Benzothia(dia)zepine compounds for the treatment of HBV and HDV

Abstract

The present disclosure provides, in part, benzothia(dia)zepine compounds, and pharmaceutical compositions thereof, and methods for treating hepatitis B virus (HBV) and hepatitis D virus (HDV) infections. The present disclosure provides, in part, benzothia(dia)zepine compounds and pharmaceutical compositions thereof useful for inhibiting HBV or HDV replication, inhibiting HBV or HDV viral entry, and methods for treating HBV infection, HDV infection, or HBV / HDV co-infection.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the 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 incorporated herein by reference. [Background technology]

[0002] Hepatitis B virus (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Approximately 2 billion people worldwide are infected with HBV, and according to the World Health Organization website, approximately 296 million people were chronically infected in 2019, with more than 500,000 deaths due to HBV infection each year. HBV can be spread from mother to child through bodily fluids, sexual intercourse, and blood products. Children born to HBV-positive mothers can also become infected unless they are vaccinated at birth.

[0003] HBV particles consist of a lipid envelope coated with hepatitis B surface antigen (HBsAg) surrounding a viral core. The core is composed of a protein shell, or capsid, constructed of 120 core protein (Cp) dimers, which contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In infected cells, the genome is found as covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is a template for viral RNA and therefore viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (so-called pregenomic RNA or pgRNA) and viral polymerase (P). After capsid assembly, P reverse-transcribes the pgRNA into rcDNA within the capsid to generate a DNA-filled viral core.

[0004] Currently, chronic HBV is primarily treated with nucleoside(t)ide analogs (e.g., entecavir), which suppress the virus while patients remain on treatment but do not eliminate the infection even after many years of treatment. Once patients begin taking nucleoside(t)ide analogs, most patients must continue taking them or risk a potentially life-threatening immune response due to viral regrowth. Furthermore, nucleoside therapy can lead to the emergence of antiviral drug resistance.

[0005] The only FDA-approved alternative to nucleoside(t)ide analogs is treatment with interferon α or pegylated interferon α. ​​Unfortunately, the incidence and profile of adverse events with interferon α can reduce tolerability, and many patients are unable to complete the therapy. Furthermore, only a small subset of patients are likely to have a sustained clinical response to a course of interferon therapy, so only a small percentage of patients are considered suitable for interferon therapy. As a result, interferon-based therapy is used in only a small percentage of all diagnosed patients who choose treatment.

[0006] Therefore, current HBV treatments can range from palliation to observation. Nucleotide analogs suppress viral production to treat symptoms but leave the infection untreated. Interferon-α has severe side effects, is poorly tolerated among patients, and has been a successful treatment strategy in only a small number of patients. There is a clear ongoing need for more effective treatments for HBV infection.

[0007] Another form of viral hepatitis is hepatitis D virus (HDV), a defective RNA virus that causes chronic viral hepatitis and eventual cirrhosis. However, the HDV life cycle depends on the presence of HBsAg for viral particle assembly. Therefore, in a small number of patients infected with HBV, HDV presents as a 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, incorporated herein by reference for its background teachings. In patients already infected with HBV, coinfection / reinfection with HDV can further exacerbate HBV symptoms and increase the likelihood of complications, rapid disease progression, and / or death. Chronic HBV / HDV infection is also associated with the development of hepatocellular carcinoma (HCC). Similar to HBV, treatment options for HDV infection or HBV / HDV coinfection are limited, including those used to treat HBV. Therefore, effective treatment options for the treatment of HDV infection or HBV / HDV coinfection / superinfection are needed.

[0008] WO2022 / 253997 relates to 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators with apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transporter (LBAT) inhibitory activity. The present invention also relates to pharmaceutical compositions containing 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. WO 2023 / 237728 to Albireo relates to methods for treating hepatitis B and / or hepatitis D with a Na+ / taurocholate cotransporting 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 reducing the concentration of hepatitis B DNA, reducing the concentration of hepatitis D DNA, reducing hepatitis B surface antigen, and reducing hepatitis B core antigen (HBcAg). NTCP functions as a cellular receptor for viral entry of HBV and HDV, which in turn is a major cause of liver disease and HCC. Additional bile acid-modulating compounds with improved profiles in terms of efficacy, safety, selectivity, and / or bioavailability are needed. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2022 / 253997 [Patent Document 2] International Publication No. 2023 / 237728 [Non-patent literature]

[0010] [Non-Patent Document 1] Sagnelli et al.,Life(Basel).2021 Feb;11(2):169,Published online 2021 Feb 22.doi:10.3390 / life11020169 Summary of the Invention

[0011] The present disclosure provides, in part, benzothia(dia)zepine compounds and pharmaceutical compositions thereof useful for inhibiting HBV or HDV replication, inhibiting HBV or HDV viral entry, and methods for treating HBV infection, HDV infection, or HBV / HDV coinfection.

[0012] In one aspect, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are described in the detailed description.

[0013] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0014] In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0015] 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.

[0016] 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 a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0017] 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 explanation of the drawings]

[0018] [Figure 1] 1 shows the ORTEP plot of Example 10b. [Figure 2] 1 shows the ORTEP plot of Example 11a. DETAILED DESCRIPTION OF THE INVENTION

[0019] Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) and is the most severe form of viral hepatitis known in humans. HDV is a single-stranded, circular RNA virus that depends on 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 therefore depends on the presence of HBV to provide the envelope proteins. New HDV progeny particles can only be produced in liver cells already infected with HBV.

[0020] Approximately 300 million people worldwide are chronically infected with HBV. An estimated 15 to 20 million people are also chronically infected with hepatitis delta. Co-infection causes more severe liver disease than HBV infection alone. It is associated with a more rapid progression to liver fibrosis, a higher risk of liver cancer, and early decompensated cirrhosis and liver failure, which can be fatal within days without transplantation. Hepatitis delta can be acquired either through coinfection with hepatitis B and hepatitis delta. It can also be acquired through coinfection with hepatitis D after a person has already acquired hepatitis B.

[0021] Currently, there is no vaccine for hepatitis delta. However, it can be prevented by receiving the hepatitis B vaccine to eliminate the risk of HBV infection. The entry inhibitor Hepcludex (myrcludex B, bulevirtide, BLV) was approved for HDV in the European Union in July 2020 and is available in France, Germany, Austria, Italy, and the UK as of June 2023. The drug binds to essential HDV receptors on hepatocytes, thereby preventing infection of the cells. BLV binding to NTCP simultaneously inhibits its natural biological function of transporting bile acids into cells. Until now, the only treatment for hepatitis delta found to be somewhat effective was pegylated interferon alpha, which works by stimulating the body's innate immune system to fight the virus.

[0022] Hepcludex is a 47-amino acid peptide that inhibits the Na+-taurocholate cotransporting polypeptide (NTCP), a viral entry receptor, requiring subcutaneous (SubQ) administration; however, the small molecule, orally bioavailable NTCP inhibitor of the present invention offers more flexible administration, increased convenience, and greater combination options with other HBV / HDV therapies.

[0023] WO 2022 / 253997 to Albireo relates to 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives of formula (I): [ka]

[0024] These compounds are bile acid modulators that have apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transport (LBAT) inhibitory activity. The present invention also relates to pharmaceutical compositions containing these compounds and to the use of these compounds in the treatment of cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal disease, and liver disease.

[0025] The applicants believe that the compound of formula (I) of WO2022 / 253997 is R 1 Note that it is chiral because there is a chiral center at the carbon atom bearing -CH2- and -NR 5 - limited to, wherein R 5 is hydrogen or C 1-4 alkyl, and R 1- is C 1-4 Limited to alkyl, R 3 is hydrogen, halo, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-4 Alkylthio, C 3-6 is limited to cycloalkylthio, amino, N-(Ci_4 alkyl)amino, and N,N-di(Ci_4 alkyl)amino. Thus, R 1 or R 3 There is no teaching or suggestion of haloalkyl substituents in or M being a substituted carbon atom. In particular, when M is a monosubstituted carbon atom, a new chiral center is introduced, resulting in four diastereomers.

[0026] In contrast, Example 10b is an exemplary compound of the present invention, having the structure and absolute stereochemistry shown below: [ka] Here, haloalkyl groups are R 1 (i.e., -CH2CH2CF2CH3) and R 3 (i.e., CF3), and M is a monosubstituted carbon atom (i.e., -CHF-), resulting in a second chiral center outside the scope of WO2022 / 253997. Applicants have discovered that one or more of these structural modifications result in unexpected improved biological activity, selectivity profile, and PK profile against HBV and HDV. The compound of Example 10b can exist as four diastereomers. [ka]

[0027] Comparative potency and transporter selectivity data for each of these four diastereomers is provided in Table 1. [Table 1]

[0028] As used herein, diastereomer 1 of Example 10b of the present invention is also referred to as compound 1.

[0029] For comparison, applicants have made and tested the compounds of Examples 9 and 13 of WO2022 / 253997 according to procedures known in the art, both of which are described in WO2022 / 253997 as racemic mixtures of the corresponding enantiomers. [ka]

[0030] Enantiomer 1 of Example 14 and Enantiomer 2 of Example 14 are the isolated R and S enantiomers (unassigned absolute stereochemistry) of Example 13. Table 8 of WO2022 / 253997 shows that while Examples 9 and 13 have similar NTCP(hLBAT) inhibitory activity, Enantiomer 2 of Example 14 is significantly more active in inhibiting NTCP(hLBAT) than Enantiomer 1 of Example 14. However, no assay data directly demonstrating biological activity against HDV or HBV are provided.

[0031] Table 2 provides comparative data on the potency and transporter selectivity of Compound 1 relative to the compounds of Examples 9 and 14 of WO2022 / 253997. [Table 2]

[0032] As shown in the table, compound 1 exhibited half-maximal inhibitory concentrations (IC ) of 7.3 and 2,400 nM against human NTCP and ASBT, respectively. 50 ) value, and a ratio of NTCP selectivity of over 320-fold (ASBT IC 50 / NTCP IC 50 Compound 1 also showed an IC of 4.2 nM without affecting cell viability. 50 prevented HBV infection of human hepatoma cells.

[0033] In contrast, Example 14 (enantiomer 2) had IC values ​​of 21 and 190 nM for human NTCP and ASBT, respectively. 50 value, and a 9-fold NTCP selectivity ratio (ASBT IC 50 / NTCP IC 50 ) This compound had an IC of 24 nM without affecting cell viability. 50 Similarly, Example 9 (best enantiomer) had an IC of 75.6 nM against human NTCP. 50 has an IC of 45 nM without affecting cell viability 50 prevented HBV infection of human hepatoma cells.

[0034] Therefore, in HBV-infected hepatoma cells, Compound 1 exhibited higher anti-HBV potency than Example 14 (enantiomer 2), with an IC 50 The IC value was about 6 times lower compared to Example 9 (best enantiomer). 50 Compound 1 also inhibited NTCP more effectively, with an IC 50 The values ​​were about 3-fold lower than those of Example 14 (enantiomer 2) and about 10-fold lower than those of Example 9 (best enantiomer). Finally, compound 1 showed about 36-fold higher NTCP selectivity (ASBT IC 50 / NTCP IC 50 ) and demonstrated its excellent selectivity.

[0035] Table 3 provides comparative monkey PK profile data for Compound 1 versus Albireo compound A7387. Data for Compound 1 were acquired using the methods and procedures described herein, while data for A7387 were digitized from Albireo 2023 AASLD Poster, 1481-C|Preclinical Characterization of a Novel, Orally Bioavailable NTCP Inhibitor, A7387. While the structure of A7387 is not disclosed in the poster, WO2023237728 provides primate in vivo results on p. 77, which references Example 14 of WO2022 / 253997 as Compound 2 and cross-references Compound 2 as A7387. [Table 3]

[0036] In monkeys, after oral administration of 3 mg / kg, Compound 1 * AUC in ng / mL 0-24 and C of 5147 ng / mL. max , which showed higher exposures, 320% and 120%, respectively, than those observed in A7387.

[0037] In monkeys, after oral administration of 10 mg / kg, Compound 1 * AUC in ng / mL 0-24 and C of 23100 ng / mL. max , which showed higher exposures, 1450% and 1260%, respectively, than those observed in A7387.

[0038] In monkeys, after oral administration of 30 mg / kg, Compound 1 * AUC in ng / mL 0-24 and C of 64,900 ng / mL. max , which showed higher exposures, 240% and 150%, respectively, than those observed in A7387.

[0039] The apparent oral PK terminal half-life of compound 1 ranged from 13 to 17 hours, 160 to 320% longer than that observed for A7387.

[0040] The features and other details of the present disclosure will be more specifically described.Before further describing the present disclosure, certain terms used in the present specification, examples and appended claims will be summarized here.These definitions should be read in light of the remainder of the present disclosure and as understood by those skilled in the art.Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0041] I. Definition As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include those described herein as C 2-6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0042] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include those described herein as C, C, C-, C-C ... 1-6 Alkoxy and C 1-4 Examples of alkoxy groups include, but are not limited to, alkoxy groups of 1 to 6 or 1 to 4 carbon atoms, referred to as alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0043] 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-.

[0044] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include those described herein as C 1-6 Alkyl and C 1-4 These include, but are not limited to, straight-chain or branched hydrocarbons of 1 to 6 or 1 to 4 carbon atoms, referred to as alkyl. 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. As used herein, the term "alkylene" refers to a biradical alkyl group.

[0045] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include those described herein as C 2-6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0046] As used herein, the term "carbonyl" refers to the biradical -C(O)-.

[0047] As used herein, the term "co-infection" refers to the simultaneous infection of a host by two or more viral pathogens.

[0048] As used herein, the term "cyano" refers to the radical --CN.

[0049] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon group, e.g., of 3 to 7 carbons (defined herein as C 3-7 monocycloalkyl), or bicyclic hydrocarbon ring structures, for example, of 5 to 12 carbons (referred to herein as C 5-12 In the case of a bicyclic cycloalkyl group, the two rings can 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, octahydropentanyl, 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.

[0050] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0051] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. For example, haloC 1-6 Alkyl refers to a straight or branched alkyl group of 1 to 6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CHF, -CHCl, -CHF, -CF, CFCH-, CHCF-, CFCCl-, and CFCF-.

[0052] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CC10-, CF30-, CHF20-CF3CH20-, and CF3CF20-.

[0053] As used herein, the term "heteroaryl" refers to a heteroaryl group defined herein as a monocyclo. 5-6 5-6 membered monocyclic aromatic groups, also referred to as heteroaryls, or bicyclos, as used herein. 8-12 Heteroaryl refers to an 8- to 12-membered bicyclic aromatic ring system containing 1 to 4 independently selected heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heteroaryl ring may be linked to adjacent radicals through a carbon or nitrogen atom. Monocyclo 5-6 Examples of heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also called thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also called 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. 8-12 Examples of heteroaryl 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[d]thiazolyl, indazolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl.

[0054] The term "heterocycloalkyl" refers to a monocycloalkyl group, e.g., C 3-7 Monocycloalkyl or bicycloalkyl groups, such as C 5-12 Bicycloalkyl refers to a cycloalkyl group in which one to three of the carbon atoms are replaced by independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO), each of which is defined herein as a monocycloalkyl group. 3-7 Heterocycloalkyl and Bicycloalkyl 5-12 It is called heterocycloalkyl. 3-7 Examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl 1,1-dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. 5-12 Examples of heterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl.

[0055] As used herein, the terms "hydroxy" and "hydroxyl" refer to the radical --OH.

[0056] 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, HOCH-, HOCHCH-, CHCH(OH)CH-, and HOCHCH(OH)CH-.

[0057] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCHO-, HOCHCHO-, CHCH(OH)CHO-, and HOCHCH(OH)CHO-.

[0058] As used herein, "R a R b NC 1-6 The term "alkyl-" refers to R a R b It refers to an alkyl group substituted with an N-group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2-, and CH3CH(NH2)CH2-.

[0059] As used herein, "R a R b NC 1-6 The term "alkoxy" refers to R a R b It refers to an alkoxy group substituted with an N-group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CHO-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CHO-.

[0060] As used herein, the term "oxo" refers to the radical =O.

[0061] As used herein, a bicyclic ring refers to, for example, [ka] When depicted as having a floating attachment point and / or floating substituents, such as, for example, R 33 It means that the group(s) can be independently attached to either or both rings.

[0062] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, livestock animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated by the methods of the present disclosure is preferably a mammal for which treatment of HBV infection is desired.

[0063] "Modulation" includes antagonism (eg, inhibition), agonism, partial antagonism and / or partial agonism.

[0064] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0065] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coating agents, 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 composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0066] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0067] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can 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 with 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)). The compounds contained in the present compositions are acidic in nature and can form 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 contained in the present compositions that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0068] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of the compound that will elicit the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect.

[0069] The term "treating" includes any effect such as alleviating, reducing, modulating, or eliminating a viral infection that results in amelioration of the disease.

[0070] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term "stereoisomer" refers to 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 atoms, although those skilled in the art will recognize that the structure may implicitly indicate chiral centers. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the nomenclature "(±)", although those skilled in the art will recognize that the structure may implicitly indicate chiral centers.

[0071] The compounds of the present 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. [ka] indicates a bond, which may be a single bond, double bond, or triple bond, as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and 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. Alternatively, substituents around a carbon-carbon double bond may be designated as "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond.

[0072] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings 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 is designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," with the term "cis" referring to substituents on the same side of the plane of the ring and the term "trans" referring to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring are designated "cis / trans."

[0073] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary and separating the resulting diastereomeric mixture by recrystallization or chromatography, followed by liberation of the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column; 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 synthesis, i.e., chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0074] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present disclosure is intended to encompass 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.

[0075] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those enumerated 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 normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0076] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H), and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those disclosed in the examples herein by substituting a non-isotopically labeled reagent for an isotopically labeled reagent.

[0077] The term "prodrug" refers to a compound that is transformed in vivo to obtain a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Transformation can occur by various mechanisms (e.g., by esterase, amidase, phosphatase, oxidative and / or reductive metabolism, etc.) in various locations (e.g., in the intestinal lumen, or during transport through the intestine, blood, or liver). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0078] II. Benzothia(dia)zepine Compounds In one aspect, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: M is NR x or CR y R z and X is N or CH; R a , R b , and R c independently for each occurrence, hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-6 monocycloalkyl; R x is hydrogen or C 1-4 is alkyl, R y and R z But hydrogen, halo, CN, C 1-4 Alkyl and haloC 1-4 independently selected from the group consisting of alkyl, R 1 is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 alkyl, -P(O)(OH)2, -S(O)2OH, or [ka] and R 2a and R 2b is independently selected from the group consisting of hydrogen, halo, OH, methyl, ethyl, and CHOH, or R 2a and R 2b together with the carbon atoms to which they are attached, C=CH2, C 3-6 forming a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group, C 3-6 a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group optionally substituted with 1 to 3 independently selected from halo and methyl groups; R 3 But hydrogen, halogen, cyano, R a R b N-, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkylthio, HaloC 1-4 Alkylthio, C 3-7 Monocycloalkyl, C 3-7 Monocycloalkyloxy, C 3-7 Monocycloalkylthio, C 3-7 Monocycloalkyl-CH2-thio, and C 5-12 bicycloalkylthio; 3-7 Monocycloalkyl, C 3-7 Monocycloalkyloxy, C 3-7 Monocycloalkylthio, C 3-7 Monocycloalkyl-CH2-thio, and C 5-12 the bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R 4 But hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, Hydroxy C 1-4Alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2-, or R 4a CH2CH2-, R 4a is optionally substituted with phenyl, imidazolyl, N-methylimidazolyl, or 1 to 3 halo groups; 3-6 It is a monocycloacrylic R 5 But phenyl, C 3-7 Monocycloalkyl, or C 5-12 Bicycloalkyl, phenyl, C 3-7 Monocycloalkyl, or C 5-12 Bicycloalkyl is halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O)q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-; q is independently, for each occurrence, selected from the group consisting of 0, 1, and 2; However, R 3 But, Haro C 1-4 alkyl, and M is CR y R z and R y and R z At least one of the following is present: halo, CN, C 1-4 Alkyl or haloC 1-4 alkyl, or R 4 But, Haro C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2- or R 4a CH2CH2-, or a combination thereof.

[0079] The following embodiments further describe compounds of Formula I, or pharmaceutically acceptable salts thereof. It will be understood that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the present invention.

[0080] In certain embodiments, the compound of formula I has formula Ia [ka] or a pharmaceutically acceptable salt thereof.

[0081] In certain embodiments, the compound of formula I has formula Ib [ka] or a pharmaceutically acceptable salt thereof.

[0082] In certain embodiments, X is N.

[0083] In certain embodiments, X is CH.

[0084] In certain embodiments, M is NR x is.

[0085] In certain embodiments, M is NH or NCH3.

[0086] In certain embodiments, M is CR y R z is.

[0087] In certain embodiments, M is —CH 2 —.

[0088] In certain embodiments, M is CR y R z and R y and R z At least one of the following is a halo, CN, or C 1-4 Alkyl or haloC 1-4 It is alkyl.

[0089] In certain embodiments, M is —CH(CH 3 )—, —CF(CH 3 )—, —CHF—, —C(CH 3 ) 2 —, or —CF 2 —.

[0090] In certain embodiments, M is —CF(CH 3 )—.

[0091] In certain embodiments, M is —C(CH 3 ) 2 —.

[0092] In certain embodiments, M is -CHF-.

[0093] In certain embodiments, M is —CF 2 —.

[0094] In certain embodiments, R 1 is C(O)OH.

[0095] In certain embodiments, R 1 is S(O)2OH.

[0096] In certain embodiments, R 1 is P(O)(OH).

[0097] In certain embodiments, R 2a and R 2b are independently selected from the group consisting of hydrogen, halo, OH, and methyl.

[0098] In certain embodiments, R 2a and R 2b is methyl.

[0099] In certain embodiments, R 2a is hydrogen and R 2b is methyl.

[0100] In certain embodiments, R 2a and R 2b together 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 to 3 halo groups.

[0101] In certain embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group.

[0102] In certain embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a cyclopropyl group.

[0103] In certain embodiments, R 3is C 5-12 It is bicycloalkylthio-.

[0104] In certain embodiments, R 3 is Haro C 3-7 It is monocycloalkylthio-.

[0105] In certain embodiments, R 3 is Haro C 1-2 It is alkyl-.

[0106] In certain embodiments, R 3 is CF3.

[0107] In certain embodiments, R 4 is Haro C 1-4 Alkyl-, hydroxy C 1-4 Alkyl-, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R 4a CH2-, or R 4a CH2CH2-.

[0108] In certain embodiments, R 4 is Haro C 1-4 It is alkyl-.

[0109] In certain embodiments, R 4 is Haro C 3-4 It is alkyl-.

[0110] In certain embodiments, R 4 is n-butyl substituted with 1 to 6 halo atoms.

[0111] In certain embodiments, R 4 is n-butyl substituted with 1 to 6 F atoms.

[0112] In certain embodiments, R 4 is -CH2CH2CF2CH3.

[0113] In certain embodiments, R 4is n-propyl substituted with 1 to 6 halo atoms.

[0114] In certain embodiments, R 4 is n-propyl substituted with 1 to 6 F atoms.

[0115] In certain embodiments, R 4 is -CH2CH2CF3.

[0116] In certain embodiments, R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 C optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl- 3-7 It is a monocycloalkyl.

[0117] In certain embodiments, R 5 teeth, [ka] is.

[0118] In certain embodiments, R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 C optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl- 5-12 It is a bicycloalkyl.

[0119] In certain embodiments, R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0120] In certain embodiments, R 5 teeth, [ka] is.

[0121] In certain embodiments, R 5 teeth, [ka] is.

[0122] In certain embodiments, X is CH and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 It is alkyl-.

[0123] In certain embodiments, X is CH and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0124] In certain embodiments, X is CH and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0125] In certain embodiments, X is CH, M is -CHF-, and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 It is alkyl-.

[0126] In certain embodiments, X is CH, M is -CHF-, and R 3 is CF3 and R 4is -CH2CH2CF2CH3.

[0127] In certain embodiments, X is CH, M is -CHF-, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0128] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 It is alkyl-.

[0129] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0130] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0131] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 alkyl-, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0132] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0133] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0134] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is Haro C 1-2 alkyl, and R 5 teeth, [ka] is.

[0135] In certain embodiments, X is CH, M is -CHF-, and R1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0136] In certain embodiments, X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 teeth, [ka] is.

[0137] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 It is alkyl-.

[0138] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0139] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0140] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4It is alkyl-.

[0141] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0142] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0143] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is Haro C 1-4 It is alkyl-.

[0144] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0145] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0146] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R4 is Haro C 1-4 alkyl-, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0147] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0148] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0149] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is Haro C 1-2 alkyl, and R 5 teeth, [ka] is.

[0150] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0151] In certain embodiments, the compound of Formula I is a compound of Formula Ia, wherein X is CH, M is -CHF-, and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 teeth, [ka] is.

[0152] In some embodiments of the present invention, the compound of formula I is represented by formula II [ka] or a pharmaceutically acceptable salt thereof, wherein M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2-, or -C(CH3)2-; R a , R b , and R c independently for each occurrence, hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-6 monocycloalkyl; R 1 is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC 1-6 alkyl, -P(O)(OH)2, -S(O)2OH, or [ka] and R 2a and R 2b is independently selected from the group consisting of hydrogen, halo, OH, methyl, ethyl, and CHOH, or R 2a and R 2b together with the carbon atoms to which they are attached, C=CH2, C 3-6 forming a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group, C 3-6 a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group optionally substituted with 1 to 3 independently selected from halo and methyl groups; R 3 But hydrogen, halogen, cyano, R a R b N-, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkylthio, HaloC 1-4 Alkylthio, C 3-7 Monocycloalkyl, C 3-7 Monocycloalkyloxy, C 3-7 Monocycloalkylthio, C 3-7Monocycloalkyl-CH2-thio, and C 5-12 bicycloalkylthio; 3-7 Monocycloalkyl, C 3-7 Monocycloalkyloxy, C 3-7 Monocycloalkylthio, C 3-7 Monocycloalkyl-CH2-thio, and C 5-12 the bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R 4 But, Haro C 3-4 is alkyl, R 5 But phenyl, C 3-7 Monocycloalkyl, or C 5-12 Bicycloalkyl, phenyl, C 3-7 Monocycloalkyl, or C 5-12 Bicycloalkyl is halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q-, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-; A compound, or a pharmaceutically acceptable salt thereof, wherein q is independently, for each occurrence, selected from the group consisting of 0, 1, and 2.

[0153] The following embodiments further describe compounds of Formula II, or pharmaceutically acceptable salts thereof. It will be understood that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the present invention.

[0154] In certain embodiments, the compound of formula II has the formula IIa [ka] or a pharmaceutically acceptable salt thereof.

[0155] In certain embodiments, the compound of formula II has formula IIb [ka] or a pharmaceutically acceptable salt thereof.

[0156] In certain embodiments, the compound of formula II has formula IIc [ka] or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, the compound of formula II has the formula IId [ka] or a pharmaceutically acceptable salt thereof.

[0158] In certain embodiments, M is —CHF—, —CH(CH 3 )—, or —CF(CH 3 )—.

[0159] In certain embodiments, M is -CHF-.

[0160] In certain embodiments, M is —CH(CH 3 )—.

[0161] In certain embodiments, M is —CF(CH 3 )—.

[0162] In certain embodiments, M is —CF 2 — or —C(CH 3 ) 2 —.

[0163] In certain embodiments, M is —CF 2 —.

[0164] In certain embodiments, M is —C(CH 3 ) 2 —.

[0165] In certain embodiments, R 1 is C(O)OH.

[0166] In certain embodiments, R 1 is S(O)2OH.

[0167] In certain embodiments, R 1 is P(O)(OH).

[0168] In certain embodiments, R 2a and R 2b are independently selected from the group consisting of hydrogen, halo, OH, and methyl.

[0169] In certain embodiments, R 2a and R 2bis methyl.

[0170] In certain embodiments, R 2a is hydrogen and R 2b is methyl.

[0171] In certain embodiments, R 2a and R 2b together 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 to 3 halo groups.

[0172] In certain embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group.

[0173] In certain embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a cyclopropyl group.

[0174] In certain embodiments, R 3 is C 5-12 It is bicycloalkylthio-.

[0175] In certain embodiments, R 3 is Haro C 3-7 It is monocycloalkylthio-.

[0176] In certain embodiments, R 3 is Haro C 1-2 It is alkyl-.

[0177] In certain embodiments, R 3 is CF3.

[0178] In certain embodiments, R 4 is n-butyl substituted with 1 to 6 halo atoms.

[0179] In certain embodiments, R 4 is n-butyl substituted with 1 to 6 F atoms.

[0180] In certain embodiments, R 4 is -CH2CH2CF2CH3.

[0181] In certain embodiments, R 4 is n-propyl substituted with 1 to 6 halo atoms.

[0182] In certain embodiments, R 4 is n-propyl substituted with 1 to 6 F atoms.

[0183] In certain embodiments, R 4 is -CH2CH2CF3.

[0184] In certain embodiments, R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 C optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl- 3-7 It is a monocycloalkyl.

[0185] In certain embodiments, R 5 teeth, [ka] is.

[0186] In certain embodiments, R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0187] In certain embodiments, R 5 teeth, [ka] is.

[0188] In certain embodiments, R 5 teeth, [ka] is.

[0189] In certain embodiments, R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3.

[0190] In certain embodiments, R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3.

[0191] In certain embodiments, R 3 is CF3 and R 4is -CH2CH2CF2CH3.

[0192] In certain embodiments, R 3 is CF3 and R 4 is -CH2CH2CF3.

[0193] In certain embodiments, M is -CHF- and R 3 is Haro C 1-4 It is alkyl-.

[0194] In certain embodiments, M is -CHF- and R 3 is CF3.

[0195] In certain embodiments, M is -CHF- and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3.

[0196] In certain embodiments, M is -CHF- and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3.

[0197] In certain embodiments, M is -CHF- and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0198] In certain embodiments, M is -CHF- and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0199] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 It is alkyl.

[0200] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl, and R 4 is -CH2CH2CF2CH3.

[0201] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl, and R 4 is -CH2CH2CF3.

[0202] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0203] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0204] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0205] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0206] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0207] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0208] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is -CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0209] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is -CH2CH2CF3, and R 5 teeth, [ka] is

[0210] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0211] In certain embodiments, M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 teeth, [ka] is.

[0212] In certain embodiments, the compound of formula II is a compound of formula IIa, wherein R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3.

[0213] In certain embodiments, the compound of formula II is a compound of formula IIa, wherein R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3.

[0214] In certain embodiments, the compound of formula II is a compound of formula IIa, wherein R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0215] In certain embodiments, the compound of formula II is a compound of formula IIa, wherein R 3 is CF3 and R 4 is -CH2CH2CF3.

[0216] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3.

[0217] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3.

[0218] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0219] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0220] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3.

[0221] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4alkyl-, and R 4 is -CH2CH2CF3.

[0222] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3.

[0223] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3.

[0224] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0225] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-4 alkyl-, and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C 1-4Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0226] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3 Alkoxy C1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0227] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 are halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O) q -, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, HaloC 1-4 Alkyl, Hydroxy C 1-4 Alkyl-, R a R b NC 1-4 Alkyl-, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, Hydroxy C 1-4 Alkoxy-, R a R b NC 1-4 Alkoxy-, C 1-3Alkoxy C 1-4 Alkyl-, HaloC 1-3 Alkoxy C 1-4 Alkyl-, R a R b NC(O)-, C 1-4 Alkyl C(O)-, C 1-4 AlkoxyC(O)-, C 1-4 Alkyl C(O)O-, C 1-4 AlkylS(O) q -, C 1-4 AlkylS(O) q NR c -, C 1-6 AlkylS(O) q C 1-4 Alkyl-, C 1-4 Alkyl C(O)C 1-6 Alkyl-, and C 1-6 Alkyl C(O)OC 1-4 and phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

[0228] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0229] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is Haro C 1-2 alkyl, and R 4 is CH2CH2CF3, and R 5 teeth, [ka] is.

[0230] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF2CH3, and R 5 teeth, [ka] is.

[0231] In certain embodiments, the compound of Formula II is a compound of Formula IIa, wherein M is -CHF- and R 1 is C(O)OH, and R 3 is CF3 and R 4 is -CH2CH2CF3, and R 5 teeth, [ka] is.

[0232] III. Pharmaceutical Compositions and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In particular, the present disclosure provides a pharmaceutical composition comprising the compound disclosed herein, formulated 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 administration form in any given case depends on the degree and severity of the condition being treated and the properties of the specific compound used. For example, the disclosed compositions can be formulated as a unit dose and / or can be formulated for oral or subcutaneous administration.

[0233] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any combination of the examples described herein, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0234] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, solid, semi-solid, or liquid forms, which contain one or more compounds of the present disclosure as an active ingredient mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient can be formulated with conventional non-toxic, pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0235] To prepare solid compositions such as tablets, the primary active ingredient is 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, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to 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.

[0236] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are 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 starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum 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) liquid retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0237] Tablets can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be produced by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field.

[0238] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, and powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the subject composition, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0239] Suspensions may contain, in addition to the subject compositions, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0240] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate; suppositories are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0241] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0242] Ointments, pastes, creams, and gels may contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0243] Powders and sprays can contain, in addition to the subject compositions, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0244] Alternatively, the compositions and compounds of the present disclosure may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Sonic nebulizers may be used because they minimize exposure of the drug to shear, which can lead to degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween®, Pluronic®, or polyethylene glycol), serum albumin, sorbitan esters, innocuous proteins such as oleic acid and lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0245] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0246] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0247] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) 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. Thus, the enteric material is not soluble up to a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or 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, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, and natural resins such as copal collophorium, as well as some commercially available enteric dispersions (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 known or can be readily determined in vitro. While the foregoing is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that it is not comprehensive and that other enteric materials exist that would meet the objectives of this disclosure.

[0248] Advantageously, the present disclosure also provides kits for use by, for example, a purchaser in need of treatment for HBV infection. Such kits include a suitable dosage form, as described above, and instructions describing how to use such dosage form to mediate, mitigate, or prevent HBV infection. The instructions may instruct the purchaser or a medical professional to administer the dosage form according to an administration mode known to those skilled in the art. Such kits may be advantageously packaged and sold in single or multiple kit units. One example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a 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 packaged. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed against the plastic foil with the side of the foil opposite 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 tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses, through which the tablets or capsules can then be removed.

[0249] For example, it may be desirable to provide a memory aid on the kit in the form of numbers next to the tablets or capsules, the numbers corresponding to the days of the regimen on which the designated tablets or capsules should be taken. Another example of such a memory aid is, for example, a calendar printed on a card, such as "Week 1, Monday, Tuesday, etc., Week 2, Monday, Tuesday, etc." Other types of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule to be taken on a given day, or several tablets or capsules. Also, a daily dose of a first compound can consist of one tablet or capsule, and a daily dose of a second compound can consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

[0250] IV. Method In a further aspect, a method of treating hepatitis B infection in a patient in need thereof is provided, comprising administering to the subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and, optionally, additional, different disclosed compound(s). In another embodiment, a method of treating hepatitis B infection in a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a disclosed compound or a disclosed pharmaceutical composition comprising two or more disclosed compounds and a pharmaceutically acceptable excipient.

[0251] With regard to HBV / HDV co-infection, HDV encodes HDAg, and HDV proteins are involved in HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with the HBV viral envelope protein HBsAg, both for entry into hepatocytes and for the assembly and release of HDV virions. See, for example, Negro, Cold Spring Harb Perspect Med. 2014 Nov 3; 4(11): a021550. doi:10.1101 / cshperspect.a021550, which is incorporated herein by reference for its background teachings. Therefore, because HDV infection depends on the presence of existing HBV infection, strategies for treating HBV / HDV co-infection can focus on targeting HBV alone, HDV alone, or both viruses together.

[0252] Accordingly, the present disclosure also contemplates a method of treating HBV or HDV infection, or HBV / HDV coinfection, in a patient in need thereof, comprising administering to the 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 of treating HBV or HDV infection, or HBV / HDV coinfection, in a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a disclosed compound, or a disclosed pharmaceutical composition or pharmaceutical compositions comprising two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0253] Without being bound by any theory, treatment methods can be promoted by various mechanisms of action. One possibility for treatment involves targeting the machinery involved in viral particle assembly. In the case of HBV, inhibiting the assembly of the HBV envelope or core by targeting HBsAg can disrupt the assembly of HBV particles. A second strategy can be to inhibit the viral replication of HBV and / or HDV. Existing antiviral therapies can apply this approach, for example, in the form of replication inhibitors that target specific viral RNA polymerases.

[0254] Accordingly, another aspect of the present disclosure is a method of inhibiting HBV or HDV viral replication in a patient in need thereof, comprising administering to the subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and, optionally, additional, different disclosed compound(s). In another embodiment, a method of inhibiting HBV or HDV viral replication in a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a disclosed compound, or a disclosed pharmaceutical composition or pharmaceutical compositions comprising two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0255] Therapeutic methods may further include targeting the bile acid transport protein network, which is thought to be a "gateway" for HBV or HDV infection entry into hepatocytes. See, for example, Slijepcevic et al., Digestive Diseases, 2017;35:251-258, incorporated herein by reference for its background teachings. The bile acid transport system, including sodium taurocholate cotransporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT), is a set of receptors that ensure effective bile acid transport between the ileum and hepatocytes. HBV / HDV coinfection of hepatocytes is thought to be mediated via the NTCP receptor and may be a therapeutic target. Without being bound by any theory, "entry inhibitors" may target any of the possible bile acid transport receptors, including, but not limited to, sodium taurocholate cotransporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT), to prevent HBV or HDV virus entry into cells. Such entry inhibitors may target all or a portion of the transport receptor to inhibit viral entry.

[0256] Accordingly, another aspect of the present disclosure is a method of inhibiting viral entry in liver cells of a patient in need thereof, comprising administering to the subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and, optionally, additional, different disclosed compound(s). In another embodiment, a method of inhibiting viral entry in liver cells of a patient in need thereof is provided, comprising administering to the subject or patient a therapeutically effective amount of a disclosed compound, or a disclosed pharmaceutical composition or pharmaceutical compositions comprising two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0257] Regardless of the targeted mechanism, treatment of patients suffering from HBV or HDV infection or HBV / HDV coinfection can 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.

[0258] Suitable dosages of the compounds described herein for use in accordance with the embodiments described herein are expected to vary depending, for example, on the particular compound used, the mode of administration, and the nature and severity of the infection being treated, as well as the particular infection being treated, and are within the purview of the treating physician. Typically, suggested dosages may range from about 0.1 to about 1000 μg / kg body weight. In some cases, the dosage of the compound may be less than 400 μg / kg body weight. In other cases, the dosage may be less than 200 μg / kg body weight. In still other cases, the dosage may range from about 0.1 to about 100 μg / kg body weight. This dosage may conveniently be administered once daily or in divided doses, for example, up to four times daily, or in sustained-release form.

[0259] The compound of the present disclosure can be administered by any conventional route, specifically enterally, topically, orally, nasally, for example, in the form of tablets or capsules, through suppositories, or parenterally, for example, in the form of injectable solutions or suspensions, for example, for intravenous, intramuscular, subcutaneous or intraperitoneal injection.Suitable formulations and pharmaceutical compositions include the formulations and pharmaceutical compositions that are formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of the formulations and pharmaceutical compositions that are known, commercially available, and currently used in clinical settings.Therefore, the compound can be formulated for oral administration, buccal administration, topical administration, parenteral administration, rectal administration, or transdermal administration, or can be formulated in a form suitable for administration by inhalation or insufflation (either oral or nasal).

[0260] For oral administration, the pharmaceutical compositions may take the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), 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 glycolate), or wetting agents (e.g., sodium lauryl sulfate). 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 can 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). The preparations can also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate.

[0261] Preparations for oral administration may also be suitably formulated to give controlled or sustained release of the active compound(s) over an extended period of time. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner known to those skilled in the art.

[0262] The disclosed compounds can also be formulated for parenteral administration, for example, by bolus injection or continuous infusion.The preparations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives.The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain additives such as suspending agents, stabilizers, and / or dispersing agents.Alternatively, the compounds can be in powder form, for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.The compounds can also be formulated for rectal administration, such as suppositories or retention enemas, containing conventional suppository bases, for example, cocoa butter or other glycerides.

[0263] Methods and compositions that include or administer a second active agent are also contemplated herein. For example, in addition to being infected with HBV, a subject or patient may also have HBV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by HBV infection. The disclosed compounds are contemplated herein in combination with at least one other agent previously shown to treat these HBV infection-related conditions.

[0264] In some cases, the disclosed compounds can be administered as part of a combination therapy with one or more antiviral agents. Exemplary antiviral agents include nucleoside analogs, interferon alpha, and other assembly effectors, such as 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, a method for treating a patient suffering from hepatitis B infection is provided herein, which comprises administering to the patient a first amount of the disclosed compound and a second amount of an antiviral agent, or other anti-HBV agent, such as a second amount of an HBV capsid assembly promoter (e.g., GLS4, BAY41-4109, AT-130, DVR-23 (e.g., as described below), [ka] NVR3-778, NVR1221 (by code), and N890 (as shown below): [ka] Other capsid inhibitors, such as those disclosed in the following patent applications, which are hereby incorporated by reference: WO2014 / 037480, WO2014 / 184328, WO2013 / 006394, WO2014 / 089296, WO2014 / 106019, WO2013 / 102655, WO2014 / 184350, WO2014 / 184365, WO2014 / 161888, WO2014 / 131847, WO2014 / 033176, WO2014 / 033167, and WO 2014 / 033170; Nucleoside analogues that interfere with viral polymerases, such as entecavir (Baraclude), lamivudine (Epivir-HBV), telbivudine (Tyzeka, Sebivo), adefovir divoxil (Hepsera), tenofovir (Viread), tenofovir alaphenylamide fumarate (TAF), prodrugs of tenofavir (e.g., AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir), and: [ka] viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9AC' and related nucleic acid-based amphiphilic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as shown below: [ka] and the BM601 shown below: [ka] Disruptors of nucleocapsid formation or integrity, such as NZ-4 / W28F: [ka] cccDNA formation inhibitors such as BSBI-25, CCC-0346, and CCC-0975 (shown below): [ka] and administering a second compound selected from the group consisting of:

[0265] 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: http: / / dx.doi.org / 10.1016 / j.intimp.2015.01.028; antiviral core protein mutants (such as Cp183-V124W and related mutants described in WO / 2013 / 010069, WO2014 / 074906 (each incorporated by reference)); RNAi, HBV Inhibitors of HBx interaction, such as RNA-targeted antisense and nucleic acid-based polymers; for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid-based polymers: (REP2139-Ca); interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peg-interferon alpha 2a), pegylated IFN2b, IFN lambda 1a, and PEG Immunostimulants such as IFN lambda 1a, lymphotoxin beta agonists such as Wellferon, Roferon, Infergen, 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, and Resiquimod; cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, and core antigen vaccines; SMAC mimetics, e.g., birinapant and other IAP antagonists;Epigenetic modulators, for example, 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 and ATR kinase inhibitors; STING agonists; ribavirin; N-acetylcysteine; NOV-205 (BAM205); nitazoxanide (Alinia), tizoxanide; SB9200 small molecule nucleic acid hybrid (SMNH); DV-601; arbidol; FXR agonists (such as GW4064 and fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins.

[0266] In some embodiments, the present disclosure provides a method of treating 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 an HBV capsid assembly promoter, an HBF viral polymerase-interfering nucleoside, a viral entry inhibitor, an HBsAg secretion inhibitor, a disruptor of nucleocapsid formation, a cccDNA formation inhibitor, an antiviral core protein mutant, an HBc-directed transbody, an RNAi targeting HBV RNA, an immunostimulant, a TLR-7 / 9 agonist, a cyclophilin inhibitor, an HBV vaccine, a SMAC mimetic, an epigenetic modulator, a kinase inhibitor, and a STING agonist. In some embodiments, the present disclosure provides a method of treating hepatitis B infection in a patient in need thereof, comprising administering an amount of the disclosed compound and another HBV therapeutic agent.

[0267] In some embodiments, the present disclosure further provides a method of treating an HBV or HDV infection or an 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 antiviral agents, wherein the one or more additional antiviral agents include one or more of an HDV therapy and an HBV agent, each selected from the group consisting of an HBV capsid assembly promoter, an HBF viral polymerase-interfering nucleoside, a viral entry inhibitor, an HBsAg secretion inhibitor, a disruptor of nucleocapsid formation, a cccDNA formation inhibitor, an antiviral core protein mutant, an HBc-directed transbody, an RNAi targeting HBV RNA, an immunostimulant, a TLR-7 / 9 agonist, a cyclophilin inhibitor, an HBV vaccine, a SMAC mimetic, an epigenetic modulator, a kinase inhibitor, and a STING agonist. In some embodiments, the disclosure provides methods of treating 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 or HDV therapeutic agent.

[0268] 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 as, greater than, or less than the effective amount of each compound administered as a monotherapy. The therapeutically effective amounts of the disclosed compounds and antiviral agents can be co-administered to a subject, i.e., can be administered simultaneously or separately to a subject in any given order by the same or different administration routes. In some cases, it may be advantageous to first start administering the disclosed compounds, for example, one or more days or one week before starting administration of the antiviral agent. Furthermore, additional drugs can be given in conjunction with the above-mentioned combination therapy.

[0269] In another embodiment, the disclosed compounds can be conjugated (e.g., covalently attached directly or via a molecular linker to a free carbon, nitrogen (e.g., amino group), or oxygen (e.g., active ester) of the disclosed compounds) with a detection moiety, e.g., a fluorophore moiety (such a moiety can re-emit a specific light frequency, e.g., 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, anthraquinone, fluorescent protein, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety can be used, for example, in methods for detecting HBV or the biological pathway of HBV infection, e.g., in vitro or in vivo, and / or in methods for evaluating new compounds for biological activity. [Example]

[0270] V. Working Examples The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art.In the description of synthetic methods described below, unless otherwise indicated, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental period and post-treatment procedures, can be selected as standard conditions for the reaction.Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions.Substituents that are incompatible with the reaction conditions will be obvious to those skilled in the art, and therefore alternative methods will be shown.The starting materials of the examples are commercially available or can be easily prepared from known materials by standard methods.

[0271] At least some of the compounds identified herein as "intermediates" are contemplated as compounds of the present disclosure. [Table 7-1] [Table 7-2]

[0272] Example 1. (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)ethane-1-sulfonic acid [ka] 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), MeMgBr (51.8 mL, 155.3 mmol, 3.0 M) was added dropwise in an ice bath under nitrogen. The mixture was stirred at room temperature for 6 hours. The resulting mixture was then quenched with saturated aqueous NH4Cl (200 mL). The mixture was extracted with EA (200 mL × 2), and the combined organic layers were 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) (R f :0.4). MS(ESI):C 13 H 23 Calculated for NO5: 273.2; Found: 174.1 [M-Boc+1] + .

[0273] 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), BAST (77.7 g, 351.6 mmol) was added dropwise in an ice bath under nitrogen, and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was slowly poured into saturated aqueous NaHCO3 solution (150 mL) at 0 °C and extracted with EA (150 mL × 2). The combined organic layers were 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) (R f :0.4). MS(ESI):C 13 H 23 Calculated for F2NO4: 295.2 MS Found: 196.2 [M-Boc+1] + .

[0274] 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 / HO = 5 / 1 (v / v) (100 mL) was added LiOH (3.4 g, 140.3 mmol). After stirring at room temperature for 4 h, the reaction mixture was diluted with water (100 mL), acidified with 1 N aqueous HCl solution until the pH was approximately 3, and concentrated to remove the organic solvent. The residue was extracted with EA (100 mL × 2). The combined organic layers were 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) (R f :0.4). MS(ESI):C 11 H 19 Calculated for F2NO4: 267.1; Found: 168.2 [M-Boc+1] + .

[0275] 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, 63.5 mmol) in an ice bath under nitrogen in small portions. After stirring for 40 min, PhNH (5.9 g, 63.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h and then concentrated. The residue was diluted with HO (150 mL) and extracted with EA (150 mL × 2). The combined organic extracts were washed with brine (150 mL), dried over anhydrous NaSO, 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) (R f :0.4). MS(ESI):C 17 H 24 Calculated for F2N2O3: 342.2; Found: 287.2 [M-tBu+1] + .

[0276] 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 hours and concentrated. The residue was diluted with DCM (100 mL) and basified with saturated aqueous NaHCO3 until the pH was approximately 8. The resulting mixture was extracted with DCM (100 mL x 4). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 1-6 (4.8 g, 89%) as a yellow oil, which was used in the next step without further purification. TLC: 8% MeOH / DCM (v / v) (R f :0.5). MS(ESI):C 12 H 16 Calculated for F2N2O: 242.2; Found: 243.2 [M+1] + .

[0277] 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) dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 4 h. The reaction was quenched with HO (2.3 mL) and 15% aqueous NaOH solution (2.3 mL) at 0 °C. The resulting mixture was dried over NaSO and 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) (R f :0.3). MS(ESI):C 12 H 18 Calculated value for F2N2: 228.1; Measured value: 229.3 [M+1] + .

[0278] 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), 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (2.3 g, 6.59 mmol) was added portionwise at room temperature. After stirring for 16 h at room temperature, the mixture was diluted with HO (30 mL) and extracted with EA (25 mL × 2). The combined organic extracts were dried over NaSO and 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) (R f :0.4). MS(ESI):C 20 H 22 Calculated for BrF5N2O3S: 544.0; Found: 545.1 [M+1] + .

[0279] 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), picolinic acid (72 mg, 0.59 mmol), KCO (1.2 g, 8.82 mmol), and CuI (38 mg, 0.59 mmol) in DMF (20 mL) was stirred at 90 °C for 3 h under a N atmosphere. The reaction mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with EA (25 mL × 3). The combined organic extracts were washed with saturated aqueous LiCl (30 mL) and brine (30 mL), dried over anhydrous NaSO, 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 in the next step without further purification. TLC: 25% EA / PE (v / v) (R f :0.4). MS(ESI):C 20 H 21 Calculated for F5N2O3S: 464.1; Found: 465.1 [M+1] + .

[0280] 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 CsCO (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 room temperature for 3 h and diluted with HO (30 mL). The resulting mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, 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 in the next step without further purification. TLC: 25% EA / PE (v / v) (R f :0.6). MS(ESI):C 21 H23 Calculated for F5N2O3S: 478.1; Found: 479.1 [M+1] + .

[0281] 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), NaSMe (1.6 g, 23.0 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL), acidified with 4 N aqueous HCl solution until the pH reached 5-6, and extracted with EA (50 mL × 3). The combined organic layer was washed with saturated aqueous LiCl (25 mL) and brine (25 mL), dried over anhydrous NaSO, and 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) (R f :0.4). MS(ESI):C 20 H 21 Calculated for F5N2O3S: 464.1; Found: 465.3 [M+1] + .

[0282] Step 11. Synthesis of (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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), sodium 2-bromoethane-1-sulfonate (611 mg, 2.91 mmol) was added, and the reaction mixture was stirred at 130 °C for 16 h. The reaction mixture was diluted with water (20 mL) and acidified with 4 N aqueous HCl solution until the pH was approximately 5. The resulting mixture was extracted with EA (25 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give Example 1 (112 mg, 20.2%) as a white solid. TLC: 5% MeOH / EA (v / v) (R f :0.5). MS(ESI):C 22 H 25 Calculated for F5N2O6S2: 572.1; Found: 573.0 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.69(s,1H), 7.47(s,1H), 7.25-7.17(m,2H), 6.83(t,J=7.2Hz,1H), 6.78-6.66(m,2H), 4.56(t,J=8.0Hz,2H), 4.20-4.05(m,1H), 4.0 0-3.82(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=18.8Hz,3H)ppm.

[0283] Example 2. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] 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 room temperature for 1 h, the reaction mixture was added with ice-cold water (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, 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) (R f :0.6) (phosphomolybdic acid). MS(ESI):C8H 14 Calculated value for O5S: 222.1; Measured value: 240.1 [M+18] + .

[0284] Step 2. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 CsCO (156 mg, 0.48 mmol) in DMF (2 mL), 10-2 (71 mg, 0.32 mmol) was added, and the reaction mixture was heated at 70 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was added to water (10 mL). The precipitate was collected by filtration, washed with water (5 mL × 3), and dried in vacuo to give crude 2-3 (120 mg) as a white solid, which was used in the next step without further purification. TLC: 40% EA / PE (v / v) (R f :0.5). MS(ESI):C 27 H 31 Calculated for F5N2O5S: 590.2; Found: 591.3 [M+1] + .

[0285] Step 3. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 / HO=2 / 1 (v / v) (3 mL) was added NaOH (22 mg, 0.55 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aqueous HCl solution, concentrated, and the organic solvent was removed. The residue was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC to give Example 2 (28 mg, 45%) as a white solid. TLC: 10% MeOH / DCM (v / v) (R f :0.5). MS(ESI):C 25 H 27 Calculated for F5N2O5S: 562.2; Found: 563.2 [M+1] + . 1 H NMR(400MHz,CD3OD,):δ 7.65(s,1H), 7.46(s,1H), 7.23-7.19(m,2H), 6.83(t,J=7.2Hz,1H), 6.73(d,J=7.2Hz,2H), 4.41-4.32(m,2H), 4.18-3.87(m,2H), 3.3 7-3.33(m,1H), 2.64(s,3H), 2.12-1.92(m,2H), 1.85-1.78(m,2H), 1.62(t,J=18.4Hz,3H), 1.35-1.31(m,2H), 1.13-1.09(m,2H)ppm.

[0286] Example 3. (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)oxetane-3-carboxylic acid [ka] 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) was added (3-(bromomethyl)oxetan-3-yl)methanol (156 mg, 0.86 mmol) and CsCO (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 × 2). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was dried in vacuo to give crude 3-1 (243 mg) as a brown solid, which was used in the next step without further purification. MS (ESI): C 25 H 29 Calculated for F5N2O5S: 564.2; Found: 565.2 [M+1] + .

[0287] Step 2. Synthesis of (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 room temperature for 5 h, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give Example 3 (60 mg, 24%) as a white solid. MS (ESI): C 25 H 27 Calculated for F5N2O6S: 578.2; Found: 579.3 [M+1] + . 1H NMR(400MHz,CD3OD):δ 7.73(s,1H), 7.49(s,1H), 7.22(dd,J=8.6,7.4Hz,2H), 6.84(t,J=7.4Hz,1H) 6.75(d,J=7.6Hz,2H), 4.97(dd,J=5.8,2.2Hz,2H), 4.75(dd,J=5.8,1.4Hz,2 H), 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=18.4Hz,3H)ppm.

[0288] Example 4. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)-3,3-difluorocyclobutane-1-carboxylic acid [ka] 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-butoxyliminium hydride in THF (18.9 mL, 18.9 mmol) at 0 °C. After stirring at 70 °C for 16 h, the reaction was quenched with saturated aqueous NH4Cl at 0 °C until no more bubbles were observed. The mixture was diluted with water (80 mL), concentrated to remove the organic solvent, and extracted with EA (30 mL × 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): CH 14 Calculated for F2O3: 208.2; Found: 209.2 [M+1] + .

[0289] 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) and 2,6-dimethylpyridine (308 mg, 2.88 mmol) in DCM (5 mL) was added TfO (400 mg, 1.92 mmol) at −78 °C. After stirring at −78 °C for 1 h, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give crude 4-3 (200 mg, 31%) as a yellow solid, which was used in the next step without further purification.

[0290] Step 3. Synthesis of (R)-isopropyl 1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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) and Cs2CO3 (205 mg, 0.63 mmol) in DMF (3 mL), 4-3 (200 mg, 0.59 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (20 mL × 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 in the next step without further purification. MS (ESI): C 29 H 33 Calculated for F7N2O5S: 654.2; Found: 655.4 [M+1] + .

[0291] Step 4. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 1 N aqueous LiOH solution (1 mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH=6 with 1 N aqueous HCl solution and then purified by preparative HPLC to give Example 4 (30 mg, 24%) as an off-white solid. MS (ESI): C 26 H 27 Calculated for F7N2O5S: 612.2; Found: 613.0 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.68(s,1H), 7.47(s,1H), 7.26-7.18(m,2H), 6.85(t,J=7.2Hz,1H), 6.76(d,J=4.0Hz,2H), 4.47(s,2H), 4.25-4.05(m,1H), 3.99-3.84(m,1) H), 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=18.4Hz,3H)ppm.

[0292] Example 5. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] Step 1. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylate (5-2). Following the same procedure to prepare 1-11, which was readily prepared by replacing aniline with 4-F-aniline, to a stirred solution of 5-1 (140 mg, 0.29 mmol) in CsCO (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 65 °C for 3 h, the reaction mixture was added to water (10 mL). The precipitate was filtered, washed with water (10 mL × 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) (R f :0.5). MS(ESI):C 27 H 30 Calculated for F6N2O5S: 608.2; Found: 609.2 [M+1] + .

[0293] Step 2. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-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 / HO = 2 / 1 (v / v) (6 mL) was added NaOH (79 mg, 1.97 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aqueous HCl solution, concentrated, and the organic solvent was removed. The residue was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give Example 5 (49 mg, 43%) as a white solid. TLC: EA / PE=1 / 1 (v / v) (R f :0.5). MS(ESI):C 25 H 26 Calculated for F6N2O5S: 580.1; Found: 581.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.64(s,1H), 7.41(s,1H), 6.97(t,J=8.4Hz,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=18.4Hz,3H), 1.35-1.34(m,2H), 1.13-1.11(m,2H)ppm.

[0294] Example 6a. (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid [ka] Step 1. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-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), methyl (R)-3-hydroxy-2-methylpropanoate (1.8 g, 15.2 mmol) and PPh3 (2.4 g, 9.3 mmol) were added. Then, DIAD (6.3 g, 31.1 mmol) was added at 110 °C under a nitrogen atmosphere. After stirring at 110 °C for 4 h, the reaction mixture was poured into water and extracted with EtOAc (200 mL × 3). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column to give 6a-1 (1.6 g, 89%) as a yellow solid. MS (ESI): C 26 H 30 Calculated for F6N2O5S: 582.1; Found: 583.2 [M+1] + .

[0295] Step 2. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-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) / HO (10 mL) was added LiOH (660 mg, 27.5 mmol). After stirring at room temperature for 4 h, the reaction mixture was poured into water. The mixture was adjusted to pH = 3 with 3 N aqueous HCl, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC to give Example 6a (600 mg, 40%) as a white solid. MS (ESI): C 24 H 26 Calculated for F6N2O5S: 568.1; Found: 569.2 [M+1] +. 1 H 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=18.4Hz,3H), 1.32(d,J=7.2Hz,3H)ppm.

[0296] Example 6b. (S)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid [ka] Following the same procedure to prepare Example 6a, by substituting 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): C 24 H 26 Calculated for F6N2O5S: 568.1; Found: 569.2 [M+1] + . 1 H 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=18.4Hz,3H), 1.32(d,J=7.2Hz,3H)ppm.

[0297] Example 7. (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid [ka] 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), TEA (2.08 g, 20.56 mmol) was added, followed by anhydrous methanesulfone (2.68 g, 15.39 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was diluted with HO (80 mL) and extracted with DCM (30 mL × 2). The combined organic extracts were dried over anhydrous NaSO 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): CH 16 Calculated value for O5S: 224.1; Measured value: 242.2 [M+18] + .

[0298] Step 2. Synthesis of (R)-ethyl 3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-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), KCO (1.29 g, 9.33 mmol) and 7-2 (1.4 g, 6.2 mmol, crude) were added sequentially. After stirring at 110 °C for 48 h, the reaction mixture was diluted with HO (80 mL) and extracted with EA (50 mL × 3). The combined organic extracts were washed with saturated aqueous LiCl (100 mL) and brine, dried over anhydrous NaSO, 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): C 27 H 32 Calculated for F6N2O5S: 610.2; Found: 611.0 [M+1] + .

[0299] Step 3. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 7). To a solution of 7-3 (1.8 g, 2.95 mmol) in CHOH / THF / HO (8 mL / 8 mL / 8 mL), LiOH . HO (1.24 g, 29.55 mmol) was added. After stirring at 35 °C for 3 hours, the reaction mixture was diluted with HO (100 mL), adjusted to pH = 2 with 2N aqueous HCl solution, and extracted with EtOAc (60 mL × 3). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by reverse column (CHCN / HO = 40% (v / v)) to give Example 7 (740 mg, 43%) as a white solid. MS (ESI): C 25 H 28Calculated for F6N2O5S: 582.2; Found: 582.8 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.61(s,1H), 7.42(s,1H), 6.96(t,J=8.8Hz,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=18.4Hz,3H), 1.33(s,6H)ppm.

[0300] Examples 8a and 8b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (8b) [ka] 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), MsCl (70.06 g, 611.64 mmol) was added dropwise at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was added with HO (500 mL) at 0 °C. The resulting mixture was extracted with DCM (1000 mL × 2). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give 8-2 (110 g, 79%) as a brown liquid, which was used in the next step without further purification.

[0301] 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) portionwise at room temperature. After stirring at 60 °C for 3 h, the mixture was cooled to room temperature, and HO (200 mL) was added at room temperature. The resulting mixture was extracted with EA (300 mL × 2). The combined organic extracts were washed with brine (300 mL), dried over anhydrous NaSO, 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. 1 H NMR (300MHz, CDCl3): δ 3.77(s,3H), 3.56(qd,J=10.2,6.4Hz,2H), 2.94-2.81(m,1H), 2.02-1.80(m,4H), 1.62(t,J=18.4Hz,3H)ppm.

[0302] 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 CsCO (151.60 g, 463.85 mmol) in ACN (500 mL) was added dropwise 8-3 (100.15 g, 386.56 mmol) at room temperature. After stirring for 4 h at room temperature, the reaction mixture was added with water (50 mL) at room temperature. The resulting mixture was extracted with EA (500 mL × 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA = 4 / 1 (v / v) to give 8-4 (80 g, 62%) as a brown liquid. MS (ESI): C 15 H 21 Calculated for F2NO3S: 333.1; Found: 334.1 [M+1] + .

[0303] 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 HO (200 mL) was added LiOH (20.26 g, 845.87 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified with 2 N aqueous HCl solution until the pH was approximately 6. The resulting mixture was extracted with EA (100 mL × 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated. The 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): C 14 H 19 Calculated for F2NO3S: 319.1; Measured: 320.1 [M+1] + .

[0304] 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 dropwise DIEA (38.85 g, 300.59 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then HO (50 mL) was added. The resulting mixture was extracted with DCM (50 mL × 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA = 7 / 3 (v / v) to give 8-6 (67 g, 89%) as a yellow solid. MS (ESI): C 14 H 17 Calculated value for F2NO2S: 301.1; Measured value: 302.1 [M+1] + .

[0305] 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) portionwise at room temperature. The resulting mixture was stirred at room temperature for 4 h, and then HO (100 mL) was added at room temperature. The resulting mixture was extracted with DCM (200 mL × 2). The combined organic extracts were washed with brine (200 mL), dried over anhydrous NaSO, 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): C 14 H 16 Calculated for BrF2NO2S: 379.0; Found: 380.0 [M+1] + . 1H NMR(300MHz,CDCl3):δ 7.39(s,1H), 7.34(s,1H), 7.14(s,1H), 3.94(s,3H), 3.53(dd,J=11.3,6.0Hz,1H), 3.02(t,J=11.9Hz, 1H), 2.68(ddd,J=16.4,9.3,5.2Hz,1H), 2.17-2.00(m,1H), 2.04-1.70(m,1H), 1.68-1.47(m,5H)ppm.

[0306] 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), 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) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 16 h, then cooled to room temperature, and water (100 mL) was added. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine (30 mL × 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): C 20 H 19 Calculated for BrF3NO2S: 473.0; Found: 474.0 [M+1] + .

[0307] 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). To a solution of 8-8 (3 g, 6.33 mmol) in THF (40 mL) and HO (20 mL) was added Oxone® (63.81 g, 379.500 mmol) at room temperature. After stirring at room temperature for 16 h, the mixture was filtered, and the filter cake was washed with ethyl acetate (25 mL × 3). The filtrate was concentrated, and the residue was diluted with saturated aqueous NaHCO3 (25 mL) and EtOAc (150 mL). The separated organic layer was washed with saturated aqueous NaHCO3 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): C 20 H 19 Calculated for BrF3NO4S: 505.0; Found: 506.0 [M+1] + .

[0308] 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 (2.81 mL, 29.622 mmol) in THF at room temperature. After stirring at 75 °C for 16 h, the mixture was cooled to 0 °C, ice water (30 mL) was added, and concentrated to remove the organic solvent. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine (10 mL × 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): C 20 H 21 Calculated for BrF3NO3S: 491.0; Found: 492.0 [M+1] + .

[0309] 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), LiHMDS (6.5 mL, 1 mol / L in THF) was added dropwise at −78 °C. After stirring at −78 °C for 30 min, NFSI (1.23 g, 3.90 mmol) was added dropwise at −78 °C. The resulting mixture was stirred at −78 °C for an additional 2 h. A saturated aqueous solution of NH4Cl was added to the reaction mixture at room temperature, followed by concentration to remove the organic solvent. The resulting mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine (10 mL × 3), dried over anhydrous NaSO, 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): C 20 H 20 Calculated for BrF4NO3S: 509.0; Found: 510.0 [M+1] + .

[0310] 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) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (602.30 mg, 3.14 mmol) and CuBr (224.87 mg, 1.57 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 16 hours, and then water (15 mL) was added at room temperature. The resulting mixture was extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine (10 mL × 3), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (PE / EA=3 / 1 (v / v)) to give 8-12 (200 mg, 51%) as a yellow solid. MS (ESI): C 21 H 20 Calculated value for F7NO3S: 499.1; Measured value: 500.1 [M+1] + .

[0311] 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 room temperature. The resulting mixture was stirred at 140 °C for 8 hours, and then water (15 mL) was added at room temperature. The mixture was acidified with saturated aqueous citric acid until the pH was approximately 5. The resulting mixture was extracted with EtOAc (15 mL × 3). The combined organic extracts were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative TLC (PE / EA=3 / 1 (v / v)) to give cis-racemic 8-13 (50 mg, 26%) as a yellow solid. MS (ESI): C 20 H 18Calculated for F7NO3S: 485.1; Measured: 486.2 [M+1] + .

[0312] 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). Racemic 8-13 (40 mg) was separated by preparative SFC under the following conditions: Column: (R,R)-WHELK-O1-Kromasil, 3 x 25 cm, 5 μm; Mobile phase A: CO2; Gradient: Isocratic 20% B; RT1 (min) = 2.6 (8-13a as a single diastereomer, stereochemistry arbitrarily assigned); RT2 (min) = 3.6 (8-13b as a single diastereomer, stereochemistry arbitrarily assigned); Sample solvent: MeOH-HPLC; Injection volume: 4 mL) to give 8-13a (15 mg) as a pale yellow solid and 8-13b (15 mg) as a pale yellow solid. MS (ESI): C 20 H 18 Calculated for F7NO3S: 485.1; Measured: 486.2 [M+1] + .

[0313] Step 14a. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxide-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) was added ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (9.20 mg, 0.045 mmol) and CsCO (20.40 mg, 0.06 mmol) at room temperature. After stirring at 80 °C for 2 h, the reaction mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine (10 mL × 3), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (PE / EA = 3 / 1 (v / v)) to give 8-14a (16 mg, 79%) as a yellow solid (single diastereomer, stereochemistry arbitrarily assigned). MS (ESI): C 27 H 28 Calculated value for F7NO5S: 611.2; Measured value: 612.1 [M+1] + .

[0314] Step 15a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxide-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, 0.025 mmol) in 1,4-dioxane (4 mL) was added LiOH (35.25 mg, 1.47 mmol) and HO (1 mL) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was diluted with water (10 mL) and concentrated to remove the organic solvent. The residue was acidified with saturated aqueous citric acid until the pH was about 5 and extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC under the following conditions: Column: SunFire Prep C18 OBD column, 19*150 mm, 5 μm, 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, stereochemistry arbitrarily assigned). MS (ESI): C 25 H 24 Calculated value for F7NO5S: 583.1; Measured value: 584.2 [M+1] + . 1 H 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=12.0Hz,1H), 5.69(d,J=45.6Hz,1H), 4.43(s,2H), 4 .19(d,J=14.4Hz,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=18.6Hz,3H), 1.33(s,2H), 1.13(s,2H)ppm.

[0315] Step 14b. Synthesis of ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxide-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, stereochemistry arbitrarily assigned). MS (ESI): C 27 H 28 Calculated value for F7NO5S: 611.2; Measured value: 612.1 [M+1] + .

[0316] Step 15b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8b). Example 8b (10 mg, 69%) was obtained as a white solid (single diastereomer, stereochemistry arbitrarily assigned) following the same procedure as described for preparing Example 8a by replacing 8-14a with 8-14b (16 mg, 0.025 mmol). Preparative HPLC conditions: Column: SunFire Prep C18 OBD column, 19 x 150 mm, 5 μm; 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; RT (min) = 5.92. MS (ESI): C 25 H 24 Calculated value for F7NO5S: 583.1; Measured value: 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=2.1Hz,1H), 6.42-6.31(m,1H), 5.69(d,J=45.0Hz,1H), 4.43(s,2H), 4 .18(d,J=15.6Hz,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=6.9Hz,3H), 1.35(s,2H), 1.12(s,2H)ppm.

[0317] 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) [ka] 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 EtN (15.97 g, 0.16 mol) in DMF (300 mL) was treated with Cu(OAc) (14.33 g, 78.90 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under an oxygen atmosphere. The mixture was cooled to room temperature and diluted with EtOAc (300 mL) and saturated aqueous NH4Cl (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. The 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): C 20 H 19 Calculated for BrF3NO2S: 473.0; Found: 473.9 [M+1] + . 1 H NMR(300MHz,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=11.1,6.0Hz,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=18.6Hz,4H)ppm.

[0318] 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 HO (500 mL) was added Oxone® (107 g, 0.31 mol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was filtered. The filtrate was concentrated to remove the organic solvent, and the residue was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, 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): C 20 H 19 Calculated for BrF3NO4S: 505.0; Found: 506.0 [M+1] + . 1 H NMR(300MHz,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 .6,12.0Hz,1H), 2.99(dd,J=12.0,5.7Hz,1H), 2.01-1.80(m,4H), 1.58(t,J=18.9Hz,3H)ppm.

[0319] 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 BH MeS in THF (48 mL) dropwise at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The reaction was quenched by the addition of HO (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 2 / 1 (v / v) as the eluent to give 9A-3 (20 g, 85.7%) as a brown solid. MS (ESI): C 20 H 21 Calculated for BrF3NO3S: 491.0; Found: 492.0 [M+1] + . 1 H NMR (300MHz, DMSO-d6): δ7.61(s,1H), 7.52(s,1H), 7.02(t,J=8.8Hz,2H), 6.64(dd,J=8.6,4.4Hz,2H), 4.21(d,J=15.1Hz,1H), 3 .98(s,3H), 3.60(dd,J=14.9,3.4Hz,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.

[0320] 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 LiHMDS (1 mol / L in THF) (2.8 mL, 10.15 mmol) dropwise at −78 °C under a N atmosphere. The reaction mixture was stirred at −78 °C for 30 min. 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 minutes. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the mixture was then extracted with EtOAc (50 mL × 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 the eluent to give 9A-4 (1.5 g, 57.9%) as a brown solid. MS (ESI): C 20 H 20 Calculated for BrF4NO3S: 509.0; Found: 510.0 [M+1] + . 1 H NMR(300MHz,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.

[0321] 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), CuBr (95.57 g, 0.67 mol) was added portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 130 °C for 16 h under a N atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of HO (10 L) at room temperature. The resulting mixture was extracted with EA (3 L × 2). The combined organic layers were washed with brine (3 L), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 3 / 1 (v / v) as an eluent to give 9A-5a (60 g, 36.1%, cis-racemic) and 9A-5b (45 g, 27.1%, trans-racemic) as yellow solids, respectively.

[0322] 9A-5a:MS(ESI):C 21 H 20 Calculated value for F7NO3S: 499.1; Measured value: 500.1 [M+1] + . 11H 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.

[0323] 9A-5b: MS (ESI): C 21 H 20 Calculated for C19H17F7NO3S: 499.1; Found: 500.1 [M+1] + . 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.

[0324] 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). To 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 hours under a 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 NaSO, and concentrated. The residue was purified by silica gel column chromatography using PE / EA = 8 / 1 (v / v) as the eluent to give 9-1a (43 g, 73.7%, cis-racemic) as a yellow oil. MS (ESI): C 20 H 18 Calculated for F7NO3S: 485.1; Measured: 486.3 [M+1] + . 1 H NMR(300MHz,DMSO-d6):δ 11.68(s,1H), 7.70(s,1H), 7.56(s,1H), 7.03(t,J=9.0Hz,2H), 6.62(dd,J=9.3,4.5Hz,2H), 6.03(d,J=44.4Hz,1H), 4. 15(d,J=15.9Hz,1H), 3.20(dd,J=15.9,11.4Hz,1H), 2.69-2.60(m,1H), 2.22-2.06(m,2H), 1.61(t,J=18.9Hz,5H)ppm.

[0325] 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 purified 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, The separation was carried out using the following procedure: 1.0 min 50% hold; back pressure (bar): 150; flow rate (mL / min): 3.0; column temperature (°C): 35; UV detection wavelength: 220 nm. (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) (t R = 0.43 min; single diastereomer) as a white solid, (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 (t R =0.69 min; single diastereomer) was obtained as a white solid.

[0326] 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). To 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) and DMSO (450 mL) was added LiCl (38.19 g, 0.90 mol) at room temperature. After stirring at 140° C. for 16 hours under a nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL×2). The combined organic layers were washed with brine (1000 mL×4), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography using PE / EA=8 / 1 (v / v) as the eluent to give 9-1b (30 g, 68.6%) as a yellow oil. MS (ESI): C 20 H 18 Calculated for F7NO3S: 485.1; Measured: 486.2 [M+1] + . 1 H NMR(300MHz,DMSO-d6):δ 11.53(s,1H), 7.68(s,1H), 7.38(s,1H), 7.06(t,J=8.7Hz,2H), 6.86-6.76(m,2H), 5.88(dd,J=44.4,7.8Hz,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=18.9Hz,3H)ppm.

[0327] 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). 1 H, 13 C. 19 The relative stereochemistry of cis-racemic 9A-5a and the corresponding trans-racemic 9A-5b was elucidated using F, HH COSY, CH HSQC, CH HMBC, HH NOESY, and FH NOESY NMR techniques. [ka] 1 H NMR (400 MHz, CDCl): δ 7.75 (s, 1H, H13), 7.53 (s, 1H, H9), 7.04-6.93 (m, 2H, H24 and H26), 6.70-6.60 (m, 2H, H23 and 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(101MHz,CDCl3):δ 157.15(d,J=240.0Hz,C25), 155.68(C11), 141.84(d,J=2.0Hz,C22), 139.50(14), 138.03(C8), 129.28(q,J=5 .0Hz,C9), 125.64(q,J=32.1Hz,C10), 123.29(t,J=238.7Hz,C2), 122.11(q,J=273.7Hz,C30), 116.57(d,J=7.6 Hz, C23 and C27), 116.21 (d, J = 22.6 Hz, C24 and 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. 19 F NMR (376 MHz, CDCl3): δ -63.33 (F31, F32, and F33), -91.54 (d, J = 240.0 Hz, F18), -92.55 (d, J = 240.1 Hz, F19), -124.24 (F28), -197.24 (F29) ppm. FH NOESY NMR data suggest that F29 correlates with H4 but not with H5. [ka] 1 H NMR(400MHz,CDCl3):δ 7.70(s,1H,H13), 7.28(s,1H,H9), 7.08-6.96(m,4H,H23,H24,H26 and H27), 5.26(dd,J=44.8,5.2Hz,1H,H16), 4.12(d,J=9.6Hz,1H,H 6'), 4.02(s,3H,H17), 3.63(d,J=15.2Hz,1H,6''), 2.47-2.37(m,1H,H5), 2.03-1.81(m,4H,H3 and H4), 1.47(t,J=18.4Hz,3H,H1)ppm. 13C NMR(101MHz,CDCl3):δ 158.58(d,J=243.2Hz,C25), 154.21(C11), 143.71(C22), 140.51(C8), 136.87(C14), 126.72(9), 1 25.51(q,J=32.1Hz,C10), 123.63(t,J=238.5Hz,C2), 122.12(q,J=273.8Hz,C30), 122.00(C23 ​​and C 27), 116.52(d,J=22.6Hz,C24 and C26), 112.83(C13), 101.97(d,J=216.1Hz,C16), 56.78(C17), 49. 38(C6), 41.51(d,J=18.7Hz,C5), 35.31(t,J=25.9Hz,C3), 23.07(t,J=27.6Hz,C1), 21.12(C4)ppm. 19 F NMR (376 MHz, CDCl): δ -63.36 (F31, F32, and F33), -90.41 (d, J = 247.8 Hz, F18), -91.48 (d, J = 238.7 Hz, F19), -119.97 (F28), -176.92 (F29) ppm. FH NOESY NMR data suggest that F29 correlates with H5 but not with H4.

[0328] Examples 9a and 9b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (9b) [ka] Step 1. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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), prepared following the same procedure described to prepare racemic 8-13, substituting 4-fluoro-iodobenzene for 3-fluoro-iodobenzene, was added cesium carbonate (40.40 mg, 0.12 mmol) and ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (19.20 mg, 0.09 mmol) dropwise at room temperature. After stirring at 80°C for 3 hours, the reaction mixture was cooled to room temperature, water (10 mL) was added, and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (PE / EA = 4 / 1 (v / v)) to give 9-2 (30 mg, 79%) as a brown solid. MS (ESI): C 27 H 28 Calculated value for F7NO5S: 611.2; Measured value: 500.2 [M+1] + .

[0329] Step 2. Synthesis of rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (1 mL) was stirred at room temperature for 16 h. The mixture was acidified with 2 N aqueous HCl solution until the pH was approximately 4. The resulting mixture was concentrated to remove the organic solvent, diluted with water (10 mL), and extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 78% B, 78% B in 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.26 to give 9-3 (15 mg) as a white solid.

[0330] Step 3. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9b). Racemic 9-3 (15 mg) was purified by preparative SFC using the following conditions: (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, stereochemistry arbitrarily assigned) (4.1 mg) as a white solid. MS (ESI): C 25 H 24 Calculated value for F7NO5S: 583.1; Measured value: 584.2 [M+1] + . 1 H 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, stereochemistry arbitrarily assigned) (2.2 mg) was obtained as a white solid. MS (ESI): C 25 H 24 Calculated value for F7NO5S: 583.1; Measured value: 584.2 [M+1] + . 1H NMR(300MHz,CD3OD):δ 7.83(s,1H), 7.55(s,1H), 6.98(t,J=8.7Hz,2H), 6.73-6.69(m,2H), 5.68(d,J=45.3Hz,1H), 4.45(s,2H), 4.20(d,J=1 5.6Hz,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.

[0331] Examples 10a and 10b. 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (10b). [ka] Step 1. Synthesis of rac-methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 CsCO (2.42 g, 7.41 mmol) in DMF (50 mL), KI (1.23 g, 7.41 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (1.04 g, 4.94 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of HO (150 mL) at room temperature. The resulting mixture was extracted with EA (50 mL × 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, 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): C 26 H 28 Calculated value for F7NO5S: 599.2; Measured value: 600.2 [M+1] + .

[0332] Step 2. Synthesis of methyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (800 mg) was purified by preparative SFC using the following conditions: Column: (R,R)-WHELK-O, 3*25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: MeOH; Flow rate: 80 mL / min; Gradient: isocratic 20% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 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, stereochemistry arbitrarily assigned) and 10-2b (240 mg) (single diastereomer, stereochemistry arbitrarily assigned) as white solids, respectively. MS (ESI): C 26 H 28 Calculated value for F7NO5S: 599.2; Measured value: 600.2 [M+1] + .

[0333] Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (3 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl solution until pH = 4 and extracted with EA (10 mL × 2). The combined organic extracts were then washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD 5 μm 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): 2.69. The collected solution was concentrated under vacuum to remove the ACN, and the resulting solution was lyophilized to give Example 10a (168 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.2 [M+1] + . 1 H NMR(300MHz,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=45.3Hz,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.

[0334] Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (3 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl solution until pH = 4 and extracted with EA (10 mL × 2). The combined organic extracts were then washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD 5 μm 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 the ACN, and the resulting solution was lyophilized to give Example 10b (163 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.2 [M+1] + . 1 H NMR(300MHz,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=45.3Hz,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.

[0335] Relative stereochemistry determination of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 10b). 1 H, 13 C. 19 The relative stereochemistry of Example 10b was elucidated using F, HH COSY, CH HSQC, CH HMBC, HH NOESY, and FH NOESY NMR techniques. [ka] 1 H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H, H13), 7.57 (s, 1H, H9), 7.06-6.91 (m, 2H, H33 and H31), 6.78-6.65 (m, 2H, H34 and 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=16.0,11.2Hz,1H,H6"), 2.82-2.62(m,1H,H5), 2.28-1.9 9(m,2H,H3), 1.81-1.65(m,2H,H4), 1.65(t,J=18.5Hz,3H,H1), 1.37(s,6H,H28 and H29)ppm. 13C NMR(75MHz,CD3OD):δ 177.77(C23), 156.90(d,J=237.4Hz,C32), 154.84(C11), 142.37(C21), 140.35(C14), 138.30(C8), 129.17(q,J=4.6H z,C9), 124.97(q,J=31.9Hz,C10), 123.79(t,J=237.6Hz,C2), 127.33-116.85(m,C36), 116.16(d,J=7.7Hz,C34 and C30 ), 115.31(d,J=22.7Hz,C31 and C33), 114.27(C13), 101.98(d,J=219.9Hz,C18), 75.47(C20), 47.68(C6), 42.65(C22) , 37.61(d,J=18.5Hz,C5), 34.36(t,J=25.9Hz,C3), 22.12(t,J=27.7Hz,C1), 21.59-21.30(m,C4), 21.19(C28 and C29). 19 F NMR (282 MHz, CD3OD): δ -64.47 (F37, F38, and F39), -92.72 (d, J = 10.9 Hz, F26 and F27), -127.48 (F35), -199.65 (F19) ppm. FH NOESY NMR data suggest that F19 correlates with H4 but not with H5.

[0336] Examples 10c and 10d. 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (10d) [ka] Step 1. Synthesis of rac-methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-racemic) (200 mg, 0.41 mmol) and CsCO (402.73 mg, 1.24 mmol) in DMF (5 mL), KI (205.19 mg, 1.24 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (137.36 mg, 0.62 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature, and then water was added to quench the reaction. The resulting mixture was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (PE / EA = 5 / 1 (v / v)) to give 10A-1 (130 mg, 52.63%, trans-racemic) as a white solid. MS (ESI): C 26 H 28 Calculated value for F7NO5S: 599.2; Measured value: 600.1 [M+1] + .

[0337] Step 2. Synthesis of methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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-difluoroxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-1) (90 mg) was purified by preparative 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): C 26 H 28 Calculated value for F7NO5S: 599.2; Measured value: 600.1 [M+1] + ) and 10A-2b (24 mg, 53%, single diastereomer, MS(ESI):C 26 H 28 Calculated value for F7NO5S: 599.2; Measured value: 600.1 [M+1] + ) was obtained as a white solid.

[0338] Step 3a. Synthesis of 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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 HO (1 mL) was stirred at 50 °C for 12 h. Then, the mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC (Column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; 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): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.1 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.75(s,1H), 7.33(s,1H), 7.09-7.04(m,4H), 5.59(dd,J=44.1,6.0Hz,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=18.3Hz,3H), 1.36(s,6H)ppm.

[0339] Step 3b. Synthesis of 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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 HO (1 mL) was stirred at room temperature for 12 h. The mixture was acidified with 2 N aqueous HCl solution until pH = 4. The resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC (Column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; 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): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.1 [M+1] + . 1 H NMR (300MHz, CD3OD): δ7.75(s,1H), 7.33(s,1H), 7.09-7.04(m,4H), 5.59(dd,J=44.1,6.0Hz,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=18.3Hz,3H), 1.36(s,6H)ppm.

[0340] Example 10c / d. rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid. [ka] Step 1. Synthesis of rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (10A-1, trans-racemic) (40 mg, 0.24 mmol) in dioxane (4 mL) was treated with water (1 mL) at room temperature under a nitrogen atmosphere for 3 minutes, followed by the dropwise addition of LiOH (47.62 mg, 2.26 mmol) at room temperature. The resulting mixture was stirred at 50° C. for 12 hours. The mixture was then acidified with concentrated aqueous HCl until pH=3. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Sunfire Prep C18 OBD column, 19*150 mm, 5 μm; 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 the resulting solution was dried by lyophilization to give Example 10c / d (10.4 mg, 48.6%, trans-racemic) as a white solid. MS (ESI): C 25 H 28 Calculated value for F7NO5S: 585.1; Measured value: 586.1 [M+1]+ . 1 H NMR(300MHz,CD3OD):δ 7.75(s,1H), 7.33(s,1H), 7.09-7.04(m,4H), 5.59(dd,J=44.1,5.8Hz,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=18.3Hz,3H), 1.36(s,6H)ppm.

[0341] 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). 1 H, 13 C. 19 The relative stereochemistry of trans-racemic Example 10c / d was elucidated using F, HH COSY, CH HSQC, CH HMBC, HH NOESY, and FH NOESY NMR techniques. [ka] 1 H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H, H13), 7.33 (s, 1H, H9), 7.12-6.99 (m, 4H, H34, H33, H31 and 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 and H3), 1.45 (t, J = 18.6 Hz, 3H, H1), 1.36 (s, 6H, H28 and H29) ppm. 13C NMR(76MHz,CD3OD):δ 178.06(C23), 155.06(d,J=228.8Hz,C32), 153.50(C11), 143.96(C21), 140.66(C14), 138.08(C8), 126. 86(C9), 124.86(q,J=31.8Hz,C10), 126.86-120.46(m,C2), 120.57(C36), 115.81(C31 and C33), 115.51( C30 and 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 and C29), 20.93-20.55 (C4) ppm. 19 F NMR (282 MHz, CD3OD): δ -64.51 (F37, F38, and F39), -92.49 (F26 and F27), -123.43 (F35), -178.25 (F19). FH NOESY NMR data suggest that F19 correlates with H5 but not with H4.

[0342] Examples 11a and 11b. (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoic acid (11b) [ka] Step 1. Synthesis of rac-methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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) was added triphenylphosphine (2.59 g, 9.89 mmol) and methyl (R)-3-hydroxy-2-methylpropanoate (0.58 g, 4.944 mmol) at room temperature under a N atmosphere. The resulting mixture was stirred at 110 °C for 6 h. The mixture was allowed to cool to room temperature. The reaction was quenched with HO at room temperature. The resulting mixture was extracted with EA (50 mL × 2). The combined organic extracts were then washed with brine (50 mL), dried over anhydrous NaSO, 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): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.2 [M+1] + .

[0343] Step 2. Synthesis of methyl (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoate (11-1) (700 mg) was purified by preparative SFC using the following conditions: Column: (R,R)-WHELK-O, 3*25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: MeOH; Flow rate: 80 mL / min; Gradient: Isocratic 30% B; Column temperature (°C): 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, stereochemistry arbitrarily assigned) and 11-2b (260 mg) (single diastereomer, stereochemistry arbitrarily assigned) as white solids, respectively. MS (ESI): C 25 H 26 Calculated value for F7NO5S: 585.1; Measured value: 586.2 [M+1] + .

[0344] Step 3a. Synthesis of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (3 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl solution until pH = 4. The resulting mixture was extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The crude product (300 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; 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 the ACN, and the resulting solution was lyophilized to give Example 11a (108 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 24 H 24 Calculated value for F7NO5S: 571.1; Measured value: 572.2 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.79(s,1H), 7.54(s,1H), 6.97(t,J=8.7Hz,2H), 6.70(dd,J=9.1,4.2Hz,2H), 5.68(d,J=45.3Hz,1H), 4.41-4.28(m,2H), 4.18(d,J=1 5.9Hz,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=7.2Hz,3H)ppm.

[0345] Step 3b. Synthesis of (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (3 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl solution until pH = 4 and extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The crude product (300 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; 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): 0.92. The collected solution was concentrated under vacuum to remove the ACN, and the resulting solution was lyophilized to give Example 11b (single diastereomer, stereochemistry arbitrarily assigned) (106 mg) as a white solid. MS (ESI): C 24 H 24 Calculated value for F7NO5S: 571.1; Measured value: 572.2 [M+1] + . 1 H NMR (300 MHz, CD3OD): δ 7.79(s,1H), 7.54(s,1H), 6.97(t,J=8.7Hz,2H), 6.70(dd,J=9.1,4.2Hz,2H), 5.68(d,J=45.3Hz,1H), 4.44-4.30(m,1H), 4.28-4.20(m,1H), 4. 18(d,J=15.9Hz,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=7.2Hz,3H)ppm.

[0346] Examples 12a and 12b. (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (12b) [ka] 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 a nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (150 mL × 2). The combined organic extracts were washed with water (200 mL × 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): C 20 H 19 Calculated for BrF3NO2S: 473.0; Found: 474.0 [M+1] + .

[0347] 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 HO (100 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (120 mL × 3). The mixture was acidified with saturated aqueous NaHCO3 until the pH was 8. The resulting mixture was extracted with EtOAc (150 mL × 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): C 20 H 19 Calculated for BrF3NO4S: 505.0; Found: 506.0 [M+1] + .

[0348] 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. The reaction mixture was then cooled to 0 °C with ice water, MeOH (50 mL) was added (dropwise) at 0 °C, and concentrated in vacuo. The residue was dissolved in water (150 mL), and the resulting mixture was extracted with EtOAc (100 mL × 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): C 20 H 21Calculated for BrF3NO3S: 491.0; Found: 492.0 [M+1] + .

[0349] 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) under a nitrogen atmosphere at −78 °C for 30 min. After stirring at −78 °C for 30 min, a solution of NFSI (3.20 g, 10.16 mmol) in THF (20 mL) was added dropwise at −78 °C. The resulting mixture was stirred at −78 °C for 3 h under a nitrogen atmosphere, followed by the addition of water (100 mL) at 0 °C. The mixture was then concentrated to remove the organic solvent, and the residue was extracted with EtOAc (80 mL × 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous NaSO, 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): C 20 H 19 Calculated for BrF5NO3S: 527.0; Found: 528.0 [M+1] + . 1 H NMR(400MHz,CDCl3):δ 7.73(s,1H), 7.63(s,1H), 7.02(t,J=8.4Hz,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.

[0350] 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 room temperature under a nitrogen atmosphere. After stirring at 130 °C for 16 h under a nitrogen atmosphere, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with water (50 mL × 5) and brine (50 mL), dried over anhydrous NaSO, 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 pale yellow oil. MS (ESI): C 21 H 19 Calculated value for F8NO3S: 517.1; Measured value: 518.0 [M+1] + .

[0351] 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 room temperature. After stirring at 140 °C for 8 h, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and acidified with citric acid (10% w / w) until the pH reached 5. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with water (50 mL × 5) and brine (50 mL), dried over anhydrous NaSO, 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 pale yellow oil. MS (ESI): C 20H 17 Calculated value for F8NO3S: 503.1; Measured value: 504.0 [M+1] + .

[0352] Step 7. Synthesis of ethyl 1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxide-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 CsCO (414.22 mg, 1.27 mmol) at room temperature. After stirring at 100° C. for 16 hours, the mixture was cooled to room temperature, diluted with water (15 mL), and extracted with EtOAc (20 mL×3). The combined organic extracts were washed with water (20 mL×5) and brine (20 mL), dried over anhydrous NaSO, 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 pale yellow oil. MS (ESI): C 27 H 27 Calculated value for F8NO5S: 629.1; Measured value: 630.1 [M+1] + .

[0353] Step 8. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxide-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-dioxide-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 preparative 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), respectively. MS(ESI): C 27 H 27 Calculated value for F8NO5S: 629.1; Measured value: 630.1 [M+1] + and 12-8b (33 mg), MS(ESI):C 27 H 29 Calculated for F6NO5S: 593.2; Measured: 630.1 [M+1] + was obtained as a white solid.

[0354] Step 9a. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (1 mL) was treated with LiOH (5.33 mg, 0.23 mmol) at room temperature. After stirring at 40 °C for 16 h, the mixture was cooled to room temperature, acidified with 2 N aqueous HCl until pH was 3, and extracted with EtOAc (15 mL × 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 60% B, 60% B in 8 min; wavelength: 254 / 220 nm) to give Example 12a (18.2 mg, 53.5%) as a white solid. MS (ESI): C 25 H 23 Calculated value for F8NO5S: 601.1; Measured value: 602.1 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.82(s,1H), 7.52(s,1H), 7.00(t,J=8.4Hz,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.

[0355] Step 9b. (S)-1-(((3-(3,3-Difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxide-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 HO (1 mL) was treated with LiOH (5.28 mg, 0.22 mmol) at room temperature. After stirring at 40 °C for 16 h, the mixture was cooled to room temperature, acidified with 2 N aqueous HCl until the pH was 3, and extracted with EtOAc (15 mL × 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45% B to 60% B, 60% B in 8 min; wavelength: 254 / 220 nm) to give Example 12b (21.2 mg, 66.9%) as a white solid. MS (ESI): C 25 H 23 Calculated value for F8NO5S: 601.1; Measured value: 602.1 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.83(s,1H), 7.52(s,1H), 7.00(t,J=8.4Hz,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.

[0356] Examples 13a and 13b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-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-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (13b) [ka] Step 1. To a stirred mixture of 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) and 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), add 1 Following the same procedure used to prepare -10, 2-bromo-4-trifluoromethyl-5-methoxyphenylsulfonyl chloride was replaced with 2,4-dibromo-5-methoxyphenylsulfonyl chloride, and the racemic version of 1-7 was prepared by using the racemic version of 3,3-difluorocyclobutanethiol (0.89 g, 7.15 mmol) in DMF (15 mL) and adding NaH (55% suspension in mineral oil) (0.446 g, 18.59 mmol) portionwise at 0 °C. After stirring at 0 °C for 30 min and at room temperature for 2 h, the mixture was stirred at 70 °C for 12 h. The mixture was then diluted with ice water (5 mL), acidified with saturated aqueous NaHSO4, and extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to give 13-2 (700 mg, 66%) as a white solid.

[0357] Step 2. Synthesis of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-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 60 °C for 16 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC to give 13-3 (0.172 g, 71%) as a white solid.

[0358] Step 3. Synthesis of methyl (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-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-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (13-3b). Racemic 13-3 (140 mg) was purified 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: 24 °C; wavelength: 205 nm). R 1 = 20.60 min (single enantiomer, stereochemistry arbitrarily assigned); and t R 2 = 27.17 min (single enantiomers, stereochemistry arbitrarily assigned) to give 13-3a (45.3 mg) and 13-3b (45.2 mg), respectively, as white solids.

[0359] Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13a). To a stirred solution of 13-3a (45.3 mg, 71.82 μmol) in THF / HO=4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (9.0 mg, 214.0 μmol). After stirring at room temperature for 12 hours, the reaction mixture was adjusted to a pH of approximately 2 using 2 N aqueous HCl. The resulting mixture was purified by preparative HPLC to afford Example 13a (24.8 mg, 56%) as a white solid (single enantiomer, stereochemistry arbitrarily assigned). MS(ESI):C 28 H 32 Calculated for F4N2O5S2: 616.2; Found: 614.9 [M-1] - . 1 H NMR(500MHz,DMSO-d6):δ 12.45(s,1H), 7.27(s,1H), 7.14(t,J=7.8Hz,2H), 6.95(s,1H), 6.70(t,J=7.3Hz,1H), 6.63 (d,J=8.1Hz,2H), 4.21(q,J=9.8Hz,2H), 4.06(d,J=16.0Hz,1H), 3.82(s,2H), 3.13(s,1H), 2.99(d,J=12.4Hz,1H), 2.64-2.50(m,2H), 2.47(s,3H), 1.98(tt,J=16.3,8.2Hz,2H), 1.83 (t,J=7.0Hz,1H), 1.63(t,J=18.9Hz,4H), 1.20(t,J=3.5Hz,2H), 1.06(q,J=3.3Hz,2H)ppm.

[0360] Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13b). Following the same procedure described in Step 4a, substituting 13-3b (45.2 mg, 71.66 μmol) for 13-3a, Example 13b (27.5 mg, 63%) was obtained as a white solid (single enantiomer, stereochemistry arbitrarily assigned). MS (ESI): C 28 H 32 Calculated for F4N2O5S2: 616.2; Found: 614.9 [M-1] - . 1 H NMR(500MHz,DMSO-d6):δ 12.45(s,1H), 7.27(s,1H), 7.14(t,J=7.8Hz,2H), 6.95(s,1H), 6.70(t,J=7.3Hz,1H), 6. 63(d,J=8.1Hz,2H), 4.21(q,J=9.8Hz,2H), 4.06(d,J=15.9Hz,1H), 3.82(s,2H), 3.26(s,1 H), 3.13(s,1H), 2.98(s,1H), 2.64-2.50(m,2H), 2.47(s,3H), 1.98(tt,J=16.2,8.0Hz,2 H), 1.83(d,J=8.4Hz,1H), 1.63(t,J=18.9Hz,4H), 1.21(d,J=3.0Hz,2H), 1.06(s,2H)ppm.

[0361] Example 14 (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] 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 room temperature for 5 h. 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 × 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous NaSO, 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) (R f :0.4). MS(ESI):C 18 H 21 Calculated for BrClF2N3O3S: 511.0; Found: 512.1 [M+1] + .

[0362] 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), Cu (150 mg, 2.35 mmol) was added, and the resulting mixture was heated at 115 °C for 5 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), and the aqueous layer was extracted with EA (50 mL × 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 in the next step without further purification. TLC: EA / PE=1 / 5 (v / v) (R f :0.5). MS(ESI):C 18 H 20 Calculated for ClF2N3O3S: 431.1; Found: 432.2 [M+1] + .

[0363] 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, 2.78 mmol) and CsCO (2.7 g, 8.4 mmol) in NMP (20 mL), MeI (1.2 g, 8.4 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. 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 × 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous NaSO, 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) (R f:0.4). MS(ESI):C 19 H 22 Calculated for ClF2N3O3S: 445.1; Found: 446.2 [M+1] + .

[0364] 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), CHCl (519 mg, 7.4 mmol) was added, and the reaction mixture was heated at 95 °C for 16 h. 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 × 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous NaSO, 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) (R f :0.6). MS(ESI):C 19 H 23 Calculated for F2N3O3S2: 443.1; Found: 444.1 [M+1] + .

[0365] Step 5. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxide-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), ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (50 mg, 0.23 mmol) was added, and the reaction mixture was heated at 65 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was added to 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 in the next step without further purification. TLC: EA / PE = 3 / 7 (v / v) (Rf: 0.5). MS (ESI): C 26 H 33 Calculated for F2N3O5S2: 569.2; Found: 570.2 [M+1] + .

[0366] Step 6. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxide-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 3 mL of MeOH / HO = 2 / 1 (v / v), NaOH (43 mg, 1.02 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was adjusted using 1N aqueous HCl solution. The aqueous layer was extracted with EA (10 mL × 3), and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give Example 14 (31 mg, 56%) as a white solid. TLC: EA / PE = 3 / 2 (v / v) (R f :0.5). MS(ESI):C 24 H29 Calculated for F2N3O5S2: 541.2; Found: 542.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.45(s,1H), 7.33-7.29(m,2H), 7.09(d,J=8.0Hz,2H), 7.04(t,J=7.2Hz,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=18.4Hz,3H), 1.34-1.31(m,2H), 1.12-1.09(m,2H)ppm.

[0367] Example 15. (R)-1-(((3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] Following the same procedure as that for preparing Example 14, but substituting 3-F-annulin for aniline, Example 15 was obtained as a white solid (16 mg). TLC: EA / PE=1 / 1 (v / v) (R f :0.3). MS(ESI):C 24 H 28 Calculated for F3N3O5S2: 559.1; Found: 560.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.50(s,1H), 7.25(q,J=8.0Hz,1H), 6.77-6.73(m,1H), 6.70-6.65(m,2H), 4.27(q,J=10.0Hz,2H), 4.14-4.07(m,1H), 3.91-3.85(m,2) H), 2.76(s,3H), 2.17(s,3H), 2.12-1.96(m,2H), 1.91-1.77(m,2H), 1.61(t,J=18.4Hz,3H), 1.33-1.31(m,2H), 1.11-1.10(m,2H)ppm

[0368] Example 16 (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] Following the same procedure as that for preparing Example 14, but substituting 4-F-aniline for aniline, Example 16 was obtained as a white solid (12 mg). TLC: EA / PE=1 / 1 (v / v) (R f :0.3). MS(ESI):C 24 H 28 Calculated for F3N3O5S2: 559.1; Found: 560.2 [M+1] + . 1 H NMR(400MHz,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), 2.9 0(s,3H), 2.14-1.92(m,6H), 1.71-1.67(m,1H), 1.59(t,J=18.4Hz,3H), 1.31-1.29(m,2H), 1.08-1.05(m,2H)ppm.

[0369] Examples 17a and 17b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-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-dioxide-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (17b) [ka] 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) in DMF (15 mL), NaH (55% suspension in mineral oil) (0.502 g, 20.92 mmol) was added portionwise at -10 °C. The reaction mixture was reacted at this temperature for 0.5 h and then stirred at room temperature for 2 h. The temperature was then raised to 70 °C, and the reaction mixture was kept under stirring for 12 h. Next, the reaction mixture was diluted with ice water (15 mL), acidified with saturated aqueous NaHSO4, and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to give 17-1 (768 mg, 64%) as an off-white solid.

[0370] Step 2. Synthesis of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-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 60 °C for 16 h. Then, the mixture was diluted with ice water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC to give 17-2 (0.222 g, 75%) as an off-white solid.

[0371] Step 3. Chiral separation of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylate (17-2). Compound 17-2 (170 mg) was separated by chiral HPLC to give 17-2a (77 mg) and 17-2b (79 mg) as white solids, respectively. The stereochemistry of the single enantiomers was arbitrarily assigned.

[0372] Preparative 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 °C, and Wavelength: 205 nm. R = 13.03 min (single enantiomer 17-2a), and t R = 18.59 min (single enantiomer 17-2b).

[0373] Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17a). To a stirred solution of 17-2a (77.3 mg, 0.12 mmol) in THF / HO = 4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (15.3 mg, 0.36 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was then acidified with 2N aqueous HCl until the pH reached approximately 2. The resulting mixture was purified by preparative HPLC to afford Example 17a (55.1 mg, 73%) as a white solid. MS (ESI): C 27 H 31 Calculated for F4N3O5S2: 617.2; Found: 616.2 [M-1] - . 1 H NMR(500MHz,DMSO-d6):δ 12.41(s,1H), 7.43(s,1H), 7.31(t,J=7.7Hz,2H), 7.09(d,J=8.0Hz,2H), 7.04(t,J=7.4H) z,1H), 4.21-4.14(m,2H), 4.10(d,J=16.1Hz,1H), 3.96(s,1H), 3.68(s,1H), 3.38(d,J=16 .4Hz,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=8.9Hz,1H), 1.59(t,J=18.9Hz,3H), 1.18(q,J=3.9Hz,2H), 1.01(q,J=3.9Hz,2H)ppm.

[0374] Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17b). To a stirred solution of 17-2b (78.9 mg, 0.12 mmol) in THF / HO = 4 / 1 (v / v) (2 mL) was added lithium hydroxide hydrate (15.6 mg, 0.37 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was then acidified with 2N aqueous HCl until the pH reached approximately 2. The resulting mixture was purified by HPLC to give Example 17b (53.9 mg, 71%). MS (ESI): C 27 H 31 Calculated for F4N3O5S2: 617.2; Found: 616.2 [M-1] - . 1 H NMR(500MHz,DMSO-d6):δ 12.42(s,1H), 7.43(s,1H), 7.31(t,J=7.8Hz,2H), 7.09(d,J=7.9Hz,2H), 7.04(t,J=7. 4Hz,1H), 4.21-4.14(m,2H), 4.10(d,J=15.8Hz,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=5.9Hz,1H), 1.59(t,J=18.9Hz,3H), 1.18(q,J=3.8Hz,2H), 1.01(q,J=3.8Hz,2H)ppm.

[0375] Examples 18a and 18b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxide-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-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid 18b [ka] 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 h. The mixture was allowed to cool to room temperature and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL × 3), and the combined organic extracts were washed with brine (10 mL × 1), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (10 / 1 (v / v)) to give 18-1 (500 mg, 59.4%) as a white solid. MS (ESI): C 21 H 23 Calculated for F4NO3S2: 477.1; Found: 478.0 [M+1] + .

[0376] 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 allowed to cool to room temperature and then quenched with water. The resulting mixture was extracted with EtOAc (5 mL × 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, 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): C 20 H 21 Calculated for F4NO3S2: 463.1; Measured: 464.0 [M+1] + .

[0377] Step 3. Synthesis of rac-ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxide-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 CsCO (224.94 mg, 0.69 mmol) in DMF (10 mL), KI (114.61 mg, 0.69 mmol) and ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (57.54 mg, 0.26 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL × 3), and the combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (PE / EA = 5 / 1 (v / v)) to give 18-3 (60 mg, 59.0%) as a white solid. MS (ESI): C 27 H 31 Calculated for F4NO5S2: 589.2; Measured: 590.1 [M+1] + .

[0378] Step 4. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxide-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-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (18-3b). Compound 18-3 (60 mg) was purified by preparative chiral HPLC using the following column conditions: 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; Run Number: 5. The collected fractions were concentrated to dryness to give 18-3a (19 mg) (RT2 = 20.3 min, single diastereomer, stereochemistry arbitrarily assigned) and 18-3b (25 mg) (RT1 = 15.8 min, single diastereomer, stereochemistry arbitrarily assigned), respectively, as white solids. MS (ESI): C 27 H 31 Calculated for F4NO5S2: 589.2; Measured: 590.2 [M+1] + .

[0379] Step 5a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxide-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 HO (1 mL) was stirred at 40 °C for 24 h. The mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD 5 μm 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 the ACN, and the resulting solution was lyophilized to give Example 18a (17 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 27 Calculated for F4NO5S2: 561.1; Measured: 562.2 [M+1] + . 1 H NMR(300MHz,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=45.3Hz,1H), 4.39-4.32(m,2H), 4.16(d,J=15.9Hz) ,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.

[0380] Step 5b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxide-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 HO (1 mL) was stirred at 40 °C for 24 h. The mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD 5 μm 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 the ACN, and the resulting solution was lyophilized to give Example 18b (22 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 27 Calculated for F4NO5S2: 561.1; Measured: 562.2 [M+1] + . 1 H NMR(300MHz,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=45.3Hz,1H), 4.36(s,2H), 4.16(d,J=15.9Hz,1 H), 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.

[0381] Examples 19a and 19b. 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (19b) [ka] 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), 4,4-difluorocyclohexan-1-one (3.03 g, 22.60 mmol) in THF (50 mL) was added PhSiH (2.45 g, 22.60 mmol) and BuSnCl (4.58 g, 15.06 mmol) at room temperature. The resulting mixture was refluxed for 24 h. The mixture was cooled to room temperature 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): C 20 H 26 Calculated for BrF4NO3S: 515.1; Found: 516.0 [M+1] + .

[0382] 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 1 M LiHMDS in THF (10.07 mL, 10.07 mmol) dropwise at −78 °C under a N atmosphere. The reaction mixture was stirred at −78 °C for 30 min. Then, a solution of NFSI (1.59 g, 5.04 mmol) in 2 mL of THF was added dropwise, and the mixture was stirred for an additional 4 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL), and the mixture was then extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, 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): C 20 H 25 Calculated for BrF5NO3S: 533.1; Found: 534.0 [M+1] + .

[0383] 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) portionwise at room temperature under a N atmosphere. The resulting mixture was stirred at 130 °C for 16 h under a N atmosphere. The mixture was allowed to cool to room temperature and then quenched with HO (5 mL). The resulting mixture was extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, 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): C 21 H 25 Calculated value for F8NO3S: 523.1; Measured value: 524.0 [M+1] + .

[0384] 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 room temperature. The resulting mixture was stirred at 100 °C for 2 h under a N atmosphere. The mixture was allowed to cool to room temperature and then quenched with HO (5 mL). The resulting mixture was extracted with EA (10 mL × 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, 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): C 20 H 23 Calculated value for F8NO3S: 509.1; Measured value: 510.0 [M+1] + .

[0385] 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 a N atmosphere. The resulting mixture was stirred at −40° C. for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (100 mL) at −40° C. The resulting mixture was extracted with EA (10 mL × 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): C 20 H 23 Calculated value for F8NO3S: 509.1; Measured value: 510.0 [M+1] + .

[0386] Step 6. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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 CsCO (125.10 mg, 0.38 mmol) in DMF (2 mL), KI (42.36 mg, 0.27 mmol) and ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (179.17 mg, 0.49 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature 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 preparative TLC (PE / EA = 4 / 1 (v / v)) to give 19-7 (60 mg, 75.7%) as a brown solid. MS (ESI): C 27 H 33 Calculated value for F8NO5S: 635.2; Measured value: 636.1 [M+1] + .

[0387] Step 7. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7b). Compound 19-7 (60 mg) was purified by preparative SFC using 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 (°C): 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 arbitrarily assigned) and 19-7b (26 mg) (RT1 = 3.3 min, single diastereomer, stereochemistry arbitrarily assigned), respectively, as white solids. MS (ESI): C 27 H 33 Calculated value for F8NO5S: 635.2; Measured value: 636.1 [M+1] + .

[0388] Step 8a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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 HO (1 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl solution until pH = 4. The resulting mixture was extracted with EA (5 mL × 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue (30 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / 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 the ACN, and the resulting solution was dried by lyophilization to give Example 19a (10 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 29 Calculated value for F8NO5S: 607.2; Measured value: 608.2 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.67(s,1H), 7.54(s,1H), 5.60(d,J=46.2Hz,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.

[0389] Step 8b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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 HO (1 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (5 mL × 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue (30 mg) was purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / 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 the ACN, and the resulting solution was dried by lyophilization to give Example 19b (10 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 29 Calculated value for F8NO5S: 607.2; Measured value: 608.2 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.67(s,1H), 7.54(s,1H), 5.60(d,J=46.2Hz,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.

[0390] Examples 20a and 20b. 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (20b). [ka] Step 1. Synthesis of rac-ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1). To a stirred solution of cis-racemic 19-6 (115 mg, 0.23 mmol) and CsCO (221.32 mg, 0.68 mmol) in DMF (5 mL), KI (112.42 mg, 0.68 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (142.37 mg, 0.68 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature 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 preparative TLC (PE / EA = 4 / 1 (v / v)) to give 20-1 (65 mg, 46.2%) as a brown solid. MS (ESI): C 26 H 33 Calculated for F8NO5S: 623.2; Measured: 624.1 [M+1] + .

[0391] Step 2. Synthesis of ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1b). Compound 20-1 (65 mg) was purified by preparative chiral HPLC using 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; run number: 5. The collected fractions were concentrated under vacuum to give 20-1a (26 mg) (RT1 = 4.3 min, single diastereomer, stereochemistry arbitrarily assigned) and 20-1b (27 mg) (RT1 = 5.9 min, single diastereomer, stereochemistry arbitrarily assigned) as white solids, respectively. MS (ESI): C 26 H 33 Calculated for F8NO5S: 623.2; Measured: 624.1 [M+1] + .

[0392] Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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 HO (1 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (5 mL × 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue (30 mg) was purified by preparative HPLC using the following conditions: Column: Xbridge Prep Shield RP18 5 μm OBD 30*150 mm 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 the ACN, and the resulting solution was dried by lyophilization to give Example 20a (14 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 31 Calculated value for F8NO5S: 609.2; Measured value: 610.2 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.67(s,1H), 7.58(s,1H), 5.64(d,J=46.5Hz,1H), 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.

[0393] Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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 HO (1 mL) was stirred at room temperature for 16 hours. The mixture was acidified with 2 N aqueous HCl until pH = 4. The resulting mixture was extracted with EA (5 mL × 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated. The residue (30 mg) was purified by preparative HPLC using the following conditions: Column: Xbridge Prep Shield RP18 5 μm OBD 30*150 mm 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 the ACN, and the resulting solution was dried by lyophilization to give Example 20b (13 mg) (single diastereomer, stereochemistry arbitrarily assigned) as a white solid. MS (ESI): C 25 H 31 Calculated value for F8NO5S: 609.2; Measured value: 610.2 [M+1] + . 1 H NMR(300MHz,CD3OD):δ 7.67(s,1H), 7.58(s,1H), 5.64(d,J=46.2Hz,1H), 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.

[0394] Example 21 (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid [ka] Step 1. Synthesis of (R)-2-bromo-N-(1-((4,4-difluorocyclohexyl)amino)-5,5-difluorohexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (21-2). Following the same procedure as 1-7, (R)-N-(4,4-difluorocyclohexyl)-5,5-difluorohexane-1,2-diamine (21-1) (500 mg, 1.85 mmol), prepared by replacing aniline with 4,4-difluorocyclohexylamine, and TEA (374 mg, 3.7 mmol) in THF (6 mL) was added with 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 room temperature for 3 h. 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 × 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, 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) (R f :0.4). MS(ESI):C 20 H 26 Calculated for BrF7N2O3S: 586.1; Found: 587.2 [M+1] + .

[0395] 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), CuI (190 mg, 1.0 mmol) was added, and the mixture was heated at 100 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NH4Cl (15 mL), and the aqueous layer was extracted with EA (20 mL × 3). The combined organic layers were 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) (R f :0.5). MS(ESI):C 20 H 25 Calculated for F7N2O3S: 506.1; Found: 507.2 [M+1] + .

[0396] 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, 0.89 mmol) and CsCO (580 mg, 1.78 mmol) in NMP (5 mL), MeI (379 mg, 2.67 mmol) was added, and the reaction was stirred at room temperature for 5 h. 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 × 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, 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) (R f :0.4). MS(ESI):C 21 H 27 Calculated for F7N2O3S: 520.2; Found: 521.2 [M+1] + .

[0397] 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), CHClSNa (203 mg, 2.9 mmol) was added, and the reaction was heated at 95 °C for 16 h. 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 × 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, 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):C 20 H 25 Calculated for F7N2O3S: 506.1; Found: 507.2 [M+1] + .

[0398] Step 5. Synthesis of ethyl (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxide-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 CsCO (293 mg, 0.9 mmol) in DMF (2 mL), ethyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (134 mg, 0.6 mmol) was added. The reaction was heated at 100 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with water (10 mL × 3), dried over anhydrous NaSO, 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) (R f :0.5). MS(ESI):C 27 H 37 Calculated for F7N2O5S: 634.2; Found: 635.2 [M+1] + .

[0399] Step 6. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxide-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 ml) in MeOH / THF / HO (1 mL / 1 mL / 0.5 mL) was added LiOH .HO (14.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction was acidified with 1N aqueous HCl. The aqueous layer was extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC to give Example 21 (20 mg, 53%) as a white solid. MS (ESI): C 25 H 33 Calculated for F7N2O5S: 606.2; Found: 607.3 [M+1] + . 1 H NMR(400MHz,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), 2.1 7(m,J=40.2Hz,4H), 2.06-1.77(m,6H), 1.65(t,J=30.1Hz,5H), 1.32(d,J=2.1Hz,6H)ppm.

[0400] Example 22 (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid [ka] Step 1. Synthesis of (R)-2-bromo-N-(1-(cyclopentylamino)-5,5-difluorohexane-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (22-2). Following the same procedure as 1-7, 22-2 was prepared by replacing aniline with cyclopentamine. To a stirred solution of (R)-N-cyclopentyl-5,5-difluorohexane-1,2-diamine (22-1) (1.0 g, 4.5 mmol) 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 room temperature for 3 h. 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 × 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous NaSO, 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) (R f :0.4). MS(ESI):C 19 H 26 Calculated for BrF5N2O3S: 536.1; Found: 537.2 [M+1] + .

[0401] 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), Cu (640 mg, 10.0 mmol) was added and heated at 115 °C for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), and the aqueous layer was extracted with EA (50 mL × 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) (R f :0.5). MS(ESI):C 19 H 25 Calculated for F5N2O3S: 456.2; Found: 457.3 [M+1] + .

[0402] 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, 2.0 mmol) and CsCO (2.0 g, 6.0 mmol) in NMP (20 mL), MeI (852 mg, 6.0 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. 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 × 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous NaSO, 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) (R f:0.4). MS(ESI):C 20 H 27 Calculated for F5N2O3S: 470.2; Found: 471.3 [M+1] + .

[0403] 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), CHCl (382 mg, 5.30 mmol) was added, and the reaction mixture was heated at 95 °C for 16 h. 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 × 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous NaSO, 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) (R f :0.6). MS(ESI):C 19 H 25 Calculated for F5N2O3S: 456.2; Found: 457.3 [M+1] + .

[0404] Step 5. Synthesis of ethyl (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 CsCO (323 mg, 0.99 mmol) in DMF (2 mL), ethyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (148 mg, 0.66 mmol) was added. The reaction was heated at 100 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL × 3). The combined organic extracts were washed with water (10 mL × 3), dried over anhydrous NaSO, 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) (R f :0.5). MS(ESI):C 26 H 37 Calculated for F5N2O5S: 584.2; Found: 585.2 [M+1] + .

[0405] Step 6. Synthesis of (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 / HO (1 mL / 1 mL / 0.5 mL) was added LiOH .HO (14.3 mg, 0.34 mmol) was added and the reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction was acidified with 1N aqueous HCl. The aqueous layer was extracted with EA (10 mL x 3), and the combined organic extracts were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC to give Example 22 (26 mg, 68%) as a white solid. MS (ESI): C 24 H 33 Calculated for F5N2O5S: 556.2; Found: 557.3 [M+1] + . 1 H NMR(400MHz,CDCl3):δ 7.45(s,1H), 7.27(s,1H), 4.06(dd,J=16.5,8.1Hz,2H), 3.86(dd,J=22.4,15.2Hz,1H), 3.16(s,1H) , 2.64(s,4H), 1.96(ddd,J=29.2,26.0,22.5Hz,5H), 1.84-1.42(m,10H), 1.32(t,J=23.8Hz,6H)ppm.

[0406] Example 23. 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-2-methyl-1,1-dioxide-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] Step 1. Synthesis of (3aR,6aS)-5,5-difluorohexahydropentalen-2(1H)-one (23-2). To a stirred solution of (3aS,6aS)-tetrahydropentalen-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 room temperature for 16 h, the reaction mixture was diluted with saturated aqueous NaHCO (200 mL). The reaction mixture was extracted with EA (150 mL × 2). The combined organic extracts were washed with brine (100 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting 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):C8H 10 Calculated for FO: 160.1; Found: 160.2 [M+H] + .

[0407] 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), NaBH (1.55 g, 40 mmol) was added in an ice bath. The reaction was stirred at room temperature for 2 h. 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 × 3). The combined organic extracts were washed with brine (100 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give crude 23-3 (2.95 g, 92%) as a colorless oil, which was used in the next step without further purification. TLC: 25% EA / PE (v / v) (R f :0.5). MS(ESI):C8H 12 Calculated for FO: 162.1; Found: 162.2 [M+H] + .

[0408] 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), DIAD (6.62 g, 32.8 mmol) was added in an ice bath. The reaction was stirred at room temperature for 6 hours. 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) (R f :0.5). MS(ESI):C 16 H 15 Calculated for F2NO2: 291.1; Found: 292.3 [M+H] + .

[0409] 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 60 °C for 5 h. The mixture was filtered, and the 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 4 N HCl in dioxane (20 mL). After stirring for 30 min, the solution was concentrated in vacuo to give the 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) (R f : 0.3). MS(ESI): C8H 13 Calculated for F2N: 161.1; Found: 162.2 [M+H] + .

[0410] 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), DIEA (2.0 g, 15.7 mmol) and HATU (2.56 g, 6.74 mmol) were added in an ice bath. After stirring for 30 min, 23-5 (885 mg, 4.49 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with HO (30 ml) and extracted with EA (40 mL × 2). The combined organic extracts were washed with brine, dried over NaSO, 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) (R f :0.3). MS(ESI):C 19 H 30 Calculated for F4N2O3: 410.2; Found: 355.2 [M+H-56] + .

[0411] 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), TFA (3.0 ml) was added in an ice bath. The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was diluted with saturated aqueous NaHCO and extracted with DCM (30 mL × 3). The combined organic extracts were dried over NaSO and 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): C 14 H 22 Calculated for F4N2O: 310.2; Found: 311.2 [M+H] + .

[0412] 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), LAH (2.5 M in THF, 1.7 ml) was added in an ice bath. The reaction mixture was stirred at 60 °C for 16 h and cooled to 0 °C. The reaction mixture was quenched with HO (160 mg), followed by 10% aqueous NaOH (w / w) (160 mg) and EtO (50 mL). The resulting mixture was dried over anhydrous NaSO and 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) (R f :0.3). MS(ESI):C 14 H 24 Calculated for F4N2: 296.2; Found: 297.1 [M+H] + .

[0413] 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 room temperature for 16 h. The reaction mixture was quenched with HO (10 mL) and extracted with EA (10 ml × 2). The combined organic extracts were washed with brine, dried over NaSO, and concentrated. The residue 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) (R f :0.3). MS(ESI):C 22 H 28 Calculated for BrF7N2O3S: 612.1; Found: 613.2 [M+H] + .

[0414] 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 a nitrogen atmosphere. The reaction was stirred at 120 °C for 16 h. The reaction mixture was quenched with HO (10 mL) and extracted with EA (20 mL × 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) (R f :0.3). MS(ESI):C 22 H 27 Calculated for F7N2O3S: 532.2; Found: 533.3 [M+H] + .

[0415] 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), MeI (0.46 mL, 7.32 mmol) was added portionwise at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was diluted with HO (20 mL). The resulting mixture was extracted with EA (30 mL × 2), and the combined organic extracts were washed with brine (10 mL × 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) (R f :0.5). MS(ESI):C 23 H 29 Calculated for F7N2O3S: 546.2; Found: 546.7 [M+H] + .

[0416] 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 h. The reaction mixture was acidified with saturated aqueous NH4Cl (10 mL) and 4 N HCl solution until pH = 5-6, and extracted with EA (10 mL × 2). The combined organic extracts were washed with saturated 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) (R f :0.3). MS(ESI):C 22 H 27 Calculated for F7N2O3S: 532.2; Found: 532.8 [M+H] +

[0417] Step 12. Synthesis of ethyl 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-2-methyl-1,1-dioxide-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 CsCO (200 mg, 0.615 mmol) in DMF (1 ml), ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (82 mg, 0.369 mmol) was added at room temperature, and the reaction mixture was stirred at 70 °C for 5 h. The mixture was then diluted with water (5 mL) and extracted with EA (10 mL × 2). The combined organic extracts were washed with saturated aqueous LiCl (10 mL) and brine (10 mL), dried over anhydrous NaSO, 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) (R f :0.5). MS(ESI):C 29 H 37 Calculated for F7N2O5S: 658.2; Found: 659.0 [M+H] + . 1 H NMR(400MHz,CD3OD):δ 7.51(s,1H), 7.40(s,1H), 4.25(s,2H), 4.13(q,J=7.1Hz,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=18.5Hz,4H), 1.30(dd,J=7.1,4.2Hz,2H), 1.24-1.13(m,3H), 1.09(dd,J=7.1,4.1Hz,2H)ppm.

[0418] Step 13. Synthesis of 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-2-methyl-1,1-dioxide-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 / HO (0.75 mL, v / v / v = 1 / 2 / 2), NaOH (12 mg, 0.303 mmol) was added and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL), acidified with 3 N HCl aqueous solution until pH = 6-7, and extracted with EA (10 mL × 2). The combined organic extracts were dried over NaSO and concentrated. The residue was purified by preparative HPLC to give Example 23 (10.6 mg, 56%) as a white solid. TLC: 10% MeOH / DCM (v / v) (R f :0.5). MS(ESI):C 27 H 33 Calculated value for F7N2O5S: 630.2, Found value: 631.2 [M+H] + . 1 H NMR(400MHz,CD3OD):δ 7.51(s,1H), 7.40(s,1H), 4.25(dd,J=20.4,9.6Hz,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=18.5Hz,4H), 1.30(dd,J=6.6,3.9Hz,2H), 1.08(d,J=2.6Hz,2H)ppm.

[0419] Examples 24a and 24b. (R)-2-Cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)propanoic acid (24b) [ka] Step 1. Synthesis of tert-butyl 2-cyclopropyl acetate (24-2). To a solution of 5 g (50 mmol) of cyclopropylacetic acid (24-1) in 25 mL of dichloromethane, one drop of DMF was added at 0 °C, followed by the dropwise addition of 6.99 g (55 mmol) of oxalyl chloride. The reaction mixture was stirred at 0 °C to 10 °C for 2 h and then concentrated under reduced pressure. The residue was briefly dried under high vacuum (approximately 5 min) and then taken up in dry THF (10 mL). The resulting mixture was cooled to 0 °C. 1 M potassium tert-butoxide in THF (45 mL, 45 mmol) was then added dropwise, and the mixture was stirred at room temperature for 2 h and then concentrated. To the residue, diethyl ether and 0.5 N aqueous NaOH solution were added. The organic layer was dried over anhydrous MgSO4 and 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.

[0420] Step 2. Synthesis of tert-butyl 3-(benzyloxy)-2-cyclopropylpropanoate (24-3). To compound 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 −78° C. After stirring the solution at −78° C. for 20 minutes, a solution of ((chloromethoxy)methyl)benzene (6 g, 38.4 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and then warmed to room temperature. After stirring at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and concentrated. The residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 24-3 (1.8 g, 26%).

[0421] 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 overnight at room temperature under an atmosphere of H. 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.

[0422] Step 4. Synthesis of tert-butyl 2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-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), triphenylphosphine (637 mg, 2.43 mmol) and 24-4 (450 mg, 2.42 mmol) were added. The solution was warmed to 110°C, and then DIAD (4.9 g, 24.2) was added. After stirring at 110°C for 4 h, the reaction mixture was cooled to room temperature and diluted with EA (20 mL). The organic layer was washed with brine, dried over 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): C 30 H 37 Calculated for F5N2O5S: 632.2; Found: 633.2 [M+1] + .

[0423] Step 5. Synthesis of tert-butyl (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)propanoate (24-5b). Compound 24-5 was separated by chiral SFC to give 24-5a and 24-5b, respectively, as white solids. The stereochemistry of the 2-cyclopropyl-3-hydroxypropanoic acid moiety was arbitrarily assigned. MS(ESI):C 30 H 37 Calculated for F5N2O5S: 632.2; Found: 633.2 [M+1] + .

[0424] Step 6a. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)propanoic acid (Example 24a). To a mixture of 24-5a (80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 ml) dropwise at room temperature. After stirring at room temperature for 5 hours, the mixture was concentrated and the residue was purified by preparative HPLC to give Example 24a (35 mg, 48%). MS (ESI): C 26 H 29 Calculated for F5N2O5S: 576.2; Found: 577.2 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 7.62(s,1H), 7.56(s,1H), 7.19(t,J=8.0Hz,2H), 6.77(t,J=7.2Hz,1H), 6.7 5-6.66(m,2H), 4.41(d,J=6.4Hz,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), 1.7 0-1.60(m,4H), 1.00-0.70(m,1H), 0.65-0.48(m,2H), 0.46-0.43(m,2H)ppm.

[0425] Step 6b. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxide-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 to prepare 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): C 26 H 29 Calculated for F5N2O5S: 576.2; Found: 577.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 7.62(s,1H), 7.56(s,1H), 7.19(t,J=8.0Hz,2H), 6.77(t,J=7.2Hz,1H), 6.7 5-6.66(m,2H), 4.41(d,J=6.4Hz,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), 1.7 0-1.60(m,4H), 1.00-0.70(m,1H), 0.65-0.48(m,2H), 0.46-0.43(m,2H)ppm.

[0426] Example 25 (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid [ka] 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 was readily prepared following the procedure for preparing 1-10 by replacing aniline with 4-fluoroaniline and 2-bromo-4-trifluoromethyl-5-methyoxybenzenesulfonyl chloride with 2,4-dibromo-5-methyoxybenzenesulfonyl chloride. To 1,1-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-1) (400 mg, 0.79 mmol) in dioxane (4 mL) under N was added Pd(dppf)Cl (57 mg, 0.079 mmol), NaCO (251 mg, 2.37 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (365 mg, 2.37 mmol) at room temperature. The mixture was stirred at 100 °C overnight, diluted with water (15 mL) at room temperature, and extracted with EA (15 mL × 3). The organic extract was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography using EA / PE as the eluent to give 25-2 (300 mg, 84%) as a pale yellow solid. MS (ESI): C 22 H 25 Calculated for F3N2O3S: 454.2; Found: 455.2 [M+1] + .

[0427] 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 / HO (4 / 1 (v / v), 6 mL), osmium tetroxide (2.5 wt% in t-BuOH, 336 mg, 0.033 mmol) and sodium periodate (570 mg, 2.64 mmol) were added at room temperature. After stirring for 3 h at room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The combined extracts were dried over anhydrous NaSO and 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): C 21 H 23 Calculated for F3N2O4S: 456.1; Found: 457.2 [M+1] + .

[0428] 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 room temperature. After stirring at room temperature for 2 days, the reaction mixture was poured into saturated aqueous NaHCO3 solution (20 mL). The resulting mixture was extracted with DCM (15 mL × 3), and the combined organic extracts were washed with brine, dried over 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): C 21 H 23 Calculated for F5N2O3S: 478.1; Found: 479.1 [M+1] + .

[0429] 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). Compound 25-4 (180 mg, 0.31 mmol) was added to a solution of NaSMe in DMF (100 mg / mL, 1.08 mL) at room temperature. After stirring at 100 °C for 3 h, the reaction mixture was diluted with water (10 mL) at room temperature and then extracted with EA (15 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography using EA / PE as the eluent to give 25-5 (150 mg, 85%) as a pale yellow solid. MS (ESI): C 20 H 21 Calculated for F3N2O4S: 442.1; Found: 443.1 [M+1] + .

[0430] 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 room temperature. After stirring at room temperature for 2 days, the reaction mixture was poured into saturated aqueous NaHCO (20 mL), and the resulting mixture was extracted with DCM (15 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous NaSO, 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): C 20 H 21 Calculated for F5N2O3S: 464.1; Found: 465.1 [M+1] + .

[0431] Step 6. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoate (25-7). To a solution of 25-6 (130 mg, 0.28 mmol) in toluene (1.5 mL), (R)-3-hydroxy-2-methylpropanoate (165 mg, 1.4 mmol) and triphenylphosphine (221 mg, 0.84 mmol) were added at room temperature. After warming the solution to 110 °C, DIAD (565 mg, 2.8 mmol) was added, and the resulting reaction mixture was stirred at 110 °C for 5 h. The mixture was then 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): C 25 H 29 Calculated for F5N2O5S: 564.2; Found: 565.1 [M+1] + .

[0432] Step 7. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid (Example 25). A solution of 25-7 (130 mg, 0.23 mmol) in THF / HO (4:1 (v / v), 5 ml) was treated with LiOH. . HO (97 mg, 2.3 mmol) was added at room temperature. After stirring overnight at room temperature, the reaction mixture was adjusted with 10% aqueous HCl until pH = 2-3. The resulting mixture was extracted with EA (10 mL × 2), and the combined organic extracts were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give Example 25 (8 mg, 6.3%) as a white solid. MS (ESI): C 24 H 27 Calculated for F5N2O5S: 550.2; Found: 551.2 [M+1]+ . 1 H NMR (400 MHz, CDCl): δ 7.51(d,J=6.8Hz,1H), 7.37(s,1H), 6.94(t,J=8.6Hz,2H), 6.81(s,1H), 6 .69(d,J=11.7Hz,2H), 4.36-4.25(m,1H), 4.21(dd,J=8.8,5.3Hz,1H), 3.9 5(d,J=15.6Hz,2H), 3.41(s,1H), 3.06(dd,J=12.4,6.9Hz,1H), 2.64(s,3 H), 2.14-1.71(m,11H), 1.61(t,J=18.4Hz,5H), 1.37(d,J=7.2Hz,4H)ppm.

[0433] Example 26 (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid [ka] Step 1. Synthesis of methyl 4-fluorobicyclo[2.2.2]octane-1-carboxylate (26-2). 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) were added to a 250 mL three-neck round-bottom flask at room temperature. The resulting mixture was stirred at 70 °C for 24 h under a nitrogen atmosphere. The mixture was cooled to room temperature and acidified with saturated aqueous citric acid until pH = 5. The resulting mixture was extracted with EtOAc (100 mL × 2). The combined organic extracts were washed with brine (100 mL × 2), dried over anhydrous NaSO, 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):C 10 H 15Calculated value for FO2: 186.1; Measured value: 187.1 [M+1] + .

[0434] Step 2. Synthesis of 4-fluorobicyclo[2.2.2]octane-1-carboxylic acid (26-3). 26-2 (8 g, 42.96 mmol), THF (80 mL), water (10 mL), and LiOH (3.09 g, 128.87 mmol) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The mixture was acidified with 2 N aqueous HCl until pH = 5 and extracted with EtOAc (100 mL × 2). The combined organic extracts were washed with brine (100 mL × 2), dried over anhydrous NaSO, 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): CH 13 Calculated value for FO2: 172.1; Measured value: 173.1 [M+1] + .

[0435] Step 3. Synthesis of tert-butyl N-{4-fluorobicyclo[2.2.2]octan-1-yl}carbamate (26-4). 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) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at 85 °C for 24 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic extracts were washed with brine (100 mL × 2), dried over anhydrous NaSO, 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):C 13 H 22 Calculated value for FNO2: 243.2; Measured value: 244.3 [M+1] + .

[0436] Step 4. Synthesis of 4-fluorobicyclo[2.2.2]octan-1-amine (26-5). 26-4 (9 g, 36.99 mmol) in dioxane (4 M, 90 mL) and HCl (gas) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (90 mL), acidified with saturated aqueous NaHCO3 until pH = 8, and extracted with EtOAc (50 mL × 2). The combined organic extracts were washed with brine (50 mL × 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): CH 14 Calculated value for FN: 143.1; Measured value: 144.2 [M+1] + .

[0437] Step 5. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (26-7). To a 500 mL three-neck round-bottom flask were added 1-(tert-butyl) 2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (30 g, 123.33 mmol) in diethyl ether (17.65 g, 147.99 mmol), THF (300 mL), and 3 M MeMgBr solution at −55° C. The resulting mixture was stirred at −20° C. for 18 hours under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NH4Cl at 0° C., concentrated, and the organic solvent was removed. The resulting mixture was extracted with EtOAc (150 mL × 3). The combined organic extracts were washed with brine (150 mL × 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): C 12 H 21 Calculated for NO5: 259.1; Found: 331.1 [M+Na+ACN] + .

[0438] Step 6. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (26-8). 26-7 (20 g, 77.13 mmol), DCM (200 mL), and DAST (37.30 g, 231.39 mmol) were added to a 500 mL three-neck round-bottom flask at 0 °C. The resulting mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. The reaction was quenched with saturated aqueous NaHCO at 0 °C, concentrated, and the organic solvent was removed. The resulting mixture was extracted with EtOAc (200 mL × 2). The combined organic extracts were washed with brine (200 mL × 2), dried over anhydrous NaSO, 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): C 12 H 21 Calculated for F2NO4: 281.1; Found: 282.1 [M+1] + .

[0439] Step 7. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (26-9). To a 100 mL three-necked round-bottom flask, 26-8 (2.8 g, 9.95 mmol), THF (30 mL), water (7.5 mL), and LiOH (0.72 g, 29.86 mmol) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The mixture was acidified with 1N aqueous HCl solution until pH = 5, concentrated, and the organic solvent was removed. The resulting mixture was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (30 mL × 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): C 11 H 19 Calculated for F2NO4: 267.1; Found: 253.1 [M-Boc+1] + .

[0440] 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). To a 50 mL three-necked round-bottom flask, 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) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (30 mL × 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): C 19 H 31 Calculated for F3N2O3: 392.2; Found: 393.2 [M+1] + .

[0441] Synthesis of Ste® (R)-2-amino-5,5-difluoro-N-(4-fluorobicyclo[2.2.2]octan-1-yl)hexanamide (26-11). To a 100 mL round-bottom flask, 26-10 (2.3 g, 5.86 mmol) and HCl in EtOAc (2 M, 25 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was basified with saturated aqueous NaHCO3 until pH = 8. The resulting mixture was extracted with EtOAc (25 mL × 2). The combined organic extracts were washed with brine (25 mL × 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): C 14 H 23 Calculated for F3N2O: 292.2; Measured: 293.2 [M+1] + .

[0442] 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). To a 50 mL round-bottom flask, 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) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (50 mL) and concentrated to remove the organic solvent. The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic extracts were washed with brine (50 mL × 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): C 21 H 27 Calculated for Br2F3N2O4S: 618.0; Found: 618.9 [M+1] + .

[0443] 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). To a 50 mL round-bottom flask, 26-12 (1.5 g, 2.42 mmol), THF (30 mL), and BHMeS (0.75 mL, 7.91 mmol) were added at room temperature. The resulting mixture was stirred at 75 °C for 16 h under a 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 room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5 / 1 (v / v)) to give 26-13 (1.0 g, 68.2%) as a brown solid. MS(ESI):C 21 H 29 Calculated for Br2F3N2O3S: 604.0; Found: 605.0 [M+1]+ .

[0444] 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). 26-13 (1.0 g, 1.65 mmol), DMSO (10 mL), KCO (0.69 g, 4.947 mmol), and CuI (0.16 g, 0.83 mmol) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 130 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1 (v / v)) to give 26-14 (200 mg, 23.1%) as a brown solid. MS (ESI): C 21 H 28 Calculated for BrF3N2O3S: 524.1; Found: 525.1 [M+1] + .

[0445] 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). To an 8 mL vial, 26-14 (200 mg, 0.38 mmol), DMF (2 mL), CsCO (373.21 mg, 1.14 mmol), and MeI (64.83 mg, 0.46 mmol) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1 (v / v)) to give 26-15 (145 mg, 70.6%) as a brown oil. MS (ESI): C 22 H 30 Calculated for BrF3N2O3S: 538.1; Found: 539.1 [M+1] + .

[0446] 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). To an 8 mL vial, 26-15 (90 mg, 0.17 mmol), DMF (3 mL), and MeSNa (64.31 mg, 0.92 mmol) were added at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (20 mL × 4). The combined organic extracts were washed with brine (10 mL × 3), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1 (v / v)) to give 26-16 (50 mg, 60.8%) as a brown solid. MS (ESI): C 22 H 31Calculated for F3N2O3S2: 492.2; Found: 493.2 [M+1] + .

[0447] 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-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (26-17). To an 8 mL vial, 26-16 (50 mg, 0.10 mmol), DMF (1 mL), ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (25.22 mg, 0.12 mmol), and CsCO (99.52 mg, 0.30 mmol) were added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (20 mL × 2). The combined organic extracts were washed with brine (20 mL × 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): C 29 H 41 Calculated for F3N2O5S2: 618.2; Found: 619.2 [M+1] + .

[0448] 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-dioxide-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 26). To an 8 mL vial, 26-17 (8 mg, 0.01 mmol), LiOH (0.93 mg, 0.04 mmol), water (1 mL), and THF (4 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was acidified with 2 N aqueous HCl until the pH was 3 and concentrated. The residue was purified by chiral preparative HPLC using the following conditions: Column: Chiral ART Amylose-C NEO, 3*25 cm, 5 μm, 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; Wavelength: 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 the resulting solution was dried by lyophilization to give Example 26 (2.5 mg, 32.7%) as a white solid. MS (ESI): C 27 H 37 Calculated for F3N2O5S2: 590.2; Found: 591.2 [M+1] + . 1 H NMR(400MHz,CD3OD):δ 7.26(s,1H), 7.06(s,1H), 4.35-4.14(m,2H), 3.89(s,1H), 2.59(dd,J=16.0,10.4Hz,1H), 2.46(s,3H), 2.34(s ,3H), 2.18(d,J=11.2Hz,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.

[0449] Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9) [ka] Step 1. Synthesis of (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane-1,5-dione (27-2). To a 50 L four-neck round-bottom flask, 5-oxohexanoic acid (27-1) (1.113 kg, 8.56 mol), THF (24 L), and TEA (0.95 kg, 9.40 mol) were added at room temperature. To the above mixture, pivaloyl chloride (1.14 kg, 9.40 mol) was added dropwise at 5 °C over 2 h. The resulting mixture was stirred at room temperature for an additional 2 h. To a 20 L four-neck round-bottom flask, (4R)-4-benzyl-1,3-oxazolidin-2-one (1.44 kg, 8.12 mol) and THF (16 L) were added at room temperature. To the above mixture, n-BuLi (3.25 L, 8.12 mol) was added dropwise at −50° C. over 4 hours. The resulting mixture was stirred at −50° C. for an additional 1 hour. The lithium reagent was then transferred to the mixed anhydride via cannula under reduced pressure in a 50-L flask. The resulting mixture was stirred at −20° C. for 4 hours under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 L). The resulting mixture was washed with aqueous NaHCO (20 L × 2) and brine (20 L × 2), dried over anhydrous NaSO, and concentrated. The residue was triturated three times with PE / EA = 20 / 1 (v / v) (60 L). The precipitate was collected and dried in vacuo to give 27-2 (1.7 kg, 68.7%) as a white solid. MS (ESI): C 16 H 19 Calculated for NO4: 289.1; Found: 290.1 ​​[M+1] + .

[0450] Step 2. Synthesis of (R)-4-benzyl-3-(5,5-difluorohexanoyl)oxazolidin-2-one (27-3). (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane-1,5-dione (27-2) (200 g, 691.25 mol) and DCE (600 mL) were added to a 2 L three-necked round-bottom flask at room temperature. BAST (382.33 g, 1728.13 mol) was added to the mixture at room temperature. The resulting mixture was stirred at 70 °C for an additional 6 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with DCM (1 L). The reaction mixture was slowly poured into saturated aqueous NaHCO3 solution. The resulting mixture was extracted with DCM (1 L × 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 eluting with PE / THF (10:1 (v / v)) to give 27-3 (153 g, 71.1%) as a brown oil. MS (ESI): C 16 H 19 Calculated for F2NO3: 311.1; Found: 312.1 [M+1] + . 1 H NMR(300MHz,DMSO-d6):δ 7.38-7.16(m,5H), 4.66(tt,J=7.8,3.1Hz,1H), 4.33(t,J=8.5Hz,1H), 4.19(dd,J=8.8,2.9H z,1H), 3.09-2.76(m,4H), 2.05-1.83(m,2H), 1.83-1.70(m,2H), 1.62(t,J=18.9Hz,3H)ppm.

[0451] 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 TiCl (649.28 g, 3.42 mol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. TEA (362.90 g, 3.59 mol) was added dropwise to the solution at 0 °C under a nitrogen atmosphere, followed by stirring at 0 °C for 2 h. ((chloromethoxy)methyl)benzene (1021 g, 6.52 mol) was added dropwise to the mixture at 0 °C and stirred at 0 °C for 2 h. The reaction was quenched with saturated aqueous NH4Cl (3.5 L) at 0 °C. The resulting mixture was separated, and the aqueous layer was extracted with DCM (2 L × 2). The combined organic layers were washed with saturated aqueous NaHCO3 (5 L × 2) 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 × 3). The precipitate was collected and dried in vacuo to give 27-4 (1160 g) as a light brown solid, which was used directly in the next step without further purification. MS (ESI): C 24 H 27 Calculated for F2NO4: 431.2; Found: 432.2 [M+1] + . 1 H NMR(400MHz,CDCl3):δ 7.43-7.17(m,10H), 4.75(ddt,J=9.3,7.9,3.3Hz,1H), 4.57(s,2H), 4.29-4.17 (m,2H), 4.16(dd,J=9.1,3.2Hz,1H), 3.80(dd,J=9.2,7.1Hz,1H), 3.71(dd,J=9. 2,5.3Hz,1H), 3.25(dd,J=13.5,3.4Hz,1H), 2.70(dd,J=13.5,9.3Hz,1H), 2.07 -1.92(m,1H), 1.96-1.86(m,1H), 1.89-1.72(m,1H), 1.61(t,J=18.4Hz,3H)ppm.

[0452] 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 HO (2 L) was added dropwise with HO (1051 g, 9.27 mol, 30%) under a nitrogen atmosphere at 0 °C for 30 min. The mixture was stirred at 0 °C for 30 min, then added with LiOH in HO (2 L). . HO (194.49 g, 4.64 mol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of NaSO (5 L) at 0 °C and then concentrated in vacuo. The resulting solution was adjusted to pH = 12 with 1 N aqueous NaOH and extracted with DCM (5 L × 3). The aqueous layer was adjusted to pH = 2 with saturated aqueous HCl (4 M). The resulting solution was extracted with EtOAc (6 L × 4). The combined organic extracts were washed with brine (15 L), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give 27-5 (600 g) as a pale yellow oil, which was used directly in the next step without further purification. MS (ESI): C 14 H 18 Calculated for F2O3: 272.1; Found: 273.1 [M+1] + .

[0453] 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 added dropwise with SOCl (1.65 kg, 13.88 mol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 (v / v)) to give 27-6 (1.5 kg, 81.4%) as a brown oil. MS (ESI): C 15 H 20Calculated for F2O3: 286.1; Found: 287.1 [M+1] + .

[0454] Step 6. Synthesis of methyl (S)-5,5-difluoro-2-(hydroxymethyl)hexanoate (27-7). 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) was added to a 20 L autoclave at room temperature. The resulting mixture was stirred at 60 °C under a hydrogen atmosphere (30 atm) for 18 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (1 L × 4). The filtrate was concentrated, and the residue was dried in vacuo to give 27-7 (460 g, 89.5%) as a pale yellow oil. MS (ESI): CH 14 Calculated for F2O3: 196.1; Found: 197.1 [M+1] + .

[0455] 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 a nitrogen atmosphere. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with water at 0 °C and then extracted with DCM (1 L × 3). The combined organic layers were washed with brine (4 L), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give 27-8 (575 g) as a light brown liquid, which was used in the next step without further purification.

[0456] Step 8. Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9). A 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 to room temperature and concentrated in vacuo. The resulting organic mixture was diluted with EtOAc (10 L), washed with water (4 L × 3) and brine (5 L), dried over anhydrous NaSO, and concentrated. The residue was dried in vacuo to give 27-9 (1020 g, 88.2%) as a light brown liquid, which was used directly in the next step without further purification. 1 H NMR (300MHz, CD3OD): δ 3.75(s,3H), 3.64(dd,J=6.0,1.8Hz,2H), 2.96-2.85(m,1H), 2.00-1.77(m,4H), 1.61(t,J=18.6Hz,3H)ppm.

[0457] Following the same procedure for cis-racemic 151-8a, 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 by replacing 2-(bromomethyl)-5,5,5-trifluoropentanoate (151-7).

[0458] Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (28-5) [ka] Step 1. Synthesis of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2). To a solution of copper iodide (15.96 g, 84.07 mmol) in tetramethylene sulfone, cesium fluoride (33.2 g, 218.6 mmol) and 2-methoxy-1-iodo-4-nitrobenzene (28-1) (24.0 g, 84.1 mmol) were added. The resulting solution was stirred at 45 °C. Trimethyl(trifluoromethyl)silane (31.05 g, 218.6 mmol) was then added dropwise at 45 °C and stirred overnight at room temperature. The mixture was then diluted with water, and the resulting mixture was extracted with MTBE (100 mL × 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 / hexane as eluent to give 28-2 (8 g, 43%) as a yellow solid.

[0459] 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, palladium (379.68 mg, 3.59 mmol) was added. The resulting mixture was hydrogenated at ambient pressure and temperature for 4 hours. 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.

[0460] Step 3. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4). To a 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 overnight at room temperature, 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 NaSO, and concentrated. The residue was purified by silica gel column chromatography to give 28-4 (6 g, 85%) as a yellow solid.

[0461] Step 4. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (28-5). To a mixture of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4) (6.0 g, 22.31 mmol) in saturated aqueous HCl (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 room temperature 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 0 °C. The resulting mixture was stirred at room temperature for 2 h and diluted with DCM (50 mL). The aqueous layer was extracted with DCM (50 mL × 3). The combined organic extracts were washed with water (50 mL) and saturated aqueous NaHCO (50 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography to give 28-5 (3 g, 38%).

[0462] Examples 151a and 151b. 3-(((2S,3R)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxide-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-dioxide-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (151b). [ka] Step 1. Synthesis of diethyl 2-(3,3,3-trifluoropropyl)malonate (151-2). Diethyl malonate (25 g, 156.08 mmol) and tetrahydrofuran (250 mL) were added to a 500 mL three-necked round-bottom flask at 0 °C. To the mixture, NaH (60% in oil, 3.12 g, 78.04 mmol) was added portionwise over 10 minutes at 0 °C. The resulting mixture was stirred at room temperature for another 30 minutes. To the mixture, 1,1,1-trifluoro-3-iodopropane (17.48 g, 78.04 mmol) was added dropwise over 5 minutes at room temperature. The resulting mixture was stirred at 80 °C for 24 hours. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (450 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (40:1 (v / v)) to give 151-2 (30 g, 75.2%) as a colorless oil. 1 H NMR (300MHz, CDCl3): δ 4.29-4.13(m,4H), 3.39(t,J=6.6Hz,1H), 2.27-2.07(m,4H), 1.27(t,J=7.2Hz,6H)ppm.

[0463] Step 2. Synthesis of 2-(ethoxycarbonyl)-5,5,5-trifluoropentanoic acid (151-3). 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) were added to a 500 mL three-neck round-bottom flask at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 8 hours. The reaction was monitored by LC-MS. The mixture was acidified with aqueous HCl (2 M) until pH = 2. The resulting mixture was extracted with EtOAc (150 mL × 4). The combi...

Claims

1. Formula II 【Chemical 104】 or a pharmaceutically acceptable salt thereof, wherein M is -CHF-, -CH(CH ３ ) -, -CF(CH ３ ) -, -CF ２ -, or -C(CH ３ ) ２ - and R ａ , R ｂ , and R ｃ independently for each occurrence, hydrogen, C １－６ Alkyl, haloC １－６ Alkyl, and C ３－６ monocycloalkyl; R １ But OH, CH ３ , —C(O)NH ２ , -C(O)OH, -C(O)OC １－６ Alkyl, -P(O)(OH) ２ , -S(O) ２ OH, or 【Chemistry 105】 and R ２ａ and R ２ｂ is hydrogen, halo, OH, methyl, ethyl, and CH ２ OH, or R ２ａ and R ２ｂ together with the carbon atoms to which they are attached, form C=CH ２ , C ３－６ Forms a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group, ３－６ a monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,3-dioxanyl group optionally substituted with 1 to 3 independently selected from halo and methyl groups; R ３ is hydrogen, halogen, cyano, R ａ R ｂ N-, C １－４ Alkyl, haloC １－４ Alkyl, C １－４ Alkoxy, HaloC １－４ Alkoxy, C １－４ Alkylthio, HaloC １－４ Alkylthio, C ３－７ Monocycloalkyl, C ３－７ Monocycloalkyloxy, C ３－７ Monocycloalkylthio, C ３－７ Monocycloalkyl-CH ２ -thio, and C ５－１２ bicycloalkylthio; ３－７ Monocycloalkyl, C ３－７ Monocycloalkyloxy, C ３－７ Monocycloalkylthio, C ３－７ Monocycloalkyl-CH ２ -thio, and C ５－１２ the bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R ４ But, Haro C ３－４ is alkyl, R ５ But phenyl, C ３－７ monocycloalkyl, or C ５－１２ bicycloalkyl, wherein the phenyl, C ３－７ monocycloalkyl, or C ５－１２ Bicycloalkyl is halo, OH, CN, HOC(O)—, R ａ R ｂ N-, R ａ R ｂ N.S. (O) ｑ -, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, HaloC １－４ Alkyl, hydroxy C １－４ Alkyl-, R ａ R ｂ NC １－４ Alkyl-, C １－４ Alkoxy, HaloC １－４ Alkoxy, hydroxy C １－４ Alkoxy-, R ａ R ｂ NC １－４ Alkoxy-, C １－３ Alkoxy C １－４ Alkyl-, haloC １－３ Alkoxy C １－４ Alkyl-, R ａ R ｂ NC(O)-, C １－４ Alkyl C(O)-, C １－４ Alkoxy C(O)-, C １－４ Alkyl C(O)O-, C １－４ AlkylS(O) ｑ -, C １－４ AlkylS(O) ｑ NR ｃ -, C １－６ AlkylS(O) ｑ C １－４ Alkyl-, C １－４ Alkyl C(O)C １－６ Alkyl-, and C １－６ Alkyl C(O)OC １－４ optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-; A compound, or a pharmaceutically acceptable salt thereof, wherein q is independently, for each occurrence, selected from the group consisting of 0, 1, and 2.

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

3. Formula II is Formula IIa 【Chemistry 106】 3. The compound of claim 1 or 2, which is: or a pharmaceutically acceptable salt thereof.

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

5. R １ But -S(O) ２ 4. The compound of claim 1, wherein R is OH, or a pharmaceutically acceptable salt thereof.

6. R １ But -P(O)(OH) ２ 4. The compound according to claim 1, wherein:

7. R ２ａ and R ２ｂ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is independently selected from the group consisting of hydrogen, halo, OH, and methyl.

8. R ２ａ and R ２ｂ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is methyl.

9. R ２ａ is hydrogen, and R ２ｂ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is methyl.

10. R ２ａ and R ２ｂ together with the carbon atoms to which they are attached, form C=CH ２ 7. The compound of claim 1, wherein the aryl group forms a cyclopropyl, cyclobutyl, or oxetanyl group, and the cyclopropyl or cyclobutyl group is optionally substituted with one to three halo groups, or a pharmaceutically acceptable salt thereof.

11. R ２ａ and R ２ｂ together with the carbon atoms to which they are attached, form C=CH ２ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the aryl group is a cyclopropyl, cyclobutyl, or oxetanyl group.

12. R ２ａ and R ２ｂ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: together with the carbon atom to which they are attached form a cyclopropyl group.

13. R ３ But, Haro C １－２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is alkyl.

14. R ３ But CF ３ 14. The compound of claim 13, wherein:

15. R ３ But C ５－１２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is bicycloalkylthio.

16. R ３ But, Haro C ３－７ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is monocycloalkylthio.

17. R ４ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is n-butyl substituted with 1 to 6 halo atoms.

18. R ４ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is n-butyl substituted with 1 to 6 F atoms.

19. R ４ But -CH ２ CH ２ CF ２ CH ３ 19. The compound of claim 18, wherein:

20. R ４ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is n-propyl substituted with 1 to 6 halo atoms.

21. R ４ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein is n-propyl substituted with 1 to 6 F atoms.

22. R ４ But -CH ２ CH ２ CF ３ 22. The compound of claim 21, wherein:

23. R ５ Halo, OH, CN, HOC(O)-, R ａ R ｂ N-, R ａ R ｂ N.S. (O) ｑ -, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, HaloC １－４ Alkyl, hydroxy C １－４ Alkyl-, R ａ R ｂ NC １－４ Alkyl-, C １－４ Alkoxy, HaloC １－４ Alkoxy, hydroxy C １－４ Alkoxy-, R ａ R ｂ NC １－４ Alkoxy-, C １－３ Alkoxy C １－４ Alkyl-, haloC １－３ Alkoxy C １－４ Alkyl-, R ａ R ｂ NC(O)-, C １－４ Alkyl C(O)-, C １－４ Alkoxy C(O)-, C １－４ Alkyl C(O)O-, C １－４ AlkylS(O) ｑ -, C １－４ AlkylS(O) ｑ NR ｃ -, C １－６ AlkylS(O) ｑ C １－４ Alkyl-, C １－４ Alkyl C(O)C １－６ Alkyl-, and C １－６ Alkyl C(O)OC １－４ C optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl- ３－７ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is monocycloalkyl.

24. R ５ but, 【Chemistry 107】 24. The compound of claim 23, wherein:

25. In certain embodiments, R ５ Halo, OH, CN, HOC(O)-, R ａ R ｂ N-, R ａ R ｂ N.S. (O) ｑ -, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, HaloC １－４ Alkyl, hydroxy C １－４ Alkyl-, R ａ R ｂ NC １－４ Alkyl-, C １－４ Alkoxy, HaloC １－４ Alkoxy, hydroxy C １－４ Alkoxy-, R ａ R ｂ NC １－４ Alkoxy-, C １－３ Alkoxy C １－４ Alkyl-, haloC １－３ Alkoxy C １－４ Alkyl-, R ａ R ｂ NC(O)-, C １－４ Alkyl C(O)-, C １－４ Alkoxy C(O)-, C １－４ Alkyl C(O)O-, C １－４ AlkylS(O) ｑ -, C １－４ AlkylS(O) ｑ NR ｃ -, C １－６ AlkylS(O) ｑ C １－４ Alkyl-, C １－４ Alkyl C(O)C １－６ Alkyl-, and C １－６ Alkyl C(O)OC １－４ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is phenyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkyl-.

26. R ５ but, 【Chemistry 108】 26. The compound of claim 25, wherein:

27. R ５ but, 【Chemistry 109】 26. The compound of claim 25, wherein:

28. 28. A pharmaceutical composition comprising the compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. 28. A method of treating hepatitis B (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

30. 30. A method of treating hepatitis B (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 28.

31. 28. A method of treating hepatitis D (HDV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

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

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

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

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