Macrocyclic inhibitors of flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-2017190737-A1
Application number	US-201715465492-A
Country	US
Kind code	A1
Filing date	Mar 21, 2017
Priority date	Jun 8, 2012
Publication date	Jul 6, 2017
Grant date	—

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

1 . A compound of Formula I:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug 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, pyridylene, pyrimidinylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally substituted with one or more (C 1 -C 4 )alkyl;
A 2 is arylene or heteroarylene, wherein A 2 is optionally 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 compound of claim 1 , wherein A 1 is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene, pyridylene or pyrimidinylene.

3 . The compound of claim 1 , wherein A 2 is isoquinolinylene, phenylene or halophenylene.

4 . The compound of 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 compound of 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 compound of claim 1 , which is a compound of Formula II:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A 1 is ethenylene,

A 1 is

X 1 is —O— or —NH—;
R 3a is H or methyl;
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 compound of claim 1 , 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 optionally substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or methyl; and R 4a is H, —OH or (C 1 -C 4 )alkoxy.

8 . (canceled)

9 . The compound of claim 1 , 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 optionally substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or methyl; and R 4a is H, —OH, (C 1 -C 4 )alkoxy or halo(C 1 -C 4 )alkoxy.

10 . A compound selected from:

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

11 . The compound of claim 1 , wherein A 2 is arylene; and A 1 is pyrazolylene, phenylene or pyridylene.

12 . (canceled)

13 . The compound of claim 1 , wherein A 2 is halophenylene; and A 1 is —O—(C 2 -C 5 )alkylene or —O—(C 2 -C 4 )alkenylene.

14 . (canceled)

15 . The compound of claim 1 , wherein A 1 is (C 2 -C 5 )alkylene or (C 2 -C 4 )alkenylene; R 5 is methyl, or R 5 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 . A compound selected from:

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

17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.

18 . The pharmaceutical composition of claim 17 , further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists; or a mixture thereof.

19 . The pharmaceutical composition of claim 18 , wherein the at least one addition therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.

20 .- 26 . (canceled)

Assignees

• Gilead Sciences Inc
• Selcia Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P31/18

  for HIV · CPC title

• A61P31/00

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