HEPATITIS B ANTIVIRAL AGENTS

• US 20170022150A1
• Filed: 07/21/2016
• Published: 01/26/2017
• Est. Priority Date: 07/22/2015
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Li, Wei, Cao, Hui, Jin, Meizhong, Kass, Jorden, Gao, Xuri, Peng, Xiaowen, Or, Yat Sun
• Granted Patent: US 10,301,255 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 255/58 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 271/12 to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin

Abstract

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

X-A₁-Y-A₂-Z-L-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-A₁-Y-A₂-Z-L-R 

 

(I),

or a pharmaceutically acceptable salt thereof, wherein;

X is an optionally substituted aryl or optionally substituted heteroaryl;

A₁ is absent, or selected from the group consisting of —

NH—

, —

NHC(O)—

, —

NHC(O)N(R₃)—

, and optionally substituted azolyl;

Y is an optionally substituted aryl or optionally substituted heteroaryl;

A₂ is absent or —

N(R₄)—

;

Z is —

CR^aR^b—

;

wherein R^a and R^b are each independently selected from the group consisting of hydrogen, OH, OMe, halogen, and methyl optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro, chloro, OH, and OMe;

wherein at least one of R^a and R^b is not hydrogen;

alternatively, R^a, R^b, and the carbon atom to which they are attached form an oxetanyl, 5- to 6-membered cyclic ketal, or —

C(═

CF₂)—

;

L is —

NR₁—

, O or —

CR₁R₂—

; and

R, R₁, R₂, R₃ and R₄ at each occurrence 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, R₁ and R₂ or R₁ and R 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 A₁ is —

NHC(O)—

, or —

NHC(O)N(R₃)—

, or an optionally substituted when possible azolyl group derived from one of the following, or a tautomer thereof, by removal of two hydrogen atoms;

3. A compound of claim 1, wherein Z is selected from the group consisting of —

CF₂—

, —

CClF—

, —

CCl₂—

, —

CH(CF₃)—

, —

C(═

CF₂)—

, —

CMe₂-,

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

C₁-C₈ alkyl, —

C₂-C₈ alkenyl, —

C₂-C₈ alkynyl, —

C₃-C₈ cycloalkyl, or 3- to 8-membered heterocyclic, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, —

CN, amino, protected amino, optionally substituted —

C₁-C₆ alkyl, optionally substituted —

C₃-C₈ cycloalkyl, optionally substituted —

C₁-C₃ alkoxy, —

C(O)OR₁₅, —

OC(O)NH—

R₁₅, —

C(O)NH-R₁₅, and —

C(O)—

R₁₅, wherein R₁₅ is 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 or optionally substituted heteroaryl.

5. A compound of claim 1, represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf):

6. A compound of claim 1, represented by Formula (IIa-1), (IIb-1), (IIc-1), (IId-1),

(IIe-1), or (IIf-1):

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

8. 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.

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

10. The method of claim 9, 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.

11. The method of claim 10, wherein the compound and the at least one additional therapeutic agent are co-formulated.

12. The method of claim 10, wherein the compound and the at least one additional therapeutic agent are co-administered.

13. The method of claim 10, 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 9, 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.

15. The method of claim 9, 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.

16. The method of claim 9, 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.