Claims for Patent: 9,873,671

Summary for Patent: 9,873,671

Title:	Azepane 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:	15/277,421
Patent Claims:	1. A compound of Formula III: ##STR00732## or a pharmaceutically acceptable salt thereof; wherein R.sup.4 is H or --C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, --OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, --OH, --CN, or --NO.sub.2; R.sup.2 is --OH, halo, --CN, --NO.sub.2, R.sup.6, or --OR.sup.6, wherein R.sup.6 is, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, --OH, --CN, or NO.sub.2; Cy is ##STR00733## R.sup.7 and R.sup.8 are, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), wherein the aryl or heteroaryl groups are optionally substituted with --C.sub.1-C.sub.3 alkyl; or R.sup.7 and R.sup.8 join to form a 3- to 10-membered ring; R.sup.11 is, independently at each occurrence, --OH, halo, --CN, --NO.sub.2, .dbd.O, --OC(O)CH.sub.3, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --O--C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, --OH, --CN, or --NO.sub.2; R.sup.12 is, independently at each occurrence, H or --C.sub.1-C.sub.6 alkyl; R.sup.13 and R.sup.14, together with the carbons to which they are attached, join to form a cyclopropyl ring; m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and x is 0, 1, 2, 3, 4, or 5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or --C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, --OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), or --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, --OH, --CN, or --NO.sub.2; R.sup.2 is --OH, halo, --CN, --NO.sub.2, R.sup.6, or --OR.sup.6, wherein R.sup.6 is, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), or --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, --OH, --CN, or --NO.sub.2; Cy is ##STR00734## R.sup.7 and R.sup.8 are, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl); or R.sup.7 and R.sup.8 join to form a 3- to 7-membered ring; R.sup.11 is, independently at each occurrence, --OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), or --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, --OH, --CN, or --NO.sub.2; R.sup.12 is, independently at each occurrence, H or --C.sub.1-C.sub.6 alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; and x is 0, 1, 2, or 3. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, OH, halo, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, or --O--C.sub.1-C.sub.6 heteroalkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or --OH; each R.sup.2 is, independently at each occurrence, OH, halo, R.sup.6, or OR.sup.6, wherein R.sup.6 is, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), wherein the alkyl and cycloalkyl groups are optionally substituted 1-3 times with halo or --OH; Cy is ##STR00735## R.sup.11 is, independently at each occurrence, OH, halo, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, or --O--C.sub.1-C.sub.6 heteroalkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or --OH; R.sup.12 is, independently at each occurrence, H or --C.sub.1-C.sub.6 alkyl; m is 0, 1, 2, or 3; n is 1, 2, or 3; and x is 0, 1, 2, or 3. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 and R.sup.8 are, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, phenyl, pyridyl, benzyl, or pyridylmethyl. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 and R.sup.8 are, independently at each occurrence, --C.sub.1-C.sub.6 alkyl, wherein the --C.sub.1-C.sub.6 alkyl groups join to form a 3- to 7-membered ring. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R.sup.1 is, independently at each occurrence, halo and x is 1, 2, or 3. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is halo, OH, --C.sub.1-C.sub.6 alkyl, or --O--C.sub.1-C.sub.6 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or OH. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R.sup.2 is, independently at each occurrence, halo or --C.sub.1-C.sub.3 alkyl-OH and y is 1 or 2. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is --OR.sup.6, wherein R.sup.6 is --C.sub.1-C.sub.6 alkyl or --C.sub.3-C.sub.10 cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally substituted 1-2 times with halo or OH. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is ##STR00736## 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein each R.sup.11 is, independently at each occurrence, halo, OH, --C.sub.1-C.sub.6 alkyl, or --O--C.sub.1-C.sub.6 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or OH. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is --O--C.sub.1-C.sub.3 alkyl, and n is 1. 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is OH or --C.sub.1-C.sub.3 alkyl-OH, and n is 1. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0. 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is halo, and n is 1. 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is --C.sub.1-C.sub.3 alkyl, and n is 1. 18. The compound of claim 1, wherein Cy is ##STR00737## 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein each R.sup.11 is, independently at each occurrence, OH or --C.sub.1-C.sub.3 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or OH, and m is 1 or 2. 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein m is 0. 21. A compound of Formula IV: ##STR00738## or a pharmaceutically acceptable salt thereof; wherein R.sup.4 is H or C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, --OH, --CN, or --NO.sub.2; each R.sup.3 is, independently at each occurrence, OH or --C.sub.1-C.sub.6 alkyl, wherein the alkyl group is substituted 1-3 times with halo or --OH; x is 0, 1, 2, 3, 4, or 5; and z is 1, 2, or 3. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, --O--C.sub.1-C.sub.6 heteroalkyl, --C.sub.3-C.sub.10 cycloalkyl, --C.sub.3-C.sub.10 heterocycloalkyl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), or --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, --OH, --CN, or --NO.sub.2; x is 0, 1, 2, or 3. 23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H or C.sub.1-C.sub.3 alkyl; each R.sup.1 is, independently at each occurrence, OH, halo, --C.sub.1-C.sub.6 alkyl, --O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 heteroalkyl, or --O--C.sub.1-C.sub.6 heteroalkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or --OH; x is 0, 1, 2, or 3. 24. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is H. 25. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein each R.sup.1 is, independently at each occurrence, halo and x is 1, 2, or 3. 26. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is --C.sub.1-C.sub.3 alkyl-OH and z is 1. 27. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 28. 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. 29. A method of eradicating 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. 30. A method of reducing the viral load associated with 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. 31. A method of reducing reoccurrence of 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. 32. A method of reducing an adverse physiological impact of 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. 33. A method of inducing remission of hepatic injury from 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. 34. A method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1. 35. A method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1. 36. The method of claim 28, further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, immunomodulatory agents, pegylated 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 agents of distinct or unknown mechanism, and a combination thereof. 37. The method of claim 36, 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. 38. The method of claim 36, 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-9yl)propyl][3-(4-mor- pholinyl)propyl]amino}methyl)phenyl]acetate). 39. The method of claim 36, 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.). 40. The method of claim 39, wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. 41. The method of claim 40, wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated. 42. The method of claim 40, wherein the interferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS). 43. The method of claim 28, further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof. 44. The method of claim 43, wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHANVAC B. 45. A method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a compound according to claim 1, alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine. 46. The method of claim 28, further comprising monitoring the HBV viral load of the subject, and wherein the method is carried out for a period of time such that the HBV virus is undetectable.

Details for Patent 9,873,671

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		2034-01-16
Glaxosmithkline Biologicals	ENGERIX-B	hepatitis b vaccine (recombinant)	Injection	103239	08/28/1989		2034-01-16
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	10/16/2002		2034-01-16
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	01/07/2004		2034-01-16
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	09/29/2011		2034-01-16