Benzothia(DIA)zepine compounds for treatment of hbv and hdv

Abstract

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

Description

[0001] BENZOTHIA(DIA)ZEPINE COMPOUNDS FOR TREATMENT OF HBV AND HDV CROSS-REFERENCE TO RELATED APPLICATION This application claims benefit of U.S. Provisional Application No.63 / 446,976, filed February 20, 2023 and U.S. Provisional Application No.63 / 534,249, filed August 23, 2023, the contents of which are hereby incorporated by reference. BACKGROUND Hepatitis B virus (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 296 million people were chronically infected in 2019 according to the World Health Organization website, 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. The HBV particle is composed of a lipid envelope studded with the hepatitis B surface antigen (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 capsid assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core. 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. 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. 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. 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 viral particle assembly. Thus, in a small set of patients infected with HBV, HDV presents as coinfection / superinfection 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 / superinfection 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 / superinfection. WO2022253997 relates to relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and / or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases. WO2023237728 to Albireo relates to methods for treating hepatitis B and / or D with an Na+ / taurocholate co-transporting polypeptide (NTCP) inhibitor such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound of formula (II), or a pharmaceutically acceptable salt thereof. Such methods can include decreasing the concentration of hepatitis B DNA, decreasing the concentration of hepatitis D DNA, decreasing hepatitis B surface antigen, and decreasing hepatitis B core antigen (HBcAg). NTCP functions as a cellular receptor for viral entry of HBV and HDV, which in turn is the major cause of liver disease and HCC. There is a need for additional bile acid modulating compounds that have an improved profile with respect to potency, safety, selectivity and / or bioavailability. SUMMARY 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. In one aspect, the disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. 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 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. 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. In another aspect, the disclosure provides a method of treating an HDV 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. In another aspect, the disclosure provides a method of treating an HDV 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. BRIEF DESCRIPTION OF DRAWINGS Figure 1 shows the ORTEP plot for Example 10b. Figure 2 shows the ORTEP plot for Example 11a. DETAILED DESCRIPTION Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV), resulting in the most severe form of viral hepatitis known in humans. HDV is a single-stranded, circular RNA virus. It relies on the hepatitis B virus (HBV) to infect and replicate in liver cells. HDV is a defective virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of HBV that provides the envelope proteins. New HDV progeny particles can only be produced in a liver cell that is already infected with HBV. Worldwide, approximately 300 million people are chronically infected with HBV. An estimated 15-20 million are also chronically infected with hepatitis delta. Coinfections lead to more serious liver disease than HBV infection alone. They are associated with faster progression to liver fibrosis, increased risk of liver cancer, and early decompensated cirrhosis and liver failure that may lead to a fatal outcome within days if not transplanted. Hepatitis delta can be acquired either through coinfection: infection with hepatitis B and delta at the same time. It can also be acquired by superinfection: infection with hepatitis D after a person has already acquired hepatitis B. There is currently no vaccine for hepatitis delta. However, it can be prevented by getting the hepatitis B vaccine to help eliminate the risk of infection with HBV. The entry inhibitor Hepcludex (myrcludex B, Bulevirtide, BLV) was approved for HDV in July of 2020 in the European Union, and as of June 2023, is available in France, Germany, Austria, Italy, and the UK. The drug binds to the essential HDV receptor on liver cells and by doing so prevents infection of the cell. Binding of BLV to NTCP simultaneously inhibits its natural biological function of transporting bile acid into the cell. Previously, the only treatment for hepatitis delta found to be somewhat effective was pegylated interferon alpha, which acts by stimulating the body's innate immune system to fight the virus. While Hepcludex is a 47-amino acid peptide, inhibiting Na+-taurocholate cotransporting polypeptide (NTCP), the viral entry receptor, requiring subcutaneous (SubQ) dosing, the small-molecule oral bioavailable NTCP inhibitors of the present invention provide more flexible dosing, increased convenience, and greater combinational options with other HBV / HDV therapies. WO2022 / 253997 to Albireo relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I): These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and / or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases. Applicants note that the Compounds of formula (I) in WO2022 / 253997 are chiral due to the presence of a chiral center at the carbon atom bearing R1. In addition, M is limited to - CH2- and -NR5-, wherein R5is hydrogen or C1-4alkyl; R1-is limited to C1-4alkyl, and R3is limited to hydrogen, halo, cyano, C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C3-6cycloalkoxy, C1-4alkylthio, C3-6cycloalkylthio, amino, N-(C1-4alkyl)amino, and N,N-di(C1-4alkyl)amino. Thus, there is no teaching or suggestion of a haloalkyl substituent at R1or R3, or of M being a substituted carbon atom. Notably, when M is a mono-substituted carbon atom, a new chiral center is introduced resulting in four diastereomers. In contrast, Example 10b is an exemplary compound of the present invention, with a structure and absolute stereochemistry as shown below: wherein haloalkyl groups are introduced at R1(i.e., -CH2CH2CF2CH3) and R3(i.e., CF3) and M is a mono-substituted carbon atom (i.e., -CHF-), resulting in a second chiral center outside the scope of WO2022 / 253997. Applicants have discovered one or more of these structural modifications results in unexpectedly improved biological activity against HBV and HDV, selectivity profiles, and PK profiles. The compound of Example 10b can exist as four diastereomers:

[0002] Potency and transporter selectivity comparison data for each of these four diastereomers are provided in TABLE 1. TABLE 1: Potency and transporter selectivity comparison data for each of the four diastereomers of the compound of Example 10b of the present invention As used herein, Diastereomer 1 of Example 10b of the present invention is also referred to as Compound 1. For comparison purposes, Applicants have made and tested the compounds of Example 9 and Example 13 of WO2022 / 253997 according to procedures known in the art. Both are described in WO2022 / 253997 as racemic mixtures of the corresponding enantiomers. Example 14, enantiomer 1 and Example 14, enantiomer 2 are the isolated R and S enantiomers (absolute stereochemistry unassigned) of Example 13. Table 8 of WO2022 / 253997 shows that Example 9 and Example 13 have similar NTCP (hLBAT) inhibitory activity but Example 14, enantiomer 2 is significantly more active at inhibiting NTCP (hLBAT) than Example 14, enantiomer1. However, no assay data is provided directly demonstrating biologic activity against HDV or HBV. TABLE 2 provides potency and transporter selectivity comparison data for Compound 1 vs the compounds of Examples 9 and 14 of WO2022 / 253997. TABLE 2: Potency and transporter selectivity comparison data As shown in the table, Compound 1 had half-maximal inhibitory concentration (IC50) values of 7.3 and 2,400 nM vs human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC50 / NTCP IC50) of >320-fold. Compound 1 also prevented HBV infection of human hepatoma cells with an IC50 of 4.2 nM without affecting cell viability. In contrast, Example 14 (enantiomer 2) had IC50 values of 21 and 190 nM vs human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC50 / NTCP IC50) of 9- fold. This compound prevented HBV infection of human hepatoma cells with an IC50 of 24 nM without affecting cell viability. Likewise, Example 9 (best enantiomer) had an IC50 of 75.6 nM vs human NTCP and prevented HBV infection of human hepatoma cells with an IC50 of 45 nM without affecting cell viability. Thus, in hepatoma cells infected with HBV, Compound 1 exhibited a higher anti- HBV potency than Example 14 (enantiomer 2), with an IC50value approximately 6-times lower. In comparison to Example 9 (best enantiomer), the IC50value was approximately 11- times lower. Compound 1 also inhibited NTCP more effectively, with an IC50value approximately 3-times lower than that of Example 14 (enantiomer 2) and approximately 10- times lower than that of Example 9 (best enantiomer. Finally, Compound 1 demonstrated a NTCP-selectivity (ASBT IC50 / NTCP IC50) that was approximately 36-times higher than that of Example 14 (enantiomer 2), indicating its superior selectivity. TABLE 3 provides monkey PK profile comparison data for Compound 1 vs Albireo compound A7387. Data for Compound 1 was acquired using methods and procedures described herein, while data for A7387 is digitized from an Albireo 2023 AASLD poster, 1481-C | PRECLINICAL CHARACTERIZATION OF THE NOVEL, ORALLY BIOAVAILABLE NTCP INHIBITOR A7387. Although the structure of A7387 was not disclosed in the poster, WO2023237728 refers to Example 14 of WO2022 / 253997 as Compound 2, and provides primate in vivo results on p.77, cross-referencing Compound 2 as A7387. TABLE 3: Monkey PK Profile Comparison for Compound 1 vs A7387 In monkeys, after an oral dose of 3 mg / kg, Compound 1 exhibited higher exposure, with an AUC0-24of 58178 hr*ng / mL and a Cmaxof 5147 ng / mL, which were 320% and 120% higher, respectively, than those observed for A7387. In monkeys, after an oral dose of 10 mg / kg, Compound 1 exhibited higher exposure, with an AUC0-24of 290412 hr*ng / mL and a Cmaxof 23100 ng / mL, which were 1450% and 1260% higher, respectively, than those observed for A7387. In monkeys, after an oral dose of 30 mg / kg, Compound 1 exhibited higher exposure, with an AUC0-24of 1082543 hr*ng / mL and a Cmaxof 64900 ng / mL, which were 240% and 150% higher, respectively, than those observed for A7387. The apparent oral PK terminal half-life of Compound 1 ranged from 13-17 hours, which were 160% - 320% longer than those observed for A7387. The features and other details of the present 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 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 C2--6alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc. 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 C1-6alkoxy and C1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc. 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. 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 C1-6alkyl and C1-4alkyl, 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. 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 C2-6alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc. The term “carbonyl” as used herein refers to the biradical -C(O)-. The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen. The term “cyano” as used herein refers to the radical -CN. The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C3-7monocycloalkyl, or bicyclic hydrocarbon ring structure of, for example, 5-12 carbons, referred to herein as C5-12bicycloalkyl. 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. The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC1-6alkyl 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-. 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-. The terms “heteroaryl” as used herein refers to a 5-6 membered monocyclic aromatic group, referred to herein as monocyclo5-6heteroaryl, or 8-12 membered bicyclic aromatic ring system, referred to herein as bicyclo8-12heteroaryl, 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 monocyclo5-6heteroaryl 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 bicyclo8-12heteroaryl 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. The term “heterocycloalkyl” refers to a monocycloalkyl group, for example a C3-7monocycloalkyl, or a bicycloalkyl group, for example C5-12bicycloalkyl, 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 mono3-7heterocycloalkyl and bi5-12heterocycloalkyl, respectively. Examples of mono3-7heterocycloalkyl 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 bi5-12heterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl. The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. 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-. 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-. The term “RaRbNC1-6alkyl-,” as used herein refers to an alkyl group substituted with a RaRbN- group, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2- and CH3CH(NH2)CH2-. The term “RaRbNC1-6alkoxy,” as used herein refers to an alkoxy group substituted with a RaRbN- groups, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-. The term “oxo” as used herein refers to the radical =O. 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 R33group(s)) can be independently attached to either or both rings. 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. The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism. 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. 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. 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. 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. 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. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. 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. The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.” Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. 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. 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. 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 as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) 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. 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 In one aspect, the present disclosure provides a compound of Formula I , or a pharmaceutically acceptable salt thereof, wherein: M is NRxor CRyRz; X is N or CH; Ra, Rband Rcare independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; Rxis hydrogen or C1-4alkyl; Ryand Rzare independently selected from the group consisting of hydrogen, halo, CN, C1-4alkyl, and haloC1-4alkyl; R1is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH or R2aand R2bare independently selected from the group consisting of hydrogen, halo, OH methyl, ethyl and CH2OH; or R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected halo or methyl groups; R3is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5-12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4is hydrogen, C1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-; R4ais phenyl, imidazolyl, N-methylimidazolyl, or C3-6monocycloaklyl optionally substituted with 1 to 3 halo groups; R5is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2; with the proviso that: R3is haloC1-4alkyl; M is CRyRzand at least one of Ryand Rzis halo, CN, C1-4alkyl, or haloC1-4alkyl; or R4is haloC1-4alkyl, hydroxyC1-4alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-; or a combination thereof. 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. In certain embodiments, the Compound of Formula I is of Formula Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the Compound of Formula I is of Formula Ib Formula Ib or a pharmaceutically acceptable salt thereof. In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, M is NRx. In certain embodiments, M is NH or NCH3. In certain embodiments, M is CRyRz. In certain embodiments, M is -CH2-. In certain embodiments, M is CRyRzand at least one of Ryand Rzis halo, CN, C1-4alkyl, or haloC1-4alkyl. In certain embodiments, M is -CH(CH3)-, -CF(CH3)-, is -CHF-, -C(CH3)2- or -CF2-. In certain embodiments, M is -CF(CH3)-. In certain embodiments, M is -C(CH3)2-. In certain embodiments, M is -CHF-. In certain embodiments, M is -CF2-. In certain embodiments, R1is C(O)OH. In certain embodiments, R1is S(O)2OH. In certain embodiments, R1is P(O)(OH)2. In certain embodiments, R2aand R2bare independently selected from the group consisting of hydrogen, halo, OH and methyl. In certain embodiments, R2aand R2bare methyl. In certain embodiments, R2ais hydrogen and R2bare methyl. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with 1-3 halo groups. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments, R3is C5-12bicycloalkylthio-. In certain embodiments, R3is haloC3-7monocycloalkylthio-. In certain embodiments, R3is haloC1-2alkyl-. In certain embodiments, R3is CF3. In certain embodiments, R4is haloC1-4alkyl-, hydroxyC1-4alkyl-, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-. In certain embodiments, R4is haloC1-4alkyl-. In certain embodiments, R4is haloC3-4alkyl-. In certain embodiments, R4is n-butyl substituted with 1 to 6 halo atoms. In certain embodiments, R4is n-butyl substituted with 1 to 6 F atoms. In certain embodiments, R4is -CH2CH2CF2CH3. In certain embodiments, R4is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R4is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R4is -CH2CH2CF3. In certain embodiments, R5is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5is In certain embodiments, R5is C5-12bicycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5is In certain embodiments, R5is In certain embodiments, X is CH, R3is haloC1-4alkyl- and R4is haloC1-4alkyl-. In certain embodiments, X is CH, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, X is CH, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R3is haloC1-4alkyl-, and R4is haloC1- 4alkyl-. In certain embodiments, X is CH, M is -CHF-, R3is CF3, and R4is -CH2CH2CF2CH3. In certain embodiments, X is CH, M is -CHF-, R3is CF3, and R4is -CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, and R4is haloC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3and R4is - CH2CH2CF2CH3. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3and R4is - CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is haloC1-4alkyl-,and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3,R4is - CH2CH2CF2CH3,and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3,R4is - CH2CH2CF3,and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is haloC1-2alkyl;and R5is or In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3,R4is - CH2CH2CF2CH3, and R5is or

[0003] In certain embodiments, X is CH, M is -CHF-, R1is C(O)OH, R3is CF3, R4is - CH2CH2CF3,and R5is or In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3is haloC1-4alkyl- and R4is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3is haloC1-4alkyl-,and R4is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3is CF3,and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3is CF3,and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is haloC1-4alkyl-,and R4is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is haloC1-4alkyl-, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF2CH3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is haloC1-2alkyl;and R5is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3,R4is -CH2CH2CF2CH3,and R5is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF3, and R5is In some embodiments of the present invention, the compound of Formula I is of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2- or -C(CH3)2-; Ra, Rband Rcare independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; R1is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH or R2aand R2bare independently selected from the group consisting of hydrogen, halo, OH methyl, ethyl and CH2OH; or R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected halo or methyl groups; R3is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5-12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4is haloC3-4alkyl; R5is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2. 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. In certain embodiments, the compound of Formula II is of Formula IIa , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IIb , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IIc , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IId , or a pharmaceutically acceptable salt thereof. In certain embodiments, M is -CHF-, -CH(CH3)- or -CF(CH3)-. In certain embodiments, M is -CHF-. In certain embodiments, M is -CH(CH3)-. In certain embodiments, M is -CF(CH3)-. In certain embodiments, M is -CF2- or -C(CH3)2-. In certain embodiments, M is -CF2-. In certain embodiments, M is -C(CH3)2-. In certain embodiments, R1is C(O)OH. In certain embodiments, R1is S(O)2OH. In certain embodiments, R1is P(O)(OH)2. In certain embodiments, R2aand R2bare independently selected from the group consisting of hydrogen, halo, OH and methyl. In certain embodiments, R2aand R2bare methyl. In certain embodiments, R2ais hydrogen and R2bare methyl. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with 1-3 halo groups. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group. In certain embodiments, R2aand R2btogether with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments, R3is C5-12bicycloalkylthio-. In certain embodiments, R3is haloC3-7monocycloalkylthio-. In certain embodiments, R3is haloC1-2alkyl-. In certain embodiments, R3is CF3. In certain embodiments, R4is n-butyl substituted with 1 to 6 halo atoms. In certain embodiments, R4is n-butyl substituted with 1 to 6 F atoms. In certain embodiments, R4is -CH2CH2CF2CH3. In certain embodiments, R4is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R4is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R4is -CH2CH2CF3. In certain embodiments, R5is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5is In certain embodiments, R5is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5is In certain embodiments, R5is In certain embodiments, R3is haloC1-4alkyl- and R4is -CH2CH2CF2CH3. In certain embodiments, R3is haloC1-4alkyl- and R4is -CH2CH2CF3. In certain embodiments, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, M is -CHF- and R3is haloC1-4alkyl-.In certain embodiments, M is -CHF- and R3is CF3.In certain embodiments, M is -CHF-, R3is haloC1-4alkyl-, and R4is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R3is haloC1-4alkyl-, and R4is -CH2CH2CF3. In certain embodiments, M is -CHF-, R3is CF3, and R4is -CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R3is CF3, and R4is -CH2CH2CF3. In certain embodiments, M is -CHF-, R1is C(O)OH, and R3is haloC1-4alkyl. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl and R4is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl and R4is - CH2CH2CF3. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3, and R4is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3, and R4is - CH2CH2CF3. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is - CH2CH2CF2CH3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is - CH2CH2CF3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3, R4is - CH2CH2CF2CH3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is - CH2CH2CF2CH3, and R5i or In certain embodiments, M is -CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is - CH2CH2CF3, and R5is In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3, R4is - CH2CH2CF2CH3,and R5is or In certain embodiments, M is -CHF-, R1is C(O)OH, R3is CF3,R4is -CH2CH2CF3,and R5is In certain embodiments, the compound of Formula II is of Formula IIa, R3is haloC1-4alkyl- and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, R3is haloC1-4alkyl- and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3is haloC1-4alkyl-, and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3is haloC1-4alkyl-, and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3is CF3, and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3is CF3, and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3and R4is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3and R4is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is -CH2CH2CF2CH3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-4alkyl-, R4is -CH2CH2CF3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF2CH3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF3, and R5is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is CH2CH2CF2CH3, and R5is

[0004] In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is haloC1-2alkyl, R4is CH2CH2CF3, and R5is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3,R4is -CH2CH2CF2CH3,and R5is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1is C(O)OH, R3is CF3, R4is -CH2CH2CF3, and R5is III. Pharmaceutical Compositions and Kits 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. 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. 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. 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. 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. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. 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. 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. 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. Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. 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. 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. 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. 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. 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. 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 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. 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. Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV / HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating an HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. 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. 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. 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. 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. 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. 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. 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). 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. 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. 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. 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. 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. 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. 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. 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. 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 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 aq. Aqueous BAST Bis(2-methoxyethyl)aminosulfur trifluorid Boc2O Di-tert-butyl dicarbonate nBuLi n-Butyllithium compd. Compound concd. Concentrated COSY Homonuclear correlation spectroscopy DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropyl ethylamine DMF N,N-Dimethylformamide DMS Dimethylsulfide DMSO Dimethyl sulfoxide EA, EtOAc Ethyl acetate Et3N Triethylamine ESI Electrospray ionization HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HMBC Heteronuclear multiple bond correlation HPLC High performance liquid chromatography HSQC Heteronuclear single quantum coherence IPA, iPrOH Isopropanol LiHMDS Lithium bis(trimethylsilyl)amide LCMS Liquid chromatography–mass spectrometry MeOH Methanol MS Mass spectrometry NOESY Nuclear Overhauser effect spectroscopy NFSI N-Fluorobenzenesulfonimide NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance PE Petroleum ether rac. Racemic rel. Relative RfRetention factor rt, r.t. Room temperature RT, tRRetention time sat. Saturated SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography Example 1. (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)ethane-1-sulfonic acid Step 1. Synthesis of (R)-ethyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (1-2). To a solution of 1-(tert-butyl) 2-ethyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (1-1) (38.0 g, 147.9 mmol) in THF (380 mL) was added MeMgBr (51.8 mL, 155.3 mmol, 3.0M) drop wise in an ice bath under nitrogen. The mixture was stirred at rt for 6 hr. The resulting mixture was then quenched with sat. aq. NH4Cl solution (200 mL). The mixture was extracted with EA (200 mL x 2) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 1-2 (32.0 g, 79%) as a yellow solid. TLC: 25% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C13H23NO5: 273.2; Found: 174.1 [M -Boc + 1]+. Step 2. Synthesis of (R)-ethyl 2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (1- 3). To a solution of 1-2 (32 g, 117.2 mmol) in THF (320 mL) was added BAST (77.7 g, 351.6 mmol) drop wise in an ice bath under nitrogen, and the reaction mixture was stirred at rt for 4 days. The reaction mixture was poured into sat aq. NaHCO3solution (150 mL) slowly at 0°C and extracted with EA (150 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (8% EA / PE (v / v)) to give 1-3 (13.8 g, 40%) as a yellow oil. TLC: 10% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C13H23F2NO4: 295.2 MS Found: 196.2 [M - Boc + 1]+. Step 3. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (1-4). To a solution of 1-3 (13.8 g, 46.8 mmol) in THF / H2O = 5 / 1 (v / v) (100 mL) was added LiOH (3.4 g, 140.3 mmol). After stirring at rt for 4 hr, the reaction mixture was diluted with water (100 mL), acidified with 1N aq. HCl solution to pH ~ 3, and concentrated to remove organic solvent. The residue was extracted with EA (100 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 1-4 (11.3 g, 90%) as a yellow oil, which was used in the next step without further purification. TLC: 35% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C11H19F2NO4: 267.1; Found: 168.2 [M - Boc + 1]+. Step 4. Synthesis of (R)-tert-butyl (5,5-difluoro-1-oxo-1-(phenylamino)hexan-2- yl)carbamate (1-5). To a stirred solution of 1-4 (11.3 g, 42.3 mmol) and DIEA (16.4 g, 127.0 mmol) in THF (100 mL) was added HATU (24.1 g, 63.5mmol) in small portions in an ice bath under nitrogen. After stirring for 40 min, PhNH2(5.9 g, 63.5mmol) was added drop wise. The resulting mixture was stirred at rt for 16 hr and then concentrated. The residue was diluted with H2O (150 mL) and extracted with EA (150 mL x 2). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EA / PE (v / v)) to give 1-5 (7.6 g, 53%) as a yellow oil. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C17H24F2N2O3: 342.2; Found: 287.2 [M - tBu + 1]+. Step 5. Synthesis of (R)-2-amino-5,5-difluoro-N-phenylhexanamide (1-6). A solution of 1-5 (7.6 g, 22.2 mmol) and TFA (20 mL) in DCM (40 mL) was stirred at room temperature for 4 hr and concentrated. The residue was diluted with DCM (100 mL) and basified to pH ~ 8 with sat. aq. NaHCO3 solution. The resulting mixture was extracted with DCM (100 mL x 4). The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was dried in vacuo to give crude 1-6 (4.8 g, 89%) as a yellow oil, which was used for the next step without further purification. TLC: 8% MeOH / DCM (v / v) (Rf: 0.5). MS (ESI): calcd. for C12H16F2N2O: 242.2; Found: 243.2 [M + 1]+. Step 6. Synthesis of (R)-5,5-difluoro-N1-phenylhexane-1,2-diamine (1-7). To a stirred solution of 1-6 (4.8 g, 19.8 mmol) in THF (100 mL) was added LAH (23.8 mL, 59.5 mmol, 2.5 M in THF) drop wise at 0°C. The resulting mixture was stirred at 70°C for 4 hr. The reaction was quenched with H2O (2.3 mL) and 15% aq. NaOH solution (2.3 mL) at 0°C. The resulting mixture was dried over Na2SO4and concentrated. The residue was purified by column chromatography (10% MeOH / DCM (v / v)) to give 1-7 (3.8 g, 84%) as a colorless oil. TLC: 10% CH3OH / DCM (v / v) (Rf: 0.3). MS (ESI): calcd. for C12H18F2N2: 228.1; Found: 229.3 [M + 1]+. Step 7. Synthesis of (R)-2-bromo-N-(5,5-difluoro-1-(phenylamino)hexan-2-yl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (1-8). To a stirred solution of 1-7 (1.0 g, 4.39 mmol) and TEA (886 mg,8.77 mmol) in THF (10 mL) was added 2-bromo-5-methoxy- 4-(trifluoromethyl)benzenesulfonyl chloride (2.3 g, 6.59 mmol) in portions at rt. After stirring at rt for 16 hr, the mixture was diluted with H2O (30 mL) and extracted with EA (25 mL x 2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (30% EA / PE (v / v)) to give 1-8 (1.6 g, 67%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C20H22BrF5N2O3S: 544.0; Found: 545.1 [M + 1]+. Step 8. Synthesis of (R)-3-(3,3-difluorobutyl)-8-methoxy-5-phenyl-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-9). A suspension of 1-8 (1.6 g, 2.94 mmol), picolinicacid (72 mg, 0.59 mmol), K2CO3(1.2 g, 8.82 mmol), and CuI (38 mg, 0.59 mmol) in DMF (20 mL) was stirred at 90°C for 3 hours under N2atmosphere. The reaction mixture was then cooled at rt, diluted with water (30 mL), and extracted with EA (25 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 1-9 (1.2 g, 88.2%) as a brown oil, which was used for the next step without further purification. TLC: 25% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C20H21F5N2O3S: 464.1; Found: 465.1 [M + 1]+. Step 9. Synthesis of (R)-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-10). To a suspension of 1-9 (1.2 g, 2.59 mmol) and Cs2CO3(1.1 g, 3.36 mmol) in NMP (10 mL) was added MeI (1.1 g, 7.77 mmol) in an ice bath. The reaction mixture was stirred at rt for 3 hr and diluted with H2O (30 mL). The resulting mixture was extracted with EA (30 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 1-10 (1.1 g, 88.9%) as a brown oil, which was used for the next step without further purification. TLC: 25% EA / PE (v / v) (Rf: 0.6). MS (ESI): calcd. for C21H23F5N2O3S: 478.1; Found: 479.1 [M + 1]+. Step 10. Synthesis of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-11). To a solution of 1-10 (1.1 g, 2.30 mmol) in DMF (6.0 mL) was added NaSMe (1.6 g, 23.0 mmol), and the reaction mixture was stirred at 100°C for 16 hr. The reaction mixture was diluted with water (30 mL), acidified with 4 N aq. HCl solution to pH 5~6, and extracted with EA (50 mL x 3). The combined organic layer was washed with sat. aq. LiCl solution (25 mL) and brine (25 mL), dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography (35% EA / PE (v / v)) to give 1-11 (1.0 g, 93.5%) as a colorless oil. TLC: 40% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C20H21F5N2O3S: 464.1; Found: 465.3 [M + 1]+. Step 11. Synthesis of (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)ethanesulfonic acid (Example 1). To a suspension of 1-11 (450 mg, 0.97 mmol) and Cs2CO3 (1264 mg, 3.88 mmol) in DMF (10 mL) was added sodium 2-bromoethane-1-sulfonate (611 mg, 2.91 mmol), and the reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was diluted with water (20 mL) and acidified with 4N aq. HCl solution to pH ~5. The resulting mixture was extracted with EA (25 mL x 3). The combined organic layer was dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 1 (112 mg, 20.2%) as a white solid. TLC: 5% MeOH / EA (v / v) (Rf: 0.5). MS (ESI): calcd. for C22H25F5N2O6S2: 572.1; Found: 573.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.47 (s, 1H), 7.25 ‒ 7.17 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.78 ‒ 6.66 (m, 2H), 4.56 (t, J = 8.0 Hz, 2H), 4.20 ‒ 4.05 (m, 1H), 4.00 ‒ 3.82 (m, 1H), 3.52 ‒ 3.38 (m, 1H), 3.37 ‒ 3.32 (m, 2H), 2.64 (s, 3H), 2.11 ‒1.92 (m, 2H), 1.86 ‒ 1.75 (m, 2H), 1.62 (t, J = 18.8 Hz, 3H) ppm. Example 2. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0005] Step 1. Synthesis of ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (2-2). To a stirred solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (2-1) (100 mg, 0.69 mmol) and TEA (209 mg, 2.07 mmol) in DCM (5 mL) was added MsCl (119 mg, 1.04 mmol). After stirring at rt for 1 hr, the reaction mixture was added ice-cold water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 2-2 (140 mg, 91%) as a yellow oil. TLC: 10% EA / PE (v / v) (Rf: 0.6) (Phosphomolybdic Acid). MS (ESI): calcd. for C8H14O5S: 222.1; Found: 240.1 [M + 18]+. Step 2. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (2-3). To a stirred solution of 1-11 (75 mg, 0.16 mmol) and Cs2CO3 (156 mg, 0.48 mmol) in DMF (2 mL) was added 10-2 (71 mg, 0.32 mmol) and the reaction mixture was heated at 70oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added into water (10 mL). The precipitate was collected by filtration, washed with water (5 mL x 3), and dried in vacuo to give crude 2- 3 (120 mg) as a white solid, which was used for the next step without further purification. TLC: 40% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C27H31F5N2O5S: 590.2; Found: 591.3 [M + 1]+. Step 3. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 2). To a stirred solution of 2-3 (80 mg, crude product, 0.11 mmol) in MeOH / H2O = 2 / 1 (v / v) (3 mL) was added NaOH (22 mg, 0.55 mmol) and the reaction mixture was stirred at rt for 2 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution and concentrated to remove organic solvent. The residue was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 2 (28 mg, 45%) as a white solid. TLC: 10% MeOH / DCM (v / v) (Rf: 0.5). MS (ESI): calcd. for C25H27F5N2O5S: 562.2; Found: 563.2 [M + 1]+.1H NMR (400 MHz, CD3OD, ): δ 7.65 (s, 1H), 7.46 (s, 1H), 7.23 ‒ 7.19 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 2H), 4.41 ‒ 4.32 (m, 2H), 4.18 ‒ 3.87 (m, 2H), 3.37 ‒ 3.33 (m, 1H), 2.64 (s, 3H), 2.12 ‒ 1.92 (m, 2H), 1.85 ‒ 1.78 (m, 2H), 1.62 (t, J = 18.4 Hz, 3H), 1.35 ‒ 1.31 (m, 2H), 1.13 ‒ 1.09 (m, 2H) ppm. Example 3. (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)oxetane-3- carboxylic acid Step 1. Synthesis of (R)-3-(3,3-difluorobutyl)-8-((3-(hydroxymethyl)oxetan-3- yl)methoxy)-2-methyl-5-phenyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-1). To a solution of 1-11 (200 mg, 0.43 mmol) in DMF (8 mL) were added (3-(bromomethyl)oxetan-3-yl)methanol (156 mg, 0.86 mmol) and Cs2CO3(420 mg, 1.29 mmol). The mixture was stirred at 70 °C overnight. The reaction mixture was treated with LiCl solution (8 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic extracts were dried with anhydrous Na2SO4and concentrated. The residue was dried in vacuo to give crude 3-1 (243 mg) as a brown solid, which was used for the next step without further purification. MS (ESI): calcd. for C25H29F5N2O5S: 564.2; Found: 565.2 [M + 1]+. Step 2. Synthesis of (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)oxetane-3-carboxylic acid (Example 3). To a solution of 3-1 (crude 243 mg, 0.43 mmol) in DCM (10 mL) was added Dess-Martin reagent (729 mg, 1.72 mmol). After stirring at rt for 5 hr, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC to give Example 3 (60 mg, 24%) as a white solid. MS (ESI): calcd. for C25H27F5N2O6S: 578.2; Found: 579.3 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.73 (s, 1H), 7.49 (s, 1H), 7.22 (dd, J = 8.6, 7.4 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H) 6.75 (d, J = 7.6 Hz, 2H), 4.97 (dd, J = 5.8, 2.2 Hz, 2H), 4.75 (dd, J = 5.8, 1.4 Hz, 2H), 4.52 (s, 2H), 4.24 ‒ 4.06 (m, 1H), 4.00 ‒ 3.85 (m, 1H), 3.60 ‒ 3.35 (m, 1H), 2.65 (s, 3H), 2.15 ‒ 1.90 (m, 2H), 1.87 ‒ 1.75 (m, 2H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Example 4. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)-3,3- difluorocyclobutane-1-carboxylic acid

[0006] Step 1. Synthesis of isopropyl 3,3-difluoro-1-(hydroxymethyl)cyclobutanecarboxylate (4-2). To a solution of diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate (4-1) (2.0 g, 7.60 mmol) in anhydrous THF (60 mL) was added 1N lithium tri-tert-butoxyalyminium hydride in THF (18.9 mL, 18.9 mmol) at 0 °C. After stirring at 70 °C for 16 hr, the reaction was quenched with saturated aq. NH4Cl solution at 0oC until no bubbling was observed. The mixture was diluted with water (80 mL), concentrated to remove organic solvent, and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1 (v / v)) to give 4-2 (0.85 g.54%) as a pale-yellow oil. MS (ESI): calcd. for C9H14F2O3: 208.2; Found: 209.2 [M + 1]+. Step 2. Synthesis of isopropyl 3,3-difluoro-1- ((((trifluoromethyl)sulfonyl)oxy)methyl)cyclobutanecarboxylate (4-3). To a solution of 4- 2 (400 mg, 1.92 mmol), 2,6-dimethylpyridine (308 mg, 2.88 mmol) in DCM (5 mL) was added Tf2O (400 mg, 1.92 mmol) at -78 °C. After stirring at -78 °C for 1 hr, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 4-3 (200 mg.31%) as a yellow solid, which was used for the next step without further purification. Step 3. Synthesis of (R)-isopropyl 1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5- phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)-3,3-difluorocyclobutanecarboxylate (4-4). To a solution of 1-11 (100 mg, 0.21 mmol), Cs2CO3 (205 mg, 0.63 mmol) in DMF (3 mL) was added 4-3 (200 mg, 0.59 mmol), and the reaction mixture was stirred at rt for 16 hr. Next, the reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with LiCl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 4-4 (160 mg.84%) as a yellow solid, which was used for the next step without further purification. MS (ESI): calcd. for C29H33F7N2O5S: 654.2; Found: 655.4 [M+1]+. Step 4. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)-3,3- difluorocyclobutanecarboxylic acid (Example 4). To a solution of 4-4 (150 mg, 0.23 mmol) in THF (4 mL) was added 1N aq. LiOH solution (1 mL) and the reaction mixture was stirred at rt for 16 hr. The reaction mixture was adjusted to pH = 6 with 1 N aq. HCl solution and then purified by prep-HPLC to give Example 4 (30 mg, 24%) as an off-white solid. MS (ESI): calcd. for C26H27F7N2O5S: 612.2; Found: 613.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.68 (s, 1H), 7.47 (s, 1H), 7.26 ‒ 7.18 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 4.0 Hz, 2H), 4.47 (s, 2H), 4.25 ‒ 4.05 (m, 1H), 3.99 ‒ 3.84 (m, 1H), 3.62 ‒ 3.40 (m, 1H), 3.15 ‒ 3.00 (m, 2H), 2.89 ‒ 2.74 (m, 2H), 2.66 (s, 3H), 2.14 ‒ 1.90 (m, 2H), 1.88 ‒ 1.74(m, 2H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Example 5. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0007] Step 1. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (5-2). To a stirred solution of 5-1 (140 mg, 0.29 mmol), which was readily prepared by following the same procedure for preparing 1-11 by replacing aniline with 4-F-aniline, and Cs2CO3 (284 mg, 0.87 mmol) in DMF (4 mL) was added ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (116 mg, 0.53 mmol). After stirring at 65oC for 3 hr, the reaction mixture was added into water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried in vacuo to give crude 5-2 (120 mg) as a white solid, which was used in the next step without further purification. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.5). MS (ESI): calcd. for C27H30F6N2O5S: 608.2; Found: 609.2 [M + 1]+. Step 2. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 5). To a stirred solution of 5-2 (120 mg, crude product, 0.20 mmol) in MeOH / H2O = 2 / 1 (v / v) (6 mL) was added NaOH (79 mg, 1.97 mmol) and the reaction mixture was stirred at rt for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution and concentrated to remove organic solvent. The residue was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 5 (49 mg, 43%) as a white solid. TLC: EA / PE = 1 / 1 (v / v) (Rf: 0.5). MS (ESI): calcd. for C25H26F6N2O5S: 580.1; Found: 581.3 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.64 (s, 1H), 7.41 (s, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.77-6.74 (m, 2H), 4.39-4.32 (m, 2H), 4.12-3.86 (m, 2H), 3.40-3.33 (m, 1H), 2.64 (s, 3H), 2.10-1.92 (m, 2H), 1.82-1.76 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.35-1.34 (m, 2H), 1.13-1.11 (m, 2H) ppm. Example 6a. (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid Step 1. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoate (5-2). To a solution of 5-1 (1.5 g, 3.1 mmol) in toluene (15 mL) was added methyl (R)-3-hydroxy-2-methylpropanoate (1.8 g, 15.2 mmol) and PPh3(2.4 g, 9.3 mmol). Then DIAD (6.3 g, 31.1 mmol) was added at 110oC under a nitrogen atmosphere. After stirring at 110oC for 4 hr, the reaction mixture was poured into water and extracted with EtOAc (200 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column to give 6a-1 (1.6 g, 89%) as a yellow solid. MS (ESI): calcd. for C26H30F6N2O5S: 582.1; Found: 583.2 [M + 1]+. Step 2. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 6a). To a solution of 6a-1 (1.6 g, 2.7 mmol) in THF (40 mL) / H2O (10 mL) was added LiOH (660 mg, 27.5 mmol). After stirring at rt for 4 hr, the reaction was poured into water. The mixture was adjusted to pH = 3 with 3 N aq. HCl solution and the resulting mixture was extracted with EA (100 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 6a (600 mg, 40%) as a white solid. MS (ESI): calcd. for C24H26F6N2O5S: 568.1; Found: 569.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.41(s, 1H), 6.98 ‒ 6.94 (m, 2H), 6.77 ‒ 6.76 (m, 2H), 4.36 ‒ 4.32 (m, 1H), 4.26 ‒ 4.23 (m, 1H), 4.08 ‒ 4.04 (m, 1H), 4.02 ‒ 3.89 (m, 1H), 3.48 ‒ 3.46 (m, 1H), 2.98 ‒ 2.85 (m, 1H), 2.64 (s, 3H), 2.07-1.93 (m, 2H), 1.81 ‒ 1.76 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H) ppm. Example 6b. (S)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid Following the same procedure for preparing Example 6a by replacing methyl (R)-3-hydroxy- 2-methylpropanoate with its enantiomer methyl (S)-3-hydroxy-2-methylpropanoate, Example 6b was obtained as a white solid. MS (ESI): calcd. for C24H26F6N2O5S: 568.1; Found: 569.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.67 (s, 1H), 7.56(s, 1H), 7.19 - 7.13 (m, 1H), 6.51 - 6.47 (m, 1H), 6.42 - 6.34 (m, 2H), 4.40 - 4.36 (m, 1H), 4.30 - 4.26 (m, 1H), 4.10 - 4.02 (m, 2H), 3.47 - 3.33 (m, 1H), 2.98 - 2.93 (m, 1H), 2.59 (S, 3H), 2.10 - 1.96 (m, 2H), 1.88 - 1.78 (m, 2H), 1.62 (t, J =18.4 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H) ppm. Example 7. (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid

[0008] Step 1. Synthesis of ethyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (7-2). To a solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (7-1) (1.5 g, 10.26 mmol) in DCM (30 mL) was added TEA (2.08 g, 20.56 mmol), followed by methanesulfonic anhydride (2.68 g, 15.39 mmol) was added at 0oC, After stirring at rt for 2 hr, the reaction mixture was diluted with H2O (80 mL) and extracted with DCM (30 mL x 2). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 7-2 (2.8 g, 100%, crude) as a pale-yellow oil, which was used in the next step without purification, MS (ESI): calcd. for C8H16O5S: 224.1; Found: 242.2 [M + 18]+. Step 2. Synthesis of (R)-ethyl 3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl- 1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (7-3). To a solution of 5-1 (1.5 g, 3.1 mmol) in DMF (10 mL) were sequentially added K2CO3 (1.29 g, 9.33 mmol) and 7-2 (1.4 g, 6.2 mmol, crude). After stirring at 110oC for 48 hr, the reaction was diluted with H2O (80 mL) and extracted with EA (50 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (100 mL) and brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE = 0% to 40% (v / v)) to give 7-3 (1.8 g, 95 %) as a yellow solid. MS (ESI): calcd. for C27H32F6N2O5S: 610.2; Found: 611.0 [M + 1]+. Step 3. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl- 1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 7). A solution of 7-3 (1.8 g, 2.95 mmol) in CH3OH / THF / H2O (8 mL / 8 mL / 8 mL) was added LiOH.H2O (1.24 g, 29.55 mmol). After stirring at 35oC for 3 hr, the reaction mixture was diluted with H2O (100 mL), adjusted to pH = 2 with 2 N aq. HCl solution, and extracted with EtOAc (60 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4and concentrated. The residue was purified by reversed column (CH3CN / H2O = 40% (v / v)) to give Example 7 (740 mg, 43%) as a white solid. MS (ESI): calcd. for C25H28F6N2O5S: 582.2; Found: 582.8 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.61 (s, 1H), 7.42 (s, 1H), 6.96 (t, J = 8.8 Hz, 2H), 6.77 ‒ 6.76 (m, 2H), 4.18 (s, 2H), 4.09 ‒ 3.88 (m, 2H), 3.47 ‒ 3.46 (m, 1H), 2.64 (s, 3H), 2.07 ‒ 1.90 (m, 2H), 1.80 ‒ 1.78 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.33 (s, 6H) ppm. Examples 8a and 8b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (8a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(3-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (8b)

[0009] Step 1. Synthesis of methyl 5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (8-2). To a stirred solution of methyl 5,5-difluoro-2-(hydroxymethyl)hexanoate (8-1) (100 g, 509.70 mmol) and TEA (154.73 g, 1529.10 mmol) in DCM (1000 mL) was added MsCl (70.06 g, 611.64 mmol) dropwise at 0°C. After stirring at rt for 2 hr, the reaction mixture was added H2O (500 mL) at 0°C. The resulting mixture was extracted with DCM (1000 mL x 2). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-2 (110 g, 79%) as a brown liquid, which was used for the next step without further purification. Step 2. Synthesis of methyl 2-(bromomethyl)-5,5-difluorohexanoate (8-3). To a stirred solution of 8-2 (110 g, 401.05 mmol) in acetone (500 mL) was added lithium bromide (104.48 g, 1203.15 mmol) in portions at rt. After stirring at 60oC for 3 hr, the mixture was allowed to cool down to rt and added H2O (200 mL) at rt. The resulting mixture was extracted with EA (300 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-3 (100 g, 96%) as a brown liquid, which was used in the next step without further purification.1H NMR (300 MHz, CDCl3): δ 3.77 (s, 3H), 3.56 (qd, J = 10.2, 6.4 Hz, 2H), 2.94 – 2.81 (m, 1H), 2.02 – 1.80 (m, 4H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Step 3. Synthesis of methyl 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5- difluorohexanoate (8-4). To a stirred solution of 2-amino-5-methoxybenzenethiol (60 g, 386.55 mmol) and Cs2CO3 (151.60 g, 463.85 mmol) in ACN (500 mL) was added 8-3 (100.15 g, 386.56 mmol) dropwise at rt. After stirring at rt for 4 hr, the reaction mixture was added water (50 mL) at rt. The resulting mixture was extracted with EA (500 mL x 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 4 / 1 (v / v) to give 8-4 (80 g, 62%) as a brown liquid. MS (ESI): calcd. for C15H21F2NO3S: 333.1; Found: 334.1 [M + 1]+. Step 4. Synthesis of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5-difluorohexanoic acid (8-5). To a stirred solution of 8-4 (94 g, 281.95 mmol) in dioxane (800 mL) and H2O (200 mL) was added LiOH (20.26 g, 845.87 mmol) at rt. The resulting mixture was stirred at rt for 2 hr. The mixture was acidified with 2 N aq. HCl solution to pH ~ 6. The resulting mixture was extracted with EA (100 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. This residue was dried in vacuo to give 8-5 (80 g, 89%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C14H19F2NO3S: 319.1; Found: 320.1 [M + 1]+. Step 5. Synthesis of 3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin- 4(5H)-one (8-6). To a stirred solution of 8-5 (80 g, 250.49 mmol) and HATU (104.77 g, 275.54 mmol) in DCM (1000 mL) was added DIEA (38.85 g, 300.59 mmol) dropwise at rt. The reaction mixture was stirred at rt for 2 hr and then added H2O (50 mL). The resulting mixture was extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 7 / 3 (v / v) to give 8-6 (67 g, 89%) as a yellow solid. MS (ESI): calcd. for C14H17F2NO2S: 301.1; Found: 302.1 [M + 1]+. Step 6. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-7). To a stirred solution of 8-6 (32 g, 106.18 mmol) in DCM (200 mL) and ACN (200 mL) was added NBS (20.79 g, 116.80 mmol) in portions at rt. The resulting mixture was stirred at rt for 4 hr and then added H2O (100 mL) at rt. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by trituration with PE / EA = 1 / 1 (v / v) (300 mL). The precipitated solid was collected by filtration, washed with PE / EA = 1 / 1 (v / v) (100 mL), and dried in vacuo to give 8-7 (22 g, 54%) as a white solid. MS (ESI): calcd. for C14H16BrF2NO2S: 379.0; Found: 380.0 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 7.34 (s, 1H), 7.14 (s, 1H), 3.94 (s, 3H), 3.53 (dd, J = 11.3, 6.0 Hz, 1H), 3.02 (t, J = 11.9 Hz, 1H), 2.68 (ddd, J = 16.4, 9.3, 5.2 Hz, 1H), 2.17 – 2.00 (m, 1H), 2.04 – 1.70 (m, 1H), 1.68 – 1.47 (m, 5H) ppm. Step 7. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-8). To a solution of 8-7 (3 g, 7.89 mmol) in DMF (30 mL) were added 1-fluoro-3-iodobenzene (1.75 g, 7.89 mmol), CuI (1.50 g, 7.89 mmol) and K2CO3(3.27 g, 23.67 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 16 hr and then cooled to rt and added water (100 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 3 / 1 (v / v) to give 8-8 (3 g, 80%) as a yellow solid. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 474.0 [M + 1]+. Step 8. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (8-9). A solution of 8-8 (3 g, 6.33 mmol) in THF (40 mL) and H2O (20 mL) was added Oxone®(63.81 g, 379.500 mmol) at rt. After stirring at rt for 16 hr, the mixture was filtered, and the filtered cake was washed with ethyl acetate (25 mL x 3). The filtrate was concentrated, and the residue was diluted with sat. aq. NaHCO3 solution (25 mL) and EtOAc (150 mL). The separated organic layer was washed with sat. aq. NaHCO3solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-9 (2.5 g, 78%) as a yellow solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+. Step 9. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-10). To a solution of 8-9 (2.5 g, 4.94 mmol) in THF (30 mL) was added 1 M BH3-Me2S in THF (2.81 mL, 29.622 mmol) at rt. After stirring at 75 °C for 16 hr, the mixture was cooled to 0oC, added ice water (30 mL), and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 5 / 1 (v / v) to give 8-10 (1.6 g, 67%) as a yellow solid. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+. Step 10. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-11). To a solution of 8- 10 (1.6 g, 3.25 mmol) in THF (20 mL) was added LiHMDS (6.5mL,1 mol / L in THF) dropwise at -78 °C. After stirring at -78 °C for 30 min, NFSI (1.23 g, 3.90 mmol) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for an additional 2 hr. The reaction mixture was added sat. aq. NH4Cl solution at rt and then concentrated to remove organic solvent. The resulting mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA = 5 / 1 (v / v) to give 8-11 (1 g, 60%) as a yellow solid. MS (ESI): calcd. for C20H20BrF4NO3S: 509.0; Found: 510.0 [M + 1]+. Step 11. Synthesis of 3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-12). To a solution of 8-11 (400 mg, 0.78 mmol) in DMF (5 mL) were added methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (602.30 mg, 3.14 mmol) and CuBr (224.87 mg,1.57 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 16 hr and then added water (15 mL) at rt. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 3 / 1 (v / v)) to give 8-12 (200 mg, 51%) as a yellow solid. MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+. Step 12. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8- 13). To a solution of 8-12 (200 mg, 0.40 mmol) in DMSO (5 mL) was added lithium chloride (509.25 mg, 12.00 mmol) at rt. The resulting mixture was stirred at 140 °C for 8 hr and then added water (15 mL) at rt. The mixture was acidified with sat. aq. citric acid solution to pH ~ 5. The resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 3 / 1 (v / v)) to give the cis- racemic 8-13 (50 mg, 26%) as a yellow solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+. Step 13. Synthesis of (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8- 13a) and (2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-13b). The racemic 8-13 (40 mg) was separated by prep-SFC with the following condition: Column: (R, R)-WHELK-O1-Kromasil, 3*25 cm, 5 μm; Mobile Phase A: CO2; Gradient: isocratic 20 % B; RT1(min) = 2.6 (8-13a as a single diastereomer, the stereochemistry was arbitrarily assigned); RT2(min) = 3.6 (8-13b as a single diastereomer, the stereochemistry was arbitrarily assigned); Sample Solvent: MeOH-HPLC; Injection Volume: 4 mL) to give 8-13a (15 mg) as light yellow solid and 8-13b (15 mg) as light yellow solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+. Step 14a. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14a). To a solution of 8-13a (15 mg, 0.03 mmol) in DMF (2 mL) were added ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (9.20 mg, 0.045 mmol) and CsCO3(20.40 mg, 0.06 mmol) at rt. After stirring at 80oC for 2 hr, the reaction mixture was cooled to rt, added water (15 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 3 / 1 (v / v)) to give 8-14a (16 mg, 79%) as a yellow solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 612.1 [M + 1]+. Step 15a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8a). To a solution of 8-14a (16 mg, 0.025mmol) in 1,4-dioxane (4 mL) were added LiOH (35.25 mg, 1.47 mmol) and H2O (1 mL) at rt. After stirring at rt for 16 hr, the reaction mixture was diluted with water (10 mL) and concentrated to remove organic solvent. The residue was acidified with sat. aq. citric acid solution to pH ~ 5 and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following condition: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 50% B to 78% B in 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 6.38 to give Example 8a (10 mg, 69%) as a white solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.82 (s, 1H), 7.64 (s, 1H), 7.22 – 7.15 (m, 1H), 6.52 – 6.50 (m, 1H), 6.47 – 6.39 (m, 1H), 6.32 (d, J = 12.0 Hz, 1H), 5.69 (d, J = 45.6 Hz, 1H), 4.43 (s, 2H), 4.19 (d, J = 14.4 Hz, 1H), 3.24 (s, 1H), 2.86 – 2.65 (m, 1H), 2.22 – 2.08 (m, 2H), 1.78 – 1.71 (m, 2H), 1.65(t, J = 18.6 Hz, 3H), 1.33 (s, 2H), 1.13 (s, 2H) ppm. Step 14b. Synthesis of ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14b). Following the same procedure as described for preparing 8-14a by replacing 8-13a with 8-13b (15 mg, 0.03 mmol), 8-14b (15 mg, 79 %) was obtained as a yellow solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 612.1 [M + 1]+. Step 15b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8b). Following the same procedure as described for preparing Example 8a by replacing 8-14a with 8-14b (16 mg, 0.025 mmol), Example 8b (10 mg, 69%) as a white solid (single diastereomer, the stereochemistry was arbitrarily assigned). Prep-HPLC condition: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 55% B to 75% B in 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.92. MS (ESI): calcd. for: C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.82 (s, 1H), 7.64 (s, 1H), 7.20 – 7.15 (m, 1H), 6.53 – 6.50 (m, 1H), 6.47 (d, J = 2.1 Hz, 1H), 6.42 – 6.31 (m, 1H), 5.69 (d, J = 45.0 Hz, 1H), 4.43 (s, 2H), 4.18 (d, J = 15.6 Hz, 1H), 3.26 (s, 1H), 2.86 – 2.65 (m, 1H), 2.19 – 2.11 (m, 2H), 1.78 – 1.71 (m, 2H), 1.66 (t, J = 6.9 Hz, 3H), 1.35 (s, 2H), 1.12 (s, 2H) ppm. Synthesis of rac-(2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1) and rac- (2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1b) Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (9A-1). A solution of 7-bromo-3-(3,3- difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-7) (20 g, 52.60 mmol), (4-fluorophenyl)boronic acid (14.72 g, 105.19 mmol), and Et3N (15.97 g, 0.16 mol) in DMF (300 mL) was treated with Cu(OAc)2 (14.33 g, 78.90 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under oxygen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (300 mL) and sat. aq. NH4Cl solution (900 mL). The resulting solution was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL x 3) and brine (300 mL), dried over anhydrous Na2SO4, and concentrated. Thie residue was dried in vacuo to give crude 9A-1 (25 g) as a black solid, which was used in the next step without purification. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 473.9 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.22 (s, 1H), 7.19 (s, 1H), 7.18 – 7.13 (m, 2H), 7.11 – 7.04 (m, 2H), 3.96 (s, 3H), 3.51 (dd, J = 11.1, 6.0 Hz, 1H), 3.10 – 2.95 (m, 1H), 2.88 – 2.77 (m, 1H), 2.15 (m, 1H), 2.05 – 1.86 (m, 1H), 1.86 – 1.74 (m, 1H), 1.61 (t, J = 18.6 Hz, 4H) ppm. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (9A-2). To a stirred solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (9A-1) (25 g, 52.71 mmol) in THF (500 mL) and H2O (500 mL) was added Oxone®(107 g, 0.31 mol) in portions at rt. The resulting mixture was stirred at rt for 16 h. The resulting mixture was filtered. The filtrate was concentrated to remove organic solvent, and the residue was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 9A-2 (24 g) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.47 (s, 1H), 7.42 (s, 1H), 7.38 – 7.24 (m, 4H), 4.00 (s, 3H), 4.09 – 3.88 (m, 1H), 3.75 (dd, J = 13.6, 12.0 Hz, 1H), 2.99 (dd, J = 12.0, 5.7 Hz, 1H), 2.01 – 1.80 (m, 4H), 1.58 (t, J = 18.9 Hz, 3H) ppm. Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-3). To a stirred solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (9A-2) (24 g, 47.40 mmol) in THF (120 mL) was added 10 M BH3•Me2S in THF (48 mL) dropwise at rt. The resulting mixture was stirred at 60 °C for 16 hr. The reaction was quenched by the addition of H2O (100 mL) at rt. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 2 / 1 (v / v) as eluent to give 9A-3 (20 g, 85.7%) as a brown solid. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ7.61 (s, 1H), 7.52 (s, 1H), 7.02 (t, J = 8.8 Hz, 2H), 6.64 (dd, J = 8.6, 4.4 Hz, 2H), 4.21 (d, J = 15.1 Hz, 1H), 3.98 (s, 3H), 3.60 (dd, J = 14.9, 3.4 Hz, 1H), 3.42 – 3.28 (m, 1H), 3.16 (s, 1H), 2.27 (s, 1H), 2.15 – 1.93 (m, 2H), 1.70 – 1.39 (m, 5H) ppm. Step 4. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-4). To a solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-3) (2.5 g, 5.07 mmol) in tetrahydrofuran (50 mL) was added dropwise LiHMDS (1 mol / L in THF) (2.8 mL, 10.15 mmol) at -78°C under N2atmosphere. The reaction mixture was stirred at -78 °C for 30 mins. Then a solution of NFSI (1.60 g, 5.07 mmol) in tetrahydrofuran (5 mL) was added dropwise and the mixture was stirred at -78 °C for 30 mins. The reaction was quenched with sat. aq. NH4Cl solution (50 mL), and then the mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as eluent to give 9A-4 (1.5 g, 57.9%) as a brown solid. MS (ESI): calcd. for C20H20BrF4NO3S: 509.0; Found: 510.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.66 (s, 1H), 7.54 (s, 1H), 7.11 – 6.96 (m, 2H), 6.66 (m, 2H), 6.12 – 5.77 (m, 1H), 4.22 – 4.11 (m, 1H), 4.05 – 3.95 (m, 3H), 3.27 – 3.12 (m, 1H), 2.68 – 2.36 (m, 1H), 2.33 – 1.90 (m, 3H), 1.73 – 1.38 (m, 4H) ppm. Step 5. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A- 5a) and rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b). To a stirred solution of rac-7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-4) (170 g, 0.33 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (384 g, 2 mol) in DMF (3.4 L) was added CuBr (95.57 g, 0.67 mol) in portions at rt under N2atmosphere. The resulting mixture was stirred at 130°C for 16 h under N2 atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (10 L) at rt. The resulting mixture was extracted with EA (3 L x 2). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as eluent to give 9A-5a (60 g, 36.1%, cis- racemate) as a yellow solid and 9A-5b (45 g, 27.1%, trans- racemate) as a yellow solid, respectively. 9A-5a: MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.67 (s, 1H), 7.10 – 7.02 (m, 23H), 6.71 – 6.60 (m, 2H), 6.10 (d, J = 44.4 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 4.06 (s, 3H), 3.22 (dd, J = 15.9, 11.4 Hz, 1H), 2.76 – 2.44 (m, 1H), 2.30 – 1.96 (m, 3H), 1.74 – 1.56 (m, 4H) ppm. 9A-5b: MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.10 (t, J = 8.7 Hz, 2H), 6.89 (s, 2H), 5.95 (dd, J = 44.1, 6.9 Hz, 1H), 4.03 (s, 3H), 4.01 – 3.59 (m, 2H), 2.45 – 2.39 (m, 1H), 2.14 – 1.89 (m, 2H), 1.86 – 1.71 (m, 1H), 1.70 – 1.55 (m, 1H), 1.49 (t, J = 18.9 Hz, 3H) ppm. Step 6a. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9- 1a). A mixture of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (60 g, 0.12 mol) (9A-5a) in DMSO (600 mL) was added LiCl (50.5 g, 1.21 mol) at room temperature. After stirring at 140°C for 16 h under nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL x 4), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 8 / 1 (v / v) as eluent to give 9-1a (43 g, 73.7%, cis- racemate) as a yellow oil. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.3 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.03 (t, J = 9.0 Hz, 2H), 6.62 (dd, J = 9.3, 4.5 Hz, 2H), 6.03 (d, J = 44.4 Hz, 1H), 4.15 (d, J = 15.9 Hz, 1H), 3.20 (dd, J = 15.9, 11.4 Hz, 1H), 2.69 – 2.60 (m, 1H), 2.22 – 2.06 (m, 2H), 1.61 (t, J = 18.9 Hz, 5H) ppm. rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) was separated by SFC (Column: (R,R)-WHELK-O1, 50*4.6 mm, 3.5 µm; Co-eluent: MeOH; Gradient (B%): 10% to 50% in 2.0 min, hold 50% for 1.0 min; Back pressure (bar): 150; Flow (mL / min): 3.0; Column temperature (oC): 35; UV detection wavelength: 220 nm) to give (2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-4) (tR = 0.43 min; single diastereomer) as a white solid; and (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (tR= 0.69 min; single diastereomer) as a white solid, respectively. Step 6b. Synthesis of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9- 1b). A mixture of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b) (45 g, 90.10 mmol) DMSO (450 mL) was added LiCl (38.19 g, 0.90 mol) at room temperature. After stirring at 140°C for 16 h under nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL x 4), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 8 / 1 (v / v) as eluent to give 9-1b (30 g, 68.6%) as a yellow oil. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 11.53 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 7.06 (t, J = 8.7 Hz, 2H), 6.86 – 6.76 (m, 2H), 5.88 (dd, J = 44.4, 7.8 Hz, 1H), 3.82 (s, 2H), 2.42 (s, 1H), 2.15 – 1.84 (m, 2H), 1.84 – 1.70 (m, 1H), 1.69 – 1.60 (m, 1H), 1.52 (t, J = 18.9 Hz, 3H) ppm. Relative stereochemistry determination of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5a) and rac-(2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b).1H,13C,19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of the cis- racemate 9A-5a and the corresponding trans- racemate 9A-5b. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H, H13), 7.53 (s, 1H, H9), 7.04 – 6.93 (m, 2H, H24&H26), 6.70 – 6.60 (m, 2H, H23&H27), 5.32 (d, J = 60.0, 1H, H16), 4.12 – 4.00 (m, 1H, H6'), 4.05 (s, 3H, H17), 3.34 (dd, J = 15.8, 11.2 Hz, 1H, H6''), 2.87 – 2.67 (m, 1H, H5), 2.13 – 1.97 (m, 2H, H3), 1.84 – 1.57 (m, 2H, H4), 1.68 (t, J = 18.4 Hz, 3H, H1) ppm.13C NMR (101 MHz, CDCl3): δ 157.15 (d, J = 240.0 Hz, C25), 155.68 (C11), 141.84 (d, J = 2.0 Hz, C22), 139.50 (14), 138.03 (C8), 129.28 (q, J = 5.0 Hz, C9), 125.64 (q, J = 32.1 Hz, C10), 123.29 (t, J = 238.7 Hz, C2), 122.11 (q, J = 273.7 Hz, C30), 116.57 (d, J = 7.6 Hz, C23&C27), 116.21 (d, J = 22.6 Hz, C24&C26), 114.07 (C13), 101.61 (d, J = 222.9 Hz, C16), 56.87 (C17), 48.50 (d, J = 2.0 Hz, C6), 37.71 (d, J = 18.6 Hz, C5), 35.00 (t, J = 26.0 Hz, C3), 23.64 (t, J = 27.7 Hz, C1), 21.78 (C4) ppm.19F NMR (376 MHz, CDCl3): δ -63.33 (F31, F32&F33), -91.54 (d, J = 240.0 Hz, F18), -92.55 (d, J = 240.1 Hz, F19), -124.24 (F28), - 197.24 (F29) ppm. F-H NOESY NMR data suggested F29 has correlation with H4 but not with H5.

[0010] 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H, H13), 7.28 (s, 1H, H9), 7.08 – 6.96 (m, 4H, H23, H24, H26&H27), 5.26 (dd, J = 44.8, 5.2 Hz, 1H, H16), 4.12 (d, J = 9.6 Hz, 1H, H6'), 4.02 (s, 3H, H17), 3.63 (d, J = 15.2 Hz, 1H, 6''), 2.47 – 2.37 (m, 1H, H5), 2.03 – 1.81 (m, 4H, H3&H4), 1.47 (t, J = 18.4 Hz, 3H, H1) ppm.13C NMR (101 MHz, CDCl3): δ 158.58 (d, J = 243.2 Hz, C25), 154.21 (C11), 143.71 (C 22), 140.51 (C8), 136.87 (C14), 126.72 (9), 125.51 (q, J = 32.1 Hz, C10), 123.63 (t, J = 238.5 Hz, C2), 122.12 (q, J = 273.8 Hz, C30), 122.00 (C23&C27), 116.52 (d, J = 22.6 Hz, C24&C26), 112.83 (C13), 101.97 (d, J = 216.1 Hz, C16), 56.78 (C17), 49.38 (C6), 41.51 (d, J = 18.7 Hz, C5), 35.31 (t, J = 25.9 Hz, C3), 23.07 (t, J = 27.6 Hz, C1), 21.12 (C4) ppm.19F NMR (376 MHz, CDCl3): δ -63.36 (F31, F32&F33), -90.41 (d, J = 247.8 Hz, F18), -91.48 (d, J = 238.7 Hz, F19), -119.97 (F28), - 176.92 (F29) ppm. F-H NOESY NMR data suggested F29 has correlation with H5 but not with H4. Examples 9a and 9b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (9a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (9b)

[0011] Step 1. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (9-2). To a stirred solution of 9-1a (30 mg, 0.06 mmol), which was prepared by following the same procedure as described for preparing the racemic 8-13 and replacing 3-fluoro-iodobenzne with 4-fluoro-iodobenzene, and cesium carbonate (40.40 mg, 0.12 mmol) in DMF (2 mL) was added ethyl 1- (bromomethyl)cyclopropane-1-carboxylate (19.20 mg, 0.09 mmol) dropwise at rt. After stirring at 80oC for 3 hr, the reaction mixture was cooled to rt, added water (10 mL), and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 4 / 1 (v / v)) to give 9-2 (30 mg, 79%) as a brown solid. MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 500.2 [M + 1]+. Step 2. Synthesis of rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (9-3). A solution of 9-2 (30 mg, 0.05 mmol) and LiOH (5.87 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 16 h. The mixture was acidified with 2 N aq. HCl solution to pH ~ 4. The resulting mixture was concentrated to remove organic solvent, diluted with water (10 mL), and extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following condition: Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 78% B in 8 min, 78% B; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.26 to give 9-3 (15 mg) as a white solid. Step 3. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9a) and 1-((((2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9b). The racemic 9-3 (15 mg) was purified by prep-SFC with the following condition: (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 25% B; Wavelength: 220 nm; RT1 (min) = 3.0; RT2 (min) = 3.5; Sample Solvent: MeOH: CAN = 2: 1 (v / v); Injection Volume: 2 mL to give Example 9a (single diastereomer, the stereochemistry was arbitrarily assigned) (4.1 mg) as a white solid. MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 7.54 (s, 1H), 6.96 (t, J = 9.0 Hz, 2H), 6.71 ‒ 6.66 (m, 2H), 5.67 (d, J = 45.3 Hz, 1H), 4.42 (s, 2H), 4.18 (d, J = 15.0 Hz, 1H), 3.27 ‒ 3.21 (m, 1H), 2.77 ‒ 2.63 (m, 1H), 2.21 ‒ 2.03 (m, 2H), 1.79 ‒ 1.57 (m, 5H), 1.31 (s, 2H), 1.07 (s, 2H) ppm; and Example 9b (single diastereomer, the stereochemistry was arbitrarily assigned) (2.2 mg) as a white solid. MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.83 (s, 1H), 7.55 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.73 ‒ 6.69 (m, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.45 (s, 2H), 4.20 (d, J = 15.6 Hz, 1H), 3.32 ‒ 3.26 (m, 1H), 2.82 ‒ 2.65 (m, 1H), 2.24 ‒ 2.07 (m, 2H), 1.79 ‒ 1.59 (m, 5H), 1.31 (s, 2H), 1.06 (s, 2H) ppm. Examples 10a and 10b.3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (10a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (10b) Step 1. Synthesis of rac- methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10-1). To a stirred solution of rac-(2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) (1.20 g, 2.47 mmol) and Cs2CO3 (2.42 g, 7.41 mmol) in DMF(50 mL) were added KI (1.23 g, 7.41 mmol) and methyl 2,2-dimethyl- 3-((methylsulfonyl)oxy)propanoate (1.04 g, 4.94 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 h. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (150 mL) at rt. The resulting mixture was extracted with EA (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc = 2 / 1 (v / v) to give 10-1 (800 mg, 54.0%) as a brown solid. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+. Step 2. Synthesis of methyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10-2a) and methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10-2b). The product rac-methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (800 mg) was purified by Prep-SFC with the following conditions: Column: (R, R)-WHELK- O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 20% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.8; RT2(min): 6.5; Sample Solvent: MeOH; Injection Volume: 9 mL. The collected fractions were concentrated, and the residue was dried in vacuo to give 10-2a (260 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) and 10-2b (240 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+. Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10a). A solution of 10-2a (260 mg, 0.43 mmol) and LiOH (31.25 mg, 1.30 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). Subsequently, the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 2.69. The collected solution was concentrated under vacuum to remove ACN and the resulting solution was lyophilized to give Example 10a (168 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.02 – 6.96 (m, 2H), 6.75 – 6.70 (m, 2H), 5.70 (d, J = 45.3 Hz, 1H), 4.29 – 4.18 (m, 3H), 3.38 – 3.34 (m, 1H), 2.80 – 2.69 (m, 1H), 2.20 – 2.07 (m, 2H), 1.79 – 1.57 (m, 5H), 1.37 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10b). A solution of 10-2b (240 mg, 0.40 mmol) and LiOH (28.85 mg, 1.20 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). Subsequently, the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 1.87. The collected solution was concentrated under vacuum to remove ACN and the resulting solution was lyophilized to give Example 10b (163 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.02 – 6.96 (m, 2H), 6.75 – 6.70 (m, 2H), 5.70 (d, J = 45.3 Hz, 1H), 4.29 – 4.18 (m, 3H), 3.38 – 3.34 (m, 1H), 2.80 – 2.66 (m, 1H), 2.20 – 2.06 (m, 2H), 1.79 – 1.57 (m, 5H), 1.37 (s, 6H) ppm. Relative stereochemistry determination of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 10b).1H,13C,19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of Example 10b. 1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H, H13), 7.57 (s, 1H, H9), 7.06 – 6.91 (m, 2H, H33&H31), 6.78 – 6.65 (m, 2H, H34&H30), 5.69 (d, J = 45.2 Hz, 1H, H18), 4.27 (d, J = 8.6 Hz, 1H, H20’), 4.23 (d, J = 8.6 Hz, 1H, H20”), 4.26 – 4.15 (m, 1H, H6’), 3.31 (dd, J = 16.0, 11.2 Hz, 1H, H6”), 2.82-2.62 (m, 1H, H5), 2.28 – 1.99 (m, 2H, H3), 1.81 – 1.65 (m, 2H, H4), 1.65 (t, J = 18.5 Hz, 3H, H1), 1.37 (s, 6H, H28&H29) ppm.13C NMR (75 MHz, CD3OD): δ 177.77 (C23), 156.90 (d, J = 237.4 Hz, C32), 154.84 (C11), 142.37 (C21), 140.35 (C14), 138.30 (C8), 129.17 (q, J = 4.6 Hz, C9), 124.97 (q, J = 31.9 Hz, C10), 123.79 (t, J = 237.6 Hz, C2), 127.33 – 116.85 (m, C36), 116.16 (d, J = 7.7 Hz, C34&C30), 115.31 (d, J = 22.7 Hz, C31&C33), 114.27 (C13), 101.98 (d, J = 219.9 Hz, C18), 75.47 (C20), 47.68 (C6), 42.65 (C22), 37.61 (d, J = 18.5 Hz, C5), 34.36 (t, J = 25.9 Hz, C3), 22.12 (t, J = 27.7 Hz, C1), 21.59 – 21.30 (m, C4), 21.19 (C28&C29).19F NMR (282 MHz, CD3OD): δ -64.47 (F37, F38&F39), -92.72 (d, J = 10.9 Hz, F26&F27), -127.48 (F35), -199.65 (F19) ppm. F-H NOESY NMR data suggested F19 has correlation with H4 but not with H5. Examples 10c and 10d.3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (10c) and 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (10d)

[0012] Step 1. Synthesis of rac-methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (9-1b). To a stirred solution of rac-(2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1b, trans- racemate) (200 mg, 0.41 mmol) and Cs2CO3 (402.73 mg, 1.24 mmol) in DMF (5 mL) were added KI (205.19 mg, 1.24 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (137.36 mg, 0.62 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at 100 °C. The mixture was allowed to cool down to room temperature, followed by adding water to quench the reaction. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-TLC (PE / EA = 5 / 1 (v / v)) to give 10A-1 (130 mg, 52.63%, trans- racemate) as a white solid. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+. Step 2. Synthesis of methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10A-2a) and methyl 3-(((2S,3S)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2b). rac- Methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-1) (90 mg) was purified by Prep- Chiral-HPLC (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 25 mL / min; Gradient: isocratic 10; Wavelength: 240 nm; RT1 (min): 5.6; RT2 (min): 7.2; Sample Solvent: EtOH--HPLC; Injection volume: 1 mL; Number of runs: 5). The collected fractions were concentrated, and the residue was dried in vacuo to give 10A-2a (25 mg, 56%, single diastereomer, MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+) and 10A-2b (24 mg, 53%, single diastereomer, MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+) as a white solid, respectively. Step 3a. Synthesis of 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10c). A solution of methyl 3-(((2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2a) (25 mg, 0.05 mmol) and LiOH (7.85 mg, 0.35 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at 50 ℃ for 12 h. Next, the mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 50% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 5.94). The collected fractions were concentrated, and the residue was lyophilized to give Example 10c (15.2 mg, 62%, single diastereomer) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 6.0 Hz, 1H), 4.26 - 4.10 (m, 3H), 3.73 - 3.59 (m, 1H), 2.45 - 2.44 (m, 1H), 2.05 - 1.75 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10d). A solution of methyl 3-(((2S,3S)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2b) (24 mg, 0.04 mmol) and LiOH (7.05 mg, 0.14 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 12 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 50% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 5.94). The collected fractions were concentrated, and the residue was lyophilized to give Example 10d (14.3 mg, 61%, single diastereomer) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 6.0 Hz, 1H), 4.26 - 4.23 (m, 2H), 4.20 - 4.11 (m, 1H), 3.74 - 3.70 (m, 1H), 2.46 - 2.44 (m, 1H), 2.05 - 1.80 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Examples 10c / d. rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid.

[0013] Step 1. Synthesis of rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10c / d). A solution of rac-ethyl 1-((((2R,3S)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (10A-1, trans- racemate) (40 mg, 0.24 mmol) in dioxane (4 mL) was treated with water (1 mL) for 3 min at room temperature under nitrogen atmosphere, followed by the addition of LiOH (47.62 mg, 2.26 mmol) dropwise at room temperature. The resulting mixture was stirred at 50℃ for 12 h. Next, the mixture was acidified to pH = 3 with concd. aq. HCl solution. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL / min mL / min; Gradient: 50% to 75 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 5.94). The collected fractions were concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 10c / d (10.4 mg, 48.6%, trans- racemate) as a white solid. MS (ESI): calcd. for C25H28F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 5.8 Hz, 1H), 4.26 - 4.13 (m, 3H), 3.74 - 3.69 (m, 1H), 2.45 - 2.41 (m, 1H), 2.05 - 1.78 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Relative stereochemistry determination of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Example 10c / d).1H,13C,19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of the trans- racemate Example 10c / d. 1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H, H13), 7.33 (s, 1H, H9), 7.12 – 6.99 (m, 4H, H34, H33 H31&H30), 5.59 (dd, J = 44.2, 5.7 Hz, 1H, H18), 4.22 (s, 2H, H20), 4.22 – 4.12 (m, 1H, H6’), 3.73 – 3.69 (m, 1H, H6”), 2.45 (s, 1H, H5), 2.05 - 1.80 (m, 4H, H4&H3), 1.45 (t, J = 18.6 Hz, 3H, H1), 1.36 (s, 6H, H28&H29) ppm.13C NMR (76 MHz, CD3OD): δ 178.06 (C23), 155.06 (d, J = 228.8 Hz, C32), 153.50 (C11), 143.96 (C21), 140.66 (C14), 138.08 (C8), 126.86 (C9), 124.86 (q, J = 31.8 Hz, C10), 126.86 – 120.46 (m, C2), 120.57 (C36), 115.81 (C31&C33), 115.51 (C30&C34), 113.16 (C13), 102.53 (d, J = 245.5 Hz, C18), 75.52 (C20), 48.77 (C6), 42.59 (C22), 41.12 (d, J = 15.2 Hz, C5), 34.86 (t, J = 25.6 Hz, C3), 22.26 – 21.27 (m, C1), 21.28 (C28&C29), 20.93 – 20.55 (C4) ppm.19F NMR (282 MHz, CD3OD): δ -64.51 (F37, F38&F39), -92.49 (F26&F27), -123.43 (F35), -178.25 (F19). F-H NOESY NMR data suggested F19 has correlation with H5 but not with H4. Examples 11a and 11b. (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (11a) and (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-methylpropanoic acid (11b)

[0014] Step 1. Synthesis of rac-methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2-methylpropanoate (11-1). To a stirred solution of rac-(2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) (1.2 g, 2.47 mmol) and DIAD (1.29 g, 9.89 mmol) in DMF (50 mL) were added triphenylphosphine (2.59 g, 9.89 mmol) and methyl (R)-3-hydroxy-2-methylpropanoate (0.58 g, 4.944 mmol) at rt under N2atmosphere. The resulting mixture was stirred at 110°C for 6 hr. The mixture was allowed to cool down to rt. The reaction was quenched with H2O at rt. The resulting mixture was extracted with EA (50 mL x 2). Next, the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 11-1 (700 mg, 48.36%) as a brown solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+. Step 2. Synthesis of methyl (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2-methylpropanoate (11-2a) and methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoate (11-2b). The product rac-methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoate (11-1) (700 mg) was purified by Prep-SFC with the following conditions: Column: (R, R)- WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 30% B; Column temperature (oC): 35; Back pressure(bar): 100; Wavelength: 220 nm; RT1(min): 3.3; RT2(min): 4.8; Sample solvent: MeOH; Injection volume: 5 mL. The collected solution was concentrated in vacuo to give 11-2a (270 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) and 11-2b (260 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+. Step 3a. Synthesis of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 11a). A solution of 11-2a (270 mg, 0.46 mmol) and LiOH (33.23 mg, 1.38 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product (300 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.05%NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 55% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 1.29. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 11a (108 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C24H24F7NO5S: 571.1; Found: 572.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97 (t, J = 8.7 Hz, 2H), 6.70 (dd, J = 9.1, 4.2 Hz, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.41 – 4.28 (m, 2H), 4.18 (d, J = 15.9 Hz, 1H), 3.28 – 3.20 (m, 1H), 3.01 – 2.93 (m, 1H), 2.77 – 2.63 (m, 1H), 2.21 – 2.04 (m, 2H), 1.81 – 1.55 (m, 5H), 1.33 (d, J = 7.2 Hz, 3H) ppm. Step 3b. Synthesis of (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 11b). A solution of 11-2b (260 mg, 0.44 mmol) and LiOH (32.02 mg, 1.33 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product (300 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 55% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 0.92. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 11b (single diastereomer, the stereochemistry was arbitrarily assigned) (106 mg) as a white solid. MS (ESI): calcd. for: C24H24F7NO5S: 571.1; Found: 572.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97 (t, J = 8.7 Hz, 2H), 6.70 (dd, J = 9.1, 4.2 Hz, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.44 – 4.30 (m, 1H), 4.28 – 4.20 (m, 1H), 4.18 (d, J = 15.9 Hz, 1H), 3.28 – 3.20 (m, 1H), 2.98 – 2.92 (m, 1H), 2.78 – 2.63 (m, 1H), 2.20 – 2.03 (m, 2H), 1.77 – 1.57 (m, 5H), 1.33 (d, J = 7.2 Hz, 3H) ppm. Examples 12a and 12b. (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (12a) and (S)-1-(((3-(3,3-difluorobutyl)-2,2- difluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (12b)

[0015] Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (12-1). A solution of 8-7 (11 g, 28.93 mmol), 1- fluoro-4-iodo- (9.63 g, 43.39 mmol), CuI (5.51 g, 28.93 mmol), and K2CO3 (11.99 g, 86.78 mmol) in DMF (110 mL) was stirred at 130 °C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to rt and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with water (200 mL x 5) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 12-1 (10.5 g, 76.5%) as a dark yellow solid. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 474.0 [M + 1]+. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (12-2). A solution of 12-1 (10.5 g, 22.14 mmol) and Oxone®(27.92 g, 166.02 mmol) in THF (200 mL) and H2O (100 mL) was stirred at rt for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (120 mL x 3). The mixture was acidified to pH 8 with sat. aq. NaHCO3. The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 12-2 (12.6 g, 89.9%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+. Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3). A solution of 12-2 (12.6 g, 24.89 mmol) and BH3·DMS (16.52 mL, 174.20 mmol) in THF (100 mL) was stirred at 60 °C for 16 h. Subsequently, the reaction mixture was allowed to cool down to 0 °C with ice- water, added MeOH (50 mL) (dropwise) at 0 °C, and concentrated under vacuum. The residue was dissolved in water (150 mL) and the resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1 (v / v)) to give 12-3 (8.2 g, 66.9%) as a light brown oil. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+. Step 4. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-4). A solution of 12-3 (2 g, 4.06 mmol) in THF (30 mL) was added with LiHMDS (2.04 g, 12.19 mmol) at -78 °C for 30 min under nitrogen atmosphere. After stirring at -78 °C for 30 min, a solution of NFSI (3.20 g, 10.16 mmol) in THF (20 mL) was added at -78 °C dropwise. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere, followed by adding water (100 mL) at 0 °C. Subsequently, the mixture was concentrated to remove organic solvent, and the residue was extracted with EtOAc (80 mL x 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 12-4 (1.6 g, 67.1%) as a yellow solid. MS (ESI): calcd. for C20H19BrF5NO3S: 527.0; Found: 528.0 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.63 (s, 1H), 7.02 (t, J = 8.4 Hz, 2H), 6.72 – 6.68 (m, 2H), 4.22 – 4.15 (m, 1H), 4.03 (s, 3H), 3.47 - 3.43 (m, 1H), 2.95 – 2.91 (m, 1H), 2.07 – 2.01 (m, 2H), 1.72 - 1.68 (m, 5H) ppm. Step 5. Synthesis of 3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-5). A solution of 12-4 (1.1 g, 2.08 mmol) in DMF (15 mL) was treated with methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (1.60 g, 8.33 mmol) and CuBr (1.79 g, 12.49 mmol) at rt under nitrogen atmosphere. After stirring at 130 °C for 16 h under nitrogen atmosphere, the mixture was cooled down to rt, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL x 5) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 12-5 (900 mg, 75.19%) as a light-yellow oil. MS (ESI): calcd. for C21H19F8NO3S: 517.1; Found: 518.0 [M + 1]+. Step 6. Synthesis of 3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-6). A solution of 12-5 (900 mg, 1.74 mmol) in DMSO (15 mL) was treated with LiCl (1.47 g, 34.78 mmol) at rt. After stirring at 140 °C for 8 h, the reaction mixture was cooled down to rt, diluted with water (50 mL), and acidified to pH 5 with citric acid (10% w / w). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL x 5) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 12-6 (700 mg, 76.0%) as a light-yellow oil. MS (ESI): calcd. for C20H17F8NO3S: 503.1; Found: 504.0 [M + 1]+. Step 7. Synthesis of ethyl 1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (12-7). A solution of 12-6 (160 mg, 0.32 mmol) in DMF (6 mL) was treated with ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane- 1-carboxylate (105.96 mg, 0.477 mmol), KI (211.04 mg, 1.27 mmol), and Cs2CO3(414.22 mg, 1.27 mmol) at rt. After stirring at 100 °C for 16 h, the mixture was cooled down to rt, diluted with water (15 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 5) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1 (v / v)) to give 12-7 (80 mg, 36.0%) as a light-yellow oil. MS (ESI): calcd. for C27H27F8NO5S: 629.1; Found: 630.1 [M + 1]+. Step 8. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (12-8a) and ethyl (S)-1-(((3-(3,3- difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (12-8b). Compound 12-7 (80 mg) was purified by prep-HPLC (Column: (R, R)-WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 30% B; Wavelength: 220 nm) to give 12-8a (35 mg), MS (ESI): calcd. for C27H27F8NO5S: 629.1; Found: 630.1 [M + 1]+and 12-8b (33 mg), MS (ESI): calcd. for C27H29F6NO5S: 593.2; Found: 630.1 [M + 1]+as a white solid, respectively. Step 9a. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 12a). A solution of 12-8a (35 mg, 0.06 mmol) in dioxane (5 mL) and H2O (1 mL) was treated with LiOH (5.33 mg, 0.23 mmol) at rt. After stirring at 40 °C for 16 h, the mixture was cooled down to rt, acidified to pH 3 with 2 N aq. HCl solution, and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 45% B to 60% B in 8 min, 60% B; Wavelength: 254 / 220 nm) to give Example 12a (18.2 mg, 53.5%) as a white solid. MS (ESI): calcd. for C25H23F8NO5S: 601.1; Found: 602.1 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.82 (s, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 6.77 (s, 2H), 4.43 (s, 2H), 4.33 - 4.21 (m, 1H), 3.59 - 3.41 (m, 1H), 3.01 - 2.81 (m, 1H), 2.17 - 1.94 (m, 3H), 1.65 - 1.56 (m, 4H), 1.37 - 1.30 (m, 2H), 1.19- 1.06 (m, 2H) ppm. Step 9b. (S)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 12b). A solution of 12-8b (33 mg, 0.05 mmol) in dioxane (5 mL) and H2O (1 mL) was treated with LiOH (5.28 mg, 0.22 mmol) at rt. After stirring at 40 °C for 16 hr, the mixture was cooled down to rt, acidified to pH 3 with 2 N aq. HCl solution, and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 45% B to 60% B in 8 min, 60% B; Wavelength: 254 / 220 nm) to give Example 12b (21.2 mg, 66.9%) as a white solid. MS (ESI): calcd. for C25H23F8NO5S: 601.1; Found: 602.1 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.83 (s, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 6.78 (s, 2H), 4.40 (s, 2H), 4.24 - 4.18 (m, 1H), 3.59 - 3.41 (m, 1H), 3.05 - 2.80 (m, 1H), 2.17 - 1.93 (m, 3H), 1.65 - 1.51 (m, 4H), 1.38 - 1.30 (m, 2H), 1.18 - 1.12 (m, 2H) ppm. Examples 13a and 13b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (13a) and (R)-1-(((3-(3,3-difluorobutyl)-7- ((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (13b) Step 1.3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-8-hydroxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (13-2) To a stirred mixture of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (13-1) (1 g, 2.04 mmol), which was prepared by following the same procedure used for preparing 1-10, replacing 2-bromo-4- trifluoromethyl-5-methoxyphenylsulfonyl chloride with 2,4-dibromo-5- methoxyphenylsulfonyl chloride, and using the racemic version of 1-7, and 3,3- difluorocyclobutanethiol (0.89 g, 7.15 mmol) in DMF (15 mL) was added NaH (55% suspension in mineral oil) (0.446 g, 18.59 mmol) portion wise at 0oC. After stirring at 0oC for 30 min and rt for 2 hr, the mixture was stirred at 70 ºC for 12 hr. subsequently, the mixture was diluted with ice water (5 mL), acidified with sat. aq. NaHSO4 solution and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water, and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep- HPLC to give 13-2 (700 mg, 66%) as a white solid. Step 2. Synthesis of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (13-3). A mixture of 13-2 (0.2 g, 0.39 mmol), cesium carbonate (0.314 g, 0.96 mmol) and methyl 1- (bromomethyl)cyclopropanecarboxylate (0.112 g, 0.58 mmol) in DMF (2 mL) was stirred at 60oC for 16 hr. The mixture was cooled to rt and filtered. The filtrate was purified by prep- HPLC to give 13-3 (0.172 g, 71%) as a white solid. Step 3. Synthesis of methyl (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3- difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (13- 3a) and methyl (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (13-3b). The racemic 13-3 (140 mg) was separated by chiral HPLC(Column: CHIRALPAK IF (250 × 21 mm, 5 µm)-II, Mobile phase: Hexane:IPA:MeOH, 80:10:10 (v / v / v); Flow Rate: 12 mL / min; Column Temperature: 24ºC; Wavelength: 205 nm. tR1 = 20.60 min (single enantiomer, the stereochemistry was arbitrarily assigned); and tR2 = 27.17 min (single enantiomer, the stereochemistry was arbitrarily assigned)) to give 13-3a (45.3 mg) and 13-3b (45.2 mg) as a white solid, respectively. Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13a). То а stirred solution of 13-3a (45.3 mg, 71.82 µmol) in THF / H2O = 4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (9.0 mg, 214.0 µmol). After stirring at rt for 12 hr, the reaction mixture was adjusted to pH ~2 using 2 N aq. HCl solution. The resulting mixture was purified by prep-HPLC to give Example 13a (24.8 mg, 56%) as a white solid (single enantiomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C28H32F4N2O5S2: 616.2; Found: 614.9 [M - 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.95 (s, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 4.21 (q, J = 9.8 Hz, 2H), 4.06 (d, J = 16.0 Hz, 1H), 3.82 (s, 2H), 3.13 (s, 1H), 2.99 (d, J = 12.4 Hz, 1H), 2.64 – 2.50 (m, 2H), 2.47 (s, 3H), 1.98 (tt, J = 16.3, 8.2 Hz, 2H), 1.83 (t, J = 7.0 Hz, 1H), 1.63 (t, J = 18.9 Hz, 4H), 1.20 (t, J = 3.5 Hz, 2H), 1.06 (q, J = 3.3 Hz, 2H) ppm. Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13b). Following the same procedure as described in Step 4a and replacing 13-3a with 13-3b (45.2 mg, 71.66 µmol), Example 13b (27.5 mg, 63%) was obtained as a white solid (single enantiomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C28H32F4N2O5S2: 616.2; Found: 614.9 [M - 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.95 (s, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 4.21 (q, J = 9.8 Hz, 2H), 4.06 (d, J = 15.9 Hz, 1H), 3.82 (s, 2H), 3.26 (s, 1H), 3.13 (s, 1H), 2.98 (s, 1H), 2.64 – 2.50 (m, 2H), 2.47 (s, 3H), 1.98 (tt, J = 16.2, 8.0 Hz, 2H), 1.83 (d, J = 8.4 Hz, 1H), 1.63 (t, J = 18.9 Hz, 4H), 1.21 (d, J = 3.0 Hz, 2H), 1.06 (s, 2H) ppm. Example 14. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid

[0016] Step 1. Synthesis of (R)-2-bromo-6-chloro-N-(5,5-difluoro-1-(phenylamino)hexan-2-yl)- 5-methoxypyridine-3-sulfonamide (14-1). To a stirred solution of (R)-5,5-difluoro-N1- phenylhexane-1,2-diamine (1-7) (1.0 g, 4.1 mmol) and TEA (1.2 g, 12.3 mmol) in DCM (20 mL) was added a solution of 2,6-dibromo-5-methoxypyridine-3-sulfonyl chloride (1.9 g, 5.3 mmol) in DCM (5 mL) at 0°C. The resulting reaction mixture was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (40 mL) and the aqueous layer was extracted with EA (40 mL x 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 5 (v / v)) to give 14-1 (1.2 g, 57%) as a yellow solid. TLC: EA / PE = 1 / 5 (v / v) (Rf: 0.4). MS (ESI): calcd. for C18H21BrClF2N3O3S: 511.0; Found: 512.1 [M + 1]+. Step 2. Synthesis of (R)-7-chloro-3-(3,3-difluorobutyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-2). To a stirred solution of 14- 1 (1.2 g, 2.4 mmol) and K2CO3(972 mg, 7.1 mmol) in DMF (30 mL) was added Cu (150 mg, 2.35 mmol) and the resulting mixture was heated at 115 °C for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl solution (100 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 14-2 (1.2 g) as a brown solid, which was used for the next step without further purification. TLC: EA / PE = 1 / 5 (v / v) (Rf: 0.5). MS (ESI): calcd. for C18H20ClF2N3O3S: 431.1; Found: 432.2 [M + 1]+. Step 3. Synthesis of (R)-7-chloro-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-3). To a stirred solution of 14-2 (1.2 g, crude product, 2.78 mmol) and Cs2CO3 (2.7 g, 8.4 mmol) in NMP (20 mL) was added MeI (1.2 g, 8.4 mmol) and the reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 4 (v / v)) to give 14-3 (1.1 g, 89%) as a yellow solid. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.4). MS (ESI): calcd. for C19H22ClF2N3O3S: 445.1; Found: 446.2 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-4). To a stirred solution of 14-3 (1.1 g, 2.5 mmol) in DMF (10 mL) was added CH3SNa (519 mg, 7.4 mmol) and the reaction mixture was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water (20 mL) and the aqueous layer was extracted with EA (25 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 4 (v / v)) to give 14-4 (450 mg, 41%) as a yellow solid. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.6). MS (ESI): calcd. for C19H23F2N3O3S2: 443.1; Found: 444.1 [M + 1]+. Step 5. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (14-5). To a stirred solution of 14-4 (50 mg, 0.11 mmol) and Cs2CO3(110 mg, 0.34 mmol) in DMF (3 mL) was added ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (50 mg, 0.23 mmol) and the reaction mixture was heated at 65oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added into water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried in vacuo to give crude 14-5 (58 mg) as a yellow solid, which was used for the next step without further purification. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.5). MS (ESI): calcd. for C26H33F2N3O5S2: 569.2; Found: 570.2 [M + 1]+. Step 6. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 14). To a stirred solution of 14-5 (58 mg, crude product, 0.10 mmol) in MeOH / H2O = 2 / 1 (v / v) 3 mL) was added NaOH (43 mg, 1.02 mmol) and the reaction mixture was stirred at rt for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3) and the combined organic extracts were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 14 (31 mg, 56%) as a white solid. TLC: EA / PE = 3 / 2 (v / v) (Rf: 0.5). MS (ESI): calcd. for C24H29F2N3O5S2: 541.2; Found: 542.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.45 (s, 1H), 7.33 ‒ 7.29 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.2 Hz,1H), 4.24 ‒ 4.04 (m, 4H), 3.79 ‒ 3.69 (m, 1H), 2.87 (s, 3H), 2.13 ‒ 1.89 (m, 6H), 1.73 ‒ 1.69 (m, 1H), 1.59 (t, J = 18.4 Hz, 3H), 1.34 ‒ 1.31 (m, 2H), 1.12 ‒ 1.09 (m, 2H) ppm. Example 15. (R)-1-(((3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-2-methyl-7-(methylthio)-1,1- dioxido-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid

[0017] Following the same procedure as that for preparing Example 14 by replacing aniline with 3- F-anuline, Example 15 was obtained (16 mg) as a white solid. TLC: EA / PE = 1 / 1 (v / v) (Rf: 0.3). MS (ESI): calcd. for C24H28F3N3O5S2: 559.1; Found: 560.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1H), 7.25 (q, J = 8.0 Hz, 1H), 6.77 ‒ 6.73 (m, 1H), 6.70 ‒ 6.65 (m, 2H), 4.27 (q, J = 10.0 Hz, 2H), 4.14 ‒ 4.07 (m, 1H), 3.91 ‒ 3.85 (m, 2H), 2.76 (s, 3H), 2.17 (s, 3H), 2.12 ‒ 1.96 (m, 2H), 1.91 ‒ 1.77 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.33 ‒ 1.31 (m, 2H), 1.11 ‒ 1.10 (m, 2H) ppm Example 16. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1- dioxido-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid Following the same procedure as that for preparing Example 14 by replacing aniline with 4- F-aniline, Example 16 was obtained (12 mg) as a white solid. TLC: EA / PE = 1 / 1 (v / v) (Rf: 0.3). MS (ESI): calcd. for C24H28F3N3O5S2: 559.1; Found: 560.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.17 ‒ 7.13 (m, 2H), 7.10 ‒ 7.04 (m, 2H), 4.27 ‒ 4.18 (m, 3H), 4.00 ‒ 3.96 (m, 1H), 3.77 ‒ 3.70 (m, 1H), 2.90 (s, 3H), 2.14 ‒ 1.92 (m, 6H), 1.71 ‒ 1.67 (m, 1H), 1.59 (t, J = 18.4 Hz, 3H), 1.31 ‒ 1.29 (m, 2H), 1.08 ‒ 1.05 (m, 2H) ppm. Examples 17a and 17b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (17a) and (R)-1-(((3-(3,3-difluorobutyl)-7- ((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3- f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (17b) Step 1. Synthesis of 3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-8-hydroxy-2- methyl-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (17-1). To a stirred mixture of 14-3 (1 g, 8.05 mmol) at -10oC in DMF (15 mL) was added NaH (55% suspension in mineral oil) (0.502 g, 20.92 mmol) portion wise. The reaction mixture was allowed to react at this temperature for 0.5 h and then stirred at rt for 2 hr. Subsequently, the temperature was raised to 70 ºC and the reaction mixture was kept under stirring for 12 hr. Next, the reaction mixture was diluted with iced water (15 mL), acidified by sat. aq. NaHSO4 solution and extracted by EtOAc (25 mL x 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 17-1 (768 mg, 64%) as an off-white solid. Step 2. Synthesis of Methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (17-2). A mixture of 17-1 (0.245 g, 0.47 mmol), cesium carbonate (0.384 g, 1.18 mmol), and methyl 1- (bromomethyl)cyclopropanecarboxylate (0.137 g, 0.71 mmol) in DMF (2.5 mL) was stirred at 60oC for 16 hr. Subsequently, the mixture was diluted with iced water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 17-2 (0.222 g, 75%) as an off-white solid. Step 3. Chiral separation of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3- difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3- f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylate (17-2). Compd.17-2 (170 mg) was separated by chiral HPLC to give 17-2a (77 mg) and 17-2b (79 mg) as a white solid, respectively. The stereochemistry of the single enantiomer was arbitrarily assigned. Prep-HPLC conditions: Column: CHIRALPAK IB (250 × 20 mm, 5 µm); Mobile phase: Hexane / IPA / MeOH = 70 / 15 / 15 (v / v / v); Flow Rate: 20 mL / min; Column Temperature: 24 ºC; and Wavelength: 205 nm. tR= 13.03 min (single enantiomer 17-2a); and tR= 18.59 min (single enantiomer 17-2b). Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17a). То а stirred solution of 17- 2a (77.3 mg, 0.12 mmol) in THF / H2O = 4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (15.3 mg, 0.36 mmol), and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 N aq. HCl solution to рН ~2. The resulting mixture was purified by prep-HPLC to give Example 17a (55.1 mg, 73%) as a white solid. MS (ESI): calcd. for C27H31F4N3O5S2: 617.2; Found: 616.2 [M – 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.41 (s, 1H), 7.43 (s, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.21 – 4.14 (m, 2H), 4.10 (d, J = 16.1 Hz, 1H), 3.96 (s, 1H), 3.68 (s, 1H), 3.38 (d, J = 16.4 Hz, 3H), 2.77 (s, 3H), 2.55 (s, 1H), 2.41 (s, 1H), 2.04 – 1.89 (m, 2H), 1.75 (s, 1H), 1.68 (d, J = 8.9 Hz, 1H), 1.59 (t, J = 18.9 Hz, 3H), 1.18 (q, J = 3.9 Hz, 2H), 1.01 (q, J = 3.9 Hz, 2H) ppm. Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17b). То а stirred solution of 17- 2b (78.9 mg, 0.12 mmol) in THF / H2O = 4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (15.6 mg, 0.37 mmol) and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 N aq. HCl solution to рН ~2. The resulting mixture was purified by HPLC to give Example 17b (53.9 mg, 71%). MS (ESI): calcd. for C27H31F4N3O5S2: 617.2; Found: 616.2 [M – 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.42 (s, 1H), 7.43 (s, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.21 – 4.14 (m, 2H), 4.10 (d, J = 15.8 Hz, 1H), 3.96 (s, 1H), 3.68 (s, 1H), 3.37 (s, 3H), 2.77 (s, 3H), 2.55 (s, 1H), 2.41 (s, 1H), 2.04 – 1.93 (m, 2H), 1.75 (s, 1H), 1.68 (d, J = 5.9 Hz, 1H), 1.59 (t, J = 18.9 Hz, 3H), 1.18 (q, J = 3.8 Hz, 2H), 1.01 (q, J = 3.8 Hz, 2H) ppm. Examples 18a and 18b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (18a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (18b) Step 1. Synthesis of 3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-methoxy-7- (methylthio)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (18-1). A solution of 8-11 (900 mg, 1.76 mmol) and MeSNa (1.23 g, 17.64 mmol) in DMF (10 mL) was stirred at 60 °C for 2 hr. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL x 3), and the combined organic extracts were washed with brine (10 mL x 1), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 / 1 (v / v)), to give 18-1 (500 mg, 59.4%) as a white solid. MS (ESI): calcd. for C21H23F4NO3S2: 477.1; Found: 478.0 [M + 1]+. Step 2. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(methylthio)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (18-2). A solution of 18-1 (500 mg, 1.05 mmol) and LiCl (443.85 mg, 10.47 mmol) in DMSO (5 mL) was stirred at 140 °C for 16 h. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1 (v / v)), to give 18- 2 (240 mg, 49.5%) as a white solid. MS (ESI): calcd. for C20H21F4NO3S2: 463.1; Found: 464.0 [M + 1]+. Step 3. Synthesis of rac-ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (18-3). To a stirred solution of 18-2 (80 mg, 0.17 mmol) and Cs2CO3(224.94 mg, 0.69 mmol) in DMF (10 mL) were added KI (114.61 mg, 0.69 mmol) and ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (57.54 mg, 0.26 mmol) dropwise at rt. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL x 3), and the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 5 / 1 (v / v)) to give 18-3 (60 mg, 59.0%) as a white solid. MS (ESI): calcd. for C27H31F4NO5S2: 589.2; Found: 590.1 [M + 1]+. Step 4. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)- 7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (18-3a) and ethyl 1-((((2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (18-3b). Compd.18-3 (60 mg) was purified by prep-Chiral-HPLC with the following conditions Column: CHIRALPAK ID, 3*25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 35 mL / min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 15.8; RT2 (min): 20.3; Sample Solvent: EtOH-HPLC; Injection Volume: 2 mL; Number of Runs: 5. The collected fractions were concentrated to dryness to give 18-3a (19 mg) (RT2 = 20.3 min, single diastereomer, the stereochemistry was arbitrarily assigned) and 18-3b (25 mg) (RT1 = 15.8 min, single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C27H31F4NO5S2: 589.2; Found: 590.2 [M + 1]+. Step 5a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 18a). A solution of 18-3a (19 mg, 0.03 mmol) and LiOH (7.72 mg, 0.32 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 24 h at 40°C. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4,and concentrated. The residue was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 4.48. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 18a (17 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H27F4NO5S2: 561.1; Found: 562.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 7.22 ‒ 7.14 (m, 2H), 6.50 ‒ 6.42 (m, 2H), 6.34 ‒ 6.30 (m, 1H), 5.58 (d, J = 45.3 Hz, 1H), 4.39 ‒ 4.32 (m, 2H), 4.16 (d, J = 15.9 Hz, 1H), 3.37 (s, 1H), 2.86 ‒ 2.72 (m, 1H), 2.41 (s, 3H), 2.23 ‒ 2.05 (m, 2H), 1.79 ‒ 1.61 (m, 5H), 1.40 ‒ 1.36 (m, 2H), 1.20 ‒ 1.17 (m, 2H) ppm. Step 5b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 18b). A solution of methyl 18-3b (25 mg, 0.04 mmol) and LiOH (10.15 mg, 0.42 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 24 h at 40°C. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 2.84. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 18b (22 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H27F4NO5S2: 561.1; Found: 562.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 7.22 - 7.14 (m, 2H), 6.50 - 6.42 (m, 2H), 6.35 - 6.29 (m, 1H), 5.58 (d, J = 45.3 Hz, 1H), 4.36 (s, 2H), 4.16 (d, J = 15.9 Hz, 1H), 3.38 (s, 1H), 2.83 - 2.72 (m, 1H), 2.41 (s, 3H), 2.23 - 2.05 (m, 2H), 1.78 - 1.61 (m, 5H), 1.40 - 1.36 (m, 2H), 1.20 - 1.17 (m, 2H) ppm.

[0018] Examples 19a and 19b.1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (19a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)- 5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (19b) Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-2). To a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-1) (3 g, 7.53 mmol), which was readily prepared by BH3 reduction of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (8-7), and 4,4-difluorocyclohexan-1- one (3.03 g, 22.60 mmol) in THF (50 mL) was added PhSiH3(2.45 g, 22.60 mmol) and Bu2SnCl2 (4.58 g, 15.06 mmol) at rt. The resulting mixture was refluxed for 24 h. The mixture was cooled to rt and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 4 / 1 (v / v), to give 19-2 (2.6 g, 66.8%) as a brown liquid. MS (ESI): calcd. for C20H26BrF4NO3S: 515.1; Found: 516.0 [M + 1]+. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-3). In a 250 mL round bottom flask, to a solution of 19-2 (2.6 g, 5.04 mmol) in THF (20 mL) was added dropwise 1M LiHMDS in THF (10.07 mL, 10.07 mmol) at -78oC under N2atmosphere. The reaction mixture was stirred at -78oC for 30 min. Then a solution of NFSI (1.59 g, 5.04 mmol) in 2 mL THF was added dropwise and the mixture was stirred for another 4 h. The reaction was quenched with sat. aq. NH4Cl solution (20 mL), and then the mixture was extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (PE / EA = 2 / 1 (v / v)) to give 19-3 (1 g, 37.2%) as a brown solid. MS (ESI): calcd. for C20H25BrF5NO3S: 533.1; Found: 534.0 [M + 1]+. Step 3. Synthesis of 3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-4). To a stirred solution of 19-3 (650 mg, 1.22 mmol) and methyl 2,2-difluoro-2-sulfoacetate (1402.05 mg, 7.30 mmol) in DMF (10 mL) was added CuBr (872.44 mg, 6.08 mmol) in portions at rt under N2atmosphere. The resulting mixture was stirred at 130°C for 16 hr under N2atmosphere. The mixture was cooled to rt and then quenched by H2O (5 mL). The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 2 / 1 (v / v), to give 19-4 (400 mg, 62.8%) as a brown solid. MS (ESI): calcd. for C21H25F8NO3S: 523.1; Found: 524.0 [M + 1]+. Step 4. Synthesis of rac-(2R,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1- dioxide (19-5). To a stirred solution of 19-4 (350 mg, 0.67 mmol) and 1-dodecanethiol (676.63 mg, 3.35 mmol) in DMF (5 mL) was added NaOMe (180.60 mg, 3.35 mmol) at rt. The resulting mixture was stirred at 100°C for 2 h under N2 atmosphere. The mixture was cooled to rt and then quenched with H2O (5 mL). The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 2 / 1 (v / v), to give 19-5 (180 mg, 52.8%) as a brown solid. MS (ESI): calcd. for C20H23F8NO3S: 509.1; Found: 510.0 [M + 1]+. Step 5. Synthesis of rac-(2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1- dioxide (19-6). To a stirred solution of 19-5 (180 mg, 0.35 mmol) in THF (10 mL) was added LiHMDS (3.50 mL, 3.5 mmol) dropwise at -40°C under N2atmosphere. The resulting mixture was stirred for 2 h at -40°C. The reaction was quenched by the addition of sat. aq. NH4Cl (100 mL) at -40°C. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 2 / 1 (v / v), to give 19-6 (120 mg, 77.0%) as a yellow solid. MS (ESI): calcd. for C20H23F8NO3S: 509.1; Found: 510.0 [M + 1]+. Step 6. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7). To a stirred solution of 19-6 (65 mg, 0.19 mmol) and Cs2CO3 (125.10 mg, 0.38 mmol) in DMF (2 mL) were added KI (42.36 mg, 0.27 mmol) and ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (179.17 mg, 0.49 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 hr. The mixture was allowed to cool down to rt and quenched with H2O (5 mL). The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 4 / 1 (v / v)) to give 19-7 (60 mg, 75.7%) as a brown solid. MS (ESI): calcd. for C27H33F8NO5S: 635.2; Found: 636.1 [M + 1]+. Step 7. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (19-7a) and ethyl 1-((((2S,3R)-3-(3,3- difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7b). Compd.19-7 (60 mg) was purified by prep-SFC with the following condition: Column: (R, R)-WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 30% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.3; RT2 (min): 4.8; Sample Solvent: MeOH; Injection Volume: 5 mL. The collected fractions were concentrated under vacuum to give 19-7a (27 mg) (RT2 = 4.8 min, single diastereomer, stereochemistry was arbitrarily assigned) and 19-7b (26 mg) (RT1 = 3.3 min, single diastereomer, stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C27H33F8NO5S: 635.2; Found: 636.1 [M + 1]+. Step 8a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 19a). A solution of 19-7a (27 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 16 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: 55% B to 78% B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 1.88. The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 19a (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H29F8NO5S: 607.2; Found: 608.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.54 (s, 1H), 5.60 (d, J = 46.2 Hz, 1H), 4.34 – 4.27 (m, 2H), 3.54 – 3.45 (m, 1H), 3.32 – 3.31 (m, 1H), 2.85 – 2.76 (m, 1H), 2.57 – 2.34 (m, 1H), 2.15 – 1.83 (m, 9H), 1.77 – 1.56 (m, 6H), 1.34 – 1.29 (m, 2H), 1.12 – 1.08 (m, 2H) ppm. Step 8b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 19b). A solution of 19-7b (26 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4,and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: 55% B to 78% B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 1.37. The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 19b (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H29F8NO5S: 607.2; Found: 608.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.54 (s, 1H), 5.60 (d, J = 46.2 Hz, 1H), 4.34 – 4.27 (m, 2H), 3.58 – 3.45 (m, 1H), 3.32 – 3.31 (m, 1H), 2.85 – 2.76 (m, 1H), 2.57 – 2.34 (m, 1H), 2.18 – 1.83 (m, 9H), 1.77 – 1.52 (m, 6H), 1.35 – 1.26 (m, 2H), 1.17 – 1.09 (m, 2H) ppm. Examples 20a and 20b.3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (20a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (20b) Step 1. Synthesis of rac-ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1). To a stirred solution of the cis- racemate 19-6 (115 mg, 0.23 mmol) and Cs2CO3 (221.32 mg, 0.68 mmol) in DMF (5 mL) were added KI (112.42 mg, 0.68 mmol) and methyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (142.37 mg, 0.68 mmol) dropwise at rt. The resulting mixture was stirred for at 100°C 16 h. The mixture was cooled to rt and quenched with H2O (5 mL). The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE / EA = 4 / 1 (v / v)) to give 20-1 (65 mg, 46.2%) as a brown solid. MS (ESI): calcd. for C26H33F8NO5S: 623.2; Found: 624.1 [M + 1]+. Step 2. Synthesis of ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (20-1a) and ethyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-5- (4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1b). Compd.20- 1 (65 mg) was purified by prep-HPLC with the following conditions: Column: CHIRALPAK IC 3*25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 25 mL / min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 4.3; RT2 (min): 5.9; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL; Number of Runs: 5. The collected fractions were concentrated under vacuum to give 20-1a (26 mg) (RT1 = 4.3 min, single diastereomer, the stereochemistry was arbitrarily assigned) and 20-1b (27 mg) (RT1 = 5.9 min, single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C26H33F8NO5S: 623.2; Found: 624.1 [M + 1]+. Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Example 20a). A solution of 20-1a (26 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: Xbridge Prep Shield RP18 5μm OBD 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 60 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 1.95. The collected fractions were concentrated under vacuum to remove ACN and the resulting solution was dried by lyophilization to give Example 20a (14 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H31F8NO5S: 609.2; Found: 610.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.5 Hz, 1 H), 4.17 (s, 2H), 3.56 ‒ 3.50 (m, 1H), 3.32 ‒ 3.18 (m, 1H), 2.88 ‒ 2.79 (m, 1H), 2.60 ‒ 2.35(m, 1H), 2.47 ‒ 1.80 (m, 9H), 1.80 ‒ 1.55(m, 6H), 1.35 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Example 20b). A solution of 20-1b (27 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: Xbridge Prep Shield RP18 5μm OBD 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40 % to 60 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 1.72. The collected fractions were concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 20b (13 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H31F8NO5S: 609.2; Found: 610.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.2 Hz, 1 H), 4.17 (s, 2H), 3.56 ‒ 3.50 (m, 1H), 3.34 ‒ 3.30 (m, 1H), 2.88 ‒ 2.79 (m, 1H), 2.60 ‒ 2.35(m, 1H), 2.47 ‒ 1.80 (m, 9H), 1.80 ‒ 1.55(m, 6H), 1.35 (s, 6H) ppm. Example 21. (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid Step 1. Synthesis of (R)-2-bromo-N-(1-((4,4-difluorocyclohexyl)amino)-5,5- difluorohexan-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (21-2). To a stirred solution of (R)-N1-(4,4-difluorocyclohexyl)-5,5-difluorohexane-1,2-diamine (21-1) (500 mg, 1.85 mmol), which was prepared by following the same procedure of 1-7 and replacing aniline with 4,4-difluorocyclohexylamine, and TEA (374 mg, 3.7 mmol) in THF (6 mL) was added a solution of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (781 mg, 2.22 mmol) in THF (2 mL) at 0°C. The resulting reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (30 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA / PE) to give 21-2 (60 mg, 55.3%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C20H26BrF7N2O3S: 586.1; Found: 587.2 [M + 1]+. Step 2. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-3). To a stirred solution of 21-2 (600 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) in DMF (5 mL) was added CuI (190 mg, 1.0 mmol) and the mixture was heated at 100 °C for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl solution (15 mL) and the aqueous layer was extracted with EA (20 mL x 3). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 21-3 (450 mg) as a yellow oil, which was used in the next step without further purification. TLC: 15% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C20H25F7N2O3S: 506.1; Found: 507.2 [M + 1]+. Step 3. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-methoxy-2- methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-4). To a stirred solution of 21-3 (450 mg, crude product, 0.89 mmol) and Cs2CO3 (580 mg, 1.78 mmol) in NMP (5 mL) was added MeI (379 mg, 2.67 mmol) and the reaction was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 21-4 (300 mg, 56%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C21H27F7N2O3S: 520.2; Found: 521.2 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-hydroxy-2- methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-5). To a stirred solution of 21-4 (300 mg, 0.58 mmol) in DMF (3 mL) was added CH3SNa (203 mg, 2.9 mmol) and the reaction was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction was quenched with ice water (12 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 21-5 (150 mg, 51%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.6). MS (ESI): calcd. for C20H25F7N2O3S: 506.1; Found: 507.2 [M + 1]+. Step 5. Synthesis of ethyl (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2,2-dimethylpropanoate (21-6). To a stirred solution of 21-5 (150 mg, 0.30 mmol) and Cs2CO3(293 mg, 0.9 mmol) in DMF (2 mL) was added ethyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (134 mg, 0.6 mmol). The reaction was heated at 100oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic layer was washed with water (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 21-6 (70 mg, 37%) as a white solid. TLC: 40% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C27H37F7N2O5S: 634.2; Found: 635.2 [M + 1]+. Step 6. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (Example 21). To a stirred solution of 21-6 (40 mg, 0.064) in MeOH / THF / H2O (1 mL / 1 mL / 0.5 mL) was added LiOH.H2O (14.3 mg, 0.34 mmol) and the reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 21 (20 mg, 53%) as a white solid. MS (ESI): calcd. for C25H33F7N2O5S: 606.2; Found: 607.3 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.26 (s, 1H), 4.09 – 4.03 (m, 2H), 3.41 (s, 2H), 3.16 (s, 2H), 2.61 (s, 2H), 2.17 (m, J = 40.2 Hz, 4H), 2.06 – 1.77 (m, 6H), 1.65 (t, J = 30.1 Hz, 5H), 1.32 (d, J = 2.1 Hz, 6H) ppm. Example 22. (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid Step 1. Synthesis of (R)-2-bromo-N-(1-(cyclopentylamino)-5,5-difluorohexan-2-yl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (22-2). To a stirred solution of (R)-N1- cyclopentyl-5,5-difluorohexane-1,2-diamine (22-1) (1.0 g, 4.5 mmol), which was prepared by following the same procedure of 1-7 and replacing aniline with cyclopentamine, and TEA (1.4 g, 13.5 mmol) in THF (10 mL) was added a solution of 2-bromo-5-methoxy-4- (trifluoromethyl)benzenesulfonyl chloride (1.9 g, 5.4 mmol) in THF (10 mL) at 0°C. The resulting reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (40 mL) and the aqueous layer was extracted with EA (40 mL x 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA / PE (v / v)) to give 22-2 (1.05 g, 49%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C19H26BrF5N2O3S: 536.1; Found: 537.2 [M + 1]+. Step 2. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-3). To a stirred solution of 22-2 (1.05 g, 2.0 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (15 mL) was added Cu (640 mg, 10.0 mmol) and heated at 115 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl (30 mL) solution, and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 22-3 (1.0 g) as a yellow oil, which was used in the next step without further purification. TLC: 15% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C19H25F5N2O3S: 456.2; Found: 457.3 [M + 1]+. Step 3. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-4). To a stirred solution of 22-3 (1.0 g, crude product, 2.0 mmol) and Cs2CO3 (2.0 g, 6.0 mmol) in NMP (20 mL) was added MeI (852 mg, 6.0 mmol) and the reaction mixture was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (50 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 22-4 (500 mg, 53%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.4). MS (ESI): calcd. for C20H27F5N2O3S: 470.2; Found: 471.3 [M + 1]+. Step 4. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-5). To a stirred solution of 22-4 (500 mg, 1.06 mmol) in DMF (10 mL) was added CH3SNa (382 mg, 5.30 mmol) and the reaction mixture was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water (20 mL) and the aqueous layer was extracted with EA (30 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 22-5 (620 mg, 64%) as a yellow solid. TLC: 30% EA / PE (v / v) (Rf: 0.6). MS (ESI): calcd. for C19H25F5N2O3S: 456.2; Found: 457.3 [M + 1]+. Step 5. Synthesis of ethyl (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (22-6). To a stirred solution of 22-5 (150 mg, 0.33 mmol) and Cs2CO3 (323 mg, 0.99 mmol) in DMF (2 mL) was added ethyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (148 mg, 0.66 mmol). The reaction was heated at 100oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic extracts were washed with water (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 22-6 (60 mg, 31%) as a white solid. TLC: 40% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for

[0019] C26H37F5N2O5S: 584.2; Found: 585.2 [M + 1]+. Step 6. Synthesis of (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 22). To a stirred solution of 22-6 (40 mg, 0.068) in MeOH / THF / H2O (1 mL / 1 mL / 0.5 mL) was added LiOH.H2O (14.3 mg, 0.34 mmol) and the reaction was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3), and the combined organic extracts were dried over anhydrous Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 22 (26 mg, 68%) as a white solid. MS (ESI): calcd. for C24H33F5N2O5S: 556.2; Found: 557.3 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.27 (s, 1H), 4.06 (dd, J = 16.5, 8.1 Hz, 2H), 3.86 (dd, J = 22.4, 15.2 Hz, 1H), 3.16 (s, 1H), 2.64 (s, 4H), 1.96 (ddd, J = 29.2, 26.0, 22.5 Hz, 5H), 1.84 – 1.42 (m, 10H), 1.32 (t, J = 23.8 Hz, 6H) ppm. Example 23.1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0020] Step 1. Synthesis of (3aR,6aS)-5,5-difluorohexahydropentalen-2(1H)-one (23-2). To a stirred solution of (3aS,6aS)-tetrahydropentalene-2,5(1H,3H)-dione (23-1) (13.8 g, 0.1 mol) in DCM (200 mL) was added DAST (48.3 g, 0.3 mol) in small portions at 0°C. After stirring at rt for 16 h, the reaction mixture was diluted with saturated aq. NaHCO3(200 ml). The reaction was extracted with EA (150 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 3 / 1 (v / v), to give 23-2 (8.0 g, 50%) as a colorless oil. TLC: 20% EA / PE (Rf: 0.4). MS (ESI): calcd. for C8H10F2O: 160.1; Found: 160.2 [M+H]+. Step 2. Synthesis of 5,5-difluorooctahydropentalen-2-ol (23-3). To a solution of 23-2 (3.16 g, 19.8 mmol) in MeOH (30 ml) was added NaBH4 (1.55 g, 40 mmol) in an ice bath. The reaction was stirred for 2 h at room temperature. The reaction was monitored by TLC. The starting material disappeared and a new spot was detected. The reaction mixture was poured into water (50 mL) and extracted with EA (70 mL x 3). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, concentrated. The residue was dried in vacuo to give crude 23-3 (2.95 g, 92%) as a colorless oil, which was used for the next step without further purification. TLC: 25% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C8H12F2O: 162.1; Found: 162.2 [M+H]+. Step 3. Synthesis of 2-(5,5-difluorooctahydropentalen-2-yl)isoindoline-1,3-dione (23-4). To a solution of 23-3 (2.95 g, 18.2 mmol), isoindoline-1,3-dione (3.21 g, 21.9 mmol), and PPh3(6.17 g, 27.3 mmol) in THF (100 ml) was added DIAD (6.62 g, 32.8 mmol) in an ice bath. The reaction was stirred at rt for 6 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography (20% EA / PE (v / v)) to give 23-4 (3.8 g, 72%) as a white solid. TLC: 15% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C16H15F2NO2: 291.1; Found: 292.3 [M+H]+. Step 4. Synthesis of 5,5-difluorooctahydropentalen-2-amine (23-5). To a solution of 23-4 (3.8 g, 13.1 mmol) in MeOH (30 ml) was added NH2NH2(4.1 g, 65.3 mmol). The reaction was stirred at 60oC for 5 h. The mixture was filtered and solid was washed with MeOH (20 mL). The filtrate was concentrated. The residue was diluted with Et2O (100 ml) and filtered. The filtrate was acidified with 4N HCl in dioxane (20 mL). After stirring for 30 min, the solution was concentrated in vacuo to give a crude product, which was mixed with ACN (40 mL). The solid was collected and dried in vacuo to give 23-5 (1.5 g, 58%) as a pale-yellow solid, which was used in the next step without further purification. TLC: 15% MeOH / DCM (v / v) (Rf: 0.3). MS (ESI): calcd. for C8H13F2N: 161.1; Found: 162.2 [M+H]+. Step 5. Synthesis of tert-butyl ((2R)-1-((5,5-difluorooctahydropentalen-2-yl)amino)-5,5- difluoro -1-oxohexan-2-yl)carbamate (23-6). To a solution of (R)-2-((tert- butoxycarbonyl)amino)-5,5-difluorohexanoic acid (1.2 g, 4.49 mmol) in DMF (15.0 ml) was added DIEA (2.0 g, 15.7 mmol) and HATU (2.56 g, 6.74 mmol) in an ice bath. After stirring for 30 min, 23-5 (885 mg, 4.49 mmol) was added. The reaction was stirred at rt for 16 h. The reaction mixture was quenched with H2O (30 ml) and extracted with EA (40 mL x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (35% EA / PE (v / v)) to give 23- 6 (1.2 g, 65%) as a colorless oil. TLC: 35% EA / PE (v / v) (Rf: 0.3). MS (ESI): calcd. for C19H30F4N2O3: 410.2; Found: 355.2 [M + H - 56]+. Step 6. Synthesis of (2R)-2-amino-N-(5,5-difluorooctahydropentalen-2-yl)-5,5- difluorohexanamide (23-7). To a solution of 23-6 (370 mg, 0.90 mmol) in DCM (9.0 ml) was added TFA (3.0 ml) in an ice bath. The reaction mixture was stirred at rt for 2 hr and concentrated. The residue was diluted with saturated aq. NaHCO3solution and extracted with DCM (30 mL x 3). The combined organic extracts were dried over Na2SO4and concentrated. The residue was dried in vacuo to give crude 23-7 (260 mg, 93%) as a yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C14H22F4N2O: 310.2; Found: 311.2 [M+H]+. Step 7. Synthesis of (2R)-N1-(5,5-difluorooctahydropentalen-2-yl)-5,5-difluorohexane- 1,2-diamine (23-8). To a solution of 23-7 (260 mg, 0.84 mmol) in THF (6 ml) was added LAH (2.5 M in THF, 1.7 ml) in an ice bath. The reaction mixture was stirred at 60oC for 16 hr and cooled to 0oC. The reaction mixture was quenched with H2O (160 mg), followed by 10% aq. NaOH solution (w / w) (160 mg) and Et2O (50 mL). The resulting mixture was dried over anhydrous Na2SO4and concentrated. The residue was dried in vacuo to give crude 23-8 (200 mg, 81%) as a yellow oil, which was used in the next step without further purification. TLC: 12% MeOH / DCM (v / v) (Rf: 0.3). MS (ESI): calcd. for C14H24F4N2: 296.2; Found: 297.1 [M+H]+. Step 8. Synthesis of 2-bromo-N-((2R)-1-((5,5-difluorooctahydropentalen-2-yl)amino)- 5,5-difluorohexan-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (23-9). To a solution of 23-8 (250 mg, 1.06 mmol) in DCM (3.0 ml) and TEA (375 mg, 3.71 mmol) was added sulfonyl chloride (373 mg, 1.06 mmol) in an ice bath. The reaction was stirred at rt for 16 hr. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (10 ml x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue which was purified by silica gel column chromatography (50% EA / PE (v / v)) to give 23-9 (400 mg, 62%) as a yellow oil. TLC: 50% EA / PE (v / v) (Rf: 0.3). MS (ESI): calcd. for C22H28BrF7N2O3S: 612.1; Found: 613.2 [M+H]+. Step 9. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-10). To a solution of 23-9 (100 mg, 0.16 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (2.0 ml) was added Cu (21 mg, 0.32 mmol) under nitrogen atmosphere. The reaction was stirred at 120oC for 16 hr. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (20 mL x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was dried in vacuo to give crude 23-10 (100 mg) as a yellow oil, which was used in the next step without further purification. TLC: 35% EA / PE (v / v) (Rf: 0.3). MS (ESI): calcd. for C22H27F7N2O3S: 532.2; Found: 533.3 [M+H]+. Step 10. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)- 8-methoxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-11). To a stirred solution of 23-10 (1.3 g, 2.44 mmol) and K2CO3(507 mg, 3.66 mmol) in NMP (13 mL) was added MeI (0.46 mL, 7.32 mmol) in portions at 0°C. After stirring at rt for 2 hr, the reaction mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EA (30 mL x 2), and the combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 3 / 1 (v / v), to give 23-11 (692 mg, 52%) as a colorless oil. TLC: 33% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C23H29F7N2O3S: 546.2; Found: 546.7 [M+H]+. Step 11. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)- 8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-12). To a solution of 23-11 (40 mg, 0.073 mmol) in DMF (0.5 ml) was added MeSNa (21 mg, 0.292 mmol), and the reaction was stirred at 100°C for 16 hr. The reaction mixture was diluted with sat aq. NH4Cl solution (10 mL), acidified to pH = 5~6 with 4 N aq. HCl solution, and extracted with EA (10 mL x 2). The combined organic extracts were washed with sat. aq. LiCl solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (60% EA / PE (v / v)) to give 23-12 (33 mg, 87%) as a colorless oil. TLC: 40% EA / PE (v / v) (Rf: 0.3). MS (ESI): calcd. for C22H27F7N2O3S: 532.2; Found: 532.8 [M+H]+Step 12. Synthesis of ethyl 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5- difluorooctahydropentalen-2-yl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (23- 13). To a solution of 23-12 (113 mg, 0.205 mmol) and Cs2CO3 (200 mg, 0.615 mmol) in DMF (1 ml) was added ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (82 mg, 0.369 mmol) at rt, and the reaction mixture was stirred at 70°C for 5 hr. Subsequently, the mixture was diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic extracts were washed with sat. aq. LiCl solution (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA / PE (v / v)) to give 23-13 (96 mg, 71%) as a white solid. TLC: 40% EA / PE (v / v) (Rf: 0.5). MS (ESI): calcd. for C29H37F7N2O5S: 658.2; Found: 659.0 [M+H]+.1H NMR (400 MHz, CD3OD): δ 7.51 (s, 1H), 7.40 (s, 1H), 4.25 (s, 2H), 4.13 (q, J = 7.1 Hz, 3H), 3.98 ‒ 3.56 (m, 1H), 3.44 ‒ 3.34 (m, 1H), 2.90 ‒ 2.49 (m, 5H), 2.39-2.16 (m, 2H), 2.17 ‒ 1.69 (m, 10H), 1.62 (t, J = 18.5 Hz, 4H), 1.30 (dd, J = 7.1, 4.2 Hz, 2H), 1.24 ‒ 1.13 (m, 3H), 1.09 (dd, J = 7.1, 4.1 Hz, 2H) ppm. Step 13. Synthesis of 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2- yl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 23). To a solution of 23-13 (20 mg, 0.030 mmol) in MeOH / THF / H2O (0.75 mL, v / v / v = 1 / 2 / 2) was added NaOH (12 mg, 0.303 mmol), and the reaction was stirred at rt for 3 hr. After completion of the reaction, the reaction mixture solution was diluted with water (5 ml), acidified to pH = 6~7 with 3N aq. HCl solution, and extracted with EA (10 mL x 2). The combined organic extracts were dried over Na2SO4and concentrated. The residue was purified by prep-HPLC to give Example 23 (10.6 mg, 56%) as a white solid. TLC: 10% MeOH / DCM (v / v) (Rf: 0.5). MS (ESI): calcd. for C27H33F7N2O5S: 630.2, Found: 631.2 [M+H]+.1H NMR (400 MHz, CD3OD): δ 7.51 (s, 1H), 7.40 (s, 1H), 4.25 (dd, J = 20.4, 9.6 Hz,2H), 4.13 (s, 1H), 4.05 ‒ 3.64 (m, 1H), 3.44 ‒ 3.34 (m, 1H), 2.88 ‒ 2.43 (m, 5H), 2.38 ‒ 2.19 (m, 2H), 2.17 ‒ 1.69 (m, 10H), 1.62 (t, J = 18.5 Hz, 4H), 1.30 (dd, J = 6.6, 3.9 Hz, 2H), 1.08 (d, J = 2.6 Hz, 2H) ppm. Examples 24a and 24b. (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (24a) and (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl- 1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (24b)

[0021] Step 1. Synthesis of tert-butyl 2-cyclopropylacetate (24-2). To a solution of 5 g (50 mmol) of cyclopropylacetic acid (24-1) in 25 ml of dichloromethane at 0oC was added a drop of DMF, followed by 6.99 g (55 mmol) of oxalyl chloride dropwise. The reaction mixture was stirred between 0°C and 10°C for 2 h and then concentrated under reduced pressure. The residue was briefly (about 5 min) dried under high vacuum and then taken up in dry THF (10 mL), and the resulting mixture was cooled to 0°C. Subsequently, 1 M potassium tert-butoxide in THF (45 mL, 45 mmol) was added dropwise, and the mixture was stirred at rt for 2 hr and then concentrated. The residue was added diethyl ether and 0.5 N aq. NaOH solution. The organic layer was dried over anhydrous MgSO4and concentrated. The residue was briefly dried in vacuo to give crude 24-2 (2.1 g, 27%) as a pale-yellow oil, which was used in the next step without further purification. Step 2. Synthesis of tert-butyl 3-(benzyloxy)-2-cyclopropylpropanoate (24-3). Compd. 24-2 (4 g, 25.6 mmol) in 30 mL of THF was added HMPA (1.38 g, 76.8 mmol) and LDA (38.4 mL, 76.8 mmoL, 2.0 mol / L in THF / n-heptane) at -78oC. After the solution was stirred at -78oC for 20 min, a solution of ((chloromethoxy)methyl)benzene (6 g, 38.4 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78oC for 2 h and then warmed to rt. After stirring at rt for 5 hr, the reaction mixture was quenched with sat. aq. NH4Cl solution (10 mL) and concentrated. The residue was diluted with DCM and washed with water. The organic layer was dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography to give 24-3 (1.8 g, 26%). Step 3. Synthesis of tert-butyl 2-cyclopropyl-3-hydroxypropanoate (24-4). A mixture of 24-3 (1 g, 3.6 mmol) and 10% Pd / C (200 mg) in MeOH (20 mL) was stirred at rt under an atmosphere of H2overnight. The mixture was filtered, and the residue was dried in vacuo to give crude 24-4 (450 mg, 67%), which was used in the next step without further purification. Step 4. Synthesis of tert-butyl 2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoate (24-5). To a solution of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-5- phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-11) (374 mg, 0.81 mmol) in toluene (4 mL) was added triphenylphosphine (637 mg, 2.43 mmol) and 24-4 (450 mg, 2.42 mmol). The solution was warmed to 110oC and then DIAD (4.9 g, 24.2) was added. After stirring at 110oC for 4 hr, the reaction mixture was cooled to rt and diluted with EA (20 mL). The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 24-5 (130 mg, 15%) as a pale-yellow solid. MS (ESI): calcd. for C30H37F5N2O5S: 632.2; Found: 633.2 [M + 1]+. Step 5. Synthesis of tert-butyl (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl- 1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin- 8-yl)oxy)propanoate (24-5a) and tert-butyl (S)-2-cyclopropyl-3-(((R)-3-(3,3- difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)propanoate (24-5b). Compd.24-5 was separated by chiral SFC to give 24-5a and 24-5b as a white solid, respectively. The stereochemistry of the 2-cyclopropyl-3-hydroxypropanoic acid moiety was arbitrarily assigned. MS (ESI): calcd. for C30H37F5N2O5S: 632.2; Found: 633.2 [M + 1]+. Step 6a. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (Example 24a). A mixture of 24-5a (80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 ml) dropwise at rt. After stirring at rt for 5 hr, the mixture was concentrated and the residue was purified by prep-HPLC to give Example 24a (35 mg, 48%). MS (ESI): calcd. for C26H29F5N2O5S: 576.2; Found: 577.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.62 (s,1H), 7.56 (s, 1H), 7.19 (t, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.75 ‒ 6.66 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.17 ‒ 4.13 (m, 1H), 3.85 ‒ 3.81 (m, 1H), 3.57 ‒ 3.52 (m, 1H), 2.62 (s, 3H), 2.13 ‒ 1.99 (m, 3H), 1.95 ‒ 1.84 (m, 1H), 1.70 ‒ 1.60 (m, 4H), 1.00 ‒ 0.70 (m, 1H), 0.65 ‒ 0.48 (m, 2H), 0.46 ‒ 0.43 (m, 2H) ppm. Step 6b. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (Example 24a). Following the same procedure for preparing Example 24a by replacing 24-5a with 24-5b (78 mg, 0.13 mmol), Example 24b (33 mg, 48%) was obtained as a white solid. MS (ESI): calcd. for C26H29F5N2O5S: 576.2; Found: 577.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.62 (s,1H), 7.56 (s, 1H), 7.19 (t, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.75 ‒ 6.66 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.17 ‒ 4.13 (m, 1H), 3.85 ‒ 3.81 (m, 1H), 3.57 ‒ 3.52 (m, 1H), 2.62 (s, 3H), 2.13 ‒ 1.99 (m, 3H), 1.95 ‒ 1.84 (m, 1H), 1.70 ‒ 1.60 (m, 4H), 1.00 ‒ 0.70 (m, 1H), 0.65 ‒ 0.48 (m, 2H), 0.46 ‒ 0.43 (m, 2H) ppm. Example 25. (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2- methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- methylpropanoic acid Step 1. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-7- vinyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-2). (R)-7-bromo-3- (3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-1) (400 mg, 0.79 mmol), which was readily prepared by following the procedure for preparing 1-10 by replacing aniline with 4- fluoroaniline and 2-bromo-4-trifluoromethyl-5-methyoxybenzene sulfonyl chloride with 2,4- dibromo-5-methyoxybenzene sulfonyl chloride, in dioxane (4 mL) was added Pd(dppf)Cl2 (57 mg, 0.079 mmol), Na2CO3 (251 mg, 2.37 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (365 mg, 2.37 mmol) at rt under N2. The mixture was stirred at 100oC overnight, diluted with water (15 mL) at rt, and extracted with EA (15 mL x 3). The organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA / PE as eluent to give 25-2 (300 mg, 84%) as a pale-yellow solid. MS (ESI): calcd. for C22H25F3N2O3S: 454.2; Found: 455.2 [M + 1]+. Step 2. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-7-carbaldehyde 1,1-dioxide (25-3). To a mixture of 25-2 (300 mg, 0.66 mmol) in dioxane / H2O (4 / 1 (v / v), 6 mL) were added osmium tetraoxide (2.5% wt in t-BuOH, 336 mg, 0.033 mmol) and sodium periodate (570 mg, 2.64 mmol) at rt. After stirring at rt for 3 hr, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined extracts were dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography using EA / PE as eluent to give 25-3 (240 mg, 80%) as a pale-yellow solid. MS (ESI): calcd. for C21H23F3N2O4S: 456.1; Found: 457.2 [M + 1]+. Step 3. Synthesis of (R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-8- methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-4). To a solution of 25-3 (220 mg, 0.48 mmol) in DCM (3 mL) was added DAST (387 mg, 2.4 mmol) at rt. After stirring at rt for 2 days, the reaction mixture was poured into sat. aq. NaHCO3solution (20 mL). The resulting mixture was extracted with DCM (15 mL x 3), and the combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 25-4 (180 mg, 78%) as a brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C21H23F5N2O3S: 478.1; Found: 479.1 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-hydroxy-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-7-carbaldehyde 1,1-dioxide (25-5). Compd.25-4 (180 mg, 0.31 mmol) was added to a solution of NaSMe in DMF (100 mg / mL, 1.08 mL) at rt. After stirring at 100oC for 3 hr, the reaction mixture was diluted with water (10 mL) at rt and then extracted with EA (15 mL x 2). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA / PE as eluent to give 25-5 (150 mg, 85%) as a pale-yellow solid. MS (ESI): calcd. for C20H21F3N2O4S: 442.1; Found: 443.1 [M + 1]+. Step 5. Synthesis of (R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-8- hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-6). To a mixture of 25-5 (130 mg, 0.29 mmol) in DCM (3 mL) was added DAST (387 mg, 2.4 mmol) at rt. After stirring at rt for 2 days, the reaction mixture was poured into sat. aq. NaHCO3solution (20 mL), and the resulting mixture was extracted with DCM (15 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 25-6 (130 mg) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H21F5N2O3S 464.1; Found: 465.1 [M + 1]+. Step 6. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4- fluorophenyl)-2-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoate (25-7). A solution of 25-6 (130 mg, 0.28 mmol) in toluene (1.5 mL) was added methyl (R)-3-hydroxy-2-methylpropanoate (165 mg, 1.4 mmol) and triphenylphosphine (221 mg, 0.84 mmol) at rt. After the solution was warmed to 110oC, DIAD (565 mg, 2.8 mmol) was added, and the resulting reaction mixture was stirred at 110oC for 5 hr. Subsequently, the mixture was concentrated, and the residue was purified by silica gel column chromatography using EA / PE as eluent to give 25-7 (130 mg, 82%) as a pale-yellow solid. MS (ESI): calcd. for C25H29F5N2O5S :564.2; Found: 565.1 [M + 1]+. Step 7. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4- fluorophenyl)-2-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoic acid (Example 25). To a solution of 25-7 (130 mg, 0.23 mmol) in THF / H2O (4:1 (v / v), 5 ml) was added LiOH.H2O (97 mg, 2.3 mmol) at rt. After stirring at rt overnight, the reaction mixture was adjusted to pH = 2~3 with 10% aqueous HCl solution. The resulting mixture was extracted with EA (10 mL x 2), and the combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by pre-HPLC to give Example 25 (8 mg, 6.3%) as a white solid. MS (ESI): calcd. for C24H27F5N2O5S: 550.2; Found: 551.2 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 6.8 Hz, 1H), 7.37 (s, 1H), 6.94 (t, J = 8.6 Hz, 2H), 6.81 (s, 1H), 6.69 (d, J = 11.7 Hz, 2H), 4.36 – 4.25 (m, 1H), 4.21 (dd, J = 8.8, 5.3 Hz, 1H), 3.95 (d, J = 15.6 Hz, 2H), 3.41 (s, 1H), 3.06 (dd, J = 12.4, 6.9 Hz, 1H), 2.64 (s, 3H), 2.14 – 1.71 (m, 11H), 1.61 (t, J = 18.4 Hz, 5H), 1.37 (d, J = 7.2 Hz, 4H) ppm. Example 26. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methyl-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0022] Step 1. Synthesis of methyl 4-fluorobicyclo[2.2.2]octane-1-carboxylate (26-2). Into a 250 mL 3-necked round-bottom flask were added 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1- carboxylic acid (26-1) (10 g, 47.12 mmol), water (100 mL), and Selectfluor (33.38 g, 94.23 mmol) at rt. The resulting mixture was stirred at 70°C for 24 hr under nitrogen atmosphere. The mixture was cooled to rt and acidified to pH = 5 with sat. aq. citric acid solution. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-2 (8 g, 91.2%) as a white solid, which was used in the next step without further purification. MS (ESI): calcd. for C10H15FO2: 186.1; Found: 187.1 [M + 1]+. Step 2. Synthesis of 4-fluorobicyclo[2.2.2]octane-1-carboxylic acid (26-3). Into a 250 mL round-bottom flask were added 26-2 (8 g, 42.96 mmol), THF (80 mL), water (10 mL), and LiOH (3.09 g, 128.87 mmol) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The mixture was acidified to pH = 5 with 2 N aq. HCl solution and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-3 (7 g, 94.6%) as a colorless oil, which was used in the next step without further purification. MS (ESI): calcd. for C9H13FO2: 172.1; Found: 173.1 [M + 1]+. Step 3. Synthesis of tert-butyl N-{4-fluorobicyclo[2.2.2]octan-1-yl}carbamate (26-4). Into a 250 mL round-bottom flask were added 26-3 (7 g, 40.65 mmol), 2-methyl-2-propanol (70 mL), DPPA (16.78 g, 60.98 mmol), and TEA (12.34 g, 121.95 mmol) at rt. The resulting mixture was stirred at 85 °C for 24 hr under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (100 mL), and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-4 (9 g, 91.0%) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C13H22FNO2: 243.2; Found: 244.3 [M + 1]+. Step 4. Synthesis of 4-fluorobicyclo[2.2.2]octan-1-amine (26-5). Into a 250 mL round- bottom flask were added 26-4 (9 g, 36.99 mmol) and HCl (gas) in dioxane (4 M, 90 mL) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The resulting mixture was diluted with water (90 mL), basified to pH = 8 with sat. aq. NaHCO3, and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-5 (5 g, 94.40%) as a white solid, which was used in the next step without further purification. MS (ESI): calcd. for C8H14FN: 143.1; Found: 144.2 [M + 1]+. Step 5. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (26-7). Into a 500 mL 3-necked round-bottom flask were added 1-(tert-butyl) 2-methyl (R)-5- oxopyrrolidine-1,2-dicarboxylate (30 g, 123.33 mmol), THF (300 mL), and 3 M MeMgBr solution in diethyl ether (17.65 g, 147.99 mmol) at -55°C. The resulting mixture was stirred at -20°C for 18 hr under nitrogen atmosphere. The reaction was quenched with sat. aq. NH4Cl at 0 °C and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1 (v / v)), to give 26-7 (20 g, 62.5%) as a colorless oil. MS (ESI): calcd. for: C12H21NO5: 259.1; Found: 331.1 [M + Na + ACN]+. Step 6. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (26-8). Into a 500 mL 3-necked round-bottom flask were added 26-7 (20 g, 77.13 mmol), DCM (200 mL), and DAST (37.30 g, 231.39 mmol) at 0°C. The resulting mixture was stirred at rt for 12 h under nitrogen atmosphere. The reaction was quenched with sat. aq. NaHCO3at 0°C and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (8 / 1 (v / v)), to give 26-8 (2.8 g, 12.9%) as a colorless oil. MS (ESI): calcd. for: C12H21F2NO4: 281.1; Found: 282.1 [M + 1]+. Step 7. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (26- 9). Into a 100 mL 3-necked round-bottom flask were added 26-8 (2.8 g, 9.95 mmol), THF (30 mL), water (7.5 mL), and LiOH (0.72 g, 29.86 mmol) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The mixture was acidified to pH = 5 with 1 N aq. HCl solution and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-9 (2.5 g) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C11H19F2NO4: 267.1; Found: 253.1 [M – Boc +1]+. Step 8. Synthesis of tert-butyl (R)-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octan-1- yl)amino)-1-oxohexan-2-yl)carbamate (26-10). Into a 50 mL 3-necked round-bottom flask were added 26-9 (2.5 g, 9.35 mmol), DMF (25 mL), HATU (4.27 g, 11.22 mmol), DIEA (1.81 g, 14.03 mmol), and 26-5 (1.61 g, 11.22 mmol) at rt. The resulting mixture was stirred at rt for 4 hr under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-10 (2.3 g, 62.6%) as a brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C19H31F3N2O3: 392.2; Found: 393.2 [M + 1]+. Ste®. Synthesis of (R)-2-amino-5,5-difluoro-N-(4-fluorobicyclo[2.2.2]octan-1- yl)hexanamide (26-11). Into a 100 mL round-bottom flask were added 26-10 (2.3 g, 5.86 mmol) and HCl in EtOAc (2 M, 25 mL) at rt. The resulting mixture was stirred at rt for 16 hr under nitrogen atmosphere. The mixture was basified to pH = 8 with saturated aq. NaHCO3solution. The resulting mixture was extracted with EtOAc (25 mL x 2). The combined organic extracts were washed with brine (25 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-11 (1.6 g, 93.4%) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C14H23F3N2O: 292.2; Found: 293.2 [M + 1]+. Step 10. Synthesis of (R)-2-((2,4-dibromo-5-methoxyphenyl)sulfonamido)-5,5-difluoro- N-(4-fluorobicyclo[2.2.2]octan-1-yl)hexanamide (26-12). Into a 50 mL round-bottom flask were added 26-11 (1.8 g, 6.16 mmol), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (2.69 g, 7.39 mmol), THF (18 mL), and TEA (1.87 g, 18.47 mmol) at rt. The resulting mixture was stirred at rt for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1 (v / v)) to give 26-12 (1.5 g, 39.3%) as a yellow solid. MS (ESI): calcd. for C21H27Br2F3N2O4S: 618.0; Found: 618.9 [M + 1]+. Step 11. Synthesis of (R)-2,4-dibromo-N-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octan-1- yl)amino)hexan-2-yl)-5-methoxybenzenesulfonamide (26-13). Into a 50 mL round-bottom flask were added 26-12 (1.5 g, 2.42 mmol), THF (30 mL), and BH3•Me2S (0.75 mL, 7.91 mmol) at rt. The resulting mixture was stirred at 75°C for 16 h under nitrogen atmosphere. The reaction was quenched with MeOH at 0°C. The resulting mixture was stirred at 75°C for 2 h. The mixture was cooled to rt and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1 (v / v)), to give 26-13 (1.0 g, 68.2%) as a brown solid. MS (ESI): calcd. for C21H29Br2F3N2O3S: 604.0; Found: 605.0 [M + 1]+. Step 12. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1- yl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26-14). Into a 40 mL vial were added 26-13 (1.0 g, 1.65 mmol), DMSO (10 mL), K2CO3 (0.69 g, 4.947 mmol), and CuI (0.16 g, 0.83 mmol) at rt. The resulting mixture was stirred at 130°C for 16 h under nitrogen atmosphere. The mixture was cooled to rt and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1 (v / v)) to give 26-14 (200 mg, 23.1%) as a brown solid. MS (ESI): calcd. for C21H28BrF3N2O3S: 524.1; Found: 525.1 [M + 1]+. Step 13. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1- yl)-8-methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26- 15). Into an 8 mL vial were added 26-14 (200 mg, 0.38 mmol), DMF (2 mL), Cs2CO3 (373.21 mg, 1.14 mmol), and MeI (64.83 mg, 0.46 mmol) at rt. The resulting mixture was stirred at rt for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1 (v / v)) to give 26-15 (145 mg, 70.6%) as a brown oil. MS (ESI): calcd. for C22H30BrF3N2O3S: 538.1; Found: 539.1 [M + 1]+. Step 14. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)-8- hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (26-16). Into an 8 mL vial were added 26-15 (90 mg, 0.17 mmol), DMF (3 mL), and MeSNa (64.31 mg, 0.92 mmol) at rt. The resulting mixture was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (20 mL x 4). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1 (v / v)), to give 26-16 (50 mg, 60.8%) as a brown solid. MS (ESI): calcd. for C22H31F3N2O3S2: 492.2; Found: 493.2 [M + 1]+. Step 15. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan- 1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (26-17). Into an 8 mL vial were added 26-16 (50 mg, 0.10 mmol), DMF (1 mL), ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (25.22 mg, 0.12 mmol), and Cs2CO3(99.52 mg, 0.30 mmol) at rt. The resulting mixture was stirred at 80°C for 16 h under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1 (v / v)), to give 26-17 (8 mg, 12.7%) as a brown solid. MS (ESI): calcd. for C29H41F3N2O5S2: 618.2; Found: 619.2 [M + 1]+. Step 16. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)- 2-methyl-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 26). Into an 8 mL vial were added 26-17 (8 mg, 0.01 mmol), LiOH (0.93 mg, 0.04 mmol), water (1 mL) and THF (4 mL) at rt. The resulting mixture was stirred at rt for 2 h under nitrogen atmosphere. The resulting mixture was acidified to pH 3 with 2 N aq. HCl solution and concentrated. The residue was purified by Chiral-Prep-HPLC with the following conditions: Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 um; Mobile 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): 0.82; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 26 (2.5 mg, 32.7%) as a white solid. MS (ESI): calcd. for C27H37F3N2O5S2: 590.2; Found: 591.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.26 (s, 1H), 7.06 (s, 1H), 4.35 ‒ 4.14 (m, 2H), 3.89 (s, 1H), 2.59 (dd, J = 16.0, 10.4 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 2.18 (d, J = 11.2 Hz, 3H), 2.03 (s, 2H), 1.94 ‒ 1.87 (m, 9H), 1.77 ‒ 1.51 (m, 6H), 1.32 (s, 2H), 1.13 (s, 2H) ppm. Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9)

[0023] Step 1. Synthesis of (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane-1,5-dione (27-2). Into a 50 L 4-necked round-bottom flask were added 5-oxohexanoic acid (27-1) (1.113 kg, 8.56 mol), THF (24 L) and TEA (0.95 kg, 9.40 mol) at room temperature. To the above mixture was added pivaloyl chloride (1.14 kg, 9.40 mol) dropwise at 5 °C over 2 h. The resulting mixture was stirred for an additional 2 h at room temperature. Into a 20 L 4-necked round- bottom flasks were added (4R)-4-benzyl-1,3-oxazolidin-2-one (1.44 kg, 8.12 mol) and THF (16 L) at room temperature. To the above mixture was added n-BuLi (3.25 L, 8.12 mol) dropwise at -50°C over 4 h. The resulting mixture was stirred at -50 °C for an additional 1 h. Then the lithium reagent was transferred to the mixed anhydride via cannula, with the 50 L flasks under reduced pressure. The resulting mixture was stirred at -20°C for 4 h under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 L). The resulting mixture was washed with aq. NaHCO3 solution (20 L x 2) and brine (20 L x 2), dried over anhydrous Na2SO4, and concentrated. The residue was triturated PE / EA = 20 / 1 (v / v) (60 L) three times. The precipitate was collected and dried in vacuo to give 27-2 (1.7 kg, 68.7%) as a white solid. MS (ESI): calcd. for C16H19NO4: 289.1; Found: 290.1 [M + 1]+. Step 2. Synthesis of (R)-4-benzyl-3-(5,5-difluorohexanoyl)oxazolidin-2-one (27-3). Into a 2 L 3-necked round-bottom flask were added(R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane- 1,5-dione (27-2) (200 g, 691.25mol) and DCE (600 mL) at room temperature. To the above mixture was added BAST (382.33 g, 1728.13 mol) at room temperature. The resulting mixture was stirred at 70 °C for an additional 6 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with DCM (1 L). The reaction was slowly poured into sat. aq. NaHCO3 solution. The resulting mixture was extracted with DCM (1 L x 2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / THF (10:1 (v / v)) to give 27-3 (153 g, 71.1%) as a brown oil. MS (ESI): calcd. for C16H19F2NO3: 311.1; Found: 312.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.38 – 7.16 (m, 5H), 4.66 (tt, J = 7.8, 3.1 Hz, 1H), 4.33 (t, J = 8.5 Hz, 1H), 4.19 (dd, J = 8.8, 2.9 Hz, 1H), 3.09 – 2.76 (m, 4H), 2.05 – 1.83 (m, 2H), 1.83 – 1.70 (m, 2H), 1.62 (t, J = 18.9 Hz, 3H) ppm. Step 3. Synthesis of (R)-4-benzyl-3-((S)-2-((benzyloxy)methyl)-5,5- difluorohexanoyl)oxazolidin-2-one (27-4). A solution of (R)-4-benzyl-3-(5,5- difluorohexanoyl)oxazolidin-2-one (27-3) (1015 g, 3.26 mol) in DCM (9.1 L) was treated with TiCl4(649.28 g, 3.42 mol) at 0°C under nitrogen atmosphere. The mixture was stirred for 30 min at 0°C. The solution was treated with TEA (362.90 g, 3.59 mol) dropwise at 0°C under nitrogen atmosphere, then stirred at 0°C for 2 h. The mixture was followed by the addition of ((chloromethoxy)methyl)benzene (1021 g, 6.52 mol) dropwise at 0°C and stirred at 0°C for 2 h. The reaction was quenched with sat. aq. NH4Cl solution (3.5 L) at 0°C. The resulting mixture was separated, and the aqueous layer was extracted with DCM (2 L x 2). The combined organic layers were washed with sat. aq. NaHCO3(5 L x 2) solution and brine (5 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by trituration with PE / EA = 30 / 1 (v / v) (60 L x 3). The precipitate was collected and dried in vacuo to give 27-4 (1160 g) as a light brown solid, which was used in the next step directly without further purification. MS (ESI): calcd. for C24H27F2NO4: 431.2; Found: 432.2[M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.43 – 7.17 (m, 10H), 4.75 (ddt, J = 9.3, 7.9, 3.3 Hz, 1H), 4.57 (s, 2H), 4.29 – 4.17 (m, 2H), 4.16 (dd, J = 9.1, 3.2 Hz, 1H), 3.80 (dd, J = 9.2, 7.1 Hz, 1H), 3.71 (dd, J = 9.2, 5.3 Hz, 1H), 3.25 (dd, J = 13.5, 3.4 Hz, 1H), 2.70 (dd, J = 13.5, 9.3 Hz, 1H), 2.07 – 1.92 (m, 1H), 1.96 – 1.86 (m, 1H), 1.89 – 1.72 (m, 1H), 1.61 (t, J = 18.4 Hz, 3H) ppm. Step 4. Synthesis of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoic acid (27-5). A solution of (R)-4-benzyl-3-((S)-2-((benzyloxy)methyl)-5,5-difluorohexanoyl)oxazolidin-2- one (27-4) (1000 g, 2.32 mol) in THF (12 L) and H2O (2 L) was treated with H2O2 (1051 g, 9.27 mol, 30%) dropwise at 0°C for 30 min under nitrogen atmosphere. The mixture was stirred at 0°C for 30 min, then treated with LiOH.H2O (194.49 g, 4.64 mol) in H2O (2 L) dropwise at 0°C. The resulting mixture was stirred at 0°C for 2 h. The reaction was quenched by the addition of Na2SO3(5 L) at 0°C, then concentrated under vacuum. The resulting solution was adjusted to pH = 12 with 1 N aq. NaOH solution and extracted with DCM (5 L x 3). The water layer was adjusted to pH = 2 with sat. aq. HCl solution (4 M). The resulting solution was extracted with EtOAc (6 L x 4). The combined organic extracts were washed with brine (15 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-5 (600 g) as a light-yellow oil, which was used in the next step directly without further purification. MS (ESI): calcd. for C14H18F2O3: 272.1; Found: 273.1 [M + 1]+. Step 5. Synthesis of methyl (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoate (27-6). A solution of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoic acid (27-5) (1.80 kg, 6.6 mol) in MeOH (9 L) was treated with SOCl2(1.65 kg, 13.88 mol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1 (v / v)) to give 27- 6 (1.5 kg, 81.4%) as a brown oil. MS (ESI): calcd. for C15H20F2O3: 286.1; Found: 287.1[M + 1]+. Step 6. Synthesis of methyl (S)-5,5-difluoro-2-(hydroxymethyl)hexanoate (27-7). Into a 20 L autoclave were added a solution of methyl (S)-2-((benzyloxy)methyl)-5,5- difluorohexanoate (27-6) (750 g, 2619.5 mmol) in MeOH (15 L) and Pd / C (111.50 g, 10%, wet.) at room temperature. The resulting mixture was stirred at 60°C for 18 h under hydrogen atmosphere (30 atm). The resulting mixture was filtered, and the filter cake was washed with MeOH (1 L x 4). The filtrate was concentrated, and the residue was dried in vacuo to give 27-7 (460 g, 89.5%) as a light-yellow oil. MS (ESI): calcd. for C8H14F2O3: 196.1; Found: 197.1 [M + 1]+. Step 7. Synthesis of methyl (S)-5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (27-8). A solution of methyl (S)-5,5-difluoro-2-(hydroxymethyl)hexanoate (27-7) (441 g, 2.25 mol) and TEA (455 g, 4.50 mol) in DCM (5 L) was treated with MsCl (309 g, 2.70 mol) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water at 0°C, then extracted with DCM (1 L x 3). The combined organic layers were washed with brine (4 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-8 (575 g) as a light- brown liquid, which was used for the next step without further purification. Step 8. Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9). The solution of methyl (S)-5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (27-8) (1150 g, 4.38 mol) and LiBr (1.52 kg, 17.50 mol) in Acetone (12 L) was stirred at 60°C for 3 h. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The resulting organic mixture was diluted with EtOAc (10 L), washed with water (4 L x 3) and brine (5 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-9 (1020 g, 88.2%) as a light-brown liquid, which was used in the next step directly without further purification.1H NMR (300 MHz, CD3OD): δ 3.75 (s, 3H), 3.64 (dd, J = 6.0, 1.8 Hz, 2H), 2.96 – 2.85 (m, 1H), 2.00 – 1.77 (m, 4H), 1.61 (t, J = 18.6 Hz, 3H) ppm. Following the same procedure for 151-8a cis-racemate by replacing methyl 2- (bromomethyl)-5,5,5-trifluoropentanoate (151-7) with methyl (R)-2-(bromomethyl)-5,5- difluorohexanoate (27-9), (2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Example 10b) was obtained as a single diastereomer. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (28-5)

[0024] Step 1. Synthesis of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2). To a solution of iodocopper (15.96 g, 84.07 mmol) in tetramethylene sulfone was added cesium fluoride (33.2 g, 218.6 mmol) and 2-methoxy-1-iodo-4-nitrobenzene (28-1) (24.0 g, 84.1 mmol). The resulting solution was stirred at 45°C. Then trimethyl(trifluoromethyl)silane (31.05 g, 218.6 mmol) was added dropwise at 45°C and stirred at room temperature overnight. Subsequently, the mixture was diluted with water and the resulting mixture was extracted with MTBE (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EtOAc / hexanes as eluent to give 28-2 (8 g, 43%) as a yellow solid. Step 2. Synthesis of 3-methoxy-4-(trifluoromethyl)aniline (28-3). To a solution of 2- methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2) (8.0 g, 35.85 mmol) in MeOH was added palladium (379.68 mg, 3.59 mmol). The resulting mixture was hydrogenated at ambient pressure and ambient temperature for 4 h. The mixture was filtered, and the filtrate was concentrated. The residue was dried in vacuo to give 28-3 (5 g, 73%), which was used in the next step without further purification. Step 3. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4). То а solution of 3-methoxy-4-(trifluoromethyl)aniline (28-3) (5.0 g, 26.17 mmol) in ACN (100 mL) was added 1-bromopyrrolidine-2,5-dione (4.63 g, 26.17 mmol) at -20°C. After stirring at rt overnight, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 mL). The mixture was washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 28-4 (6 g, 85%) as a yellow solid. Step 4. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (28-5). A mixture of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4) (6.0 g, 22.31 mmol) in sat. aq. HCl solution (8.03 g, 223.09 mmol) and water (100 mL) was added a solution of sodium nitrite (1.85 g, 26.77 mmol) in water (5 mL) at -10°C. After stirring at rt for 1 h, the mixture was added to a mixture of sulfuryl dichloride (26.3 g, 223.09 mmol) and copper chloride (218.4 mg, 2.23 mmol) in water (200 mL) at 0oC. The resulting mixture was stirred at rt for 2 h and diluted with DCM (50 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic extracts were washed with water (50 mL) and saturated aqueous NaHCO3(50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 28-5 (3 g, 38%). Examples 151a and 151b.3-(((2S,3R)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (151a) and 3-(((2R,3S)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (151b) Step 1. Synthesis of diethyl 2-(3,3,3-trifluoropropyl)malonate (151-2). Into a 500 mL 3- necked round-bottom flask were added diethyl malonate (25 g, 156.08 mmol) and tetrahydrofuran (250 mL) at 0°C. To the above mixture was added NaH (60% in oil, 3.12 g, 78.04 mmol) in portions at 0 °C over 10 min. The resulting mixture was stirred for an additional 30 min at rt. To the above mixture was added 1,1,1-trifluoro-3-iodopropane (17.48 g, 78.04 mmol) dropwise at rt over 5 min. The resulting mixture was stirred at 80 °C for 24 h. The reaction was monitored by LC-MS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (450 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (40:1 (v / v)) to give 151-2 (30 g, 75.2%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ 4.29 – 4.13 (m, 4H), 3.39 (t, J = 6.6 Hz, 1H), 2.27 – 2.07 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H) ppm. Step 2. Synthesis of 2-(ethoxycarbonyl)-5,5,5-trifluoropentanoic acid (151-3). Into a 500 mL 3-necked round-bottom flask were added diethyl 2-(3,3,3-trifluoropropyl)malonate (151- 2) (25 g, 97.57 mmol), EtOH (250 mL) and KOH (6.02 g, 107.33 mmol) at rt. The resulting mixture was stirred at rt for 8 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was acidified to pH = 2 with aq. HCl solution (2 M). The resulting mixture was extracted with EtOAc (150 mL x 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1 (v / v)) to give 151-3 (21 g, 94.3%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 8.65 (br.s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.7 Hz, 1H), 2.39 – 2.06 (m, 4H), 1.30 (t, J = 7.0 Hz, 3H) ppm. Step 3. Synthesis of 5,5,5-trifluoro-2-(hydroxymethyl)pentanoic acid (151-4). To a stirred solution of 2-(ethoxycarbonyl)-5,5,5-trifluoropentanoic acid (151-3) (20 g, 87.66 mmol) in i- PrOH (200 mL) was added LiBH4(2 M in THF, 87.70 mL, 175.40 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt for 3 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was acidified to pH = 2 with aq. HCl solution (2 N). The resulting mixture was extracted with EtOAc (200 mL x 5). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (4:1 (v / v)) to give 151-4 (15 g, 91.9%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 6.38 (br.s, 2H), 3.93 – 3.77 (m, 2H), 2.74 – 2.59 (m, 1H), 2.37 – 2.07 (m, 2H), 2.06 – 1.75 (m, 2H) ppm. Step 4. Synthesis of methyl 5,5,5-trifluoro-2-(hydroxymethyl)pentanoate (151-5). Into a 500 mL 3-necked round-bottom flask were added 5,5,5-trifluoro-2-(hydroxymethyl)pentanoic acid (151-4) (20 g, 107.45 mmol), H2SO4 (6.32 g, 64.47 mmol) and MeOH (200 mL) at rt. The resulting mixture was stirred at 60 °C for 4 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 4 / 1 (v / v) to 151-5 (21 g, 97.6%) as a yellow liquid.1H NMR (300 MHz, CDCl3): δ 3.80 (dd, J = 5.4, 2.7 Hz, 2H), 3.75 (s, 3H), 2.70 – 2.56 (m, 1H), 2.28 – 2.11 (m, 2H), 2.06 (br.s, 1H), 2.02 – 1.77 (m, 2H) ppm. Step 5. Synthesis of methyl 5,5,5-trifluoro-2-(((methylsulfonyl)oxy)methyl)pentanoate (151-6). To a stirred mixture of methyl 5,5,5-trifluoro-2-(hydroxymethyl)pentanoate (151-5) (15 g, 74.94 mmol) and TEA (22.75 g, 224.82 mmol) in DCM (150 mL) was added MsCl (10.30 g, 89.93 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h under nitrogen atmosphere. The reaction was monitored by GC- MS. The resulting mixture was extracted with CH2Cl2(150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to give 151-6 (17 g, 81.5%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 4.45 – 4.31 (m, 2H), 3.76 (s, 3H), 3.03 (s, 3H), 2.94 – 2.79 (m, 1H), 2.32 – 2.07 (m, 2H), 2.06 – 1.79 (m, 2H) ppm. Step 6. Synthesis of methyl 2-(bromomethyl)-5,5,5-trifluoropentanoate (151-7). Into a 250 mL 3-necked round-bottom flask were added methyl 5,5,5-trifluoro-2- (((methylsulfonyl)oxy)methyl)pentanoate (151-6) (15 g, 53.91 mmol), LiBr (14.04 g, 161.73 mmol) and acetone (150 mL) at rt. The resulting mixture was stirred at 60°C for 3 h under nitrogen atmosphere. The reaction was monitored by GC-MS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / THF (9:1 (v / v)) to give 151-7 (11 g, 77.6%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 3.76 (s, 3H), 3.61 – 3.48 (m, 2H), 2.94 – 2.80 (m, 1H), 2.29 – 2.09 (m, 2H), 2.08 – 1.84 (m, 2H) ppm. Step 7. Synthesis of 2-bromo-4-methoxy-5-(trifluoromethyl)aniline (151-9). Into a 50 L 4- necked round-bottom flask were added 4-methoxy-3-(trifluoromethyl)aniline (1100 g, 5.75 mol) and THF (22 L). To the above mixture was added NBS (1057.56 g, 5.75 mol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 10°C for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by LC-MS), the reaction was quenched with sat. aq. Na2SO3solution (25 L) at 5 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (25 L x 3). The combined organic layers were washed with brine (25 L x 2), dried over anhydrous Na2SO4, and concentrated. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (15:1 (v / v)) to give 151-9 (1067 g, 68.6%) as a yellow solid. MS (ESI): calcd. for C8H7BrF3NO: 269.0; Found: 311.0 [M +ACN+ 1]+. Step 8. Synthesis of 4-methoxy-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)aniline (151-10). Into a 20 L 4-necked round-bottom flask were added 2-bromo-4-methoxy-5- (trifluoromethyl)aniline (151-9) (1000 g, 3.95 mol), dioxane (10 L), PMBSH (913.79 g, 5.92 mol), DIEA (1.53 kg, 11.85 mol), Pd2(dba)3(85.04 g, 0.093 mol) and Xantphos (107.43 g, 0.186 mol) at room temperature. The resulting mixture was stirred at 120 °C for 24 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 L x 2). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA / DCM (5 / 1 / 0.1 (v / v / v)) to give crude 151-10 (1167 g, containing some ligands) as a brown oil, which was directly used in the next step without further purification. MS (ESI): calcd. for C16H16F3NO2S: 343.1; Found: 344.1 [M + 1]+. Step 9. Synthesis of 6,6'-disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151- 11). Into a 20 L 4-necked round-bottom flask were added 4-methoxy-2-((4- methoxybenzyl)thio)-5-(trifluoromethyl)aniline (151-10) (1160 g, 3.40 mol), TFA (4 L) and MsOH (1.2 L) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and diluted with EtOAc (15 L). The mixture was acidified to pH = 9 with saturated aq. NaHCO3solution. The resulting solution was stirred at rt for 16 h under oxygen atmosphere. The resulting mixture was separated, and the aqueous layer was extracted with EtOAc (8 L x 2). The combined organic layers were washed with brine (10 L x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1 (v / v)) to give 151-11 (500 g, 33.1%) as a light brown solid. MS (ESI): calcd. for C16H14F6N2O2S2: 444.0; Found: 445.0 [M + 1]+. Step 10. Synthesis of methyl 2-(((2-amino-5-methoxy-4- (trifluoromethyl)phenyl)thio)methyl)-5,5,5-trifluoropentanoate (151-12). A solution of 6,6'-disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151-11) (20.27 g, 45.6 mmol), Cs2CO3(55.72 g, 171 mmol), and sodium dithionite (29.77 g, 171 mmol) in DMF (280 mL) was stirred for 20 min, then the mixture was treated with methyl 2-(bromomethyl)-5,5,5- trifluoropentanoate (151-7) (15 g, 57 mmol) in DMF (57 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The solution was diluted with H2O (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 6 / 1 (v / v) to give 151-12 (11.2 g, 48.6%) as a light brown oil. MS (ESI): calcd. for C15H17F6NO3S: 405.1; Found: 406.1 [M + 1]+. Step 11. Synthesis of 8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-13). A solution of methyl 2-(((2-amino-5- methoxy-4-(trifluoromethyl)phenyl)thio)methyl)-5,5,5-trifluoropentanoate (151-12) (10.22 g, 25.21 mmol) in THF (100 mL) was treated with LiHMDS (50.41 mL, 50.41 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. aq. NH4Cl solution at room temperature, then the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to give 151-13 (8.6 g, 91.4%) as an off-white solid. MS (ESI): calcd. for C14H13F6NO2S: 373.1; Found: 374.1 [M + 1]+. Step 12. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-14). A solution of 8- methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin- 4(5H)-one (151-13) (8.56 g, 22.93 mmol), (4-fluorophenyl)boronic acid (9.63 g, 68.79 mmol) and TEA (9.28 g, 91.72 mmol) in DMF (86 mL) was treated with Cu(OAc)2(6.25 g, 34.40 mmol) at room temperature under oxygen atmosphere. The resulting mixture was stirred at 80°C for 16 h under oxygen atmosphere. The mixture was allowed to cool down to room temperature and diluted with sat. aq. NH4Cl solution (200 mL). The resulting solution was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1 (v / v)) to give 151-14 (10.6 g, 92.8%) as a yellow solid. MS (ESI): calcd. C20H16F7NO2S: 467.1; Found: 468.1 [M + 1]+. Step 13. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (151-15). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-14) (10.62 g, 22.72 mmol) and oxone (104.74 g, 170.40 mmol) in THF (200 mL) and H2O (100 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (150 mL x 3). The mixture was acidified to PH = 8 with sat. aq. NaHCO3solution. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 5 / 1 (v / v) to give 151-15 (10.6 g, 93.4%) as a yellow solid. MS (ESI): calcd. for C20H16F7NO4S: 499.1; Found: 500.2 [M + 1]+. Step 14. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-16). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (151-15) (4 g, 8.0 mmol) and BH3·Me2S (8 mL, 80 mmol) in THF (40 mL) was stirred at 60°C for 16 h. After the reaction was completed, the mixture was allowed to cool to 0°C with ice-water. The mixture was quenched with MeOH (8 mL) (dropwise) at 0°C, then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the mixture was extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to give 151-16 (3.6 g, 93.6%) as a white solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.1 [M + 1]+. Step 15. Synthesis of rac-cis-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)- 3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151- 17a) and rac-trans-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-17b). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-16) (3.6 g, 7.42 mmol) in THF (60 mL) was treated with LiHMDS (8.9 mL, 8.9 mmol) at -78 °C for 10 min under nitrogen atmosphere. The mixture was stirred for 30 min, followed by the addition of a solution of NFSI (2.11 g, 6.68 mmol) in THF (35 mL) dropwise at -78°C. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. aq. NH4Cl solution (100 mL) at 0°C, then the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to give 151-17a (cis-racemate, 498 mg) as a yellow solid and 151-17b (trans-racemate, 1.92 g) as a yellow solid. 151-17a (cis-racemate): MS (ESI): calcd. for C20H17F8NO3S: 503.1; Found: 504.2 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.72 (s, 1H), 7.50 (s, 1H), 7.03 – 6.91 (m, 2H), 6.69 – 6.58 (m, 2H), 5...

Claims

CLAIMS:

1. A compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2-, or -C(CH3)2-; Ra, Rband Rcare independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; R1is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH orR2aand R2bare independently selected from the group consisting of hydrogen, halo, OH, methyl, ethyl and CH2OH; or R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected from halo and methyl groups; R3is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5-12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4is haloC3-4alkyl; R5is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituentsindependently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is -CHF-.

3. The compound of claim 1 or 2, wherein Formula II is of Formula IIa, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is -C(O)OH.

5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is -S(O)2OH.

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is -P(O)(OH)2,7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare independently selected from the group consisting of hydrogen, halo, OH and methyl.

8. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare methyl.

9. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen and R2bare methyl.

10. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with 1-3 halo groups.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether with the carbon atom to which they are attached form a cyclopropyl group.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is haloC1-2alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3is CF3.

15. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is C5-12bicycloalkylthio.

16. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is haloC3-7monocycloalkylthio.

17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4is n-butyl substituted with 1 to 6 halo atoms.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R4is n-butyl substituted with 1 to 6 F atoms.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R4is -CH2CH2CF2CH3.

20. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4is n-propyl substituted with 1 to 6 halo atoms.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R4is n-propyl substituted with 1 to 6 F atoms.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R4is -CH2CH2CF3.

23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R5is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-,C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein25. The compound according to an one of claims 1- 22, or a pharmaceutically acceptable salt thereof, wherein In certain embodiments, R5is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R5is28. A pharmaceutical composition comprising a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. 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 1-27, or a pharmaceutically acceptable salt thereof.

30. 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 28.

31. 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 1-27, or a pharmaceutically acceptable salt thereof.

32. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 28.

33. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, for use in therapy.

34. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, for use as a medicament.

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