Hepatitis B antiviral agents

Patent metadata

Field	Value
Publication number	US-10179131-B2
Application number	US-201615209150-A
Country	US
Kind code	B2
Filing date	Jul 13, 2016
Priority date	Jul 13, 2015
Publication date	Jan 15, 2019
Grant date	Jan 15, 2019

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs 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 selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , and —NR 1 R 2 ;
B is selected from the group consisting of hydrogen, CN, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 3 -C 6 cycloalkyl;
X is selected from the group consisting of optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
Y is 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, optionally substituted heteroaryl, —C(O)R 1 , —C(O)NR 1 R 2 , —C(O)N(R 1 )S(O) 2 R 3 , —S(O) 2 R 3 , —S(O) 2 NR 1 R 2 , —NR 1 R 2 , —N(R 1 )C(O)R 3 , —N(R 1 )C(O)NR 1 R 2 , —N(R 1 )C(O)OR 3 and —P(O)(OR 3 ) 2 ; provided that the meaning of optionally substituted —C 1 -C 8 -alkyl does not encompass —CN or —C(O)R 1 ;
R 1 and R 2 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 1 and R 2 are taken together with the atom to which they are attached to form an optionally substituted 3- to 10-membered heterocyclic; and
R 3 at each occurrence is selected from the group consisting of 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; and
Z is

 or CH 2 -M, wherein M is selected from the group consisting of

wherein M is optionally substituted; T is O, NR 1 or CR 1a R 2a ; n′ is 1, 2 or 3; R′ is 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, —CN, —OR 1 , and —NR 1 R 2 ; and R 1a and R 2a 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 1a and R 2a are taken together with the carbon atom to which they are attached to form an optionally substituted C 3 -C 10 -cycloalkyl or an optionally substituted 3 to 10-membered heterocyclic.

2. The compound of claim 1 , wherein at least one of A and X is independently selected from the following groups by removal of one hydrogen atom:

wherein each of the above shown groups is optionally substituted and is connected to the dihydropypyrimidine ring through a carbon atom.

3. The compound of claim 1 , wherein Y is selected from the following groups:

wherein each of the above shown groups is optionally substituted.

4. The compound of claim 1 , wherein X is selected from the groups set forth below:

wherein each of the above shown groups is optionally substituted.

5. The compound of claim 1 , wherein A is optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , —OR 1 , or —NR 1 R 2 , wherein R 1 and R 2 are as defined in claim 1 .

6. The compound of claim 1 , represented by Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf), or a pharmaceutically acceptable salt thereof:

wherein A 1 at each occurrence is independently an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S; A 2 at each occurrence is independently an optionally substituted phenyl or 6-membered heteroaryl group; A 3 an optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , —OR 1 , or —NR 1 R 2 ; and X, Z, R 1 , and R 2 are as defined in claim 1 .

7. The compound of claim 1 , represented by Formula (IVa), (IVb), or (IVc), or a pharmaceutically acceptable salt thereof;

wherein A 1 is an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S; A 2 is an optionally substituted phenyl or 6-membered heteroaryl group; A 3 is an optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, —CN, —C(O)R 1 , —CO 2 R 1 , —C(O)NR 1 R 2 , —OR 1 , or —NR 1 R 2 ; Y′ is selected from the group consisting of —SO 2 R 3 , —SO 2 NR 1 R 2 , —C(O)R 3 , —CN, —N(R 1 )C(O)R 3 , —N(R 1 )C(O)NR 1 R 2 , —N(R 1 )C(O)OR 3 , and —P(O)(OR 1 ) 2 ; and X, Z, R 1 , R 2 and R 3 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

Assignees

• Enanta Pharm Inc

Inventors

• Qiu Yao-Ling
• Cao Hui
• Li Wei
• Peng Xiaowen
• Jin Meizhong
• Kass Jorden
• Gao Xuri
• Or Yat Sun

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D451/06

  Oxygen atoms · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title