DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS

• US 20160185777A1
• Filed: 12/30/2015
• Published: 06/30/2016
• Est. Priority Date: 12/30/2014
• Status: Active Grant

• Current Assignee: Novira Therapeutics, Inc. (Johnson & Johnson)
• Original Assignee: Novira Therapeutics, Inc. (Johnson & Johnson)
• Inventors: Hartman, George D., Kuduk, Scott
• Granted Patent: US 9,527,845 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 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 39/292 Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C12N 2730/10111 Orthohepadnavirus, e.g. hepatitis B virus
• CPC Class Codes: C12N 2730/10134 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2730/10171 Demonstrated in vivo effect
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

Claims

1. A compound of Formula III:

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

C(O)—

.

3. The compound of claim 1, wherein R¹ is —

C(O)NR^dR^e, —

C(O)NR^dOR^e, or —

C(O)NR^dNR^d.

4. The compound of claim 1, wherein R¹ is —

C(O)NR^dR^e, wherein R^d is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH and R^e is selected from H, C₁-C₆-alkyl, C₁-C₆-alkyl-OH, C₃-C₈-cycloalkyl, C₂-C₈-heterocyclyl, C₆-C₁₂-aryl, C₁-C₉-heteroaryl, and —

O—

C₁-C₆-alkyl and wherein R^d and R^e optionally form a heterocyclic ring;

or

R¹ is —

C(O)NR^dOR^e, wherein R^e is selected from, C₁-C₆-alkyl-OC₁-C₆-alkyl, C₀-C₆-alkyl-C₃-C₈-cycloalkyl, C₂-C₈-heterocyclyl, C₆-C₁₂-aryl, and C₁-C₉-heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —

OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, and —

O—

C₁-C₆-alkyl.

5. The compound of claim 1, wherein each R² is independently selected from H or C₁-C₄-alkyl;

and R³ is H.

6. The compound of claim 1, wherein R⁴ is (CR⁸R⁹)_p—

C₁-C₅-heteroaryl or (CR⁸R⁹)_p—

C₆-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —

OH, halo, CN, and C₁-C₆-alkyl;

R⁸ is H or C₁-C₆-alkyl;

R⁹ is H or C₁-C₆-alkyl; and

p is 0 or 1.

7. The compound of claim 1, wherein R⁴ is C₁-C₅-heteroaryl or C₆-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from —

OH, halo, CN, and C₁-C₆-alkyl.

8. The compound of claim 1, wherein R⁴ is:

9. The compound of claim 1, wherein R⁷ is H.

10. The compound of claim 1 selected from:

37. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

38. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1.

39. A method of inhibiting and/or reducing the formation or presence of HBV DNA-containing particles and/or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1.

40. The method of claim 38, further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and a combination thereof.

41. The method of claim 40, wherein the therapeutic agent is a reverse transcriptase inhibitor, and is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, and Etravirine.

42. The method of claim 40, wherein the therapeutic agent is a TLR agonist, and wherein the TLR agonist is a TLR-7 agonist selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

43. The method of claim 40, wherein the therapeutic agent is an interferon selected from the group consisting of interferon alpha (IFN-α

), interferon beta (IFN-β

), interferon lambda (IFN-λ

), and interferon gamma (IFN-γ

).

44. The method of claim 43, wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1.

45. The method of claim 44, wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated.

46. The method of claim 38, further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.

47. The method of claim 46, wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHANVAC B.

11-36. -36. (canceled)