Compositions and methods for inhibiting viral infection

Patent metadata

Field	Value
Publication number	US-11427595-B2
Application number	US-201916660285-A
Country	US
Kind code	B2
Filing date	Oct 22, 2019
Priority date	Oct 22, 2018
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

Described herein are compounds, agents, compositions, and methods related to the treatment of a viral infection (e.g., Hepatitis C viral infection). In particular, the compounds, agents, compositions, and methods described herein inhibit viral entry into a target cell.

First claim

What is claimed is:

1. A compound having the structure of Formula (I) or (III)

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,
wherein:
X is O;
W is —YR A , wherein Y is O or NH, and R A is H, or (C 1 -C 8 )alkyl optionally substituted with a OH, O(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
A has the structure of formula (IV);
wherein formula (IV) is

 wherein;
A 1 is N or CR 10 , wherein R 10 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;
A 2 is N or CR 11 , wherein R 11 H, halogen, (C 1 -C 8 )haloalkyl, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;
A 3 is N or CR 12 , wherein R 12 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl; or A 2 is CR 11 and A 3 is CR 12 , and wherein R 11 and R 12 form the ring structure:

A 4 is N or CR 13 , wherein R 13 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;

R 2 is phenyl or a 6-membered heteroaryl having a N atom, and where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , CN, or SMe;
R 3 is H, phenyl, (C 1 -C 8 )alkyl, 5-6 membered heteroaryl comprising a heteroatom selected from N, O and S, (C 2 -C 8 )alkenyl, (C 1 -C 8 )haloalkyl, —C(O)NH 2 , —C(O)NMe 2 or —CO 2 H, where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with a OH, O(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; and wherein when R 3 is not H; R 3 is syn to R 2 or R 3 is trans to R 2 ;
R 4 is H, (C 1 -C 8 )alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from the group consisting of N, O and S, (C 1 -C 8 )haloalkyl, C 3 -C 8 cycloalkyl, NH(aryl), NH(CN), CO 2 (alkyl), or NH(C 1 -C 8 alkyl), where the phenyl can be optionally substituted with a halogen, OH, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with halogen, O(C 1 -C 8 )alkyl, C(O)-lower alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
Z is O, NH, Se, N(alkyl), N(CN), CN or CR C R F ; wherein R C and R F independently are H, (C 1 -C 8 )alkyl or CN;
R 5 is H, (C 1 -C 8 )alkyl or phenyl, where the (C 1 -C 8 )alkyl can be optionally substituted with 1 or 2 halogen, OH or O(C 1 -C 8 )alkyl;
D is a 5-6 membered heteroaryl comprising 1 or 2 heteroatoms selected from N, O and S;
or D is a 5-6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S; and
provided that the compound is not (−)-6, (+)-6, (−)-6-OH, racemates of (−)-6 or (+)-6, structural isomers of (−)-6-OH or enantiomers of (−)-6-OH,

2. The compound according to claim 1 , wherein at least one of R 10 , R 11 , R 12 or R 13 is a (C 1 -C 8 )alkoxy.

3. The compound according to claim 1 , wherein:
the compound has the structure of formula (I);
W is OH;
X is O;
Z is O;
R 2 is a phenyl optionally substituted with a halogen, O(C 1 -C 8 )alkyl, NH 2 , N[(C 1 -C 4 )alkyl] 2 , or CN;
R 3 is a phenyl;
R 2 is syn relative to R 3 ;
R 5 is H or (C 1 -C 8 )alkyl; and
R 4 is (C 1 -C 8 )alkyl or phenyl, where the phenyl can be optionally substituted with a halogen, OH, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with halogen, O(C 1 -C 8 )alkyl, C(O)-lower alkyl or (C 2 -C 8 )alkenyl.

4. The compound according to claim 1 , wherein the compound is of Formula (I).

5. The compound according to claim 1 , wherein;
the compound has the structure of formula (I);
W is OH;
X is O;
Z is O;
R 2 is

R 3 is a phenyl;
R 2 is syn relative to R 3 ;
R 5 is H or (C 1 -C 8 )alkyl; and
R 4 is (C 1 -C 8 )alkyl,

6. The compound according to claim 1 , wherein R 3 is syn to R 2 .

7. A compound selected from the following compounds;

8. A composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or excipient.

9. The compound of claim 1 , wherein ring A is

10. The compound of claim 1 , wherein
W is OH;
X is O;
Z is O;
R 2 is a phenyl optionally substituted with a halogen, O(C 1 -C 8 )alkyl, NH 2 , N[(C 1 -C 4 )alkyl] 2 , or CN; and
R 3 is phenyl or 5-6 membered heteroaryl comprising a heteroatom selected from N, O and S, where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 .

11. The compound of claim 1 , where the compound has the structure of Formula (I);
A has the structure of formula (IV) and,
A 1 is N or CR 10 , wherein R 10 is H, OMe or F;
A 2 is N, or CR 11 , wherein CR 11 is H, F, OMe or CF 3 , and A 3 is N or CR 12 , wherein CR 12 is H, F, Cl, Br or OMe, or
A 2 is CR 11 and A 3 is CR 12 , wherein R 11 and R 12 form the ring structure

Assignees

• Univ Boston
• Stanford Res Inst Int

Inventors

• Porco Jr John A
• Zhang Wenhan
• Wang Tony Tianyi
• Liu Shufeng

Classifications

• C07D491/153

  the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom · CPC title

• C07D491/147

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title

• A61K45/06

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

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D491/048 Primary

  the oxygen-containing ring being five-membered · CPC title