HEPATITIS B ANTIVIRAL AGENTS

• US 20160289212A1
• Filed: 04/01/2016
• Published: 10/06/2016
• Est. Priority Date: 04/01/2015
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Li, Wei, Kass, Jorden, Jin, Meizhong, Qiu, Yao-Ling, Cao, Hui, Gao, Xuri, Peng, Xiaowen, Or, Yat Sun
• Granted Patent: US 10,442,788 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 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• 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:

X-A-Y-Z-L-R₁  (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-L-R₁ 

 

(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 an optionally substituted azole group;

alternatively, A and X are taken together to form an optionally substituted fused bicyclic azole group;

where said fused bicyclic azole group is connected to Y group via the 5-membered azole moiety;

alternatively, A and Y are taken together to form an optionally substituted fused bicyclic azole group;

where said fused bicyclic azole group is connected to X group via the 5-membered azole moiety;

Z is —

S(O)₂—

, —

C(O)—

, or —

C(O)C(O)—

;

L is —

NR₂—

or —

CR₁R₂—

; and

R₁ and R₂ at each occurrence are independently selected from the group of 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 —

C₃-C₈ cycloalkenyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;

or alternatively, R₁ and R₂ are taken together with the atom to which they are attached to form an optionally substituted C₃-C₁₂ cycloalkyl, optionally substituted —

C₃-C₁₂ cycloalkenyl, or an optionally substituted 3- to 12-membered heterocyclic.

2. The compound of claim 1, wherein A is selected from the following:

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

4. The compound of claim 1, represented by Formula (IIa-1), (IIa-2), (IIa-3), (IIb-1), (IIb-2) or (IIb-3), or a pharmaceutically acceptable salt thereof:

5. The compound of claim 1, represented by (IIa-a), (IIa-b), (IIa-c), (IIb-a), (IIb-b) or (IIb-c), or a pharmaceutically acceptable salt thereof:

6. The compound of claim 1, represented by Formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh), or a pharmaceutically acceptable salt thereof:

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the hydroxy prodrug group is phosphate, sulfamate, or an acyl group derived from an amino acid.

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 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 claim 1 or a pharmaceutically acceptable salt thereof.

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, 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 the compound and the at least one additional therapeutic agent are co-administered.

14. 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.

15. 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, antiviral compounds of distinct or unknown mechanism, and combination thereof.

16. 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, antiviral compounds of distinct or unknown mechanism, and combination thereof.

17. 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, antiviral compounds of distinct or unknown mechanism, and combination thereof.

18. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the hydroxy prodrug group is phosphate, sulfamate, or an acyl group derived from an amino acid.