HCV polymerase inhibitors

Patent metadata

Field	Value
Publication number	US-9481703-B2
Application number	US-201514634449-A
Country	US
Kind code	B2
Filing date	Feb 27, 2015
Priority date	Sep 4, 2013
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

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 selected from the groups (i) to (iv):

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 12 is H;
R 13 is H;
R 14 is H or C 1 -C 6 alkyl, phenyl, naphthyl or a 5 to 12 membered mono or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which phenyl, naphthyl or heteroaryl is optionally substituted with 1, 2 or 3 R 22 ;
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 form 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 ; or
R 15′ is H and R 15 and R 24 together with the atoms to which they are attached, form a 5-membered ring;
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 20 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl or C 3 -C 7 cycloalkylC 1 -C 3 alkyl;
each R 21 is independently H, C 1 -C 24 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 or C 3 -C 7 cycloalkenyl;
each R 22 is independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, phenyl, hydroxyC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, carboxyC 1 -C 6 alkyl, oxo, OR 20 , SR 20 , N(R 20 ) 2 , CN, NO 2 , C(O)OR 20 , C(O)N(R 20 ) 2 and NHC(O)R 20 , or any two R 22 groups attached to adjacent ring carbon atoms can combine to form —O—R 23 —O—;
R 23 is [C(R 33 ) 2 ] n ;
R 24 is H, or R 24 and R 15 together with the atoms to which they are attached, form a 5-membered ring;
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 R 1 is a triphosphate of the formula:

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein R 1 is the group (iv):

wherein U is O and R 24 is H.

9. The compound according to claim 8 , wherein
R 24 is H;
R 14 is optionally substituted phenyl;
one of R 15 and R 15′ is H and the other is C 1 -C 3 alkyl;
R 6 is C 1 -C 8 alkyl.

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

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

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

13. A method for the treatment of hepatitis C virus infection comprising the administration of a compound according to claim 1 to a subject in need thereof.

14. The compound according to claim 8 , wherein R 14 is phenyl.

15. The compound according to claim 8 , wherein one of R 15 and R 15′ is H and the other is methyl.

16. The compound according to claim 8 , wherein R 15′ is hydrogen, and R 15 is other than hydrogen and the configuration at the asymmetric carbon atom is that of an L-amino acid, selected from L-Ala, L-Val, L-Ile and L-Phe.

17. The compound according to claim 16 , wherein R 15′ is hydrogen and R 15 is methyl.

18. The compound according to claim 8 , wherein R 6 is C 1 -C 3 alkyl, selected from methyl, ethyl, propyl and isopropyl.

19. The compound according to claim 17 , wherein R 16 is isopropyl.

20. The compound according to claim 7 , wherein R 2 is H and B is the group (b)

wherein R 7 and R 8 are H.

21. The compound according to claim 8 , wherein R 2 is H and B is the group (b)

wherein R 7 and R 8 are H.

22. The compound according to claim 17 , wherein R 2 is H and B is the group (b)

wherein R 7 and R 8 are

Assignees

• Medivir Ab

Inventors

• Kalayanov Genadiy
• Torssell Staffan
• Wahling Horst

Classifications

• C07H19/06 Primary

  Pyrimidine radicals · CPC title

• C07H19/10 Primary

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

• A61P31/00

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

• C07H19/173

  with 2-deoxyribosyl as the saccharide radical · CPC title

• C07H19/073

  with 2-deoxyribosyl as the saccharide radical · CPC title