HCV polymerase inhibitors

Patent metadata

Field	Value
Publication number	US-10106571-B2
Application number	US-201715823224-A
Country	US
Kind code	B2
Filing date	Nov 27, 2017
Priority date	Sep 4, 2013
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The invention provides compounds of the formula:

wherein B is a nucleobase selected from the groups (a) to (d):

and the other variables are as defined in the claims,

which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.

First claim

The invention claimed is:

1. A compound represented by formula I:

wherein:
B is a nucleobase selected from the groups (a) to (d):

wherein Y is N or C(R 19 );

R 1 is group (v):

R 2 is H, C(═O)R 30 , C(═O)CHR 31 NH 2 , CR 32 R 32′ OC(═O)CHR 33 NH 2 or CR 32 R 32′ OC(═O)R 30 ;
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 18 , SR 18 or N(R 18 ) 2 ;
R 6 , R 9 , R 10 and 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, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, OR 18 , SR 18 , N(R 18 ) 2 , NHC(O)OR 18 , NHC(O)N(R 18 ) 2 , CN, NO 2 , C(O)R 18 , C(O)OR 18 , C(O)N(R 18 ) 2 and NHC(O)R 18 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group can be optionally substituted with halo or C 3 -C 5 cycloalkyl;
R 15 and R 15′ are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, phenyl and benzyl, or R 15 and R 15′ together with the carbon atom to which they are attached from a C 3 -C 7 cycloalkylene group, wherein each C 1 -C 6 alkyl is optionally substituted with a group selected from halo, OR 18 and SR 18 , and each C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C 1 -C 3 alkyl, halo and OR 18 ;
R 16 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, benzyl, phenyl or adamantyl, any of which is optionally substituted with 1, 2 or 3 groups, each independently selected from halo, OR 18 and N(R 18 ) 2 ;
each R 18 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 7 cycloalkyl;
R 19 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, OR 18 or N(R 18 ) 2 ;
each R 30 is independently selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
each R 31 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and benzyl;
each R 32 and R 32′ is independently selected from H and C 1 -C 3 alkyl;
each R 33 is independently selected from H and C 1 -C 6 alkyl;
U is O or S;

or a pharmaceutically acceptable salt and/or solvate thereof.

2. The compound according to claim 1 , wherein B is the group (a′):

wherein
R 5 is H or F, and R 6 is N(R 18 ) 2 or NHCOC 1 -C 6 alkyl.

3. The compound according to claim 2 , wherein R 6 is NH 2 .

4. The compound according to claim 1 , wherein B is the group (b′):

wherein R 8 is H or F.

5. The compound according to claim 4 , wherein R 8 is H.

6. The compound according to claim 1 , wherein B is the group (c′):

wherein R 9 is OH or C 1 -C 6 alkoxy, and R 10 is NH 2 or NHCOC 1 -C 6 alkyl.

7. The compound according to claim 1 ,
wherein U is O.

8. The compound according to claim 1 , wherein R 2 is H.

9. The compound according to claim 8 , wherein
both R 15 are H or C 1 -C 6 alkyl, both R 15′ are H and
both R 16 are C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.

10. The compound according to claim 9 , wherein both R 15 are ethyl, n-propyl, isopropyl, n-butyl or isobutyl, both R 15′ are H, and both R 16 are methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

11. The compound according to claim 10 , wherein both R 16 are C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl.

12. The compound according to claim 11 , wherein both R 16 are methyl, ethyl, propyl or isopropyl.

13. The compound according to claim 12 , wherein both R 16 are isopropyl.

14. A pharmaceutical composition comprising a compound according to claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

15. A pharmaceutical composition comprising a compound according to claim 1 , further comprising one or more additional other antiviral agent(s).

16. A method for the treatment of hepatitis C virus infection comprising the administration of a compound according to claim 1 .

Assignees

• Medivir Ab

Inventors

• Kalayanov Genadiy
• Torssell Staffan
• Wahling Horst

Classifications

• A61K45/06

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

• A61P31/14

  for RNA viruses · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• C07H19/10

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

• C07H19/11

  containing cyclic phosphate · CPC title