Pteridines useful as HCV inhibitors and methods for the preparation thereof

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
• R1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C1-6alkyl, C2-6alkenyl,
• C2-6alkynyl, C1-14alkoxyC1-4alkyl, diC1-14alkylaminoC1-4alkyl, piperidin-1-yl-C1-4alkyl, arylC1-6alkyl, wherein the aryl group may be further substituted with C1-4alkyl, or C1-4alkoxy;
• L is —NR8—, —NR8—C1-6alkanediyl-, —NR8—CO—C1-6alkanediyl-, —NR8—SO2—C1-6alkanediyl-, —O—, —O—C1-6alkanediyl-, —O—CO—, —O—CO—C1-6alkanediyl-, —S—, —S—C1-6alkanediyl-, or
• wherein the dotted ring together with N and Z form a Het1 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;
• R2 represents hydrogen, hydroxyC1-6alkyl, C3-7cycloalkyl, aryl, Het1, or Het2, wherein said C3-7cycloalkyl, aryl, Het1, and Het2 are each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl,
• C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CONR4aR4b, —OR7, —OCOR6, —OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCONR4aR4b. —NR4aSOR5, —NR4aSO2R5, —SR5, —SOR7, —SO2R7, —SO3R7, —SO2NR4aR4b, morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C1-4alkyl may be further substituted with —COOR7;
• R3 represents a C1-6alkyl, C3-7cycloalkyl, aryl, arylC1-6alkyl, Het1, Het2 or Het2-C1-6alkyl, each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CONR4aR4b, —OR7—OCOR6—OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCOOR7, —NR4aCONR4aR4b, —NR4aSOR5, —NR4aSO2R5, —SR5, —SOR7, —SO2R5, —SO3R7, —SO2NR4aR4b;
• and wherein R4a and R4b 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 R4a and R4b is independently hydrogen, C1-4alkyl, hydroxyC1-4alkyl, Het1-C1-4alkyl, polyhaloC1-4alkyl, cyano, or nitro;
• each R5 is independently hydrogen, or C1-4alkyl;
• each R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• R8 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkylcarbonyl, aminoC1-10alkyl, aryl, arylcarbonyl, arylC1-10alkyl, Het1, Het1C1-6alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkylcarbonyl, phenyl,
• C1-4alkylphenyl, phenylcarbonyl, aminophenyl, aminoC1-4alkylphenyl, aminophenylcarbonyl, halo, —OR6, —NR4aR4b, —SR5, —SOR5, —NR4aSOR5, —NR4aSO2R5, —SO2R5, —OCOR6, —NR4aCOR6, —NR4aCONR4aR4b, —NR4aCOOR6, —OCONR4aR4b, —COOR6, —SO3R6, —CONR4aR4b, —SO2NR4aR4b, cyano, polyhalo-C1-4alkyl, and nitro;
• Het1 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 C1-6alkyl, C1-6alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxy-carbonyl, C3-7cycloalkyl, 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 C1-4alkyl;
• Het2 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 C1-6alkyl, optionally mono- or disubstituted aminoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 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 C1-4alkyl;
• and
• aryl as a group or part of a group is phenyl.

A compound of the formula (VII):

• or a salt, stereoisomeric form, or racemic mixture thereof, wherein
• R1 is hydrogen or amino;
• R8 is hydrogen, C1-6alkyl, phenylC1-4alkyl;
• R9 represents hydrogen, C1-4alkyl, —COR6, COOR7, or —CONR4aR4b;
• R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• each R4a and R4b is independently hydrogen, C1-4alkyl, 2-oxo-pyrrolidin-1-yl-C1-4alkyl;
• with the proviso that when R8 is hydrogen, R9 is not hydrogen.

A compound of the formula (VIII):

• or a salt, stereoisomeric form, or racemic mixture thereof, wherein
• R1 is independently hydrogen or amino;
• R8 is hydrogen, C1-6alkyl, phenylC1-4alkyl;
• R9 represents hydrogen, C1-4alkyl, —COR6, COOR7, or —CONR4aR4b;
• R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• each R4a and R4b is independently hydrogen, C1-4alkyl, 2-oxo-pyrrolidin-1-yl-C1-4alkyl;
• with the proviso that when R8 is hydrogen, R9 is not hydrogen.

A pharmaceutical composition comprising a compound of the formula (VII):

• or a salt, stereoisomeric form, or racemic mixture thereof, wherein
• R1 is hydrogen or amino;
• R8 is hydrogen, C1-6alkyl, phenylC1-4alkyl;
• R9 represents hydrogen, C1-4alkyl, —COR6, COOR7, or —CONR4aR4b;
• R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• each R4a and R4b is independently hydrogen, C1-4alkyl, 2-oxo-pyrrolidin-1-yl-C1-4alkyl;
• with the proviso that when R8 is hydrogen, R9 is not hydrogen.

A pharmaceutical composition comprising a compound of the formula (VII):

• or a salt, stereoisomeric form, or racemic mixture thereof, wherein
• R1 is hydrogen or amino;
• R8 is hydrogen, C1-6alkyl, phenylC1-4alkyl;
• R9 represents hydrogen, C1-4alkyl, —COR6, COOR7, or —CONR4aR4b;
• R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• each R4a and R4b is independently hydrogen, C1-4alkyl, 2-oxo-pyrrolidin-1-yl-C1-4alkyl;
• with the proviso that when R8 is hydrogen, R9 is not hydrogen, and further comprising one or more other anti-HCV agents.

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
• R1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C1-6alkyl, C2-6alkenyl,
• C2-6alkynyl, C1-14alkoxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl, piperidin-1-yl-C1-4alkyl, arylC1-6alkyl, wherein the aryl group may be further substituted with C1-4alkyl, or C1-4alkoxy;
• L is —NR8—, —NR8—C1-6alkanediyl-, —NR8—CO—C1-6alkanediyl-, —NR8—SO2—C1-6alkanediyl-, —O—, —O—C1-6alkanediyl-, —O—CO—, —O—CO—C1-6alkanediyl-, —S—, —S—C1-6alkanediyl-, or
• wherein the dotted ring together with N and Z form a Het1 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;
• R2 represents hydrogen, hydroxyC1-6alkyl, C3-7cycloalkyl, aryl, Het1, or Het2, wherein said C3-7cycloalkyl, aryl, Het1, and Het2 are each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl,
• C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CONR4aR4b, —OR7, —OCOR6, —OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCONR4aR4b. —NR4aSOR5, —NR4aSO2R5, —SR5, —SOR7, —SO2R4a, —SO3R7, —SO2NR4aR4b, morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C1-4alkyl may be further substituted with —COOR7;
• R3 represents a C1-6alkyl, C3-7cycloalkyl, aryl, arylC1-6alkyl, Het1, Het2 or Het2-C1-6alkyl, each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CON4aR4b, —OR7, —OCOR6, —OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCOOR7, —NR4aCONR4aR4b, —NR4aSOR4b, —NR4aSO2R5, —SR5, —SOR7, —SO2R5, —SO3R7, —SO2NR4aR4b;
• and wherein R4a and R4b 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 R4a and R4b is independently hydrogen, C1-4alkyl, hydroxyC1-4alkyl, Het1-C1-4alkyl, polyhaloC1-4alkyl, cyano, or nitro;
• each R5 is independently hydrogen, or C1-4alkyl;
• each R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• R8 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkylcarbonyl, aminoC1-10alkyl, aryl, arylcarbonyl, arylC1-10alkyl, Het1, Het1C1-6alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkylcarbonyl, phenyl,
• C1-4alkylphenyl, phenylcarbonyl, aminophenyl, aminoC1-4alkylphenyl, aminophenylcarbonyl, halo, —OR6, —NR4aR4b, —SR5, —SOR5, —NR4aSOR5, —NR4aSO2R5, —SO2R5, —OCOR6, —NR4aCOR6, —NR4aCONR4aR4b, —NR4aCOOR6, —OCONR4aR4b, —COOR6, —SO3R6, —CONR4aR4b, —SO2NR4aR4b, cyano, polyhalo-C1-4alkyl, and nitro;
• Het1 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 C1-6alkyl, C1-6alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxy-carbonyl, C3-7cycloalkyl, 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 C1-4alkyl;
• Het2 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 C1-6alkyl, optionally mono- or disubstituted aminoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 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 C1-4alkyl;
• and
• aryl as a group or part of a group is phenyl.

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
• R1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C1-6alkyl, C2-6alkenyl,
• C2-6alkynyl, C1-4alkoxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl, piperidin-1-yl-C1-4alkyl, arylC1-6alkyl, wherein the aryl group may be further substituted with C1-4alkyl, or C1-4alkoxy;
• L is —NR8—, —NR8—C1-6alkanediyl-, —NR8—CO—C1-6alkanediyl-, —NR8—SO2—C1-6alkanediyl-, —O—, —O—C1-6alkanediyl-, —O—CO—, —O—CO—C1-6alkanediyl-, —S—, —S—C1-6alkanediyl-, or
• wherein the dotted ring together with N and Z form a Het1 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;
• R2 represents hydrogen, hydroxyC1-6alkyl, C3-7cycloalkyl, aryl, Het1, or Het2, wherein said C3-7cycloalkyl, aryl, Het1, and Het2 are each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl,
• C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CONR4aR4b, —OR7, —OCOR6, —OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCONR4aR4b, —NR4aSOR5, —NR4aSO2R5, —SR5, —SOR7, —SO2R5, —SO3R7, —SO2NR4aR4b, morpholin-4-yl, phenyl, aminophenyl, and aminophenylcarbonyl, and wherein the C1-4alkyl may be further substituted with —COOR7;
• R3 represents a C1-6alkyl, C3-7cycloalkyl, aryl, arylC1-6alkyl, Het1, Het2 or Het2-C1-6alkyl, each independently optionally substituted with one or more substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, polyhaloC1-4alkyl, halo, cyano, nitro, —COR6, —COOR7, —CONR4aR4b, —OR7, —OCOR6, —OCONR4aR4b, —NR4aR4b, —NR4aCOR6, —NR4aCOOR7, —NR4aCONR4aR4b, —NR4aSOR5, —NR4aSO2R5, —SR5, —SOR7, —SO2R5, —SO3R7, —SO2NR4aR4b;
• and wherein R4a and R4b 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 R4a and R4b is independently hydrogen, C1-4alkyl, hydroxyC1-4alkyl, Het1-C1-4alkyl, polyhaloC1-4alkyl, cyano, or nitro;
• each R5 is independently hydrogen, or C1-4alkyl;
• each R6 is independently hydrogen, or C1-4alkyl;
• each R7 is independently hydrogen, or C1-4alkyl;
• and
• R8 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkylcarbonyl, aminoC1-10alkyl, aryl, arylcarbonyl, arylC1-10alkyl, Het1, Het1C1-6alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-10alkylcarbonyl, phenyl,
• C1-10alkylphenyl, phenylcarbonyl, aminophenyl, aminoC1-4alkylphenyl, aminophenylcarbonyl, halo, —OR6, —NR4aR4b, —SR5, —SOR5, —NR4aSOR5, —NR4aSO2R5, —SO2R5, —OCOR6, —NR4aCOR6, —NR4aCONR4aR4b, —NR4aCOOR6, —OCONR4aR4b, —COOR6, —SO3R6, —CONR4aR4b, —SO2NR4aR4b, cyano, polyhalo-C1-4alkyl, and nitro;
• Het1 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 C1-6alkyl, C1-6alkoxy, halo, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxy-carbonyl, C3-7cycloalkyl, 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 C1-4alkyl;
• Het2 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 C1-6alkyl, optionally mono- or disubstituted aminoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, halo, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, polyhaloC1-4alkyl, carboxyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 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 C1-4alkyl;
• and
• aryl as a group or part of a group is phenyl.