Hepatitis B Antiviral Agents

• US 20160332996A1
• Filed: 05/12/2016
• Published: 11/17/2016
• Est. Priority Date: 05/13/2015
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Li, Wei, Cao, Hui, Jin, Meizhong, Gao, Xuri, Peng, Xiaowen, Kass, Jorden, Or, Yat Sun
• Granted Patent: US 10,738,035 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• 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 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• 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 405/12 linked by a chain containing hetero atoms as chain links

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 is an optionally substituted aryl or optionally substituted heteroaryl;

A is absent, —

NHCO—

or optionally substituted azolyl;

Y is an optionally substituted arylamino or optionally substituted heteroarylamino;

wherein the said amino group is directly connected to A, X when A is absent or Z;

Z is —

S(O)₂—

, —

C(O)—

, or —

C(O)C(O)—

;

L is —

NR₂—

, O or —

CR₁R₂—

; and

R₁ and R₂ at each occurrence are each 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 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and

alternatively, R₁ and R₂ are taken together with the atom to which they are attached to form an optionally substituted C₃-C₈ cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic.

2. A compound of claim 1, wherein X and A are taken together to form an optionally substituted fused bicyclic azolyl group;

wherein the said azolyl group is connected to Y.

3. A compound of claim 1, wherein Y and A are taken together to form an optionally substituted fused bicyclic azolylamino group;

wherein the said amino group is connected to X.

4. A compound of claim 1, wherein A is —

NHC(O)—

or a group derived from an azole group selected from the following by removal of two hydrogen atoms;

5. A compound of claim 1, wherein Y is selected from the following:

6. A compound of claim 1, wherein Y is selected from the following:

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

8. A compound of claim 1, represented by Formulae (IIa-1)-(IIa-8), (IIb-1)-(IIb-8), or (IIc-1)-(IIc-8), or a pharmaceutically acceptable salt thereof:

9. A compound of claim 1, represented by Formula (IIa-5-A), (IIb-5-B), or (IIc-5C), or a pharmaceutically acceptable salt thereof:

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

11. A compound of claim 1, represented by Formulae (IIIa-1)-(IIIa-8), (IIIb-1)-(IIIb-8), or (IIIc-1)-(IIIc-8), or a pharmaceutically acceptable salt thereof:

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

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

14. A compound of claim 1, represented by Formula (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt thereof:

15. A compound of claim 1, represented by Formula (VIa-1), (VIb-1), (VIc-1), (VIa′

-1), (VIb′

-1), or (VIc′

-1), or a pharmaceutically acceptable salt thereof;

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

17. 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.

18. 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.

19. The method of claim 18, 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, inhibitor or modulator of cccDNA transcription, and agents of distinct or unknown mechanism, and a combination thereof.

20. The method of claim 19, wherein said compound and the at least one additional therapeutic agent are co-formulated.

21. The method of claim 19, wherein said compound and the at least one additional therapeutic agent are co-administered.

22. The method of claim 19, wherein the at least one additional therapeutic agent is administered to the subject at a lower dose or frequency as compared to the dose or frequency of the least one additional therapeutic agent that is required in the absence of said compound to prophylactically treat an HBV infection.

23. The method of claim 18, wherein the subject is 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, inhibitor or modulator of cccDNA transcription, antiviral compounds of distinct or unknown mechanism, and combination thereof.

24. The method of claim 18, wherein the administering of the compound reduces viral load in the subject 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, inhibitor or modulator of cccDNA transcription, antiviral compounds of distinct or unknown mechanism, and combinations thereof.

25. The method of claim 18, 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, inhibitor or modulator of cccDNA transcription, antiviral compounds of distinct or unknown mechanism, and combination thereof.