Benzimidazole-imidazole derivatives

Patent metadata

Field	Value
Publication number	US-9427428-B2
Application number	US-201013508186-A
Country	US
Kind code	B2
Filing date	Nov 3, 2010
Priority date	Nov 4, 2009
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

Inhibitors of HCV replication of formula I

including stereochemically isomeric forms, and salts, solvates thereof, wherein R and R′ are, each independently, —CR 1 R 2 R 3 , aryl, heteroaryl or heteroC 4-6 cycloalkyl, whereby aryl and heteroaryl may optionally be substituted with 1 or 2 substituents selected from halo and methyl.

The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.

First claim

The invention claimed is:

1. A compound of formula I

or a stereoisomeric form thereof, wherein:
A is naphthylene, which is optionally substituted with 1, 2 or 3 substituents selected from halo and C 1-3 alkyl;
R and R′ are, each independently, —CR 1 R 2 R 3 , aryl, heteroaryl or heteroC 4-6 cycloalkyl, whereby aryl and heteroaryl may optionally be substituted with 1 or 2 substituents selected from halo and methyl; and wherein
R 1 is hydrogen;
C 1-4 alkyl optionally substituted with methoxy or dimethylamino;
phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4 alkoxy, and trifluoromethoxy;
1,3-benzodioxolanyl;
benzyl optionally substituted with 1, 2 or 3 substituents independently selected from halo and methoxy;
C 3-6 cycloalkyl;
heteroaryl;
heteroC 4-6 cycloalkyl; or
heteroarylmethyl;

R 2 is hydrogen, hydroxyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 alkylcarbonylamino, C 1-4 alkyloxycarbonylamino, C 1-4 alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl;
R 3 is hydrogen,
or R 1 and R 3 together form a cyclopropyl group;
or R 2 and R 3 form oxo;
or a pharmaceutically acceptable salt or a solvate thereof;
wherein the compound is not

2. The compound according to claim 1 wherein A is 2,6-naphthylene optionally substituted with 1, 2 or 3 substituents selected from halo and C 1-3 alkyl.

3. The compound according to claim 1 , wherein R 1 is different from unsubstituted 2-propyl and when R 1 in R is 1-methoxyethyl, then R 1 in R′ is different from 1-methoxyethyl.

4. The compound according to claim 1 wherein
R 1 is other than 2 propyl when R 2 is methoxycarbonylamino; and
R 1 in R′ is other than 1-methoxyethyl when R 2 in R′ is methoxycarbonylamino.

5. The compound according to claim 1 wherein R and R′ are different from one another.

6. The compound according to claim 1 wherein R and R′ are the same.

7. The compound according to claim 1 wherein R and R′ each independently are —CR 1 R 2 R 3 .

8. The compound according to claim 7 wherein each R 2 independently is C 1-4 alkylcarbonylamino or C 1-4 alkyloxycarbonylamino.

9. The compound according claim 7 wherein each R 2 independently is methoxycarbonylamino.

10. The compound according claim 7 wherein each R 1 independently is selected from branched C 3-4 alkyl, methoxyC 2-3 alkyl, cyclopentyl, and phenyl.

11. The compound according to claim 7 wherein R 1 in R is 1-methylpropyl, 2-methylpropyl, 2-methoxyethyl, cyclopentyl or phenyl; and R 1 in R′ is 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1-methoxyethyl, cyclopentyl, or phenyl.

12. The compound according to claim 7 wherein both the carbon atoms in R and R′ bearing the R 1 , R 2 and R 3 substituent have the S-configuration.

13. The compound according to claim 1 wherein the compound is of formula Ia

14. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

15. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

16. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

17. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

18. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

19. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

20. The compound according to claim 19 in its 0.2HCl.4H 2 O form or .H 2 SO 4 form.

21. A compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

22. The compound according to claim 21 in its 0.2HCl.4H 2 O form.

23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

24. A product comprising (a) a compound as defined by claim 1 , and (b) another HCV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.

25. The product according to claim 24 wherein the other HCV inhibitor is a HCV protease inhibitor.

26. The product according to claim 25 wherein the HCV protease inhibitor is selected from the group consisting of telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC435350 (TMC435), MK-7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095, GS 9256, VX-985, IDX-375 (HCV NS4A protease co-factor inhibitor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450, EP-013420 (and congeners), and VBY-376.

27. The product according to claim 25 wherein the HCV protease inhibitor is selected from the group consisting of TMC435350 (TMC435), MK-7009, and ITMN-191 (R-7227).

28. The product according to claim 24 wherein the other HCV inhibitor is a HCV nucleoside or non-nucleoside polymerase inhibitor.

29. The product according to claim 28 wherein the HCV polymerase inhibitor is selected from the group consisting of R7128, PSI-7851, PSI 7977, IDX-189, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728, GL-60667, ABT-072, AZD-2795, and 13-cyclohexyl-3-methoxy-17,23-dimethyl-7H-10,6-(methanoiminothioiminoethanooxyethanoiminomethano)indolo[2,1-a][2]benzazepine-14,24-dione 16,16-dioxide.

30. The product according to claim 28 wherein the HCV polymerase inhibitor is PSI-6130 or a prodrug thereof.

31. The product according to claim 28 wherein the HCV polymerase inhibitor is

or a pharmaceutically acceptable salt or solvate thereof.

32. A product comprising (a) a compound as defined by claim 1 , and (b) an immunomodulatory agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.

Assignees

• Vandyck Koen
• Last Stefaan Julien
• Houpis Ioannis Nicolaos
• Raboisson Pierre Jean-Marie Bernard
• Janssen Sciences Ireland Uc

Inventors

• Vandyck Koen
• Last Stefaan Julien
• Houpis Ioannis Nicolaos
• Raboisson Pierre Jean-Marie Bernard

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K45/06

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

• C07D403/14 Primary

  containing three or more hetero rings · CPC title