Macrocyclic inhibitors of flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-9873716-B2
Application number	US-201514740680-A
Country	US
Kind code	B2
Filing date	Jun 16, 2015
Priority date	Jun 8, 2012
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

Provided are compounds of Formula I:

and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.

First claim

What is claimed is:

1. A method for treating a hepatitis C virus infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein:
A 1 is (C 2 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, —O—(C 2 -C 4 )alkylene, —O—(C 2 -C 4 )alkenylene, arylene, aryl(C 1 -C 2 )alkylene, heterocycloalkylene, pyrazolylene, pyrimidinylene,

or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl;
A 2 is arylene or heteroarylene, wherein A 2 is unsubstituted or substituted with halo;
X 1 is —O—, —NH—or —N((C 1 -C 4 )alkyl)-;
R 1a and R 1b are independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
R 3a and R 3b are independently H or (C 1 -C 8 )alkyl;
R 4a and R 4b are independently H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl;
R 5 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl, or
R 5 forms a cyclic moiety along with —N((C 1 -C 4 )alkyl)- of X 1 or arylene of A 2 ; and
R 6 is H or (C 1 -C 4 )alkyl.

2. The method according to claim 1 , wherein A 1 is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.

3. The method according to claim 1 , wherein A 2 is isoquinolinylene, phenylene or halophenylene.

4. The method according to claim 1 , wherein X 1 is —O— or —NH—; one of R 1a and R 1b is H and the other is methyl; R 2 is iso-propyl; R 5 is methyl and R 6 is H or methyl.

5. The method according to claim 1 , wherein R 3a is H or methyl; R 3b is H; R 4a is H, —OH, methoxy, trifluoroethoxy; and R 4b is H.

6. The method according to claim 1 , wherein the compound of formula I is a compound of Formula II:

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer, thereof, wherein:
A 1 is ethenlene,

A 2 is

X 1 is —O—or —NH—;
R 3a is H or (C 1 -C 4 )alkyl;
R 4a is H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl; and
R 5 is H or (C 1 -C 4 )alkyl.

7. The method according to claim 6 , wherein A 2 is heteroarylene; A 1 is (C 2 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, wherein A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or (C 1 -C 8 )alkyl; and R 4a is H, —OH or (C 1 -C 4 )alkoxy.

8. The method according to claim 1 , wherein the compound of Formula I is

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

9. The method according to claim 6 , wherein A 2 is arylene; and A 1 is (C 2 -C 5 )alkylene, (C 2 C 5 )alkenylene, (C 2 -C 5 )alkynylene, —O—(C 2 -C 5 )alkylene, —O—(C 2 -C 4 )alkenylene, wherein A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or (C 1 -C 4 )alkyl; and R 4a is H, —OH, (C 1 -C 4 )alkoxy or halo(C 1 -C 4 )alkoxy.

10. The method according to claim 1 , wherein the compound of Formula I is

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

11. The method of claim 6 , wherein A 2 is arylene; and A 1 is pyrazolylene, phenylene or pyrimidinylene.

12. The method according to claim 1 , wherein the compound of Formula I is

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

13. The method according to claim 1 , wherein A 2 is haloarylene; and A 1 is —O—(C 2 -C 5 )alkylene or —O—(C 2 -C 4 )alkenylene.

14. The method according to claim 1 , wherein the compound of Formula I is

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer thereof.

15. The method of claim 1 , wherein A 1 is (C 2 -C 5 )alkylene or (C 2 -C 5 )alkenylene; R 5 is methyl, or R 6 form

along with arylene of A 2 , or R 5 form

along with —N((C 1 -C 4 )alkyl)- of X 1 ; and R 6 is H or methyl.

16. The method according to claim 1 , wherein the compound of Formula I is

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

Assignees

• Gilead Sciences Inc
• Cypralis Ltd

Inventors

• Aciro Caroline
• Dean David Kenneth
• Dunbar Neil Andrew
• Highton Adrian John
• Jansa Petr
• Karki Kapil Kumar
• Keats Andrew J
• Lazarides Linos
• Mackman Richard L
• Pettit Simon N
• Poullennec Karine G
• Schrier Adam James
• Siegel Dustin
• Steadman Victoria Alexandra

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P31/18

  for HIV · CPC title