| 摘要 |
This invention provides quinazoline derivatives represented by the structural formula: (I); wherein: R2 is hydrogen, NR′R″, C1-7 alkyl, arylC1-7 alkyl or C3-10 cycloalkyl; R4 is amino, C1-7 alkyl, C2-7 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, aryl, heterocyclic, arylalkyl, heterocyclic-substituted C1-7 alkyl or C3-10 cycloalkyl-C1-7 alkyl; R5 is hydrogen or C1-7 alkyl, or R5 and R4 together with the nitrogen atom to which they are attached form a heterocyclic ring; Y is a single bond, C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene; R6 is halogen, heteroaryl or aryl; R′ and R″ are each independently hydrogen, C1-7 alkyl-carbonyl or C1-7 alkyl; provided that R4 is not phenyl substituted with morpholino when R2 is H and R5 is H, and provided that when NR4R5 is piperazinyl, said NR4R5 is either non-substituted or substituted with methyl or acetyl; a pharmaceutically acceptable addition salt, a stereoisomer, a mono- or a di-N-oxide, a solvate or a pro-drug thereof, for the treatment of viral infections. |
| 主权项 |
1. A method for treating an infection due to a virus from the Flaviridae family by administering to a patient in need thereof an effective amount of a quinazoline derivative according to the structural formula (I) wherein, R2 is NR′R″; R4 is selected from the group consisting of C1-7 alkyl; C2-7 alkenyl; C3-10 cycloalkyl; C3-10 cycloalkenyl; arylalkyl; heterocyclic-substituted C1-7 alkyl and C3-10 cycloalkyl-C1-7 alkyl; and wherein said R4 is optionally substituted with one or more R7; R5 is hydrogen or C1-7 alkyl; or R5 and R4, together with the nitrogen atom to which they are attached, form a 5 to 7-membered heterocyclic ring comprising a nitrogen atom and further optionally comprising at least one heteroatom independently selected from N, O and S, said ring being optionally substituted with one or more R7; Y is a single bond; R6 is selected from the group consisting of halogen; fused benzo-C5-8 cycloalkyl optionally substituted with oxo; heteroaryl and aryl, wherein said heteroaryl or aryl is optionally substituted with one or more R8; each R7 is independently selected from the group consisting of halogen; nitro; hydroxyl; sulfhydryl; hydroxylamino; cyano; amino; C1-7 alkyl; halo C1-7 alkyl; C2-7 alkenyl; C2-7 alkynyl; C1-7 alkoxy; halo C1-7 alkoxy; C1-7 alkylthio; formyl; —CO—NHR9; —CO—NR9R9′; —CS—NHR9; —NR12—CO—NHR12; —NR12—CS—NHR12; —SO2NH2; —NR12—SO2R11; —NR12—COR10; —NR12—CSR10; alkoxyamino; mercaptoamino; thioalkylamino; alkylamino; alkenylamino; alkynylamino; alkylsulfoxide; alkylsulfone; hydroxyalkylamino; mercaptoalkylamino; hydrazino; alkylhydrazino; C3-10 cycloalkyl; aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl; alkanoyl, alkoxy, hydroxy-C1-7 alkoxy, hydroxy-C1-7 alkyl, di-C1-7 alkyl-amino C1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C3-7 cycloalkyl)aminocarbonyl, di-(C3-7 cycloalkyl)aminocarbonyl, mono-(C1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C1-7 alkyl)aminocarbonyl, di-(C1-7 alkyl)aminocarbonyl, mono-(hydroxy-C1-7 alkyl)aminocarbonyl, formylamino, —SO2NH2, arylamino-C1-7 alkyl, C1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C1-7 alkyl carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof; and thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof; each R9 is independently selected from the group consisting of halogen; nitro; hydroxyl; sulfhydryl; hydroxylamino; cyano; amino; C1-7 alkyl; halo C1-7 alkyl; C2-7 alkenyl; C2-7 alkynyl; C1-7 alkoxy; halo C1-7 alkoxy; C1-7 alkylthio; formyl; —CO—NHR9; —CO—NR9R9′; —CS—NHR9; —NR12—CO—NHR12; —NR12—CS—NHR12; SO2N H2, R12—SO2R11; R12—COR10, R12—CSR10, alkoxyamino; mercaptoamino; thioalkylamino; alkylamino; alkenylamino; alkynylamino; alkylsulfoxide; alkylsulfone; hydroxyalkylamino; mercaptoalkylamino; hydrazino; alkylhydrazino; C3-10 cycloalkyl; aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl; alkanoyl, alkoxy, hydroxy-C1-7 alkoxy, hydroxy-C1-7 alkyl, di-C1-7 alkyl-amino C1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C3-7 cycloalkyl)aminocarbonyl, di-(C3-7 cycloalkyl)aminocarbonyl, mono-(C1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C1-7 alkyl)aminocarbonyl, di-(C1-7 alkyl)aminocarbonyl, mono-(hydroxy-C1-7 alkyl)aminocarbonyl, formylamino, —SO2NH2, arylamino-C1-7 alkyl, C1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C1-7 alkyl or heterocyclyl, wherein said heterocyclyl is optionally substituted with C3-7 alkenyloxycarbonyl, C1-7 alkyl or C1-7 alkyloxycarbonyl; carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof; and thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof; R9 and R9′ are each independently selected from the group consisting of hydrogen; C3-10 cycloalkyl optionally substituted with one more substituents independently selected from the group consisting of cyano, halogen, hydroxy, amino, C1-7 alkyl and C1-7 alkoxy; C1-7 alkoxy; halo C1-7 alkoxy; C1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, and heterocyclyl optionally substituted with C1-7 alkyl; halo C1-7 alkyl; heterocyclyl optionally substituted with C1-7 alkyl; aryl and arylC1-7 alkyl wherein the aryl moiety is optionally substituted with one or more halogen; or R9 and R9′ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group; R10 and R11 are each independently selected from the group consisting of C1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen and hydroxy; C1-7 alkoxy optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, halogen, and heterocyclyl; heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of C1-7 alkyl, acylamino and oxo; C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of amino and hydroxy; and amino optionally substituted with one or more substituents independently selected from the group consisting of C1-7 alkyl wherein said C1-7 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C1-7 alkylamino, cyano, dialkylamino, halogen and heterocyclyl; R12 is selected from the group consisting of hydrogen and C1-7 alkyl, wherein said C1-7 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen and hydroxy; R′ and R″ are each independently selected from the group consisting of hydrogen and C1-7 alkyl-carbonyl; R15 is selected from the group consisting of C3-10 cycloalkyl, heteroaryl and aryl wherein said heteroaryl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-7 alkyl and wherein said C3-10 cycloalkyl is optionally substituted, at the carbon position adjacent to the nitrogen atom to which it is attached, with aryl or heteroaryl wherein said aryl is optionally substituted with halogen; and each R16 is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-7 alkyl, C1-7 alkoxy, di-(C1-7 alkyl)amino, mono-(C1-7 alkyl)amino, carboxamido, —SO2NH2, carbamoyl, —NR12—SO2R11 and phenoxy; provided that when NR4R5 is piperazinyl, said NR4R5 is either non-substituted or substituted with methyl or acetyl, and/or a pharmaceutically acceptable addition salt thereof and/or a stereo-isomer thereof and/or a mono- or a di-N-oxide thereof. |
