HEPATITIS B ANTIVIRAL AGENTS

• US 20190119288A1
• Filed: 12/14/2018
• Published: 04/25/2019
• Est. Priority Date: 06/10/2016
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Cao, Hui, Peng, Xiaowen, Li, Wei, Kass, Jorden, Gao, Xuri, Jin, Meizhong, Or, Yat Sun
• Granted Patent: US 10,640,511 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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.

Claims

1. A compound represented by Formula (I):

2. The compound of claim 1, wherein A and X are each independently selected from the following by removal of one hydrogen atom:

3. The compound of claim 1, wherein R is selected from optionally substituted methyl, optionally substituted ethyl, —

(CH₂)_nOR₁₁, —

(CH₂)_nOC(O)R₁₁, —

(CH₂)_nC(O)OR₁₁, —

(CH₂)_nC(O)NR₁₁R₁₂, —

(CH₂)_nOC(O)OR₁₁, —

(CH₂)_nO—

C(O)NR₁₁R₁₂, —

(CH₂)_nNR₁₁R₁₂, —

(CH₂)_nNR₁₁C(O)R₁₁, —

(CH₂)_nNR₁₁C(O)OR₁₁, —

(CH₂)_nNR₁₁C(O)NR₁₁R₁₂, —

(CH₂)_nS(O)R₁₂, —

(CH₂)_nOS(O)₂R₁₂, —

(CH₂)_nS(O)₂OR₁₁, —

(CH₂)_nNR₁₁ S(O)₂R₁₂, —

(CH₂)_nS(O)₂NR₁₁R₁₂;

—

(CH₂)_nNR₁₁S(O)₂NR₁₁R₁₂;

—

(CH₂)_nOP(O)(OR₁₁)₂, —

(CH₂)_nP(O)(OR₁₁)₂, —

(CH₂)_nNR₁₁P(O)(OR₁₂)₂, and —

(CH₂)_nP(O)(NR₁₁R₁₂)₂, wherein R₁₁ and R₁₂ at each occurrence are each 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.

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

5. The compound of claim 1, wherein Z is —

(CH₂)_n′

-M, n′

is 1, 2, or 3, M is hydrogen, —

OR₁₁, protected hydroxy, —

CR₁₁R₁₂R₃, —

NR₁₁R₁₂, protected amino or M is selected from the groups set forth below;

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

7. The compound of claim 1, represented by Formula (IIa-3) or (IIb-3), or a pharmaceutically acceptable salt thereof,

8. The compound of claim 1, represented by Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof,

9. The compound of claim 1, represented by Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring

10. The compound of claim 1, represented by Formula (IV) or a pharmaceutically acceptable salt thereof,

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

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

13. 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 Formula (I).

14. The method of claim 13, 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, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof.

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

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

17. The method of claim 14, 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.

18. The method of claim 14, 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.

19. The method of claim 14, 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.

20. The method of claim 14, 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.