HEPATITIS B ANTIVIRAL AGENTS
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Abstract
The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Citations
49 Claims
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1. A compound of Formula IV:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 29, 30, 31, 38)
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2. The compound of claim 1, wherein the compound of Formula IV is of the Formula IVa:
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3. The compound of claim 1, wherein
each R5 is independently selected at each occurrence from the group consisting of CH3, C1-C6 alkoxy, halo, — - CN, —
NO2, —
C1-C6 haloalkyl, —
C1-C6 dihaloalkyl, —
C1-C6 and trihaloalkyl;R10 is OH, halo, C1-C6 alkyl, C1-C6 alkyl-OH, —
C1-C6 chloroalkyl, —
C1-C6 dichloroalkyl, —
C1-C6 trichloroalkyl, —
C1-C6 fluoroalkyl, —
C1-C6 difluoroalkyl, —
C1-C6 trifluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, a C3-C10 heterocycloalkyl, aryl, heteroaryl, —
C1-C4 alkyl-(C3-C10 cycloalkyl), —
C1-C4 alkyl-(C3-C10 heterocycloalkyl), —
C1-C4 alkyl-(aryl), or —
C1-C4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R2;R11 is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted with 1-3 substituents selected from R2; R2 is independently selected at each occurrence from the group consisting of halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, C(O)—
C1-C6 alkyl, and C(O)—
C1-C6 alkoxy.
- CN, —
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4. The compound of claim 1, wherein each R5 is independently selected at each occurrence from the group consisting of CH3, C1-C6 alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl;
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R10 is OH, halo, C1-C6 alkyl, C1-C6 alkyl-OH, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl, C1-C6 trifluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, aryl, heteroaryl, —
C1-C4 alkyl-(C3-C10 cyclo alkyl), —
C1-C4 alkyl-(C3-C10 heterocycloalkyl), —
C1-C4 alkyl-(aryl), or —
C1-C4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R2;R11 is a bond or C1-C3 alkylene; R2 is independently selected at each occurrence from the group consisting of halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, and C(O)—
C1-C6 alkyl, and C(O)—
C1-C6 alkoxy.
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5. The compound of claim 1, wherein R5 is 3-F, 3-Cl, 3-CH3, 3-CH2F, 3-CHF2, 4-F, 3-CH3-4-F, 3-Cl-4-F, 3-Br-4-F, 3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5-difluoro.
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6. The compound of claim 1, wherein w is 1 or 2.
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7. The compound of claim 1, wherein
R11 is a bond or C1-C3 alkylene; -
R10 is OH, halo, C1-C6 alkyl, C1-C6 alkyl-OH, —
C1-C6 chloroalkyl, —
C1-C6 dichloroalkyl, —
C1-C6 trichloroalkyl, —
C1-C6 fluoroalkyl, —
C1-C6 difluoroalkyl, —
C1-C6 trifluoroalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, or phenyl, wherein the C3-C10 cycloalkyl, a C3-C10 heterocycloalkyl, or phenyl groups are optionally substituted with 1-5 substituents selected from halo, —
C1-C6 alkyl, and —
C1-C6 alkoxy; andz is 0 or 1.
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8. The compound of claim 1, wherein the compound of Formula I is of the Formula IVb:
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9. The compound of claim 1, wherein the compound of Formula I is of the Formula IVc:
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10. The compound of claim 8, G2 is C1-C4 alkyl or halo, and G2 is in the 2, 3, or 4 position of the phenyl ring.
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29. A composition comprising a compound according to any one of claim 1, or a salt, solvate or N-oxide-thereof.
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30. The composition of claim 29, wherein the composition is pharmaceutical and further comprises at least one pharmaceutically acceptable carrier.
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31. 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.
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38. The method of any of claim 31, 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, a TLR-agonist, and agents of distinct or unknown mechanism, and a combination thereof.
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2. The compound of claim 1, wherein the compound of Formula IV is of the Formula IVa:
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11. A compound of Formula V:
- View Dependent Claims (12, 13, 14, 47)
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12. The compound of claim 11, wherein
each R5 is independently selected at each occurrence from the group consisting of OH, C1-C6 alkyl, C1-C6 alkoxy, halo, — - CN, —
NO2, C1-C6 chloroalkyl, —
C1-C6 dichloroalkyl, —
C1-C6 trichloroalkyl, —
C1-C6 fluoroalkyl, —
C1-C6 difluoroalkyl and —
C1-C6 trifluoroalkyl; andR2 is independently selected at each occurrence from the group consisting of halo, —
OH, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, and C(O)—
C1-C6 alkyl.
- CN, —
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13. The compound of claim 11, wherein
each R5 is independently selected at each occurrence from the group consisting of — - OH, C1-C6 alkyl, C1-C6 alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl;
R2 is independently selected at each occurrence from the group consisting of —
OH, halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, and C(O)—
C1-C6 alkyl.
- OH, C1-C6 alkyl, C1-C6 alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl;
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14. The compound of claim 11 wherein each R5 is independently selected at each occurrence from the group consisting of —
- OH, C1-C6 alkyl, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; and
each R2 is independently selected at each occurrence from the group consisting of halo, —
C1-C6 alkyl, or —
C1-C6 alkoxy.
- OH, C1-C6 alkyl, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; and
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47. 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 11.
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12. The compound of claim 11, wherein
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15. A compound of Formula VI:
- View Dependent Claims (16, 17, 22, 48)
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16. The compound of claim 15, wherein
each R5 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, — - CN, —
NO2, —
C1-C6 haloalkyl, —
C1-C6 dihaloalkyl, and —
C1-C6 trihaloalkyl;R10 is OH, halo, C1-C6 alkyl, C1-C6 alkyl-OH, —
C1-C6 haloalkyl, —
C1-C6 dihaloalkyl, —
C1-C6 trihaloalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, a C3-C10 heterocycloalkyl, aryl, heteroaryl, —
C1-C4 alkyl-(C3-C10 cycloalkyl), —
C1-C4 alkyl-(C3-C10 heterocycloalkyl), —
C1-C4 alkyl-(aryl), or —
C1-C4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R2;R11 is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted with 1-3 substituents selected from R2; R2 is independently selected at each occurrence from the group consisting of halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, C(O)—
C1-C6 alkyl, and C(O)—
C1-C6 alkoxy.
- CN, —
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17. The compound of claim 15, wherein
each R5 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; -
R10 is OH, halo, C1-C6 alkyl, C1-C6 alkyl-OH, C1-C6 fluoroalkyl, C1-C6 difluoroalkyl, C1-C6 trifluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, a C3-C10 heterocycloalkyl, aryl, heteroaryl, —
C1-C4 alkyl-(C3-C10 cycloalkyl), —
C1-C4 alkyl-(C3-C10 heterocycloalkyl), —
C1-C4 alkyl-(aryl), or —
C1-C4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R2;R11 is a bond or C1-C3 alkylene; R2 is independently selected at each occurrence from the group consisting of halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, and C(O)—
C1-C6 alkyl, and C(O)—
C1-C6 alkoxy.
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22. The compound of claim 15, wherein the compound of Formula VI is of the Formula VIb:
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48. 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 15.
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16. The compound of claim 15, wherein
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18-21. -21. (canceled)
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23. A compound of Formula VII:
- View Dependent Claims (24, 49)
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24. The compound of claim 23, wherein
each R5 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, — - CN, —
NO2, —
C1-C6 haloalkyl, —
C1-C6 dihaloalkyl, and —
C1-C6 trihaloalkyl;R11 is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted with 0-3 substituents selected from R2; R2 is independently selected at each occurrence from the group consisting of halo, —
CN, —
NO2, —
C1-C6 alkyl, —
C1-C6 alkoxy, —
C1-C6 fluoroalkyl, —
C1-C6 heteroalkyl, C(O)—
C1-C6 alkyl, and C(O)—
C1-C6 alkoxy.
- CN, —
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49. 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 23.
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24. The compound of claim 23, wherein
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25-28. -28. (canceled)
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32-37. -37. (canceled)
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39-46. -46. (canceled)
Specification
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Current AssigneeNovira Therapeutics, Inc. (Johnson & Johnson)
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Original AssigneeNovira Therapeutics, Inc. (Johnson & Johnson)
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InventorsHARTMAN, George D., FLORES, Osvaldo A.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current424/85.4
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CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/167 having the nitrogen of a ca...A61K 31/18 Sulfonamides compounds cont...A61K 31/397 having four-membered rings,...A61K 31/40 having five-membered rings ...A61K 31/4015 having oxo groups directly ...A61K 31/407 condensed with other hetero...A61K 31/445 Non condensed piperidines, ...A61K 31/4453 only substituted in positio...A61K 31/451 having a carbocyclic group ...A61K 31/454 containing a five-membered ...A61K 31/4545 containing a six-membered r...A61K 31/495 having six-membered rings w...A61K 31/496 Non-condensed piperazines c...A61K 31/513 having oxo groups directly ...A61K 31/52 Purines, e.g. adenineA61K 31/522 having oxo groups directly ...A61K 31/536 ortho- or peri-condensed wi...A61K 31/5375 1,4-Oxazines, e.g. morpholineA61K 31/551 having two nitrogen atoms, ...A61K 31/675 : having nitrogen as a ring h...A61K 31/7072 : having two oxo groups direc...A61K 38/21 : Interferons [IFN]A61K 45/06 : Mixtures of active ingredie...A61P 1/16 : for liver or gallbladder di...A61P 31/12 : AntiviralsA61P 31/20 : for DNA virusesA61P 43/00 : Drugs for specific purposes...C07C 211/46 : AnilineC07C 211/48 : N-alkylated aminesC07C 211/50 : with at least two amino gro...C07C 311/46 : Y being a hydrogen or a car...C07D 205/04 : having no double bonds betw...C07D 207/08 : with hydrocarbon radicals, ...C07D 207/09 : Radicals substituted by nit...C07D 207/12 : Oxygen or sulfur atomsC07D 207/14 : Nitrogen atoms not forming ...C07D 207/16 : Carbon atoms having three b...C07D 207/48 : Sulfur atomsC07D 211/22 : by oxygen atomsC07D 211/32 : by oxygen atomsC07D 211/42 : attached in position 3 or 5C07D 211/46 : having a hydrogen atom as t...C07D 211/48 : having an acyclic carbon at...C07D 211/50 : Aroyl radicalC07D 211/52 : having an aryl radical as t...C07D 211/58 : attached in position 4C07D 211/62 : attached in position 4C07D 211/96 : Sulfur atomC07D 213/74 : Amino or imino radicals sub...C07D 213/82 : in position 3C07D 265/30 : not condensed with other ringsC07D 265/32 : with oxygen atoms directly ...C07D 295/195 : Radicals derived from nitro...C07D 295/26 : Sulfur atomsC07D 401/06 : linked by a carbon chain co...C07D 401/12 : linked by a chain containin...