Hepatitis C virus inhibitors

Patent metadata

Field	Value
Publication number	US-9326973-B2
Application number	US-201313735224-A
Country	US
Kind code	B2
Filing date	Jan 7, 2013
Priority date	Jan 13, 2012
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.

First claim

What is claimed is:

1. A combination comprising an NS5A-targeting compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
L is absent or selected from C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 4 alkynyl, and C 3 cycloalkyl
A is absent or selected from isoquinolinyl, naphthyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, and quinolinyl;
B is selected from anthracenyl, benzofuranyl, bicycloalkyl, indanyl, indolyl, naphthyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrahydronaphthyl, thienyl, and

each X is independently selected from O and NR q′ , wherein R q′ is selected from hydrogen, alkyl, hydroxy, and —NH 2 ;
each R 1 is independently selected from alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heterocyclyl, and hydroxyalkyl;
each R 1a is independently selected from hydrogen and alkyl; or
R 1 and R 1a , together with the carbon atom to which they are attached, form a saturated or unsaturated 3- to 6-membered spirocyclic ring, wherein the spirocyclic ring, when between 4- and 6-members, can be optionally fused to a phenyl ring, and wherein each ring system is optionally substituted with one or two groups independently selected from alkyl and halo;
each R f is independently selected from hydrogen, methyl, hydroxy, and —NH 2 (R z ), wherein R z is alkyl;
each R p is independently selected from hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl;
each R q is independently selected from hydrogen, alkyl, halo, and —P(O)—(OR) 2 , wherein each R is the same or a different alkyl group; and
each R 2 is independently selected from hydrogen, alkenylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkylcarbonylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, alkyl, alkylcarbonyl, alkylcarbonylalkylcarbonyl, alkylcarbonylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylsulfanylalkylcarbonyl, arylsulfinyl, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkyloxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, (heterocyclyl)alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR c R d )alkylcarbonyl, (NR c R d )carbonyl, (NR c R d )carbonylalkylcarbonyl, (NR c R d )carbonylcarbonyl, and

wherein R and R′ are each alkyl, or, together with the carbon atom to which they are attached, form a five- or six-membered ring optionally containing one oxygen or nitrogen atom; or
R 2 and R f , together with the nitrogen atom to which they are attached, forms a five- or six-membered ring optionally substituted with one or two groups independently selected from alkoxycarbonylamino and oxo; or
R 2 and R f , together with the nitrogen atom to which they are attached, form

and an NS5A synergist of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:
L is absent or selected from —O—, —CH 2 —O—CH 2 —, —OCH 2 —, C 2 alkyl, C 2 alkynyl, cyclopropyl, ethynylbenzyl, phenyl, pyrazinyl, and pyridinyl;
A is selected from aryl, cycloalkenyl, and heteroaryl;
B is selected from aryl, bicycloalkyl, cycloalkenyl, and heteroaryl;
each R 1 is independently selected from

each m is independently 0, 1, or 2;
each X is independently selected from CH 2 , NH, and NR a ; wherein R a is alkyl;
each R 2 is independently selected from alkyl, halo, and hydroxy; wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon, a bridged four- or five-membered ring with another carbon atom on the ring, or a spirocyclic three- to six-membered ring with the carbon atom to which it is attached; wherein each ring is optionally substituted with one or two groups independently selected from alkyl, halo, and haloalkyl; or
R 2 , together with the carbon atom to which it is attached, forms a C 2 olefin;
each R 3 is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, (NR c R d )alkenyl, and (NR c R d )alkyl;
each R 4 is independently selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;
each R 5 is independently selected from hydrogen and alkyl;
each R p is independently selected from hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; and
each R q is independently selected from hydrogen, alkyl, halo, and —P(O)—(OR) 2 , wherein each R is the same or a different alkyl group;

which, when administered, provides synergistic anti-HCV activity against variants that contain mutation(s) conferring resistance to the NS5A-targeting compound alone.

2. The combination of claim 1 which comprises two or more pharmaceutically acceptable carriers.

3. The combination of claim 1 wherein the NS5A-targeting compound and the NS5A synergist are combined in the same pharmaceutically acceptable carrier.

4. A composition comprising a combination of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The composition of claim 4 further comprising one or two additional compounds having anti-HCV activity.

6. The composition of claim 5 wherein at least one of the additional compounds is an interferon or a ribavirin.

7. The composition of claim 6 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, pegylated interferon lambda, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

8. The composition of claim 5 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

9. A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a combination of claim 1 , or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 further comprising administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the combination, or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 wherein at least one of the additional compounds is an interferon or a ribavirin.

12. The method of claim 11 wherein interferon is selected from interferon alpha 2B, pegylated interferon alpha, pegylated interferon lambda, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

13. The method of claim 10 wherein at least one of the additio

Assignees

• Bristol Myers Squibb Co

Inventors

• Hewawasam Piyasena
• Kadow John F
• Lopez Omar D
• Meanwell Nicholas A
• Tu Yong
• Wang Alan Xiangdong
• Xu Ningning
• Gupta Samayamunthula Venkata Satya Arun Kumar
• Srinivasu Pothukanuri
• Kumar Indasi Gopi
• Kumar Ponugupati Suresh
• Belema Makonen
• Fridell Robert A
• Gao Min
• Lemm Julie A
• O'Boyle Ii Donald R
• Sun Jin-Hua
• Wang Chunfu
• Wang Ying-Kai

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

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

• A61K31/4178 Primary

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K45/06

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

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title