HEPATITIS B ANTIVIRAL AGENTS

• US 20170217974A1
• Filed: 02/01/2017
• Published: 08/03/2017
• Est. Priority Date: 02/02/2016
• Status: Active Application

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Jin, Meizhong, Kass, Jorden, Li, Wei, Or, Yat Sun, Cao, Hui, Gao, Xuri, Peng, Xiaowen, Qiu, Yao-Ling
• Granted Patent: US 10,280,175 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof:

X-A-Y-Z-R  (I)

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):

X-A-Y-Z-R 

 

(I),

or a pharmaceutically acceptable salt thereof, wherein;

X and Y are each independently selected from optionally substituted aryl or optionally substituted heteroaryl;

A is —

NHC(O)—

,

2. The compound of claim 1, wherein A is —

NHC(O)—

, and is connected to groups X and Y through either the carbon or nitrogen atom.

3. The compound of claim 1, wherein R is

4. The compound of claim 3, wherein one R₁₀ group is selected from hydrogen, hydroxy, protected hydroxy, amino, protected amino, optionally substituted —

C₁-C₆ alkyl, optionally substituted heteroaryl, or —

O-(hydroxy prodrug group); and

the hydroxy prodrug group is phosphate, sulfate, or an acyl group derived from an amino acid.

5. The compound of claim 1, represented by Formula (Va-1), (Va-2), (Vb-1), (Vb-2), (Vc-1), (Vc-2), (Vd-1), or (Vd-2) or a pharmaceutically acceptable salt thereof:

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

7. The compound of claim 1, represented by Formula (VIb) or (VII), or a pharmaceutically acceptable salt thereof:

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

9. 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.

10. A method of treating or preventing an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or a combination of compounds of Formula (I).

11. The method of claim 10, 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, RNA interference (RNAi) or small interfering RNA (siRNA), and agents of distinct or unknown mechanism, and a combination thereof.

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 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.

14. The method of claim 11, 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, RNA interence (RNAi) or small interfering RNA (siRNA), antiviral compounds of distinct or unknown mechanism, and combination thereof.

15. The method of claim 11, 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, RNA interence (RNAi) or small interfering RNA (siRNA), antiviral compounds of distinct or unknown mechanism, and combination thereof.

16. The method of claim 11, 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, RNA interence (RNAi) or small interfering RNA (siRNA), antiviral compounds of distinct or unknown mechanism, and combination thereof.