5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-9408863-B2
Application number	US-201214232536-A
Country	US
Kind code	B2
Filing date	Jul 10, 2012
Priority date	Jul 13, 2011
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention relates to 5′-Substituted Nucleoside Analogs of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, Z, R 1 , R 2 , R 3 and R 3′ are as defined herein. The present invention also relates to compositions comprising at least one 5′-Substituted Nucleoside Analog, and methods of using the 5′-Substituted Nucleoside Analogs for treating or preventing HCV infection in a patient.

First claim

What is claimed is:

1. A compound having the structure:

or a pharmaceutically acceptable salt thereof,
wherein:
X is O, S or CH 2 ;
Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl, —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl group), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 4 to 7-membered heterocycloalkyl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;
B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups:

R 1 is H, —C(O)—C 1-6 alkyl,

R 2 is H or —C(O)—C 1-6 alkyl, or R 1 and R 2 join to form a group having the formula:

R 3 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl;
R 3′ is C1, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl;
R 4 , R 5 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 20 , —SR 20 or —N(R 20 ) 2 ;
R 6 , R 9 , R 10 , R 11 are each independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR 20 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NHC(O)OR 20 , —NHC(O)N(R 20 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group can be optionally substituted with a halo group;
R 12 is H or —(C 1 -C 6 alkylene)-T-R 21 ;
R 13 is H or —(C 1 -C 6 alkylene)-T-R 21 , or R 12 and R 13 can join to form a C 2 -C 4 alkylene group between the oxygen atoms that R 12 and R 13 are attached to, wherein said C 2 -C 4 alkylene group is substituted with at least one C 6 -C 10 aryl group;
R 14 is H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R 22 ;
R 15 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 20 , —SR 20 , guanidino, —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —NHC(O)R 20 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 20 ;
R 16 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 20 , —SR 20 , guanidino, —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —NHC(O)R 20 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 20 ;
R 17 is H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m -C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl or adamantyl, wherein said C 1 -C 20 alkyl group, said C 2 -C 20 alkenyl group, said C 6 -C 10 aryl group and said adamantyl group can be optionally substituted with up to three groups, each independently selected from halo, —OR 20 , —C(O)OR 20 , CN, NO 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —N(R 20 ) 2 , —C(O)N(R 20 ) 2 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NHC(O)R 20 , —NHC(O)OR 20 and —NHC(O)N(R 20 ) 2 and;
R 18 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;
each occurrence of R 20 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m , —(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 4 to 7-membered heterocycloalkyl group, said -(5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R 26 ;
each occurrence of R 21 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —OR 20 , —O—(C 1 -C 6 haloalkyl) or —N(R 20 ) 2 , wherein said C 2 -C 6 alkenyl group, said C 2 -C 6 alkynyl group, said C 3 -C 7 cycloalkyl group, said C 3 -C 7 cycloalkenyl group, said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 ;
R 22 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, halo, —OR 20 , —SR 20 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 20 ) 2 , —C(O)OR 20 , —C(O)N(R 20 ) 2 and —NHC(O)R 20 , or any two R 22 groups on adjacent ring carbon atoms can combine to form —O—R 23 —O—;
R 23 is —[C(R 24 ) 2 ] n —;
each occurrence of R 24 is independently H or C 1 -C 6 alkyl;

Assignees

• Verma Vishal A
• Arasappan Ashok
• Njoroge F George
• Chen Kevin X
• Merck Sharp & Dohme

Inventors

• Verma Vishal A
• Arasappan Ashok
• Njoroge F George
• Chen Kevin X

Classifications

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title