US20230165843A1 - Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivatives - Google Patents

Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivatives Download PDF

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US20230165843A1
US20230165843A1 US17/781,730 US202017781730A US2023165843A1 US 20230165843 A1 US20230165843 A1 US 20230165843A1 US 202017781730 A US202017781730 A US 202017781730A US 2023165843 A1 US2023165843 A1 US 2023165843A1
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hbv
inhibitors
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halogen
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Bailing YANG
Gudmundsson KRISTJAN
Liuyu DONG
James Chen
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Gannex Pharma Co Ltd
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    • A61K31/425—Thiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of pharmaceuticals for treating or preventing hepatitis B virus (HBV) infection. Specifically, the present invention relates to the use of phenylisoxazolyl methylene-naphthalene-ether derivatives for the treatment or prevention of HBV infection, pharmaceutical compositions comprising phenylisoxazolyl methylene-naphthalene-ether derivatives and other anti-HBV agents, and pharmaceutical use of phenylisoxazolyl methylene-naphthalene-ether derivatives.
  • HBV hepatitis B virus
  • Hepatitis B virus is a hepatotropic, enveloped, partially double-stranded DNA virus. It is most commonly spread from mother to child at birth (perinatal transmission) and also can be transmitted by blood or body fluid.
  • HBV generates a covalently closed circular DNA (cccDNA), secrets HBV surface antigen to suppress the immune system, and caused persistent (chronic) infection which is hard to eradicate.
  • HBV infection is a major public health threat in the world with over 257 million people chronically infected and caused over 887000 deaths every year. (Revill, P. A. et al, Lancet Gastroenterol. Hepatol. 2019, 4(7), 545-558).
  • chronic hepatitis B virus (HBV) infection caused more than half of the deaths due to liver cirrhosis and about half the cases of hepatocellular carcinoma in the region (Sarin, S. K. et al Lancet Gastroenterol.
  • nucleot(s)ide inhibitors such as Tenofovir disoproxil (Viread), Tenofovir alafenamide (Vemlidy), Entecavir (Baraclude), Telbivudine (Tyzeka or Sebivo), Lamivudine (Epivir-HBV, Zeffix, or Heptodin) and immunomodulators, such as pegylated Interferon alfa-2a (Pegasys).
  • nucleot(s)ide inhibitors such as Tenofovir disoproxil (Viread), Tenofovir alafenamide (Vemlidy), Entecavir (Baraclude), Telbivudine (Tyzeka or Sebivo), Lamivudine (Epivir-HBV, Zeffix, or Heptodin)
  • immunomodulators such as pegylated Interferon alfa-2a (Pegasys).
  • Farnesoid X receptor is a member of the nuclear receptor family, which includes steroid receptors, retinoid receptors, and thyroid hormone receptors (Radreau P, Porcherot M, Ramière C, et al. Reciprocal regulation of farnesoid X receptor ⁇ activity and hepatitis B virus replication in differentiated HepaRG cells and primary human hepatocytes. FASEB J. 2016; 30(9):3146-54). FXR is mainly expressed in the liver, kidney, small intestine and adrenal glands. After HBV infects cells, HBV cccDNA enters the nucleus and begins to transcribe a variety of HBV RNAs.
  • the pregenomic RNA is reverse-transcribed to form HBV DNA, and the remaining RNAs are translated to form HBsAg, HBeAg, HBcAg, HBx, etc.
  • HBV DNA The pregenomic RNA is reverse-transcribed to form HBV DNA, and the remaining RNAs are translated to form HBsAg, HBeAg, HBcAg, HBx, etc.
  • These viral proteins and nucleic acids are assembled together in the endoplasmic reticulum, and then virus particles are formed and are released out of cells.
  • the transcription of HBV cccDNA can be regulated by nuclear receptors, such as HNF-4 ⁇ and FXR.
  • FXR agonists inhibit the formation of stable transcription complexes between cccDNA and HBx by activating FXR, thereby affecting the stability of cccDNA, inhibiting the transcriptional activity of cccDNA, and achieving the purpose of reducing viral DNA and HBsAg (Mouzannar K, Fusil F, Lacombe B, et al. Farnesoid X receptor- ⁇ is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. FASEB J. 2019; 33(2):2472-2483).
  • the inventors of the present invention found that the phenylisoxazolyl methylene-naphthalene-ether derivatives represented by formula (I), as an efficient small molecule FXR agonist, has anti-HBV activity.
  • In vitro primary human hepatocyte infection test results show that the phenylisoxazolyl methylene-naphthalene-ether derivatives represented by formula (I) can effectively inhibit HBV DNA, HBV RNA and HBsAg.
  • the present invention relates to the use of phenylisoxazolyl methylene-naphthalene-ether derivatives for the treatment or prevention of HBV infection, pharmaceutical compositions comprising phenylisoxazolylmethylene-naphthalene-ether derivatives and other anti-HBV agents, and pharmaceutical use of phenylisoxazolyl methylene-naphthalene-ether derivatives.
  • C1-6 alkyl denotes an alkyl radical having from 1 up to 6, particularly up to 4 carbon atoms, the radicals being either linear or branched with single or multiple branching, for example, butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl; propyl, such as n-propyl or isopropyl; ethyl or methyl; more particularly, methyl, iso-propyl or tert-butyl.
  • C1-6 alkoxy refers to “C1-6 alkyl-O—”, and is particularly methoxy, ethoxy, isopropyloxy or tert-butoxy.
  • C3-6 cycloalkyl refers to a cyclic alkyl radical having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the C3-6 cycloalkyl can be optionally substituted by C1-6 alkyl and/or halogen.
  • C4-7 alkylcycloalkyl refers to a combination of alkyl and a cycloalkyl group such that the total number of carbon atoms is 4 to 7.
  • C4 alkylcycloalkyl includes methylenecyclopropyl.
  • the term “5-10 membered aryl” refers to a 5-10 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system. Typically, the aryl is a 5 or 6 membered ring system.
  • heteroaryl refers to a 5-10 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system having 1 to 4 heteroatoms.
  • heteroaryl is a 5 or 6 membered ring system.
  • heteroaryl as used herein may encompass monovalent or divalent heteroaryls.
  • halogen refers to one or more of fluoro, chloro, bromo and iodo, and more particularly, fluoro or chloro.
  • C1-6 haloalkyl refers to an alkyl radical that is substituted by one or more halo radicals, and is particularly C1-6 fluoroalkyl or C1-6 chloroalkyl, such as trifluoromethyl and 2,2,2-trifluoroethyl.
  • salts refers to salts which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • auxiliary materials may include any or all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents and antifungal agents), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • hepatitis B virus or “HBV” refers to a member of the Hepadnaviridae family having a small double-stranded DNA genome of approximately 3,200 base pairs and a tropism for liver cells. “HBV” includes hepatitis B virus that infects any of a variety of mammalian (e.g., human, non-human primate, etc.) and avian (duck, etc.) hosts.
  • mammalian e.g., human, non-human primate, etc.
  • avian duck, etc.
  • HBV includes any known HBV genotype, e.g., serotype A, B, C, D, E, F, and G; any HBV serotype or HBV subtype; any HBV isolate; HBV variants, e.g., HBeAg-negative variants, drug-resistant HBV variants (e.g., lamivudine-resistant variants; adefovir-resistant mutants; tenofovir-resistant mutants; entecavir-resistant mutants; etc.); and the like.
  • HBV genotype e.g., serotype A, B, C, D, E, F, and G
  • HBV serotype or HBV subtype e.g., HBeAg-negative variants
  • drug-resistant HBV variants e.g., lamivudine-resistant variants; adefovir-resistant mutants; tenofovir-resistant mutants; entecavir-resistant mutants; etc.
  • the term “therapeutically effective amount” refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • the present invention relates to a pharmaceutical composition comprising an HBsAg inhibitor and a nucleos(t)ide analogue, in a pharmaceutically acceptable carrier.
  • the term “compound of formula (I)” includes phenylisoxazolyl methylene-naphthalene-ether derivatives of the formula (I), prodrugs thereof, salts of the compound and/or prodrugs, hydrates or solvates of the compound, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers isotopically labeled compounds (including deuterium substitutions) and polymorphs of the compound.
  • Salts of the compound of formula (I) may be made by methods known to a person skilled in the art. For example, treatment of a compound of formula (I) with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compound of formula (I).
  • alkaline salts of the carboxylic acid such as sodium, potassium, lithium, calcium, magnesium, aluminium, zinc, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
  • Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of formula (I) and these should be considered to form a further aspect of the invention.
  • the present invention provides a method of treating or preventing infection with hepatitis B virus in a human or animal, comprising administering to the human or animal in need thereof a therapeutically effective amount of a phenylisoxazolyl methylene-naphthalene-ether derivatives having a structure of formula (I), and a pharmaceutically acceptable salt, ester or stereoisomer thereof:
  • R1, R2 and R3 are independently selected from H, halogen, and unsubstituted or halogen substituted C1-6 alkyl and unsubstituted or halogen substituted C1-6 alkoxy, provided that at least one of R1, R2 and R3 is not hydrogen, R0 is selected from unsubstituted or halogen substituted C1-6 alkyl, C3-6 cycloalkyl, C4-7 alkylcycloalkyl;
  • X1 and X2 are independently selected from H and halogen
  • Z is a residue selected from 5-10 membered aryl or 5-10 membered heteroaryl optionally having one or more hetero atoms selected from N, O and S, wherein the 5-10 membered aryl or 5-10 membered heteroaryl is substituted by R4 and is optionally further substituted by R5;
  • R4 is selected from —COOH, —CH2COOH, —NHSO2CF3, —SO2NH—C1-6 alkyl, —SO3H, —CONHSO2-C1-6alkyl, —CONHSO2-C3-6cycloalkyl, —CONHSO2-5-10 membered aryl and —CONHSO2-5-10 membered aryl substituted by C1-6 alkyl at the aryl, and R5 is selected from H, C1-6 alkyl, halogen, C1-6 haloalkyl, —O—(C1-6 alkyl) and —NH—(C1-6 alkyl).
  • R1, R2 and R3 are independently selected from H, halogen and C1-3 perfluoroalkoxy, such as H, Cl, F and —O—CF3.
  • both of R1 and R2 are Cl, and R3 is H.
  • both of R1 and R2 are Cl, and R3 is F.
  • both of R1 and R2 are Cl, and R3 is —O—CH3.
  • R1 is —O—CF3, and both of R2 and R3 are H.
  • R0 is isopropyl or cyclopropyl.
  • Z is a phenyl, which is optionally substituted by 1-5 halogen atoms.
  • Z is a 5-10 membered heteroaryl having one or more hetero atoms selected from N, O and S.
  • Z is a 5-6 membered heteroaryl having one or more hetero atoms selected from N, O and S.
  • Z is a R4 and optionally R5 substituted pyridyl.
  • R4 is selected from —COOH, —CH2COOH, —CONHSO2-C1-6 alkyl and —CONHSO2-C3-6 cycloalkyl. In more preferred embodiment of the present invention. R4 is —COOH or —CH2COOH. In a most preferred embodiment of the present invention, R4 is —COOH.
  • R5 is one selected from H, C1-3 alkyl and halogen.
  • Z is pyridyl; R4 is —COOH— and R5 is H or halogen.
  • the halogen in the aforesaid substituents is fluoro or chloro.
  • the compound having the formula (I) is of one of the following structures:
  • the method for preparing the compound of formula (I) can include the following four general routes (Route A, Route B, Route C, and Route D), among which:
  • X is a halogen
  • R1, R2 and R3 are independently selected from H, halogen, and unsubstituted or halogen substituted C1-6 alkyl and unsubstituted or halogen substituted C1-6 alkoxy provided that at least one of R1, R2 and R3 is not hydrogen, R0 is selected from unsubstituted or halogen substituted C1-6 alkyl, C3-6 cycloalkyl, C4-7 alkylcycloalkyl;
  • Z is a residue selected from 5-10 membered heteroaryl having one or more hetero atoms selected from N, O and S, wherein residue Z is substituted by R4 and optionally further substituted by R5;
  • R4 is selected from —COOH, —CH2COOH, —NHSO2CF3, —SO2NH—C1-6 alkyl, —S03H, —CONHSO2-C1-6 alkyl, —CONHSO2-C3-6 cycloalkyl, —CONHSO2-5-10 membered aryl and —CONHSO2-5-10 membered aryl substituted by C1-6 alkyl at the aryl, and R5 is selected from H, C1-6 alkyl, halogen and C1-6 haloalkyl; optionally
  • ester precursors when Z is substituted with R4 selected from —COOH and —CH2COOH, ester precursors can be converted to free acids by hydrolysis using conditions well known to those skilled in the art,
  • X is preferably bromine or iodine, and more preferably bromine.
  • Compound (B2) is converted to boronic ester of the formula (B3), preferably, under Pd-catalyzed conditions;
  • Compound (B3) is converted to naphthol (A2) by oxidation, with oxidants such as NaClO2 or H2O2;
  • X3 is a halogen, preferably bromine or iodine, and more preferably bromine.
  • Compound (C2) is converted to boronic ester (C3), preferably, under Pd-catalyzed conditions;
  • Compound (C3) is converted to naphthol (C4) by oxidation, with oxidants such as NaClO2 or H2O2;
  • X4 is a halogen, preferably bromine or iodine, and more preferably bromine.
  • the phenylisoxazolyl methylene-naphthalene-ether derivative having the structure of formula (I), or pharmaceutically acceptable salts, esters or stereoisomers thereof (“compound of formula (I)” for short) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the compound of formula (I) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of formula (I), with any dose of other therapeutic agents.
  • the compound of formula (I) is co-administered with other anti-HBV agents, either as part of the same pharmaceutical composition or in separate pharmaceutical compositions. These agents also can be administered at their own schedule and through different route.
  • Co-administration includes administration of a unit dose of a compound of formula (I) before or after administration of a unit dose of one or more other anti-HBV agents.
  • the compound of formula (I) may be administered within seconds, minutes, or hours of administration of one or more other anti-HBV agents.
  • a unit dose of the compound of formula (I) is administered first, followed by administration of one or more other anti-HBV agents within seconds, minutes, or hours.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • the method of treating or preventing infection with hepatitis B virus in a human or animal comprises administering the phenylisoxazolylmethylene-naphthalene-ether derivative having the structure of formula (I), its pharmaceutically acceptable salt, and ester or stereoisomer in combination with one or more other anti-HBV agents.
  • the other anti-HBV agents may be selected from antisense oligonucleotide targeting viral mRNA (ASO), short interfering RNAs (siRNA), B- and T-lymphocyte attenuator inhibitors, CCR2 chemokine antagonist, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, fatty acid synthase inhibitors, cyclophilin inhibitors, cytokines, Endonuclease modulator, epigenetic modifiers, gene modifiers or editors, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV vaccines, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitors,
  • ASO antisense
  • the other anti HBV agents can be selected from HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hepatitis b surface antigen (HBsAg) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, fatty acid synthase inhibitors, HBV antibodies, CCR2 chemokine antagonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, PD-1 inhibitors, PD-L1 inhibitors, KDM inhibitors, and HBV replication inhibitors.
  • HBV vaccines HBV DNA polymerase inhibitors, immuno
  • the other anti HBV agent is a nucleot(s)ide.
  • HBV DNA polymerase inhibitors include adefovir (HEPSERA*), emtricitabine (EMTRIVA), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA), pradefovir, devudine, ribavirin, lamivudine (EPIV R-V
  • the compound of formula (I) is administered in combination with entecavir or tenofovir.
  • the other anti HBV agent is an immunomodulator.
  • immunomodulators include TLR agonist R07020531, GS-9620, GS-9688.
  • immunomodulator also includes PD-1 inhibitors such as nivolumab, pembrolizumab, pidilizumab, BGB-108, camrelizumab (SHR-1210), PDR-001, PF-06801591, IBI-308, cemiplimab, camrelizumab, sintilimab, tislelizumab (BGB-A317), BCD-100, JNJ-63723283, Zimberelimab (GLS-010, WBP-3055), Balstilimab (AGEN2034), and dostarlimab (TSR-042)
  • PD-1 inhibitors such as nivolumab, pembrolizumab, pidilizumab, BGB-108, camrelizumab (SHR-1210), PDR-001, PF-
  • immunomodulator also include PD-L1 inhibitors such as atezolizumab (RG-7446), avelumab, BGB-A333, BMS-936559 (MDX-1105), durvalumab, CX-072, GX-P2 and envafolimab (KN035, ASC022).
  • PD-L1 inhibitors include small molecule inhibitors such as GS-4224, INCB086550.
  • the compound of formula (I) is administered in combination with KN035 (ASC022).
  • HBV vaccines include both prophylactic and therapeutic vaccines.
  • HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/FlBV7M (LBVP-0101; LBVW-0101), DTwP-Hepb-FIib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223 192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), recomb
  • the compound of formula (I) is administered in combination with ABX203, AIC 649, INO-1800, HB-110, TG1050, HepTcell, VR-CHB01, VBI-2601 or CARG-201.
  • the other anti HBV agent is antisense oligonucleotide targeting viral mRNA (ASO).
  • ASO antisense oligonucleotide targeting viral mRNA
  • antisense oligonucleotide include Ionis-HBVRx and Ionis-HBV-LRx.
  • the other anti HBV agent is short interfering RNAs (siRNA).
  • short interfering RNAs include JNJ-3989 (ARO-HBV), Vir-2218 (ALN-HBV02), and DCR-HBVS.
  • the other anti HBV agent is a hepatitis surface antigen (HBsAg) Inhibitor.
  • HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-203 and REP-006, REP-9 AC, as well as inhibitors targeting the PAPD 57.
  • the other anti HBV agent is a HB Viral Entry Inhibitor, such as Myrcludex B, or an antibody targeting at preS.
  • the other anti HBV agent is a fatty acid synthase inhibitor, such as TVB-2640, TVB-3150, TVB-3199, TVB-3166, TVB-3567 and TVB-3664.
  • the other anti HBV agent is a capsid inhibitor.
  • HBsAg inhibitors include ABI-H0731, ABI-H2158, ABI-H3733, CB-HBV-001, JNJ-6379, JNJ-0440, QL-007, RG-7907 and RO7049389.
  • the other anti-HBV agent is ordinary or long-acting interferon.
  • the examples include Pegasys and PEG-INTRON.
  • the compound of formula (I) of the present invention is combined with Pegasys.
  • the present invention provides use of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof in the preparation of a pharmaceutical composition for anti-hepatitis B virus.
  • the phenylisoxazolyl methylene-naphthalene-ether derivative having the structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof are as defined above.
  • the anti-HBV pharmaceutical composition comprises as an active ingredient a phenylisoxazolyhnethylene-naphthalene-ether derivative having a structure of formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof and one or more other anti-HBV agents.
  • the other anti-HBV agents are as defined above.
  • the present invention provides an pharmaceutical composition for anti-hepatitis B virus comprising a therapeutically effective amount of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof and one or more other anti-HBV agents, and a pharmaceutically acceptable auxiliary material.
  • a phenylisoxazolyl methylene-naphthalene-ether derivative having the structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof are as defined above, and the other anti-HBV agents are as defined above.
  • the pharmaceutical composition of the present invention are suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration, and the like, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known to those skilled in the art of pharmacy.
  • compositions include those suitable for various administration routes, including oral administration.
  • the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product.
  • Compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition is a tablet.
  • the compound may be administered to an individual in an effective amount.
  • the amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration.
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the frequency of dosage of the compound of the present disclosure are will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection.
  • FIG. 1 is EC50 curves of inhibition HBV DNA in PHH Cells
  • FIG. 2 is EC50 curves of HBsAg inhibition in PHH Cells
  • FIG. 3 is EC50 curves of HBV RNA inhibition in PHH Cells.
  • FIG. 4 is HBV DNA level in AAV-HBV mouse serum before and after treatment of compound 33.
  • FIG. 5 is HBV RNA level in AAV-HBV mouse serum before and after treatment of compound 33.
  • FIG. 6 is HBsAg level in AAV-HBV mouse serum before and after treatment of compound 33.
  • IR (cm-1) major stretches at 1591.94 (C ⁇ O stretch), 1412.27, 1556.70 (C—C stretch), 1364.37, 1389.89 (C—H deformation), 1218.41, 1250.94 (C ⁇ N stretch), 791.88 (C—Cl stretch).
  • the PHH cells were seeded into the 48-well plates at the density of 1.32 ⁇ 105 cells/well.
  • the PHH cells seeding date was defined as day 0.
  • the PHH cells were infected with HBV (D type) at 1600 GE/cell on day 1.
  • the culture medium containing compounds was refreshed on day 2, 4, 6 and day 8.
  • the cells were treated with CCK8 and culture supernatant and cells were collected.
  • FXR Compounds were tested at 10000.0, 3000.0, 1000.0, 300.0, 100.0, 30.0, and 10.0 nM, and ETV was tested at 0.2000, 0.0667, 0.0222, 0.0074, 0.0025, 0.0008, and 0.0003 nM.
  • 1% DMSO was used as non-treatment control.
  • the supernatants on day 9 were collected, and analyzed for HBV DNA by qPCR, HBV RNA by RT-qPCR, HBsAg and HBeA by ELISA.
  • DNA in the culture supernatants was isolated with the QIAamp 96 DNA Blood Kit according to the manual and quantified by the qPCR. 80 ⁇ l of the culture supernatants sample was used to extract DNA. The elution volume was 120 ⁇ l.
  • the PCR mix (8 ⁇ l/well) and the samples (2 ⁇ l/well) or plasmid standards (2 ⁇ l/well) were added to the 384-well optical reaction plate and performed using the following program: 95C for 10 min, then cycling at 95° C. 15 sec, 60° C. 1 min for 40 cycles.
  • RNA in the culture supernatants was isolated with the PureLinkTM Pro 96 Viral RNA Kit according to the manual. 35 ⁇ l of the culture supernatants sample was used to extract RNA. The elution volume was 100 ⁇ l. HBV RNA was quantified by RT-qPCR.
  • HBsAg and HBeAg in the samples harvested on day 9 were measured by the HBsAg ELISA kit (Autobio) and HBeAg ELISA kit (Autobio) according to the manual.
  • HBsAg ELISA kit Autobio
  • HBeAg ELISA kit Autobio
  • PHH assay Chemiluminescence Apparatu was used to measure HBsAg according to the Antu HBsAg ELISA kit manual.
  • CCK-8 working solution (diluted with fresh culture medium at ratio of 1:9) was added to the cell plates.
  • the plates were incubated at 37° C., 5% CO2 incubator for approximate 30 min.
  • the ODs were measured by microplate reader (OD450 nm/OD630 nm).
  • HBV DNA inhibition (1 ⁇ HBV DNA copy number of test sample/avg. HBV DNA copy number of 1% DMSO control) ⁇ 100%
  • % HBV RNA inhibition (1 ⁇ HBV RNA copy number of test sample/avg. HBV RNA copy number of 1% DMSO control) ⁇ 100%
  • % HBsAg inhibition (1 ⁇ HBsAg quantity of sample/HBsAg quantity of 1% DMSO control) ⁇ 100%
  • % HBeAg inhibition (1 ⁇ HBeAg quantity of sample/HBeAg quantity of 1% DMSO control) ⁇ 100%
  • % Cell viability value of sample/a value of 1% DMSO ⁇ 100%.
  • the EC50 and CC50 values were determined by dose-response curves fitted by GraphPad Prism using “log (agonist) vs. response-variable slope”.
  • Compound 1, 22, and 27 had dose-dependent inhibition of extracellular HBV DNA HBsAg and HBV RNA.
  • ETV showed significant inhibition of HBV DNA, but no significant inhibition of HBV HBsAg and HBV RNA.
  • mice of 5-week old were given rAAV8-1.3HBV (1 ⁇ 1011 v.g.) via tail vein to establish infection on Day ⁇ 28.
  • blood was drawn from submandibular vein to determine the level of HBV DNA, and HBsAg.
  • 40 mice were chosen based on HBV DNA, and HBsAg results, and were randomly assigned to 5 groups. After the mice were infected with HBV virus for 28 days, treatment was given orally once per day, for 4 weeks.
  • Group 1 was given vehicle (0.5% CMC-Na, 10 ml/kg), Group 2 was given positive control ETV (0.1 mg/kg). Groups 3, 4, and 5 were given Compound 33 at 10 mg/kg, 30 mg/kg, and 60 mg/kg, respectively. Blood was drawn from submandibular vein every week to determine the concentration of HBV DNA, HBV RNA, and HBsAg. On Day 28, blood was taken from the heart.
  • HBV DNA determination by qPCR DNA in the mice plasma was isolated with the QIAamp 96 DNA Blood Kit according to the manual and quantified by the qPCR, and performed using the following program: 95C for 10 min, then cycling at 95 V 15 sec, 60° C. 1 min for 40 cycles.
  • RNA in the mice plasma was isolated with the PureLinkTM Pro 96 Viral RNA/DNA Kit according to the manual. 20 ⁇ l of the plasma was used to extract RNA
  • HBsAg determination by ELISA HBsAg in the samples was measured by the HBsAg ELISA kit (Autobio) according to the manual. Briefly, after the plasma was diluted 1200 ⁇ in a coated plate, and incubate with the enzyme conjugated (37V, 60 min), and the plate was washed 5 time. Substrate was added, and it was kept from light at room temperature for 10 min and intensity was measured by a plated reader.
  • Average ⁇ Standard deviation was calculated for each group, and analyzed with Student's t-test.
  • the HBV DNA in the high dose group (60 mg/kg) was significantly lower than that of the vehicle group.
  • the log 10[DNA copy/uL] of the high dose group was 0.77-1.12 lower than the vehicle group (p ⁇ 0.05).
  • the HBV RNA in the high dose group (60 mg/kg) was significantly lower than that of the vehicle group.
  • the log 10[RNA copy/uL] of the high dose group was 0.60-0.66 lower than the vehicle group (p ⁇ 0.01).
  • ETV treatment showed no significant effect on HBV RNA as compared to the vehicle group.
  • the HBsAg in the high dose group (60 mg/kg) was lowered by 0.38 log 10 [IU/ml] as compared to the vehicle group.
  • ETV treatment showed no significant effect on HBsAg as compared to the vehicle group.

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