HEPATITIS B ANTIVIRAL AGENTS

• US 20130251673A1
• Filed: 12/21/2012
• Published: 09/26/2013
• Est. Priority Date: 12/21/2011
• Status: Active Grant

• Current Assignee: Novira Therapeutics, Inc. (Johnson & Johnson)
• Original Assignee: Novira Therapeutics, Inc. (Johnson & Johnson)
• Inventors: HARTMAN, George D., FLORES, Osvaldo A.
• Granted Patent: US 8,629,274 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• 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 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/536 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/675 : having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7072 : having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/21 : Interferons [IFN]
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/46 : Aniline
• CPC Class Codes: C07C 211/48 : N-alkylated amines
• CPC Class Codes: C07C 211/50 : with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/48 : Sulfur atoms
• CPC Class Codes: C07D 211/22 : by oxygen atoms
• CPC Class Codes: C07D 211/32 : by oxygen atoms
• CPC Class Codes: C07D 211/42 : attached in position 3 or 5
• CPC Class Codes: C07D 211/46 : having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/48 : having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/50 : Aroyl radical
• CPC Class Codes: C07D 211/52 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 211/96 : Sulfur atom
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 265/32 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/195 : Radicals derived from nitrogen analogues of carboxylic acids
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links

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.

Claims

1. A compound of Formula IV:

2. The compound of claim 1, wherein the compound of Formula IV is of the Formula IVa:

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.

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;

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.

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.

6. The compound of claim 1, wherein w is 1 or 2.

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; and

z is 0 or 1.

8. The compound of claim 1, wherein the compound of Formula I is of the Formula IVb:

9. The compound of claim 1, wherein the compound of Formula I is of the Formula IVc:

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.

29. A composition comprising a compound according to any one of claim 1, or a salt, solvate or N-oxide-thereof.

30. The composition of claim 29, wherein the composition is pharmaceutical and further comprises at least one pharmaceutically acceptable carrier.

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.

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.

11. A compound of Formula V:

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; and

R² 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.

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.

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.

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.

15. A compound of Formula VI:

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.

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.

22. The compound of claim 15, wherein the compound of Formula VI is of the Formula VIb:

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.

18-21. -21. (canceled)

23. A compound of Formula VII:

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.

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.

25-28. -28. (canceled)

32-37. -37. (canceled)

39-46. -46. (canceled)