Macrocyclic inhibitors of flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-RE47334-E
Application number	US-201715715080-A
Country	US
Kind code	E1
Filing date	Sep 25, 2017
Priority date	Jun 8, 2012
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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 compound of Formula I:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;

 pyrazolylene, phenylene or pyrimidinylene,
wherein B is arylene, heteroarylene, cycloalkylene or heterocycloalkylene;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, heteroarylene or cycloalkylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
X 1 is a bond, —O—, —NH—, —N((C 1 -C 4 )alkyl)- or heterocycloalkylene;
R 1 and R 2 are independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, halo, cyano or (C 1 -C 4 )alkanoyl; or
R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—, —C(═S)— or —C(═N(C 1 -C 4 )alkyl)-;
R 3 is H or (C 1 -C 4 )alkyl which is optionally substituted with halo, cyano, hydroxy or (C 1 -C 4 )alkoxy;
R 4a and R 4b are independently H, (C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 4 )alkyl, wherein each of R 4a and R 4b is optionally substituted with one or more substituent selected from the group consisting of cyano, (C 1 -C 8 )alkoxy, —COOH, —C(O)O—(C 1 -C 8 )alkyl, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —C(O)-mono(C 1 -C 8 )alkylamino, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)— heterocycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each substituent is optionally substituted with one or more halo, heterocycloalkyl or aryl, or R 4a and R 4b are independently (C 1 -C 4 )alkoxy or halo(C 1 -C 4 )alkoxy;
R 5a and R 5b are independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl or heterocycloalkyl(C 1 -C 4 )alkyl, wherein R 5a and R 5b are independently optionally substituted with one or more substituent selected from the group consisting of —N 3 , cyano, —COOH, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl, or one of R 5a and R 5b is heteroarylheteroaryl(C 1 -C 4 )alkyl; or
R 5a and R 5b together form a spirocycle having Formula (a):

wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH 2 , —C(O)O—(C 1 -C 8 )alkyl, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)—(C 1 -C 8 )alkyl, —C(O)-heterocycloalkyl, —S(O) 2 R 10 , —OSi(R 10 ) 3 , (C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy, (C 1 -C 8 )alkanoyl and aryl(C 1 -C 4 )alkyl;
R 6a , R 6b , R 7a and R 7b are independently H, hydroxyl, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, —CH 2 CH 2 CR 9 (═N(C 1 -C 4 )alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 or —N(R 9 ) 2 , wherein each of R 6a , R 6b , R 7a and R 7b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 8 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 , —OC(O)—(C 1 -C 8 )alkyl —C(O)O—(C 1 -C 8 )alkyl and (C 1 -C 8 )alkanoyl, wherein each —OC(O)—(C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy is optionally substituted with one or more amino, —OC(O)O—(C 1 -C 8 )alkyl or —Si(R 10 ) 3 ; or
R 6a and R 6b together form a spirocycle having Formula (a);
each R 8 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein R 8 is optionally substituted with —OR, —N(R 9 ) 2 , —CON(R 9 ) 2 or cyano;
each R 9 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each R 10 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, cycloalkyl(C 1 -C 4 )alkyl or aryl, wherein R 10 is optionally substituted with one or more halo;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.

2. The compound of claim 1 , wherein A is methylene.

3. The compound of claim 1 , wherein A 1 is ethenylene, propenylene, ethylene, propylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.

4. The compound of claim 1 , wherein A 1 is

5. The compound of claim 1 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene.

6. The compound of claim 1 , wherein A 2 is —CH(R 8 )-quinolinylene, —CH(R 8 )-isoquinolinylene, —CH(R 8 )-naphthyridinylene, —CH(R 8 )-cinnolinylene, —CH(R 8 )-quinoxalinylene, —CH(R 8 )-phenylene or —CH(R 8 )-halophenylene.

7. The compound of claim 1 , wherein A 2 is

8. The compound of claim 1 , wherein X 1 is —O— or —NH—.

9. The compound of claim 1 , wherein R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—.

10. The compound of claim 1 , wherein R 3 is H.

11. The compound of claim 1 , wherein R 6a is H and R 6b is H or (C 1 -C 4 )alkyl, or R 6a and R 6b together form a spirocycle having Formula (a).

12. The compound of claim 1 , wherein R 6a and R 6b form

13. The compound of claim 1 , wherein R 3 is H; R 5a is H; R 5b is H, (C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, azido(C 1 -C 8 )alkyl, aryl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl or arylheterocycloalkyl(C 1 -C 4 )alkyl; R 6a is H; and R 6b is H, (C 1 -C 4 )alkyl or hydroxy(C 1 -C 4 )alkyl.

14. The compound of claim 1 , wherein X 1 is —O— or —NH—; R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—; R 3 is H; R 4a is H; R 4b is methyl; R 5a is H and R 5b is iso-propyl, propenyl or propynyl; and R 8 is methyl.

15. 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 2 is —CH(R 8 )-

Assignees

• Gilead Sciences Inc
• Cypralis Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/18

  for HIV · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title