Macrocyclic inhibitors of Flaviviridae viruses

Patent metadata

Field	Value
Publication number	US-9642889-B2
Application number	US-201514719242-A
Country	US
Kind code	B2
Filing date	May 21, 2015
Priority date	Jun 8, 2012
Publication date	May 9, 2017
Grant date	May 9, 2017

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 disease selected from the group consisting of dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis, comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein:
A is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;
A 1 is (C 1 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aryl(C 1 -C 2 )alkylene, heteroaryl(C 1 -C 2 )alkylene, cycloalkyl(C 1 -C 2 )alkylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally replaced by —O—, —S(O) n —, —NH— or —N((C 1 -C 4 )alkyl)-, and wherein a sp 3 or sp 2 carbon atom of A 1 is optionally substituted with one or more groups selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl, arylheterocycloalkyl(C 1 -C 4 )alkyl, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 and —N(R 9 ) 2 ;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, cycloalkylene, (C 1 -C 3 )alkylene, (C 2 -C 3 )alkenylene or (C 2 -C 3 )alkynylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
L 1 is —O—C(O)—, —O—CH 2 —, —NR 11 —CH 2 —, —NH—C(R 10 ) 2 — or —NH—S(O) 2 —, wherein each R 10 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl; and R 11 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl;
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(O)—(C 1 -C 4 )alkyl; 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, hydroxyl 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 R 4a and R 4b is optionally substituted with one or more substituents selected from the group consisting of cyano, —COOH, halo, hydroxyl, amino, (C 1 -C 8 )alkoxy, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl;
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 each R 5a and R 5b is optionally substituted with one or more substituents 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, (C 1 -C 8 )alkoxy, aryl and heteroaryl, 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) optionally has one or more substituents selected from the group consisting of oxo, ═N(C 1 -C 4 )alkoxy, halo, hydroxyl, —NH 2 , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —OC(O)R 9 , —C(O) 2 R 9 , and —S(O) 2 R 9 ;
R 6a and R 6b are independently H, hydroxyl, (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 and —N(R 9 ) 2 , wherein each of R 6a and R 6b is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 and (C 1 -C 8 )alkanoyl; 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, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.

2. The method of claim 1 , wherein the disease is Hepatitis C virus.

3. A method for providing immunomodulation to 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, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein:
A is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;
A 1 is (C 1 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aryl(C 1 -C 2 )alkylene, heteroaryl(C 1 -C 2 )alkylene, cycloalkyl(C 1 -C 2 )alkylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally replaced by —O—, —S(O) n —, —NH— or —N((C 1 -C 4 )alkyl)-, and wherein a sp 3 or sp 2 carbon atom of A 1 is optionally substituted with one or more groups selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl, arylheterocycloalkyl(C 1 -C 4 )alkyl, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 and —N(R 9 ) 2 ;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, cycloalkylene, (C 1 -C 3 )alkylene, (C 2 -C 3 )alkenylene or (C 2 -C 3 )alkynylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
L 1 is —O—C(O)—, —O—CH 2 —, —NR 11 —CH 2 —, —NH—C(R 10 ) 2 — or —NH—S(O) 2 —, wherein each R 10 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl; and R 11 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl;
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(O)—(C 1 -C 4 )alkyl; 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, hydroxyl or (C 1 -C 4 )alkoxy;
R 4a and R 4b are independently H, (C 1 -C 8 )alkyl

Assignees

• Selcia Ltd
• Gilead Sciences Inc

Inventors

• Aciro Caroline
• Chiva Jean Yves
• Dean David Kenneth
• Highton Adrian John
• Jansa Petr
• Keats Andrew John
• Lazarides Linos
• Mackman Richard
• Poullennec Karine G
• Schrier Adam James
• Siegel Dustin Scott
• Steadman Victoria Alexandra
• Watt Greg

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

• A61P31/14

  for RNA viruses · CPC title

• A61P29/00

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