compound according to claim 28, wherein R.sup.8 is C.sub.1-6alkyl or phenylC.sub.1-4alkyl and R.sup.9 is hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b.

31. The compound according to claim 30, wherein R.sup.8 is C.sub.1-6alkyl and R.sup.9 is hydrogen.

32, The compound according to claim 22 that is ##STR00099## ##STR00100##

33. A pharmaceutical composition comprising a compound according to claim 22 and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition according to claim 33, further comprising one or more other anti-hepatitis C virus agents.

Description

DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 illustrates the mean plasma and tissue concentrations (n=3) of compound nr. 21 after a single oral administration at 20 mg base-eq./kg in the male Swiss SPF (CD1)-mice.

DISCLOSURE OF THE INVENTION

[0021] The present invention thus relates to the use of a compound of the formula (I) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV. Said compound is a pteridine of the formula (I):

##STR00001## [0022] an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein [0023] R.sup.1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-4alkoxyC.sub.1-4alkyl, diC.sub.1-4alkylaminoC.sub.1-4alkyl, piperidin-1-yl-C.sub.1-4alkyl, arylC.sub.1-6alkyl, wherein the aryl group may be further substituted with C.sub.1-4alkyl, or C.sub.1-4alkoxy; [0024] L is NR.sup.8, NR.sup.8C.sub.1-6alkanediyl-, NR.sup.8COC.sub.1-6alkanediyl-, NR.sup.8SO.sub.2 C.sub.1-6alkanediyl-, O, OC.sub.1-6alkanediyl-, OCO, OCOC.sub.1-6alkanediyl-, S, SC.sub.1-6alkanediyl-, or

##STR00002## [0025] wherein the dotted ring together with N and Z form a Het.sup.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; [0026] Z represents N or CH; [0027] R.sup.2 represents hydrogen, hydroxyC.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, Het.sup.1, or Het.sup.2, wherein said C.sub.3-7cycloalkyl, aryl, Het.sup.1, and Het.sup.2 are each independently optionally substituted with one or more substituents selected from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, SO.sub.2NR.sup.4aR.sup.4b, morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C.sub.1-4alkyl may be further substituted with COOR.sup.7; [0028] R.sup.3 represents a C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, arylC.sub.1-6alkyl, Het.sup.1, Het.sup.2or Het.sup.2-C.sub.1-6alkyl, each independently optionally substituted with one or more substituents selected from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCOOR.sup.7, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, SO.sub.2NR.sup.4aR.sup.4b; and wherein R.sup.4a and R.sup.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; [0029] each R.sup.4a and R.sup.4b is independently hydrogen, C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl, Het.sup.1 polyhaloC.sub.1-4alkyl, cyano, or nitro; [0030] each R.sup.5 is independently hydrogen, or C.sub.1-4alkyl; [0031] each R.sup.6 is independently hydrogen, or C.sub.1-4alkyl; [0032] each R.sup.7 is independently hydrogen, or C.sub.1-4alkyl; and [0033] R.sup.8 is hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkylcarbonyl, amino-C.sub.1-10alkyl, aryl, arylcarbonyl, arylC.sub.1-10alkyl, Het.sup.1, Het.sup.1C.sub.1-6alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.1-4alkylcarbonyl, phenyl, C.sub.1-4alkylphenyl, phenylcarbonyl, aminophenyl, aminoC.sub.1-4alkylphenyl, aminophenylcarbonyl, halo, OR.sup.6, NR.sup.4aR.sup.4b, SR.sup.5, SOR.sup.5, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SO.sub.2R.sup.5, OCOR.sup.6, NR.sup.4aCOR.sup.6, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aCOOR.sup.6, C.sub.1-4alkyl, and nitro;

[0034] Het.sup.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.sub.1-6alkyl, C.sub.1-6alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC.sub.1-4alkyl, carboxyl, C.sub.1-6alkoxy-carbonyl, C.sub.3-7cycloalkyl, 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.sub.1-4alkyl;

[0035] Het.sup.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.sub.1-6alkyl, optionally mono- or disubstituted aminoC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhalo-C.sub.1-4alkyl, carboxyl, C.sub.1-6alkoxycarbonyl, C.sub.3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het.sup.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.sub.1-4alkyl; and [0036] aryl as a group or part of a group is phenyl.

[0037] The present invention further relates to the use of a compound of the formula (II) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV. Said compound is a pteridine of the formula (II):

##STR00003## [0038] an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof; wherein R.sup.1, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8, Het.sup.1, and Het.sup.2 have the meaning as indicated above; wherein [0039] R.sup.9 represents C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, SO.sub.2NR.sup.4aR.sup.4b, morpholin-4-yl, phenyl, aminophenyl, or aminophenyl-carbonyl, and wherein the C.sub.1-4alkyl may be further substituted with COOR.sup.7; and [0040] n is 0, 1, 2, 3, or 4.

[0041] The present invention further relates to the use of a compound of the formula (III) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV. Said compound is a pteridine of the formula (III):

##STR00004## [0042] an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof; wherein R.sup.1, L, R.sup.2, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8, Het.sup.1, and Het.sup.2 have the meaning as indicated above; wherein [0043] R.sup.10 represents C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCOOR.sup.7, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, and SO.sub.2NR.sup.4aR.sup.4b; and [0044] m is 0, 1, 2, 3, or 4.

[0045] The present invention further relates to the use of a compound of the formula (IV) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV. Said compound is a pteridine of the formula (IV):

##STR00005## [0046] an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein R.sup.1, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8, Het.sup.1, and Het.sup.2 have the meaning as indicated above; wherein [0047] R.sup.9 represents C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4a, R.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, SO.sub.2NR.sup.4aR.sup.4b, morpholin-4-yl, phenyl, aminophenyl, or aminophenyl-carbonyl, and wherein the C.sub.1-4alkyl may be further substituted with COOR.sup.7; [0048] R.sup.10 represents C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, polyhaloC.sub.1-4alkyl, halo, cyano, nitro, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, OCOR.sup.6, OCONR.sup.4aR.sup.4b, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aCOOR.sup.7, NR.sup.4aCONR.sup.4aR.sup.4b, NR.sup.4aSOR.sup.5, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, SOR.sup.7, SO.sub.2R.sup.5, SO.sub.3R.sup.7, and SO.sub.2NR.sup.4aR.sup.4b; [0049] n is 0, 1, 2, 3, or 4; and [0050] m is 0, 1, 2, 3, or 4.

[0051] The present invention further relates to the use of a compound of the formula (V) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV. Said compounds are pteridines of the formula (V):

##STR00006## [0052] a salt, stereoisomeric form, and racemic mixture thereof, wherein [0053] R.sup.1 is hydrogen or amino; [0054] R.sup.8 is hydrogen, C.sub.1-6alkyl, aminoC.sub.1-4alkyl, phenylC.sub.1-4alkyl, pyrrolidin-1-yl-C.sub.1-4alkyl, or C.sub.1-6alkoxycarbonyl; [0055] each R.sup.9 represents, independently, hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b; [0056] n is 0, 1, 2, 3, or 4; [0057] R.sup.11 represents hydrogen, halo, or NR.sup.4aR.sup.4b, wherein R.sup.4a and R.sup.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; [0058] R.sup.12 represents hydrogen, halo, C.sub.1-4alkyl, or polyhaloC.sub.1-4alkyl; [0059] R.sup.6 is hydrogen, or C.sub.1-4alkyl; [0060] R.sup.7 is hydrogen, or C.sub.1-4alkyl; and [0061] R.sup.4a and R.sup.4b, independently, are hydrogen, C.sub.1-4alkyl, 2-oxo-pyrrolidin-1-yl-C.sub.1-4alkyl.

[0062] One embodiment relates to the use of the compounds of formulae (II), (IV), or (V) as specified above, wherein n is 1.

[0063] In a further aspect the invention relates to a method of inhibiting HCV replication in a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formulae (I), (II), (III), (W), or (V) as specified above or as further specified hereinafter. In a particular embodiment, the method of inhibiting HCV replication in a mammal infected with HCV comprises the administration of an HCV inhibitory effective amount of a compound of formulae (II), (IV), or (V) wherein n is 1.

[0064] In a further aspect the invention relates to a method of treating a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formulae (I), (II), (III), (IV), or (V) as specified above or as further specified hereinafter. In a particular embodiment, the method of treating a mammal infected with HCV comprises the administration of an HCV inhibitory effective amount of a compound of formulae (II), (IV), or (V) wherein n is 1.

[0065] In a further embodiment, the present invention relates to the use of a compound of the formula (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV. Said compound is a pteridine of the formula (VI):

##STR00007## [0066] a salt, stereoisomeric form, and racemic mixture thereof, wherein R.sup.1, R.sup.8, R.sup.9, R.sup.11, R.sup.12, R.sup.6 are as defined above.

[0067] In a further embodiment the invention relates to a method of inhibiting HCV replication in a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formula (VI) as specified above or as further specified hereinafter.

[0068] In a further embodiment the invention relates to a method of treating a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formula (VI) as specified above or as further specified hereinafter.

[0069] Still further embodiments of the invention relate to the use of the compounds of the formulae (V) or (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV. Said compounds are pteridines of the formulae (V) or (VI) wherein, where applicable n is 1, and

[0070] R.sup.1 is hydrogen or amino;

[0071] R.sup.8 is hydrogen, C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0072] R.sup.9 represents hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b;

[0073] R.sup.11 represents hydrogen, fluoro, or pyrrolidin-1-yl;

[0074] R.sup.12 represents halo, C.sub.1-4alkyl, or polyhaloC.sub.1-4alkyl;

[0075] R.sup.6 is hydrogen, or C.sub.1-4alkyl;

[0076] R.sup.7 is hydrogen, or C.sub.1-4alkyl; and

[0077] R.sup.4a and R.sup.4b, independently, are hydrogen, C.sub.1-4alkyl, 2-oxo-pyrrolidin-1-yl-C.sub.1-4alkyl.

[0078] Further embodiments of the invention relate to the method of inhibiting HCV replication in a mammal infected with HCV, and to the method of treating a mammal infected with HCV, said methods comprising the administration of an HCV inhibitory effective amount of a compound of formulae (V) or (VI) wherein, where applicable n is 1, and R.sup.1, R.sup.8, R.sup.9, R.sup.11, R.sup.12 are as defined in the previous paragraph.

[0079] Yet still further embodiments of the invention relate to the use of the compounds of the formulae (V) or (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV. Said compounds are pteridines of the formulae (V) or (VI) wherein, where applicable n is 1, and

[0080] R.sup.1 is hydrogen;

[0081] R.sup.8 is hydrogen, C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0082] R.sup.9 represents hydrogen, C.sub.1-4alkyl, or COOR.sup.7;

[0083] R.sup.11 represents fluoro, or pyrrolidin-1-yl;

[0084] R.sup.12 represents halo, or C.sub.1-4alkyl; and

[0085] R.sup.7 is hydrogen, or C.sub.1-4alkyl.

[0086] Thus, further embodiments of the invention relate to a method of inhibiting HCV replication in a mammal infected with HCV, and to a method of treating a mammal infected with HCV, said methods comprising the administration of an HCV inhibitory effective amount of a compound of formulae (V) or (VI) wherein, where applicable n is 1, and R.sup.1, R.sup.8, R.sup.9, R.sup.11, R.sup.12 are as defined in the previous paragraph.

[0087] In a further embodiment, the present invention relates to a pteridine of the formula (VII):

##STR00008##

[0088] a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0089] R.sup.1 is hydrogen or amino;

[0090] R.sup.8 is hydrogen, C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0091] R.sup.9 represents hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b;

[0092] R.sup.6 is independently hydrogen, or C.sub.1-4alkyl;

[0093] each R.sup.7 is independently hydrogen, or C.sub.1-4alkyl; and

[0094] each R.sup.4a and R.sup.4b is independently hydrogen, C.sub.1-4alkyl, 2-oxo-pyrrolidin-1-yl-C.sub.1-4alkyl;

[0095] with the proviso that when R.sup.8 is hydrogen, R.sup.9 is not hydrogen.

[0096] In a further embodiment, the present invention relates to a pteridine of the formula (VII), a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0097] R.sup.8 is C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0098] R.sup.1, R.sup.4a, R.sup.4b, R.sup.6, R.sup.7, and R.sup.9 are as recited in the previous paragraph.

[0099] In a further embodiment, the present invention relates to a pteridine of the formula (VII), a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0100] R.sup.9 represents C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b;

[0101] R.sup.1, R.sup.4a, R.sup.4b, R.sup.6, R.sup.7, and R.sup.8 are as recited in the second previous paragraph.

[0102] In a further embodiment, the present invention relates to a pteridine of the formula (VIII):

##STR00009##

[0103] a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0104] R.sup.1 is independently hydrogen or amino;

[0105] R.sup.8 is hydrogen, C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0106] R.sup.9 represents hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b;

[0107] R.sup.6 is independently hydrogen, or C.sub.1-4alkyl;

[0108] each R.sup.7 is independently hydrogen, or C.sub.1-4alkyl; and

[0109] each R.sup.4a and R.sup.4b is independently hydrogen, C.sub.1-4alkyl, with the proviso that when R.sup.8 is hydrogen, R.sup.9 is not hydrogen.

[0110] In a further embodiment, the present invention relates to a pteridine of the formula (VIII), a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0111] R.sup.9 represents C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b;

[0112] R.sup.1, R.sup.4a, R.sup.4b, R.sup.6, R.sup.7, and R.sup.8 are as recited in the previous paragraph.

[0113] In a further embodiment, the present invention relates to a pteridine of the formula (VIII), a salt, stereoisomeric form, and racemic mixture thereof, wherein

[0114] R.sup.8 is C.sub.1-6alkyl, phenylC.sub.1-4alkyl;

[0115] R.sup.1, R.sup.4a, R.sup.4b, R.sup.6, R.sup.7, and R.sup.9 are as recited in the second previous paragraph.

[0116] In a further embodiment, the present invention relates to a pteridine of the formula (VII) or (VIII) as set forth above, wherein

[0117] R.sup.1 is hydrogen;

[0118] R.sup.8 is hydrogen;

[0119] R.sup.9 represents C.sub.1-4alkyl.

[0120] In a further embodiment, the present invention relates to a pteridine of the formula (VII) or (VIII) as set forth above, wherein

[0121] R.sup.1 is hydrogen;

[0122] R.sup.8 is C.sub.1-6alkyl;

[0123] R.sup.9 represents hydrogen.

[0124] A method of treating clinical conditions relating to HCV infection in a mammal, said method comprising the administration of an HCV inhibitory effective amount of a compound of formula (V) wherein R.sup.1, R.sup.8, R.sup.9, R.sup.11, R.sup.12 are as defined hereinafter.

[0125] A method as in the previous paragraph wherein the clinical conditions are other than liver fibrosis.

[0126] The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) show activity against the HCV virus and are therefore useful as a medicament, and in the manufacture of a medicament for preventing, treating or combating infection, clinical conditions, or a disease associated with HCV infection.

[0127] The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) show activity against the HCV virus and are therefore useful as a medicament, and in the manufacture of a medicament for preventing, treating or combating clinical conditions associated with HCV infection other than liver fibrosis.

[0128] The term C.sub.1-2alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 2 carbon atoms, such as, for example, methyl, ethyl, and the like.

[0129] The term C.sub.1-4alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, the groups defined for C.sub.1-2alkyl and propyl, butyl, 2-methyl-propyl and the like.

[0130] The term C.sub.1-6alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, the groups defined for C.sub.1-4alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.

[0131] The term C.sub.1-10alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as, for example, the groups defined for C.sub.1-6alkyl and heptyl, octyl, nonyl, decyl and the like.

[0132] The term C.sub.2-4alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 4 carbon atoms, such as, for example, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, and the like. Preferred are C.sub.2-4alkenyls having one double bond.

[0133] The term C.sub.2-6alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, the groups defined for C.sub.2-4alkenyl and pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1-methyl-pent-2-enyl and the like. Preferred are C.sub.2-6alkenyls having one double bond.

[0134] The term C.sub.2-10alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 10 carbon atoms, such as, for example, the groups defined for C.sub.2-6alkenyl and hept-1 -enyl, hept-2-enyl, 2-methyl-hept-1 -enyl, oct-3-enyl, non-4-enyl, 1-methyl-non-2-enyl and the like. Preferred are C.sub.2-10alkenyls having one double bond.

[0135] The term C.sub.2-4alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 4 carbon atoms, such as, for example, ethynyl, prop-1-ynyl, but-1-ynyl, but-2-ynyl, and the like. Preferred are C.sub.2-4alkynyls having one triple bond.

[0136] The term C.sub.2-6alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, the groups defined for C.sub.2-4alkynyl and pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, 1-methyl-pent-2-ynyl, pent-2-en-4-ynyl and the like. Preferred are C.sub.2-6alkynyls having one triple bond.

[0137] The term C.sub.2-10alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 10 carbon atoms, such as, for example, the groups defined for C.sub.2-6alkynyl and hept-1-ynyl, hept-2-ynyl, 2-methyl-hept-1-ynyl, oct-3-ynyl, non-4-ynyl, 1-methyl-non-2-ynyl and the like. Preferred are C.sub.2-10alkynyls having one triple bond.

[0138] The term C.sub.1-6alkanediyl as a group or part of a group defines bivalent straight and branched chained hydrocarbons having from 1 to 6 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl, or 1,1-ethanediyl, 1,3-propanediyl, 1,3-butanediyl, 1,4-butanediyl, 1,3 -pentanediyl, 1,5-pentanediyl, 1,4-hexanediyl, 1,6-hexanediyl, and the like.

[0139] The term C.sub.3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0140] The term aryl as a group or part of a group is meant to include phenyl or naphtyl. In a preferred embodiment, the term aryl as a group or part of a group is phenyl.

[0141] The term halo is generic to fluoro, chloro, bromo or iodo.

[0142] As used in the foregoing and hereinafter polyhaloC.sub.1-4alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C.sub.1-4alkyl, for example, 1,1,1-trifluoroethyl, 1,1-difluoro-ethyl, the polyhalomethyl groups mentioned hereinafter, and the like. A preferred subgroup of polyhaloC.sub.1-4alkyl is polyhalomethyl, wherein the latter as a group or part of a group is defined as mono- or polyhalo-substituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC.sub.1-4alkyl, they may be the same or different.

[0143] The term protecting group refers to an amino-protecting group such as such as C.sub.1-10alkoxy-carbonyl, arylC.sub.1-10alkoxy-carbonyl, like benzoyl, anisoyl-, isobutyroyl-, acetyl-, or tert-butylbenzoyl (Breipohl et al. (1997) Tetrahedron 53, 14671-14686). The protecting group may be as well an acid-labile protecting group such as dimethoxytrityl.

[0144] It should also be noted that the radical positions on any molecular moiety used in the definitions, unless indicated otherwise, may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

[0145] When any variable (e.g. halogen or C.sub.1-4alkyl) occurs more than one time in any constituent, each definition is independent.

[0146] The N-oxide forms of the present compounds are meant to comprise any one of the compounds of the present invention wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

[0147] For therapeutic use, the salts of the compounds of the present invention are those wherein the counter-ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter-ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of the present invention. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

[0148] The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, hemisulphuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecyl-sulphuric, heptanoic, hexanoic, benzoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

[0149] Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form.

[0150] The compounds of the present invention containing an acidic proton may also be converted into their non-toxic metal or amine addition base salt form by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Alternatively, when a carboxyl moiety is present on a compound of the present invention, the compound may also be supplied as a salt with a pharmaceutically acceptable cation.

[0151] Conversely said base addition salt forms can be converted by treatment with an appropriate acid into the free acid form.

[0152] The term salts also comprises the hydrates and the solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

[0153] In the event that any of the substituents of the compounds of the present invention contain chiral centers, as some, indeed, do, the compounds the present invention include all stereoisomeric forms thereof, both as isolated stereoisomers and mixtures of these stereoisomeric forms.

[0154] The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

[0155] Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms enantiomerically pure and diastereomerically pure should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

[0156] Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0157] The diastereomeric racemates of the compounds of the present invention can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography. The present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, within the definition of Het.sup.2, for example an 1,2,4-oxadiazole may be substituted with a hydroxy or a mercapto group in the 5-position, thus being in equilibrium with its respective tautomeric form as depicted below.

##STR00010##

[0158] The term prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of the present invention. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8.sup.th ed, McGraw-Hill, Int. Ed. 1992, Biotransformation of Drugs, p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. For example, a substituent containing sulfhydryl could be coupled to a carrier which renders the compound biologically inactive until removed by endogenous enzymes or, for example, by enzymes targeted to a particular receptor or location in the subject.

[0159] Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.

[0160] The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0161] Whenever used hereinafter, the term compounds of formula (I), compounds of formula (II), compounds of formula (III), compounds of formula (IV), compounds of formula (V), compounds of formula (VI), compounds of formula (VII), compounds of formula (VIII), compounds of formulas (V) to (VIII), or the compounds of present invention or similar term is meant to include the compounds of general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues. An interesting subgroup of the compounds of formula (V) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms of the compounds of formula (V).

[0162] Embodiments of the present invention are those compounds of the present invention or any of the subgroups thereof wherein the 4-pyridyl forms a N-oxide, for example the N-oxide of compound nr. 24.

##STR00011##

[0163] Further embodiments of the present invention are those compounds of the present invention or any of the subgroups of compounds of the present invention wherein the compound occurs as an acid-addition salt, wherein the salt preferably is selected from hydrochloride, hydrobromide, trifluoroacetate, fumarate, chloroacetate, methanesulfonate, oxalate, acetate and citrate.

[0164] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C.sub.1-6alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, di-C.sub.1-4alkylaminoC.sub.1-4alkyl, piperidin-1-yl-C.sub.1-4alkyl, arylC.sub.1-6alkyl, wherein the aryl group may be further substituted with C.sub.1-4alkyl, or C.sub.1-4alkoxy.

[0165] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, di-C.sub.1-4alkylaminoC.sub.1-4alkyl, arylC.sub.1-6alkyl, wherein the aryl group may be further substituted with C.sub.1-4alkoxy.

[0166] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C.sub.1-2alkyl, C.sub.1-2alkoxyC.sub.1-2alkyl, di-C.sub.1-2alkylaminoC.sub.1-2alkyl, piperidin-1-yl-C.sub.1-2alkyl, arylC.sub.1-2alkyl, wherein the aryl group may be further substituted with C.sub.1-2alkoxy.

[0167] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from methyl, methoxyethyl, dimethylaminoethyl, piperidin-1-ylethyl, benzyl, wherein the phenyl group may be further substituted with methoxy.

[0168] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen, amino, or monosubstituted amino, wherein the substituent of the amino may be selected from methoxyethyl, dimethylaminoethyl, piperidin-1-ylethyl, and benzyl, wherein the phenyl group is further substituted with methoxy.

[0169] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.1 is independently hydrogen or amino.

[0170] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.8 is hydrogen, C.sub.1-10alkyl, aminoC.sub.1-10alkyl, arylC.sub.1-10alkyl, Het.sup.1C.sub.1-6alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, halo, OR.sup.6, NR.sup.4aR.sup.4b, SR.sup.5, and polyhaloC.sub.1-4alkyl.

[0171] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein R.sup.8 is hydrogen, C.sub.1-6alkyl, aminoC.sub.1-6alkyl, arylC.sub.1-6alkyl, Het.sup.1C.sub.1-6alkyl, or C.sub.1-6alkoxy-carbonyl.

[0172] Further embodiments of the present invention are those compounds of formula compounds of the present invention or any subgroup thereof wherein R.sup.8 is hydrogen, C.sub.1-6alkyl, aminoC.sub.1-4alkyl, phenylC.sub.1-4alkyl, pyrrolidin-1-ylC.sub.1-4alkyl, or C.sub.1-6alkoxy-carbonyl.

[0173] Further embodiments of the present invention are those compounds of formula compounds of the present invention or any subgroup thereof wherein each R.sup.9 represents, independently, hydrogen, C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl, halo, COR.sup.6, COOR.sup.7, CONR.sup.4aR.sup.4b, OR.sup.7, NR.sup.4aR.sup.4b, NR.sup.4aCOR.sup.6, NR.sup.4aSO.sub.2R.sup.5, SR.sup.5, or morpholin-4-yl, and wherein the C.sub.1-4alkyl may be further substituted with COOR.sup.7.

[0174] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein each R.sup.9 represents, independently, hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b, and wherein the C.sub.1-4alkyl may be further substituted with COOR.sup.7.

[0175] Further embodiments of the present invention are those compounds of the present invention or any subgroup thereof wherein each R.sup.9 represents, independently, hydrogen, C.sub.1-4alkyl, COR.sup.6, COOR.sup.7, or CONR.sup.4aR.sup.4b.

[0176] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.11 represents hydrogen, fluoro, or pyrrolidin-1-yl.

[0177] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.11 represents hydrogen or fluoro.

[0178] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.12 represents halo, C.sub.1-4alkyl, or polyhaloC.sub.1-4alkyl.

[0179] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.12 represents halo, or polyhaloC.sub.1-4alkyl.

[0180] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.12 represents chloro, bromo, fluoro, or trifluoromethyl.

[0181] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.11 represents fluoro, and R.sup.12 represents chloro, or bromo.

[0182] Further embodiments of the present invention are those compounds of formulae (V), (VI) or any of the subgroups thereof wherein R.sup.11 represents hydrogen, and R.sup.12 represents chloro, bromo, fluoro, or trifluoromethyl.

[0183] Compounds of particular interest are those compounds of formula (V) listed in Table 1 below, in particular compounds number 1, number 7, number 21, number 23, number 24, and number 25, and its N-oxides, salts and stereoisomers.

[0184] A number of synthetic routes may be employed to produce the compounds of the invention. In general, they may be synthesized using reactions known in the art. Any art-known method for synthesis may be employed. However, the following synthetic routes are convenient for preparation of the invention compounds.

[0185] The compounds of the formula (V) may be synthesized following a procedure adapted from Wamhoff, H.; Kroth, E. Synthesis, 1994, 405-410 as described in Scheme 1.

##STR00012##

[0186] Basically, a methyl 3-amino-2-pyrazinecarboxylate (1a) is reacted with acylchloride in the presence of a suitable solvent such as chloroform or pyridine to afford 3-acylamino-pyrazin-2-carboxylates (1b). Said 3-acylaminopyrazin-2-carboxylates (1b) are converted with for example ammonium hydroxide into 3-acylaminopyrazin-2-amides (1d). Optionally, 3-acylaminopyrazine-2-carboxamides (1d) may already be obtained by acylation of 3-amino-2-pyrazinecarboxamide (1c).

[0187] The 3-acylaminopyrazin-2-amides (1d) are then cyclized by the addition of a base to form pteridin-4-ol derivatives of formula (1e). The alcohol may then be replaced by a halogen with the help of a halogenating agent such as thionyl chloride in a suitable solvent like chloroform, dichloroethane or tetrahydrofuran (THF) in presence of a catalytic amount of dimethylformamide (DMF). Following, a nucleophilic substitution is performed on compound (1f) with an amine or an alcohol of formula HLR.sup.2, together with a suitable base, such as TEA or DIPEA in an organic solvent such as DCM, THF or DMF, yielding the pteridine compounds of formula (1g).

[0188] Alternatively, the pteridin-4-ol may be converted in a one-pot procedure into the pteridines of formula (V) by reacting compounds of formula (1e) with an amine or alcohol of the formula HLR.sup.2 together with a suitable base, such as TEA or DIPEA in the presence of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoro-phosphate (PyBOP). In the formula HLR.sup.2, H is hydrogen, and L and R.sup.2 have the meanings indicated above in the definition of the substituents of compound of formula (V).

##STR00013##

[0189] Alternatively, the compounds of the formula (V) can be prepared from the corresponding pteridinones as starting materials followed by their conversion to the iminochlorides and the subsequent displacement of the chlorine atom with an appropriate amine such as a 4-aminopyridine as shown below in Scheme 2.

[0190] (i) thionyl chloride, DMF; (ii) 4-aminonicotinic acid methyl ester, TEA; (iii) NaOH; (iv) PyBOP, TEA, HNR.sup.4aR.sup.4b.

[0191] Schemes 3 and 4, shown below, provide alternative routes to pyridyl nucleus and further substitutions thereof.

##STR00014##

##STR00015##

[0192] Compounds embodied in the present invention are shown below in Table 1:

##STR00016##

TABLE-US-00001 TABLE 1 # R.sup.1 L R.sup.2 R.sup.3 1 H NH [00017] [00018] 2 H N(CH.sub.3) [00019] [00020] 3 H N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3) [00021] [00022] 4 H N[CH.sub.2CH.sub.2C(CH.sub.3).sub.3] [00023] [00024] 5 H N(CH.sub.2Ph) [00025] [00026] 6 H NH [00027] [00028] 7 H NH [00029] [00030] 8 H NH [00031] [00032] 9 H NH [00033] [00034] 10 H N(CH.sub.3) [00035] [00036] 11 H NH CH.sub.2CH.sub.2OH [00037] 12 H [00038] [00039] [00040] 13 H NH [00041] [00042] 14 H NH [00043] [00044] 15 H NH [00045] [00046] 16 H NH [00047] [00048] 17 H [00049] [00050] [00051] 18 H NH [00052] [00053] 19 H NH [00054] [00055] 20 H N(CH.sub.2CH.sub.2CH.sub.2NH.sub.2) [00056] [00057] 21 H NH [00058] [00059] 22 H [00060] [00061] [00062] 23 H NH [00063] [00064] 24 H NH [00065] [00066] 25 H NH [00067] [00068] 26 H NH [00069] [00070] 27 H NH [00071] [00072]

[0193] The manner of administration and formulation of the compounds useful in the invention and their related compounds will depend on the nature of the condition, the severity of the condition, the particular subject to be treated, and the judgment of the practitioner; formulation will depend on mode of administration. As the compounds of the invention are small molecules, they are conveniently administered by oral administration by compounding them with suitable pharmaceutical excipients so as to provide tablets, capsules, syrups, and the like. Suitable formulations for oral administration may also include minor components such as buffers, flavoring agents and the like. Typically, the amount of active ingredient in the formulations will be in the range of 5%-95% of the total formulation, but wide variation is permitted depending on the carrier. Suitable carriers include sucrose, pectin, magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

[0194] The compounds useful in the invention may also be administered through suppositories or other transmucosal vehicles. Typically, such formulations will include excipients that facilitate the passage of the compound through the mucosa such as pharmaceutically acceptable detergents.

[0195] The compounds may also be administered topically, or in formulation intended to penetrate the skin. These include lotions, creams, ointments and the like which can be formulated by known methods.

[0196] The compounds may also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal injection. Typical formulations for such use are liquid formulations in isotonic vehicles such as Hank's solution or Ringer's solution.

[0197] Alternative formulations include nasal sprays, liposomal formulations, slow-release formulations, and the like, as are known in the art.

[0198] Any suitable formulation may be used. A compendium of art-known formulations is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pa. Reference to this manual is routine in the art.

[0199] The dosages of the compounds of the invention will depend on a number of factors which will vary from patient to patient. However, it is believed that generally, the daily oral dosage will utilize 0.001-100 mg/kg total body weight, preferably from 0.01-50 mg/kg and more preferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending on the conditions being treated and the judgment of the practitioner.

[0200] It should be noted that the compounds of the invention can be administered as individual active ingredients, or as mixtures of several embodiments of this formula. In addition, the compounds of the invention may be used as single therapeutic agents or in combination with other therapeutic agents.

[0201] Due to their favorable antiviral properties, as will be apparent from the examples, the compounds of the present invention are useful in the treatment of individuals infected by HCV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with flaviviruses. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HCV and other pathogenic flaviviruses, such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus. The conditions associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviruses the conditions include yellow fever, dengue fever, hemorraghic fever and encephalitis.

[0202] The compounds of the present invention or any subgroup thereof may therefore be used as medicines against the above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HCV-infected subjects of an amount effective to combat the conditions associated with HCV and other pathogenic flaviviruses. Consequently, the compounds of the present invention can be used in the manufacture of a medicament useful for treating conditions associated with HCV and other pathogenic flaviviruses.

[0203] In an embodiment, the invention relates to the use of a compound of formula (V) or any subgroup thereof as defined herein in the manufacture of a medicament for treating or combating infection or disease associated with HCV infection in a mammal. The invention also relates to a method of treating a flaviviral infection, or a disease associated with flavivirus infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (V) or a subgroup thereof as defined herein.

[0204] In another embodiment, the present invention relates to the use of formula (V) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, in particular HCV. In another embodiment, the present invention relates to the use of formula (V) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, wherein said HCV is inhibited in its replication.

[0205] Also, the combination of previously known anti-HCV compound, such as, for instance, interferon- (IFN-), pegylated interferon- and/or ribavirin, and a compound of the present invention can be used as a medicine in a combination therapy. The term combination therapy relates to a product containing mandatory (a) a compound of the present invention, and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV type 1. Thus, to combat or treat HCV infections, the compounds of this invention may be co-administered in combination with for instance, interferon- (IFN-), pegylated interferon- and/or ribavirin, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease, NS3 helicase and NSSB polymerase.

[0206] Accordingly, the present invention relates to the use of a compound of formula (V) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (V) and (pegylated) IFN- and/or ribavirin.

[0207] It will be appreciated by the person skilled in the art that the compounds of formula (V) may be tested in a cellular HCV replicon system based on Lohmann et al. (1999) Science 285:110-113, with the further modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624 (incorporated herein by reference), which is further exemplified in the examples section. This model, while not a complete infection model for HCV, is widely accepted as the most robust and efficient model of autonomous HCV RNA replication currently available. Compounds exhibiting anti-HCV activity in this cellular model are considered as candidates for further development in the treatment of HCV infections in mammals. It will be appreciated that it is important to distinguish between compounds that specifically interfere with HCV functions from those that exert cytotoxic or cytostatic effects in the HCV replicon model, and as a consequence cause a decrease in HCV RNA or linked reporter enzyme concentration. Assays are known in the field for the evaluation of cellular cytotoxicity based for example on the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. Furthermore, cellular counter screens exist for the evaluation of non-selective inhibition of linked reporter gene activity, such as firefly luciferase. Appropriate cell types can be equipped by stable transfection with a luciferase reporter gene whose expression is dependent on a constitutively active gene promoter, and such cells can be used as a counter-screen to eliminate non-selective inhibitors. All patents, patent applications and articles referred to before or below are incorporated herein by reference.

EXAMPLES

[0208] The following examples are intended to illustrate, but not to limit the invention.

Example 1

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 1

[0209] ##STR00073##

[0210] 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic acid methyl ester 102

[0211] Pyridine (7.75 g, 98.0 mmol) was added at 0 C. under N.sub.2 to a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester 101 (1.5 g, 9.80 mmol) and 5-bromo-2-fluorobenzoylchloride (9.45 g, 49.0 mmol) in CH.sub.2Cl.sub.2. The reaction mixture was warmed at 40 C. for 4 h, then cooled down at room temperature. The reaction mixture was quenched with 20 mL of ethanol, evaporated, partitioned between CH.sub.2Cl.sub.2 and 1N NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and evaporated. The crude material was triturated in EtOH, filtered, washed with EtOH and ether to give 2.6 g of 3-(5-bromo-2-fluorobenzoyl-amino)pyrazine-2-carboxylic acid methyl ester 102 as a white powder (LCMS analysis).

[0212] 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxamide 103

[0213] A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic acid methyl ester 102 (2.6 g, 7.34 mmol) and NH.sub.4OH (15 mL) in ethanol (50 mL) was heated at reflux for 10 min. Then, the reaction mixture was cooled at room temperature and the precipitate was filtered off, washed with ethanol and ether to give 2.1 g of the title product 103 as a white powder (LCMS analysis).

[0214] 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104

[0215] A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxamide 103 (2.3 g, 6.78 mmol) and KOH (3.81 g, 67.8 mmol) in H.sub.2O (60 mL) and DMSO (20 mL) was stirred at room temperature for 45 min. Acidification to pH 5 (pH paper control) with AcOH followed by addition of 50 mL of ice-cold water afforded a precipitate, which was filtered off, washed with H.sub.2O, acetonitrile and ether to give 1.83 g of the title product 104 as a white powder (LCMS analysis).

[0216] 2-(5-bromo-2-fluorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 1

[0217] Triethylamine (1.04 mL, 7.17 mmol) was added to a solution of 2-(5-bromo-2-fluoro-phenyl)pteridin-4-one 104 (800mg, 2.49 mmol), 4-aminopyridine (469 mg, 4.98 mmol) and PyBOP (2.59 g, 4.98 mmol) in CH.sub.2Cl.sub.2. After 12 h, the reaction mixture was partitioned between CH.sub.2Cl.sub.2/Petroleum ether (2:1, 300 mL) and ice-cold 1N HCl (300 mL). The pH of the water phase was adjust to 12 with conc. NaOH and extracted with AcOEt, dried (Na.sub.2SO.sub.4) and evaporated. The residue was triturated in CH.sub.2Cl.sub.2/Petroleum ether (2:1, 15 mL), filtered off, and washed with ether. The product was purified by column chromatography (AcOEt/CH.sub.2Cl.sub.2/MeOH, 5:4:1) to give 325 mg of the title product 1 as a yellow powder (LCMS analysis).

Example 2

[0218] Synthesis of 4-[[2-(5-Bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid, compound no. 16, and 4-[[2-(5-bromo-2-fluorophenyl) pteridin-4-yl]amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]nicotinamide, Compound No. 21

##STR00074##

[0219] 2-(5-Bromo-2-fluorophenyl)-4-Chloropteridine 106

[0220] Thionyl chloride (371 mg, 3.11 mmol) was added to the stirred suspension of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 (200 mg, 0.623 mmol) in chloroform (5 mL) and dry DMF (100 L). The reaction mixture was refluxed under nitrogen for 1 h (starting material gone by HPLC). The solvent was removed in vacuo. Then the residue was triturated in Et.sub.2O and filtered off to give 210 mg of the title product 106 as a yellow solid (LCMS analysis).

[0221] 4-[[2-(5-Bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic Acid Methyl Ester 107

[0222] To a solution of 2-(5-bromo-2-fluorophenyl)-4-chloropteridine 106 (200 mg, 0.589 mmol), 4-aminonicotinic acid methyl ester (224 mg, 1.47 mmol) in dichloroethane (5 mL), was added dropwise triethylamine (300 L, 2.07 mmol). The resulting mixture was heated at 70 C. for 15 min, then quenched with silica and purified by column chromatography (AcOEt/CH.sub.2Cl.sub.2/triethylamine, 70/19/1). Crystallization from AcOEt/Et.sub.2O afforded 200 mg of the title product 107 as yellow prisms (LCMS analysis).

[0223] 4-[[2-(5-Bromo-2-fluorophenyppteridin-4-yl]amino]nicotinic acid 16

[0224] A solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid methyl ester 107 (200 mg, 0.439 mmol) and NaOH (44 mg, 1.10 mmol) in THF/MeOH/H.sub.2O (3:2:1, 5 mL), was stirred at room temperature for 3 h. The solvent was evaporated, and the residue dissolved in H.sub.2O, neutralized with AcOH, filtered off, and successively washed with H.sub.2O, MeOH and Ether to give 160 mg of the title product 16 as a yellow powder (LCMS analysis).

[0225] 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]-N-[3-(2-Oxopyrrolidin-1-yl)-propyl]nicotinamide 21

[0226] Triethylamine (140 L, 1.00 mmol) was slowly added to a solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid 16 (150 mg, 0.340 mmol), PyBOP (0.350 mg, 0.68 mmol), and 1-(3-aminopropyl)pyrrolidinone (97 mg, 0.68 mmol) in CH.sub.2Cl.sub.2 (10 mL). After 15 min at room temperature, the reaction mixture was evaporated and the residue purified by column chromatography (AcOEt/CH.sub.2Cl.sub.2, 2:1+1% triethylamine to AcOEt/CH.sub.2Cl.sub.2/MeOH, 7:2:1+1% triethylamine). The yellow powder was recrystallized from EtOH to give 58 mg of the title product 21 as yellow prisms (LCMS analysis).

Example 3

Synthesis of 2-(5-Bromo-2-pyrrolidin-1-ylphenyl)-4-(3-methyl-4-pyridylamino)pteridine, Compound No. 6

[0227] ##STR00075##

[0228] 2-(5-Bromo-2-pyrrolidin-1-ylphenyl)pteridin-4-one 110

[0229] A solution of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 in pyrrolidine was heated in a microwave cavity (Power=270 W, Temp=110 C.) for 12 min. The pyrrolidine was evaporated, then residue partitioned between NaHCO.sub.3 0.5 N and CH.sub.2Cl.sub.2, dried (Na.sub.2SO.sub.4) and evaporated. Trituration in Et.sub.2O afforded the title product 110 as a yellow powder (LCMS analysis).

[0230] 2-(5-Bromo-2-pyrrolidin-1-ylphenyl)-4-(3-methyl-4-pyridylamino)pteridine 6

[0231] The title product was synthesized by reaction of the 2-(5-bromo-2-pyrrolidin-1-yl-phenyl)pteridin-4-one 110 and 4-amino-3-methylpyridine following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).

Example 4

Synthesis of 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine, Compound No. 3

[0232] ##STR00076##

[0233] 4-butylaminopyridine 113

[0234] A solution of 4-chloropyridine (2.0 g, 17.6 mmol), 50% butylamine in water (30 mL) was heated at 150 C. in a sealed tube for 24 h. The reaction mixture was evaporated, partitioned between 0.1 N NaOH and CH.sub.2Cl.sub.2, dried (Na.sub.2SO.sub.4) and evaporated. Crystallization in ether/petroleum ether 4:1 afforded 2.4 g of the title product 113 as a white powder (LCMS analysis).

[0235] 4-[(butyl)(4-pyridypamino]-2-(5-bromo-2-fluorophenyl)pteridine 3

[0236] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-butylaminopyridine 113 following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).

Example 5

[0237] Synthesis of 2-(3-fluorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 27

##STR00077##

[0238] The title product was synthesized by reaction of the 2-(3-fluorophenyl)pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)-amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 6

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-[(methyl)(4-pyridyl)amino] pteridine, Compound No. 2

[0239] ##STR00078##

[0240] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(methylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluoropheny)pteridine 3.

Example 7

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-[(3,3-dimethylbutyl)(4-pyridyl)amino] pteridine, Compound No. 4

[0241] ##STR00079##

[0242] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(3,3-dimethylbutylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 8

Synthesis of 4-[(benzyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl) pteridine, Compound No. 5

[0243] ##STR00080##

[0244] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(benzylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 9

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(3-methyl-4-pyridylamino) pteridine, Compound No. 7

[0245] ##STR00081##

[0246] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 10

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(phenylamino)pteridine, Compound No. 8

[0247] ##STR00082##

[0248] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with aniline following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 11

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(2-tolylamino)pteridine, Compound No. 9

[0249] ##STR00083##

[0250] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 2-methylaniline following the procedure described for 4-[(butyl)(4-pyridypamino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 12

Synthesis of 2-(5-bromo-2-fluorophenyl)-4[4-(2-pyridyl)piperazin-1-yl]pteridine, Compound No. 12

[0251] ##STR00084##

[0252] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 1-(2-pyridyl)piperazine following the procedure described for 4-[(butyl)(4-pyridypamino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 13

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-[(methyl)(phenyl)amino]pteridine, Compound No. 10

[0253] ##STR00085##

[0254] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with N-methylaniline following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 14

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(2-hydroxyethylamino)pteridine, Compound No. 11

[0255] ##STR00086##

[0256] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 2-hydroxyethylamine following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 15

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(4-morpholinophenylamino) pteridine, Compound No. 14

[0257] ##STR00087##

[0258] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(4-morpholino)aniline following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 16

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-(2-methyl-4-pyridylamino)pteridine, Compound No. 15

[0259] ##STR00088##

[0260] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-2-methylpyridine following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 17

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-[[2-(pyrrolidin-1-yl)ethyl]-(4-pyridyl)-amino]pteridine, Compound No. 17

[0261] ##STR00089##

[0262] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-[2-(pyrrolidin-1-yl)ethylamino]pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)-pteridine 3.

Example 18

Synthesis of 2-(5-bromo-2-fluorophenyl)-4-[(phenethyl)(4-pyridyl)amino]-pteridine, Compound No. 22

[0263] ##STR00090##

[0264] The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(phenethylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridy)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 19

Synthesis of 2-(2-methyl-6-pyridyl)-4-[(3-methyl-4-pyridyl)amino]pteridine, Compound No. 19

[0265] ##STR00091##

[0266] The title product was synthesized by reaction of the 2-(2-methyl-6-pyridyl)pteridin-4-one with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 20

Synthesis of 2-(3-chlorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 18

[0267] ##STR00092##

[0268] The title product was synthesized by reaction of the 2-(3-chlorophenyl)pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)-amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 21

Synthesis of 2-(5-chloro-2-fluorophenyl)-4-(3-ethyl-4-pyridylamino)pteridine, Compound No. 23

[0269] ##STR00093##

[0270] The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-ethylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 22

Synthesis of 2-(5-chloro-2-fluorophenyl)-4-(3-methyl-4-pyridylamino)pteridine, Compound No. 25

[0271] ##STR00094##

[0272] The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 23

Synthesis of 2-(5-chloro-2-fluorophenyl)-4-(4-pyridylamino)pteridine, Compound No. 24

[0273] ##STR00095##

[0274] The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

Example 24

Synthesis of 2-(3-trifluoromethylphenyl)-4-(4-pyridylamino)pteridine, Compound No. 26

[0275] ##STR00096##

[0276] The title product was synthesized by reaction of the 2-(3-trifluoromethylphenyl)-pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.

[0277] In Table 2 below, the LCMS data for the synthetized compounds is shown:

TABLE-US-00002 Compound Number LCMS data 1 m/z : 397, 398, 399, 400 RT: 2.30 13 m/z : 455, 456, 457, 458, RT: 4.06 21 m/z: 565, 566, 567, 568, RT: 3.12 6 m/z : 462, 463, 464, 465, RT: 2.73 3 m/z : 453, 454, 455, 456, RT: 3.45 2 m/z : 411, 412, 413, 414, RT = 2.49 4 m/z : 481, 482, 483, 484, RT = 4.23 5 m/z : 487, 488, 489, 490, RT: 3.49 7 m/z : 411, 412, 413, 414, RT: 2.49 8 m/z: 396, 397, 398, 399, RT: 4.52 9 m/z : 410, 411, 412, 413, RT: 4.59 12 m/z : 466, 467, 468, 469, RT: 3.31 10 m/z : 410, 411, 412, 413, RT: 4.70 11 m/z : 364, 365, 366, 367, RT = 2.67 14 m/z : 419, 420, RT: 4.27 15 m/z: 411, 412, 413, 414, RT: 2.49 22 m/z: 501, 502, RT: 3.50 19 m/z : 330, RT: 1.40 18 m/z : 335, 336, 337, RT: 2.37 25 m/z : 367, 368, 369, RT: 2.44 24 m/z : 353, 354, 355, RT: 2.29 m/z is the mass-to-charge ratio RT is the retention time

Example 25

Activity of Compounds of Formula (V) in HCV Replicon Assays

[0278] Stable Replicon Cell Reporter Assays:

[0279] The compounds of the present invention are examined for activity in the inhibition of HCV RNA replication in a cellular assay. The assay demonstrates that the present compounds exhibit activity against HCV replicons functional in a cell culture. The cellular assay is based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method is as follows.

[0280] The assay utilizes the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc). This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NSSB regions of HCV type lb translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo.sup.R, neomycine phosphotransferase). The construct is bordered by 5 and 3 NTRs (non-translated regions) from HCV type 1b. Continued culture of the replicon cells in the presence of G418 (neo.sup.R) is dependent on the replication of the HCV RNA. The stably transfected replicon cells that express HCV RNA, which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds.

[0281] Cellular Assay Experimental Method:

[0282] The replicon cells are plated in 384 well plates in the presence of the test and control compounds which are added in various concentrations. Following an incubation of three days, HCV replication is measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound on luciferase activity is monitored on the Huh-Luc cells, enabling a dose-response curve for each test compound. EC50 values are then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.

[0283] The compounds tested were found to have activities as follows:

TABLE-US-00003 TABLE 3 HCV Replicon Compound activity Number (M) 1 0.352 13 4.9 21 0.058 6 18 3 2.2 27 3.0 2 3.65 4 0.48 5 0.99 7 0.95 8 >32 9 11 12 >32 10 11 11 >32 14 8.7 15 3.56 22 1.96 19 12 18 1.5 23 0.52 25 0.48 24 0.78 26 2.0

Example 26

Pharmacokinetic Profile of Compound No. 21 in Male Swiss SPF (CDM)-Mice

[0284] Compound nr. 21 was dissolved in a 10% hydroxypropyl--cyclodextrin (HP--CD) solution at a final concentration of 1 mg base-eq./ml, .pH 4.36.

[0285] Three animals were administered orally the solution of compound nr. 21 to obtain a dose of 20 mg base-eq./kg. Blood samples were taken at 30 min, 1, 2, 4, 8 and 24 h after oral dose administration. Plasma was obtained following centrifugation at 4 C. for 10 minutes at approximately 1900g.

[0286] From each orally dosed animal individual samples of heart and liver were dissected and weighed. Tissue samples were homogenized in demineralized water.

[0287] Plasma and tissue samples were analysed for compound nr. 21, using a qualified research LC-MS/MS method.

[0288] A limited pharmacokinetic analysis was performed using WinNonlin Professional (Version 4.0.1). A non-compartmental analysis using the lin/log trapezoidal rule with lin/log interpolation was used for all data. The variability between animals is indicated by the standard deviation (st dev).

[0289] An overview of the mean plasma and tissue concentrations and some basic pharmacokinetic parameters can be found in Table 4 and FIG. 1.

[0290] Conclusion: The analysed concentration of the oral formulation was 1.0 mg base-eq./ml resulting in an exact dose of 20 mg base-eq./kg orally. No stability problems were observed on the day of dosing.

[0291] Plasma

[0292] After a single oral administration of the compound nr 21 at 20 mg base-eq./kg levels were quantifiable up to 8 h post dose (Table 4 and FIG. 1). The mean maximum plasma concentration (C.sub.max) was 220 ng/ml observed at 0.5 h post dose (T.sub.max), indicating a rapid absorption of the compound. The mean half-life (t.sub.1/2 (2-8 h)) was 2.9 h. The exposure as calculated by AUC.sub.0-inf was 332 ng.h/ml.

[0293] Tissue

[0294] As can be seen in FIG. 1, the studied tissues together with plasma had quite similar concentration time profiles, indicating distribution equilibrium between plasma and tested tissues. The mean maximum tissue concentrations (C.sub.max) were achieved at the same time as in plasma at 0.5 h post dose, indicating a rapid equilibrium. The highest concentration was observed in the liver (4057 ng/g) followed by heart (678 ng/g) with a tissue to plasma ratios of 24 and 3.8 respectively (Table 4 and FIG. 1). The mean half-life (t.sub.1/2(2-8h)) estimated for the liver was 3.5 h and 3.4 h for the heart which was comparable with that of plasma (2.9 h). Tissue levels declined in a similar pattern to plasma and at 8 h post dose only low levels of the compound were still detectable, indicating no major evidence for retention.

TABLE-US-00004 TABLE 4 Mean plasma and tissue levels (n = 3) together with some basic pharmacokinetic parameters of compound nr. 21 after a single oral administration at 20 mg base-eq./kg in the male Swiss SPF (CD1)-mice Compound nr. 21 (ng/ml or g/ml) Time Plasma stdev Heart stdev Liver stdev 0.5 220 100 678 258 4057 1730 1 166 160 557 403 2937 1852 2 21.7 6.7 92.9 49.9 611 131 4 20.3 5.1 83.6 35.9 627 189 8 5.52 1.20 29.1 6.0 201 59 24 BQL .sup.1) BQL .sup.1) BQL .sup.1) C.sub.max (ng/ml) 220 678 4057 T.sub.max (h) 0.5 0.5 0.5 t.sub.1/2 (2-8 h) (h) 2.9 3.4 3.5 AUC.sub.(0-8)(ng .Math. h/ml) 309 1119 6965 AUC.sub.0-inf (ng .Math. h/ml) 332 1262 7973 Ratio tissue/plasma 3.8 .sup.2) 24 .sup.2) .sup.1) BQL = below the limit of quantification. LLOQ was 0.500 ng/ml for plasma and ranged between 5.00 and 13.16 ng/g for tissue. .sup.2) value based upon the AUC.sub.inf