ZHONG MIN (US)
WALKER MICHAEL (US)
BURES MARK (US)
PAJOUHESH HASSAN (US)
ZHANG KEN (US)
WO2021110883A1 | 2021-06-10 | |||
WO2020194531A1 | 2020-10-01 | |||
WO2011000883A2 | 2011-01-06 | |||
WO2021110884A1 | 2021-06-10 | |||
WO2021110885A1 | 2021-06-10 | |||
WO2021110886A1 | 2021-06-10 | |||
WO2021110887A1 | 2021-06-10 | |||
WO2020161216A1 | 2020-08-13 | |||
WO2020161217A1 | 2020-08-13 | |||
WO2019234077A1 | 2019-12-12 | |||
WO2014037480A1 | 2014-03-13 | |||
WO2014184328A1 | 2014-11-20 | |||
WO2013006394A1 | 2013-01-10 | |||
WO2014089296A2 | 2014-06-12 | |||
WO2014106019A2 | 2014-07-03 | |||
WO2013102655A1 | 2013-07-11 | |||
WO2014184350A1 | 2014-11-20 | |||
WO2014184365A1 | 2014-11-20 | |||
WO2014161888A1 | 2014-10-09 | |||
WO2014131847A1 | 2014-09-04 | |||
WO2014033176A1 | 2014-03-06 | |||
WO2014033167A1 | 2014-03-06 | |||
WO2014033170A1 | 2014-03-06 | |||
WO2013010069A1 | 2013-01-17 | |||
WO2014074906A1 | 2014-05-15 |
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CLAIMS: 1. A compound of Formula II , or a pharmaceutically acceptable salt thereof, wherein: L is C1-4alkylene or C(O); M is NRx or CR2R3; Rx is hydrogen or C1-4alkyl; R0 is -C(O)OH, -C(O)OC1-6alkyl, or -S(O)2OH; R1 is selected from the group consisting of hydrogen, halo, C1-4alkyl and haloC1- 4alkyl; R2 and R3 are independently selected from the group consisting of hydrogen, halo and methyl; R4 is independently selected from the group consisting of hydrogen, halo, cyano, C1- 4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio; R5 is an C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, C3-7monocycloalkyl, -L-C3- 7monocycloalkyl, mono3-7heterocycloalkyl, -L-mono3-7heterocycloalkyl, -L-phenyl, monocyclo5-6heteroaryl or -L-monocyclo5-6heteroaryl group, wherein the C3- 7monocycloalkyl, -L-C3-7monocycloalkyl, mono3-7heterocycloalkyl, -L-mono3- 7heterocycloalkyl, -L-phenyl, monocyclo5-6heteroaryl or -L-monocyclo5-6heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is NRx. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein M is NH or NCH3. 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein M is CH2, CF or CF2. 5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R0 is -C(O)OH or -C(O)OC1-4alkyl. 6. The compound of claims 5, or a pharmaceutically acceptable salt thereof, wherein R0 is -C(O)OH. 7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or F. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R1 is F. 9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is methylthio. 10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or haloC1-6alkyl. 11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 is R5 is C3-7monocycloalkyl, -L-C3-7monocycloalkyl, mono3-7heterocycloalkyl or -L-mono3-7heterocycloalkyl group, wherein the C3- 7monocycloalkyl, -L-C3-7monocycloalkyl, mono3-7heterocycloalkyl or -L-mono3- 7heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1- 4alkylthio. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R5 is C3-7monocycloalkyl or mono3-7heterocycloalkyl, wherein the C3- 7monocycloalkyl or mono3-7heterocycloalkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R5 is C3-7monocycloalkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R5 is a mono3-7heterocycloalkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of wherein: R6 is independently selected for each occurrence from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio; R6a is hydrogen or C1-6alkyl; X1 is O, S or NR6; v is 0, 1, 2 or 3; and w is 0, 1 or 2. 16. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 is a -L-phenyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 17. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R5 is monocyclo5-6heteroaryl or -L-monocyclo5-6heteroaryl group, wherein the monocyclo5-6heteroaryl or -L-monocyclo5-6heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio. 18. The compound of claims 17, or a pharmaceutically acceptable salt thereof, wherein R5 is R6 is independently selected for each occurrence from the group consisting of halo, OH, CN, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkylthio; R6a is hydrogen or C1-6alkyl; X2 is O or S; v is 0, 1, 2 or 3; and w is 0, 1 or 2. 19. A compound, or a pharmaceutically acceptable salt thereof, selected form the group consisting of . 20. A pharmaceutical composition comprising a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 21. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof. 22. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 20. 23. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof. 24. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 20. |
group; wherein: R 9 is independently selected for each occurrence from the group consisting of halogen, CN, NO 2 , OH, R a R b N-, C 1-4 alkyl and haloC 1-4 alkyl; and s is selected from the group consisting of 0, 1, 2 and 3. [0083] In certain embodiments, s is 0. [0084] In certain embodiments, R 7 is C 1-6 alkyl, C2-6alkenyl, or C2-6alkynyl, wherein the C1- 6alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, CN, NO 2 , OH and R a R b N-. [0085] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a C 3-7 monocycloalkyl or C 5-12 bicycloalkyl, wherein the C 3-7 monocycloalkyl or C 5-12 bicycloalkyl is optionally substituted with 1-6 R 8 group. [0086] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a C 3-7 monocycloalkyl optionally substituted with 1-6 R 8 group. [0087] In certain embodiments, R 7 is R 7a ; and R 7a is a C 3-7 monocycloalkyl optionally substituted with 1-6 R 8 group. [0088] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a mono 3-7 heterocycloalkyl, or bi 5-12 heterocycloalkyl, wherein the mono 3- 7 heterocycloalkyl, or bi 5-12 heterocycloalkyl is optionally substituted with 1-6 R 8 groups. [0089] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a mono 3-7 heterocycloalkyl optionally substituted with 1-6 R 8 groups. [0090] In certain embodiments, R 7 is R 7a ; and R 7a is a mono 3-7 heterocycloalkyl optionally substituted with 1-6 R 8 groups. [0091] In certain embodiments, R 7 is -L-R 7a ; and R 7a is wherein: R 10 is hydrogen or C 1-6 alkyl; X 3 is O, S or NR 8 ; v is 0, 1, 2 or 3; and w is 0, 1 or 2. [0092] In certain embodiments, R 7 is R 7a ; and wherein: R 10 is hydrogen or C 1-6 alkyl; X 3 is O, S or NR 8 ; v is 0, 1, 2 or 3; and w is 0, 1 or 2. [0093] In certain embodiments, R 7 is -L-R 7a ; L is C 1-4 alkylene or haloC 1-4 alkylene; and R 7a is a phenyl optionally substituted with 1-6 R 8 groups. [0094] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a phenyl optionally substituted with 1-6 R 8 groups. [0095] In certain embodiments, R 7 is benzyl optionally substituted with 1-6 R 8 groups. [0096] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a monocyclo 5-6 heteroaryl or bicyclo 8-12 heteroaryl group, wherein the monocyclo 5-6 heteroaryl or bicyclo 8-12 heteroaryl group is optionally substituted with 1-6 R 8 groups. [0097] In certain embodiments, R 7 is -L-R 7a ; and R 7a is a monocyclo 5-6 heteroaryl optionally substituted with 1-6 R 8 groups. [0098] In certain embodiments, R 7 is R 7a ; and R 7a is a bicyclo 8-12 heteroaryl optionally substituted with 1-6 R 8 groups. [0099] In certain embodiments, R 7 is -L-R 7a ; R 7a is R 10 is hydrogen or C 1-6 alkyl; X 4 is O or S; v is 0, 1, 2 or 3; and w is 0, 1 or 2. [0100] In certain embodiments, R 7 is R 7a ; R 7a is R 10 is hydrogen or C 1-6 alkyl; X 4 is O or S; v is 0, 1, 2 or 3; and w is 0, 1 or 2. [0101] In another aspect, the present disclosure provides a compound of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: L is C 1-4 alkylene or C(O); M is NR x or CR 2 R 3 ; R x is hydrogen or C 1-4 alkyl; R 0 is -C(O)OH, -C(O)OC 1-6 alkyl, or -S(O) 2 OH; R 1 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl and haloC 1- 4 alkyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, halo and methyl; R 4 is independently selected from the group consisting of hydrogen, halo, cyano, C 1- 4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio; R 5 is an C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-7 monocycloalkyl, -L-C 3- 7 monocycloalkyl, mono 3-7 heterocycloalkyl, -L-mono 3-7 heterocycloalkyl, -L-phenyl, monocyclo 5-6 heteroaryl or -L-monocyclo 5-6 heteroaryl group, wherein the C 3- 7 monocycloalkyl, -L-C 3-7 monocycloalkyl, mono 3-7 heterocycloalkyl, -L-mono 3- 7 heterocycloalkyl, -L-phenyl, monocyclo 5-6 heteroaryl or -L-monocyclo 5-6 heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0102] The following embodiments further describe a compound of Formula II, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. [0103] In certain embodiments, M is NR x . [0104] In certain embodiments, M is NH or NCH3. [0105] In certain embodiments, M is CH 2 , CF or CF 2 . [0106] In certain embodiments, R 0 is -C(O)OH or -C(O)OC 1-4 alkyl. [0107] In certain embodiments, R 0 is -C(O)OH. [0108] In certain embodiments, R 0 is S(O) 2 OH. [0109] In certain embodiments, R 1 is hydrogen or F. [0110] In certain embodiments, R 1 is F. [0111] In certain embodiments, R 0 is -C(O)OH or -C(O)OC 1-4 alkyl and R 1 is hydrogen or F. [0112] In certain embodiments, R 0 is -C(O)OH and R 1 is F. [0113] In certain embodiments, R 4 is methylthio. [0114] In certain embodiments, R 5 is an C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl or haloC 1-6 alkyl group. [0115] In certain embodiments, R 5 is C 3-7 monocycloalkyl, -L-C 3-7 monocycloalkyl, mono 3- 7 heterocycloalkyl or -L-mono 3-7 heterocycloalkyl group, wherein the C 3-7 monocycloalkyl, -L- C 3-7 monocycloalkyl, mono 3-7 heterocycloalkyl or -L-mono 3-7 heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0116] In certain embodiments, R 5 is C 3-7 monocycloalkyl or mono 3-7 heterocycloalkyl group, wherein the C 3-7 monocycloalkyl or mono 3-7 heterocycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0117] In certain embodiments, R 5 is C 3-7 monocycloalkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0118] In certain embodiments, R 5 is a mono 3-7 heterocycloalkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0119] In certain embodiments, R 5 is selected from the group consisting of wherein: R 6 is independently selected for each occurrence from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio; R 6a is hydrogen or C 1-6 alkyl; X 1 is O, S or NR 6 ; v is 0, 1, 2 or 3; and w is 0, 1 or 2. [0120] In certain embodiments, R 5 is a -L-phenyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0121] In certain embodiments, R 5 is monocyclo 5-6 heteroaryl or -L-monocyclo 5-6 heteroaryl group, wherein the monocyclo5-6heteroaryl or -L-monocyclo5-6heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0122] In certain embodiments, R 5 is monocyclo5-6heteroaryl optionally substituted with 1- 3 substituents independently selected from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio. [0123] In certain embodiments, R 5 is R 6 is independently selected for each occurrence from the group consisting of halo, OH, CN, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylthio; R 6a is hydrogen or C 1-6 alkyl; X 2 is O or S; v is 0, 1, 2 or 3; and w is 0, 1 or 2. III. Pharmaceutical Compositions and Kits [0124] In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations 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. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. [0125] In another aspect, 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. [0126] 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. [0127] For preparing solid compositions such as tablets, 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. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0128] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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 alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the 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. [0129] 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. [0130] 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. In addition to the subject composition, 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. [0131] 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. [0132] 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 in the body cavity and release the active agent. [0133] 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. [0134] 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. [0135] 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. [0136] 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. Ordinarily, 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. [0137] Pharmaceutical 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. [0138] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure 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. 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. [0139] In another aspect, 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 and the pH of the distal ileum is about 7.5. Accordingly, 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 as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure. [0140] Advantageously, the disclosure also provides kits for use by e.g., a consumer in need of HBV infection treatment. Such kits 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. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such 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. Next, 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. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably 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. [0141] It may be desirable to provide 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. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ...” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, 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. The memory aid should reflect this. IV. Methods [0142] In a further aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, 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). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, 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. [0143] With regard to HBV/HDV coinfection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of the HDV virions. See for example, Negro, Cold Spring Harb Perspect Med.2014 Nov 3;4(11):a021550. doi: 10.1101/cshperspect.a021550, herein incorporated by reference with regard to such background teaching. Thus, because HDV infection is dependent on the presence of an existing HBV infection, strategies for treating HBV/HDV coinfection may focus on targeting HBV alone, HDV alone or both viruses together. [0144] Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV/HDV coinfection, 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). In another embodiment, a method for treating an HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof is provided, 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. [0145] Without being bound by any theory, methods of treatment may be facilitated by various mechanisms of action. One possibility for treatment involves targeting machinery involved in viral particle assembly. In the case of HBV, inhibiting assembly of the HBV envelope or core by targeting HBsAg would disrupt assembly of the HBV particles. A second strategy would be to inhibit viral replication of HBV and/or HDV. Existing antiviral therapies may apply this approach in the form of replication inhibitors that target, for example, a specific viral RNA polymerase. [0146] Thus, another aspect of the disclosure is a method for inhibiting HBV or HDV viral replication 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). In another embodiment, a method for inhibiting HBV or HDV viral replication in a patient in need thereof is provided, 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. [0147] Methods of treatment may further include targeting the network of bile acid transport proteins that are believed to be the “gateway” of entry for HBV or HDV infection into the hepatocyte. See for example, Slijepcevic et al., Digestive Diseases, 2017;35:251-258, herein incorporated by reference with regard to such background teaching. The bile acid transport system comprising the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) are a set of receptors that ensure effective bile acid transport between the ileum and hepatocyte. HBV/HDV coinfection of hepatocytes is believed to be mediated via the NTCP receptor, making it a possible target for treatment. Without being bound by any theory, an “entry inhibitor” may target any of the possible bile acid transport receptors, including, but not limited to the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) to prevent entry of either HBV or HDV virus into the cells. Such entry inhibitors may target all or a portion of the transport receptors to inhibit viral entry. [0148] Thus, another aspect of the disclosure is a method of inhibiting viral entry in hepatocytes 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). In another embodiment, a method inhibiting viral entry in hepatocytes in a patient in need thereof is provided, 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. [0149] Regardless of the mechanism targeted, treatment for patients dealing with HBV or HDV infection or HBV/HDV coinfection may be measured by seroconversion of any of the viral antigens, including but not limited to HBsAg or HBeAg, or maintenance of undetectable levels of these antigens. [0150] For use in accordance with the aspects described herein, the appropriate dosage of the compounds described herein is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 μg/kg body weight. In some cases, the administration dose of the compound may be less than 400 μg/kg body weight. In other cases, the administration dose may be less than 200 μg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 μg/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. [0151] 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. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally). [0152] For oral administration, pharmaceutical 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). Tablets may be coated by methods well known in the art. 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). Preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate. [0153] 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. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan. [0154] 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. The 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. Alternatively, 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. [0155] Also contemplated herein are methods and compositions that include a second active agent or administering a second active agent. For example, in addition to being infected with HBV, a subject or patient 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. 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. [0156] In some cases, 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 α, 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). For example, provided herein is 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 WO2014033170; Nucleos(t)ide analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and: 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: ; and 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. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cp183-V124W and related mutations as described in WO/2013/010069, WO2014/074906, each incorporated by reference); inhibitors of HBx- interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS- HBV), or 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, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); Non-Interferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) and Interleukin-7 (CYT107); TLR-7/9 agonists such as GS- 9620, CYT003, Resiquimod; Cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, Core antigen vaccine; SMAC mimetics such as birinapant and other IAP-antagonists; Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. 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. [0157] In some embodiments, 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. In some embodiments, 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 therapeutic. [0158] In some embodiments, the disclosure further provides a method of treating HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies and one or more of 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. In some embodiments, the disclosure provides a method of treating a HBV or HBV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic. [0159] In some embodiments, 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. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy. [0160] In another embodiment, 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). 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. Such disclosed compounds conjugated to 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. V. Examples [0161] 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. [0162] At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile Boc 2 O Di-tert-butyl dicarbonate nBuLi n-Butyllithium DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropyl ethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1’-Bis(diphenylphosphino)ferrocene EA, EtOAc Ethyl acetate Et 3 N Triethylamine HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HPLC High performance liquid chromatography LCMS Liquid chromatography–mass spectrometry MeOH Methanol NMO N-Methylmorpholine-N-Oxide NBS N-Bromosuccinimide PE Petroleum ether iPrOH Isopropanol rt, r.t. Room temperature SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl [0163] Example 1. (E)-3-((3-Butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-(pyrid in-4-yl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acryl ic acid [0164] Step 1. Synthesis of 2-(benzylamino)hexanoic acid (1-2). A solution of 2- aminohexanoic acid (1-1) (30 g, 228.7 mmol) and benzaldehyde (24.27 g, 228.7 mmol) in aqueous 2 N aq. NaOH (50 mL) was stirred at 0°C for 0.5 h, and then NaBH 4 (2.60 g, 68.6 mmol) was added at 0 °C in portions. After stirring at rt for 1 hr, an additional equivalent of benzaldehyde (24.27 g, 228.7 mmol) was added. The resulting mixture was stirred for 0.5 h at 0 °C, and then NaBH 4 (2.60 g, 68.6 mmol) was added at 0 °C in portions. After stirring at rt for 2 hr, the reaction mixture was diluted with H 2 O (50 mL). The mixture was extracted with DCM (100 mL x 2) and then the aqueous layer acidified with 6 N aq. HCl to pH ~6. The precipitated solid was collected through filtration and dried in vacuo to give 1-2 (31 g, 61%) as a white solid. MS (ESI): calcd. for C 13 H 19 NO 2 : 221; Found: 222 [M+1] + . [0165] Step 2. Synthesis of 2-[benzyl(methyl)amino]hexanoic acid (1-3). A solution of 2-(benzylamino)hexanoic acid (1-2) (31 g, 140.1 mmol) and HCHO (40.92 g, 504.3 mmol) in formic acid (58.03 g, 1260.7 mmol) was stirred at 100 °C for 5 hr. The resulting mixture was concentrated, and the residue was triturated with H 2 O (30 mL). The precipitated solid was collected, washed with H 2 O (30 mL), dried in vacuo to give 1-3 (20 g, 61%) as a white solid. MS (ESI): calcd. for C 14 H 21 NO 2 : 235; Found: 236 [M+1] + ; 1 H NMR: (300 MHz, DMSO-d 6 ): δ 7.38 ‒ 7.18 (m, 5H), 3.74 (d, J = 13.8 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 3.18 (t, J = 7.5 Hz, 1H), 2.19 (s, 3H), 1.73 ‒ 1.63 (m, 1H), 1.61 (dd, J = 7.8, 5.4 Hz, 1H), 1.45 ‒ 1.20 (m, 4H), 0.87 (t, J = 6.3 Hz, 3H) ppm. [0166] Step 3. Synthesis of 2-[benzyl(methyl)amino]hexanamide (1-4). To a stirred mixture of 2-[benzyl(methyl)amino]hexanoic acid (1-3) (20 g, 85.0 mmol), DIPEA (21.97 g, 170.0 mmol), and HATU (35.55 g, 93.5 mmol) in DMF (200 mL) was added NH4Cl (6.82 g, 127.48 mmol) in portions at rt. After stirring at rt for 5 hr, the resulting mixture was diluted with H 2 O (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 3/1 (v/v) as eluent to afford 1-4 (15 g, 75%) as a yellow oil. MS (ESI): calcd. for C 14 H 22 N 2 O: 234; Found: 235 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.31 ‒ 7.16 (m, 5H), 6.96 (s, 2H), 3.70 ‒ 3.56 (m, 2H), 3.51 (d, J = 13.8 Hz, 1H), 3.05 (t, J = 7.2 Hz, 1H), 2.70 (s, 3H), 1.82 ‒ 1.71 (m, 1H), 1.39 ‒ 1.29 (m, 4H), 0.94 ‒ 0.83 (m, 3H) ppm. [0167] Step 4. Synthesis of (1-aminohexan-2-yl)(benzyl)methylamine (1-5). To a stirred solution of 2-[benzyl(methyl)amino]hexanamide (1-4) (15 g, 64.01 mmol) in THF (100 mL) was added BH 3 -Me 2 S (12.14 mL, 128.0 mmol) dropwise at 0 °C. After stirring at 75 °C for 16 hr, the reaction was quenched with MeOH (50 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 2 h and then concentrated under reduced pressure to give 1-5 (13 g, 55%) as a colorless oil, which was used for the next step directly without further purification. MS (ESI): calcd. for C 14 H 24 N 2 : 222; Found: 223 [M+1] + . [0168] Step 5. Synthesis of tert-butyl N-{2-[benzyl(methyl)amino]hexyl}carbamate (1- 6). To a stirred solution of (1-aminohexan-2-yl)(benzyl)methylamine (1-5) (13 g, 35.4 mmol) and TEA (10.75 g, 106.2 mmol) in DCM (100 mL) at rt was added Boc 2 O (15.45 g, 70.8 mmol) in portions. After stirring at rt for 16 hr, the reaction mixture was diluted with H 2 O (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 3/1 (v/v) as eluent to give 1- 6 (9 g, 79%) as a colorless oil. MS (ESI): calcd. for C 19 H 32 N 2 O 2 : 320; Found: 321 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.29 (d, J = 4.5 Hz, 4H), 7.27 ‒ 7.15 (m, 1H), 6.63 (s, 1H), 3.59 (s, 2H), 3.11 (dt, J = 13.2, 6.6 Hz, 1H), 2.96 ‒ 2.82 (m, 1H), 2.76 ‒ 2.57 (m, 2H), 2.10 (s, 3H), 1.41 (s, 1H), 1.39 (s, 9H), 1.36 ‒ 1.16 (m, 2H), 1.09 (t, J = 7.2 Hz, 2H), 0.92 ‒ 0.88 (m, 3H) ppm. [0169] Step 6. Synthesis of tert-butyl N-[2-(methylamino)hexyl]carbamate( 1-7). To a solution of tert-butyl N-{2-[benzyl(methyl)amino]hexyl}carbamate (1-6) (9 g, 28.08 mmol) in 100 mL MeOH was added Pd/C (10%, 2g) under nitrogen atmosphere. After stirring at rt for 16 h under hydrogen atmosphere, the reaction mixture was slushed with N2 and filtered through a Celite ® 545 plug. The filtrate was concentrated, and the residue was dried in vacuo to give 1-7 (5 g, 77%) as a colorless oil. MS (ESI): calcd. for C 12 H 26 N 2 O 2 : 230; Found: 231 [M+1] + . [0170] Step 7. Synthesis of tert-butyl N-[2-(N-methyl2,4-dibromo-5- methoxybenzenesulfonamido)hexyl]carbamate (1-8). To a stirred solution of tert-butyl N- [2-(methylamino)hexyl]carbamate (1-7) (5 g, 21.7 mmol) and TEA (4.39 g, 43.4 mmol) in THF (100 mL) was added 2,4-dibromo-5-methoxybenzenesulfonyl chloride (7.91 g, 21.7 mmol) in portions at rt. After stirring at rt for 16 hr, the resulting mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was triturated with PE/EA = 1/1 (30 mL). The precipitated solid was washed with PE/EtOAc = 1/1 (v/v) (10 mL) and dried in vacuo to give 1-8 (10 g, 83%) as a white solid. MS (ESI): calcd. for C 19 H 30 Br 2 N 2 O 5 S: 556; Found: 557 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.66 ‒ 7.55 (m, 1H), 6.58 (t, J = 6.0 Hz, 1H), 3.95 (d, J = 2.7 Hz, 3H), 3.74 ‒ 3.61 (m, 2H), 2.97 (q, J = 6.3 Hz, 2H), 2.85 (s, 3H), 1.34 (s, 9H), 1.15 ‒ 1.11 (m, 5H), 0.77 (t, J = 6.9 Hz, 3H) ppm. [0171] Step 8. Synthesis of tert-butyl tert-butyl 7-bromo-3-butyl-8-methoxy-2-methyl- 3,4-dihydrobenzo[f][1,2,5]thiadiazepine-5(2H)-carboxylate 1,1-dioxide (1-9). A mixture of tert-butyl N-[2-(N-methyl2,4-dibromo-5-methoxybenzenesulfonamido)hexyl] carbamate (1-8) (10 g, 17.91 mmol) and K 2 CO 3 (7.43 g, 53.73 mmol), and Cu (5.69 g, 89.55 mmol) in DMF (100 mL) was stirred for 24 h at 115 °C under N 2 atmosphere. The resulting mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/THF = 4/1 (v/v) as eluent to give 1-9 (6.6 g, 77%) as a brown solid. MS (ESI): calcd. for C 19 H 29 BrN 2 O 5 S: 476; Found: 477 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.72 (d, J = 8.1 Hz, 1H), 7.44 ‒ 7.31 (m, 1H), 4.06 (d, J = 8.7 Hz, 1H), 3.97 (d, J = 2.7 Hz, 2H), 3.80 (dd, J = 23.1, 15.0 Hz, 1H), 2.97 (dd, J = 25.5, 15.3 Hz, 2H), 2.41 (d, J = 3.6 Hz, 2H), 1.45 (s, 3H), 1.37 (s, 9H), 1.28 (s, 4H), 0.97-0.78 (m, 3H) ppm. [0172] Step 9. Synthesis of 7-bromo-3-butyl-8-methoxy-2-methyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-10). A solution of tert-butyl 7- bromo-3-butyl-8-methoxy-2-methyl-3,4-dihydrobenzo[f][1,2,5]t hiadiazepine-5(2H)- carboxylate 1,1-dioxide (1-9) (340 mg, 0.71 mmol) and trifluoroacetic acid (2 mL) in DCM (2 mL) was stirred for 1 hr at rt. The resulting mixture was concentrated under vacuum and the residue was diluted with EA (10 mL). The mixture was basified with sat. aqueous NaHCO 3 solution to pH = 8. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was dried n vacuo to give 1-11 (250 mg, 93%) as a yellow solid. MS (ESI): calcd. for C 14 H 21 BrN 2 O 3 S: 376; Found: 377 [M+1] + . [0173] Step 10. Synthesis of 7-bromo-3-butyl-8-methoxy-2-methyl-5-(pyridin-3-yl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-11). To a solution of 7- bromo-3-butyl-8-methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][ 1,2,5]thiadiazepine 1,1- dioxide (1-10) (250 mg, 0.66 mmol) and 3-iodopyridine (203.75 mg, 0.99 mmol) in DMF (10 mL) were added Cs 2 CO 3 (647.67 mg, 1.98 mmol) and Pd(PPh3)4 (38.28 mg, 0.03 mmol) and XPhos (31.59 mg, 0.06 mmol). After stirring at 120 °C for 16 hr under a nitrogen atmosphere, the resulting mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 1/1 (v/v) as eluent to give 1-11 (180 mg, 60%) as a brown solid. MS (ESI): calcd. for C 19 H 24 BrN 3 O 3 S: 453; Found: 454 [M+1] + . [0174] Step 11. Synthesis of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-(pyridin-3- yl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-12). A solution of 7- bromo-3-butyl-8-methoxy-2-methyl-5-(pyridin-3-yl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-12) (180 mg, 0.39 mmol) and (methylsulfanyl)sodium (138.81 mg, 1.98 mmol) in DMF (3 mL) was stirred at 80 °C for 16 h. The resulting mixture was extracted with EA (15 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 1/2 (v/v) as eluent to give 1-12 (130 mg, 81%) as a brown solid. MS (ESI): calcd. for C 19 H 25 N 3 O 3 S 2 : 407; Found: 408 [M+1] + . [0175] Step 12. Synthesis of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]th iadiazepin-8-yl)oxy)-2- fluoroacrylate (1-13). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (127.79 mg, 0.59 mmol) in DMA (3 mL) was added 60% NaH in paraoil (39.26 mg, 0.98 mmol) at 0 o C under an atmosphere of N 2 . The mixture was allowed to warm to rt and stirred for 1 hr. Subsequently, 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-(pyridin-3-yl)-2 ,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (80 mg, 0.20 mmol) in DMA (2 mL) was added. After stirring at 70°C for 5 hr, the mixture was allowed to cool down to rt and acidified to pH = 1 with 1N aq. HCl. The resulting mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 1/1 (v/v) as eluent to give ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)- 1,1-dioxido-5-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,2, 5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (1-13) as a brown solid. MS (ESI): calcd. for C 24 H 30 FN 3 O 5 S 2 : 523; Found: 524 [M+1] + . [0176] Step 13. Synthesis of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- (pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin -8-yl)oxy)-2-fluoroacrylic acid (Example 1). A solution of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 5-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazep in-8-yl)oxy)-2-fluoroacrylate (1- 13) (50 mg, 0.10 mmol) and LiOH (6.86 mg, 0.29 mmol) in dioxane (4 mL) and H 2 O (1 mL) was stirred for 2 h at rt. The mixture was acidified to pH = 4 with 2N aq. HCl. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue (50 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% PhaseB up to 75% in 8 min); Detector, UV 254 nm) to give Example 1 (15 mg, 32%) as a white solid. MS (ESI): calcd. for C 22 H 26 FN 3 O 5 S 2 : 495, Found: 496 [M+1] + ; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.96 (s, 2H), 7.60 (d, J = 18.0 Hz, 1H), 7.54 (d, J = 12.0 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.10 (d, J = 15.9 Hz, 1H), 3.91 ‒ 3.89 (m, 1H), 3.08 ‒ 2.96 (m, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 1.72 ‒ 1.61 (m, 1H), 1.53 ‒ 1.49 (m, 1H), 1.48 ‒ 1.35 (m, 4H), 0.94 ‒ 0.85 (m, 3H) ppm. [0177] Example 2. (Z)-3-((3-butyl-5-(4,4-difluorocyclohexyl)-2-methyl-7-(methy lthio)-1,1- dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)o xy)-2-fluoroacrylic acid [0178] Step 1. Synthesis of tert-butyl 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-3,4- dihydrobenzo[f][1,2,5]thiadiazepine-5(2H)-carboxylate 1,1-dioxide (2-1). A solution of tert-butyl 7-bromo-3-butyl-8-methoxy-2-methyl-3,4-dihydrobenzo[f][1,2,5 ]thiadiazepine- 5(2H)-carboxylate 1,1-dioxide (1-9) (6.0 g, 12.6 mmol) and (methylsulfanyl)sodium (4.4 g, 62.85 mmol) in dimethylformamide (100 mL) was stirred for 16 hr under an atmosphere of N 2 . The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 2/1 (v/v) as eluent to give 2-1 (5.0 g, 92%) as a brown solid. MS (ESI): calcd. for C 19 H 30 N 2 O 5 S 2 : 430; Found: 431 [M+1] + . [0179] Step 2. Synthesis of tert-butyl (Z)-3-butyl-8-((3-ethoxy-2-fluoro-3-oxoprop-1-en- 1-yl)oxy)-2-methyl-7-(methylthio)-3,4-dihydrobenzo[f][1,2,5] thiadiazepine-5(2H)- carboxylate 1,1-dioxide (2-2). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (3.0 g, 14.0 mmol) in DMA (60 mL) was added 60% NaH in paraoil (930 mg, 2.3 mmol) at 0 o C under an atmosphere of N 2 . The mixture was allowed to warm to rt and stirred for 1 hr. tert- Butyl 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-3,4-dihydrobenzo[f ][1,2,5]thiadiazepine- 5(2H)-carboxylate 1,1-dioxide (2-1) (2.0 g, 4.64 mmol) in DMA (20 mL) was added. After stirring at 70°C for 5 hr, the mixture was allowed to cool down to rt and acidified to pH = 1 with 1N aq. HCl solution. The resulting mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatography using PE/EtOAc = 3/1 (v/v) to give 2-2 (1.4 g, 55%) as a brown solid. MS (ESI): calcd. for C 24 H 35 FN 2 O 7 S 2 : 546; Found: 547 [M+1] + . [0180] Step 3. Synthesis of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fl uoroacrylate (2-3). To a stirred solution of tert-butyl (Z)-3-butyl-8-((3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)oxy)-2 - methyl-7-(methylthio)-3,4-dihydrobenzo[f][1,2,5]thiadiazepin e-5(2H)-carboxylate 1,1- dioxide (2-2) (1.4 g, 2.56 mmol) in DCM (20 mL) was added TFA (20 mL). After stirring at rt for 5 hr, the resulting mixture was concentrated. The residue was diluted with EA (10 mL) and adjusted pH to ~ 8 using sat aq. Na 2 CO 3 . The resulting mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was dried in vacuo to give crude 2-3 (1.0 g, 87%) as a yellow solid, which was used for the next step without further purification. MS (ESI): calcd. for C 19 H 27 FN 2 O 5 S 2 : 446; Found: 447 [M+1] + . [0181] Step 4. Synthesis of ethyl (Z)-3-((3-butyl-5-(4,4-difluorocyclohexyl)-2-methyl-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]th iadiazepin-8-yl)oxy)-2- fluoroacrylate (2-4). To a stirred solution of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)- 1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylate (2-3) (50 mg, 0.11 mmol) and 4,4-difluorocyclohexan-1-one (45.05 mg, 0.34 mmol) in tetrahydrofuran (10 mL) was added phenylsilane (36.35 mg, 0.34 mmol) and dibutyldichlorostannane (51.03 mg, 0.17 mmol) at rt. After stirring at 60 °C for 72 h, the mixture was allowed to cool down to rt and concentrated. The residue was purified by Prep- TLC (PE/EtOAc = 2/1 (v/v)) to give 2-4 (35 mg, 55%) as a brown solid. MS (ESI): calcd. for C 25 H 35 F 3 N 2 O 5 S 2 : 564; Found: 565 [M+1] + . [0182] Step 5. Synthesis of ((Z)-3-((3-butyl-5-(4,4-difluorocyclohexyl)-2-methyl-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]th iadiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 2). A solution of ethyl (Z)-3-((3-butyl-5-(4,4- difluorocyclohexyl)-2-methyl-7-(methylthio)-1,1-dioxido-2,3, 4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacry late (2-4) (35 mg, 0.06 mmol) and LiOH (4.45 mg, 0.19 mmol) in dioxane (4 mL) and H 2 O (1 mL) was stirred for 2 h at rt. The resulting mixture was diluted with water (10 mL), acidified to pH = 4 with 0.1 N aq. HCl solution, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, Water (0.05% FA) and ACN (45% PhaseB up to 75% in 7 min); Detector: UV 254 nm) to give Example 2 (8 mg, 24%) as a white solid. MS (ESI): calcd. for C 23 H 31 F 3 N 2 O 5 S 2 : 536; Found: 537 [M+1] + ; 1 H NMR (300 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.36 (d, J = 5.4 Hz, 1H), 6.82 (s, 1H), 3.80 (s, 1H), 3.51 (s, 1H), 3.33 ‒ 3.31 (m, 2H), 2.74 ‒ 2.60 (m, 2H), 2.54 (s, 3H), 2.28 ‒ 1.93(m, 6H), 1.90 ‒ 1.70 (m, 2H), 1.51 ‒ 1.46 (m, 2H), 1.36 ‒ 1.30 (m, 4H), 1.26 ‒ 1.23 (m, 1H), 0.97 ‒ 0.87 (m, 3H) ppm. [0183] Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. Table 1: Representative Examples of the present invention V. Biological Data [0184] HepG2-NTCP infection protocol [0185] HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture using HepG2-NTCP growth medium (DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 µg/mL G418 (Alfa Aesar, Cat# J62671), 50U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 µg/mL blasticidin (Sigma, Cat# 15205)). Prior to infection, the cells were washed twice with 1× DPBS (Invitrogen, Cat# 14190-136) and treated with 3 mL of 0.05% trypsin (Invitrogen, Cat# 25200-056) to dissociate the cells. Following dissociation, 10 mL of HepG2-NTCP growth medium was added to the cells to neutralize the trypsin and the cells were then centrifuged at 1,300 rpm for 5 minutes. Following centrifugation, the cells were resuspended in 10 mL of HepG2-NTCP growth medium, counted, and then centrifuged at 1,300 rpm for 5 minutes. The cell pellet was resuspended in DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540) to a density of 5.6 × 10 5 cells/mL and infected with HBV at an MOI of 50. Immediately after infection, 90 µL of the cell/HBV mixture was added to a 96-well plate containing 10 µL of compound and incubated at 37⁰C for 24 hours (2% final DMSO concentration). After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 72 hours. At the end of the incubation, the plates were spun at 1,800 rpm for 8 minutes and the supernatant was removed for HBeAg quantification using electrochemiluminescence enzyme-linked immunosorbent assays (ECL-ELISA). [0186] To conduct the HBeAg ECL-ELISA, Lumitrack high-binding 96-well plates (Greiner, Cat# 655074) were treated with 625 ng/mL HBeAg mAb (Biocheck, Cat# 70426) in 1× DPBS for 2 hours at 25⁰C with shaking. The HBeAg mAb solution was then removed and the plates treated with 1× DPBS containing 0.5% bovine serum albumin (BSA) (Sigma, Cat# A7030-100g) for 2 hours at 25⁰C with shaking. The HBeAg-coated plates were then washed 4 times with 1× DPBS containing 0.05% Tween 20 (DPBS-T) (Thermo Fisher Scientific, Cat# J61544-K2). Following the wash, 90 µL of HRP-conjugated antibody (Fitzgerald, Cat# 61-H10K), diluted 1:8,000 in 1× DPBS-T containing 0.5% BSA, was added to the HBeAg-coated plates along with 10 µL of sample. The plates were then incubated for 2 hours at 25 ⁰C with shaking. Following the incubation, the sample was then removed and 200 µL of 1× PBS-T was added and the plates were incubated for 10 minutes at 25⁰C with shaking. The plates were then washed 6 times with 1× PBS-T and blotted dry.80 µL of ECL substrate (Millipore, Cat# WBKLS0500) was then added to the plate and the luminescence was measured using a Tecan M1000 Pro plate reader. [0187] Other assays are known in the art, see for example, Lempp et al., Nature Communications, 2019, 10:2265, https://doi.org/10.1038/s41467-019-10211-2, Grosser et al., Frontiers in Molecular Biosciences, 2021, 8: doi: 10.3389/fmolb.2021.689757. [0188] Table 2 provides assay data for exemplified compounds of the invention grouped in the following ranges: A indicates EC 50 < 100 nM; B indicates EC 50 of ≥100 to <1,000 nM; C indicates EC 50 of ≥1,000 to <5,000 nM. Table 2. Assay data for exemplified compounds of the invention. INCORPORATION BY REFERENCE [0189] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0190] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0191] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.
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