Patent Description:
The present invention relates to N-substituted <NUM>-(<NUM>,<NUM>-aryloxazolo-<NUM>-yl)phenyl compounds and their corresponding derivatives that have anti-virus activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.

The present invention relates to compounds of formula (I),
<CHM>
wherein A<NUM> to A<NUM> and R<NUM> are as described below, or a pharmaceutically acceptable salt thereof.

Hepatitis B virus (HBV) is one of the most dangerous human pathogens. A safe and effective vaccine has been available for longer than two decades; however, WHO estimated that approximately <NUM> million people are chronically infected with HBV. Chronic Hepatitis B (CHB) infection predisposes its host to severe liver disease, including liver cirrhosis and hepatocellular carcinoma, if left untreated. HBV infection is ranked among the top unmet medical need worldwide. The currently approved drugs have contributed to substantial progress in CHB treatment; however, the cure rate remains less than <NUM>%.

The control of viral infection needs an effective immune surveillance. Upon recognition of viral infection, the host innate immune system could respond within minutes to impede viral replication and limits the development of a chronic and persistent infection. The secretion of antiviral cytokines from infected hepatocytes and intra-hepatic immune cells is critically important for the clearance of viral infection. However, chronically infected patients only display a weak immune response due to various escape strategies adopted by the virus to counteract the host cell recognition systems and the subsequent antiviral responses.

Many observations showed that several HBV viral proteins could counteract the initial host cellular response by interfering with the viral recognition signaling system and subsequently the interferon (IFN) antiviral activity. Among these, the excessive secretion of HBV empty subviral particles (SVPs, HBsAg) may contribute to immune tolerant state observed in CHB patients. The persistent exposure to HBsAg and other viral antigens can lead to HBV-specific T-cell functional impairment and depletion (<NPL>; <NPL>; <NPL>;). Moreover, HBsAg has been reported to suppress immune cell functions, including monocytes, dendritic cells (DCs) and natural killer (NK) cells (<NPL>;<NPL>; <NPL>; <NPL>).

HBsAg is an important biomarker for prognosis and treatment response in CHB. However, the achievement of HBsAg loss and seroconversion is rarely achieved in CHB patients. HBsAg loss with or without anti-HBsAg seroconversion remains the ideal clinical treatment endpoints. Current therapies, such as nucleos(t)ide analogues, are effective in supressing HBV DNA, but are not effective in reducing HBsAg level. Nucleos(t)ide analogs, even with prolonged therapy, have demonstrated HBsAg clearance rates comparable to those observed naturally (<NPL>; <NPL>; <NPL>). Therefore, there is an urgent need for the development of novel therapeutic agents that could efficiently reduce HBsAg. (<NPL>; <NPL>; <NPL>;<NPL>).

<CIT> and<NPL> disclose structurally related compounds.

Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as HBV inhibitors and for the treatment or prophylaxis of HBV infection. The compounds of formula (I) show superior anti-HBV activity. In addition, the compounds of formula (I) also show good safety and good PK profiles.

The present invention relates to a compound of formula (I)
<CHM>
wherein.

As used herein, the term "C<NUM>-<NUM>alkyl" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing <NUM> to <NUM>, particularly <NUM> to <NUM> or <NUM> to <NUM> carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Particular "C<NUM>-<NUM>alkyl" groups are methyl, ethyl, propyl, isopropyl, isobutyl and tert-butyl.

The term "C<NUM>-<NUM>alkoxy" alone or in combination signifies a group C<NUM>-<NUM>alkyl-O-, wherein the "C<NUM>-<NUM>alkyl" is as defined above; for example methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, <NUM>-butoxy, tert-butoxy, pentoxy, hexyloxy and the like. Particular "C<NUM>-<NUM>alkoxy" groups are methoxy, ethoxy, and propoxy.

The term "halogen" denotes fluoro, chloro, bromo, or iodo.

The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in<NPL>. Particular are the sodium salts of the compounds of formula (I).

The present invention provides (i) a compound having the general formula (I):
<CHM>
wherein.

A further embodiment of the present invention is (ii) a compound of formula (I) according to (i), wherein.

A further embodiment of the present invention is (iii) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein A<NUM> is CH.

A further embodiment of the present invention is (iv) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein A<NUM> is CR<NUM>; wherein R<NUM> is H or halogen.

A further embodiment of the present invention is (v) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein A<NUM> is CR<NUM>; wherein R<NUM> is H, For Cl.

A further embodiment of the present invention is (vi) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein A<NUM> is CR<NUM>; wherein R<NUM> is H or halogen.

A further embodiment of the present invention is (vii) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein A<NUM> is CR<NUM>; wherein R<NUM> is H or F.

A further embodiment of the present invention is (viii) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein R<NUM> is tetrahydrofuran-<NUM>-yl, <NUM>-methyloxetan-<NUM>-yl, <NUM>-hydroxy-<NUM>-methyl-ethyl, <NUM>-bicyclo[<NUM>. <NUM>]pentanyl, <NUM>-fluoro-<NUM>-bicyclo[<NUM>. <NUM>]pentanyl, <NUM>,<NUM>-dioxothiolan-<NUM>-yl, <NUM>,<NUM>-dioxothian-<NUM>-yl, tert-butyl, cyclopropyl, <NUM>-methyltetrahydrofuran-<NUM>-yl, <NUM>-oxabicyclo[<NUM>. <NUM>]octan-<NUM>-yl, <NUM>,<NUM>-dioxan-<NUM>-yl, <NUM>-hydroxyethyl, cyclobutyl, tetrahydropyran-<NUM>-yl, oxazol-<NUM>-yl, <NUM>-methyloxazol-<NUM>-yl, <NUM>-pyridyl or <NUM>-methyloxazol-<NUM>-yl.

A further embodiment of the present invention is (ix) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein.

wherein with the proviso that A<NUM>, A<NUM>, A<NUM> and A<NUM> are not CH simultaneously.

A further embodiment of the present invention is (x) a compound of formula (I) according to (i), or a pharmaceutically acceptable salt thereof, wherein.

In another embodiment (xi) of the present invention, particular compounds of the present invention are selected from:.

In another embodiment (xii) of the present invention, particular compounds of the present invention are selected from:.

The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, A<NUM> to A<NUM> and R<NUM> are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. <CHM>
<CHM>
wherein R<NUM> is OH or halogen; LG is OH or halogen.

A compound of formula IV reacts with an acyl chloride V in the presence of a base, such as DIPEA, in a solvent, such as THF, to give a compound of formula VI. The compound of formula VI can also be formed with heating in the presence of a solvent such as pyridine. Cyclization of a compound of formula VI with POCl<NUM>, affords a compound of formula VII. The compound of formula VII can also be formed in the presence of CuI, N,N'-dimethylethylenediamine and a base, such as Cs<NUM>CO<NUM>, in a suitable solvent such as <NUM>,<NUM>-dioxane. Hydrogenation of a compound of formula VII in the presence of a catalyst, such as palladium on carbon, under a hydrogen atmosphere, in a suitable solvent, such as MeOH or a mixed solution of THF and EtOH, affords a compound of formula IX. The compound of formula IX can also be prepared by reaction of a compound of formula IV and a carboxylic acid VIII in the presence of an acid, such as polyphosphoric acid. Then a compound of formula IX reacts with a compound of formula X in the presence of a coupling reagent, such as HATU, EDCI or T<NUM>P, and a base, such as TEA or DIPEA, in a solvent such as DMF or DCM, to afford a compound of formula I. The compound of formula I can also be prepared by reaction of a compound of formula IX and a compound of formula Xin the presence of a base, such as TEA or DIPEA, in a suitable solvent, such as DCM or pyridine. The compound of formula I can also be prepared by reaction of a compound of formula IX and a compound of formula X by heating under a neat condition.

This invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:.

The base in step (a) can be for example TEA or DIPEA;.

The coupling reagent in step (a) can be for example HATU, EDCI or T<NUM>P;.

A compound of formula (I) when manufactured according to the above process is also an object of the invention.

The compound of this invention also shows good safety and PK profile.

The invention also relates to a compound of formula (I) for use as therapeutically active substance. Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about <NUM> to about <NUM>. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH <NUM>. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to reduction of HBsAg and HBeAg in HBV patients. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about <NUM> to <NUM>/kg, alternatively about <NUM> to <NUM>/kg of patient body weight per day, with the typical initial range of compound used being <NUM> to <NUM>/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about <NUM> to about <NUM> of the compound of the invention.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., <NPL>; <NPL>; and <NPL>. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

An example of a suitable oral dosage form is a tablet containing about <NUM> to <NUM> of the compound of the invention compounded with about <NUM> to <NUM> anhydrous lactose, about <NUM> to <NUM> sodium croscarmellose, about <NUM> to <NUM> polyvinylpyrrolidone (PVP) K30, and about <NUM> to <NUM> magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example <NUM> to <NUM>, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a <NUM> micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of HBV infection.

The compounds of the invention have anti-HBV activity. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.

The invention also relates to the use of a compound of formula (I) for the inhibition of HBeAg.

The invention further relates to the use of a compound of formula (I) for the inhibition of HBsAg.

The invention relates to the use of a compound of formula (I) for the inhibition of HBV DNA.

The invention relates to the use of a compound of formula (I) for use in the treatment or prophylaxis of HBV infection.

The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention.

The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of HBV infection.

Another embodiment includes a method for the treatment or prophylaxis of HBV infection, which method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The invention relates in particular to a compound of formula (I) for use in the treatment or prophylaxis of HBV infection.

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad <NUM>/<NUM> Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL <NUM>Å, particle size: <NUM>-<NUM>; ii) <NPL>, particle size: <NUM>-<NUM> micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co. , Ltd, pore: <NUM>-<NUM> or <NUM>-<NUM>.

Intermediates and final compounds were purified by preparative HPLC on reversed phase column using X Bridge™ Perp C<NUM> (<NUM>, OBD™ <NUM> × <NUM>) column or SunFire™ Perp C<NUM> (<NUM>, OBD™ <NUM> × <NUM>) column.

Chiral Separation was conducted on Thar <NUM> preparative SFC using ChiralPak AD-10µ (<NUM> × <NUM> I. ) with mobile phase A for CO<NUM> and B for ethanol. LC/MS spectra were obtained using a Waters UPLC-SQD Mass. Standard LC/MS conditions were as follows (running time: <NUM> minutes):.

NMR Spectra were obtained using Bruker Avance <NUM>.

All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

To PPA (<NUM>, <NUM> mmol) at <NUM> were added simultaneously <NUM>-amino-<NUM>-fluorophenol (<NUM>, <NUM> mmol) and <NUM>-aminobenzoic acid (<NUM>, <NUM> mmol). The resulting mixture was then heated to <NUM> for <NUM>. The solution was then poured into water. The resulting precipitate was collected by filtration and washed with water (<NUM>), a mix solution of methanol and water (<NUM>, methanol/water=<NUM>/<NUM>) and saturated aqueous NaHCO<NUM> (<NUM>). The filter cake was collected and purified by silica gel column eluted with DCM to DCM/MeOH=<NUM>/<NUM> to give <NUM>-(<NUM>-fluoro-<NUM>,<NUM>-benzoxazol-<NUM>-yl)aniline (<NUM>) as a light yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> -<NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-fluorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by preparative HPLC to afford Int-<NUM> as a light yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-chlorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by preparative HPLC to afford Int-<NUM> as a light yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-fluorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by silica gel column to afford Int-<NUM> as a light yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-fluorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by silica gel column to afford Int-<NUM> as a pink solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-nitrobenzoic acid chloride (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) in THF (<NUM>) was added <NUM>-amino-<NUM>-hydroxypyridine (<NUM>, <NUM> mmol). The mixture was stirred at <NUM> for <NUM>. Then the resulting mixture was filtered and washed with MTBE (<NUM>) to give N-(<NUM>-hydroxy-<NUM>-pyridyl)-<NUM>-nitro-benzamide (<NUM>) as a light grey solid. (ESI+) [(M+H)+]:<NUM>.

A mixture of N-(<NUM>-hydroxy-<NUM>-pyridyl)-<NUM>-nitro-benzamide (<NUM>, <NUM> mmol) in POCl<NUM> (<NUM>) was heated to <NUM> for <NUM>. The mixture was concentrated and then poured into ice-cold saturated aqueous NaHCO<NUM>. The resulting precipitate was collected by filtration and washed with ACN (<NUM>). The solid was collected to afford <NUM>-(<NUM>-nitrophenyl)oxazolo[<NUM>,<NUM>-b]pyridine (<NUM>) as a light grey solid. MS obsd (ESI+) [(M+H)+]: <NUM>.

To a solution of <NUM>-(<NUM>-nitrophenyl)oxazolo[<NUM>,<NUM>-b]pyridine (<NUM>, <NUM> mmol) in THF (<NUM>) and ethanol (<NUM>) was added Pd/C (<NUM>, <NUM> mmol) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with H<NUM> several times. The mixture was stirred under H<NUM> balloon at <NUM> for <NUM>. The mixture was then filtered to remove Pd/C and concentrated to afford the crude product. The crude product was purified by preparative HPLC to give <NUM>-oxazolo[<NUM>,<NUM>-b]pyridin-<NUM>-ylaniline (Int-<NUM>) (<NUM>) as a white solid. MS obsd (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a solution of <NUM>-nitrobenzoic acid chloride (<NUM>, <NUM> mmol) in pyridine (<NUM>) was added <NUM>-bromo-<NUM>,<NUM>-difluoro-aniline (<NUM>, <NUM> mmol) in one portion. The reaction mixture was stirred at <NUM> for <NUM> and concentrated. The residue was diluted with DCM (<NUM>) and was washed with saturated aqueous NaHCO<NUM> (<NUM> × <NUM>). The organic layer was concentrated to give the crude product. The crude product was purified by silica gel column (PE/EtOAc= <NUM>/<NUM>) to give N-(<NUM>-bromo-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-nitro-benzamide (<NUM>) as a white solid. (ESI+)[(M+H)+]: <NUM>.

To a solution of N-(<NUM>-bromo-<NUM>,<NUM>-difluoro-phenyl)-<NUM>-nitro-benzamide (<NUM>, <NUM> mmol), N,N'-dimethylethylenediamine (<NUM>, <NUM> mmol) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) in <NUM>,<NUM>-dioxane (<NUM>) was added copper(I) iodide (<NUM>, <NUM> mmol) in one portion under nitrogen atmosphere. The reaction mixture was stirred at <NUM> for <NUM> and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by silica gel column (PE/EtOAc= <NUM>) to give <NUM>,<NUM>-difluoro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-benzoxazole (<NUM>) as a white solid. (ESI+)[(M+H)+]: <NUM>.

<CHM>
To a solution of <NUM>,<NUM>-difluoro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-benzoxazole (<NUM>, <NUM> mmol) in methanol (<NUM>) was added palladium on carbon (<NUM>, <NUM> mmol) in one portion under nitrogen atmosphere. The reaction system was degassed and purged with H<NUM> (<NUM> psi) and stirred at <NUM> for <NUM>. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC to give <NUM>-(<NUM>,<NUM>-difluoro-<NUM>,<NUM>-benzoxazol-<NUM>-yl)aniline (Int-<NUM>) (<NUM>) as a white solid.

(ESI+)[(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>, <NUM>-difluorophenol (<NUM>, <NUM> mmol) in DCM (<NUM>) was added nitric acid (<NUM>) dropwise under nitrogen atmosphere at <NUM>. After addition, the resulting reaction was stirred at <NUM> for <NUM>. The mixture was poured into ice-water (<NUM>), extracted with DCM (<NUM> × <NUM>). The combined organic layer was washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by silica gel column to give <NUM>, <NUM>-difluoro-<NUM>-nitro-phenol (<NUM>) as a yellow solid.

A mixture of <NUM>, <NUM>-difluoro-<NUM>-nitro-phenol (<NUM>, <NUM> mmol) and Pd/C (<NUM>) in ethanol (<NUM>) was stirred at <NUM> for <NUM> under H<NUM> atmosphere (<NUM> mmHg). The mixture was filtered and the filtrate was concentrated to give <NUM>-amino-<NUM>, <NUM>-difluoro-phenol (<NUM>) as a light yellow solid.

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>, <NUM>-difluoro-phenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by preparative HPLC to afford Int-<NUM> as an off-white solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-chloro-<NUM>-picoline instead of <NUM>-bromo-<NUM>,<NUM>-difluoro-aniline. The product was purified by silica gel column to afford Int-<NUM> as a yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-chloro-<NUM>-methoxy-<NUM>-nitropyridine (<NUM>, <NUM> mmol) and ammonium chloride (<NUM>, <NUM>. 1mmol) in ethanol (<NUM>) and water (<NUM>) was added iron (<NUM>, <NUM> mmol) in one portion under nitrogen atmosphere. The reaction mixture was stirred at <NUM> for <NUM>. The reaction mixture was filtered, and the filtrate was extracted with DCM (<NUM> × <NUM>). The combined organic layers were dried over Na<NUM>SO<NUM> and concentrated to give the crude product. The crude product was purified by silica gel column to give <NUM>-chloro-<NUM>-methoxy-pyridin-<NUM>-amine (<NUM>) as yellow oil. (ESI+)[(M+H)+]: <NUM>.

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-chloro-<NUM>-methoxy-pyridin-<NUM>-amine instead of <NUM>-bromo-<NUM>,<NUM>-difluoro-aniline. The product was purified by preparative HPLC to afford Int-<NUM> as a yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-chlorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by trituration to afford Int-<NUM> as a light brown solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>,<NUM>-difluoro-phenol instead of <NUM>-amino-<NUM>-fluorophenolThe product was collected by filtration to afford Int-<NUM> as a black solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-bromo-<NUM>,<NUM>-difluoro-aniline instead of <NUM>-bromo-<NUM>,<NUM>-difluoro-aniline. The product was purified by silica gel column to afford Int-<NUM> as a yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-amino-<NUM>-chlorophenol instead of <NUM>-amino-<NUM>-fluorophenol. The product was purified by silica gel column to afford Int-<NUM> as a yellow solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

A solution of <NUM>-hydroxytetrahydro-<NUM>-pyran-<NUM>-carboxylic acid (<NUM>, <NUM> mmol) was mixed with pyridine (<NUM>, <NUM>µL, <NUM> mmol) and DCM (<NUM>). After cooling to <NUM>, acetyl chloride (<NUM>, <NUM>µL, <NUM> mmol) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for <NUM>. The reaction was diluted with DCM (<NUM>) and washed with saturated aqueous NH<NUM>Cl (<NUM>) and brine (<NUM>). The organic phase was dried over Na<NUM>SO<NUM> and concentrated in vacuum. The crude product (Int-<NUM>)was used for next step without further purification. (ESI+) [(M-H)+]: <NUM>.

The title compound was prepared in analogy to the procedure described for the preparation of Int-<NUM>, by using <NUM>-hydroxycyclopropanecarboxylic acid instead of <NUM>-hydroxytetrahydro-<NUM>-pyran-<NUM>-carboxylic acid. The product Int-<NUM> was used for next step without further purification.

To a solution of triphosgene (<NUM>, <NUM> mmol) in DCM (<NUM>) was added a solution of tetrahydrofuran-<NUM>-ol (<NUM>, <NUM> mmol) and pyridine (<NUM>, <NUM>, <NUM> mmol) in DCM (<NUM>) dropwise at <NUM>. The mixture became orange and a yellow precipitate appeared. The mixture was allowed to warm to room temperature and stirred for <NUM>. Aqueous HCl (<NUM>. 1N, <NUM>) was added and the organic layer was separated. The organic layer was washed with <NUM> N HCl (<NUM> × <NUM>), brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated in vacuum to give light brown oil which became solid upon standing in the freezer for <NUM>. The crude product Int-<NUM> was used for next step without further purification.

To a solution of <NUM>-(<NUM>-fluorobenzo[d]oxazol-<NUM>-yl)aniline (Int-<NUM>, as the "AMINE" in Table <NUM>) (<NUM>, <NUM> mmol) and tetrahydrofuran-<NUM>-carboxylic acid (<NUM>, <NUM> mmol, as the "ACID" or "ACYL CHLORIDE" in Table <NUM>) in DCM (<NUM>) was added HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM>µL, <NUM> mmol). Then the mixture was stirred at <NUM> for <NUM>. The reaction mixture was concentrated in vacuum and the residue was triturated in water (<NUM>). The resulting mixture was filtered and the filter cake was washed with a mixed solution of water (<NUM>) and methanol (<NUM>). The cake was collected and dried in vacuum to give N-[<NUM>-(<NUM>-fluoro-<NUM>,<NUM>-benzoxazol-<NUM>-yl)phenyl]tetrahydrofuran-<NUM>-carboxamide (Example <NUM>)(<NUM>) as a pink solid. (ESI+) [(M+H)+]: <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

The following Example <NUM> to Example <NUM> were prepared in analogy to the procedure described for the preparation of Example <NUM>, replacing <NUM>-(<NUM>-fluorobenzo[d]oxazol-<NUM>-yl)aniline (Int-<NUM>) with "AMINE", tetrahydrofuran-<NUM>-carboxylic acid with "ACID" or "ACYL CHLORIDE". The "AMINE", "ACID" and "ACYL CHLORIDE" are the reagents indicated in Table <NUM>.

The two enantiomers (Example <NUM>-a, Example <NUM>-b) were obtained through SFC [Instrument: Thar <NUM> preparative SFC (SFC-<NUM>), Phenomenex Lux Cellulose-<NUM>, <NUM>×<NUM> I. , <NUM>; Mobile phase: A for CO<NUM> and B for MEOH; Gradient: B <NUM>%; Flow rate: <NUM> /min; Back pressure: <NUM> bar; Column temperature: <NUM>; elution order was Example <NUM>-a, Example <NUM>-b] chiral separation of N-(<NUM>-oxazolo[<NUM>,<NUM>-b]pyridin-<NUM>-ylphenyl)-<NUM>,<NUM>-dioxo-thiolane-<NUM>-carboxamide (Example <NUM>).

The two enantiomers (Example <NUM>-a, Example <NUM>-b) were obtained through SFC [Instrument: SFC <NUM>, Column: ChiralCel OJ, <NUM>×<NUM> I. , <NUM>; Mobile phase: A for CO<NUM> and B for Methanol (<NUM>% NH<NUM>OH); Gradient: B <NUM>%; Flow rate: <NUM>/min; Back pressure: <NUM> bar; Column temperature: <NUM>; elution order was Example <NUM>-a, Example <NUM>-b] chiral separation of N-[<NUM>-(<NUM>-chloro-<NUM>,<NUM>-benzoxazol-<NUM>-yl)phenyl]tetrahydrofuran-<NUM>-carboxamide (Example <NUM>).

Detailed procedures regarding primary human hepatocyte (PHH) HBV natural infection assay are described as below. One tube of frozen PHH (<NUM> million cells) is thawed in <NUM> water bath and then transferred to <NUM> of PHH thawing medium (Sigma, InVitroGRO HT Medium, Cat. S03319) with gently mixing. The cells were then centrifuged at <NUM>/min for <NUM>, the supernatant was discarded and the tube was refilled with <NUM> of PHH plating medium (Sigma , InVitroGRO CP Medium, Cat. The tube was shaken very gently to re-suspend all cells, and then <NUM>µL of cells were transferred to each well <NUM>-well collagen I coated plate with appropriate liquid handling equipment, e.g. Integra VIAFLO384 or Agilent Bravo. The cells were then cultured for <NUM> hours in a cell incubator. For HBV infection, after PHH attachment on the culture plate, the plating medium was removed and replenished with PHH culture medium containing HBV virus. The PHH culture medium was prepared with Dulbecco's Modified Eagle Medium (DMEM)/F12 (<NUM>: <NUM> in volume ratio) containing <NUM>% fetal bovine serum (Gibco, Cat. <NUM>), <NUM> ng/mL human epidermal growth factor (Gibco, Cat. PHG0311L), <NUM> ng/mL dexamethasone (Sigma, Cat. D4902-<NUM>), <NUM> ng/mL human recombinant insulin (Gibco, Cat. <NUM>) and <NUM> U/mL penicillin. HBV virus at <NUM> genome equivalent (GE) per cell with <NUM>% PEG8000 (Sigma, Cat. P1458) containing culture medium were added to the PHH culture medium for infection. The cells were then cultured for <NUM> hours in cell incubator. Then the cell culture supernatant was removed. The HBV-infected PHH were cultured with sandwich culture method with PHH culture medium containing <NUM>% DMSO and <NUM>/mL matrix gel for <NUM> hours. The supernatant was then refreshed with PHH culture medium containing different concentrations of testing compounds for two times with <NUM>-hour interval. At the end of treatment, the supernatant was collected for viral markers measurements, including HBsAg, HBeAg, HBV DNA and cytotoxicity. HBsAg and HBeAg were detected using alphalisa method using their specific antibodies. For HBV DNA detection, HBV DNA Quantitative Fluorescence Diagnostic Kit (Sansure Biotech Inc. ) was used following the manufacture's protocol. Cytotoxicity was determined using Cell Counting Kit-<NUM> (CCK8, Dojindo Molecular Technologies, Inc.

The compounds of the present invention were tested for their capacity to inhibit HBsAg and HBeAg as described herein. The Examples were tested in the above assay and found to have IC<NUM> below <NUM>. Results of PHH assay are given in Table <NUM>.

Claim 1:
A compound of the formula (I),
<CHM>
wherein
R<NUM> is tetrahydrofuran-<NUM>-yl, <NUM>-hydroxyethyl, tert-butyl, tetrahydrothiopyran-<NUM>-yl, <NUM>-methyltetrahydrofuran-<NUM>-yl, propyl, <NUM>,<NUM>-dioxothiolan-<NUM>-yl, <NUM>-furyl, <NUM>-methyloxetan-<NUM>-yl, <NUM>-hydroxy-<NUM>-methyl-ethyl, <NUM>-bicyclo[<NUM>.<NUM>]pentanyl, <NUM>-fluoro-<NUM>-bicyclo[<NUM>.<NUM>]pentanyl, <NUM>,<NUM>-dioxothian-<NUM>-yl, cyclopropyl, <NUM>-methyltetrahydrofuran-<NUM>-yl, <NUM>-oxabicyclo[<NUM>.<NUM>]octan-<NUM>-yl, <NUM>,<NUM>-dioxan-<NUM>-yl, cyclobutyl, <NUM>-acetoxytetrahydropyran-<NUM>-yl, <NUM>,<NUM>-difluorocyclopropyl, tetrahydropyran-<NUM>-yl, oxetan-<NUM>-yl, <NUM>,<NUM>-dioxothietan-<NUM>-yl, <NUM>-methylcyclopropyl, <NUM>-oxabicyclo[<NUM>.<NUM>]hexan-<NUM>-yl, <NUM>-methylcyclobutyl, <NUM>-acetoxycyclopropyl, tetrahydrofuran-<NUM>-yloxy, <NUM>-methoxycarbonyl-<NUM>-bicyclo[<NUM>.<NUM>]pentanyl, <NUM>-ethyloxetan-<NUM>-yl, oxazol-<NUM>-yl, <NUM>-methyloxazol-<NUM>-yl, <NUM>-pyridyl, <NUM>-methyloxazol-<NUM>-yl, thiazol-<NUM>-yl, <NUM>-pyridyl, <NUM>-methyloxetan-<NUM>-yl, <NUM>-methyl-<NUM>-oxo-cyclobutyl, methoxy, ethoxy, isopropoxy, <NUM>-methoxyethyl or <NUM>-methyl-<NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl;
A<NUM> is N or CR<NUM>; wherein R<NUM> is H or halogen; wherein with the proviso that when R<NUM> is <NUM>-pyridyl, A<NUM> is CF;
A<NUM> is N or CR<NUM>; wherein R<NUM> is H or halogen;
A<NUM> is N or CR<NUM>; wherein R<NUM> is H, halogen, C<NUM>-<NUM>alkyl, or C<NUM>-<NUM>alkoxy;
A<NUM> is N or CR<NUM>; wherein R<NUM> is H or halogen; wherein with the proviso that when R<NUM> is C<NUM>-<NUM>alkyl or C<NUM>-<NUM>alkoxy, A<NUM> is N;
wherein with the proviso that A<NUM>, A<NUM>, A<NUM> and A<NUM> are not CH simultaneously;
or a pharmaceutically acceptable salt thereof.