Hepatitis B antiviral agents

Patent metadata

Field	Value
Publication number	US-11760755-B2
Application number	US-202016892373-A
Country	US
Kind code	B2
Filing date	Jun 4, 2020
Priority date	Jun 4, 2019
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, thereof:which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

First claim

What is claimed:

1. A compound represented by Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:
A is optionally substituted aryl or optionally substituted heteroaryl;
B is selected from the group consisting of hydrogen, halo, CN, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 3 -C 6 cycloalkyl;
X is optionally substituted aryl or optionally substituted heteroaryl;
Alternatively, B and X are taken together with the carbon atom to which they are attached to form an optionally substituted —C 4 -C 12 cycloalkenyl or optionally substituted 4- to 12-membered heterocyclic;
Y is —CO 2 R 2 , optionally substituted aryl or optionally substituted heteroaryl;
R 1 at each occurrence is independently halo, CN, —N 3 , optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
R 2 is hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic;
u is 0, 1, 2, 3, 4 or 5;
W is —CR 11 R 12 —, —O—, or —NR 11 —;
L is —SO 2 — or —C(O)—;
Q is absent, —CR 11 R 12 —, —O—, or —NR 11 —;
R 11 and R 12 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
alternatively R 11 and R 12 are taken together with the carbon or nitrogen atom to which they are attached to form an optionally substituted —C 3 -C 8 cycloalkyl or optionally substituted 3- to 8-membered heterocyclic; and
R is an optionally substituted bridged ring.

2. The compound of claim 1 , wherein R is

wherein n at each occurrence is independently selected from 0, 1, 2, or 3; T at each occurrence is independently selected from C(R 10 ) and N; E at each occurrence is independently selected from —C(R 10 ) 2 —, —N(R 10 )—, O, S, S(O), and S(O) 2 ; wherein R 10 at each occurrence is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and -L 1 -R 11 ; wherein L 1 is —O—, —S—, —NR 12 —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R 12 )—, —N(R 12 )C(O)—, —OC(O)N(R 12 )—, —N(R 12 )C(O)O—, —N(R 11 )C(O)N(R 12 )—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 12 )—, or —N(R 12 )S(O) 2 —; and R 11 and R 12 are as defined in claim 1 .

3. The compound of claim 1 , wherein R is selected from the groups below,

each of which is optionally further substituted, wherein R 50 at each occurrence is independently selected from the group consisting of hydrogen, halo, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and -L 1 -R 11 ; L 1 is —O—, —S—, —NR 12 —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R 12 )—, —N(R 12 )C(O)—, —OC(O)N(R 12 )—, —N(R 12 )C(O)O—, —N(R 11 )C(O)N(R 12 )—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 12 )—, or —N(R 12 )S(O) 2 —; and R 11 and R 12 are as defined in claim 1 .

4. The compound of claim 1 , represented by Formula (IIa-3), (IIb-3), (IIc-3), (IId-3), (IIe-3), or (IIf-3), or a pharmaceutically acceptable salt thereof,

wherein A 1 is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, N, and S; A 2 is an optionally substituted phenyl, thiophenyl or 6-membered heteroaryl; X 1 is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; and Y, L, Q, R 11 , R 12 , and R are as defined in claim 1 .

5. The compound of claim 1 , represented by Formula (IIa-5), (IIb-5) or (IIc-5) or a pharmaceutically acceptable salt thereof,

wherein X 1 is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; R 20 is R 11 ; and R, R 2 , L, Q, and R 11 are as defined in claim 1 .

6. The compound of claim 1 , represented by Formula (IIa-7), (IIb-7), (IIc-7), (IId-7), (IIe-7), or (IIf-7), or a pharmaceutically acceptable salt thereof,

wherein X 1 is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; R 20 is R 11 ; and R, R 2 and R 11 are as defined in claim 1 .

7. The compound of claim 1 , represented by Formula (IIa-8), (IIb-8), (IIc-8), (IId-8), (IIe-8), or (IIf-8), or a pharmaceutically acceptable salt thereof,

wherein X 1 is optionally substituted methyl, halo, CN, OR 11 , or NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; R 20 is R 11 ; and R, R 2 and R 11 are as defined in claim 1 .

8. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

Compound
Structure

1

2

3

4

Assignees

• Enanta Pharm Inc

Inventors

• Qiu Yao-Ling
• Peng Xiaowen
• Gao Xuri
• Li Wei
• Cao Hui
• Suh Byung-Chul
• Kass Jorden
• Zhang Jiajun
• Or Yat Sun

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D453/00 Primary

  Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids · CPC title

• A61K38/21

  Interferons {[IFN]} · CPC title

• A61P31/20

  for DNA viruses · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title