Hepatitis B antiviral agents

• US 10,179,131 B2
• Filed: 07/13/2016
• Issued: 01/15/2019
• Est. Priority Date: 07/13/2015
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Cao, Hui, Li, Wei, Peng, Xiaowen, Jin, Meizhong, Kass, Jorden, Gao, Xuri, Or, Yat Sun
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US15/209,150
• Publication Number:
  US 20170014408A1
• Time in Patent Office: 916 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5386 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/683 Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 239/20 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/08 Bridged systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

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.

Claims

1. A compound represented by Formula (I):

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:

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

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

5. The compound of claim 1, wherein A is optionally substituted —

C₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, —

C(O)R₁, —

CO₂R₁, —

C(O)NR₁R₂, —

OR₁, or —

NR₁R₂, wherein R₁ and R₂ 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:

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

9. A pharmaceutical composition, comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier or excipient.

10. A method of treating or preventing an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1.

11. The method of claim 10, further comprising administering to the subject at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, TLR-agonist, inducer of cellular viral RNA sensor, or a therapeutic vaccine.

12. The method of claim 11, wherein the compound and the at least one additional therapeutic agent are co-formulated.

13. The method of claim 11, wherein the compound and the at least one additional therapeutic agent are co-administered.

14. The compound of claim 1, wherein M is substituted with one or more substituents selected from halo, ═

O, ═

NR₁, —

OR₁, —

NR₁R₂, —

CN, —

CO₂R₁, —

C(O)NR₁R₂, —

S(O)₂R₃, —

C(O)NR₁S(O)₂R₃, and optionally substituted methyl.

15. The compound of claim 1, wherein Z is selected from the groups below:

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