4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections

Patent metadata

Field	Value
Publication number	US-9259426-B2
Application number	US-37443307-A
Country	US
Kind code	B2
Filing date	Jul 20, 2007
Priority date	Jul 20, 2006
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

This invention provides quinazoline derivatives represented by the structural formula: (I); wherein: R 2 is hydrogen, NR′R″, C 1-7 alkyl, arylC 1-7 alkyl or C 3-10 cycloalkyl; R 4 is amino, C 1-7 alkyl, C 2-7 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, aryl, heterocyclic, arylalkyl, heterocyclic-substituted C 1-7 alkyl or C 3-10 cycloalkyl-C 1-7 alkyl; R 5 is hydrogen or C 1-7 alkyl, or R 5 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring; Y is a single bond, C 1-7 alkylene, C 2-7 alkenylene or C 2-7 alkynylene; R 6 is halogen, heteroaryl or aryl; R′ and R″ are each independently hydrogen, C 1-7 alkyl-carbonyl or C 1-7 alkyl; provided that R 4 is not phenyl substituted with morpholino when R 2 is H and R 5 is H, and provided that when NR 4 R 5 is piperazinyl, said NR 4 R 5 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.

First claim

The invention claimed is:

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,
R 2 is NR′R″;
R 4 is selected from the group consisting of C 1-7 alkyl; C 2-7 alkenyl; C 3-10 cycloalkyl; C 3-10 cycloalkenyl; arylalkyl; heterocyclic-substituted C 1-7 alkyl and C 3-10 cycloalkyl-C 1-7 alkyl; and wherein said R 4 is optionally substituted with one or more R 7 ;
R 5 is hydrogen or C 1-7 alkyl; or R 5 and R 4 , 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 R 7 ;
Y is a single bond;
R 6 is selected from the group consisting of halogen; fused benzo-C 5-8 cycloalkyl optionally substituted with oxo; heteroaryl and aryl, wherein said heteroaryl or aryl is optionally substituted with one or more R 8 ;
each R 7 is independently selected from the group consisting of halogen; nitro; hydroxyl; sulfhydryl; hydroxylamino; cyano; amino; C 1-7 alkyl; halo C 1-7 alkyl; C 2-7 alkenyl; C 2-7 alkynyl; C 1-7 alkoxy; halo C 1-7 alkoxy; C 1-7 alkylthio; formyl; —CO—NHR 9 ; —CO—NR 9 R 9 ′; —CS—NHR 9 ; —NR 12 —CO—NHR 12 ; —NR 12 —CS—NHR 12 ; —SO 2 NH 2 ; —NR 12 —SO 2 R 11 ; —NR 12 —COR 10 ; —NR 12 —CSR 10 ; alkoxyamino; mercaptoamino; thioalkylamino; alkylamino; alkenylamino; alkynylamino; alkylsulfoxide; alkylsulfone; hydroxyalkylamino; mercaptoalkylamino; hydrazino; alkylhydrazino; C 3-10 cycloalkyl; aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl; alkanoyl, alkoxy, hydroxy-C 1-7 alkoxy, hydroxy-C 1-7 alkyl, di-C 1-7 alkyl-amino C 1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C 3-7 cycloalkyl)aminocarbonyl, di-(C 3-7 cycloalkyl)aminocarbonyl, mono-(C 1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C 1-7 alkyl)aminocarbonyl, di-(C 1-7 alkyl)aminocarbonyl, mono-(hydroxy-C 1-7 alkyl)aminocarbonyl, formylamino, —SO 2 NH 2 , arylamino-C 1-7 alkyl, C 1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C 1-7 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 R 9 is independently selected from the group consisting of halogen; nitro; hydroxyl; sulfhydryl;
hydroxylamino; cyano; amino; C 1-7 alkyl; halo C 1-7 alkyl; C 2-7 alkenyl; C 2-7 alkynyl; C 1-7 alkoxy; halo C 1-7 alkoxy; C 1-7 alkylthio; formyl; —CO—NHR 9 ; —CO—NR 9 R 9 ′; —CS—NHR 9 ; —NR 12 —CO—NHR 12 ; —NR 12 —CS—NHR 12 ; SO 2 N H 2 , R 12 —SO 2 R 11 ; R 12 —COR 10 , R 12 —CSR 10 , alkoxyamino; mercaptoamino; thioalkylamino; alkylamino; alkenylamino; alkynylamino; alkylsulfoxide; alkylsulfone; hydroxyalkylamino; mercaptoalkylamino; hydrazino; alkylhydrazino; C 3-10 cycloalkyl; aryl optionally substituted with arylcarbonyl, aryloxy, (O,O-dialkylphosphonyl)-alkyl; alkanoyl, alkoxy, hydroxy-C 1-7 alkoxy, hydroxy-C 1-7 alkyl, di-C 1-7 alkyl-amino C 1-7 alkyl, ω-carboxy-alkanoylamino, mono-(C 3-7 cycloalkyl)aminocarbonyl, di-(C 3-7 cycloalkyl)aminocarbonyl, mono-(C 1-7 alkyl)aminocarbonyl, mono-(ω-dimethylamino-C 1-7 alkyl)aminocarbonyl, di-(C 1-7 alkyl)aminocarbonyl, mono-(hydroxy-C 1-7 alkyl)aminocarbonyl, formylamino, —SO 2 NH 2 , arylamino-C 1-7 alkyl, C 1-7 alkylsulfonyl, heterocyclyl-carbonyl, heterocyclyl-C 1-7 alkyl or heterocyclyl, wherein said heterocyclyl is optionally substituted with C 3-7 alkenyloxycarbonyl, C 1-7 alkyl or C 1-7 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;
R 9 and R 9 ′ are each independently 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, amino, C 1-7 alkyl and C 1-7 alkoxy; C 1-7 alkoxy; halo C 1-7 alkoxy; C 1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, alkylamino, cyano, dialkylamino, and heterocyclyl optionally substituted with C 1-7 alkyl; halo C 1-7 alkyl; heterocyclyl optionally substituted with C 1-7 alkyl; aryl and arylC 1-7 alkyl wherein the aryl moiety is optionally substituted with one or more halogen; or R 9 and R 9 ′ together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group;
R 10 and R 11 are each independently selected from the group consisting of C 1-7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of amino, cyano, halogen and hydroxy; C 1-7 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 C 1-7 alkyl, acylamino and oxo; C 3-10 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 C 1-7 alkyl wherein said C 1-7 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of amino, C 1-7 alkylamino, cyano, dialkylamino, halogen and heterocyclyl;
R 12 is selected from the group consisting of hydrogen and C 1-7 alkyl, wherein said C 1-7 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 C 1-7 alkyl-carbonyl;
R 15 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 independently selected from the group consisting of halogen and C 1-7 alkyl and wherein said C 3-10 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 R 16 is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-7 alkyl, C 1-7 alkoxy, di-(C 1-7 alkyl)amino, mono-(C 1-7 alkyl)amino, carboxamido, —SO 2 NH 2 , carbamoyl, —NR 12 —SO 2 R 11 and phenoxy; provided that when NR 4 R 5 is piperazinyl, said NR 4 R 5 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.

2. A method according to claim 1 , wherein said virus belongs to a genus selected from the group consisting of Genus Flavivirus , Genus Hepacivirus and Genus Pestivirus.

3. A method according to claim 1 , wherein said virus is hepatitis C virus.

4. A method according to claim 1 , wherein Y is a bond, and R 6 is selected from the group consisting of 3,4-dimethoxyphenyl, 4-acetamidophenyl, 4-chlorophenyl and 4-fluorophenyl.

5. A method according to

Assignees

• Gao Ling-Jie
• HERDEWIJN Piet André Maurits Maria
• De Jonghe Steven Cesar Alfons
• Watkins William John
• Chong Lee Shun
• Gilead Sciences Inc

Inventors

• Gao Ling-Jie
• HERDEWIJN Piet André Maurits Maria
• De Jonghe Steven Cesar Alfons
• Watkins William John
• Chong Lee Shun

Classifications

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/78

  with hetero atoms directly attached in position 2 · CPC title