WO2023164186A1 - Benzothia(dia)zepine compounds for treatment of hbv and hdv - Google Patents

Abstract

The present disclosure provides, in part, benzothia(dia)zepine compounds of formula II, and pharmaceutical compositions thereof, and methods of treating Hepatitis B (HBV) and Hepatitis D (HDV) infections.

Description

BENZOTHIA(DIA)ZEPINE COMPOUNDS FOR TREATMENT OF HBV AND HDV CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No.63/314,113, filed February 25, 2022, the contents of which are hereby incorporated by reference. BACKGROUND [0002] Hepatitis B (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths. 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. [0003] 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. In an infected cell, 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. 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. [0004] At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g., entecavir) that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleos(t)ide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance. [0005] The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon α or pegylated interferon α. Unfortunately, the adverse event incidence and profile of interferon α can result in poor tolerability, and many patients are unable to complete therapy. Moreover, 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. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment. [0006] Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon α has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections. [0007] Another form of viral hepatitis is Hepatitis D virus (HDV), a defective RNA virus that causes chronic viral hepatitis and eventual cirrhosis. However, the HDV life cycle is dependent on the presence of HBsAg for assembly. Thus, in a small set of patients infected with HBV, HDV presents as coinfection with HBV. See for example, Sagnelli et al., Life (Basel).2021 Feb; 11(2): 169, Published online 2021 Feb 22. doi: 10.3390/life11020169, herein incorporated by reference with regard to such background teaching. For patients already infected with HBV, coinfection with HDV can further exacerbate the symptoms of HBV, increasing the likelihood of complications, rapid disease progression and/or death. Chronic HBV/HDV infection is also associated with the development of hepatocellular carcinoma (HCC). Like HBV, treatment options for HDV infection or HBV/HDV coinfection, are limited and include those used to treat HBV. Thus, there is a need for effective therapeutic options for the treatment of HDV infection or HBV/HDV coinfection. [0008] WO2021/110883, WO2021/110884, WO2021/110885, WO2021/110886, WO2021/110887, WO2020/161216, WO2020/161217 and WO2019/234077 relate to 1,5- benzothiazepine and 1,2,5-benzothiadiazepine derivatives described as bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity. The compounds are further described as being useful to in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases. [0009] LBAT functions as a cellular receptor for viral entry of the hepatitis B virus (HBV) and hepatitis D virus (HDV), which in turn is the major cause of liver disease and hepatocellular carcinoma. There is a need for additional bile acid modulating compounds that have an improved profile with respect to potency, selectivity and/or bioavailability. SUMMARY [0010] The present disclosure provides, in part, benzothia(dia)zepine compounds and pharmaceutical compositions thereof, useful for inhibition of HBV or HDV replication, inhibition of HBV or HDV viral entry, and methods of treating HBV infections, HDV infection or HBV/HDV coinfection. [0011] In one aspect, the disclosure provides a compound of Formula I:

Formula I or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. [0012] 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. [0013] In another aspect, 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. [0014] In another aspect, 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. DETAILED DESCRIPTION [0015] 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. Definitions [0016] The term “alkenyl” as used herein 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 C_2-6alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc. [0017] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C_1-6alkoxy and C_1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc. [0018] The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH₃CH₂OCH₂-, CH₃OCH₂CH₂- and CH₃OCH₂-, etc. [0019] The term “alkyl” as used herein 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 C_1-4 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. The term “alkylene” as used herein refers to a biradical alkyl group. [0020] The term “alkynyl” as used herein 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 C_2-6alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc. [0021] The term “carbonyl” as used herein refers to the biradical -C(O)-. [0022] The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen. [0023] The term “cyano” as used herein refers to the radical -CN. [0024] The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C_3-7monocycloalkyl, or bicyclic hydrocarbon ring structure of, for example, 5-12 carbons, referred to herein as C_{5- 12}bicycloalkyl. For bicyclic cycloalkyl groups, the two rings may be attached through the same or different carbons. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl and cyclopropyl. Exemplary bicycloalkyl groups include, but are not limited to, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, decahydronaphthalene, octahydro- 1H-indene, bicyclo[4.2.0]octanyl, bicyclo[4.1.0]heptanyl, octahydropentalenyl, bicyclo[3.2.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, and bicyclo[1.1.1]pentanyl. [0025] The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. [0026] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC_1-6alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH₂F, -CHCl₂, -CHF₂, -CF₃, CF₃CH₂-, CH₃CF₂-, CF₃CCl₂- and CF₃CF₂-. [0027] The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl₃O-, CF₃O-, CHF₂O- CF₃CH₂O-, and CF₃CF₂O-. [0028] The terms “heteroaryl” as used herein refers to a 5-6 membered monocyclic aromatic group, referred to herein as monocyclo_5-6heteroaryl, or 8-12 membered bicyclic aromatic ring system, referred to herein as bicyclo_8-12heteroaryl, containing one to four independently selected heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, the heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of monocyclo_5-6heteroaryl 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and tetrazolyl. Examples of bicyclo_8-12heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl. [0029] The term “heterocycloalkyl” refers to a monocycloalkyl group, for example a C_{3- 7}monocycloalkyl, or a bicycloalkyl group, for example C_5-12bicycloalkyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO₂), herein referred to as mono_{3- 7}heterocycloalkyl and bi_5-12heterocycloalkyl, respectively. Examples of mono_{3- 7}heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl 1,1- dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. Examples of bi_5-12heterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl. [0030] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. [0031] The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH₂-, HOCH₂CH₂-, CH₃CH(OH)CH₂- and HOCH₂CH(OH)CH₂-. [0032] The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH₂O-, HOCH₂CH₂O-, CH₃CH(OH)CH₂O- and HOCH₂CH(OH)CH₂O-. [0033] The term “R^aR^bNC_1-6 alkyl-,” as used herein refers to an alkyl group substituted with a R^aR^bN- group, as defined herein. Examples include but are not limited to NH₂CH₂-, NH(CH₃)CH₂-, N(CH₃)₂CH₂CH₂- and CH₃CH(NH₂)CH₂-. [0034] The term “R^aR^bNC_1-6alkoxy,” as used herein refers to an alkoxy group substituted with a R^aR^bN- groups, as defined herein. Examples include but are not limited to NH₂CH₂-, NH(CH₃)CH₂O-, N(CH₃)₂CH₂CH₂O-, and CH₃CH(NH₂)CH₂O-. [0035] The term “oxo” as used herein refers to the radical =O. [0036] As used herein, when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example as in

, it signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R³³ group(s)) can be independently attached to either or both rings. [0037] 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. [0038] The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. [0039] The term “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. [0040] The term “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. [0041] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. [0042] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present 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, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. 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. [0043] The term “therapeutically effective amount” or “effective amount” as used herein 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. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. [0044] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. [0045] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “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. [0046] 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. [0047] 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.” [0048] 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. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. 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. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. [0049] 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. In one embodiment, 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. [0050] 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. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. [0051] Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. 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. [0052] The term “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. Benzothia(dia)zepine Compounds [0053] In one aspect, the present disclosure provides a compound of Formula I

, or a pharmaceutically acceptable salt thereof, wherein: M is NR^x or CR^yR^z; One of R^1a and R^1b is R⁰; and the other of R^1a and R^1b is selected from the group consisting of hydrogen, halo, C_1-4alkyl and haloC_1-4alkyl; R^1c is hydrogen or C_1-4alkyl; R⁰ is -C(O)OH, -C(O)OC_1-6alkyl, -P(O)(OH)₂, -S(O)₂OH or ; R², R³ and R⁴ are independently selected from the group consisting of hydrogen, halogen, cyano, C_1-4 alkyl, C_3-6 cycloalkyl, C_1-4 alkoxy, C_3-6cycloalkyloxy, C_1-4alkylthio, C_{3- 6}cycloalkylthio, haloC_1-4alkyl, haloC_3-6cycloalkyl, haloC_1-4alkoxy, haloC_3-6hcycloalkyloxy, haloC_1-4alkylthio, haloC_3-6cycloalkylthio, amino, N-(C_1-4 alkyl)amino and N,N-di(C_{1- 4} alkyl)amino; R⁵ and R⁶ are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, haloC_1-6alkyl, haloC_1-6alkenyl, haloC_1-6alkynyl, C_1-3alkoxyC_1-3alkyl, and C_3-6cycloalyl-C_1-4alkylene-; or R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl, wherein the C_3-7monocycloalkyl or C_5-12bicycloalkyl is optionally substituted with 1-6 substituents independently selected from the group consisting of halogen, CN, NO₂, OH, R^aR^bN-, C_1-4alkyl and haloC_1-4alkyl; R⁸ is independently selected for each occurrence from the group consisting of halogen, OH, CN, NO₂, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)_q-, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6alkyl, hydroxyC_1-6alkyl-, R^aR^bNC_1- 6alkyl-, HOC(O)C_1-6alkyl-, R^aR^bNC_1-6alkylNR^c-, C_1-6alkylNR^aC_1-6alkylNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy-, R^aR^bNC_1-6alkoxy-, C_1-6alkoxyC_1-6alkyl-, haloC_{1- 6}alkoxyC_1-6alkyl-, R^aR^bNC(O)-, C_1-6alkylC(O)-, C_1-6alkoxyC(O)-, C_1-6alkylC(O)O-, C_1- 6alkylS(O)q-, C_1-6alkylS(O)qNR^c-, C_1-6alkylS(O)qC_1-6alkyl-, C_1-6alkylS(O)qNR^aC_1-6alkyl-, C_{3- 6}cycloalkylS(O)_qC_1-6alkyl-, C_1-6alkylC(O)C_1-6alkyl-, and C_1-6alkylC(O)OC_1-6alkyl-; R^a, R^b and R^c are independently selected for each occurrence from the group consisting of hydrogen, C_1-6 alkyl, haloC_1-6 alkyl and C_3-6 monocycloalkyl; R^x, R^y and R^z are independently selected from the group consisting of hydrogen, halo, CN, NO₂, C_1-4alkyl, and haloC_1-4C_1-4alkyl; q is independently selected for each occurrence from the group consisting of 0, 1 and 2; and r is 0, 1, 2, 3, 4 or 5. [0054] The following embodiments further describe a compound of Formula I, 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. [0055] In certain embodiments, M is NR^x. [0056] In certain embodiments, M is NR^x, and R^x is H or CH₃. [0057] In certain embodiments, M is NR^x and R^x is CH₃. [0058] In certain embodiments, M is CR^yR^z , R^y is halo, and R^z is halo. [0059] In certain embodiments, M is CR^yR^z, R^y is hydrogen, and R^z is halo. [0060] In certain embodiments, R⁰ is -C(O)OH, -C(O)OC_1-6alkyl or -S(O)₂OH. [0061] In certain embodiments, R^1a is R⁰. [0062] In certain embodiments, R^1a is C(O)OH. [0063] In certain embodiments, R^1a is S(O)₂OH. [0064] In certain embodiments, R^1b is hydrogen or F. [0065] In certain embodiments, R^1b is F. [0066] In certain embodiments, R^1a is -C(O)OH and R^1b is F. [0067] In certain Embodiments, R^1c is hydrogen. [0068] In certain Embodiments, R^1a is -C(O)OH; R^1b is F; and R^1c is hydrogen. [0069] In certain embodiments, R² is hydrogen. [0070] In certain embodiments, R³ is hydrogen. [0071] In certain embodiments, R² and R³ are hydrogen. [0072] In certain embodiments, R⁴ is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino and dimethylamino. [0073] In certain embodiments, R⁴ is methylthio. [0074] In certain embodiments, R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C_1-6alkyl. [0075] In certain embodiments, R⁵ is C_1-6alkyl and R⁶ is hydrogen. [0076] In certain embodiments, R⁵ is C_3-4alkyl and R⁶ is hydrogen. [0077] In certain embodiments, R⁵ is n-butyl and R⁶ is hydrogen. [0078] In certain embodiments, R⁵ and R⁶ are independently selected from the group consisting of hydrogen, C_1-6alkenyl, C_1-6alkynyl, haloC_1-6alkyl, haloC_1-6alkenyl, haloC_{1- 6}alkynyl, C_1-3alkoxyC_1-3alkyl, and C_3-6cycloalyl-C_1-6alkylene-; or R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl, wherein the C_3-7monocycloalkyl or C_5-12bicycloalkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, CN, NO₂, OH, R^aR^bN-, C_1-4alkyl and haloC_1-4alkyl. [0079] In certain embodiments, R⁵ and R⁶ are independently selected from the group consisting of hydrogen, C_1-6alkenyl, C_1-6alkynyl, haloC_1-6alkyl, haloC_1-6alkenyl, haloC_{1- 6}alkynyl, C_1-3alkoxyC_1-3alkyl, and C_3-6cycloalyl-C_1-4alkylene-. [0080] In certain embodiments, R⁵ isC_1-6alkenyl, C_1-6alkynyl, haloC_1-6alkyl, haloC_{1- 6}alkenyl, haloC_1-6alkynyl, C_1-3alkoxyC_1-3alkyl, or C_3-6cycloalyl-C_1-4alkylene-; and R⁶ is hydrogen. [0081] In certain embodiments, R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl, wherein the C_3-7monocycloalkyl or C_5-12bicycloalkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, CN, NO₂, OH, R^aR^bN-, C_1-4alkyl and haloC_1-4alkyl. [0082] In certain embodiments, R⁵ and R⁶ together with the carbon atom to which they are attached form a

, , , ,

or

group;

wherein: R⁹ is independently selected for each occurrence from the group consisting of halogen, CN, NO₂, OH, R^aR^bN-, C_1-4alkyl and haloC_1-4alkyl; and s is selected from the group consisting of 0, 1, 2 and 3. [0083] In certain embodiments, s is 0. [0084] In another aspect, the present disclosure provides a compound of Formula II

Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is NR^x or CR²R³; R^x is hydrogen or C_1-4alkyl; R⁰ is -C(O)OH, -C(O)OC_1-6alkyl or -S(O)₂OH; R¹ is hydrogen, halo, C_1-4alkyl or haloC_1-4alkyl; 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, C_{1- 4}alkyl, haloC_1-4alkyl, C_1-4alkoxy and C_1-4alkylthio; R⁵ is haloC_3-4alkyl, hydroxyC_3-4alkyl, aminoC_3-4alkyl, cyanoC_2-4alkyl, C_3-5alkenyl, C_{3- 4}alkynyl, methoxyethyl, ethoxymethyl, and C_3-6cycloalyl-ethylene-; R⁶ is hydrogen; or R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl group; and R⁷ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy, and C_1-4alkylthio. [0085] 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. [0086] In certain embodiments, M is NR^x. [0087] In certain embodiments, M is NH or NCH₃. [0088] In certain embodiments, M is CH₂, CHF, CF₂ or C(CH₃)₂. [0089] In certain embodiments, R⁰ is -C(O)OH, -C(O)OC_1-4alkyl. [0090] In certain embodiments, R⁰ is -C(O)OH. [0091] In certain embodiments, R⁰ is S(O)₂OH. [0092] In certain embodiments, R¹ is hydrogen or F. [0093] In certain embodiments, R¹ is F. [0094] In certain embodiments, R⁰ is -C(O)OH or -C(O)OC_1-4alkyl and R¹ is hydrogen or F. [0095] In certain embodiments, R⁰ is -C(O)OH and R¹ is F. [0096] In certain embodiments, R⁴ is methylthio. [0097] In certain embodiments, R⁵ is haloC_3-4alkyl, hydroxyC_3-4alkyl, aminoC_3-4alkyl, cyanoC_2-4alkyl, C_3-5alkenyl, C_3-4alkynyl, methoxyethyl, ethoxymethyl or C_3-6cycloalyl- ethylene-. [0098] In certain embodiments, R⁵ is haloC_3-4alkyl. [0099] In certain embodiments, R⁵ is n-butyl substituted with 1 to 6 halo atoms. [0100] In certain embodiments, R⁵ is n-butyl substituted with 1 to 6 F atoms. [0101] In certain embodiments, R⁵ is -CH₂CH₂CF₂CH₃. [0102] In certain embodiments, R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl group. [0103] In certain embodiments, R⁵ and R⁶ together with the carbon atom to which they are attached form a

,

, or group.

III. Pharmaceutical Compositions and Kits [0104] 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. [0105] 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. [0106] 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. [0107] 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. [0108] 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. [0109] 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. [0110] 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. [0111] 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. [0112] 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. [0113] 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. [0114] 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. [0115] 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. [0116] 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. [0117] 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. [0118] 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. [0119] 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. [0120] 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. [0121] 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 [0122] 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. [0123] 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. [0124] 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 a 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. [0125] 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. [0126] 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. [0127] 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. [0128] 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. [0129] 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. [0130] 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. [0131] 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). [0132] 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. [0133] 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. [0134] 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. [0135] 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. [0136] 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. [0137] 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. [0138] 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. [0139] 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. [0140] 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 [0141] 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. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile Boc₂O 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 Et₃N 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 [0142] Example 1. (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan]-8-yl)oxy)acrylic acid

[0143] Step 1. Synthesis of spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2). Bicyclo[2.2.1]heptan-2-one (1-1) (15 g, 136.4 mmol) was dissolved in EtOH/H₂O = 50 mL/50 mL, TMSCN (20 g, 204.5 mmol), CsF (31 g, 204.5 mmol), and (NH₄)₂CO₃ (39 g, 409.1 mmol) were added. Then the reaction mixture was stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2) (21 g, 85%) as a white solid. MS (ESI): calcd.: 180.1, Found: 181.3 [M+1]⁺. [0144] Step 2. Synthesis of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3). Spiro[bicyclo[2.2.1]heptane-2,4'-imidazolidine]-2',5'-dione (1-2) (21 g, 117.0 mmol) was dissolved in saturated aq. NaOH (200 mL). Then the reaction mixture was reflux for 3 days and acidified with 6N HCl solution to pH = 5. The reaction mixture was concentrated under reduced pressure to afford 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3) as a white solid (27 g, 30%). MS (ESI): calcd.: 155.1, Found: 156.3 [M+1]⁺ . [0145] Step 3. Synthesis of 2-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2- carboxylic acid (1-4). To a solution of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (1-3) (27 g, 35.1 mmol) and NaOH (3 g, 77.2 mmol) in H₂O (70 mL) was added Boc₂O (9 g, 40 mmol) in acetone dropwise between 10 - 20 °C. The reaction mixture was stirred at rt overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidified with 6N aq. HCl solution to pH = 2 and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-2- carboxylic acid (1-4) (9 g, 89%) as a white solid. MS (ESI): calcd.: 255.2, Found: 156.3 [M - 100+1]⁺ . [0146] Step 4. Synthesis of tert-butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5). A 250 mL flask was charged with 2-(tert- butoxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (1-4) (9 g, 35.3 mmol), TEA (3.2 g, 32.1 mmol) and THF (100 mL). Then isobutyl carbonochloridate (4.4 g, 32.1 mmol) was added at 0 °C. The reaction mixture was stirred at rt for 0.5 h. Then aniline (3 g, 32.1 mmol) was added. The reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was diluted with water and extracted with EA (100 mL x 3). The combined organic layers were dried by Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford tert-butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5) (4.95 g, 43%) as a white solid. TLC: 10% PE/DCM (v/v) (R_f: 0.6); MS (ESI): calcd.: 330.2, Found: 275.2 [M-56+1]⁺. [0147] Step 5. Synthesis of 2-amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide (1- 6). To a stirred solution of tert-Butyl 2-(phenylcarbamoyl)bicyclo[2.2.1]heptan-2- ylcarbamate (1-5) (4.95 g, 15 mmol) in DCM (50 mL) was added CF₃COOH (6 mL) at 0 °C. The reaction mixture was stirred at rt overnight. After completion of the reaction (monitored by TLC), the reaction mixture was basified with K₂CO₃ solution to pH = 9. Then reaction mixture was extracted with DCM (70 mL x 3). The combined organic layers were dried by Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2-amino-N- phenylbicyclo[2.2.1]heptane-2-carboxamide (1-6) (2.9 g, 85%) as a white solid. TLC: 5 % PE/DCM (v/v) (R_f: 0.5); MS (ESI): calcd.: 230.1, Found: 231.3 [M+1]⁺. [0148] Step 6. Synthesis of 2-((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1- 7).2-amino-N-phenylbicyclo[2.2.1]heptane-2-carboxamide (1-6) (2.9 g, 12.6 mmol) was dissolved in THF (50mL), LiAlH₄ (1.9 g, 50.4 mmol) was added at 0 °C slowly. The reaction mixture was warmed up to 75 °C and stirred overnight. After completion of the reaction by TLC, the reaction mixture was cooled to 0 °C, quenched with 1.9 mL water and 1.9 mL 15 % aqueous NaOH, filtered, washed with THF (50 mL). The organic layer was dried by Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1-7) (2.5 g, 95%) as a white solid. MS (ESI): calcd.: 216.2, Found: 217.4 [M+1]⁺. [0149] Step 7. Synthesis of 2,4-dibromo-5-methoxy-N-(2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)benzenesulfonamide (1-8). To a mixture of 2-((phenylamino)methyl)bicyclo[2.2.1]heptan-2-amine (1-7) (2.4 g, 11.1 mmol) and TEA (2.8 g, 27.8 mmol) in THF (50mL), was added, 2,4-dibromo-5-methoxybenzenesulfonyl chloride (6.03 g, 16.7 mmol) at 0 °C slowly. The reaction mixture was stirred at rt rt overnight. The reaction mixture was quenched with water (50 mL), extracted with EA (70 mL x 3). The combined organic layers were dried by Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with PE in DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v) to afford 2,4-dibromo-5-methoxy-N-(2- ((phenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)benzenesulfonamide (1-8) (2.97 g, 50%) as a white solid. TLC: 20% PE/DCM (v/v) (R_f: 0.4); MS (ESI): calcd.: 542.0, Found: 543.0 [M+1]⁺. [0150] Step 8. Synthesis of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-9). To a solution of 2,4-dibromo-5-methoxy-N-(2-((phenylamino)methyl)bicyclo[2.2.1]heptan-2- yl)benzenesulfonamide (1-8) (2.7 g, 5.0 mmol) in DMF (30 mL), K₂CO₃ (1.95 g, 10.0 mmol) and CuI (95 mg, 0.5 mmol) were added. The reaction mixture was stirred at rt under N₂ atmosphere for 15 min. TDA-1 (323.5 mg, 1.0 mmol) was added, and the reaction mixture was stirred at 130 °C overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with EA (3x70 ml). The combined organic layers were washed with brine (30 ml), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'- bicyclo[2.2.1]heptane] 1,1-dioxide (1-9) (1.97 g, 85%) as a white solid. TLC: 20% PE/DCM (v/v) (R_f: 0.5); MS (ESI): calcd.: 462.1, Found: 463.2 [M+1]⁺. [0151] Step 9. Synthesis of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-10). To a stirred solution of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-9) (500 mg, 1.1 mmol) in NMP (10 ml), Cs₂CO₃ (705 mg, 2.2 mmol) was added at 0 °C and reaction mixture was stirred for 15 minutes. Methyl iodide (768 mg, 5.4 mmol) was then added at 0 °C. The reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EA (50 mL) and the organic layer was washed with water (40 mL). The organic part was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE/DCM = 1/1 (v/v), then PE/DCM = 1/8 (v/v)) to afford 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-10) (506 mg, 98%) as a white solid. TLC: 20% PE/DCM (v/v) (R_f: 0.7); MS (ESI): calcd.: 476.1, Found: 477.2 [M+1]⁺. [0152] Step 10. Synthesis of 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro- 2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-11). To a solution of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-10) (506 mg, 1.06 mmol) in DMF (10mL), CH₃SNa (744 mg, 10.63 mmol) was added and the reaction mixture was stirred for 6 hours at 80 °C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (30 ml) and the aqueous laver was extracted with EA (30 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO_4, filtered_, and concentrated under vacuum. The residue was purified by column chromatography, eluting with 25% PE in DCM, then 100% DCM to afford 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptane] 1,1-dioxide (1-11) (299 mg, 66%) as a white solid. TLC: 10% PE/DCM (v/v) (R_f: 0.4); MS (ESI): calcd.: 430.1, MS Found: 431.2 [M+1]⁺. [0153] Step 11. Synthesis of ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan]- 8-yl)oxy)acrylate (1-12). To a stirred solution of ethyl 3-bromo-2,2-difluoropropanoate (389 mg, 1.79 mmol) in THF (4 mL), NaH (72 mg, 1.79 mmol) was added slowly under N₂ atmosphere. The reaction mixture was stirred at 30 °C for 2 hours.8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'- bicyclo[2.2.1]heptane] 1,1-dioxide (1-11) (155 mg, 0.36 mmol) was disoolved in DMF (2 mL) and added to the above reaction mixture slowly. Cs₂CO₃ (350 mg, 1.08 mmol) was added. The reaction mixture was warmed up to 70 °C and stirred for 2 hours. The reaction mixture was partitioned between water and EA (30 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL) and dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum. The residue was purified by prep-HPLC to afford ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan]-8-yl)oxy)acrylate (1-12) (122 mg, 62%) as a white solid. MS (ESI): calcd.: 546.2; Found: 547.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.84 ‒ 7.74 (m, 1H), 7.56 (s, 1H), 7.23 ‒ 7.21 (m, 2H), 7.06 ‒ 6.84 (m, 4H), 4.42 ‒ 4.24 (m, 3H), 2.96 ‒ 2.62 (m, 4H), 2.33 ‒ 2.13 (m, 4H), 2.09 ‒ 1.37 (m, 6H), 1.29 ‒ 1.05 (m, 6H) ppm. [0154] Step 12. Synthesis of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan]-8- yl)oxy)acrylic acid (Example 1). Ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'- bicyclo[2.2.1]heptan]-8-yl)oxy)acrylate (1-12) (122 mg, 0.22 mmol) was dissolved in 1,4- dioxane/H₂O (9 mL/3 mL), LiOH (28 mg, 0.67 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water and acidified with KHSO₄ solution to pH = 4, extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried by Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,2'-bicyclo[2.2.1]heptan]-8- yl)oxy)acrylic acid (Example 1) (70 mg, 59%) as a white solid. MS (ESI): calcd.: 518.1, Found: 519.2 [M+1]⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.52 (s, 1H), 7.31 ‒ 7.27 (m, 3H), 7.03 ‒ 6.86 (m, 4H), 4.39 ‒ 4.26 (m, 1H), 3.00 ‒ 2.70 (m, 4H), 2.28 ‒ 2.03 (m, 5H), 1.99 ‒ 1.10 (m, 8H) ppm. [0155] Example 2. (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8-yl)oxy)acrylic acid

[0156] Step 1. Synthesis of tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2). To a solution of 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (2-1) (20 g, 93 mmol) in THF (400 mL) was added TEA (7.6 g, 84 mmol), then the isobutyl carbonochloridate (8.6 g, 84 mmol) was added at 0 °C slowly. The mixture was stirred for 0.5 h followed by addition of a solution of aniline (7.8 g, 84 mmol) in THF (80 mL) dropwise. The mixture was stirred at rt for 16 h. The reaction mixture was then concentrated under reduced pressure to afford tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2) (15 g, 56%) as a white solid, which was used for next step without further purification. MS (ESI): calcd.: 290.1, Found: 235.1 [M-56+1] ⁺. [0157] Step 2. Synthesis of 1-amino-N-phenylcyclobutanecarboxamide (2-3). To a solution of tert-butyl 1-(phenylcarbamoyl)cyclobutylcarbamate (2-2) (15 g, 51.72 mmol) in DCM (150 mL) was added TFA (30 mL) at rt. The mixture was stirred at rt for 16 h. The reaction solution was concentrates under reduced pressure. The residue was diluted with DCM and basified with aqueous K₂CO₃ solution to pH = 9. The aqueous layer was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-amino-N- phenylcyclobutanecarboxamide (2-3) (7.5 g) as a yellow solid, which was used for next step without further purification. MS (ESI): calcd.: 190.1, Found: 191.1. [0158] Step 3. Synthesis of N-((1-aminocyclobutyl)methyl)aniline (2-4). To a solution of 1-amino-N-phenylcyclobutanecarboxamide (2-3) (7.5 g, 39.47 mmol) in THF (75 mL) at 0 °C was added LiAlH₄ (4.5 g, 118.42 mmol) slowly. The reaction mixture was stirred at 75 °C for 4 h. The reaction mixture was cooled to rt and quenched by adding water (4.5 mL) and then 15% aqueous NaOH solution (4.5 mL) at 0 °C. The reaction mixture was concentrated under reduced pressure to afford N-((1-aminocyclobutyl)methyl)aniline (2-4) (6.5 g, 94%) as a celadon solid, which was used for next step without further purification. MS (ESI): calcd.: 176.1, Found: 177.4 [M+1] ⁺. [0159] Step 4. Synthesis of 2,4-dibromo-5-methoxy-N-(1- ((phenylamino)methyl)cyclobutyl)benzenesulfonamide (2-5). To a solution of N-((1- aminocyclobutyl)methyl)aniline (2-4) (6.5 g, 36.93 mmol) in DCM (70 mL) was added TEA (9.32 g, 92.32 mmol) at rt, then 2,4-dibromo-5-methoxybenzenesulfonyl chloride (20 g, 55.4 mmol) was added at 0 °C slowly. The mixture was stirred at rt for 2 h. The reaction mixture was extracted with DCM (150 mL x 3), washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: DCM = 100:1 ~ 0:1 (v/v)) to afford 2,4-dibromo-5- methoxy-N-(1-((phenylamino)methyl)cyclobutyl)benzenesulfonamide (2-5) as a white solid (6.8 g, 37%). TLC: PE/DCM = 1/2 (v/v) (R_f: 0.4); MS (ESI): calcd.: 504.2, Found: 505.0 [M+1] ⁺. [0160] Step 5. Synthesis of 7-bromo-8-methoxy-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-6). To a solution of 2,4-dibromo-5-methoxy-N-(1-((phenylamino)methyl)cyclobutyl)benzenesulfonamide (2-5) (3 g, 5.95 mmol) in DMF (20 mL) was added K₂CO₃ (1.64 g, 11.9 mmol) and CuI (114 mg, 0.6 mmol). The mixture was stirred at rt for 15 min under N₂, TDA-1 (1.03 mg, 1.19 mmol) was added at rt. The mixture was stirred at 130 °C for 16 h under N₂. The reaction was cooled to rt, diluted with ethyl acetate (80 mL x 3), and filtered. The filtrate was washed with brine and dried over sodium sulfate. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 100% PE to 100% EA to afford 7-bromo- 8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-6) as a white solid (2.53 g, 89%). TLC: PE/EA = 5/1 (v/v) (R_f: 0.4); MS (ESI): calcd.: 422.2, Found: 423.2 [M+1] ⁺. [0161] Step 6. Synthesis of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-7): To a solution of 7- bromo-8-methoxy-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-6) (2.53 g, 5.99 mmol) in DMF (25 mL) was added Cs₂CO₃ (2.16 g, 6.59 mmol) and MeI (4.13 g, 29.95 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was extracted with EA (80 mL x 3), washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: EA = 100:1 ~ 0:1 (v/v)) to afford 7-bromo-8- methoxy-2-methyl-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-7) as a yellow solid (1.8 g, 69%). TLC: PE/EA = 5/1 (v/v) (R_f: 0.5); MS (ESI): calcd.: 436.1, Found: 437.1 [M+1]⁺. [0162] Step 7. Synthesis of 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5-dihydro- 2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-8). To a solution of 7-bromo-8-methoxy-2-methyl-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (2-7) (1.8 g, 4.13 mmol) in DMF (20 mL) was added NaSMe (2.9 g, 41.3 mmol) at rt. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (40 mL) and filtered. The filtrate was washed with brine and dried over sodium sulfate. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 100% PE to 100% EA to afford 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutane] 1,1-dioxide (1-8) as a white solid (900 mg, 56%). TLC: PE/EA = 2/1 (v/v) (R_f: 0.5); MS (ESI): calcd.: 390.1, Found: 391.2 [M+1] ⁺. [0163] Step 8. Synthesis of ethyl (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8- yl)oxy)acrylate (2-9). A mixture of ethyl 3-bromo-2,2-difluoropropanoate (1.09 g, 5 mmol) and NaH (60%, 200 mg, 5 mmol) in DMF (10 mL) was stirred at 25 °C for 3 h.8-Hydroxy-2- methyl-7-(methylthio)-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'- cyclobutane] 1,1-dioxide (2-8) (400 mg, 1.03 mmol) and Cs₂CO₃ (1.01 g, 3.09 mmol) in DMF (4 mL) were added. The reaction mixture was stirred at 70 °C for 16 h. After the reaction was cooled to rt, the reaction mixture was quenched with saturated NH₄Cl aqueous solution at 0 °C, then extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (PE: EA = 100:1 ~ 0:1 (v/v)) to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8-yl)oxy)acrylate (2-9) as a yellow solid (380 mg, 75%). TLC: PE/EA = 4/1 (v/v) (R_f: 0.4); MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] ⁺. [0164] Step 9. Synthesis of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8- yl)oxy)acrylic acid (Example 2). To a solution of (Z)-2-fluoro-3-((2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8- yl)oxy)acrylate (2-9) (200 mg, 0.40 mmol) in dioxane (18 mL) and H₂O (6 mL) was added LiOH (28 mg, 1.2 mmol) at 0 °C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was acidified with aqueous NaHSO4 solution to pH = 4, extracted with ethyl acetate (50 mL x 3), and filtered. The filtrate was washed with brine, dried over sodium sulfate, and filtered. After removal of the solvent in vacuo, the residue was purified by prep-HPLC to afford (Z)-2-fluoro-3-((2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8-yl)oxy)acrylic acid (Example 2) as a white solid (20 mg, 10%). MS (ESI): calcd.: 478.1, Found: 479.2 [M+1]⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.53 (s, 1H), 7.33-7.26 (m, 3H), 7.07-7.06 (m, 2H), 6.96 (s, 1H), 6.92- 6.89 (m, 1H), 4.90 (s, 1H), 2.50 (s, 3H),2.32-2.29(M, 2H), 2.26 (s, 3H), 1.85-1.76 (m, 4H) ppm. [0165] Example 3, 3a and 3b. (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 3), (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 3a), and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 3b)

[0166] Step 1. Synthesis of 2-cyclopropylethyl trifluoromethanesulfonate (3-2). A solution of 2-cyclopropylethanol (3-1) (5.5 g, 62.7 mmol) in anhydrous DCM (120 mL) was added 2,6-Lutidine (10 g, 94.0 mmol) and stirred for 30 min at 0 °C. Tf₂O (25 g, 87.8 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with ice water (150 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2-cyclopropylethyl trifluoromethanesulfonate (3-2) (12 g, 87%) as a brown oil, which was used for next step directly without further purification. [0167] Step 2. Synthesis of ethyl 4-cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3). A solution of ethyl 2-(diphenylmethyleneamino)acetate (10 g, 37.4 mmol) in anhydrous THF (200 mL) was added t-BuOK (5 g, 44.6 mmol) at 0 °C and stirred for 30 min. 2-cyclopropylethyl trifluoromethanesulfonate (3-2) (12 g, 55.0 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ice water (200 mL) and extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford ethyl 4- cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3) (12 g, 96%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 335.2, Found: 336.3 [M+1]⁺. [0168] Step 3. Synthesis of ethyl 2-amino-4-cyclopropylbutanoate (3-4). A mixture of ethyl 4-cyclopropyl-2-(diphenylmethyleneamino)butanoate (3-3) (12 g, 35.8 mmol) and HCl (6 N, 60 mL, 360 mmol) in EA (50 mL) was stirred at rt for 2 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EA (80 mL x 2). The aqueous phase was basified with NH₃ ^.H₂O to pH = 9 - 10 and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford ethyl 2-amino-4-cyclopropylbutanoate (3-4) (4.6 g.75%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 171.1, Found: 172.3 [M+1] ⁺. [0169] Step 4. Synthesis of ethyl 2-(tert-butoxycarbonylamino)-4- cyclopropylbutanoate (3-5). A mixture of ethyl 2-amino-4-cyclopropylbutanoate (3-4) (4.6 g, 26.9 mmol), Et₃N (4.0 g, 40.4 mmol), and Boc₂O (7.0 g, 32.3 mmol) in anhydrous DCM (150 mL) was stirred at rt overnight. The reaction mixture was quenched with ice water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford ethyl 2-(tert- butoxycarbonylamino)-4-cyclopropylbutanoate (3-5) (6.9 g, 94%) as a yellow oil, which was used for next step directly without further purification. MS (ESI): calcd.: 271.2, Found: 216.2 [M–56+1] ⁺. [0170] Step 5. Synthesis of 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6). To a solution of ethyl 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoate (3-5) (6.9 g, 25.4 mmol) in MeOH/H₂O (50 mL/ 50 mL) was added LiOH (3 g, 71.4 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (100 mL), acidified with 3N aq. HCl solution to pH = 4, extracted with DCM (150 mL x 3), The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6) (4.38 g, 71%) as a yellow solid, which was used for next step directly without further purification. MS (ESI): calcd.: 243.2, Found: 188.2 [M–56+1]⁺. [0171] Step 6. Synthesis of tert-butyl 4-cyclopropyl-1-oxo-1-(phenylamino)butan-2- ylcarbamate (3-7). A mixture of 2-(tert-butoxycarbonylamino)-4-cyclopropylbutanoic acid (3-6) (4.38 g, 18 mmol), HATU (10 g, 26.3 mmol), and DIEA (7 g, 54 mmol) in anhydrous DMF (100 mL) was stirred at rt for 30 min, then to this mixture was added PhNH₂ (2 g, 21.5 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (150 mL), and filtrated. The filtrate was concentrated under reduced pressure to afford tert-butyl 4- cyclopropyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (3-7) (5.5 g, 96%) as a yellow solid, which was used for next step directly without further purification. MS (ESI): calcd.: 318.2, Found: 263.2 [M-56+1] ⁺. [0172] Step 7. Synthesis of 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8). To a solution of tert-butyl 4-cyclopropyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (3-7) (5.5 g, 17.3 mmol) in EA (50 mL) was added 4N HCl in dioxane (43 mL, 173 mmol). The reaction mixture was stirred at rt overnight, quenched with ice water (100 mL), basified with NaHCO₃ to PH = 8, and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 10% to 20% MeOH in DCM to afford 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8) (3.2 g, 85%) as a yellow oil. MS (ESI): calcd: 218.1, Found: 219.2 [M+1]⁺. [0173] Step 8. Synthesis of 4-cyclopropyl-N’-phenylbutane-1,2-diamine (3-9). To a solution of 2-amino-4-cyclopropyl-N-phenylbutanamide (3-8) (3.2 g, 14.7 mmol) in anhydrous THF (100 mL) was added LiAlH₄ (2.8 g, 73.4 mmol) slowly at rt. Then reaction mixture was allowed warm to 70 °C and stirred for 3 h. The reaction mixture was cooled to rt, quenched with ice water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 15% to 20% MeOH in DCM to afford 4-cyclopropyl-N’-phenylbutane-1,2-diamine (3-9) (3 g, 100%) as a yellow oil. MS (ESI): calcd.: 204.2, Found: 205.4 [M+1]⁺. [0174] Step 9. Synthesis of 2,4-dibromo-N-(4-cyclopropyl-1-(phenylamino)butan-2-yl)- 5-metho xybenzenesulfonamide (3-10). To a solution of 4-cyclopropyl-N’-phenylbutane- 1,2-diamine (3-9) (3 g, 14.7 mmol) in DCM (100 mL) was added Et3N (3.7 g, 36.7 mmol) and 2,4-dibromo-5-methoxybenzenesulfonyl chloride (8 g, 22 mmol). The reaction mixture was stirred at rt for 3 h, quenched with ice water (100 mL), extracted with EA (100 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (40 % - 45 % EA in PE) to afford 2,4-dibromo-N-(4-cyclopropyl-1-(phenylamino)butan-2-yl)-5- methoxybenzenesulfonamide (3-10) (4.5 g, 58%) as a yellow solid. MS (ESI): calcd.: 530.0, Found: 531.0 [M+1]⁺. [0175] Step 10. Synthesis of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11). To a solution of 2,4- dibromo-N-(4-cyclopropyl-1-(phenyl amino)butan-2-yl)-5-methoxybenzenesulfonamide (3- 10) (4.5 g, 8.5 mmol) in anhydrous DMF (40 mL) was added K₂CO₃ (2.35 g, 17 mmol) and CuI (323 mg, 1.7 mmol). The reaction mixture was degassed for 5 minutes under N₂ atmosphere and stirred at rt for 30 min. To the mixture was then added TDA-1 (550 mg, 1.7 mmol). The reaction mixture was stirred at 130 °C overnight. The reaction mixture was quenched with ice water (50 mL), extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% to 35% EA in PE) to afford 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11) (2.5 g, 65%) as a yellow solid. MS (ESI): calcd.: 450.1, Found: 450.9 [M+1]⁺. [0176] Step 11. Synthesis of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12). To a solution of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-11) (1.5 g, 3.3 mmol) in NMP (5 mL) was added Cs₂CO₃ (2.2 g, 6.6 mmol) and MeI (2.3 g, 18 mmol). The reaction mixture was stirred at rt for 3 h, quenched with ice water (30 mL), and extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (65% to 80% MeCN in H₂O) to afford 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12) (880 mg, 57%) as a yellow solid. MS (ESI): calcd.: 464.1, Found: 465.1 [M+1]⁺. [0177] Step 12. Synthesis of 3-(2-cyclopropylethyl)-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-13). To a solution of 7-bromo-3-(2-cyclopropylethyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-12) (880 mg, 1.9 mmol) in anhydrous DMF (8 mL) was added MeSNa (1.4 g, 19 mmol). The reaction mixture was stirred at 80 °C overnight, quenched with ice water (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (50% to 60% MeCN in H₂O) to afford 3-(2-cyclopropylethyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-13) (700 mg, 88%) as a yellow solid. MS (ESI): calcd.: 418.1, Found: 419.1 [M+1]⁺. [0178] Step 13. Synthesis of ethyl (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylate (3-14). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (1.1 g, 5.0 mmol) in anhydrous DMF (5 mL) was added NaH (200 mg, 60%, 5.0 mmol) and stirred at 30 °C for 2 hours. To the mixture was added 3-(2-cyclopropylethyl)-8-hydroxy-2- methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-13) (420 mg, 1.0 mmol). The reaction mixture was then stirred at 70 °C overnight, quenched with ice water (50 mL), extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography (80% MeCN in H₂O) to afford (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (3-14) (400 mg, 75%) as a white solid. MS (ESI): calcd.: 534.2, Found: 535.2 [M+1]⁺. [0179] Step 14. Synthesis of (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 3). To a solution of (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (3-14) (400 mg, 0.75 mmol) in dioxane (5 mL) and H₂O (1.5 mL) was added LiOH (95 mg, 2.25 mmol). The reaction mixture was stirred at rt for 4 h and extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse column (40% to 43% MeCN in H₂O) to afford (Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 3) (80 mg, 21%) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] ⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.56 (s, 1H), 7.26 (d, J = 17.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 4.10 - 4.00 (m, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 1.74 - 1.65 (m, 2H) , 1.42 - 1.28 (m, 3H), 0.78 - 0.68 (m, 1H), 0.45 – 0.42 (m, 2H), 0.14 - 0.03 (m, 2H) ppm. [0180] Step 15. Synthesis of (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 3a) and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 3b): The racemic sample (Example 3) (70 mg) was separated by SFC to afford: (S,Z)-3-((3-(2-cyclopropylethyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 3a) (10 mg, 2.6 %) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] ⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.53 (s, 1H), 7.30 (d, J = 17.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 4.13 - 3.98 (m, 2H), 2.57 (s, 3H), 2.34 (s, 3H), 1.75 - 1.65 (m, 2H) , 1.40 - 1.26 (m, 3H), 0.77 - 0.69 (m, 1H), 0.45 - 0.41 (m, 2H), 0.14 - 0.03 (m, 2H) ppm and (R,Z)-3-((3-(2-cyclopropylethyl)-2-methyl- 7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)- 2-fluoroacrylic acid (Example 3b) (10 mg, 2.6%) as a white solid. MS (ESI): calcd.: 506.1, Found: 507.2 [M+1] ⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.54 (s, 1H), 7.30 (d, J = 17.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 4.14 - 3.98 (m, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 1.74 - 1.65 (m, 2H) , 1.40 - 1.32 (m, 3H), 0.78 - 0.68 (m, 1H), 0.45 - 0.41 (m, 2H), 0.14 - 0.03 (m, 2H) ppm. [0181] Example 4, 4a and 4b. (E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4), (S,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4a), and (R,E)- 3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4b)

[0182] Step 1. Synthesis of diethyl 2-acetamido-2-(but-3-enyl)malonate (4-2). A stirred suspension of sodium hydride (60%, 4.60 g, 115 mmol) in anhydrous DMF (100 ml) at 0 °C was added a solution of diethyl acetamidomalonate (22.68 g, 105 mmol) in anhydrous DMF (80 mL) dropwise. The reaction mixture was stirred for 20 minutes at rt and then 4- bromo-1-butene (4-1) (7.5 mL, 74.1 mmol) was added. The light brown solution was then stirred at 90 °C for 4 h. The reaction mixture was quenched with saturated aqueous NH₄Cl and extracted with EA (3 × 200 mL). The combined organic layers were washed with water (200 mL), brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (40% EA in PE) to afford diethyl 2-acetamido-2-(but-3-enyl)malonate (4-2) (15.1 g, 75%) as a yellow oil. TLC: 40% EA/PE (v/v) (R_f: 0.4); MS (ESI): calcd.: 271.1, Found: 272.1 [M + 1]⁺. [0183] Step 2. Synthesis o 2-aminohex-5-enoic acid (4-3). A mixture of diethyl 2- acetamido-2-(but-3-enyl)malonate (4-2) (15.1 g) was refluxed in 100 mL of 10 w% NaOH for 4 h. The solution was neutralized with 6N HCl and the solvent was evaporated. The residue was diluted with 100 mL of methanol and filtered. The filtrate was evaporated. The residue was added 100 mL of 1N HCl. The resulting mixture was refluxed for 3 h. The solvent was evaporated, and the residue was taken up in 150 mL of methanol and the mixture was stirred overnight at rt. The precipitate was filtered and dried in vacuo to afford 2- aminohex-5-enoic acid (4-3) (4.53 g, 63%) as a white solid. MS (ESI): calcd.: 129.0, Found: 130.2 [M+1] ⁺. [0184] Step 3. Synthesis of 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4). A mixture of 2-aminohex-5-enoic acid (4-3) (4.53 g, 35 mmol), Et3N (10.5 g, 100 mmol), and Boc₂O (21.8 g, 100 mmol) in MeOH (50 mL) was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and acidified with 1.5N HCl. The reaction mixture was extracted with EA (150 mL x 2). The combined organic layers were washed with ice-cold water (150 mL), brine (150 mL), dried over anhydrous Na₂SO_4, filtered, and concentrated to afford 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4) (6.65 g.83%) as a white solid. MS (ESI): calcd.: 229.0, Found: 174 [M-56+1] ⁺. [0185] Step 4. Synthesis of tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5). To a stirred solution of 2-(tert-butoxycarbonylamino)hex-5-enoic acid (4-4) (6.55 g, 28.6 mmol) in DMF (50 mL) was added Et₃N (5.78 g, 57.2 mmol) and T3P (50 w%, 43.5 g, 68.6 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then aniline (3.46 g, 37.2 mmol) was added. The reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (50 mL) and diluted with EA (200 mL). The organic layer was washed with ice-cold water (200 mL), brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5) as a yellow solid (7.13 g, 82%) TLC: 5% MeOH/DCM (v/v) (R_f: 0.4); MS (ESI): calcd.: 304.0, Found: 249.2 [M- 56+1]⁺. [0186] Step 5. Synthesis of 2-amino-N-phenylhex-5-enamide (4-6). To a solution of tert-butyl 1-oxo-1-(phenylamino)hex-5-en-2-ylcarbamate (4-5) (7.13 g, 23.4 mmol) in DCM (50 mL) at 0 °C was added a solution of CF₃COOH (14 mL). The reaction mixture was stirred for 3 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The residue was quenched with saturated NaHCO₃ solution. The aqueous layer was extracted with EA (200 mL x 2). The combined organic layers were washed brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentered to afford 2-amino-N-phenylhex-5-enamide (4-6) as a colorless gum (4.53 g, 95%). TLC: 40% EA/PE (v/v) (R_f: 0.4); MS (ESI): calcd.: 204.0, Found: 204 [M + 1] ⁺. [0187] Step 6. Synthesis of N1-phenylhex-5-ene-1,2-diamine (4-7). To a solution of 2- amino-N-phenylhex-5-enamide (4-6) (4.53 g, 22.2 mmol) in THF (50mL) at 0 °C was added LiAlH₄ (2M solution in THF, 55.5ml, 111 mmol). The reaction mixture was heated for 4 hours at 75 °C. The reaction mixture was cooled to 0 °C and quenched with methanol at 0 °C. The reaction mixture was concentrated under vacuum. The residue was partitioned between water (50 mL) and EA (50 mL). The aqueous laver was extracted with EA (250 mL x 2). The combined organic layers were washed with water (250 mL), brine (250 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (10% MeOH in DCM) to afford N1-phenylhex-5-ene-1,2-diamine (4-7) as a yellow oil (3.92 g, 93%). TLC: 40% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 190.0, Found: 191.2 [M+1]⁺. [0188] Step 7. Synthesis of 4-dibromo-5-methoxy-N-(1-(phenylamino)hex-5-en-2- yl)benzenesulfonamide (4-8). To a stirred solution of N1-phenylhex-5-ene-1,2-diamine (4-7) (3.92 g, 20.6 mmol) in DCM (50 mL) and Et₃N (5.2 g, 51.5 mmol) and 2,4-dibromo-5- methoxybenzenesulfonyl chloride (11.2 g, 30.9 mmol) were added and the reaction mixture was stirred for 2 hours at rt. After completion of the reaction (monitored by TLC), the organic part was filtered and concentrated under vacuum to afford 2,4-dibromo-5-methoxy-N-(1- (phenylamino)hex-5-en-2-yl)benzenesulfonamide (4-8) as a yellow solid (6.91 g, 65%). TLC: 20% EA/PE (v/v) (R_f: 0.6); MS (ESI): calcd.: 515.9, Found: 517.1 [M+1]⁺. [0189] Step 8. Synthesis of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-9). To a solution of 2,4-dibromo-5- methoxy-N-(1-(phenylamino)hex-5-en-2-yl)benzenesulfonamide (4-8) (6.91 g, 13.4 mmol) in DMF (30 mL), K₂CO₃ (3.6 g, 26.8 mmol) and CuI (255 mg, 1.34 mmol) were added. The reaction mixture was degassed for 5 minutes under N₂ atmosphere and TDA-1 (866 mg, 2.68 mmol) were added. The reaction mixture was heated for 16 hours at 130 °C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (25 mL). The aqueous layer was extracted with a 1:1 mixture of EA and PE (50 mL x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na₂SO_4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (15% EA in PE) to afford 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine (4-9) as a brown gum (3.0 g, 51%). TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 436.0, Found: 437.1 [M+1]⁺. [0190] Step 9. Synthesis of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10). To a stirred solution of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine (4-9) (3.0 g, 6.9 mmol) in NMP (10 mL), Cs₂CO₃ (4.5 g, 13.8 mmol) was added at 0 °C and reaction mixture was stirred for 15 minutes. Methyl iodide (4.9 g, 34.5 mmol) was then added drop wise at 0 °C and the reaction mixture was stirred for 16 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EA (100 mL) and the organic layer was washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography, eluting with 18% EA /PE (v/v) to afford 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10) as a white solid (2.33 g, 75%). TLC: 20% EA/PE (v/v) (R_f: 0.7); MS (ESI): calcd.: 450.0, Found: 451.1 [M+1]⁺. [0191] Step 10. Synthesis of 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11). To a solution of 7-bromo-3-(but-3-en-1-yl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-10) (2.33 g, 5.18 mmol) in DMF (10mL), CH₃SNa (1.8 g, 25.9 mmol) was added and the reaction mixture was stirred for 6 hours at 80 °C. After completion of the reaction (monitored by TLC) the reaction mixture was quenched with ice water (30 ml) and the aqueous layer was extracted with EA (2 x 30 mL). The combined organic layers were washed with water (30mL), brine (30 m), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (35% EA in PE) to afford 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11) as a white solid (1.4 g, 68%). TLC: 20% EA/PE (v/v) (R_f: 0.4); MS (ESI): calcd.: 404.0, Found: 405.1 [M+1]⁺. [0192] Step 11. Synthesis of (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylate (4-12). A mixture of 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11) (1.4g, 3.46 mmol), DABCO (194 mg, 1.73 mmol), and tert-butyl propiolate (680 mg, 5.4mmol) in THF (5 mL) was stirred for 3 hours at rt. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layers were extracted with EA (20 mL x 2). The combined organic layers were washed with water (10 mL x 2), dried over anhydrous Na₂SO_4, filtered and concentrated in vacuo. The residue was purified by column chromatography (12% EA/PE (v/v)) to afford the title compound (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl- 7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylate (4-12) as a white solid (1.6 g, 89%). TLC: 10% EA/PE (v/v) (R_f: 0.4); MS (ESI): calcd.: 530.2, Found: 531.1 [M+1]⁺. [0193] Step 12. Synthesis of (E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4). A mixture of (E)-tert-butyl3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylate (4-12) (160 mg, 0.3 mmol) and TFA (0.4 mL) in DCM (5 mL) stirred for 3 h at rt. The reaction mixture was quenched with H₂O (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford (E)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4) (75 mg, 53%) as a white solid. TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (d, J = 12 Hz, 1H), 7.47 (s, 1H), 7.18 (t, J = 7.2 Hz, 3H), 6.75 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 5.87-5.80 (m, 1H), 5.54 (d, J = 12 Hz, 1H), 5.10 (d, J = 16 Hz, 1H), 5.00 (d, J = 8.4 Hz, 1H), 4.08 (d, J = 16 Hz, 1H), 3.86 (brs, 1H), 3.41-3.32 (m, 1H), 2.51-2.49 (m, 3H), 2.40 (s, 3H), 2.20-2.09 (m, 2H), 1.74-1.59 (m, 2H) ppm. [0194] Step 13. Synthesis of (S,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4a) and (R,E)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 4b). Racemic Example 4 (75 mg) was separated by SFC to afford: (S,E)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4a) (11 mg, 7.7%) as a white solid. TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1]⁺ ; ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J = 12 Hz, 1H), 7.60 (s, 1H), 7.29 (s, 2H), 6.95-6.91 (m, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.87-5.77 (m, 1H), 5.60 (d, J = 12 Hz, 1H), 5.08 (d, J = 16 Hz, 1H), 5.02 (d, J = 9.6 Hz, 1H), 4.05 (d, J = 17.2 Hz, 1H), 3.87 (brs, 1H), 3.60-3.47 (m, 1H), 2.68 (s, 3H), 2.29 (s, 3H), 1.82- 1.74 (m, 2H) , 1.62-1.52 (m, 2H) ppm and (R,E)-3-((3-(but-3-en-1-yl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 4b) (16 mg, 11.3%) as a white solid. TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 474.1, Found: 475.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 12 Hz, 1H), 7.60 (s, 1H), 7.29 (s, 2H), 6.95-6.91 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.87-5.77 (m, 1H), 5.60 (d, J = 12 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 5.03 (d, J = 12 Hz, 1H), 4.05 (d, J = 14.4 Hz, 1H), 3.95-3.84 (m, 1H), 3.60-3.46 (m, 1H), 3.09-3.02 (m,1H), 2.68 (s, 3H), 2.29 (s, 3H), 1.84-1.71 (m, 2H) , 1.62-1.47 (m, 2H) ppm. [0195] Example 5, 5a and 5b. (Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5), (S,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5a), and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5b)

[0196] Step 1. Synthesis of (Z)-ethyl 3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (5-1). Into an 8 mL vial purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-bromo-2, 2-difluoropropanoate (540 mg, 2.5 mmol), anhydrous DMA (5 mL), and NaH (100 mg, 2.5 mmol) at 60 °C. After completion of the reaction (monitored by GCMS), 3-(but-3-en-1-yl)-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (4-11) (202 mg, 0.5 mmol) and CS₂CO₃ (652 mg, 2 mmol) was added into the vial. The resulting mixture was stirred for 3 h at 60 °C. The reaction mixture was then cooled to 0 °C and quenched with aqueous NH₄Cl. The resulting mixture was extracted with EA (50 mL x3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (1/5) (v/v) to afford (Z)-ethyl 3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5 tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylate (5-1) (180 mg, 69%) as a light yellow solid. TLC: 10% EA/PE (v/v) (R_f: 0.4); MS (ESI): calcd.:520.2, Found: 521.1 [M + 1]⁺. [0197] Step 2. Synthesis of (Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5). Into a 50-mL round-bottom flask, was placed (Z)-ethyl 3-((3-(but-3-en-1- yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (5-1) (180 mg, 0.35 mmol), dioxane (12 mL) and H₂O (4 mL). The reaction mixture was cooled to 0 °C. Then the LiOH (40 mg, 1.0 mmol) was placed into the flask. The resulting solution was stirred for 6 h at rt. The resulting solution was quenched with H₂O (20 mL) and acidified with aqueous NaHSO₄ solution to pH = 5. The resulting solution was extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford (Z)-3-((3-(but-3-en-1-yl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 5) (95 mg, 55%) as a white solid. TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 492.1, Found: 493.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.53 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.78 (t, J = 7.6 Hz, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.81-5.74 (m, 1H), 5.04 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10 Hz, 1H), 3.93-3.90 (m, 1H), 3.34-3.26 (m, 1H), 2.54 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H), 2.18-2.10 (m, 2H), 1.71-1.58 (m, 1H) , 1.54-1.48 (m, 1H) ppm. [0198] Step 3. Synthesis of (S,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5a) and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5b): Racemic Example 5 (95 mg) was separated by SFC to afford (S,Z)-3-((3- (but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5a) (32 mg, 19%) as a white solid, TLC: 20% EA/PE (v/v) (R_f: 0.5); MS (ESI): calcd.: 492.1, Found: 493.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (s, 1H), 7.35 (d, J = 17.2 Hz, 1H), 7.23 (t, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.86-5.76 (m, 1H), 5.07 (d, J = 17.2 Hz, 1H), 5.01 (d, J = 10 Hz, 1H), 4.03-3.96 (m, 1H), 3.94-3.84 (m, 1H), 3.52-3.39 (m, 1H), 2.64 (s, 3H), 2.28 (s, 3H), 2.25-2.13 (m, 2H), 1.77-1.71 (m, 1H), 1.60-1.52 (m, 1H) ppm and (R,Z)-3-((3-(but-3-en-1-yl)-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 5b) (26 mg, 15%) as a white solid, TLC: 20% EA/PE (v/v) (R_f: 0.5); MS Calcd.: 492.1, Found: 493.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.56 (s, 1H), 7.40 (d, J = 17.2 Hz, 1H), 7.20 (t, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (t, J = 6.8 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.84-5.77 (m, 1H), 5.07 (d, J = 17.2 Hz, 1H), 5.01 (d, J = 10 Hz, 1H), 4.03-3.96 (m, 1H), 3.94-3.84 (m, 1H), 3.52-3.39 (m, 1H), 2.61 (s, 3H), 2.26 (s, 3H), 2.21-2.13 (m, 2H), 1.80-1.64 (m, 1H) , 1.60-1.49 (m, 1H) ppm. [0199] Examples 6 and 7. (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylamide (Example 6) and (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylonitrile (Example 7)

[0200] Step 1. Synthesis of 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2). То а solution of 2-aminohexanoic acid (6-1) (25 g, 0.19 mol) in water (250 mL) and THF (250 mL), NаНСО₃ (48 g, 0.57 mol) and Boc₂O (52.2 ml, 0.23 mol) were added. The reaction mixture was stirred for 16 h at rt. After completion of the reaction, the reaction was acidified using NaHSO₄. The reaction mixture was extracted with EtOAc (150 mL x 2). The combined organic layer was washed with ice-cold water (150 mL) and brine (150 mL), dried over anhydrous Na₂SO₄, and concentrated to afford 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2) (42 g, 95%). [0201] Step 2. Synthesis of tert-butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (6- 3). A solution of 2-((tert-Butoxycarbonyl)amino)hexanoic acid (6-2) (5 g, 0.02 mol) in CH₂Cl₂ (150 mL) was cooled and then added EDC·HCl (5g, 26 mmol), HOBt (7.2 g, 22 mmol), and TEA (5 g, 50 mmol). The mixture was stirred for 1 h. Then aniline (1.86 g, 20 mmol) was added. The resulting mixture was stirred at rt overnight. The organic layer was washed with water and concentrated to afford tert-butyl (1-oxo-1-(phenylamino)hexan-2- yl)carbamate (6-3) (6 g, 90%). [0202] Step 3. Synthesis of 2-Amino-N-phenylhexanamide (6-4). To а solution of tert- butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (6-3) (6 g, 19.6 mol) in 1,4-dioxane (500 mL) at 0 °C was added а solution of HCl in 1,4-dioxane (4 М, 199 mL). The reaction mixture was stirred for 16 h at rt. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was basified with saturated NаНСО₃ solution. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layer was washed brine (200 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford 2-Amino-N-phenylhexanamide (6-4) (3.8 g, 95%). [0203] Step 4. Synthesis of Nl-Phenylhexane-1,2-diamine (6-5). То а solution of 2- amino-N-phenylhexanamide (6-4) (10 g, 0.05 mol) in THF (320 mL) at 0 °C was added borane dimethylsulfide (2М solution in THF, 117 ml, 0.23 mol). The reaction mixture was heated at 75 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with methanol (150 mL) and then stirred for 30 min at rt. The reaction mixture was concentrated under vacuum. To the resulting crude material was added solution of HCl (3 М, 100 mL). The obtained residue was quenched with saturated NаOН solution. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layer was washed brine (200 mL) and dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford Nl-Phenylhexane-1,2-diamine (6-5) (8 g, 85%). [0204] Step 5. Synthesis of 2,4-Dibromo-5-methoxy-N-1-{phenylamino)hexan-2- yl)benzenesulfonamide (6-6). То а solution of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (52 g, 0.14 mol) in THF (500 mL) at 0 °C were added N¹-phenylhexane-1,2-diamine (6-5) (21 g, 0.11 mol) and triethylamine (45.5 ml, 0.33 mol). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated under vacuum and the obtained residue was dissolved in EtOAc (400 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to afford 2,4-Dibromo-5-methoxy-N-1-{phenylamino)hexan-2- yl)benzenesulfonamide (6-6) (65 g, 65%). [0205] Step 6. Synthesis of 7-Bromo-З-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro- 1,2,5-benzothiadiazepine 1,1-dioxide (6-7). То а solution of 2,4-dibromo-5-methoxy-N-(1- (phenylamino)hexan-2-yl)benzenesulfonamide (6-6) (65 g, 0.11 mol) in DMF (200 mL), К₂СO₃ (58 g, 0.42 mol) and copper powder (14.1 g, 0.22 mol) were added. The reaction mixture was degassed for 5 minutes under N₂ atmosphere, and the reaction mixture was then heated at 115 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (500 mL). The aqueous layer was extracted with MTBE (250 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography to afford 7-Bromo-З-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine 1,1-dioxide (6-7) (20 g, 43%). MS (ESI): calcd.: 440.0, 441.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.20 – 7.11 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.1 Hz, 2H), 4.34 (d, J = 15.5 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 2.86 (s, 1H), 1.57 (s, 1H), 1.49 – 1.24 (m, 5H), 0.89 (td, J = 7.2, 2.0 Hz, 3H) ppm. [0206] Step 7. Synthesis of 7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (6-8). То а stirred solution of 7-bromo-3- butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothia-diazepine 1,1-dioxide (6-7) (10 g, 22.75 mmol) in DMFA (50 mL) were added Сs₂СO₃ (14.75 g, 45.67 mmol) and then iodomethane (7.1 ml, 0.11 mol). The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and the aqueous layer was extracted with MTBE (150 mL x 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum to afford 7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine 1,1-dioxide (6-8) (7 g, 68%). MS (ESI): calcd.: 452.0, Found 453.0 [M+1]⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.51 (d, J = 2.2 Hz, 2H), 7.20 (t, J = 7.9 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 2H), 4.08 (d, J = 16.0 Hz, 1H), 3.99 (s, 4H), 3.26 (s, 1H), 2.59 (s, 3H), 1.61 (d, J = 8.2 Hz, 2H), 1.53 – 1.34 (m, 4H), 0.97 (t, J = 6.5 Hz, 3H) ppm. [0207] Step 8. Synthesis of 3-Butyl-8-hydroxy-2-methyl-7-{methylthio)-5-phenyl- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (6-9). To a mixture of NaH (1.6 g, 33.3 mmol) in DMF (20 mL) was bubbled CH₃SH (5 eq). This mixture added tо а solution of 7 -bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothia- diazepine 1,1-dioxide (6-8) (3 g, 6.61 mmol) in DMF (50 mL). The reaction mixture was heated at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL) and dried over anhydrous Na₂SO₄. The organic part was concentrated under vacuum to afford 3- butyl-8-hydroxy-2-methyl-7-{methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine 1,1-dioxide (6-9) (2.3 g, 77%). MS (ESI): calcd.: 406.0, Found 407.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.27 (s, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.98 (s, 1H), 6.66 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 2H), 3.97 (d, J = 16.1 Hz, 1H), 3.89 (s, 1H), 3.17 (s, 1H), 2.41 (s, 3H), 2.33 (s, 3H), 1.66 – 1.55 (m, 1H), 1.48 (s, 1H), 1.34 (q, J = 7.7, 7.2 Hz, 4H), 1.00 – 0.81 (m, 3H) ppm. [0208] Step 9. Synthesis of ethyl (2Z)-3-[3-butyl-2-methyl-7-(methylsulfanyl)-1,1- dioxo-5-phenyl-2,3,4,5-tetrahydro-1-lambda-6,2,5-benzothiadiazepin-8-yl]oxy)-2- fluoroprop-2-enoate (6-10). To a stirred mixture of 3-butyl-8-hydroxy-2-methyl-7- (methylthio)-5)phenyl-2,3,4,5_tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (6-9) (1 g, 2.46 mmol) in DMA (15ml) at 0 °C, NaH (50%, 0.35 g, 7.38mmol) was added portion wise. The reaction mixture was stirred for 30 min. at 0 °C. A solution of 3-bromo-2,2- difluoropropanoate (1.2 g, 5.56mmol) in DMA (5ml) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 2N HCl to pH ~ 3. The aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄. The organic part was concentrated under vacuum. The residue was purified by HPLC to afford ethyl (2Z)-3-[3-butyl-2-methyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl- 2,3,4,5-tetrahydro-1-lambda-6,2,5-benzothiadiazepin-8-yl]oxy)-2-fluoroprop-2-enoate (6-10) (0.22 g, 17%). MS (ESI): calcd.: 522.2, Found 523.2 [M+1]⁺; ¹H NMR (400 MHz, CD₃CN): δ 7.63 (s, 1H), 7.53 (d, J = 18.1 Hz, 1H), 7.29 – 7.17 (m, 3H), 6.82 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.12 – 3.93 (m, 2H), 3.27 (t, J = 13.1 Hz, 1H), 2.54 (d, J = 5.0 Hz, 3H), 2.43 (s, 3H), 1.62 (d, J = 8.8 Hz, 2H), 1.44 (dq, J = 17.2, 6.8 Hz, 4H), 1.35 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0209] Step 10. Synthesis (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (6- 11). То а stirred solution of ethyl (Z}-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-fluoroacrylate (6-10) (180 mg, 0.35 mmol) in 1, 4-dioxane/water (4/1, 5 mL), lithium hydroxide (4 mg, 0.95 mmol) was added. The reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction mixture was acidified with 1.5 N aq. HCl solution to рН ~ 4. The aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with water (5 mL) and brine solution (5 mL), dried over anhydrous Na₂SO_4, filtered, and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylic acid (6-11) (60 mg, 35%). MS (ESI): calcd.: 494.2, Found 493.2 [M-1]-; ¹H NMR (400 MHz, DMSO-d₆): δ 7.33 (s, 1H), 7.15 (dd, J = 13.5, 6.0 Hz, 3H), 6.99 (d, J = 18.2 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 8.1 Hz, 2H), 4.03 (d, J = 16.0 Hz, 1H), 3.87 (s, 1H), 2.39 (s, 3H), 1.55 (d, J = 44.6 Hz, 2H), 1.35 (s, 4H), 0.92 (d, J = 7.1 Hz, 3H) ppm. [0210] Step 11. Synthesis of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylamide (Example 6): To a stirring suspension of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (6-11) (90 mg, 181.97 µmol), ammonium chloride (19.46 mg, 363.85 µmol), and DIPEA (141.07 mg, 1.09 mmol) in anhydrous DMF (2 mL) HATU (89.92 mg, 236.5 µmol) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under educed pressure. The residue was purified by HPLC to afford (Z)-3-((3- butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylamide (Example 6) (36 mg, 40%). MS (ESI): calcd.: 493.1, Found: 492.0 [M-1]-; ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (s, 1H), 7.65 (s, 1H), 7.63 – 7.51 (m, 2H), 7.23 – 7.11 (m, 3H), 6.74 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 8.1 Hz, 2H), 4.05 (d, J = 16.0 Hz, 1H), 3.86 (s, 1H), 2.41 (s, 3H), 1.61 (d, J = 7.2 Hz, 1H), 1.51 (s, 1H), 1.35 (s, 4H), 0.92 (d, J = 6.9 Hz, 3H) ppm. [0211] Step 12. Synthesis of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylonitrile (Example 7): A mixture of (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylamide (Example 6) (36 mg, 0.072 mmol) and DIPEA (28.29 mg, 0.219 mmol) was dissolved in CH₂Cl₂ (2 mL) at 0 °C. Trifluoroacetyl 2,2,2-trifluoroacetate (19.92 mg, 0.095 mmol) was then added. The resulting mixture was stirred at rt overnight and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylonitrile (Example 7) (19.7 mg, 57%). MS (ESI): calcd.: 475.1, Found: 476.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO- d₆): δ 8.19 (d, J = 19.9 Hz, 1H), 7.76 (d, J = 2.9 Hz, 1H), 7.18 (q, J = 7.6, 5.7 Hz, 3H), 6.75 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.06 (d, J = 16.2 Hz, 1H), 3.85 (s, 1H), 2.56 (d, J = 16.3 Hz, 3H), 2.41 (s, 3H), 1.62 (s, 1H), 1.52 (s, 1H), 1.35 (s, 4H), 0.92 (d, J = 6.9 Hz, 3H) ppm. [0212] Example 8. (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid

[0213] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (7-2). To a stirred solution of 3-butyl-2-(2-fluoroethyl)-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (7-1) (100 mg, 0.24 mmol) in DMA (5mL) at 0 °C, NaH (50%, 35 mg, 0.73 mmol) was added portion wise and the reaction mixture was stirred for 30 min at 0 °C. A solution of 3-bromo-2,2- difluoropropanoate (0.12 g, 0.55 mmol) in DMA (2 mL) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 2N HCl to pH ~ 3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to afford ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (7-2) (38 mg, 30%). MS (ESI): calcd. for C₂₆H₃₂F₂N₂O₅S₂: 554.1, Found: 555.2 [M+1]⁺; ¹H NMR (600 MHz, DMSO-d₆): δ 7.78 (d, J = 18.6 Hz, 1H), 7.57 (s, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.05 (s, 1H), 6.86 – 6.68 (m, 3H), 4.50 (dq, J = 9.6, 5.5, 4.8 Hz, 1H), 4.43 (dt, J = 9.5, 5.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 3.71 (s, 2H), 2.97 (s, 2H), 2.52 (s, 1H), 2.33 (s, 3H), 1.64 (s, 1H), 1.57 (d, J = 7.5 Hz, 1H), 1.40 (dd, J = 14.7, 7.5 Hz, 2H), 1.29 (s, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H) ppm. [0214] Step 2. Synthesis of (Z)-3-((3-butyl-2-(2-fluoroethyl)-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 8). То а stirred solution of ethyl (Z)-3-((3-butyl-2-(2-fluoroethyl)-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- fluoroacrylate (7-2) (30 mg, 0.058 mmol) in 1, 4-dioxane/ water (4/1, 5 mL), lithium hydroxide (1 mg, 0.25 mmol) was added and the reaction mixture was stirred 2 h at rt. After completion of the reaction, the reaction mixture was acidified with 1.5 N aq. HCl solution to рН ~ 4. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by HPLC to afford (Z)-3-((3-butyl- 2-(2-fluoroethyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 8) (14 mg, 50%). MS (ESI): calcd. for C₂₄H₂₈F₂N₂O₅S₂: 526.1, Found: 525.2 [M −1]⁻; ¹H NMR (400 MHz, DMSO-d₆): δ 13.71 (s, 1H), 7.74 (d, J = 18.5 Hz, 1H), 7.55 (s, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.07 (s, 1H), 6.80 (d, J = 8.9 Hz, 3H), 4.54 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 3.72 (s, 1H), 3.02 (s, 2H), 2.35 (s, 4H), 1.73 – 1.52 (m, 2H), 1.41 (d, J = 7.4 Hz, 2H), 1.29 (s, 2H), 0.88 (t, J = 7.4 Hz, 3H) ppm. [0215] Example 9. (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1-yl)oxy)-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide

[0216] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (8-2). To a reactor containing a solution of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (8-1) (250.0 mg, 614.91 µmol) in DMA (3mL) at 0 °C was added sodium hydride (73.69 mg, 3.07 mmol). The mixture was stirred for 10 minutes. After that, the reaction mixture was cooled to -30 °C and ethyl 3- bromo-2,2-difluoropropanoate (533.13 mg, 2.46 mmol) was added. The resulting mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by HPLC to afford ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (8-2) (151 mg, 47%). [0217] Step 2: Synthesis of (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1-yl)oxy)-2- methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (Example 9). To a solution of ethyl (Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-fluoroacrylate (8-2) (75.0 mg, 143.5 µmol) in DCM (2 mL) at -78 °C was added diisobutylaluminum hydride (61.25 mg, 430.7 µmol) dropwise. The resulting mixture was stirred at -78 °C for 30 minutes. The reaction was then quenched with water at rt and concentrated in vacuo. The residue was purified by HPLC to afford (Z)-3-butyl-8-((2-fluoro-3-hydroxyprop-1-en-1- yl)oxy)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (Example 9) (15.8 mg, 22%). MS (ESI): calcd.: 480.62, Found: 481.0 [M+1] ⁺; ¹H NMR (400 MHz, CD₃CN): δ 7.52 (s, 1H), 7.26 - 7.17 (m, 3H), 6.79 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 20.4 Hz, 1H), 4.19 (s, 1H), 4.14 (s, 1H), 4.03 (d, J = 15.7 Hz, 2H), 3.24 (s, 1H), 2.51 (s, 3H), 2.42 (s, 3H), 1.67 – 1.57 (m, 2H), 1.42 (dq, J = 14.2, 9.0, 7.5 Hz, 4H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0218] Example 10. (E)-(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)vinyl)phosphonic acid

[0219] Step 1. Synthesis of diethyl ethynylphosphonate (9-2). Ethynylmagnesium bromide (0.5 M in THF, 37.67 mmol, 75.34 mL) was added dropwise to a solution diethyl phosphorochloridate (9-1) (6.5 g, 37.67 mmol) in anhydrous THF (75 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. the reaction mixture was quenched with saturated NH₄Cl (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with H₂O (100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford diethyl ethynylphosphonate (9-2) (150 mg, 2.5%). MS (ESI): calcd.: 162.0, Found: 163.0 [M+1]⁺. [0220] Step 2. Synthesis of (E)-diethyl (2-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)vinyl)phosphonate (9-3). To a solution of 3-Butyl-8-hydroxy-2-methyl-7- {methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (90 mg, 221.37 µmol) and diethyl ethynylphosphonate (9-2) (108 mg, 664.69 µmol) in THF (2 mL) was added DABCO (4.97 mg, 44.31 µmol). The reaction mixture was stirred at rt overnight. Then the mixture was diluted with Н₂O (10 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified with prep-HPLC to afford (E)-diethyl (2-((3-butyl-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)vinyl)phosphonate (9-3) (75 mg, 60%). MS (ESI): calcd.: 568.2, Found: 569.0 [M+1]⁺; ¹H NMR (400 MHz, CD₃CN): δ 7.57 (s, 1H), 7.36 (dd, J = 13.2, 10.5 Hz, 1H), 7.30 – 7.17 (m, 3H), 6.83 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H), 5.24 (dd, J = 13.2, 9.3 Hz, 1H), 4.18 – 3.93 (m, 6H), 3.28 (d, J = 26.8 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H), 1.62 (q, J = 7.5, 6.9 Hz, 2H), 1.54 – 1.36 (m, 4H), 1.38 – 1.20 (m, 6H), 0.98 (t, J = 7.0 Hz, 3H) ppm. [0221] Step 3. Synthesis of (E)-(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)vinyl)phosphonic acid (Example 10). To a solution of (E)-diethyl(2-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)vinyl)phosphonate (9-3) (30.0 mg, 52.75 µmol), pyridine (526.75 µmol, 40 µl) in anhydrous DCM (2 mL) was added TMSBr (1.05 mmol, 140.0 µl). The reaction mixture was stirred at rt overnight. After completion of the reaction (monitored by LCMS), the mixture was poured into water (10 mL). The resulting solution was acidified with 5 N aq. HCl solution to pH ~ 2 and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na₂SO_4, filtered, and concentrated in vacuo. The residue was purified with prep-HPLC to afford (E)-(2-((3-butyl-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)vinyl)phosphonic acid (Example 10) (20.5 mg, 76%). MS (ESI): calcd.: 512.1, Found: 511.0 [M−1]⁻; ¹H NMR (400 MHz, CD₃CN): δ 7.52 (s, 1H), 7.28 (s, 1H), 7.18 (dd, J = 13.7, 5.5 Hz, 3H), 6.78 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.0 Hz, 2H), 5.42 (s, 1H), 3.99 (d, J = 17.7 Hz, 2H), 3.22 (s, 1H), 2.54 (d, J = 10.1 Hz, 3H), 2.35 (s, 3H), 1.56 (s, 2H), 1.38 (d, J = 23.2 Hz, 4H), 0.94 (t, J = 7.0 Hz, 3H) ppm. [0222] Example 11, 11a and 11b. (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11), (S,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11a), and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b)

[0223] Step 1. Synthesis of ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2). A solution of ethyl 2-[(diphenylmethylidene)amino]acetate (10-1) (30 g, 112.22 mmol), K₂CO₃ (46.53 g, 336.66 mmol), 1-bromo-4-fluorobutane (34.79 g, 224.44 mmol), and tetrabutylammonium bromide (7.24 g, 22.44 mmol) in CH₃CN (500 mL) was stirred for 72 h at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/THF (1/1) (v/v) to afford ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2) (30 g, 78%) as a brown oil. MS (ESI): calcd. for C₂₁H₂₄FNO₂: 341.1, Found: 342.1 [M+1]⁺. [0224] Step 2. Synthesis of 2-[(diphenylmethylidene)amino]-6-fluorohexanoic acid (10- 3). A mixture of ethyl 2-[(diphenylmethylidene)amino]-6-fluorohexanoate (10-2) (30 g, 87.87 mmol) and NaOH (5.27 g, 131.80 mmol) in methanol (300 mL) and water (75 mL) was stirred for 5 h at 50 °C. The mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL). The aqueous layer was acidified with 0.5 M aq. HCl solution to pH = 6 and then extracted with CH₂Cl₂ (100 mL x 3). The combined organic layers were concentrated under reduced pressure to afford 2-[(diphenylmethylidene)amino]- 6-fluorohexanoic acid (10-3) (15 g, 54%) as a yellow oil. MS calcd. for C₁₉H₂₀FNO₂: 313.1, Found: 314.1 [M+1]⁺. [0225] Step 3. Synthesis of 2-[(diphenylmethylidene)amino]-6-fluoro-N- phenylhexanamide (10-4). A solution of 2-[(diphenylmethylidene)amino]-6-fluorohexanoic acid (10-3) (14 g, 44.68 mmol), aniline (4.99 g, 53.61 mmol), T3P (28.43 g, 89.35 mmol) and TEA (13.56 g, 134.03 mmol) in CH₃CN (300 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) (v/v) to afford 2- [(diphenylmethylidene)amino]-6-fluoro-N-phenylhexanamide (10-4) (14 g, 81%) as a yellow oil. MS (ESI): calcd. for C₂₅H₂₅FN₂O: 388.2, Found: 389.2 [M+1]⁺. [0226] Step 4. Synthesis of 2-amino-6-fluoro-N-phenylhexanamide (10-5). A solution of 2-[(diphenylmethylidene)amino]-6-fluoro-N-phenylhexanamide (10-4) (14 g, 36.04 mmol) in 4N HCl/methanol (70 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (100 mL x 3), basified with sodium bicarbonate solution (100 mL), and extracted with EtOAc (100 mL x 3). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/10) (v/v) to afford 2-amino-6-fluoro-N-phenylhexanamide (10-5) (4.5 g, 56%) as a yellow solid. MS (ESI): calcd. for C12H17FN₂O: 224.1, Found: 225.1 [M+1]⁺. Step 5. Synthesis of 6-fluoro-N1-phenylhexane-1,2-diamine (10-6). A solution of 2-amino- 6-fluoro-N-phenylhexanamide (10-5) (4 g, 17.84 mmol) and BH₃-Me₂S (2.72 mL, 28.71 mmol) in THF (100 mL) was stirred for 16 h at 75 °C under nitrogen atmosphere. The reaction was quenched with MeOH (100 mL). The resulting mixture was stirred for 1 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 6-fluoro-N1-phenylhexane-1,2-diamine (10-6) (2 g, 53%) as a yellow oil. MS (ESI): calcd. for C₁₂H₁₉FN₂: 210.2, Found: 211.2 [M+1]⁺. [0227] Step 6. Synthesis of 2,4-dibromo-N-[6-fluoro-1-(phenylamino)hexan-2-yl]-5- methoxybenzenesulfonamide (10-7). A solution of 6-fluoro-N1-phenylhexane-1,2-diamine (10-6) (2 g, 9.51 mmol), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (3.81 g, 10.46 mmol), and TEA (3.85 g, 38.04 mmol) in THF (40 mL) was stirred for 4 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 2,4-dibromo-N-[6-fluoro-1- (phenylamino)hexan-2-yl]-5-methoxybenzenesulfonamide (10-7) (2.1 g, 41%) as a white solid. MS (ESI): calcd. for C₁₉H₂₃Br₂FN₂O₃S: 536.0, Found: 537.0 [M+1]^+. [0228] Step 7. Synthesis of 7-bromo-3-(4-fluorobutyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-8). A solution of 2,4-dibromo-N- [6-fluoro-1-(phenylamino)hexan-2-yl]-5-methoxybenzenesulfonamide (10-7) (2.1 g, 3.90 mmol), K₂CO₃ (2 g, 14.47 mmol), TMEDA (100 mg, 0.86 mmol), and CuI (2 g, 10.50 mmol) in dioxane (40 mL) was stirred for 4 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) (v/v) to afford 7-bromo-3-(4-fluorobutyl)- 8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-8) (1.1 g, 62%) as a yellow oil. MS (ESI): calcd. for C₁₉H₂₂BrFN₂O₃S: 456.1, Found: 457.1 [M+1]⁺. [0229] Step 8. Synthesis of 7-bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9). A solution of 7-bromo- 3-(4-fluorobutyl)-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (10-8) (1.1 g, 2.41 mmol), Cs₂CO₃ (1.57 g, 4.81 mmol), and MeI (0.51 g, 3.61 mmol) in DMF (30 mL) was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford 7- bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9) (1.3 g, 90%) as a brown solid. MS (ESI): calcd. for C₂₀H₂₄BrFN₂O₃S: 470.1, Found: 471.1[M+1]⁺. [0230] Step 9. Synthesis of 3-(4-fluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10). A solution of 7-bromo-3-(4-fluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-9) (1.25 g, 2.65 mmol) and MeSNa (557.50 mg, 7.96 mmol) in DMF (20 mL) was stirred for 2 h at 80 °C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 3-(4-fluorobutyl)- 8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10) (800 mg, 71%) as a brown yellow oil. MS (ESI): calcd. for C₂₀H₂₅FN₂O₃S₂: 424.1, Found: 425.1 [M+1]⁺. [0231] Step 10. Synthesis of ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylate (10-11). To a solution of ethyl 3-bromo-2,2-difluoropropanoate (92.01 mg, 0.42 mmol) in DMA (5 mL) was added sodium hydride (28.26 mg, 0.71 mmol) at 0 °C. The mixture was stirred at for 1 h.3-(4-fluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (10-10) (60 mg, 0.14 mmol) in DMA (5 mL) was added. The resulting mixture was stirred for 3 h at 70 °C. The mixture was acidified with 1N HCl to pH = 1. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA = 2/1 (v/v) to afford ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylate (10-11) (40 mg, 52%) as a brown solid. MS (ESI): calcd. for C₂₅H₃₀F₂N₂O₅S₂: 540.2, Found: 541.2 [M+1]⁺. [0232] Step 11. Synthesis of (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11). A mixture of ethyl (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2- methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylate (10-11) (40 mg, 0.07 mmol) and LiOH (3.66 mg, 0.15 mmol) in dioxane/H₂O (4 mL/1 mL) was stirred at rt for 3 h. The mixture was acidified with 2N HCl to pH = 4. The resulting mixture was extracted with EA (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19 x 150mm; mobile phase, Water (0.05% FA) and ACN (45% PhaseB up to 75% in 8 min); Detector, UV 254 nm) to afford (Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 11) (12 mg, 32%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆F₂N₂O₅S₂: 512.2, Found: 513.2 [M+1]⁺; ¹H NMR (300 MHz, DMSO-d_6,): δ 7.66 (d, J = 18.0 Hz, 1H), 7.53 (s, 1H), 7.23-7.12 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.05 (d, J = 15.9 Hz, 1H), 3.88-3.86 (m, 1H), 3.31-3.21 (m, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 1.97-1.30 (m, 6H) ppm. [0233] Step 12. Synthesis of (S,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11a) and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b): Racemic (Example 11) (30 mg) was purified by Chiral- HPLC using the following conditions: column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; M obile Phase A: Hex (0.1% TFA), M obile Phase B: CAN (0.1% isopropyl amine); Flow rate: 35 mL/min; Gradient: 50% B to 50% B in 12 min to afford (S,Z)-2-fluoro-3-((3-(4- fluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acrylic acid (Example 11a) (13.1 mg, 48%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆F₂N₂O₅S₂: 512.2, Found: 513.2 [M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆, ): δ 7.66 (d, J = 18.6 Hz, 1H), 7.54 (s, 1H), 7.35-7.12 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.1 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.06 (d, J = 15.3 Hz, 1H), 3.88-3.86 (m, 1H), 3.29-3.24 (m, 1H), 2.50 (s, 3H), 2.41 (s,3H), 1.78-1.37 (m, 6H) ppm and (R,Z)-2-fluoro-3-((3-(4-fluorobutyl)-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)acrylic acid (Example 11b) (14.1 mg, 49%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆F₂N₂O₅S₂: 512.2, Found: 513.2 [M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 7.66 (d, J =19.2 Hz, 1H), 7.53 (s, 1H), 7.20-7.15 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 4.56 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.88-3.86 (m, 1H), 3.32 (s, 1H), 2.50 (s, 3H), 2.41 (s, 3H), 1.75-1.44 (m, 6H) ppm. [0234] Example 12. Synthesis of (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid

[0235] Step 1. Synthesis of 2-{[(2-amino-5-methoxyphenyl) sulfanyl] methyl} hexanoic acid (11-2). Into a 500 mL round-bottom flask were added 2-amino-6-methoxybenzothiazole (11-1) (28.1 g, 155.91 mmol), ethylene glycol (140 mL), and 50% aqueous KOH (150 mL) at 0 °C. The resulting mixture was stirred for 16 h at 120 °C under nitrogen atmosphere. The mixture was cooled down to rt. The resulting mixture was added 2-(bromomethyl) hexanoic acid (27.17 g, 129.92 mmol) in 50 mL THF. The resulting mixture was stirred for 3 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The mixture was acidified with 4 N aq. HCl solution to pH 2. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) (v/v) to afford 2-{[(2-amino-5-methoxyphenyl) sulfanyl] methyl} hexanoic acid (11-2) (21.6 g, 59%) as a yellow solid. MS (ESI): calcd. for C₁₄H₂₁NO₃S: 283.1, Found: 284.1 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 7.09 – 6.99 (m, 1H), 6.87 – 6.74 (m, 2H), 3.77 (s, 3H), 3.09 – 3.01 (m, 1H), 2.96 – 2.88 (m, 1H), 2.65 – 2.49 (m, 1H), 1.74 – 1.57 (m, 1H), 1.38 – 1.23 (m, 5H), 0.94 – 0.83 (m, 3H) ppm. [0236] Step 2. Synthesis of 3-butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4- one (11-3). Into a 1000 mL 3-necked round-bottom flask were added 2-{[(2-amino-5- methoxyphenyl) sulfanyl] methyl}hexanoic acid (11-2) (21.6 g, 76.22 mmol) and DCM (400 mL) at rt. To a stirred solution was added HATU (34.78 g, 91.464 mmol) batchwise under nitrogen atmosphere. The resulting mixture was stirred for 10 min at rt. To the above mixture was added DIPEA (11.82 g, 91.464 mmol) dropwise. The resulting mixture was stirred for 4 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (100 mL) at 0 °C. The resulting mixture was extracted with DCM (400 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) to afford 3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-3) (17.9 g, 89%) as a yellow solid. MS (ESI): calcd. for C₁₄H₁₉NO₂S: 265.1, Found: 266.1 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.31 (s, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.7, 3.2 Hz, 1H), 3.83 (s, 3H), 3.53 – 3.48 (m, 1H), 3.02 - 2.94 (m, 1H), 2.66 – 2.57 (m, 1H), 1.97 – 1.85 (m, 1H), 1.43 – 1.12 (m, 6H), 0.86 (t, J = 8.0 Hz, 3H) ppm. [0237] Step 3. Synthesis of 7-bromo-3-butyl-8-methoxy-3,5-dihydro-2H-1,5- benzothiazepin-4-one (11-4). Into a 500 mL 3-necked round-bottom flask were added 3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-3) (17.9 g, 67.45 mmol), DCM (200 mL), and NBS (18.01 g, 101.18 mmol) at rt. The resulting mixture was stirred for 4 h at rt under nitrogen atmosphere. The reaction was quenched with water at rt. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-8- methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-4) (13.9 g, 60%) as a dark yellow solid. MS (ESI): calcd. for C₁₄H₁₈BrNO₂S: 343.0, Found: 344.1 [M+1]⁺. [0238] Step 4. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3-dihydro-1,5- benzothiazepin-4-one (11-5). Into a 500 mL round-bottom flask were added 7-bromo-3- butyl-8-methoxy-3,5-dihydro-2H-1,5-benzothiazepin-4-one (11-4) (13.9 g, 40.375 mmol), copper(I) iodide (1.54 g, 8.07 mmol), DMSO (280 mL), iodophenyl (12.36 g, 60.56 mmol), and K₂CO₃ (11.24 g, 80.75 mmol) at rt. The resulting mixture was stirred for 1 h at 130 °C under nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) to afford 7-bromo-3-butyl-8-methoxy-5-phenyl- 2,3-dihydro-1,5-benzothiazepin-4-one (11-5) (10.4 g, 61%) as a brown oil. MS (ESI): calcd. for C₂₀H₂₂BrNO₂S: 419.1, Found: 420.1 [M + 1]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 7.45 – 7.33 (m, 3H), 7.39 – 7.21 (m, 2H), 7.17 – 7.06 (m, 2H), 3.91 (s, 3H), 2.95 (t, J = 12 Hz, 1H), 2.71 – 2.60 (m, 1H), 1.81 – 1.69 (m, 1H), 1.43 – 1.19 (m, 6H), 0.90 – 0.79 (m, 3H) ppm. [0239] Step 5. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H-1,5- benzothiazepine (11-6). Into a 500 mL round-bottom flask were added 7-bromo-3-butyl-8- methoxy-5-phenyl-2,3-dihydro-1,5-benzothiazepin-4-one (11-5) (13.8 g, 32.82 mmol) and BH₃-Me₂S (10 mL, 105.45 mmol) at rt. The resulting mixture was stirred for 16 h at 75 °C. The reaction was quenched with MeOH at 0 °C. The resulting mixture was stirred for 2 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (200 mL) and DCM (100 mL). The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous MgSO₄. After filtration, the filtrate was concentrated under reduced pressure to afford 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4- dihydro-2H-1,5-benzothiazepine (11-6) (9.3 g, 70%) as a colorless oil, which was used for the next step directly without further purification. MS (ESI): calcd. for C₂₀H₂₄BrNOS: 405.1, Found: 406.1 [M+1]⁺. [0240] Step 6. Synthesis of 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H- 1lambda6,5-benzothiazepine-1,1-dione (11-7). Into a 500 mL 3-necked round-bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-3,4-dihydro-2H-1,5-benzothiazepine (11- 6) (9.3 g, 22.88 mmol), tetrahydrofuran (186 mL), water (93 mL), and Oxone (98.45 g, 160.19 mmol) at 0 °C. The resulting mixture was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (200 mL). The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford 7-bromo-3-butyl-8- methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-7) (5 g, 50%) as an off-white solid. MS (ESI): calcd. for C₂₀H₂₄BrNO₃S: 437.1, Found: 438.1 [M+1]⁺. [0241] Step 7. Synthesis of 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-8). Into a 100 mL 3-necked round- bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-7) (500 mg, 1.14 mmol) and THF (10 mL) at rt. To the above mixture was added LiHMDS (572.55 mg, 3.42 mmol) dropwise at - 78 °C. The resulting mixture was stirred for additional 1 h at -78 °C. The reaction was added methyl iodide (178.08 mg, 1.25 mmol) at -78 °C. The resulting mixture was stirred for 6 h at rt under nitrogen atmosphere. The reaction was quenched by the addition of sat. aqueous NH₄Cl (10 mL) at -30 °C. The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-8) (450 mg, 87%) as a yellow solid. MS (ESI): calcd. for C₂₁H₂₆BrNO₃S: 451.1, Found: 452.1 [M+1]⁺. [0242] Step 8. Synthesis of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9). Into a 8 mL vial were added 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-8) (200 mg, 0.44 mmol), DMF (5 mL) and (methylsulfanyl)sodium (170.39 mg, 2.43 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) (v/v) to afford 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9) (130 mg, 73%) as a colorless oil. MS (ESI): calcd. for C₂₁H₂₇NO₃S₂: 405.1, Found: 406.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO- d₆): δ 10.74 (s, 1H), 7.37 (s, 1H), 7.17 - 7.11 (m, 2H), 7.00 (d, J = 4.0 Hz, 1H), 6.70 – 6.61 (m, 1H), 6.56 – 6.47 (m, 2H), 4.20 (d, J = 16.0 Hz, 1H),3.43 – 3.35 (m, 1H) 3.08 - 3.02 (m, 1H), 2.35 (s, 3H), 2.30 (s, 1H), 1.45 - 1.25 (m, 6H), 0.95 – 0.82 (m, 3H) ppm. [0243] Step 9. Synthesis of tert-butyl (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (11-10). Into a 8 mL vial were added 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (11-9) (130 mg, 0.32 mmol), THF (3 mL), tert-butyl prop-2-ynoate (60.66 mg, 0.48 mmol) and DABCO (3.60 mg, 0.032 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) to afford tert-butyl(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (11-10) (100 mg, 59%) as an off-white solid. MS (ESI): calcd. for C₂₈H₃₇NO₅S₂: 531.2, Found: 532.2 [M+1]⁺. [0244] Step 10. Synthesis of (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 12). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (11-10) (100 mg, 0.18 mmol), DCM (2 mL, 31.46 mmol) and trifluoroacetic acid (0.3 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 60% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 12) (17.1 mg, 19%) as a white solid. MS (ESI): calcd. for C₂₄H₂₉NO₅S₂: 475.1, Found: 476.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 7.77 (d, J = 24.5, 12.4 Hz, 1H), 7.57 (s, 1H), 7.23 - 7.10 (m, 3H), 6.84 – 6.69 (m, 3H), 5.53 (d, J = 16 Hz, 1H), 4.29 - 4.07 (m, 1H), 2.37 (s, 3H), 2.05 - 1.93 (m, 1H), 1.63 - 1.55 (m, 1H), 1.37 - 1.23 (m, 6H), 0.87 (t, J = 8 Hz, 3H) ppm. [0245] Example 13. Synthesis of (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid

[0246] Step 1. Synthesis of 7-bromo-3-butyl-8-methoxy-2,2-dimethyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (2-2). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-1) (100 mg, 0.228 mmol) and tetrahydrofuran (3 mL) at room temperature. To a stirred mixture were added LiHMDS (57.26 mg, 0.342 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution was added MeI (97.13 mg, 0.684 mmol) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt. The reaction was quenched with sat. NH₄Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA = 5/1 (v/v) to afford 7-bromo-3-butyl-8-methoxy-2,2- dimethyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-2) (60 mg, 56%) as a light yellow solid. [0247] Step 2. Synthesis of 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-2,2-dimethyl-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-2) (60 mg, 0.129 mmol), DMF (2 mL) and NaSMe (49.58 mg, 0.710 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3) (52 mg, 96%) as a colorless oil. MS (ESI): calcd. for C₂₂H₂₉NO₃S₂: 419.2, Found: 420.2 [M+1]⁺. [0248] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (12-4). Into a 8 mL vial were added 3-butyl-8-hydroxy-2,2-dimethyl-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3) (52 mg, 0.124 mmol), THF (2 mL), tert-butyl prop-2-ynoate (23.45 mg, 0.186 mmol), and DABCO (2.78 mg, 0.025 mmol) at rt. The resulting mixture was stirred for 5 h at tt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (6/1) to afford tert- butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (12-4) (50 mg, 74%) as a white solid. MS (ESI): calcd. for C₂₉H₃₉NO₅S₂: 545.2, Found: 546.2 [M+1]⁺. [0249] Step 4. Synthesis of (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 13). Into a 8 mL vial were added tert-butyl (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (12-4) (50 mg, 0.092 mmol), DCM (1 mL), and trifluoroacetic acid (1 mL) at rt. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150 mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2,2-dimethyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 13) (10 mg, 22%) as a white solid. MS (ESI): calcd. for C₂₅H₃₁NO₅S₂: 489.2, Found: 490.3 [M + 1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 12.34 (s, 1H), 7.75 (d, J = 12.4 Hz, 1H), 7.55 (s, 1H), 7.19 (t, J = 7.7 Hz, 3H), 6.76 - 6.67 (m, 3H), 5.53 (d, J = 12.4 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H), 3.31 - 3.17 (m, 1H), 2.41 (s, 3H), 2.11 - 2.05 (m, 1H), 1.69 - 1.63 (m, 1H), 1.48 - 1.23 (m, 8H), 1.06 (s, 3H), 0.96 - 0.76 (m, 4H) ppm. [0250] Example 14. (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid

[0251] Step 1. Synthesis of 7-bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2). Into a 8 mL vial were added 7- bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-1) (150 mg, 0.342 mmol) and THF (4 mL) at rt. To a stirred mixture were added LiHMDS (114.51 mg, 0.684 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added NFSI (539.48 mg, 1.710 mmol,) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt under nitrogen atmosphere. The reaction was quenched with sat. aqueous NH₄Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) (v/v) to afford 7- bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2) (90 mg, 55%) as a light yellow solid. [0252] Step 2. Synthesis of 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3). Into a 8 mL vial were added 7-bromo-3-butyl-2,2-difluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-2) (90 mg, 0.190 mmol), DMF (2 mL) and NaSMe (73.13 mg, 1.045 mmol) at rt. The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3) (80 mg, 99%) as a colorless oil. [0253] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (13-4). Into a 8 mL vial were added 3-butyl-2,2-difluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (13-3) (80 mg, 0.187 mmol), THF (2 mL), tert-butyl prop-2-ynoate (35.41 mg, 0.280 mmol) and DABCO (4.20 mg, 0.037 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) to afford tert- butyl (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (13-4) (60 mg, 58%) as a white solid. MS (ESI): calcd. for C₂₇H₃₃F₂NO₅S₂: 553.2, Found: 576.2 [M+23]⁺. [0254] Step 4. Synthesis of (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 14). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (13-4) (60 mg, 0.108 mmol), DCM (2 mL) and trifluoroacetic acid (2 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford (E)-3-((3-butyl-2,2-difluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 14) (10 mg, 19%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 12.32 (s, 1H), 7.81 (d, J = 12 Hz, 1H), 7.71 (s, 1H), 7.28 - 7.21 (m, 3H), 6.81 (t, J = 7.2 Hz, 1H), 6.79 - 6.70 (m, 2H), 5.57 (d, J = 12 Hz, 1H), 4.35 - 4.31 (m, 1H),3.49 - 3.41 (m, 1H), 2.83 - 2.79 (m, 1H), 2.44 (s, 3H), 1.72 - 1.62 (m, 2H), 1.58 - 1.33 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H) ppm. [0255] Examples 15, 15a, 15b, 16, 16a and 16b. rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15), rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16), (E)-3- (((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15a), (E)-3-(((2R,3R)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b), (E)-3-(((2S,3R)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a), and (E)-3-(((2R,3S)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b)

[0256] Step 1. Synthesis of 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-2). Into a 50 mL 3-necked round- bottom flask were added 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-1) (1 g, 2.28 mmol) and THF (10 mL) at rt. To a stirred mixture were added LiHMDS (1145.10 mg, 6.84 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added NFSI (863.17 mg, 2.73 mmol) portion wise at -78 °C. The resulting mixture was stirred at rt for 6 h. The reaction was then quenched with sat. aqueous NH₄Cl at 0 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl- 2-fluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-2) (600 mg, 58%) as a pale-yellow solid. MS (ESI): calcd. for C₂₀H₂₃BrFNO₃S: 455.1, Found: 456.2 [M+1]⁺. [0257] Step 2. Synthesis of 3-butyl-2-fluoro-8-hydroxy-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-3). Into a 40 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-2) (600 mg, 1.31 mmol), DMF (12 mL) and NaSMe (506.75 mg, 7.23 mmol) at rt. The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-butyl-2-fluoro-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-3) (400 mg, 74%) as a colorless oil. MS (ESI): calcd. for C₂₀H₂₄FNO₃S₂: 409.1, Found: 409.1 [M+1]⁺. [0258] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (14-4). Into a 40 mL vial were added 3-butyl-2-fluoro-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (14-3) (400 mg, 0.97 mmol), THF (16 mL), tert-butyl prop-2-ynoate (184.83 mg, 1.46 mmol) and DABCO (21.91 mg, 0.19 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1) (v/v) to afford tert-butyl (E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (14-4) (390 mg, 75%) as an off-white solid. MS (ESI): calcd. for C₂₇H₃₄FNO₅S₂: 535.2, Found: 536.2 [M+1]⁺. [0259] Step 4. Synthesis of rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15) and rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16). Into a 8 mL vial were added tert-butyl(E)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (14-4) (200 mg, 0.37 mmol), DCM (2 mL) and trifluoroacetic acid (1 mL) at rt. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated to afford rac-(E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15) (85 mg, 47%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 7.75 (d, J = 12.3 Hz, 1H), 7.61 (s, 1H), 7.24 (t, J = 8.1 Hz, 3H), 7.12 (s, 1H), 6.84 (t, J = 7.8 Hz, 3H), 5.84 - 5.69 (m, 1H), 5.54 (d, J = 12.3 Hz, 1H), 3.96 - 3.80 (m, 2H), 2.44 - 2.37 (m, 4H), 1.61 (s, 1H), 1.46 - 1.20 (m, 5H), 0.86 (t, J = 7.1 Hz, 3H) ppm and rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16) (72 mg, 40%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 7.75 (d, J = 12.3 Hz, 1H), 7.61 (s, 1H), 7.24 (t, J = 8.1 Hz, 3H), 7.12 (s, 1H), 6.84 (t, J = 7.8 Hz, 3H), 5.84 - 5.69 (m, 1H), 5.54 (d, J = 12.3 Hz, 1H), 3.96 - 3.80 (m, 2H), 2.44 - 2.37 (m, 4H), 1.61 (s, 1H), 1.46 - 1.20 (m, 5H), 0.86 (t, J = 7.1 Hz, 3H) ppm. [0260] Step 5. Synthesis of (E)-3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15a), (E)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b), (E)-3-(((2S,3R)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a), and (E)-3- (((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b): Rac-(E)-3- (((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15) (85 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: ACN=3: 1; Injection Volume: 0.8 mL; The collected fractions were combined and concentrated under vacuum to afford (E)-3-(((2S,3S)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15a) (21.7 mg, 26%) as a white solid. MS (ESI): calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 12.38 (s, 1H), 7.75 (d, J = 12.2 Hz, 1H), 7.62 (s, 1H), 7.25 - 7.21 (m, 2H), 7.12 (s, 1H), 6.85 - 6.81 (m, 3H), 5.77 (d, J = 44 Hz, 1H), 5.54 (d, J = 12.0 Hz, 1H), 4.03 - 3.76 (m, 2H), 2.37 (s, 4H), 1.62 - 1.58 (m, 1H), 1.46 - 1.21 (m, 5H), 0.86 (t, J = 7.2 Hz, 3H) ppm and (E)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 15b) (32.7 mg, 39%) as a white solid. MS calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 7.74 (d, J = 12.2 Hz, 1H), 7.61 (s, 1H), 7.25 - 7.23 (m, 2H), 7.12 (s, 1H), 6.85 - 6.81 (m, 3H), 5.77 (d, J = 40.0 Hz, 1H), 5.53 (d, J = 12.2 Hz, 1H), 3.95 - 3.76 (m, 2H), 2.37 (s, 4H), 1.62 - 1.59 (m, 1H), 1.46 - 1.24 (m, 6H), 0.86 (t, J = 7.2 Hz, 3H) ppm. Rac-(E)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16) (72 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; M obile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: ACN=3: 1; Injection Volume: 0.8 mL; The collected fractions were combined and concentrated under vacuum to afford (E)-3- (((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16a) (11.1 mg, 15%). MS (ESI): calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO- d6): δ 12.26 (s, 1H), 7.79 (d, J = 12.0 Hz, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.22 - 7.18 (m, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 44.0 Hz, 1H), 5.55 (d, J = 12.0 Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 3.30 - 3.15 (m, 1H), 2.66 - 2.56 (m, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.37 - 1.29 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm and (E)-3-(((2R,3S)-3- butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 16b) (12.1 mg, 17%) as a white solid. MS calcd. for C₂₃H₂₆FNO₅S₂: 479.1, Found: 480.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.20 - 7.18 (m, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.68 - 6.66 (m, 2H), 5.90 (d, J = 44 Hz, 1H), 5.55 (d, J = 12.0 Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 3.22 - 3.16 (m, 1H), 2.63 - 2.55 (m, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. [0261] Example 17. (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid

[0262] Step 1. Synthesis of 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2). Into a 8 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-1) (150 mg, 0.329 mmol) and tetrahydrofuran (5 mL) at rt. To a stirred mixture were added LiHMDS (110.00 mg, 0.658 mmol) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To a stirred solution were added methyl iodide (93.31 mg, 0.658 mmol) in THF (2 mL) dropwise at -78 °C. The resulting mixture was stirred for 6 h at rt. The reaction was quenched with sat. aqueous NH₄Cl at -20 °C. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2) (100 mg, 65%) as a light yellow solid. [0263] Step 2. Synthesis of 3-butyl-2-fluoro-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-3). Into a 8 mL vial were added 7-bromo-3-butyl-2-fluoro-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-2) (100 mg, 0.213 mmol), DMF (3 mL) and NaSMe (81.94 mg, 1.171 mmol) at rt. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4:1) (v/v) to afford 3-butyl-2-fluoro-8-hydroxy-2-methyl-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-3) (70 mg, 78%) as a colorless oil. MS (ESI): calcd. for C₂₁H₂₆FNO₃S₂: 423.1, Found: 424.1 [M+H]⁺. [0264] Step 3. Synthesis of tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (15-4). Into a 8 mL vial were added 3-butyl-2-fluoro-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (15-3) (70 mg, 0.165 mmol), THF (3 mL), tert-butyl prop-2-ynoate (31.27 mg, 0.247 mmol), and DABCO (3.71 mg, 0.033 mmol) at rt. The resulting mixture was stirred for 5 h at rt under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (6/1) (v/v) to afford tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylate (15-4) (40 mg, 44%) as a white solid. MS (ESI): calcd. for C₂₈H₃₆FNO₅S₂: 549.2, Found: 572.2 [M+23]⁺. [0265] Step 4. Synthesis of (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 17). Into a 8 mL vial were added tert-butyl (E)-3-((3-butyl-2-fluoro-2-methyl-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)acrylate (15-4) (40 mg, 0.073 mmol), DCM (2 mL) and trifluoroacetic acid (2 mL) at rt. The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following condition: Column: XBridge Prep C18 OBD 19 x 150 mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated to afford (E)-3-((3-butyl-2-fluoro-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acrylic acid (Example 17) (9.5 mg, 26%) as a white solid. MS (ESI): calcd. for C₂₄H₂₈FNO₅S₂: 493.1, Found: 494.3 [M+1]⁺; ¹H NMR (400 MHz, Methanol-d₄): δ 7.77 - 7.68 (m, 1H), 7.67 (s, 1H), 7.29 - 7.15 (m, 3H), 6.99 - 6.77 (m, 4H), 5.55 (s, 1H),4.36 - 4.30 (m, 1H), 2.30 (s, 3H), 1.74 - 1.28 (m, 11H), 0.87 (s, 3H) ppm. [0266] Examples 18, 18a, 18b, 19, 19a and 19b. rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 18), rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19), (Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18a), (Z)-3- (((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18b), (Z)-3- (((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19a), and (Z)-3- (((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19b)

[0267] Step 1. Synthesis of ethyl (Z)-3-((3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylate (16-2). Into a 40 mL vial were added ethyl 3-bromo-2,2-difluoropropanoate (278 mg, 1.28 mmol), DMA (10 mL), and sodium hydride (92.64 mg, 3.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at rt. To a stirred solution was added 3-butyl-2-fluoro-8-hydroxy-7- (methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (16-1) (527 mg, 1.28 mmol) at rt. The resulting mixture was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was acidified with 1N aq. HCl solution to pH 5 at rt. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) (v/v) to afford ethyl (Z)-3-((3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- fluoroacrylate (16-2) (408 mg, 60%) as a brown oil. MS (ESI): calcd. for C₂₀H₂₄FNO₃S₂: 525.1, Found: 526.1 [M+1]⁺. [0268] Step 2. Synthesis of rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18) and rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19). Into a 40 mL vial were added ethyl (Z)-3-((3-butyl-2-fluoro-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylate (16-2) (408 mg, 0.78 mmol), dioxane (10 mL), water (2 mL) and lithiumol (55.77 mg, 2.32 mmol) at rt. The resulting mixture was stirred for 2 h at rt. The mixture was acidified with 1N HCl to pH 5 and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD 19 x 150mm 5 um; Mobile Phase A: water (0.05% HCOOH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 56% B in 8 min; Detector: UV 220 nm). The collected fractions were combined and concentrated under vacuum to afford rac-(Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18) (130 mg, 34%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.62 - 7.54 (m, 2H), 7.25 - 7.18 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 5.90 (d, J= 44 Hz, 1H), 4.15 (d, J = 16 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 (s, 3H), 1.54 - 1.45 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm and rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7- (methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- fluoroacrylic acid (Example 19) (130 mg, 34%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.62 - 7.54 (m, 2H), 7.25 - 7.18 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 5.90 (d, J= 44 Hz, 1H), 4.15 (d, J = 16 Hz, 1H), 3.21 - 3.14 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 (s, 3H), 1.54 - 1.45 (m, 4H), 1.37 - 1.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. [0269] Step 3. Synthesis of (Z)-3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido- 5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18a), (Z)-3-(((2S,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18b), (Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19a), and (Z)- 3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19b): Rac-(Z)- 3-(((2R,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18) (130 mg) was purified by Prep-HPLC using the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1 (min): 10; RT2 (min): 12; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected fractions was combined and concentrated under vacuum to afford (Z)-3-(((2R,3S)- 3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 18a) (36.2 mg, 38%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 13.65 (s, 1H), 7.74 - 7.67 (d, J = 4.9 Hz, 1H), 7.26 (s, 1H), 7.22 - 7.18 (m, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 5.90 (d, 40 Hz, 1H), 4.17 (d, J = 16 Hz, 1H), 3.19 (dd, J = 16.0, 12.0 Hz, 1H), 2.50 (s, 1H), 2.45 (s, 3H), 1.52 - 1.48 (m, 4H), 1.37 - 1.30 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H) ppm and (Z)-3-(((2S,3R)-3-butyl- 2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 18b) (27.5 mg, 21%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 13.59 (s, 1H), 7.71 - 7.66 (m, 2H), 7.25 (s, 1H), 7.21 - 7.17 (m, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 5.89 (d, J = 44 Hz, 1H), 4.17 (d, J = 16.0 Hz, 1H), 3.20 - 3.14 (m, 1H), 2.57 (s, 1H), 2.44 (s, 3H), 1.52 - 1.47 (m, 4H), 1.36 - 1.31 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) ppm. Rac-(Z)-3-(((2R,3R)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19) (10 mg) was purified by Prep-HPLC with the following conditions: Column: CHIRAL ART Amylose-C NEO, 3 x 25 cm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: IPA; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected fractions was combined and concentrated under vacuum to afford (Z)-3-(((2R,3R)-3-butyl-2- fluoro-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-fluoroacrylic acid (Example 19a) (1.1 mg.11%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, CD₃OD): δ 8.50 (s, 1H), 7.65 (s, 1H), 7.31 - 7.21 (m, 3H), 6.98 (s, 1H), 6.96 - 6.86 (m, 3H), 5.40 (d, J = 40 Hz, 1H), 4.10 - 3.85 (m, 2H), 2.39 (s, 1H), 2.30 (s, 3H), 1.70 - 1.63 (m, 1H), 1.55 - 1.21 (m, 5H), 0.87 (m, 3H) ppm and (Z)-3-(((2S,3S)-3-butyl-2-fluoro-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-fluoroacrylic acid (Example 19b) (2 mg, 21%) as a white solid. MS (ESI): calcd. for C₂₃H₂₅F₂NO₅S₂: 497.1, Found: 498.2 [M+1]⁺; ¹H NMR (400 MHz, CD₃OD): δ 7.68 (s, 1H), 7.46 (d, J = 16 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.00 - 6.89 (m, 4H), 5.42 (d, J = 44 Hz, 1H), 4.10 - 3.84 (m, 2H), 2.39 (s, 1H), 2.30 (s, 3H), 1.69 - 1.63 (m, 1H), 1.56 - 1.54 (m, 1H), 1.54 - 1.21 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H) ppm. [0270] 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

115

V. Biological Data [0271] HepG2-NTCP infection protocol [0272] 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 × 10⁵ 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). [0273] 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. [0274] 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. [0275] Following the described HepG2-NTCP infection protocol, assay data for exemplified compounds of the invention can be grouped in the following ranges: A indicates EC₅₀ < 100 nM; B indicates EC₅₀ of ≥100 to <1,000 nM; C indicates EC₅₀ of ≥1,000 to <5,000 nM.

INCORPORATION BY REFERENCE [0276] 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 [0277] 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. [0278] 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.

Claims

CLAIMS: 1. A compound of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is NR^x or CR²R³; R^x is hydrogen or C_1-4alkyl; R⁰ is -C(O)OH, -C(O)OC_1-6alkyl or -S(O)₂OH; R¹ is hydrogen, halo, C_1-4alkyl or haloC_1-4alkyl; 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, C_{1- 4}alkyl, haloC_1-4alkyl, C_1-4alkoxy and C_1-4alkylthio; R⁵ is haloC_3-4alkyl, hydroxyC_3-4alkyl, aminoC_3-4alkyl, cyanoC_2-4alkyl, C_3-5alkenyl, C_{3- 4}alkynyl, methoxyethyl, ethoxymethyl, and C_3-6cycloalyl-ethylene-; R⁶ is hydrogen; or R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl group; and R⁷ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, OH, CN, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy, and C_1-4alkylthio.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is NR^x.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein M is NH or NCH₃.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is CH₂, CHF, CF₂ or C(CH₃)₂.

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)OC_1-4alkyl.

6. The compound of claim 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 haloC_3-4alkyl, hydroxyC_3-4alkyl, aminoC_3-4alkyl, cyanoC_2-4alkyl, C_3-5alkenyl, C_3-4alkynyl, methoxyethyl, ethoxymethy or C_3-6cycloalyl- ethylene-.

11. The compound according to any one of claims 10, or a pharmaceutically acceptable salt thereof, wherein R⁵ is haloC_3-4alkyl.

12. The compound according to any one of claims 11, or a pharmaceutically acceptable salt thereof, wherein R⁵ is n-butyl substituted with 1 to 6 halo atoms.

13. The compound according to any one of claims 12, or a pharmaceutically acceptable salt thereof, wherein R⁵ is n-butyl substituted with 1 to 6 F atoms.

14. The compound according to any one of claims 13, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -CH₂CH₂CF₂CH₃.

15. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ together with the carbon atom to which they are attached form a C_3-7monocycloalkyl or C_5-12bicycloalkyl group.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ together with the carbon atom to which they are attached form a

or

group.

17. A compound selected from the group consisting of:

,

and

.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. 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 1-17, or a pharmaceutically acceptable salt thereof.

20. 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 18.

21. 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 1-17, 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 18.