PYRIDO(3,2-d)PYRIMIDINES USEFUL FOR TREATING VIRAL INFECTIONS

• US 20080182870A1
• Filed: 12/21/2007
• Published: 07/31/2008
• Est. Priority Date: 12/26/2006
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Chou, Chien-hung, Mishra, Ruchika, Chong, Lee S., Zhang, Jennifer R., Bondy, Steven S., Watkins, William John
• Granted Patent: US 8,729,089 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Pyrido(3,2-d)pyrimidine derivatives represented by the structural formula (I):

wherein:

• • R₄ is hydrogen, and
  • R₁, R₂ and R₃ together provide a specific substitution pattern,
    pharmaceutical acceptable addition salts, stereochemical isomeric forms, N-oxides, solvates and pro-drugs thereof, are useful in the treatment of hepatitis C.

Claims

1. A pyrido(3,2-d)pyrimidine derivative represented by the structural formula (I):

3. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein

R₂ is XR₇ or is selected from the group consisting of N-morpholinyl, N-thiomorpholinyl, N-thiomorpholinyl dioxide, cyclopropyl, N-piperidinyl and N-pyrrolidinyl, wherein said N-pyrrolidinyl is optionally substituted with C_1-4 alkylsulfonyl;

X is selected from the group consisting of O, S, NR₁₃ and CH₂;

R₇ is selected from the group consisting of C_1-20 alkyl, C_3-10 cycloalkyl, aryl, heterocyclyl and aryl-C_1-4 alkyl;

wherein said C_1-20 alkyl is substituted with one or more substituents independently selected from the group consisting of methylsulfonyl, heterocyclyl, carbamoyl, halogen and C_1-4 alkoxy when X is NR₁₃,

or said C_1-20 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C_1-4 alkoxy, halo-C_1-4 alkoxy or heterocyclyl-oxy C_1-4 alkoxy when X is O;

wherein said C_3-10 cycloalkyl is substituted with one or more substituents independently selected from the group consisting of C_1-20 alkyl and cyano when X is O, S, CH₂ or NR₁₃;

wherein said aryl is substituted with one heterocyclyl group and optionally further substituted with one or more halogen when X is NR₁₃;

wherein said aryl is optionally substituted with one or more halogen or with one heterocyclyl group when X is O, S or CH₂;

and wherein said heterocyclyl is optionally substituted with one or more C_1-20 alkyl,

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

4. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein:

R₁ is selected from the group consisting of —

NH—

CHR₅R₆ and —

NH—

R₈,

R₅ and R₆ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl, aryl and heterocyclyl,

wherein said aryl is substituted with one or more substituents selected from the group consisting of cyano, trifluoromethoxy, C_1-4 alkyl optionally substituted with —

SO₂NHR₁₃, C_1-4 alkoxy, di-C_1-4 alkylamino, mono-C_1-4 alkylamino, —

SO₂NHR₁₃, —

CON(R₁₃)₂, —

NR₁₂COR₁₀, —

SO₂R₁₃, —

NHSO₂R₁₃, heterocyclyl optionally substituted with C_1-4 alkyl, and phenoxy; and

said aryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, nitro and trifluoromethyl;

wherein said C_1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-4 alkoxy, aryl, heterocyclyl, —

P(O)(OR₁₃)₂, carbamoyl, and —

SO₂NHR₁₃;

R₈ is selected from the group consisting of C_3-10 cycloalkyl substituted at the carbon position adjacent to the N atom of R₁ with aryl or heteroaryl wherein said aryl is optionally substituted with halogen;

phenyl; and

4-fluorophenyl,

or a pharmaceutical acceptable addition salt or a stereochemically isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

5. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein:

R₃ is selected from the group consisting of mono-substituted or disubstituted aryl and mono-substituted or disubstituted heterocyclyl,

wherein at least one substituent of said aryl or heterocyclyl is independently selected from the group consisting of oxo, C_1-6 alkyl substituted with one or more hydroxy and optionally further substituted with one or more halogen, —

CONHR₉, —

NR₁₂COR₁₀, —

NR₁₂SO₂R₁₁, —

SO₂NHR₁₄, —

SO₂R₁₅, heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, halogen, amino, C_1-6 alkyl and C_1-6 alkoxy;

and wherein a further substituent of said aryl or heterocyclyl is independently selected from the group consisting of halogen, amino, C_1-4 alkylamino, hydroxy, oxo, cyano, C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen and hydroxy, C_1-6 alkoxy, —

CONHR₉, —

NR₁₂COR₁₀, —

NR₁₂SO₂R₁₁, —

SO₂NH₂, —

SO₂NHR₁₄, —

SO₂R₁₅, heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, halogen, amino, C_1-6 alkyl and C_1-6 alkoxy;

each R₁₀ is independently selected from the group consisting of C_1-6 alkyl substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen, hydroxy and heterocyclyl;

C_1-6 alkoxy substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen, and heterocyclyl;

heterocyclyl substituted with one or more substituents independently selected from the group consisting of acylamino and oxo, and optionally further substituted with one or more substituents selected from the group consisting of C_1-6 alkyl and hydroxyl;

C_3-10 cycloalkyl substituted with one or more substituents independently selected from the group consisting of cyano, amino, and hydroxy; and

amino optionally substituted with one or more substituents independently selected from the group consisting of C_3-10 cycloalkyl and C_1-6 alkyl wherein said C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen and heterocyclyl,

or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

6. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₂ is selected from the group consisting of mono-C_2-20 alkyl-amino, mono-C_3-10 cycloalkyl-amino, benzylamino, C_1-4 alkoxy and C_1-4 alkylthio, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

7. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₂ is selected from the group consisting of ethoxy, isopropylamino, 2,2,2-trifluoroethylamino, 2,2-difluoroethylamino, methanesulfonylethylamino, cyclopropylamino and cyclopropyl, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

8. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₃ is a mono-substituted or disubstituted phenyl group, wherein at least one substituent of said phenyl group is located in para position with respect to the pyrido(3,2-d)pyrimidinyl core, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

9. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₃ is a mono-substituted or disubstituted phenyl group, wherein at least one substituent of said phenyl group is located in meta position with respect to the pyrido(3,2-d)pyrimidinyl core, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

10. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₃ is selected from the group consisting of phenyl, 4-fluorophenyl, 4-methylphenyl, 3-chloro-4ethoxyphenyl, 3-ethoxy-4-fluorophenyl, 3-methyl-4-fluorophenyl, 3,4-dichlorophenyl and 3,4-methylenedioxy-phenyl, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

11. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₅ is hydrogen and R₆ is selected from the group consisting of C_1-4 alkyl, C_3-10 cycloalkyl, heterocyclylic and phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C_1-4 alkyl, C_1-4 alkoxy, dimethylamino, diethylamino and phenoxy, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

12. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₁ is selected from the group consisting of 4-fluorobenzylamino, 2,2,2-trifluoroethylamino and 4-sulfonamidobenzylamino, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

13. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₅ is hydrogen and R₆ is selected from the group consisting of trifluoromethyl, naphthyl, imidazol-2-yl and thien-2-yl, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

14. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein R₈ is selected from the group consisting of phenyl, pyridazinyl and pyrazolyl and wherein said R₈ is optionally substituted with a substituent selected from the group consisting of halogen and methyl, or a pharmaceutically acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

15. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein:

R₁ is selected from the group consisting of 2,2,2-trifluoroethylamino, 4-fluorobenzylamino, 3,4-difluorobenzylamino, 2,6-difluoro-4-methoxybenzyl-amino, 4-chloro-2,6-difluorobenzylamino, 4-chloro-2-fluorobenzylamino, 2,4,6-trifluoro-benzylamino, 4-chloro-3-fluorobenzylamino, 2,3,4-trifluoro-benzylamino, 3-chloro-4-fluorobenzylamino, 2-chloro-4-fluorobenzylamino, 3-fluoro-4-trifluoromethyl-amino, 3,5-difluorobenzylamino, 3,4,5-trifluoro-benzylamino, 3-fluorobenzylamino, 3-chloro-2-fluorobenzylamino, 4-fluoroanilino, anilino, 6-methyl-pyridazin-3-ylamino, pyridin-2-ylmethylamino, pyridin-3-ylmethylamino, 2-morpholin-4-ylethylamino, 2,2-difluoroethylamino, 2-methoxyethylamino, 4-sulfonamido-benzylamino, 1-(4-fluoro-phenyl)-cyclopropylamino, 2,4-difluorobenzylamino, 1-phenylethyl-amino, thiazol-2-ylmethylamino, oxazol-4-ylmethylamino, isoxazol-3-ylmethyl-amino, 4-(N-isopropylmethanesulfonamido)benzylamino, phenethyl-amino, 4-methanesulfonylbenzylamino, 4-pyrrolidin-1-yl-benzylamino, 4-(4-methylpiperazin-1-yl)benzylamino, (N,N-dimethylbenzamido)methylamino, 4-[1,2,3]thiadiazol-4-ylbenzylamino, 2-fluoro-4-sulfonamidobenzylamino, 4-[1,3,4]-oxadiazol-2-ylmethylamino, thiazol-5-ylmethylamino, 1-(4-sulfonamidobenzene)-ethylamino, 4-[1,2,4](triazol-1-ylbenzylamino, oxazol-2-ylmethylamino, 2-[1,2,4]triazol-1-ylethylamino, 1-(4-[1,2,4]triazol-1-yl-phenyl)-ethylamino, 2-(phosphonic acid diethyl ester)ethylamino, 2-sulfonamidoethylamino, propion-amidoamino, 4-carboxamidobenzylamino, 4-(N,N-dimethylcarboxamido)-benzylamino, and 4-(N-methylmethanesulfonamido)-benzylamino;

R₂ is selected from the group consisting of tetrahydrofuran-3-yloxy, ethoxy, hydroxy, n-propionamido-amino, 2-methyl-2-hydroxy-propylamino, methoxy, 3-methanesulfonyl-pyrrolidin-1-yl, N-methanesulfonylethyl-N-methylamino, 1-isopropyl-piperidin-4-ylamino, ethylamino, pyridin-3-ylmethylamino, N-morpholin-4-ylethylamino, 2,2,2-trifluoroethylamino, 2-methoxyethylamino, isopropylamino, dimethylamino, diethylamino, cyclopentoxy, cyclobutoxy, propyl, methanesulfonylethylamino, 2,2-difluoroethylamino, cyclopropoxy, cyclopropyl-amino, 4-[1,2,4]triazol-1-yl-anilino, 3-fluoroanilino, 2-methoxy-ethoxy, tetrahydro-furan-3-ylamino, oxetan-3-yloxy, 1-methylcyclopropoxy, 2-hydroxyethylamino, 1-cyano-cyclopropylamino, N-morpholinyl, N-thiomorpholinyl, N-thiomorpholinyl dioxide, cyclopropyl, N-piperidinyl and N-pyrrolidinyl, wherein said N-pyrrolidinyl is optionally substituted with C_1-4 alkylsulfonyl;

R₃ is selected from the group consisting of optionally mono-substituted or disubstituted aryl and optionally mono-substituted or disubstituted heterocyclyl, wherein each substituent of said aryl or heterocyclyl is independently selected from the group consisting of halogen, hydroxyl, amino, C_1-4 alkylamino, hydroxyl, oxo, cyano, C_1-6 alkyl, C_1-6 alkoxy, —

CONHR₉, —

NR₁₂COR₁₀, —

NR₁₂SO₂R₁₁, —

SO₂NH₂, —

SO₂NHR₁₄, —

SO₂R₁₅, heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, halogen, amino, C_1-6 alkyl and C_1-6 alkoxy; and

wherein said C_1-6 alkyl is optionally substituted with hydroxyl;

R₉ is selected from the group consisting of hydrogen, C_3-10 cycloalkyl optionally substituted with one more substituents independently selected from the group consisting of cyano, halogen, hydroxy, oxo, amino, C_1-6 alkyl and C_1-6 alkoxy;

C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen, and heterocyclyl;

C_1-6 alkoxy;

heterocyclyl optionally substituted with one or more C_1-6 alkyl; and

phenyl optionally and independently substituted with one or more halogen;

R₁₀ and R₁₁ are each independently selected from the group consisting of C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen, hydroxy and heterocyclyl;

C_1-6 alkoxy optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen, and heterocyclyl;

heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-6 alkyl, acylamino and oxo;

C_3-10 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of amino or hydroxy;

amino optionally substituted with one or more substituents independently selected from the group consisting of C_3-10 cycloalkyl and C_1-6 alkyl wherein said C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen and heterocyclyl; and

heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and C_1-4 alkyl;

R₁₂ is selected from the group consisting of hydrogen and C_1-6 alkyl, wherein said C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen and hydroxy;

R₁₄ is selected from the group consisting of heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-4 alkyl and C_1-4 alkyloxycarbonyl, and C_1-4 alkyl optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and C_1-4 alkoxy; and

R₁₅ is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-4 alkyl, C_1-4 alkoxycarbonyl and C_1-4alkyloxycarbonylamino;

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

16. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein:

R₁ is selected from the group consisting of —

NH—

CHR₅R₆ and —

NH—

R₈;

R₅ and R₆ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl, aryl and heterocyclyl, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C_1-4 alkyl optionally substituted with C_1-4 alkylaminosulfonyl, C_1-4 alkoxy, di-C_1-4 alkylamino, mono-C_1-4 alkylamino, carboxamido, sulfamoyl, carbamoyl, C_1-4 alkylsulfonyl, sulfonamido, C_1-4 alkylsulfonamido, heterocyclyl optionally substituted with C_1-4 alkyl, and phenoxy;

wherein said C_1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-4 alkoxy, aryl, heterocyclyl, di-C_1-6 alkylphosphonate, carboxamido, sulfamoyl and C_1-4 alkylaminosulfonyl;

R₈ is selected from the group consisting of C_3-10 cycloalkyl, heteroaryl and aryl wherein said heteroaryl or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-4 alkyl and wherein said C_3-10 cycloalkyl is optionally substituted at the carbon position adjacent to the N atom of R₁ with aryl or heteroaryl wherein said aryl is optionally substituted with halogen;

R₂ is selected from the group consisting of tetrahydrofuran-3-yloxy, ethoxy, hydroxy, n-propionamido-amino, 2-methyl-2-hydroxy-propylamino, methoxy, 3-methanesulfonyl-pyrrolidin-1-yl, N-methanesulfonylethyl-N-methylamino, 1-isopropyl-piperidin-4-ylamino, ethylamino, pyridin-3-ylmethylamino, N-morpholin-4-ylethylamino, 2,2,2-trifluoroethylamino, 2-methoxyethylamino, isopropylamino, dimethylamino, diethylamino, cyclopentoxy, cyclobutoxy, propyl, methanesulfonyl-ethylamino, 2,2-difluoroethylamino, cyclopropoxy, cyclopropylamino, 4-[1,2,4]triazol-1-yl-anilino, 3-fluoroanilino, 2-methoxyethoxy, tetrahydrofuran-3-ylamino, oxetan-3-yloxy, 1-methylcyclopropoxy, 2-hydroxy-ethylamino, 1-cyano-cyclopropylamino, N-morpholinyl, N-thiomorpholinyl, N-thiomorpholinyl dioxide, cyclopropyl, N-piperidinyl and N-pyrrolidinyl, wherein said N-pyrrolidinyl is optionally substituted with C_1-4 alkylsulfonyl; and

R₃ is selected from the group consisting of optionally mono-substituted or disubstituted aryl and optionally mono-substituted or disubstituted heterocyclyl, wherein each substituent of said aryl or heterocyclyl is independently selected from the group consisting of halogen, amino, C_1-4 alkylamino, hydroxyl, oxo, cyano, C_1-6 alkyl, C_1-6 alkoxy, —

CONHR₉, —

NR₁₂COR₁₀, —

NR₁₂SO₂R₁₁, —

SO₂NH₂, —

SO₂NHR₁₄, —

SO₂R₁₅, heterocyclyl optionally substituted with one or more substituents selected from the group consisting of hydroxyl, oxo, halogen, amino, C_1-6 alkyl and C_1-6 alkoxy; and

wherein said C_1-6 alkyl is optionally substituted with hydroxyl;

R₉ is selected from the group consisting of hydrogen, C_3-10 cycloalkyl optionally substituted with one more substituents independently selected from the group consisting of cyano, halogen, hydroxy, oxo, amino, C_1-6 alkyl and C_1-6 alkoxy;

C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, halogen, and heterocyclyl;

C_1-6 alkoxy;

heterocyclyl optionally substituted with one or more C_1-6 alkyl; and

phenyl optionally and independently substituted with one or more halogen;

R₁₀ and R₁₁ are each independently selected from the group consisting of C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen, hydroxy and heterocyclyl;

C_1-6 alkoxy optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen, and heterocyclyl;

heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-6 alkyl, acylamino and oxo;

C_3-10 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of amino or hydroxy;

amino optionally substituted with one or more substituents independently selected from the group consisting of C_3-10 cycloalkyl and C_1-6 alkyl wherein said C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C_1-4 alkylamino, cyano, di-C_1-4 alkylamino, halogen and heterocyclyl; and

heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and C_1-4 alkyl;

R₁₂ is selected from the group consisting of hydrogen and C_1-6 alkyl, wherein said C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen and hydroxy;

R₁₄ is selected from the group consisting of heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-4 alkyl and C_1-4 alkyloxycarbonyl, and C_1-4 alkyl optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl and C_1-4 alkoxy; and

R₁₅ is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C_1-4 alkyl, C_1-4 alkoxycarbonyl and C_1-4 alkyloxycarbonylamino;

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

17. A pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, wherein:

R₁ is selected from the group consisting of —

NH—

CHR₅R₆ and —

NH—

R₈;

R₅ and R₆ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl, aryl and heterocyclyl, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C_1-4 alkyl optionally substituted with C_1-4 alkylaminosulfonyl, C_1-4 alkoxy, di-C_1-4 alkylamino, mono-C_1-4 alkylamino, carboxamido, sulfamoyl, carbamoyl, C_1-4 alkylsulfonyl, sulfonamido, C_1-4 alkylsulfonamido, heterocyclyl optionally substituted with C_1-4 alkyl, and phenoxy;

wherein said C_1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-4 alkoxy, aryl, heterocyclyl, di-C_1-6 alkylphosphonate, carboxamido, sulfamoyl and C_1-4 alkylaminosulfonyl;

R₈ is selected from the group consisting of C_3-10 cycloalkyl, heteroaryl and aryl wherein said heteroaryl or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen and C_1-4 alkyl and wherein said C_3-10 cycloalkyl is optionally substituted at the carbon position adjacent to the N atom of R₁ with aryl or heteroaryl wherein said aryl is optionally substituted with halogen;

R₂ is selected from the group consisting of tetrahydrofuran-3-yloxy, ethoxy, hydroxy, n-propionamido-amino, 2-methyl-2-hydroxy-propylamino, methoxy, 3-methanesulfonyl-pyrrolidin-1-yl, N-methanesulfonylethyl-N-methylamino, 1-isopropylpiperidin-4-ylamino, ethylamino, pyridin-3-ylmethylamino, N-morpholin-4-ylethylamino, 2,2,2-trifluoroethylamino, 2-methoxyethylamino, isopropylamino, dimethylamino, diethylamino, cyclopentoxy, cyclobutoxy, propyl, methane-sulfonylethylamino, 2,2-difluoroethylamino, cyclopropoxy, cyclopropylamino, 4-[1,2,4]triazol-1-yl-anilino, 3-fluoroanilino, 2-methoxy-ethoxy, tetrahydrofuran-3-ylamino, oxetan-3-yloxy, 1-methylcyclopropoxy, 2-hydroxyethylamino, 1-cyano-cyclopropylamino, N-morpholinyl, N-thiomorpholinyl, N-thiomorpholinyl dioxide, cyclopropyl, N-piperidinyl and N-pyrrolidinyl, wherein said N-pyrrolidinyl is optionally substituted with C_1-4 alkylsulfonyl; and

R₃ is selected from the group consisting of 4-fluorophenyl, 5-amino-pyrazin-2-yl, 4-(N-(2-dimethylaminoethyl)carbamoyl)phenyl, 3-chloro-4-fluorophenyl, 4-(N-cyclopropylcarbamoyl)phenyl, 3-methylsulfonamido-phenyl, 4-cyclopropyl-carboxamidophenyl, 3-sulfamoyl-4-fluorophenyl, 4-hydroxyacetamido-phenyl, 4-(2-amino-acetamido)phenyl, 4-[N-(2-morpholinyl)ethylureyl]phenyl, 4-(morpholine-4-carboxamido)phenyl, 4-(pyrrolidine-1-carboxamido)phenyl, 4-(N-cyclopropyl-ureyl)phenyl, 4-ureylphenyl, 4-[N-(4-hydroxy-pyrrolidin-2-one)]phenyl, 1H-indazol-5-yl, 1,3-dihydro-2-oxo-indol-5-yl, 2-cyclopropanecarboxamido-pyrimidin-5-yl, 3-(2-pyrrolidin-1-yl-ethanesulfonamido)phenyl, 3-(cyclopropanesulfonamido)-phenyl, 4-sulfamoylphenyl, 3-(N,N-dimethyl-sulfonylurea)phenyl, 3-sulfamoyl-phenyl, 4-(3-hydroxy-2-oxo-pyrrolidin-1-yl)phenyl, 2-fluoropyridin-5-yl, 4-(4-hydroxypyrrolidin-2-carboxamido)phenyl, 4-(pyrrolidin-2-carboxamido)phenyl, 4-(pyrrolidin-3-carboxamido)-3-fluorophenyl, 4-(pyrrolidin-3-carboxamido)phenyl, 4-(2-(pyrrolidin-1-yl)-ethoxycarbonylamino)-phenyl, 3-(4-(tert-butoxycarbonyl-amino)-piperidin-1-sulfonyl)-4-chlorophenyl, 3-(N-(1-(tert-butoxycarbonyl)-pyrrolidin-3-yl)-sulfamoyl)-4-fluorophenyl, 4-(methoxycarbonyl-amino)-phenyl, 3-(N-(1-(tert-butoxycarbonyl)-piperidin-4-yl)-sulfamoyl)-4-chloro-phenyl3-(N-(1-(tert-butoxycarbonyl)-piperidin-4-yl)-sulfamoyl)-4-fluoro-phenyl, 4-(2-pyrrolidin-1-yl-ethaneureyl)phenyl, 4-(N-(2-hydroxy-1,1-dimethyl-ethyl)-carbamoyl)phenyl, 4-(N-(2-(pyrrolidin-1-yl)-1,1-dimethyl-ethyl)carbamoyl)phenyl, 2-amino-thiazol-5-yl, 5-hydroxymethylfuran-2-yl, 4-(N-pyrrolidin-2-one)-phenyl, 4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenyl, 4-carbamoylphenyl, 4-(N-cyclopropyl-carbamoyl)phenyl, 4-(N-1-cyano-1-cyclopropylcarbamoyl)-phenyl, 4-(N-1-amino-1-cyclopropyl-carbamoyl)-phenyl, 4-(N-1-hydroxy-1-cyclopropylcarboxamido)-phenyl, 3-(N-(2-hydroxyethyl)methylsulfonamido)-phenyl, 4-(N-(2-(morpholin-4-yl)-1,1-dimethyl-ethyl)carbamoyl)phenyl, 4-(2-oxo-pyrrolidin-1-yl)phenyl, 4-(2-amino-2-methylpropionamido)phenyl, 4-(N-cyclopropylcarbamoyl)phenyl, 4-(3-hydroxy-2-aminopropionamido)phenyl, 3-cyclopropanesulfonamido-4-fluoro-phenyl, 4-(2-amino-propionamido)-phenyl, 4-(3-hydroxy-2-amino-butylamido)phenyl, 3,5-dimethyl-isoxazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 5-pyrrolidin-1-ylpyrazin-2-yl, 2-trifluoromethylpyridin-4-yl, 2-aminopyridin-4-yl, 4-hydroxyphenyl, 2-pyrrolidin-1-yl-thiazol-4-yl, 2-methoxypyridin-4-yl, 2-cyanopyridin-4-yl, 2-aminopyrimidin-5-yl, 3-cyanophenyl, 4-(1-methylpyrrolidine-3-carboxamido)-3-fluorophenyl, 4-(1-methylpyrrolidine-3-carboxamido)-phenyl, 3-cyclopropanesulfonamido-4-fluoro-phenyl, 1H-pyrazol-4-yl, 3-(N-(1-isopropyl-piperidin-4-yl)sulfamoyl)-4-chloro-phenyl, 3-(N-(2-pyrrolidin-1-yl-ethyl)sulfamoyl)-4-chlorophenyl, 3-(4-isopropyl-piperazin-1-sulfonyl)-4-chlorophenyl, 3-(N-pyrrolidin-3-yl-sulfamoyl)-4-chloro-phenyl, 3-(N-(2-methoxyethyl)sulfamoyl)-4-chlorophenyl, 3-(N-piperidin-4-ylsulfamoyl)-4-chlorophenyl, pyridazin-4-yl, 4-cyanophenyl, 4-fluoro-3-(piperazin-1-sulfonyl)-phenyl, 4-fluoro-3-(4-tert-butoxycarbonyl-piperazin-1-sulfonyl)-phenyl, 4-isopropylamino-pyrazol-1-yl, [1,2,4]triazol-1-yl, imidazol-1-yl, imidazol-2-yl, 6-oxo-1,6-dihydro-pyridin-3-yl, 2-oxo-1,2-dihydro-pyridin-4-yl, 3-hydroxy-2-oxo-pyrrolidin-1-yl and 4-chlorophenyl,

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof.

18. A pharmaceutical composition comprising:

one or more pharmaceutically acceptable carriers,

a pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof, and

optionally one or more antiviral agents.

19. A method of treatment of a patient suffering from a viral infection, comprising administering to said patient an effective amount of a pyrido(3,2-d)pyrimidine derivative according to claim 1 or 2, or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof or a prodrug thereof, and optionally, simultaneously or sequentially, one or more other antiviral agents.

20. A method of treatment according to claim 19, wherein said viral infection is a HCV infection.

21. A method of treatment according to claim 19, wherein said therapeutically effective amount is from 0.1 mg to 5 mg per day per kg bodyweight of said patient.

2. A pyrido(3,2-d)pyrimidine derivative represented by having the structural formula (I):