HEPATITIS B ANTIVIRAL AGENTS

• US 20170253609A1
• Filed: 03/06/2017
• Published: 09/07/2017
• Est. Priority Date: 03/07/2016
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Gao, Xuri, Li, Wei, Cao, Hui, Jin, Meizhong, Kass, Jorden, Peng, Xiaowen, Or, Yat Sun
• Granted Patent: US 10,179,792 B2
• Time in Patent Office: Days
• 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 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/223 of alpha-aminoacids
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/39 having oxygen in the same ring
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/426 : 1,3-Thiazoles
• CPC Class Codes: A61K 31/439 : the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/44 : Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4402 : only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4409 : only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4425 : Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
• CPC Class Codes: A61K 31/445 : Non condensed piperidines, e.g. piperocaine
• 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 31/5377 : not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/655 : Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• 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: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/07 : Optical isomers
• CPC Class Codes: C07B 59/001 : Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 235/56 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/16 : the ring being unsaturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/44 : the bicyclo ring system containing eight carbon atoms
• CPC Class Codes: C07C 2602/46 : the bicyclo ring system containing nine carbon atoms
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 311/53 : X and Y not being nitrogen atoms, e.g. N-sulfonylcarbamic acid
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/42 : Y being a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/62 : having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• 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 211/54 : Sulfur atoms
• CPC Class Codes: C07D 213/52 : Sulfur atoms
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/02 : not condensed with other rings
• CPC Class Codes: C07D 261/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/20 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 263/52 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 277/26 : Radicals substituted by sulfur atoms
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain
• CPC Class Codes: C07D 303/26 : having one or more free hydroxyl radicals
• CPC Class Codes: C07D 303/34 : with hydrocarbon radicals, substituted by sulphur, selenium or tellurium atoms
• CPC Class Codes: C07D 307/32 : Oxygen atoms
• CPC Class Codes: C07D 307/33 : in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 309/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 313/04 : not condensed with other rings
• CPC Class Codes: C07D 317/72 : spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 327/10 : two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 493/04 : Ortho-condensed systems
• CPC Class Codes: C07D 493/08 : Bridged systems

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof:

X-A-Y-L-R  (I)

which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Claims

1. A compound represented by Formula (I):

X-A-Y-L-R 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein;

X and Y are each independently selected from optionally substituted aryl and optionally substituted heteroaryl;

A is selected from the group consisting of —

NHC(O)—

,

2. The compound of claim 1, wherein R is —

C(R₁₀)₃,

3. The compound of claim 1, represented by Formula (IIIa), (IIIa-1), or (IIIa-2), or a pharmaceutically acceptable salt thereof:

4. The compound of claim 1, represented by Formula (IVa), (IVb), (IVc), (IVd), or (IVe) or a pharmaceutically acceptable salt thereof:

5. The compound of claim 1, represented by Formula (Va), (Vb), (Vc), (Vd), or (Ve), or a pharmaceutically acceptable salt thereof:

6. The compound of claim 1, represented by Formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe), or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1, represented by Formula (VIIa-1), (VIIb-1), (VIIc-1), (VIId-1), or (VIIe-1), or a pharmaceutically acceptable salt thereof:

8. The compound of claim 1, represented by Formula (VIIIa), (VIIIb), (VIIIc), or (VIIId), or a pharmaceutically acceptable salt thereof:

9. The compound of claim 1, represented by Formula (VIIIa-1), (VIIIb-1), (VIIIc-1), or (VIIId-1), or a pharmaceutically acceptable salt thereof:

10. The compound of claim 1, selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition, comprising a compound or a combination of compounds according to claim 1, in combination with a pharmaceutically acceptable carrier or excipient.

12. A method of treating or preventing an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds according to claim 1.

13. The method of claim 12, further comprising administering to the subject at least one additional therapeutic agent selected from the group consisting of HBV polymerase inhibitors, interferon, viral entry inhibitors, viral maturation inhibitors, capsid assembly or core protein inhibitors or modulators, reverse transcriptase inhibitors, TLR-agonists, inducers of cellular viral RNA sensor, therapeutic vaccines, RNA interence (RNAi) or small interfering RNA (siRNA) and combinations thereof.

14. The method of claim 13, wherein the compound and the at least one additional therapeutic agent are co-formulated.

15. The method of claim 13, wherein the at least one additional therapeutic agent is administered at a lower dose and/or frequency than that which is therapeutically effective when said agent is administered alone.