Inhibitors of influenza viruses replication

Patent metadata

Field	Value
Publication number	US-9345708-B2
Application number	US-201414305393-A
Country	US
Kind code	B2
Filing date	Jun 16, 2014
Priority date	Jun 17, 2009
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A compound is represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

First claim

What is claimed is:

1. A compound represented by structural formula (IA):

or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is —R*, —F, —Cl, —CN, —OR*, —CO 2 R*, —NO 2 , or —CON(R*) 2 ;
Z 2 is —R*, —OR*, —CO 2 R*, —NR* 2 , or —CON(R*) 2 ;
Z 3 is —H, —OH, halogen, —NH 2 ; —NH(C 1 -C 4 alkyl); —N(C 1 -C 4 alkyl) 2 , —O(C 1 -C 4 alkyl), or C 1 -C 6 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —O(C 1 -C 4 alkyl);
R 1 is —H, C 1 -C 6 alkyl, —S(O) 2 —R″, or —C(O)OR″;
R 2 is —H; —F; —NH 2 ; —NH(C 1 -C 4 alkyl); —N(C 1 -C 4 alkyl) 2 ; —C═N—OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, —OCH 3 , and —CH 3 ; or C 1 -C 4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —O(C 1 -C 4 alkyl);
R 3 is —H, —Cl, —F, —Br, —OH, —O(C 1 -C 4 alkyl), —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —CN, or C 1 -C 4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OCO(C 1 -C 4 alkyl), —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), and C 1 -C 4 alkoxy;
R 4 is:

 wherein:
ring E is a C 4 -C 8 non-aromatic carbocycle optionally further substituted with one or more instances of J A ;
ring F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of J E1 ;
each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more instances of J A ;
each J A is independently selected from the group consisting of halogen, cyano, oxo, —NCO, and Q 1 -R 5 ; or optionally two J A , together with the atom(s) to which they are attached, independently form a 4-8 membered ring that is optionally substituted with one or more instances of J E1 ;
Q 1 is independently a bond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO 2 —, —OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO 2 —, —OC(O)NR—, —S(O)—, —SO 2 —, —N(R)SO 2 —, —SO 2 NR′—, —NRSO 2 NR′—, or —(CR 6 R 7 ) p —Y 1 —;
Q 2 is independently —O—, —CO 2 —, —OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO 2 —, —OC(O)NR—, —CO 2 SO 2 —, —P(O) 2 O—, or —(CR 6 R 7 ) p —Y 1 —;
Y 1 is independently —O—, —CO 2 —, —OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO 2 —, or —OC(O)NR—;
R 5 is:
i) —H;
ii) an optionally substituted C 1 -C 6 alkyl group;
iii) an optionally substituted C 3 -C 7 non-aromatic carbocycle; or
iv) an optionally substituted 4-7 membered non-aromatic heterocycle; or
optionally, together with R and the nitrogen atom to which R is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle, wherein the alkyl group represented by R 5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OCO(C 1 -C 4 alkyl), —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), C 1 -C 4 alkoxy, an optionally substituted C 3 -C 7 non-aromatic carbocycle, and an optionally substituted 4-7 membered non-aromatic heterocycle; wherein each of said carbocycles and heterocycles represented by R 5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C 1 -C 4 alkyl, —O(C 1 -C 4 alkyl), —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(O)(C 1 -C 4 alkyl), —OC(O)(C 1 -C 4 alkyl), —C(O)O(C 1 -C 4 alkyl) and —CO 2 H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OCO(C 1 -C 4 alkyl), —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), and C 1 -C 4 alkoxy;

each of R 8 and R 9 is independently —H, halogen, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 2 -C 4 alkoxyalkyl, —O(C 1 -C 4 alkyl), —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;
R 11 , R 12 , R 13 and R 14 are each independently —H, halogen, or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkoxy, C 1 -C 6 cyanoalkoxy, C 1 -C 6 hydroxyalkoxy, and C 2 -C 6 alkoxyalkoxy; or optionally, R 13 and R 14 , together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl;
R 21 , R 22 , R 23 and R 24 are each independently —H, halogen, —OH, or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkoxy, C 1 -C 6 cyanoalkoxy, C 1 -C 6 hydroxyalkoxy, and C 2 -C 6 alkoxyalkoxy;
R 6 and R 7 are each independently —H or C 1 -C 6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkoxy, C 1 -C 6 cyanoalkoxy, C 1 -C 6 hydroxyalkoxy, and C 2 -C 6 alkoxyalkoxy, or optionally R 6 and R 7 , together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl;
R and R′ are each independently —H or C 1 -C 6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkoxy, C 1 -C 6 cyanoalkoxy, C 1 -C 6 hydroxyalkoxy, and C 2 -C 6 alkoxyalkoxy; or optionally R′, together with R 5 and the nitrogen atom to which R′ is attached, form a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of J D1 ;
each J D1 is independently selected from the group consisting of halogen, cyano, oxo, —R a , —OR b , —SR b , —SOR a , —SO 2 R a , —NHR c , —C(O)R b , —C(O)OR b , —OC(O)R b , —NHC(O)R b , —C(O)NHR c , —NHC(O)NHR c , —NHC(O)OR b , —OCONHR c , —NHC(O)NHC(O)OR b , —N(CH 3 )R c , —N(CH 3 )C(O)R b , —C(O)N(CH 3 )R c , —N(CH 3 )C(O)NHR c , —N(CH 3 )C(O)OR b , —OCON(CH 3 )R c , —C(O)NHCO 2 R b , —C(O)N(CH 3 )CO 2 R b , —N(CH 3 )C(O)NHC(O)OR b , —NHSO 2 R b , —SO 2 NHR b , —SO 2 N(CH 3 )R b , and —N(CH 3 )SO 2 R b ;
R″ is independently:
i) a C 1 -C 6 -alkyl optionally substituted with one or more substituents selected independently from the group consisting of halogen, cyano, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 aminoalkoxy, C 1 -C 6 cyanoalkoxy, C 1 -C 6 hydroxyalkoxy, and C 2 -C 6 alkoxyalkoxy; or
ii) a C 3 -C 6 carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 -hydro

Assignees

• Vertex Pharma

Inventors

• Charifson Paul S
• Clark Michael P
• Bandarage Upul K
• Bethiel Randy S
• Court John J
• Deng Hongbo
• Davies Ioana
• Duffy John P
• Farmer Luc J
• Gao Huai
• Gu Wenxin
• Jacobs Dylan H
• Kennedy Joseph M
• Ledeboer Mark W
• Ledford Brian
• Maltais Francois
• Perola Emanuele
• Wang Tiansheng
• Wannamaker M Woods
• Byrn Randal
• Zhou Yi
• Lin Chao
• Jiang Min
• Jones Steven
• Germann Ursula A
• Salituro Francesco G
• Kwong Ann Dak-Yee

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title