HEPATITIS B ANTIVIRAL AGENTS

• US 20170014408A1
• Filed: 07/13/2016
• Published: 01/19/2017
• 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
• Granted Patent: US 10,179,131 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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. A 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. A compound of claim 1, wherein Y is selected from following group:

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

5. A 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, and —

NR₁R₂, wherein R₁ and R₂ are as defined in claim 1.

6. A compound of claim 1, wherein Z is hydrogen or —

CH₂M;

wherein M is hydrogen, —

CN, —

NO₂, —

OR₁, protected hydroxy, —

CR′

R_1aR_2a, —

NR₁R₂, protected amino, —

CO₂R₁, or —

C(O)NR₁R₂;

R′

is selected from the group consisting of hydrogen, optionally substituted —

C₁-C₈ alkyl, optionally substituted —

C₂-C₈ alkenyl, optionally substituted —

C₂-C₈ alkynyl, optionally substituted —

C₃-C₈ cycloalkyl, —

CN, —

OR₁, and —

NR₁R₂;

R_1a and R_2a are independently selected from the group consisting of hydrogen, optionally substituted —

C₁-C₈ alkyl, optionally substituted —

C₂-C₈ alkenyl, optionally substituted —

C₂-C₈ alkynyl, optionally substituted —

C₃-C₈ 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 C₃-C₁₀-cycloalkyl or an optionally substituted 3 to 10-membered heterocyclic; and

R₁ and R₂ are as defined in claim 1.

7. A compound of claim 1, wherein Z is CH₂M, wherein M is selected from the groups set forth below:

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

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

10. The compound of claim 1, selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition, comprising a compound or a combination of compounds according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

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

13. The method of claim 12, further comprising administering to the individual 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, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof.

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

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

16. The method of claim 13, wherein administering the compound allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.

17. The method of claim 12, wherein before administering the therapeutically effective amount of the compound of Formula (I), the individual is known to be refractory to a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.

18. The method of claim 12, wherein the administering of the compound reduces viral load in the individual to a greater extent compared to the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.

19. The method of claim 12, wherein the administering of the compound causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.