Compounds and methods for antiviral treatment

Patent metadata

Field	Value
Publication number	US-9593108-B2
Application number	US-201013259283-A
Country	US
Kind code	B2
Filing date	Apr 5, 2010
Priority date	Apr 6, 2009
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present invention is directed to compounds and forms and pharmaceutical compositions thereof useful for treating a viral infection, or for affecting viral activity by modulating viral replication.

First claim

What is claimed is:

1. A compound of Formula (Ia):

or a salt, hydrate, solvate, racemate, enantiomer, diastereomer, or stereoisomer thereof, wherein
X is hydrogen, halogen, cyano, nitro, carboxyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, formyl, amino, C 1-8 alkyl-amino, amino-carbonyl, C 1-8 alkyl-amino-carbonyl or C 1-8 alkyl-sulfonyl-;
Y is phenyl, pyridinyl or pyrimidinyl each substituted with —SO 2 N(R 4 )—R 5 , wherein phenyl, pyridinyl and pyrimidinyl are each optionally substituted with one or two additional substituents independently selected from halogen, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino or C 1-8 alkyl-amino;
Z is C 1-8 alkyl, C 2-8 alkenyl-C 1-8 alkyl, C 2-8 alkynyl-C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, carboxyl, C 3-14 cycloalkyl, C 3-14 cycloalkenyl, C 3-14 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl, wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three or four substituents each selected from hydroxy, cyano, nitro, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, C 1-8 alkyl-carbonyloxy or amino-sulfonyl;
R 1b , R 1c , and R 1d are each selected from hydrogen, halogen, hydroxy, cyano, nitro, C 1-8 alkyl, methyl, ethyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, C 2-8 alkenyl, halo-C 2-8 alkenyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, C 1-8 alkyl-carbonyloxy, C 1-8 alkyl-carbonyloxy-C 1-8 alkyl, C 1-8 alkyl-carbonyloxy-C 1-8 alkoxy, amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, amino-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-carbonyl-amino, carboxyl-amino, amino-carbonyl, amino-carbonyl-amino, C 1-8 alkyl-amino-carbonyl-amino, C 1-8 alkyl-sulfonyl-amino, C 1-8 alkylthio, C 1-8 alkyl-sulfonyl, C 1-8 alkyl-sulfinyl, C 3-14 cycloalkyl, cyclopropyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-C 1-8 alkoxy, C 3-14 cycloalkyloxy, aryl, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryloxy, aryl-carbonyl-amino, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryloxy, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyloxy or heterocyclyl-carbonyloxy,
wherein each instance of C 3-14 cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four substituents each selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, amino-C 1-8 alkyl or C 1-8 alkyl-amino-C 1-8 alkyl;
R 4 is hydrogen or C 1-8 alkyl, optionally substituted on C 1-8 alkyl with one or more substituents each selected from halogen, hydroxy, cyano or C 1-8 alkoxy; and
R 5 is hydrogen, C 1-8 alkyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, cyano-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl, wherein each instance of aryl, heteroaryl, heterocyclyl and C 3-14 cycloalkyl is optionally substituted with one or two substituents each selected from halogen, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino or C 1-8 alkyl-amino.

2. The compound of claim 1 , wherein
X is hydrogen, cyano, amino-carbonyl or C 1-8 alkyl-amino-carbonyl;
Z is C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14 cycloalkenyl, C 3-14 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl, wherein each instance of aryl and heteroaryl is optionally substituted with a substituent selected from cyano, halogen, C 1-8 alkyl, C 1-8 alkoxy, amino or C 1-8 alkyl-amino
R 1b , R 1c , and R 1d are each selected from hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, halo-C 2-8 alkenyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, C 1-8 alkyl-carbonyloxy, amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkyl-sulfinyl, C 1-8 alkyl-sulfonyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-C 1-8 alkoxy, C 3-14 cycloalkyloxy, aryl, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryloxy, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryloxy, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy or heterocyclyloxy;
R 4 is hydrogen or C 1-8 alkyl; and
R 5 is hydrogen, C 1-8 alkyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, cyano-C 1-8 alkyl, C 3-14 cycloalkyl or C 3-14 cycloalkyl-C 1-8 alkyl, wherein each instance of C 3-14 cycloalkyl is optionally substituted with one or two substituents each selected from halogen, C 1-8 alkyl or halo-C 1-8 alkyl.

3. The compound of claim 1 , wherein
X is cyano;
Z is C 1-8 alkyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl, wherein each instance of aryl and heteroaryl is optionally substituted with a substituent selected from cyano, halogen, C 1-8 alkyl, C 1-8 alkoxy, amino or C 1-8 alkyl-amino;
R 1b , R 1c , and R 1d are each selected from hydrogen, halogen, cyano, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkyl-sulfinyl, C 1-8 alkyl-sulfonyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-C 1-8 alkoxy, C 3-14 cycloalkyloxy, aryl, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryloxy, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryloxy, heterocyclyl, heterocyclyl-C 1-8 alkyl or heterocyclyl-C 1-8 alkoxy;
R 4 is hydrogen; and
R 5 is C 1-8 alkyl, halo-C 1-8 alkyl, C 3-14 cycloalkyl or C 3-14 cycloalkyl-C 1-8 alkyl, wherein each instance of C 3-14 cycloalkyl is optionally substituted with one or two substituents each selected from C 1-8 alkyl or halo-C 1-8 alkyl.

4. The compound of claim 1 , wherein
Z is cyclobutyl, cyclopentyl or cyclopropyl-C 1-8 alkyl;
R 1b , R 1c , and R 1d are each selected from hydrogen, chloro, fluoro, cyano, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, difluoromethoxy or cyclopropyl; and
R 5 is isopropyl, tert-butyl, difluoroisopropyl, trifluoroisopropyl, trifluoro-tert-butyl, cyclopropyl, cyclobutyl or 1-cyclopropyl-ethyl, wherein each instance of cyclopropyl is optionally substituted with one or two substituents each selected from methyl or trifluoromethyl.

5. The compound of claim 1 , wherein R 1b , R 1b , and R 1d are each independently selected from hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, hydroxy-C 1-8 alkyl, halo-C 1-8 alkyl, halo-C 2-8 alkenyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, C 1-8 alkyl-carbonyloxy, amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkyl-sulfinyl, C 1-8 alkyl-sulfonyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-C 1-8 alkoxy, C 3-14 cycloalkyloxy, aryl, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryloxy, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryloxy, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy or heterocycly

Assignees

• Maccoss Malcolm
• Njoroge F George
• Nomeir Amin
• Chen Guangming
• Karp Gary Mitchell
• Lennox William Jospeh
• Li Chunshi
• Morrill Christie
• Paget Steven D
• Ren Hongyu
• Zhang Nanjing
• Zhang Xiaoyan
• Ptc Therapeutics Inc

Inventors

• Maccoss Malcolm
• Njoroge F George
• Nomeir Amin
• Chen Guangming
• Karp Gary Mitchell
• Lennox William Jospeh
• Li Chunshi
• Morrill Christie
• Paget Steven D
• Ren Hongyu
• Zhang Nanjing
• Zhang Xiaoyan

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D403/04

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