Pteridines useful as HCV inhibitors and methods for the preparation thereof

1. A method of treating hepatitis C virus (HCV) infection comprising

administering to a mammal identified as infected with HCV, wherein the mammal does not have liver fibrosis, chronic hepatitis, and/or cirrhosis, a compound having the formula (I) for a time and in an amount effective to diminish HCV viral load in the mammal

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 is N or CH;

R 2 is 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 is 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, amino-C 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 3 to 12 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, 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.

2. The method of claim 1 , 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 is 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 5 , —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 ; and

n is 0, 1, 2, 3, or 4.

3. The method of claim 1 , 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 is 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 ; and

m is 0, 1, 2, 3, or 4.

4. The method of claim 1 , 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 is 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 is 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.

5. The method of claim 1 , 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 is, 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 is 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 is 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.

6. The method of claim 5 , wherein the compound has the formula (VI):

or a salt, stereoisomeric form, or racemic mixture thereof.

7. The method of claim 1 wherein the mammal does not have liver fibrosis.

8. The method of claim 1 , wherein the mammal does not have chronic hepatitis, and/or cirrhosis.

9. The method of claim 1 , wherein the compounds having the formula (I) is administered in combination with another anti-HCV compound.

10. The method of claim 9 , wherein the other anit-HCV compound is interferon-α, pegylated interferon-α, ribavirin, or a combination thereof.

11. The method of claim 1 , wherein the HCV viral load is diminished to undetectable levels.

12. The method of claim 1 , wherein the viral load is determined by detecting HCV RNA in the blood of the mammal.