Claims for Patent: 9,518,057

Summary for Patent: 9,518,057

Title:	Derivatives and methods of treating hepatitis B infections
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.
Inventor(s):	Hartman; George D. (Lansdale, PA), Kuduk; Scott (Harleysville, PA)
Assignee:	NOVIRA THERAPEUTICS, INC. (Doylestown, PA)
Application Number:	14/984,325
Patent Claims:	1. A compound having the structure of Formula III: ##STR00369## or a pharmaceutically acceptable salt thereof, wherein Y is --C(O)--; R.sup.1 is C.sub.3-C.sub.8-cycloalkyl or C.sub.2-C.sub.8-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.2 is, at each occurrence, independently selected from H, --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.3 is selected from H, --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.4 is selected from (CR.sup.8R.sup.9).sub.p--C.sub.1-C.sub.9-heteroaryl and (CR.sup.8R.sup.9).sub.p--C.sub.6-C.sub.12-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from --OH, halo, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.7 is selected from H, C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.8 is, at each occurrence, independently selected from H, --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.9 is, at each occurrence, independently selected from H and C.sub.1-C.sub.6-alkyl; and p is 0, 1, 2, 3, or 4. 2. The compound of claim 1, wherein R.sup.1 is C.sub.3-C.sub.6-cycloalkyl or C.sub.2-C.sub.5-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH. 3. The compound of claim 1, wherein each R.sup.2 is independently H or C.sub.1-C.sub.4-alkyl; and R.sup.3 is H. 4. The compound of claim 1, wherein R.sup.4 is C.sub.1-C.sub.5-heteroaryl or C.sub.6-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from --OH, halo, CN, and C.sub.1-C.sub.6-alkyl. 5. The compound of claim 1, wherein R.sup.4 is ##STR00370## ##STR00371## 6. The compound of claim 1, wherein R.sup.7 is H. 7. The compound of claim 1, selected from ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## and pharmaceutically acceptable salts thereof. 8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 9. 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. 10. A method of inhibiting or reducing the formation or presence of HBV DNA-containing particles 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. 11. The method of claim 9 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, capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and a combination thereof. 12. The method of claim 11, 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. 13. The method of claim 11, 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-mo- rpholinyl)propyl]amino}methyl)phenyl]acetate). 14. The method of claim 11, wherein the therapeutic agent is an interferon selected from the group consisting of interferon alpha (IFN-.alpha.), interferon beta (IFN-.beta.), interferon lambda (IFN-.lamda.) and interferon gamma (IFN-.gamma.). 15. The method of claim 14, wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. 16. The method of claim 15, wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated. 17. The method of claim 9, further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof. 18. The method of claim 17, wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHANVAC B. 19. The compound of claim 1, wherein R.sup.1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, and bicycle[3.1.0]hexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from --OH, halo, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, --O--C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH. 20. The compound of claim 1, wherein R.sup.1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, and bicyclol[3.1.0]hexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from --OH and halo.

Details for Patent 9,518,057

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	RECOMBIVAX, RECOMBIVAX HB	hepatitis b vaccine (recombinant)	Injection	101066	July 23, 1986		2034-12-30
Glaxosmithkline Biologicals	ENGERIX-B	hepatitis b vaccine (recombinant)	Injection	103239	August 28, 1989		2034-12-30
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	June 04, 2004		2034-12-30