Elimination of hepatitis b virus with antiviral agents

Patent metadata

Field	Value
Publication number	US-11629125-B2
Application number	US-202016998944-A
Country	US
Kind code	B2
Filing date	Aug 20, 2020
Priority date	Mar 9, 2016
Publication date	Apr 18, 2023
Grant date	Apr 18, 2023

Abstract

The present invention is directed to compounds, compositions and methods for preventing, treating or curing Hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment, prevention or eradication of HBV infection.

First claim

We claim:

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein
when R 1 and R 1′ are attached to a carbon, they are, independently, hydrogen, halogen, SF 5 , CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, cyano, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxyalkyl;
when R 1 and R 1′ are attached to a nitrogen, they are, independently, hydrogen, C 2-6 alkoxy, C 3-6 alkoxyalkyl, C 2-6 alkenyl, alkoxycarbonyl, carbonylalkyl, carbonyl aryl, C 1-6 alkyl, heterocyclylalkyl, C 2-6 hydroxyalkyl, or S(O) 2 R′;
each R′ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or if two R′ reside on the same nitrogen atom, they can come together to form a C 3-6 ring optionally containing a N, O, or S heteroatom;
the R′ groups, other than H, can optionally be substituted with one or more substituents, which substituents are, independently, halo, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate;
u and v are independently 0, 1, 2, 3, 4 or 5;
K is a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a five-membered heteroaromatic ring containing one, two, or three heteroatoms which are, independently, N, O, or S; or a C 4-14 bicyclic ring;
L is a five-membered heteroaromatic ring containing one, two, or three heteroatoms which are, independently, N, O, or S,
W is

R 14 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl,
R 15 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, S, or Se, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, S or Se; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, S, or Se;
R 15 is optionally substituted with one or more substituents which are, independently, halogen, SF 5 , CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, cycloalkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxyalkyl; or is optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where substituents on the substituted aryl and substituted heteroaryl are selected from the group consisting of halogen, SF 5 , CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C(O)R′, C 1-6 alkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and C 1-6 alkyl, or
R 14 and R 15 can come together with the nitrogen to which they are attached form a 6-10 membered bicyclic or bridged ring or a 3 to 8 membered saturated ring; such bicyclic, bridged and saturated ring moiety optionally containing one or more additional heteroatoms which are, independently, O, S or N, and optionally being substituted with one or more substituents each independently selected from the group consisting of halogen, CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, and C 1-6 hydroxyalkyl.

2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier.

3. A method for treating a host infected with HBV, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the host in need of treatment thereof.

4. The method of claim 3 , wherein the treating a host infected with HBV suppresses HDV infection.

5. The compound of claim 1 , wherein R 1′ is halogen or CN.

6. The compound of claim 1 , wherein R 1 is methyl.

7. The compound of claim 1 , wherein L is an optionally substituted pyrrole.

8. The compound of claim 1 , wherein K is optionally substituted pyridyl.

9. The compound of claim 1 , wherein R 14 is C 2-6 alkenyl or C 2-6 alkynyl.

Assignees

• Univ Emory

Inventors

• Schinazi Raymond F
• Boucle Sebastien
• Amblard Franck
• Sari Ozkan
• Bassit Leda

Classifications

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title