HCV NS-3 serine protease inhibitors

Patent metadata

Field	Value
Publication number	US-10172846-B2
Application number	US-201715470599-A
Country	US
Kind code	B2
Filing date	Mar 27, 2017
Priority date	Jan 30, 2004
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Methods drawn to peptidomimetic compounds which inhibit the NS3 protease of the hepatitis C virus (HCV), are described. The compounds have the formula (VI) where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

First claim

The invention claimed is:

1. A compound of formula VIga:

wherein
A is C(═O)OR 1 or C(═O)NHSO 2 R 2 ; wherein
R 1 is hydrogen or C 1 -C 6 alkyl; and
R 2 is C 1 -C 6 alkyl, C 0 -C 6 alkylcarbocyclyl, or C 0 -C 3 alkylheterocyclyl, each of which is optionally substituted with 1 to 3 substituents which are each independently halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, YC(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, YS(═O)pNRaRb, Y—C(═O)ORb, or Y—NRaC(═O)ORb;

Y is independently a bond or C 1 -C 3 alkylene;
p is independently 1 or 2;
Ra is independently H or C 1 -C 3 alkyl;
Rb is independently H, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, or C 0 -C 3 alkylheterocyclyl;
Rd is H or C 1 -C 3 alkyl;
q′ is 0 and k is 1;
Rz is H, or together with the asterisked carbon forms an olefinic bond;
Rq is H or C 1 -C 6 alkyl;
W is —O— or —S—;
R 8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings, each of which has 4-7 ring atoms and each of which has 0 to 4 hetero atoms selected from S, O, and N, the ring system being optionally spaced from W by a C 1 -C 3 alkyl group; any of which R 8 groups can be optionally mono, di, or tri substituted with R 9 , wherein
R 9 is independently halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, YNRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y-NHSOpRb, YS(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, or Y—NRaC(═O)ORb; wherein said carbocyclyl or heterocyclyl moiety is optionally substituted with R 10 ; wherein
R 10 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, amino, sulfonyl, (C 1 -C 3 alkyl)sulfonyl, NO 2 , OH, SH, halo, haloalkyl, carboxyl, or amido;
J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain, which chain is optionally interrupted by one to three heteroatoms that are each independently —O—, —S—, or —NR 12 —, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R 14 ;
R 12 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or COR 13 ;
R 13 is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, or C 0 -C 3 alkylheterocyclyl;
each R 14 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, halo, amino, oxo, thio, or C 1 -C 6 thioalkyl;
G is —O—, —NRy-, or NRjNRj-;
Ry is H or C 1 -C 3 alkyl;
Rj is H;
U is ═O or is absent;
R 16 is H; or R 16 is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, or C 0 -C 3 alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 CO—, Y—NRaRb, Y—O—Rb, YC(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y-NHSOpRb, Y—S(═O)pRb, YS(═O)pNRaRb, Y—C(═O)ORb, or Y—NRaC(═O)ORb;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl, C 0 -C 3 alkylaryl, C 3 -C 7 cycloalkyl, or phenyl, each of which is optionally substituted with 1 to 3 substituents which are each halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, YC(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y-NHSOpRb, Y—S(═O)pRb, YS(═O)pNRaRb, Y—C(═O)Orb, or Y—NRaC(═O)ORb.

3. The compound according to claim 1 , wherein said compound has the partial structure that is:

4. The compound according to claim 3 , wherein Rq is C 1 -C 3 alkyl.

5. The compound according to claim 1 , wherein A is C(═O)OR 1 , wherein R 1 is H or C 1 -C 6 alkyl.

6. The compound according to claim 1 , wherein W is —O—.

7. The compound according to claim 1 wherein R 8 is optionally substituted C 0 -C 3 alkylcarbocyclyl or optionally substituted C 0 -C 3 alkylheterocyclyl.

8. The compound according to claim 7 , wherein R 8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-napthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R 9 as defined.

9. The compound according to claim 8 , wherein R 8 is:

wherein R 9a is C 1 -C 6 alkyl; C 1 -C 6 alkoxy; thioC 1 -C 3 alkyl; amino optionally substituted with C 1 -C 6 alkyl; C 0 -C 3 alkylaryl; C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R 10 wherein R 10 is C 1 -C 6 alkyl; C 0 -C 3 alkyl; C 3 -C 7 cycloalkyl; C 1 -C 6 alkoxy; amino optionally mono- or di-substituted with C 1 -C 6 alkyl; amide; or C 1 -C 3 alkylamide; and
R 9b is C 1 -C 6 alkyl, C 1 -C 6 -alkoxy, amino, di(C 1 -C 3 alkyl)amino, (C 1 -C 3 alkyl)amide, NO 2 , OH, halo, trifluoromethyl, or carboxyl.

10. The compound according to claim 9 , wherein R 9a is aryl or heteroaryl, either of which is optionally substituted with R 10 as defined.

11. The compound according to claim 9 , wherein R 9a is:

wherein R 10 is H; C 1 -C 6 alkyl; C 0 -C 3 alkylcycloalkyl; amino optionally mono- or di-substituted with C 1 -C 6 alkyl; amido; or (C 1 -C 3 alkyl)amide.

12. The compound according to claim 9 , wherein R 9a is optionally substituted phenyl.

13. The compound according to claim 9 , wherein R 9b is C 1 -C 6 -alkoxy.

14. The compound according to claim 1 , wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain.

15. The compound according to claim 1 , wherein R 16 is H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.

16. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 , further comprising an additional HCV antiviral.

18. The pharmaceutical composition of claim 17 , wherein the additional HCV antiviral is a nucleoside analogue polymerase inhibitor, a protease inhibitor, ribavirin, or interferon.

19. A method of treating hepatitis C virus (HCV) infection comprising administering to an individual afflicted with or at risk of HCV infection, an effective amount of a compound of claim 1 .

20. The method of claim 19 , further comprising administering to the individual, an additional HCV antiviral.

21. The method of claim 20 , wherein the additional HCV antiviral is a nucleoside analogue polymerase inhibitor, a protease inhibitor, ribavirin, or interferon.

Assignees

• Medivir Ab

Inventors

• Rosenquist Asa
• Thorstensson Fredrik
• Johansson Per-Ola
• Kvarnstrom Ingemar
• Samuelsson Bertil
• Wallberg Hans

Classifications

• A61P43/00

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

• A61P31/12

  Antivirals · CPC title

• A61P31/00

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

• A61P31/14

  for RNA viruses · CPC title

• C07K5/06052

  Val-amino acid · CPC title