Claims for Patent: 9,527,845

Summary for Patent: 9,527,845

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:	14/984,293
Patent Claims:	1. A compound of Formula III: ##STR00097## or a pharmaceutically acceptable salt thereof, wherein Y is --C(O)--; R.sup.1 is --C(O)NR.sup.dR.sup.e, --C(O)NR.sup.dOR.sup.e, or --C(O)NR.sup.dNR.sup.d; 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-C6-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; R.sup.d is selected from H, C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH; R.sup.e is selected from H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-OH, C.sub.1-C.sub.6-alkyl-OC.sub.1-C.sub.6-alkyl, C.sub.0-C.sub.6-alkyl-C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.8-heterocyclyl, C.sub.6-C.sub.12-aryl, and C.sub.1-C.sub.9-heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl 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, and --O--C.sub.1-C.sub.6-alkyl; alternatively, R.sup.d and R.sup.e are optionally joined to form a heterocyclic ring, which is 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, and --O--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(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from the group consisting of H, C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-OH, R.sup.e is selected from the group consisting of H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-OH, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.8-heterocyclyl, C.sub.6-C.sub.12-aryl, C.sub.1-C.sub.9-heteroaryl, and --O--C.sub.1-C.sub.6-alkyl, or R.sup.d and R.sup.e optionally form a heterocyclic ring; or R.sup.1 is --C(O)NR.sup.dOR.sup.e, wherein R.sup.e is selected from the group consisting of C.sub.1-C.sub.6-alkyl-OC.sub.1-C.sub.6-alkyl, C.sub.0-C.sub.6-alkyl-C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.8-heterocyclyl, C.sub.6-C.sub.12-aryl, and C.sub.1-C.sub.9-heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, or 3 groups, each independently selected from the group consisting of --OH, halo, CN, C.sub.1-C6-alkyl, C.sub.1-C.sub.6-haloalkyl, and --O--C.sub.1-C.sub.6-alkyl. 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 (CR.sup.8R.sup.9).sub.p-C.sub.1-C.sub.5-heteroaryl or (CR.sup.8R.sup.9).sub.p-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; R.sup.8 is H or C.sub.1-C.sub.6-alkyl; R.sup.9 is H or C.sub.1-C.sub.6-alkyl; and p is 0 or 1. 5. 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. 6. The compound of claim 1, wherein R.sup.4 is: ##STR00098## ##STR00099## 7. The compound of claim 1, wherein R.sup.7 is H. 8. The compound of claim 1 selected from: ##STR00100## ##STR00101## ##STR00102## ##STR00103## and pharmaceutically acceptable salts thereof. 9. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 10. 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. 11. 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. 12. The method of claim 10, 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. 13. The method of claim 12, 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. 14. The method of claim 12, 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). 15. The method of claim 12, 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.). 16. The method of claim 15, wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. 17. The method of claim 16, wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated. 18. The method of claim 10, further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof. 19. The method of claim 18, wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHANVAC B.

Details for Patent 9,527,845

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	RECOMBIVAX, RECOMBIVAX HB	hepatitis b vaccine (recombinant)	Injection	101066	07/23/1986		2034-12-30
Glaxosmithkline Biologicals	ENGERIX-B	hepatitis b vaccine (recombinant)	Injection	103239	08/28/1989		2034-12-30
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2034-12-30
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	06/13/2008		2034-12-30