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

Patent metadata

Field	Value
Publication number	US-2016257673-A1
Application number	US-201614990322-A
Country	US
Kind code	A1
Filing date	Jan 7, 2016
Priority date	Jul 20, 2006
Publication date	Sep 8, 2016
Grant date	—

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

1 - 29 . (canceled)

30 . A compound represented by 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 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 ; alkoxylamino; 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, halo-C 1-7 alkoxy, hydroxy-C 1-7 alkoxy, hydroxy-C 1-7 alkyl, di-C 1-7 alkylamino 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 8 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 ; alkoxylamino; 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, halo-C 1-7 alkoxy, hydroxy-C 1-7 alkoxy, hydroxy-C 1-7 alkyl, di-C 1-7 alkylamino 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.

31 . A compound according to claim 30 , 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.

32 . The compound of claim 30 , wherein R 2 is NH 2 .

33 . A compound selected from the group consisting of:
2-amino-6-(3,4-dimethoxyphenyl)-4-(N-morpholino)-quinazoline, 2-amino-6-(3,4-dimethoxyphenyl)-4-[N-(3-bromo)-anilino)]-quinazoline, 2-amino-6-(3,4-dimethoxyphenyl)-4-[N-(3-methylphenylcarbamoyl)-piperazin-1-yl]-quinazoline, 2-amino-6-(3,4-dimethoxyphenyl)-4-[N-(4-methylphenyl)piperazin-1-yl]-quinazoline, 2

Assignees

• Gilead Sciences Inc

Inventors

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

Classifications

• C07D239/86

  with hetero atoms directly attached in position 4 · CPC title

• C07D239/88

  Oxygen atoms · CPC title

• C07D239/78

  with hetero atoms directly attached in position 2 · CPC title

• C07D413/04 Primary

  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