WO2023069544A1 - Composés d'hétéroaryl-carboxamide à 5 chaînons pour le traitement du vhb - Google Patents

Composés d'hétéroaryl-carboxamide à 5 chaînons pour le traitement du vhb Download PDF

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WO2023069544A1
WO2023069544A1 PCT/US2022/047165 US2022047165W WO2023069544A1 WO 2023069544 A1 WO2023069544 A1 WO 2023069544A1 US 2022047165 W US2022047165 W US 2022047165W WO 2023069544 A1 WO2023069544 A1 WO 2023069544A1
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mmol
pharmaceutically acceptable
solution
compound
methyl
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PCT/US2022/047165
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English (en)
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Thilo Heckrodt
Michael Walker
Min Zhong
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Assembly Biosciences, Inc.
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Publication of WO2023069544A1 publication Critical patent/WO2023069544A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C07D417/08—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 carbon chain containing alicyclic rings

Definitions

  • HBV Hepatitis B
  • HBV BACKGROUND Hepatitis B
  • HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV-positive mothers may also be infected, unless vaccinated at birth.
  • the hepatitis virus particle is composed of a lipid envelope studded with surface protein (HBsAg) that surrounds the viral core.
  • the core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins.
  • rcDNA relaxed circular DNA
  • the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus.
  • the cccDNA is the template for viral RNAs and thus viral proteins.
  • Cp In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core.
  • pregenomic RNA the so-called pregenomic RNA or pgRNA and viral polymerase (P).
  • P viral polymerase
  • nucleotide therapy may lead to the emergence of antiviral drug resistance.
  • the only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon ⁇ or pegylated interferon ⁇ .
  • interferon ⁇ or pegylated interferon ⁇ .
  • the adverse event incidence and profile of interferon ⁇ can result in poor tolerability, and many patients are unable to complete therapy.
  • only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients is likely to have a sustained clinical response to a course of interferon therapy.
  • interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment.
  • current HBV treatments can range from palliative to watchful waiting.
  • Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact.
  • Interferon ⁇ has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients.
  • the disclosure provides, in part, 5-membered heteroaryl carboxamide compounds and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating HBV infections.
  • the disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description.
  • the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • FIGURE 1 illustrates the ORTEP plot for compound CP-AIA-227-2.
  • FIGURE 2 illustrates the relative stereochemistry scheme of compound CP-AIA-227-2.
  • DETAILED DESCRIPTION The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2-6alkenyl.
  • exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-).
  • alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C 1-6 alkoxy and C1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH 3 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 - and CH 3 OCH 2 -, etc.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C 1-6 alkyl and C1-4 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2- methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc.
  • alkylene refers to a biradical alkyl group.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc.
  • carbonyl refers to the biradical -C(O)-.
  • cyano refers to the radical -CN.
  • halo or “halogen” as used herein refer to F, Cl, Br or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • haloC 1-6 alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH 2 O-, and CF3CF2O-.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic ring system containing one to four independently selected heteroatoms, such as nitrogen, oxygen and sulfur.
  • heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen.
  • 5-6 membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also referred to as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H- 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also referred to as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-thiadiazol
  • hydroxy and “hydroxyl” as used herein refers to the radical -OH.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH 2 -, HOCH 2 CH 2 -, CH 3 CH(OH)CH 2 - and HOCH 2 CH(OH)CH 2 -.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH 2 O-, HOCH 2 CH 2 O-, CH 3 CH(OH)CH 2 O- and HOCH 2 CH(OH)CH 2 O-.
  • R a R b N C 1-6 alkyl- refers to an alkyl group substituted with a R a R b N- group, as defined herein. Examples include but are not limited to NH 2 CH 2 -, NH(CH 3 )CH 2 -, N(CH 3 )2CH 2 CH 2 - and CH 3 CH(NH 2 )CH 2 -.
  • R a R b NC 1-6 alkoxy refers to an alkoxy group substituted with a R a R b N- groups, as defined herein.
  • Examples include but are not limited to NH 2 CH 2 -, NH(CH 3 )CH 2 O-, N(CH 3 ) 2 CH 2 CH 2 O-, and CH 3 CH(NH 2 )CH 2 O-.
  • the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • the mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
  • modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • pharmaceutically acceptable include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutical composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • terapéuticaally effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, via disruption of HBV core protein assembly, that results in the improvement of the disease.
  • “Disruption” includes inhibition of HBV viral assembly and infection.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries.
  • Carreira and Kvaerno Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • Certain isotopically-labeled disclosed compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver).
  • Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). II.
  • L 1 and L 2 are independently selected from the group consisting of a bond, C1- 4alkylene, C1-4alkenylene, C1-4alkynylene, haloC1-4alkylene, hydroxyC1-4alkylene, O, NR c , C(O), C(O)O, C(O)NR c , S(O)t, S(O)tNR c , C1-4alkyleneS(O)t and haloC1-4alkyleneS(O)t;
  • L 3 is C 1-6 alkylene, C2-6alkenylene or C2-6alkynylene, wherein the C 1-6 alkylene, C2- 6alkenylene, C2-6alkynylene is optionally substituted with 1-10 substituents independently selected from the group consisting of hydrogen, halogen, OH, CN, NO
  • R 5d and R 10 are independently selected from the group consisting of: ;
  • R 5e is p is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3;
  • r is independently selected for each occurrence from the group consisting of 0, 1 and 2;
  • t is independently selected for each occurrence from the group consisting of 0, 1 and 2;
  • v is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3;
  • w is independently selected for each occurrence from the group consisting of 0, 1 and 2.
  • X 1 is S.
  • X 1 is NR x1 .
  • X 1 is NR x1 and R x1 is hydrogen of methyl. In certain embodiments, X 1 is NR x1 and R x1 is methyl. In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is C1-4alkylene. In certain embodiments, p is 0.
  • R 0 is R 9 ; wherein: R 9 is R 12 S(O)t-C 1-6 alkylene-, R 12 S(O)tNH-C 1-6 alkylene-, R 12 C(O)NH-C 1-6 alkylene-, R 12 S(O)t-haloC 1-6 alkylene-, R 12 S(O)tNH-haloC 1-6 alkylene-, or R 12 C(O)NH-haloC 1-6 alkylene-; and R 12 is R a R b N-, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.
  • R 1 is ; R 11 is independently selected for each occurrence from the group consisting of halogen, CN, C 1-6 alkyl and haloC 1-6 alkyl; and z1 is 0, 1, 2 or 3. In certain embodiments, R 11 is independently selected for each occurrence from the group consisting of halogen and CN. In certain embodiments, R 11 is independently selected for each occurrence from the group consisting of F, Cl, Br and I. In certain embodiments, R 1 is selected from the group consisting of: In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, X 1 is NR x1 , R x1 is hydrogen or methyl, and R 1 is In certain embodiments, R 2 is hydrogen. In certain embodiments, X 1 is NR x1 , R x1 is hydrogen or methyl, R 1 is , and R 2 is hydrogen. In certain embodiments, R 3 is In certain embodiments, R 3 is In certain embodiments, R 3 is In certain embodiments
  • R 3 is In certain embodiments, R 3 is In certain embodiments, R 4 is R 5a -L 1 -, R 5b -L 1 -, R 5d -L 1 -, R 5e -L 1 - or R 6 . In certain embodiments, R 4 is R 5a -L 1 -, R 5d -L 1 -, R 5e -L 1 - or R 6 . In certain embodiments, R 4 is R 5a -L 1 -, R 5d -L 1 - or R 5e -L 1 -. In certain embodiments, L 1 is a bond, C 1-4 alkylene, haloC 1-4 alkylene or hydroxyC 1- 4 alkylene.
  • L 1 is a bond.
  • R 4 is R 6 .
  • R 4 is R 5a -L 1 -.
  • R 4 is R 5d -L 1 -.
  • R 4 is R 5e -L 1 - .
  • R 4 is R 5a .
  • R 4 is R 5d .
  • R 4 is R 5e .
  • R 4 is In certain embodiments, L 2 is a bond, C 1-4 alkyl, haloC 1-4 alkyl. In certain embodiments, L 2 is a bond.
  • R 6 is R 9 , wherein: R 9 is R 12 S(O)t-C 1-6 alkylene-, R 12 S(O)tNH-C 1-6 alkylene-, R 12 C(O)NH-C 1-6 alkylene-, R 12 S(O)t-haloC 1-6 alkylene-, R 12 S(O)tNH-haloC 1-6 alkylene-, or R 12 C(O)NH-haloC 1-6 alkylene-; and R 12 is R a R b N-, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.
  • R 7 is hydrogen, halogen, methyl, methoxy or OH. In certain embodiments, R 7 is hydrogen or OH. In certain embodiments, R 7 is OH. In certain embodiments, R 8 is hydrogen, halogen, methyl, methoxy or OH. In certain embodiments, R 8 is hydrogen or OH. In certain embodiments, R 8 is OH. In certain embodiments, X 1 is NR x1 ; R x1 is hydrogen or methyl; R 1 is R 2 is H; R 3 is ; and R 8 is hydrogen, OH or C 1-6 alkoxy.
  • the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • compositions include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • the disclosure provides a pharmaceutical composition comprises a compound according to any combination of the Examples described herein, or a pharmaceutically acceptable salt and/or stereoisomer thereof.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non- toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stea
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such
  • kits for use by e.g., a consumer in need of HBV infection treatment include a suitable dosage form such as those described above and instructions describing the method of using such dosage form tomediate, reduce or prevent HBV infection.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, .. . etc.... Second Week, Monday, Tuesday, ...” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • an indicated administration dose may be in the range between about 0.1 to about 1000 ⁇ g/kg body weight.
  • the administration dose of the compound may be less than 400 ⁇ g/kg body weight.
  • the administration dose may be less than 200 ⁇ g/kg body weight.
  • the administration dose may be in the range between about 0.1 to about 100 ⁇ g/kg body weight.
  • the dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.
  • a compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g., in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection.
  • Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting.
  • compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, eth
  • Preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate.
  • Preparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period.
  • the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.
  • a disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents.
  • the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • methods and compositions that include a second active agent or administering a second active agent.
  • a subject or patient in addition to being infected with HBV, can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • HBV infection-related co-morbidities i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these HBV-infection- related conditions.
  • a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals.
  • Example antivirals include nucleoside analogs, interferon ⁇ , and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl- 2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1).
  • HAPs heteroaryldihydropyrimidines
  • a method of treating a patient suffering from hepatitis B infection comprising administering to the patient a first amount of a disclosed compound and a second amount of an antiviral, or other anti HBV agent, for example a second amount of a second compound selected from the group consisting of: an HBV capsid assembly promoter (for example, GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below), ; NVR 3-778, NVR1221 (by code); and N890 (as depicted below): other capsid inhibitors such as those disclosed in the following patent applications hereby incorporated by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and WO201403
  • L-FMAU Clevudine
  • LB80380 Besifovir
  • viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives
  • HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below:
  • BM601 as depicted below: disruptors of nucleocapsid formation or integrity such as NZ-4/W28F:
  • cccDNA formation inhibitors such as BSBI-25, CCC-0346, CCC-0975 (as depicted below): HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int.
  • RNAi for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi
  • antisense ISIS- HBV
  • nucleic acid based polymer (REP 2139-Ca)
  • immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda 1a and PEG IFN lambda 1a, Wellferon, Roferon
  • OICR-9429 OICR-9429
  • PARP inhibitors APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists
  • kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors
  • STING Agonists Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins.
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
  • HBV capsid assembly promoters HBF viral polymerase interfering nucleosides
  • viral entry inhibitors HBsAg secretion inhibitors
  • cccDNA formation inhibitors disruptors of nu
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV capsid assembly promoter.
  • the first and second amounts together comprise a pharmaceutically effective amount.
  • the first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
  • Therapeutically effective amounts of a disclosed compound and antiviral may be co- administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration.
  • a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of a disclosed compound), with a detection moiety, for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation).
  • a detection moiety for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation).
  • Contemplated fluorophores include AlexaFluor ® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like.
  • a detection moiety may be used in e.g., a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Method A X-Bridge BEH C-18 (3x50 mmx2.5 ⁇ m); Mobile phase: A; 0.025% formic acid in H 2 O; B; CH 3 CN; Injection volume: 2 ⁇ L; Flow rate:1.2 mL/min, column temperature: 50 o C; Gradient program: 2% B to 98% B in 2.2 min, hold until 3 min, at 3.2 min B conc. is 2 % till up to 4 min.
  • Method B X-select CSH 18 (3x50 mmx2.5 ⁇ m); Mobile phase: A; 0.025% formic acid in H 2 O; B; CH 3 CN; Injection volume: 2 ⁇ L; Flow rate:1.2 mL/min, column temperature: 50 o C; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % till up to 4 min.
  • Method C X-select CSH 18 (3x50 mmx2.5 ⁇ m); Mobile phase: A; 0.05% formic acid in H 2 O:CH 3 CN (95:5); B; 0.05% formic acid in CH 3 CN; Injection volume: 2 ⁇ L; Flow rate: 1.2 mL/min, column temperature: 50 o C; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % till up to 4 min.
  • Method D X-select CSH C18 (3x50 mmx2.5 ⁇ m); Mobile phase: A; 2 mM in Ammonium Bicarbonate; B; CH 3 CN; Injection volume: 2 ⁇ L; Flow rate: 1.2 mL/min, column temperature: 50 o C; Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B conc. is 0 % until up to 4 min.
  • Method E X-select CSH 18 (3x50 mmx2.5 ⁇ m); Mobile phase: A; 0.05% formic acid in H 2 O; B; CH 3 CN; Injection volume: 2 ⁇ L; Flow rate:1.5 mL/min, column temperature: 50 oC; Gradient program: 0% B to 100% B in 1.5 min, hold till 2.2 min, at 2.6 min B conc. is 0 % until up to 3 min.
  • General Procedure for Amidation Method A (amide coupling using EDC . HCl): To a stirred solution of carboxylic acid (1 eq.) in 1,4-dioxane (5.84 mL/mmol) were added EDC .
  • Method B (amide coupling using HATU): To a stirred solution of acid compound (1.1-1.2 eq.) in DMF/DCM (1.01 mL/mmol) at 0 o C, DIPEA (2-3 eq.) and HATU (1.5-2.5 eq.) were added and stirred for 5 min. To this solution, corresponding amine (1 eq.) was added. The resulting reaction mixture was stirred at room temperature for 12-16 hr. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound.
  • Method C AlMe3 mediated amidation: To a stirred solution of corresponding anilines (1.1 eq.) in DCM/Toluene (3 mL/mmol) at 0 °C under Argon atmosphere, AlMe3 (2M in toluene, 2.5 eq.) was added and the reaction mixture was stirred at 0 °C for 10 min and continued stirring at room temperature for 1h. To this solution, corresponding ester compound (1 eq.) was added at 0 °C under Argon atmosphere and the resulting reaction mixture was refluxed at 100 °C for 16 hr.
  • Method A n-BuLi, LiHMDS, LDA, LTMP method at low temperature: To a stirred solution of a substituted alkyne (5 eq.) in anhydrous THF (0.2 M) in an inert atmosphere was added n-BuLi, LiHMDS, LDA or LTMP (5 eq.) slowly via glass syringe at - 78 o C. After stirring at -78 o C for 30 min, a solution of a carbonyl-bearing substrate (1 eq.) in anhydrous THF (0.2 M) was added.
  • reaction mixture was slowly warmed to rt and stirred for another 4 h. Subsequently, the reaction was quenched by adding sat. aq. NH4Cl and concentrated to removed organic solvent. The residue was extracted with EtOAc several times, and the organic combined organic layers washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by CombiFlash ® column chromatography or prep-HPLC to afford the desired compound.
  • Method B NaH, EtMgBr, iPrMgBr method at 0 o C or rt: To a stirred solution of a substituted alkyne (5 eq.) in anhydrous THF (0.2 M) in an inert atmosphere was added NaH, EtMgBr or iPrMgBr (5 eq.) slowly at 0 o C. After stirring at 0 o C for 30 min, a solution of a carbonyl-bearing substrate (1 eq.) in anhydrous THF (0.2 M) was added. The reaction mixture was warmed to rt and stirred for another 4 h. Subsequently, the reaction was quenched by adding sat. aq.
  • Method A A mixture of a halo compound (1 eq.), a substituted alkyne (1 eq.), CuI (0.05 eq.) Pd(dppf)Cl2 (0.025 eq.), and DIEA (1.5 eq.) in DMF (0.2 M) was stirred at rt or an elevated temperature under an inert atmosphere for 2 to 48 h.
  • N-(3-Chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide N-(3-Chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide.
  • 3-chloro-4- fluoroaniline 18 g, 124 mmol
  • Et3N 16 g, 160 mmol
  • HATU 63 g, 160 mmol
  • Step 1 Synthesis of 3,3-difluorocyclobutanone (1-2): To a solution of 1-1 (12.6 g, 0.12 mmol) in DCM (300 mL) were added SiO2 (5.0 g, 100 - 200 mesh) and PCC (42 g, 0.19 mmol) at rt.
  • Example 1 (2.1 g, 34%) as a white solid.
  • Step 1 Synthesis of 1,1,1-trifluoro-4-(trimethylsilyl)but-3-yn-2-ol (2-2): A solution of trimethylsilylacetylene (22.5 g, 230 mmol) in anhydrous Et2O (500 mL) was added n-BuLi (2.5 M in hexanes, 100 mL) at -78 °C. After stirring at -78 °C for 30 min, R-1 (50 g, 352 mmol) was added dropwise, and the resulting mixture was stirred at -78 °C for another 4 h.
  • reaction was quenched with water (10 mL) and diluted with THF (500 mL), followed by NaBH4 (9.6 g, 253 mmol) in one portion. After stirred at rt overnight, the reaction mixture was poured into sat. NH4Cl (aq.) (2 L) and stirred for 2-3 hr. The mixture was concentrated to remove most of the organic solvent. The residue was extracted with DCM (500 mL x 3) and the combined organic layer was dried over anhydrous Na2SO4.
  • Step 2 Synthesis of tert-butyldimethyl(1,1,1-trifluoro-4-(trimethylsilyl)but-3-yn- 2-yloxy)silane (2-3): A solution of 2-2 (20 g, 102 mmol) in DCM (200 mL) was added imidazole (8.16 g, 120 mmol) and TBSCl (22.5 g, 150 mmol) at 0 o C.
  • Example 2 SFC separation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(4,4,4- trifluoro-3-hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide.
  • Example 2 was separated by SFC to give two diastereomerically pure isomers Example 2a as white solid (340 mg, 33 %) and Example 2b as white solid (340 mg, 33 %). The stereochemistry was arbitrarily assigned.
  • reaction mixture was added dropwise to a freshly prepared LDA (9 mmol, 2.25 eq.) in THF (25 mL) at -78 °C and stirred at the same temperature for 1 h.
  • a solution of Intermediate 8 (75.0 mg, 199.56 ⁇ mol) in THF (2 mL) was added dropwise to reaction.
  • the resulting mixture was stirred at -70 °C for 30 min and left to warm gradually to rt. After 4 h the mixture was poured into saturated NH4Cl solution, extracted with EtOAc (50 mL x 3).
  • Example 7 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-methyloxetan-3-yl)ethynyl)- octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide
  • 3-ethynyl-3-methyloxetane (191.87 mg, 2.0 mmol) in anhydrous THF (10 mL) was added dropwise n-butyllithium (110.81 mg, 1.73 mmol, 690 ⁇ L) at -78 °C.
  • n-butyllithium 110.81 mg, 1.73 mmol, 690 ⁇ L
  • Example 8 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-methyl- cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide
  • Step 1 Synthesis of 3-ethynylcyclobutanone (8-2). To a flask with 3-ethynyl-1,1- dimethoxycyclobutane (8-1) (3.0 g, 21.4 mmol) was added trifluoroacetic acid (10 mL). The resulting mixture was stirred at rt for 2 h.
  • Step 2 Synthesis of 3-ethynyl-1-methylcyclobutan-1-ol (8-3). A 2.27 M solution of methyl magnesium chloride in THF (7 mL, 3 eq.) was added dropwise to a stirred solution of 8-2 (0.5 g, 5.3 mmol) in THF (20 mL) at 0-10 °C.
  • Step 3 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- methyl-cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 8).
  • n-BuLi 238.04 mg, 3.72 mmol, 1.52 mL, 14.0 eq.
  • reaction mixture was cooled to -78 °C and THF solution of Intermediate 8 (100.0 mg, 266.08 ⁇ mol) was added at this temperature.
  • the reaction mixture was stirred at the same temperature for 30 min, then warm up to RT and stirred overnight.
  • 5 mL of water and 10 mL of ethyl acetate were added to reaction mixture.
  • the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep- HPLC to give Example 9 (29 mg, 24%).
  • 4-ethynylpyridin-2-amine 94.28 mg, 798.04 ⁇ mol, 6.0 eq.
  • n-butyllithium 2.5M in n-hexane, 1.6 mmol, 0.64 mL, 12.0 eq. at -78 °C.
  • N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-methylpyridin-3- yl)ethynyl)-octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide A suspension of N-(3-chloro-4-fluorophenyl)-4-(5-ethynyl-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (70.0 mg, 174.19 ⁇ mol), which was readily prepared by reacting Intermediate 8 with ethynylmagnesium bromide, 5-bromo-2-methylpyridine (89.92 mg, 522.75 ⁇ mol, 3.0 eq.), triethylamine (176.32 mg, 1.74 mmol, 240.0 ⁇ l, 10.0 eq.), copper(I) iodide (3.32 mg, 17.43 ⁇ mol
  • Step 2 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(3,3-difluorobut-1-yn-1-yl)- 5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.
  • Example 14 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-(1-methyl-1H- imidazol-4-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((3,3-dimethoxycyclobutyl)- ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (14- 1).
  • Step 2 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- (trifluoromethyl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 15).
  • Example 16, 16a and 16b N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (16), N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (16a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5
  • Step 1 Synthesis of 1,1-difluoro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (16-2).
  • THF trimethylsilylacetylene
  • n-BuLi 24 mL, 2.5 M, 61 mmol
  • 16-1 5 g, 53 mmol
  • Step 2 Synthesis of 1,1-difluoro-2-methyl-but-3-yn-2-ol (16-3). To a solution of 16-2 (3.0 g, 16 mmol) in MeOH (150mL) was added K2CO3 (2 eq., 32 mmol, 4.4 g). The mixture stirred vigorously for 16 h at room temperature. After reaction completed, the mixture was filtered.
  • Step 4 N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 16a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3- hydroxy-3-methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 16b).
  • Example 16 was separated by SFC to give Example 16a and Example 16b, respectively.
  • the stereochemistry of the chiral alcohol residue was arbitrarily assigned.
  • Example 17 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-methoxy- cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide
  • Step 1 Synthesis of 1-ethynyl-3-methoxycyclobutan-1-ol (17-2).
  • ethynylmagnesium bromide (2.71 g, 20.97 mmol, 41.95 mL, 3.0 eq.) in dry THF was dropwise added 17-1 (700.0 mg, 6.99 mmol) at 0 °C under an Argon atmosphere.
  • Example 18 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-(pyridin-3- yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide Step 1. Synthesis of 1-ethynyl-3-(pyridin-3-yl)cyclobutan-1-ol (18-2).
  • Step 2 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3- (pyridin-3-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 18).
  • n-BuLi 2.5M in hexane, 1.05 mL, 14 eq.
  • 18-2 225 mg, 1.3 mmol, 7 eq.
  • Step 1 Synthesis of 3-(pyridin-2-yl)-1-[2-(trimethylsilyl)ethynyl]cyclobutan-1-ol (20-1).
  • ethynyltrimethylsilane 3.0 g, 30.57 mmol, 4.32 mL, 1.5 eq.
  • THF 100 mL
  • n-butyllithium 1.96 g, 30.57 mmol, 12.23 mL, 1.5 eq.
  • the reaction mixture was stirred at -78 °C to -20 °C for 1 h.
  • Example 21 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-(2-hydroxypropan-2- yl)pyridin-3-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide Step 1. Synthesis of 2-(5-ethynylpyridin-2-yl)propan-2-ol (21-2).
  • Step 2 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-(2-hydroxypropan- 2-yl)pyridin-3-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 21).
  • Example 22 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((5-(2-hydroxypropan-2- yl)pyridin-2-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide Step 1. Synthesis of 2-(6-ethynylpyridin-3-yl)propan-2-ol (22-2). To a solution of 22-1 (1.5 g, 10.32 mmol) in THF (100 mL) was added chloro(methyl)magnesium (1.93 g, 25.8 mmol, 8.6 mL, 2.5 eq.) in THF at -20 °C.
  • Example 23 N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 23), N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 23a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Ex
  • Step 3 Synthesis of 1,1-difluorobut-3-yn-2-ol (23-4).
  • Compound 23-3 (15 g, 84 mmol) was dissolved in THF/Et2O, followed by TBAF (168 mL, 168 mmol). The mixture was stirred for 16 h at rt overnight. After the reaction was completed, the mixture was washed with water and NaHSO4. The organic layer was distilled to give 23-4 (8 g, 62% yield) as a pale-yellow oil.
  • Example 23 (10 mg, 12 % yield) as an off-white solid.
  • Step 7 Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3- hydroxybut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 23a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3- hydroxybut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 23b).
  • Example 23 was separated by chiral HPLC to give Example 23a and Example 23b.
  • Example 23a, tR 27.9 min; MS (ESI): calcd.
  • Example 24 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-(pyridin-2- yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide
  • 2-bromopyridine 336.69 mg, 2.13 mmol
  • n-butyllithium 123.0 mg, 1.92 mmol, 9.0 eq.
  • Example 25 N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-(2- hydroxypropan-2-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide Step 1. Synthesis of methyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate (25- 2).
  • Step 2 Synthesis of 1-ethynyl-3-(2-hydroxypropan-2-yl)cyclobutan-1-ol (25-3). To a THF solution (25 mL) of methylmagnesium chloride (8.43 mL, 3M in THF, 25.3 mmol, 6.0 equiv) at -30 °C was added dropwise a THF solution (5 mL) of 25-2 (649.82 mg, 4.22 mmol) under an Ar atmosphere.
  • 25-4 400.0 mg, 1.49 mmol
  • THF 10 mL
  • n-butyllithium (1.23 mL, 2.5 M in hexane, 3.08 mmol, 14.5 eq.
  • Tetracycline-free treatment medium 15 mL DMEM/F12 (1:1), 1x Pen/step, with 2% FBS, Tet-system approved (Clontech, cat#: 631106) were then added to mix, transferred into a 50 ml conical tube (Falcon, cat#: 21008-918,) and spun at 1300 rpm for 5 min. Pelleted cells were then re-suspended/washed with 50 mL of 1X DPBS (Invitrogen, cat#: 14190-136) 2 times and 50 mL treatment medium twice. HepAD38 cells were then re-suspended with 10 mL of treatment medium, syringed, and counted.
  • Wells of 96-well clear bottom TC plate (Corning, cat#: 3904,) were seeded at 50,000 cells/well in 180 ⁇ L of treatment medium, and 20 ⁇ L of either 10% DMSO (Sigma, cat#: D4540) as controls or a 10X solution of test compounds in 10% DMSO in treatment media was added for a final compound concentration starting at 10 ⁇ M, and plates were incubated in 5% CO2 incubator at 37°C for 5 days. Subsequently viral load production was assayed by quantitative PCR (qPCR) of the HBV core sequence.
  • qPCR quantitative PCR
  • PCR reaction mixture containing forward primers HBV-f 5'- CTGTGCCTTGGGTGGCTTT-3’ (IDT DNA), Reverse primers HBV-r 5'- AAGGAAAGAAGTCAGAAGGCAAAA-3' (IDT DNA), Fluorescent TaqMan tm Probes HBV-probe 5′-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTC/3IABkFQ -3′ (IDT DNA), 10 ⁇ L/well of PerfeCTa ® qPCR ToughMix ® (Quanta Biosciences, Cat#: 95114- 05K), and 6 ⁇ L/well of DEPC water (Alfa Aesar, cat#: J62087) was prepared.
  • Cell viability assay was performed with CellTiter-Glo Luminescent Cell Viability Assay (Promega, cat#: G7573) with modification.
  • Mixed appropriate amount of CellTiter-Glo (CTG) 1X DPBS in a 1:1 ratio added 100 uL of the mixture to each well followed completely removal of all supernatants in each well without touching cell surface.
  • CCG CellTiter-Glo
  • EC50 or CC50 values were calculated through curve-fitting of the four-parameter nonlinear-logistic-regression model (GraphPad Prism or Dotmatics). CC 50 values were all >10 ⁇ M.
  • Tables 2-5 give the viral load lowering EC50 values for exemplified compounds of the invention grouped in the following ranges: A indicates EC50 ⁇ 1 nM; B indicates EC50 ⁇ 1 nM and ⁇ 10 nM; C indicates EC50 of ⁇ 10 to ⁇ 100 nM; and D indicates EC50 of ⁇ 100 nM. Table 2. Viral Load Lowering for Examples 1-75.
  • AIA-227 was separated by SFC to give AIA-227-1 (4 mg) as a white solid and AIA-227-2 (4 mg) as a white solid.
  • AIA-227-2 Alternative synthesis of 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5- hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4- carboxamide.
  • dimethylsulfone 77.0 g, 818.7 mmol
  • n-BuLi 327.5 mL, 818.7 mmol, 2.5M
  • a crystal with size of 0.08 x 0.10 x 0.20mm of compound AIA-227-2 was obtained from EtOH after 20 days of volatilization and was used for X-ray diffraction data collection.
  • the crystal belongs to monoclinic crystal system, with a space group P21/c.
  • the structure was solved by direct methods and all of the non-H atoms were refined against F 2 by full-matrix least-squares methods using the SHELXTL program. All H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7531 and 0.6017, respectively.
  • the final R, wR2, GOF are 0.0457, 0.1293 and 1.024, respectively.

Abstract

La présente invention concerne, en partie, des composés d'hétéroaryl-carboxamide à 5 chaînons, et des compositions pharmaceutiques de ceux-ci, utiles pour la rupture d'un ensemble protéine centrale du VHB, et des procédés de traitement d'une infection par le virus de l'hépatite B (VHB).
PCT/US2022/047165 2021-10-20 2022-10-19 Composés d'hétéroaryl-carboxamide à 5 chaînons pour le traitement du vhb WO2023069544A1 (fr)

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