2′-disubstituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-9457039-B2
Application number	US-201314436687-A
Country	US
Kind code	B2
Filing date	Oct 11, 2013
Priority date	Oct 17, 2012
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

2′-disubstituted substituted nucleoside derivatives of formula (I) and pharmaceutically acceptable salts thereof are disclosed: (1), wherein A is N 3 or NH 2 and X, Y, R 1 , R 2 , R 3 , R 4 , R 5 and R 18 are as defined herein. Compositions comprising at least one 2′-disubstituted nucleoside derivative, and methods of using the 2′-disubstituted nucleoside derivatives for treating or preventing HCV infection in a patient are disclosed.

First claim

The invention claimed is:

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
A is —NH 2 ;
X is O, N, S or CH 2 ;
Y is N or —C(R 6 )—;
R 1 is H,

R 2 is H, —C(O)—(C 1 -C 6 alkyl) or

or R 1 and R 2 join to form a group having the formula:

R 3 is 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 and R 5 are each independently selected from H, —OR 12 , —NHC(O)OR 12 , —NHC(O)N(R 12 ) 2 , —N(R 12 ) 2 and —NHC(O)R 12 ;
R 6 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 12 , —SR 12 , —N(R 12 ) 2 , C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl;
R 7 is H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, or —(C 1 -C 3 alkylene)-C(O)O—(C 1 -C 6 alkyl), 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 13 ,
R 8 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 12 , —SR 12 , guanidino, —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NHC(O)R 12 , 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 12 ;
R 9 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 12 , —SR 12 , guanidino, —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NHC(O)R 12 , 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 12 ;
R 10 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 —(C 1 -C 3 alkylene) m -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 12 , —C(O)OR 12 , 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 12 ) 2 , —C(O)N(R 12 ) 2 —SR 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 12 ) 2 , —NHC(O)R 12 , —NHC(O)OR 12 and —NHC(O)N(R 12 ) 2 ;
R 11 is H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl or —(C 1 -C 3 alkylene) m -adamantyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, wherein said C 1 -C 20 alkyl group, said C 2 -C 20 alkenyl group, said C 6 -C 10 aryl group, said adamantyl 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, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR 12 , —SR 12 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 12 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 and —NHC(O)R 12 , —NHC(O)OR 12 and —NHC(O)N(R 12 ) 2 ;
each occurrence of R 12 is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl) m -(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 16 ;
R 13 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, halo, —OR 12 , —SR 12 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 and —NHC(O)R 12 , or any two R 13 groups on adjacent ring carbon atoms can combine to form —O—R 14 —O—;
R 14 is [C(R 15 ) 2 ] n —;
each occurrence of e is independently H or C 1 -C 6 alkyl;
R 16 represents from one to five substituent groups, each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, —OR 17 , —SR 17 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 17 ) 2 , —C(O)OR 17 , —C(O)N(R 17 ) 2 and —NHC(O)R 17 ;
each occurrence of R 17 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) m -(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);
R 18 is H, C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, or CN; and
each occurrence of m is independently 0 or 1, and
each occurrence of n is independently 1, 2, or 3.

2. The compound of claim 1 , wherein X is O.

3. The compound of claim 2 , wherein R 3 is methyl.

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H,

R 2 is H, or R 1 and R 2 join to form a group having the formula:

R 4 is H, OH or —N(R 12 ) 2 ;
R 5 is H or NH 2 ,
R 18 is H, —CN or —OCH 3 ;
R 7 is —(C 1 -C 3 alkylene)-C(O)O—(C 1 -C 6 alkyl) or phenyl, wherein said phenyl group can be optionally substituted with a halo group;
R 8 and R 9 are each independently H or C 1 -C 6 alkyl;
R 10 is C 1 -C 6 alkyl; and
R 11 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.

5. The compound of claim 4 , wherein R 1 is:

6. The compound of claim 4 , whe

Assignees

• Merck Sharp & Dohme

Inventors

• Girijavallabhan Vinay
• Bogen Stephane
• Pan Weidong
• Dang Qun
• Davies Ian

Classifications

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• C07H7/06

  Heterocyclic radicals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title