EP4669638A1 - BENZOTHIA(DIA)ZEPIN COMPOUNDS FOR THE TREATMENT OF HBV AND HDV - Google Patents

BENZOTHIA(DIA)ZEPIN COMPOUNDS FOR THE TREATMENT OF HBV AND HDV

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Publication number
EP4669638A1
EP4669638A1 EP24760850.8A EP24760850A EP4669638A1 EP 4669638 A1 EP4669638 A1 EP 4669638A1 EP 24760850 A EP24760850 A EP 24760850A EP 4669638 A1 EP4669638 A1 EP 4669638A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
mmol
pharmaceutically acceptable
acceptable salt
haloc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24760850.8A
Other languages
German (de)
French (fr)
Inventor
Min Zhong
Jiaxin Yu
Michael Walker
Jian Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Assembly Biosciences Inc
Original Assignee
Assembly Biosciences Inc
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Filing date
Publication date
Application filed by Assembly Biosciences Inc filed Critical Assembly Biosciences Inc
Publication of EP4669638A1 publication Critical patent/EP4669638A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • HBV hepatitis B surface antigen
  • the core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins.
  • cccDNA covalently closed circular DNA
  • the cccDNA is the template for viral RNAs and thus viral proteins.
  • Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After capsid assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core.
  • nucleos(t)ide analogs e.g., entecavir
  • nucleos(t)ide analogs that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment.
  • nucleos(t)ide analogs Once a patient starts taking nucleos(t)ide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance.
  • the only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon ⁇ or pegylated interferon ⁇ . Unfortunately, the adverse event incidence and profile of interferon ⁇ can result in poor tolerability, and many patients are unable to complete therapy.
  • interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment.
  • current HBV treatments can range from palliative to watchful waiting.
  • Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact.
  • Interferon ⁇ has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.
  • HDV hepatitis D virus
  • HBsAg HBsAg for viral particle assembly.
  • Sagnelli et al. Life (Basel).2021 Feb; 11(2): 169, Published online 2021 Feb 22. doi: 10.3390/life11020169, herein incorporated by reference with regard to such background teaching.
  • HBV/HDV infection is also associated with the development of hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • treatment options for HDV infection or HBV/HDV coinfection are limited and include those used to treat HBV.
  • WO2022253997 relates to relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I).
  • bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity.
  • ASBT apical sodium-dependent bile acid transporter
  • LBAT liver bile acid transport
  • the invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.
  • WO2023237728 to Albireo relates to methods for treating hepatitis B and/or D with an Na+/taurocholate co-transporting polypeptide (NTCP) inhibitor such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound of formula (II), or a pharmaceutically acceptable salt thereof.
  • NTCP Na+/taurocholate co-transporting polypeptide
  • Such methods can include decreasing the concentration of hepatitis B DNA, decreasing the concentration of hepatitis D DNA, decreasing hepatitis B surface antigen, and decreasing hepatitis B core antigen (HBcAg).
  • NTCP functions as a cellular receptor for viral entry of HBV and HDV, which in turn is the major cause of liver disease and HCC.
  • HBV and HDV hepatitis B core antigen
  • the present disclosure provides, in part, benzothia(dia)zepine compounds and pharmaceutical compositions thereof, useful for inhibition of HBV or HDV replication, inhibition of HBV or HDV viral entry, and methods of treating HBV infections, HDV infection or HBV/HDV coinfection.
  • the disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description.
  • the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating an HDV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • 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.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Figure 1 shows the ORTEP plot for Example 10b.
  • Figure 2 shows the ORTEP plot for Example 11a.
  • Hepatitis delta also known as hepatitis D
  • HDV hepatitis delta virus
  • HDV hepatitis B virus
  • Hepatitis delta can be acquired either through coinfection: infection with hepatitis B and delta at the same time. It can also be acquired by superinfection: infection with hepatitis D after a person has already acquired hepatitis B. There is currently no vaccine for hepatitis delta. However, it can be prevented by getting the hepatitis B vaccine to help eliminate the risk of infection with HBV.
  • the entry inhibitor Hepcludex myrcludex B, Bulevirtide, BLV
  • the entry inhibitor Hepcludex was approved for HDV in July of 2020 in the European Union, and as of June 2023, is available in France, Germany, Austria, Italy, and the UK. The drug binds to the essential HDV receptor on liver cells and by doing so prevents infection of the cell.
  • pegylated interferon alpha acts by stimulating the body's innate immune system to fight the virus.
  • Hepcludex is a 47-amino acid peptide, inhibiting Na+-taurocholate cotransporting polypeptide (NTCP), the viral entry receptor, requiring subcutaneous (SubQ) dosing
  • the small-molecule oral bioavailable NTCP inhibitors of the present invention provide more flexible dosing, increased convenience, and greater combinational options with other HBV/HDV therapies.
  • WO2022/253997 to Albireo relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I): These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity.
  • ASBT apical sodium-dependent bile acid transporter
  • LBAT liver bile acid transport
  • the invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases.
  • the Compounds of formula (I) in WO2022/253997 are chiral due to the presence of a chiral center at the carbon atom bearing R 1 .
  • M is limited to - CH 2 - and -NR 5 -, wherein R 5 is hydrogen or C 1-4 alkyl; R 1- is limited to C 1-4 alkyl, and R 3 is limited to hydrogen, halo, cyano, C 1-4 alkyl, C3-6cycloalkyl, C 1-4 alkoxy, C3-6cycloalkoxy, C1- 4 alkylthio, C 3-6 cycloalkylthio, amino, N-(C 1 - 4 alkyl)amino, and N,N-di(C 1 - 4 alkyl)amino.
  • Example 10b is an exemplary compound of the present invention, with a structure and absolute stereochemistry as shown below: wherein haloalkyl groups are introduced at R 1 (i.e., -CH 2 CH 2 CF 2 CH 3 ) and R 3 (i.e., CF 3 ) and M is a mono-substituted carbon atom (i.e., -CHF-), resulting in a second chiral center outside the scope of WO2022/253997.
  • R 1 i.e., -CH 2 CH 2 CF 2 CH 3
  • R 3 i.e., CF 3
  • M is a mono-substituted carbon atom (i.e., -CHF-)
  • Applicants have discovered one or more of these structural modifications results in unexpectedly improved biological activity against HBV and HDV, selectivity profiles, and PK profiles.
  • the compound of Example 10b can exist as four diastereomers:
  • TABLE 1 Potency and transporter selectivity comparison data for each of these four diastereomers are provided in TABLE 1.
  • TABLE 1 Potency and transporter selectivity comparison data for each of the four diastereomers of the compound of Example 10b of the present invention
  • Diastereomer 1 of Example 10b of the present invention is also referred to as Compound 1.
  • Applicants have made and tested the compounds of Example 9 and Example 13 of WO2022/253997 according to procedures known in the art. Both are described in WO2022/253997 as racemic mixtures of the corresponding enantiomers.
  • Example 14, enantiomer 1 and Example 14, enantiomer 2 are the isolated R and S enantiomers (absolute stereochemistry unassigned) of Example 13.
  • Example 9 and Example 13 have similar NTCP (hLBAT) inhibitory activity but Example 14, enantiomer 2 is significantly more active at inhibiting NTCP (hLBAT) than Example 14, enantiomer1.
  • hLBAT NTCP
  • enantiomer1 is significantly more active at inhibiting NTCP (hLBAT) than Example 14, enantiomer1.
  • no assay data is provided directly demonstrating biologic activity against HDV or HBV.
  • TABLE 2 provides potency and transporter selectivity comparison data for Compound 1 vs the compounds of Examples 9 and 14 of WO2022/253997.
  • Example 14 (enantiomer 2) had IC50 values of 21 and 190 nM vs human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC 50 /NTCP IC 50 ) of 9- fold.
  • Example 9 (best enantiomer) had an IC50 of 75.6 nM vs human NTCP and prevented HBV infection of human hepatoma cells with an IC50 of 45 nM without affecting cell viability.
  • Compound 1 exhibited a higher anti- HBV potency than Example 14 (enantiomer 2), with an IC 50 value approximately 6-times lower. In comparison to Example 9 (best enantiomer), the IC 50 value was approximately 11- times lower.
  • Compound 1 also inhibited NTCP more effectively, with an IC 50 value approximately 3-times lower than that of Example 14 (enantiomer 2) and approximately 10- times lower than that of Example 9 (best enantiomer. Finally, Compound 1 demonstrated a NTCP-selectivity (ASBT IC 50 /NTCP IC 50 ) that was approximately 36-times higher than that of Example 14 (enantiomer 2), indicating its superior selectivity.
  • TABLE 3 provides monkey PK profile comparison data for Compound 1 vs Albireo compound A7387.
  • Data for Compound 1 was acquired using methods and procedures described herein, while data for A7387 is digitized from an Albireo 2023 AASLD poster, 1481-C
  • WO2023237728 refers to Example 14 of WO2022/253997 as Compound 2, and provides primate in vivo results on p.77, cross-referencing Compound 2 as A7387.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C 2--6 alkenyl.
  • exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-).
  • alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C 1-6 alkoxy and C 1-4 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH 3 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 - and CH 3 OCH 2 -, etc.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C 1-6 alkyl and C 1-4 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2- methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc.
  • alkylene refers to a biradical alkyl group.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C 2-6 alkynyl.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc.
  • carbonyl refers to the biradical -C(O)-.
  • coinfection refers to simultaneous infection of a host by more than one viral pathogen.
  • cyano refers to the radical -CN.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C 3-7 monocycloalkyl, or bicyclic hydrocarbon ring structure of, for example, 5-12 carbons, referred to herein as C 5- 12 bicycloalkyl.
  • the two rings may be attached through the same or different carbons.
  • Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl and cyclopropyl.
  • Exemplary bicycloalkyl groups include, but are not limited to, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, decahydronaphthalene, octahydro- 1H-indene, bicyclo[4.2.0]octanyl, bicyclo[4.1.0]heptanyl, octahydropentalenyl, bicycl
  • halo or “halogen” as used herein refer to F, Cl, Br or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • haloC 1-6 alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH 2 F, -CHCl 2 , -CHF 2 , -CF 3 , CF 3 CH 2 -, CH 3 CF 2 -, CF 3 CCl 2 -, and CF 3 CF 2 -.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl 3 O-, CF 3 O-, CHF 2 O- CF 3 CH 2 O-, and CF 3 CF 2 O-.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic group, referred to herein as monocyclo 5-6 heteroaryl, or 8-12 membered bicyclic aromatic ring system, referred to herein as bicyclo 8-12 heteroaryl, containing one to four independently selected heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, the heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen.
  • Examples of monocyclo 5-6 heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also referred to as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also referred to as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and
  • bicyclo 8-12 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[c]isothiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl.
  • heterocycloalkyl refers to a monocycloalkyl group, for example a C 3- 7 monocycloalkyl, or a bicycloalkyl group, for example C 5-12 bicycloalkyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO 2 ), herein referred to as mono 3- 7 heterocycloalkyl and bi 5-12 heterocycloalkyl, respectively.
  • heteroatoms such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO 2 )
  • Examples of mono 3- 7 heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl 1,1- dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl.
  • Examples of bi 5-12 heterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl.
  • hydroxy and “hydroxyl” as used herein refers to the radical -OH.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH 2 -, HOCH 2 CH 2 -, CH 3 CH(OH)CH 2 - and HOCH 2 CH(OH)CH 2 -.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH 2 O-, HOCH 2 CH 2 O-, CH 3 CH(OH)CH 2 O- and HOCH 2 CH(OH)CH 2 O-.
  • R a R b NC 1-6 alkyl- refers to an alkyl group substituted with a R a R b N- group, as defined herein. Examples include but are not limited to NH 2 CH 2 -, NH(CH 3 )CH 2 -, N(CH 3 ) 2 CH 2 CH 2 - and CH 3 CH(NH 2 )CH 2 -.
  • R a R b NC 1-6 alkoxy refers to an alkoxy group substituted with a R a R b N- groups, as defined herein.
  • Examples include but are not limited to NH 2 CH 2 -, NH(CH 3 )CH 2 O-, N(CH 3 ) 2 CH 2 CH 2 O-, and CH 3 CH(NH 2 )CH 2 O-.
  • the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • the mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
  • modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • pharmaceutically acceptable include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutical composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • terapéuticaally effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries.
  • Carreira and Kvaerno Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • Certain isotopically-labeled disclosed compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver).
  • Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). II.
  • Benzothia(dia)zepine Compounds
  • the present disclosure provides a compound of Formula I , or a pharmaceutically acceptable salt thereof, wherein: M is NR x or CR y R z ; X is N or CH; R a , R b and R c are independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl and C 3-6 monocycloalkyl; R x is hydrogen or C 1-4 alkyl; R y and R z are independently selected from the group consisting of hydrogen, halo, CN, C 1-4 alkyl, and haloC 1-4 alkyl; R 1 is 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 R 2a and R 2b are independently selected from the group consisting
  • the Compound of Formula I is of Formula Ia or a pharmaceutically acceptable salt thereof.
  • the Compound of Formula I is of Formula Ib Formula Ib or a pharmaceutically acceptable salt thereof.
  • X is N.
  • X is CH.
  • M is NR x .
  • M is NH or NCH 3 .
  • M is CR y R z .
  • M is -CH 2 -.
  • M is CR y R z and at least one of R y and R z is halo, CN, C 1- 4 alkyl, or haloC 1-4 alkyl.
  • M is -CH(CH 3 )-, -CF(CH 3 )-, is -CHF-, -C(CH 3 ) 2 - or -CF 2 -.
  • M is -CF(CH 3 )-.
  • M is -C(CH 3 ) 2 -.
  • M is -CHF-.
  • M is -CF 2 -.
  • R 1 is C(O)OH.
  • R 1 is S(O) 2 OH. In certain embodiments, R 1 is P(O)(OH) 2 .
  • R 3 is C 5-12 bicycloalkylthio-. In certain embodiments, R 3 is haloC 3-7 monocycloalkylthio-. In certain embodiments, R 3 is haloC 1-2 alkyl-. In certain embodiments, R 3 is CF 3 .
  • R 4 is haloC 1-4 alkyl-, hydroxyC 1-4 alkyl-, CH 3 SO 2 CH 2 CH 2 -, CH 3 SO 2 CH 2 CH 2 CH 2 -, R 4a CH 2 - or R 4a CH 2 CH 2 -.
  • R 4 is haloC 1-4 alkyl-.
  • R 4 is haloC 3-4 alkyl-.
  • R 4 is n-butyl substituted with 1 to 6 halo atoms.
  • R 4 is n-butyl substituted with 1 to 6 F atoms.
  • R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • R 4 is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R 4 is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R 4 is -CH 2 CH 2 CF 3 .
  • R 5 is C 3-7 monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1- 3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1-4 alkyl-, R a R b NC(O)-, C 1-4 alkylC(O)-, C 1-4 alkoxyC(O)-, C 1-4 alkylC(O)O
  • R 5 is In certain embodiments, R 5 is C5-12bicycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O)q-, C 1-4 alkyl, C2-4alkenyl, C2-4alkynyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C1- 3alkoxyC 1-4 alkyl-, haloC1-3alkoxyC 1-4 alkyl-, R a R b NC(O)-, C 1-4 alkylC(O)-, C 1-4 alkoxyC(O)-, C 1-4 alkylC
  • R 5 is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, R a R b N-, R a R b NS(O)q-, C 1-4 alkyl, C2-4alkenyl, C2-4alkynyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1- 3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1-4 alkyl-, R a R b NC(O)-, C 1-4 alkylC(O)-, C 1-4 alkoxyC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylS
  • R 5 is In certain embodiments, R 5 is In certain embodiments, R 5 is In certain embodiments, R 5 is In certain embodiments, X is CH, R 3 is haloC 1-4 alkyl- and R 4 is haloC 1-4 alkyl-. In certain embodiments, X is CH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, X is CH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, X is CH, M is -CHF-, R 3 is haloC 1-4 alkyl-, and R 4 is haloC1- 4alkyl-.
  • X is CH, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, X is CH, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, and R 4 is haloC 1-4 alkyl-. In certain embodiments, X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 and R 4 is - CH 2 CH 2 CF 2 CH 3 .
  • X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 and R 4 is - CH 2 CH 2 CF 3 .
  • X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, R 4 is haloC 1-4 alkyl- , and R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1- 4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alk
  • X is CH
  • M is -CHF-
  • R 1 is C(O)OH
  • R 3 is CF 3
  • R 4 is - CH 2 CH 2 CF 2 CH 3
  • R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1- 4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1- 4 alkyl-, haloC 1-3 alkoxyC 1-4 alkyl-, R a R b NC
  • X is CH
  • M is -CHF-
  • R 1 is C(O)OH
  • R 3 is CF 3
  • R 4 is - CH 2 CH 2 CF 3
  • R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1- 4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1- 4alkyl-, haloC1-3alkoxyC 1-4 alkyl-, R a R b NC(O)
  • X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-2 alkyl, R 4 is haloC 1-2 alkyl;and R 5 is or
  • X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3, R 4 is - CH 2 CH 2 CF 2 CH 3 , and R 5 is or
  • X is CH, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 , R 4 is - CH 2 CH 2 CF 3, and R 5 is or
  • the compound of Formula I is of Formula Ia, X is CH, R 3 is haloC 1-4 alkyl- and R 4 is haloC 1-4 alkyl-.
  • the compound of Formula I is of Formula Ia, X is CH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula I is of Formula Ia, X is CH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 3 is haloC 1-4 alkyl- , and R 4 is haloC 1-4 alkyl-.
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 3 is CF 3, and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 3 is CF 3, and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, R 4 is haloC 1-4 alkyl-, and R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1-4 alkyl-, haloC 1-3 al
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 1 is C(O)OH, R 3 is CF 3 , R 4 is -CH 2 CH 2 CF 2 CH 3 , and R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1-3 alkoxy
  • the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 1 is C(O)OH, R 3 is haloC1-2alkyl, R 4 is haloC1-2alkyl;and R 5 is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 1 is C(O)OH, R 3 is CF 3, R 4 is -CH 2 CH 2 CF 2 CH 3, and R 5 is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R 1 is C(O)OH, R 3 is CF 3 , R 4 is -CH 2 CH 2 CF 3 , and R 5 is In some embodiments of the present invention, the compound of Formula I is of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH 3 )-, -CF(CH 3 )-,
  • R 4 is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R 4 is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R 4 is -CH 2 CH 2 CF 3 .
  • R 5 is C 3-7 monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1- 3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1-4 alkyl-, R a R b NC(O)-, C 1-4 alkylC(O)-, C 1-4 alkoxyC(O)-, C 1-4 alkylC(O)O
  • R 5 is In certain embodiments, R 5 is In certain embodiments, R 5 is In certain embodiments, R 5 is In certain embodiments, R 3 is haloC 1-4 alkyl- and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, R 3 is haloC 1-4 alkyl- and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, M is -CHF- and R 3 is haloC 1-4 alkyl- . In certain embodiments, M is -CHF- and R 3 is CF 3.
  • M is -CHF-, R 3 is haloC 1-4 alkyl-, and R 4 is - CH 2 CH 2 CF 2 CH 3 . In certain embodiments, M is -CHF-, R 3 is haloC 1-4 alkyl-, and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 3 .
  • M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 , and R 4 is - CH 2 CH 2 CF 3 .
  • M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, R 4 is - CH 2 CH 2 CF 2 CH 3 , and R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1- 4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1- 4 alky
  • M is -CHF-
  • R 1 is C(O)OH
  • R 3 is haloC 1-4 alkyl-
  • R 4 is - CH 2 CH 2 CF 3
  • R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1- 4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1- 4alkyl-, haloC1-3alkoxyC 1-4 alkyl-, R a R b NC
  • M is -CHF-
  • R 1 is C(O)OH
  • R 3 is CF 3
  • R 4 is -CH 2 CH 2 CF 3
  • R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1- 4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1- 4 alkyl-, R a R b NC(O)-,
  • M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-2 alkyl, R 4 is - CH 2 CH 2 CF 2 CH 3 , and R 5 i or In certain embodiments, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-2 alkyl, R 4 is - CH 2 CH 2 CF 3 , and R 5 is In certain embodiments, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 , R 4 is - CH 2 CH 2 CF 2 CH 3, and R 5 is or In certain embodiments, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3, R 4 is -CH 2 CH 2 CF 3, and R 5 is In certain embodiments, the compound of Formula II is of Formula IIa, R 3 is haloC 1- 4 alkyl- and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula II is of Formula IIa, R 3 is haloC 1- 4 alkyl- and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, the compound of Formula II is of Formula IIa, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 2 CH 3 . In certain embodiments, the compound of Formula II is of Formula IIa, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 3 . In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R 3 is haloC 1-4 alkyl-, and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 3 is haloC 1-4 alkyl-, and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 3 is CF 3 , and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 2 CH 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 and R 4 is -CH 2 CH 2 CF 3 .
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is haloC 1-4 alkyl-, R 4 is -CH 2 CH 2 CF 2 CH 3 , and R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC
  • the compound of Formula II is of Formula IIa
  • M is -CHF-
  • R 1 is C(O)OH
  • R 3 is haloC 1-4 alkyl-
  • R 4 is -CH 2 CH 2 CF 3
  • R 5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of 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, hydroxyC 1-4 alkyl-, R a R b NC 1-4 alkyl-, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkoxy-, R a R b NC 1-4 alkoxy-, C 1-3 alkoxyC 1-4 alkyl-, haloC 1-3 alkoxyC 1-4 al
  • the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is haloC1-2alkyl, R 4 is CH 2 CH 2 CF 3 , and R 5 is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3, R 4 is -CH 2 CH 2 CF 2 CH 3, and R 5 is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R 1 is C(O)OH, R 3 is CF 3 , R 4 is -CH 2 CH 2 CF 3 , and R 5 is III.
  • compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • a pharmaceutical composition comprises a compound according to any combination of the Examples described herein, or a pharmaceutically acceptable salt and/or stereoisomer thereof.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non- toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stea
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such
  • kits for use by e.g., a consumer in need of HBV infection treatment include a suitable dosage form such as those described above and instructions describing the method of using such dosage form tomediate, reduce or prevent HBV infection.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ...” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • HDV encodes HDAg, the HDV protein responsible for HDV RNA replication.
  • HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of the HDV virions.
  • HBV viral envelope protein HBsAg HBV viral envelope protein
  • the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV/HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for treating an HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • methods of treatment may be facilitated by various mechanisms of action.
  • Another possibility for treatment involves targeting machinery involved in viral particle assembly.
  • inhibiting assembly of the HBV envelope or core by targeting HBsAg would disrupt assembly of the HBV particles.
  • a second strategy would be to inhibit viral replication of HBV and/or HDV.
  • Existing antiviral therapies may apply this approach in the form of replication inhibitors that target, for example, a specific viral RNA polymerase.
  • another aspect of the disclosure is a method for inhibiting HBV or HDV viral replication in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).
  • a method for inhibiting HBV or HDV viral replication in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.
  • Methods of treatment may further include targeting the network of bile acid transport proteins that are believed to be the “gateway” of entry for HBV or HDV infection into the hepatocyte. See for example, Slijepcevic et al., Digestive Diseases, 2017;35:251-258, herein incorporated by reference with regard to such background teaching.
  • the bile acid transport system comprising the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) are a set of receptors that ensure effective bile acid transport between the ileum and hepatocyte. HBV/HDV coinfection of hepatocytes is believed to be mediated via the NTCP receptor, making it a possible target for treatment.
  • an “entry inhibitor” may target any of the possible bile acid transport receptors, including, but not limited to the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) to prevent entry of either HBV or HDV virus into the cells.
  • treatment for patients dealing with HBV or HDV infection or HBV/HDV coinfection may be measured by seroconversion of any of the viral antigens, including but not limited to HBsAg or HBeAg, or maintenance of undetectable levels of these antigens.
  • the appropriate dosage of the compounds described herein is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician.
  • an indicated administration dose may be in the range between about 0.1 to about 1000 ⁇ g/kg body weight.
  • a compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g., in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection.
  • Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting.
  • the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
  • pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period.
  • 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, oil
  • Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • methods and compositions that include a second active agent or administering a second active agent.
  • a subject or patient in addition to being infected with HBV, can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • HBV infection-related co-morbidities i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these HBV-infection- related conditions.
  • L-FMAU Clevudine
  • LB80380 Besifovir
  • viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives
  • HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: and BM601 as depicted below: disruptors of nucleocapsid formation or integrity such as NZ-4/W28F: cccDNA formation inhibitors such as BSBI-25, CCC-0346, CCC-0975 (as depicted below): HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int.
  • OICR-9429 OICR-9429
  • PARP inhibitors APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists
  • kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors
  • STING Agonists Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins.
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
  • HBV capsid assembly promoters HBF viral polymerase interfering nucleosides
  • viral entry inhibitors HBsAg secretion inhibitors
  • cccDNA formation inhibitors disruptors of nu
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic.
  • the disclosure further provides a method of treating HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies and one or more of HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, S
  • the disclosure provides a method of treating a HBV or HBV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic.
  • the first and second amounts together comprise a pharmaceutically effective amount.
  • the first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
  • Therapeutically effective amounts of a disclosed compound and antiviral may be co- administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration.
  • a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of a disclosed compound), with a detection moiety, for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation).
  • a detection moiety for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation).
  • Contemplated fluorophores include AlexaFluor ® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like.
  • a detection moiety may be used in e.g., a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Example 1 (112 mg, 20.2%) as a white solid.
  • TLC 5% MeOH/EA (v/v) (Rf: 0.5).
  • Step 1 Synthesis of ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (2-2).
  • ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (2-1) 100 mg, 0.69 mmol
  • TEA 209 mg, 2.07 mmol
  • MsCl 119 mg, 1.04 mmol
  • Step 1 Synthesis of isopropyl 3,3-difluoro-1-(hydroxymethyl)cyclobutanecarboxylate (4-2).
  • diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate (4-1) (2.0 g, 7.60 mmol) in anhydrous THF (60 mL) was added 1N lithium tri-tert-butoxyalyminium hydride in THF (18.9 mL, 18.9 mmol) at 0 °C.
  • THF 1N lithium tri-tert-butoxyalyminium hydride
  • Step 3 Synthesis of (R)-isopropyl 1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5- phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)-3,3-difluorocyclobutanecarboxylate (4-4).
  • Step 1 Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (5-2).
  • Step 4b Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17b).
  • Compd.18-3 (60 mg) was purified by prep-Chiral-HPLC with the following conditions Column: CHIRALPAK ID, 3*25 cm, 5 ⁇ m; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 35 mL/min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 15.8; RT2 (min): 20.3; Sample Solvent: EtOH-HPLC; Injection Volume: 2 mL; Number of Runs: 5.
  • Example 18a (17 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Example 18b (22 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Compd.19-7 (60 mg) was purified by prep-SFC with the following condition: Column: (R, R)-WHELK-O, 3*25 cm, 5 ⁇ m; Mobile Phase A: CO 2 , 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.
  • Example 19a (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Example 19b (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Compd.20- 1 (65 mg) was purified by prep-HPLC with the following conditions: Column: CHIRALPAK IC 3*25 cm, 5 ⁇ m; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 25 mL/min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 4.3; RT2 (min): 5.9; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL; Number of Runs: 5.
  • Example 20a 14 mg (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Example 20b 13 mg (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid.
  • Step 1 Synthesis of (3aR,6aS)-5,5-difluorohexahydropentalen-2(1H)-one (23-2).
  • Step 1 Synthesis of tert-butyl 2-cyclopropylacetate (24-2).
  • cyclopropylacetic acid (24-1) in 25 ml of dichloromethane at 0 o C was added a drop of DMF, followed by 6.99 g (55 mmol) of oxalyl chloride dropwise.
  • the reaction mixture was stirred between 0°C and 10°C for 2 h and then concentrated under reduced pressure.
  • the residue was briefly (about 5 min) dried under high vacuum and then taken up in dry THF (10 mL), and the resulting mixture was cooled to 0°C.
  • Step 4 Synthesis of tert-butyl 2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoate (24-5).
  • Step 6b Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (Example 24a). Following the same procedure for preparing Example 24a by replacing 24-5a with 24-5b (78 mg, 0.13 mmol), Example 24b (33 mg, 48%) was obtained as a white solid. MS (ESI): calcd.
  • Example 25 (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2- methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- methylpropanoic acid
  • Step 1 Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-7- vinyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-2).
  • 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
  • Selectfluor 33.38 g, 94.23 mmol
  • the resulting mixture was stirred at 70°C for 24 hr under nitrogen atmosphere.
  • Step 4 Synthesis of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoic acid (27-5).
  • 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
  • MeOH MeOH
  • Pd/C 111.50 g, 10%, wet.
  • Step 8 Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9).
  • the solution of methyl (S)-5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (27-8) (1150 g, 4.38 mol) and LiBr (1.52 kg, 17.50 mol) in Acetone (12 L) was stirred at 60°C for 3 h. The mixture was allowed to cool down to room temperature and concentrated under vacuum.
  • Step 1 Synthesis of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2).
  • cesium fluoride 33.2 g, 218.6 mmol
  • 2-methoxy-1-iodo-4-nitrobenzene (28-1) (24.0 g, 84.1 mmol).
  • the resulting solution was stirred at 45°C.
  • trimethyl(trifluoromethyl)silane 31.05 g, 218.6 mmol
  • the resulting mixture was stirred at 80 °C for 24 h.
  • the reaction was monitored by LC-MS.
  • the mixture was allowed to cool down to rt.
  • the resulting mixture was extracted with EtOAc (300 mL x 2).
  • the combined organic layers were washed with brine (450 mL), dried over anhydrous Na 2 SO 4 , and concentrated.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (40:1 (v/v)) to give 151-2 (30 g, 75.2%) as a colorless oil.
  • diethyl 2-(3,3,3-trifluoropropyl)malonate (151- 2) (25 g, 97.57 mmol), EtOH (250 mL) and KOH (6.02 g, 107.33 mmol) at rt.
  • the resulting mixture was stirred at rt for 8 h under nitrogen atmosphere.
  • the reaction was monitored by LC-MS.
  • EtOAc 150 mL x 4
  • the combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , and concentrated.
  • Step 19 Synthesis of methyl 3-(((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (151-20a) and methyl 3-(((2R,3S)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (151-20b).
  • Example 151b was obtained (single diastereomer, 272 mg, 58.6%) as a yellow solid.
  • Chiral HPLC condition Column: Sunfire Prep C18 OBD Column, 19*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 40% B to 75% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.28.
  • Chiral HPLC condition Column: Sunfire Prep C18 OBD Column, 19*150mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 45% B to 75 % B in 8 min; Wavelength: 254 nm/220 nm).
  • Step 1 Synthesis of dimethyl 2-(3-oxopropyl)malonate (153-2).
  • a solution of dimethyl malonate (153-1) (100 g, 756.92 mmol) in MeOH (1 L) was treated with sodium methoxide (4.09 g, 75.69 mmol) for 2 min at room temperature under nitrogen atmosphere, followed by the addition of acrolein (55.17 g, 983.99 mmol) dropwise at 0 °C.
  • the resulting mixture was stirred at room temperature for 16 h.
  • the resulting mixture was concentrated under reduced pressure.
  • the resulting mixture was extracted with EtOAc (1 L x 2).
  • the combined organic layers were washed with brine (1 L), dried over anhydrous Na 2 SO 4 , and concentrated.
  • Step 8 Synthesis of methyl 2-(((2-amino-5-methoxy-4- (trifluoromethyl)phenyl)thio)methyl)-5,5-difluoropentanoate (153-9).
  • a solution of 6,6'- disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151-11) (15 g, 33.75 mmol) in DMF (150 mL) was treated with Cs2CO3 (32.99 g, 101.26 mmol) for 2 mins at room temperature under nitrogen atmosphere followed by the addition of Na2S2O4 (23.51 g, 135.01 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h.
  • methyl 2-(bromomethyl)-5,5-difluoropentanoate (153-8) (8.27 g, 33.75 mmol) dropwise at room temperature over 10 mins.
  • the resulting mixture was stirred at room temperature for an additional 3 h.
  • the reaction was quenched with water at room temperature.
  • the resulting mixture was extracted with EtOAc (150 mL x 2).
  • the combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , and concentrated.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-9 (10.7 g, 81.8%) as a white solid.
  • Example 153b (282 mg, 90.4%, single diastereomer) was obtained as a white solid.
  • Prep-HPLC condition Column: Sunfire Prep C18 OBD Column, 19*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 50% B to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.26.
  • Step 1 Synthesis of (2,2-difluorocyclopropane-1,1-diyl)bis(methylene) diacetate (154-2).
  • 2-methylenepropane-1,3-diyl diacetate (154-1) (20 g, 116.2 mmol) and DME (100 mL) at room temperature.
  • ClCF 2 CO2Na 106.26 g, 697 mmol
  • the resulting mixture was stirred at 80°C for an additional 1 h. The mixture was allowed to cool down to room temperature.
  • the resulting mixture was stirred at room temperature for 4 hr under nitrogen atmosphere.
  • the precipitate was collected by filtration and washed with water (40 mL x 2).
  • the resulting mixture was extracted with EtOAc (30 mL x 2).
  • the combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na 2 SO 4 , and concentrated.
  • Example 154b was obtained (14 mg, 33.1%, single diastereomer, the stereochemistry is arbitrarily assigned) as a yellow solid.
  • Prep-HPLC condition Column: Sunfire Prep C18 OBD Column, 19*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 55% B to 70 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 7.58.
  • Step 1 Synthesis of butyl 3-chloropropane-1-sulfonate (156-2).
  • the reaction mixture was stirred at -78 o C for 3 h and then warmed up to 0 °C. Subsequently, sat. aq. NH4Cl solution (100 mL) was added to quench the reaction, and the resulting mixture was then separated into phases.
  • N-butyllithium (23% in hexanes) (6.32 mL, 15.45 mmol) was added dropwise to a solution of butyl cyclopropanesulfonate (156-3) (2.5 g, 14.03 mmol) in THF (50 mL) at -78°C.
  • a solution of anhydrous DMF (2.17 mL, 28.04 mmol) in THF (5 mL) was added dropwise to the reaction mixture and the resulting mixture was warmed to room temperature for 4 h. Subsequently, the reaction mixture was quenched with sat. aq. NH 4 Cl solution, and the phases were subsequently separated.
  • Butyl 1- formylcyclopropane-1-sulfonate (156-5) (1.8 g) was dissolved in methanol (18 mL) and cooled to 0°C.
  • Sodium borohydride (133 mg, 3.5 mmol) was added to the reaction mixture in portions, and the resulting mixture was stirred at rt for 3 h.
  • the reaction mixture was concentrated, and the residue was diluted with DCM (30 mL). The mixture was washed with water (10 mL x 3) and brine (10 mL), dried over Na 2 SO 4 , and concentrated.
  • the residue was purified by flash chromatography to give 156-5 (120 mg, 33.0%) as a yellow oil. Step 5.
  • Triphenylphosphine (54.6 mg, 0.21 mmol), butyl 1-(hydroxymethyl)cyclopropane-1-sulfonate (156-5) (43.4 mg, 0.21 mmol) and DIAD (42.1 mg, 2.1 mmol) were added sequentially to an ice-cooled solution of 3-(3,3- difluorobutyl)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (155-1) (50 mg, 0.1 mmol) in THF (2.5 mL). The reaction mixture was stirred at room temperature overnight and then concentrated.
  • Example 156 (9.3 mg, 30.8%) as an off-white solid.
  • Step 1 Synthesis of diethyl (1-formylcyclopropyl)phosphonate (157-2).
  • Examples 158a and 158b (S)-3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (158a) and (R)-3-((5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (158b)
  • Step 1 Synthesis of 1-amino-3,3-diethylcyclobutane-1-carbonitrile (159-2).
  • Step 2 Synthesis of N-(1-cyano-3,3-diethylcyclobutyl)acetamide (159-3).
  • 159-3 N-(1-cyano-3,3-diethylcyclobutyl)acetamide
  • 159-2 1-amino-3,3-diethylcyclobutane-1-carbonitrile
  • acetyl anhydride 10.56 g, 103.53 mmol
  • Step 3 Synthesis of 1-carboxy-3,3-diethylcyclobutan-1-aminium chloride (159-4).
  • Step 1 Synthesis of (R)-tert-butyl 1-(4-fluorophenylamino)-4-(methylthio)-1-oxobutan- 2-ylcarbamate (160-2).
  • Step 3 Synthesis of (R)-N1-(4-fluorophenyl)-4-(methylthio)butane-1,2-diamine (160-4). To a stirred solution of (R)-2-amino-N-(4-fluorophenyl)-4-(methylthio)butanamide (160-3) (3.4 g, 14 mmol) in anhydrous THF (34 mL) was added LiAlH 4 (1.6 g, 42 mmol) portion- wise below 10 o C under Ar atmosphere.
  • Example 160 (110 mg, 68%) as a white solid.
  • Step 1 Synthesis of ethyl 2-((diphenylmethylene)amino)hex-5-enoate (163-2).
  • ethyl 2-((diphenylmethylene)amino)acetate (163-1) (10.0 g, 37.4 mmol)
  • K2CO3 (15.5 g, 112.2 mmol)
  • TBAB 1.2 g, 3.74 mmol
  • 4- bromobut-1-ene 7.5 g, 56.2 mmol
  • HepG2-NTCP HBV infection protocol HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture using DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 ⁇ g/mL G418 (Alfa Aesar, Cat# J62671), 50 U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 ⁇ g/mL blasticidin (Sigma, Cat# 15205).
  • the cells Prior to infection, the cells were washed twice with 1 ⁇ DPBS (Invitrogen, Cat# 14190-136) and treated with 3 mL of 0.05% trypsin (Invitrogen, Cat# 25200-056) to dissociate the cells. Following dissociation, 10 mL of HepG2-NTCP growth medium was added to the cells to neutralize the trypsin and the cells were then counted and centrifuged at 1,300 rpm for 5 minutes.
  • 1 ⁇ DPBS Invitrogen, Cat# 14190-136
  • trypsin Invitrogen, Cat# 25200-056
  • the cells were resuspended in DMEM supplemented with 5% FBS, 50 U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540) to a density of 8 ⁇ 10 5 cells/mL and infected with HBV at an MOI of 50.
  • 50 ⁇ L of the cell/HBV mixture was added to a 96-well plate containing 50 ⁇ L of compound and incubated at 370C for 24 hours (2% final DMSO concentration).
  • the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50 U/mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 72 hours.
  • the plates were spun at 1,800 rpm for 8 minutes and the supernatant was removed for HBeAg quantification using electrochemiluminescence enzyme-linked immunosorbent assays (ECL-ELISA).
  • HBeAg ECL-ELISA Lumitrack high-binding 96-well plates (Greiner, Cat# 655074) were treated with 625 ng/mL HBeAg mAb (Biocheck, Cat# 70426) in 1 ⁇ DPBS for 2 hours at 250C with shaking. The HBeAg mAb solution was then removed and the plates treated with 1 ⁇ DPBS containing 0.5% bovine serum albumin (BSA) (Sigma, Cat# A7030-100g) for 2 hours at 250C with shaking. The HBeAg-coated plates were then washed 4 times with 1 ⁇ DPBS containing 0.05% Tween 20 (DPBS-T) (Thermo Fisher Scientific, Cat# J61544-K2).
  • BSA bovine serum albumin
  • HRP-conjugated antibody (Fitzgerald, Cat# 61-H10K), diluted 1:8,000 in 1 ⁇ DPBS-T containing 0.5% BSA, was added to the HBeAg- coated plates along with 15 ⁇ L of each sample. The plates were then incubated for 2 hours at 25 0C with shaking. Following the incubation, the sample was then removed and 200 ⁇ L of 1 ⁇ PBS-T was added and the plates were incubated for 10 minutes at 250C with shaking.
  • ECL substrate (Millipore, Cat# WBKLS0500) was then added to the plate and the luminescence was measured using a Tecan M1000 Pro plate reader.
  • ECL substrate Millipore, Cat# WBKLS0500
  • Tecan M1000 Pro plate reader Other assays are known in the art, see for example, Lempp et al., Nature Communications, 2019, 10:2265, https://doi.org/10.1038/s41467-019-10211-2, Grosser et al., Frontiers in Molecular Biosciences, 2021, 8: doi: 10.3389/fmolb.2021.689757.
  • TABLE 5 shows assay data for exemplified compounds of the invention following the described HepG2-NTCP HBV infection protocol, grouped in the following ranges: A indicates EC50 ⁇ 10 nM; B indicates 10 nM ⁇ EC50 ⁇ 100 nM; C indicates100 nM ⁇ EC50 ⁇ 500 nM; and D indicates EC 50 of ⁇ 500 nM.
  • A indicates EC50 ⁇ 10 nM
  • B indicates 10 nM ⁇ EC50 ⁇ 100 nM
  • C indicates100 nM ⁇ EC50 ⁇ 500 nM
  • D indicates EC 50 of ⁇ 500 nM.
  • HepG2-NTCP HDV infection protocol HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture in DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 ⁇ g/mL G418 (Alfa Aesar, Cat# J62671), 50 U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 ⁇ g/mL blasticidin (Sigma, Cat# 15205).10,000 HepG2-NTCP cells were seeded in 96-well plate in 50 ⁇ L DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540).
  • NTCP assay protocol 50,000 HEK293 cells were seeded in 96-well plate in 100 ⁇ L Eagle’s Minimum Essential Medium (EMEM) supplemented with 10% FBS and a transfection mix (Lipofectamine 3000) containing human NTCP-expression DNA plasmids. The cells were incubated at 37 °C in 5% CO 2 for 24 h. After incubation, compounds were dispensed to the wells using a Tecan D300e dispenser in a serial dilution (4-fold, 8 doses) and the cells were incubated at 37 °C in 5% CO 2 for 1 h.
  • EMEM Eagle’s Minimum Essential Medium
  • NBD nitrobenzoxadiazole
  • TCA Taurocholic acid
  • ASBT assay protocol 20,000 HEK293T cells stably overexpressing human apical sodium-dependent bile salt transporter (ASBT) were seeded in a 96- well plate in 100 ⁇ L DMEM/High glucose with L-glutamine medium supplemented with 10% FBS containing puromycin (0.9 mg/mL) and incubated at 37 °C in 5% CO 2 in the presence of serially diluted compounds (3-fold serial dilution in DMSO, 8 concentrations) in DMEM (with 10% FBS) for 30 minutes.
  • NxT Flow Cytometer (Invitrogen) was used, and NBD’s fluorescence intensity was measured at 488 nm excitation. Linerixibat and DMSO treated cells were used as positive and negative controls, respectively. Statistical Analysis Percentage inhibitions were calculated cells respect to the assay controls. Further data analysis was performed using validated statistical software (GraphPad Prism) to calculate the average EC50 or IC50 value from X experiments for the test compound. Study design of pharmacokinetics Non-human primates (NHPs) were dosed with Example 10b via oral gavage at single dose levels ranging between 3 to 30 mg/kg.
  • NDPs Non-human primates
  • Plasma samples were collected via cephalic and saphenous vein from all animals into EDTA-k2 tubes and stored under chilled conditions until centrifugation at 4 o C to obtain plasma. Plasma samples were labeled and stored at -80 o C until analysis. Bioanalysis Example 10b plasma concentrations were assessed via liquid chromatography- tandem mass spectrometry. The lower limit of quantitation was 3 ng/mL. Reference: J Pharmacol. Exp. Ther.2013, 344, 673–685. VII.
  • the crystal belongs to the monoclinic crystal system, with a space group P 1211.
  • Example 10b The structure was solved by direct methods and all the non-H atoms were refined against F 2 by full-matrix least-squares methods using the SHELXT structure solution program. Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.5846, respectively.
  • the final R, wR 2 , GOF are 0.0494 (I > 2 ⁇ (I)), 0.1317 and 1.053, respectively. There is one C 25 H 26 F 7 NO 5 S molecule in the asymmetric unit.
  • the ORTEP plot for Example 10b is presented in Figure.1. The stereochemistry of Example 10b is shown below.
  • Example 11a A crystal with size of 0.07 x 0.07 x 0.05 mm of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoic acid (Example 11a), which was synthesized using methyl (R)-3-hydroxy-2-methylpropanoate as a starting material (Scheme 11), was obtained from CHCl 3 /hexane (1/1.2 (v/v)) after 5 days of volatilization and was used for X-ray diffraction data collection.
  • the crystal belongs to orthorhombic crystal system, with a space group P212121.
  • the structure was solved by direct methods and all the non-H atoms were refined against F 2 by full-matrix least-squares methods using the SHELXT structure solution program.
  • Example 11a Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.3680, respectively.
  • the final R, wR 2 , GOF are 0.0685(I > 2 ⁇ (I)), 0.1650 and 1.015, respectively.
  • the ORTEP plot for Example 11a is presented in Figure.2. The stereochemistry of Example 11a is shown below. The depictions of stereochemistry in the chemical structures of related examples are based on this assignment. Stereochemistry of Example 11a based on ORTEP plot assignments.

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Abstract

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

Description

BENZOTHIA(DIA)ZEPINE COMPOUNDS FOR TREATMENT OF HBV AND HDV CROSS-REFERENCE TO RELATED APPLICATION This application claims benefit of U.S. Provisional Application No.63/446,976, filed February 20, 2023 and U.S. Provisional Application No.63/534,249, filed August 23, 2023, the contents of which are hereby incorporated by reference. BACKGROUND Hepatitis B virus (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 296 million people were chronically infected in 2019 according to the World Health Organization website, and every year HBV infection causes more than one half million deaths. HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV- positive mothers may also be infected, unless vaccinated at birth. The HBV particle is composed of a lipid envelope studded with the hepatitis B surface antigen (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After capsid assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core. At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g., entecavir) that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleos(t)ide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance. The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon α or pegylated interferon α. Unfortunately, the adverse event incidence and profile of interferon α can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients is likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment. Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon α has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections. Another form of viral hepatitis is hepatitis D virus (HDV), a defective RNA virus that causes chronic viral hepatitis and eventual cirrhosis. However, the HDV life cycle is dependent on the presence of HBsAg for viral particle assembly. Thus, in a small set of patients infected with HBV, HDV presents as coinfection/superinfection with HBV. See for example, Sagnelli et al., Life (Basel).2021 Feb; 11(2): 169, Published online 2021 Feb 22. doi: 10.3390/life11020169, herein incorporated by reference with regard to such background teaching. For patients already infected with HBV, coinfection/superinfection with HDV can further exacerbate the symptoms of HBV, increasing the likelihood of complications, rapid disease progression and/or death. Chronic HBV/HDV infection is also associated with the development of hepatocellular carcinoma (HCC). Like HBV, treatment options for HDV infection or HBV/HDV coinfection, are limited and include those used to treat HBV. Thus, there is a need for effective therapeutic options for the treatment of HDV infection or HBV/HDV coinfection/superinfection. WO2022253997 relates to relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases. WO2023237728 to Albireo relates to methods for treating hepatitis B and/or D with an Na+/taurocholate co-transporting polypeptide (NTCP) inhibitor such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound of formula (II), or a pharmaceutically acceptable salt thereof. Such methods can include decreasing the concentration of hepatitis B DNA, decreasing the concentration of hepatitis D DNA, decreasing hepatitis B surface antigen, and decreasing hepatitis B core antigen (HBcAg). NTCP functions as a cellular receptor for viral entry of HBV and HDV, which in turn is the major cause of liver disease and HCC. There is a need for additional bile acid modulating compounds that have an improved profile with respect to potency, safety, selectivity and/or bioavailability. SUMMARY The present disclosure provides, in part, benzothia(dia)zepine compounds and pharmaceutical compositions thereof, useful for inhibition of HBV or HDV replication, inhibition of HBV or HDV viral entry, and methods of treating HBV infections, HDV infection or HBV/HDV coinfection. In one aspect, the disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating an HDV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating an HDV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF DRAWINGS Figure 1 shows the ORTEP plot for Example 10b. Figure 2 shows the ORTEP plot for Example 11a. DETAILED DESCRIPTION Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV), resulting in the most severe form of viral hepatitis known in humans. HDV is a single-stranded, circular RNA virus. It relies on the hepatitis B virus (HBV) to infect and replicate in liver cells. HDV is a defective virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of HBV that provides the envelope proteins. New HDV progeny particles can only be produced in a liver cell that is already infected with HBV. Worldwide, approximately 300 million people are chronically infected with HBV. An estimated 15-20 million are also chronically infected with hepatitis delta. Coinfections lead to more serious liver disease than HBV infection alone. They are associated with faster progression to liver fibrosis, increased risk of liver cancer, and early decompensated cirrhosis and liver failure that may lead to a fatal outcome within days if not transplanted. Hepatitis delta can be acquired either through coinfection: infection with hepatitis B and delta at the same time. It can also be acquired by superinfection: infection with hepatitis D after a person has already acquired hepatitis B. There is currently no vaccine for hepatitis delta. However, it can be prevented by getting the hepatitis B vaccine to help eliminate the risk of infection with HBV. The entry inhibitor Hepcludex (myrcludex B, Bulevirtide, BLV) was approved for HDV in July of 2020 in the European Union, and as of June 2023, is available in France, Germany, Austria, Italy, and the UK. The drug binds to the essential HDV receptor on liver cells and by doing so prevents infection of the cell. Binding of BLV to NTCP simultaneously inhibits its natural biological function of transporting bile acid into the cell. Previously, the only treatment for hepatitis delta found to be somewhat effective was pegylated interferon alpha, which acts by stimulating the body's innate immune system to fight the virus. While Hepcludex is a 47-amino acid peptide, inhibiting Na+-taurocholate cotransporting polypeptide (NTCP), the viral entry receptor, requiring subcutaneous (SubQ) dosing, the small-molecule oral bioavailable NTCP inhibitors of the present invention provide more flexible dosing, increased convenience, and greater combinational options with other HBV/HDV therapies. WO2022/253997 to Albireo relates to 1,5-benzothiazepine and 1,2,5- benzothiadiazepine derivatives of formula (I): These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases. Applicants note that the Compounds of formula (I) in WO2022/253997 are chiral due to the presence of a chiral center at the carbon atom bearing R1. In addition, M is limited to - CH2- and -NR5-, wherein R5 is hydrogen or C1-4alkyl; R1- is limited to C1-4alkyl, and R3 is limited to hydrogen, halo, cyano, C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C3-6cycloalkoxy, C1- 4alkylthio, C3-6cycloalkylthio, amino, N-(C1-4alkyl)amino, and N,N-di(C1-4alkyl)amino. Thus, there is no teaching or suggestion of a haloalkyl substituent at R1 or R3, or of M being a substituted carbon atom. Notably, when M is a mono-substituted carbon atom, a new chiral center is introduced resulting in four diastereomers. In contrast, Example 10b is an exemplary compound of the present invention, with a structure and absolute stereochemistry as shown below: wherein haloalkyl groups are introduced at R1 (i.e., -CH2CH2CF2CH3) and R3 (i.e., CF3) and M is a mono-substituted carbon atom (i.e., -CHF-), resulting in a second chiral center outside the scope of WO2022/253997. Applicants have discovered one or more of these structural modifications results in unexpectedly improved biological activity against HBV and HDV, selectivity profiles, and PK profiles. The compound of Example 10b can exist as four diastereomers:
Potency and transporter selectivity comparison data for each of these four diastereomers are provided in TABLE 1. TABLE 1: Potency and transporter selectivity comparison data for each of the four diastereomers of the compound of Example 10b of the present invention As used herein, Diastereomer 1 of Example 10b of the present invention is also referred to as Compound 1. For comparison purposes, Applicants have made and tested the compounds of Example 9 and Example 13 of WO2022/253997 according to procedures known in the art. Both are described in WO2022/253997 as racemic mixtures of the corresponding enantiomers. Example 14, enantiomer 1 and Example 14, enantiomer 2 are the isolated R and S enantiomers (absolute stereochemistry unassigned) of Example 13. Table 8 of WO2022/253997 shows that Example 9 and Example 13 have similar NTCP (hLBAT) inhibitory activity but Example 14, enantiomer 2 is significantly more active at inhibiting NTCP (hLBAT) than Example 14, enantiomer1. However, no assay data is provided directly demonstrating biologic activity against HDV or HBV. TABLE 2 provides potency and transporter selectivity comparison data for Compound 1 vs the compounds of Examples 9 and 14 of WO2022/253997. TABLE 2: Potency and transporter selectivity comparison data As shown in the table, Compound 1 had half-maximal inhibitory concentration (IC50) values of 7.3 and 2,400 nM vs human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC50/NTCP IC50) of >320-fold. Compound 1 also prevented HBV infection of human hepatoma cells with an IC50 of 4.2 nM without affecting cell viability. In contrast, Example 14 (enantiomer 2) had IC50 values of 21 and 190 nM vs human NTCP and ASBT, respectively, with an NTCP-selectivity ratio (ASBT IC50/NTCP IC50) of 9- fold. This compound prevented HBV infection of human hepatoma cells with an IC50 of 24 nM without affecting cell viability. Likewise, Example 9 (best enantiomer) had an IC50 of 75.6 nM vs human NTCP and prevented HBV infection of human hepatoma cells with an IC50 of 45 nM without affecting cell viability. Thus, in hepatoma cells infected with HBV, Compound 1 exhibited a higher anti- HBV potency than Example 14 (enantiomer 2), with an IC50 value approximately 6-times lower. In comparison to Example 9 (best enantiomer), the IC50 value was approximately 11- times lower. Compound 1 also inhibited NTCP more effectively, with an IC50 value approximately 3-times lower than that of Example 14 (enantiomer 2) and approximately 10- times lower than that of Example 9 (best enantiomer. Finally, Compound 1 demonstrated a NTCP-selectivity (ASBT IC50/NTCP IC50) that was approximately 36-times higher than that of Example 14 (enantiomer 2), indicating its superior selectivity. TABLE 3 provides monkey PK profile comparison data for Compound 1 vs Albireo compound A7387. Data for Compound 1 was acquired using methods and procedures described herein, while data for A7387 is digitized from an Albireo 2023 AASLD poster, 1481-C | PRECLINICAL CHARACTERIZATION OF THE NOVEL, ORALLY BIOAVAILABLE NTCP INHIBITOR A7387. Although the structure of A7387 was not disclosed in the poster, WO2023237728 refers to Example 14 of WO2022/253997 as Compound 2, and provides primate in vivo results on p.77, cross-referencing Compound 2 as A7387. TABLE 3: Monkey PK Profile Comparison for Compound 1 vs A7387 In monkeys, after an oral dose of 3 mg/kg, Compound 1 exhibited higher exposure, with an AUC0-24 of 58178 hr*ng/mL and a Cmax of 5147 ng/mL, which were 320% and 120% higher, respectively, than those observed for A7387. In monkeys, after an oral dose of 10 mg/kg, Compound 1 exhibited higher exposure, with an AUC0-24 of 290412 hr*ng/mL and a Cmax of 23100 ng/mL, which were 1450% and 1260% higher, respectively, than those observed for A7387. In monkeys, after an oral dose of 30 mg/kg, Compound 1 exhibited higher exposure, with an AUC0-24 of 1082543 hr*ng/mL and a Cmax of 64900 ng/mL, which were 240% and 150% higher, respectively, than those observed for A7387. The apparent oral PK terminal half-life of Compound 1 ranged from 13-17 hours, which were 160% - 320% longer than those observed for A7387. The features and other details of the present disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I. Definitions The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2--6alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc. The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C1-6alkoxy and C1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc. The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2- and CH3OCH2-, etc. The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2- methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc. The term “alkylene” as used herein refers to a biradical alkyl group. The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc. The term “carbonyl” as used herein refers to the biradical -C(O)-. The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen. The term “cyano” as used herein refers to the radical -CN. The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C3-7monocycloalkyl, or bicyclic hydrocarbon ring structure of, for example, 5-12 carbons, referred to herein as C5- 12bicycloalkyl. For bicyclic cycloalkyl groups, the two rings may be attached through the same or different carbons. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl and cyclopropyl. Exemplary bicycloalkyl groups include, but are not limited to, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, decahydronaphthalene, octahydro- 1H-indene, bicyclo[4.2.0]octanyl, bicyclo[4.1.0]heptanyl, octahydropentalenyl, bicyclo[3.2.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, and bicyclo[1.1.1]pentanyl. The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC1-6alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, -CF3, CF3CH2-, CH3CF2-, CF3CCl2-, and CF3CF2-. The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH2O-, and CF3CF2O-. The terms “heteroaryl” as used herein refers to a 5-6 membered monocyclic aromatic group, referred to herein as monocyclo5-6heteroaryl, or 8-12 membered bicyclic aromatic ring system, referred to herein as bicyclo8-12heteroaryl, containing one to four independently selected heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, the heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of monocyclo5-6heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also referred to as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also referred to as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and tetrazolyl. Examples of bicyclo8-12heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl. The term “heterocycloalkyl” refers to a monocycloalkyl group, for example a C3- 7monocycloalkyl, or a bicycloalkyl group, for example C5-12bicycloalkyl, wherein 1-3 of the carbon atoms are replaced with independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including its oxidation states: S(O) and SO2), herein referred to as mono3- 7heterocycloalkyl and bi5-12heterocycloalkyl, respectively. Examples of mono3- 7heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl 1,1- dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. Examples of bi5-12heterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl. The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2- and HOCH2CH(OH)CH2-. The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O- and HOCH2CH(OH)CH2O-. The term “RaRbNC1-6 alkyl-,” as used herein refers to an alkyl group substituted with a RaRbN- group, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2- and CH3CH(NH2)CH2-. The term “RaRbNC1-6alkoxy,” as used herein refers to an alkoxy group substituted with a RaRbN- groups, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-. The term “oxo” as used herein refers to the radical =O. As used herein, when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example as in it signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R33 group(s)) can be independently attached to either or both rings. The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired. The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). II. Benzothia(dia)zepine Compounds In one aspect, the present disclosure provides a compound of Formula I , or a pharmaceutically acceptable salt thereof, wherein: M is NRx or CRyRz; X is N or CH; Ra, Rb and Rc are independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; Rx is hydrogen or C1-4alkyl; Ry and Rz are independently selected from the group consisting of hydrogen, halo, CN, C1-4alkyl, and haloC1-4alkyl; R1 is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH or R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH methyl, ethyl and CH2OH; or R2a and R2b together with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected halo or methyl groups; R3 is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1- 4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3- 7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3- 7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5- 12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4 is hydrogen, C1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-; R4a is phenyl, imidazolyl, N-methylimidazolyl, or C3-6monocycloaklyl optionally substituted with 1 to 3 halo groups; R5 is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3- 7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2; with the proviso that: R3 is haloC1-4alkyl; M is CRyRz and at least one of Ry and Rz is halo, CN, C1-4alkyl, or haloC1-4alkyl; or R4 is haloC1-4alkyl, hydroxyC1-4alkyl, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-; or a combination thereof. The following embodiments further describe a compound of Formula I, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. In certain embodiments, the Compound of Formula I is of Formula Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the Compound of Formula I is of Formula Ib Formula Ib or a pharmaceutically acceptable salt thereof. In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, M is NRx. In certain embodiments, M is NH or NCH3. In certain embodiments, M is CRyRz. In certain embodiments, M is -CH2-. In certain embodiments, M is CRyRz and at least one of Ry and Rz is halo, CN, C1- 4alkyl, or haloC1-4alkyl. In certain embodiments, M is -CH(CH3)-, -CF(CH3)-, is -CHF-, -C(CH3)2- or -CF2-. In certain embodiments, M is -CF(CH3)-. In certain embodiments, M is -C(CH3)2-. In certain embodiments, M is -CHF-. In certain embodiments, M is -CF2-. In certain embodiments, R1 is C(O)OH. In certain embodiments, R1 is S(O)2OH. In certain embodiments, R1 is P(O)(OH)2. In certain embodiments, R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH and methyl. In certain embodiments, R2a and R2b are methyl. In certain embodiments, R2a is hydrogen and R2b are methyl. In certain embodiments, R2a and R2b 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 1-3 halo groups. In certain embodiments, R2a and R2b together with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group. In certain embodiments, R2a and R2b together with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments, R3 is C5-12bicycloalkylthio-. In certain embodiments, R3 is haloC3-7monocycloalkylthio-. In certain embodiments, R3 is haloC1-2alkyl-. In certain embodiments, R3 is CF3. In certain embodiments, R4 is haloC1-4alkyl-, hydroxyC1-4alkyl-, CH3SO2CH2CH2-, CH3SO2CH2CH2CH2-, R4aCH2- or R4aCH2CH2-. In certain embodiments, R4 is haloC1-4alkyl-. In certain embodiments, R4 is haloC3-4alkyl-. In certain embodiments, R4 is n-butyl substituted with 1 to 6 halo atoms. In certain embodiments, R4 is n-butyl substituted with 1 to 6 F atoms. In certain embodiments, R4 is -CH2CH2CF2CH3. In certain embodiments, R4 is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R4 is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R4 is -CH2CH2CF3. In certain embodiments, R5 is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5 is In certain embodiments, R5 is C5-12bicycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5 is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5 is In certain embodiments, R5 is In certain embodiments, X is CH, R3 is haloC1-4alkyl- and R4 is haloC1-4alkyl-. In certain embodiments, X is CH, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, X is CH, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R3 is haloC1-4alkyl-, and R4 is haloC1- 4alkyl-. In certain embodiments, X is CH, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF2CH3. In certain embodiments, X is CH, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, and R4 is haloC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3 and R4 is - CH2CH2CF2CH3. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3 and R4 is - CH2CH2CF3. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is haloC1-4alkyl-, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is haloC1-2alkyl;and R5 is or In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF2CH3, and R5 is or
In certain embodiments, X is CH, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF3, and R5 is or In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3 is haloC1-4alkyl- and R4 is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3 is haloC1-4alkyl-, and R4 is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3 is CF3, and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R3 is CF3, and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, and R4 is haloC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is haloC1-4alkyl-, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1- 4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1- 4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is haloC1-2alkyl;and R5 is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF2CH3, and R5 is In certain embodiments, the compound of Formula I is of Formula Ia, X is CH, M is - CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is In some embodiments of the present invention, the compound of Formula I is of Formula II Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2- or -C(CH3)2-; Ra, Rb and Rc are independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; R1 is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH or R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH methyl, ethyl and CH2OH; or R2a and R2b together with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected halo or methyl groups; R3 is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1- 4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3- 7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3- 7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5- 12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4 is haloC3-4alkyl; R5 is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3- 7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2. The following embodiments further describe a compound of Formula II, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. In certain embodiments, the compound of Formula II is of Formula IIa , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IIb , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IIc , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula II is of Formula IId , or a pharmaceutically acceptable salt thereof. In certain embodiments, M is -CHF-, -CH(CH3)- or -CF(CH3)-. In certain embodiments, M is -CHF-. In certain embodiments, M is -CH(CH3)-. In certain embodiments, M is -CF(CH3)-. In certain embodiments, M is -CF2- or -C(CH3)2-. In certain embodiments, M is -CF2-. In certain embodiments, M is -C(CH3)2-. In certain embodiments, R1 is C(O)OH. In certain embodiments, R1 is S(O)2OH. In certain embodiments, R1 is P(O)(OH)2. In certain embodiments, R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH and methyl. In certain embodiments, R2a and R2b are methyl. In certain embodiments, R2a is hydrogen and R2b are methyl. In certain embodiments, R2a and R2b 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 1-3 halo groups. In certain embodiments, R2a and R2b together with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group. In certain embodiments, R2a and R2b together with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments, R3 is C5-12bicycloalkylthio-. In certain embodiments, R3 is haloC3-7monocycloalkylthio-. In certain embodiments, R3 is haloC1-2alkyl-. In certain embodiments, R3 is CF3. In certain embodiments, R4 is n-butyl substituted with 1 to 6 halo atoms. In certain embodiments, R4 is n-butyl substituted with 1 to 6 F atoms. In certain embodiments, R4 is -CH2CH2CF2CH3. In certain embodiments, R4 is n-propyl substituted with 1 to 6 halo atoms. In certain embodiments, R4 is n-propyl substituted with 1 to 6 F atoms. In certain embodiments, R4 is -CH2CH2CF3. In certain embodiments, R5 is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5 is In certain embodiments, R5 is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, R5 is In certain embodiments, R5 is In certain embodiments, R3 is haloC1-4alkyl- and R4 is -CH2CH2CF2CH3. In certain embodiments, R3 is haloC1-4alkyl- and R4 is -CH2CH2CF3. In certain embodiments, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, M is -CHF- and R3 is haloC1-4alkyl-. In certain embodiments, M is -CHF- and R3 is CF3. In certain embodiments, M is -CHF-, R3 is haloC1-4alkyl-, and R4 is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R3 is haloC1-4alkyl-, and R4 is -CH2CH2CF3. In certain embodiments, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF3. In certain embodiments, M is -CHF-, R1 is C(O)OH, and R3 is haloC1-4alkyl. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl and R4 is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl and R4 is - CH2CH2CF3. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, and R4 is - CH2CH2CF2CH3. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, and R4 is - CH2CH2CF3. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is - CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is - CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2- 4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1- 4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1- 4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1- 4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1- 4alkyl-. In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is - CH2CH2CF2CH3, and R5 i or In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is - CH2CH2CF3, and R5 is In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is - CH2CH2CF2CH3, and R5 is or In certain embodiments, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is In certain embodiments, the compound of Formula II is of Formula IIa, R3 is haloC1- 4alkyl- and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, R3 is haloC1- 4alkyl- and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3 is haloC1-4alkyl-, and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3 is haloC1-4alkyl-, and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R3 is CF3, and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3 and R4 is -CH2CH2CF2CH3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3 and R4 is -CH2CH2CF3. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is -CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1- 4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-4alkyl-, R4 is -CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF2CH3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is phenyl optionally substituted with one to six substituents independently selected from the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-. In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is CH2CH2CF2CH3, and R5 is
In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is haloC1-2alkyl, R4 is CH2CH2CF3, and R5 is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF2CH3, and R5 is In certain embodiments, the compound of Formula II is of Formula IIa, M is -CHF-, R1 is C(O)OH, R3 is CF3, R4 is -CH2CH2CF3, and R5 is III. Pharmaceutical Compositions and Kits In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. In another aspect, the disclosure provides a pharmaceutical composition comprises a compound according to any combination of the Examples described herein, or a pharmaceutically acceptable salt and/or stereoisomer thereof. Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non- toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure. Advantageously, the disclosure also provides kits for use by e.g., a consumer in need of HBV infection treatment. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form tomediate, reduce or prevent HBV infection. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ...” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. IV. Methods In a further aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. With regard to HBV/HDV coinfection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of the HDV virions. See for example, Negro, Cold Spring Harb Perspect Med.2014 Nov 3;4(11):a021550. doi: 10.1101/cshperspect.a021550, herein incorporated by reference with regard to such background teaching. Thus, because HDV infection is dependent on the presence of an existing HBV infection, strategies for treating HBV/HDV coinfection may focus on targeting HBV alone, HDV alone or both viruses together. Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV/HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating an HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. Without being bound by any theory, methods of treatment may be facilitated by various mechanisms of action. One possibility for treatment involves targeting machinery involved in viral particle assembly. In the case of HBV, inhibiting assembly of the HBV envelope or core by targeting HBsAg would disrupt assembly of the HBV particles. A second strategy would be to inhibit viral replication of HBV and/or HDV. Existing antiviral therapies may apply this approach in the form of replication inhibitors that target, for example, a specific viral RNA polymerase. Thus, another aspect of the disclosure is a method for inhibiting HBV or HDV viral replication in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for inhibiting HBV or HDV viral replication in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. Methods of treatment may further include targeting the network of bile acid transport proteins that are believed to be the “gateway” of entry for HBV or HDV infection into the hepatocyte. See for example, Slijepcevic et al., Digestive Diseases, 2017;35:251-258, herein incorporated by reference with regard to such background teaching. The bile acid transport system comprising the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) are a set of receptors that ensure effective bile acid transport between the ileum and hepatocyte. HBV/HDV coinfection of hepatocytes is believed to be mediated via the NTCP receptor, making it a possible target for treatment. Without being bound by any theory, an “entry inhibitor” may target any of the possible bile acid transport receptors, including, but not limited to the sodium taurocholate co-transporting polypeptide (NTCP) and apical sodium dependent bile acid transporter (ASBT) to prevent entry of either HBV or HDV virus into the cells. Such entry inhibitors may target all or a portion of the transport receptors to inhibit viral entry. Thus, another aspect of the disclosure is a method of inhibiting viral entry in hepatocytes in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method inhibiting viral entry in hepatocytes in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient. Regardless of the mechanism targeted, treatment for patients dealing with HBV or HDV infection or HBV/HDV coinfection may be measured by seroconversion of any of the viral antigens, including but not limited to HBsAg or HBeAg, or maintenance of undetectable levels of these antigens. For use in accordance with the aspects described herein, the appropriate dosage of the compounds described herein is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 μg/kg body weight. In some cases, the administration dose of the compound may be less than 400 μg/kg body weight. In other cases, the administration dose may be less than 200 μg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 μg/kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form. A compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g., in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally). For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan. A disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Alternatively, the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Also contemplated herein are methods and compositions that include a second active agent or administering a second active agent. For example, in addition to being infected with HBV, a subject or patient can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV. Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these HBV-infection- related conditions. In some cases, a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals. Example antivirals include nucleoside analogs, interferon α, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl- 2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, provided herein is a method of treating a patient suffering from hepatitis B infection comprising administering to the patient a first amount of a disclosed compound and a second amount of an antiviral, or other anti HBV agent, for example a second amount of a second compound selected from the group consisting of: an HBV capsid assembly promoter (for example, GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below), NVR 3-778, NVR1221 (by code); and N890 (as depicted below): other capsid inhibitors such as those disclosed in the following patent applications hereby incorporated by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and WO2014033170; Nucleos(t)ide analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and: viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: and BM601 as depicted below: disruptors of nucleocapsid formation or integrity such as NZ-4/W28F: cccDNA formation inhibitors such as BSBI-25, CCC-0346, CCC-0975 (as depicted below): HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cp183-V124W and related mutations as described in WO/2013/010069, WO2014/074906, each incorporated by reference); inhibitors of HBx- interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS- HBV), or nucleic acid based polymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda 1a and PEG IFN lambda 1a, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); Non-Interferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) and Interleukin-7 (CYT107); TLR-7/9 agonists such as GS- 9620, CYT003, Resiquimod; Cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, Core antigen vaccine; SMAC mimetics such as birinapant and other IAP-antagonists; Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic. In some embodiments, the disclosure further provides a method of treating HBV or HDV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies and one or more of HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a HBV or HBV infection or HBV/HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic. In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co- administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy. In another embodiment, a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of a disclosed compound), with a detection moiety, for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation). Contemplated fluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety may be used in e.g., a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity. V. Examples The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile aq. Aqueous BAST Bis(2-methoxyethyl)aminosulfur trifluorid Boc2O Di-tert-butyl dicarbonate nBuLi n-Butyllithium compd. Compound concd. Concentrated COSY Homonuclear correlation spectroscopy DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropyl ethylamine DMF N,N-Dimethylformamide DMS Dimethylsulfide DMSO Dimethyl sulfoxide EA, EtOAc Ethyl acetate Et3N Triethylamine ESI Electrospray ionization HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HMBC Heteronuclear multiple bond correlation HPLC High performance liquid chromatography HSQC Heteronuclear single quantum coherence IPA, iPrOH Isopropanol LiHMDS Lithium bis(trimethylsilyl)amide LCMS Liquid chromatography–mass spectrometry MeOH Methanol MS Mass spectrometry NOESY Nuclear Overhauser effect spectroscopy NFSI N-Fluorobenzenesulfonimide NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance PE Petroleum ether rac. Racemic rel. Relative Rf Retention factor rt, r.t. Room temperature RT, tR Retention time sat. Saturated SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography Example 1. (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)ethane-1-sulfonic acid Step 1. Synthesis of (R)-ethyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (1-2). To a solution of 1-(tert-butyl) 2-ethyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (1-1) (38.0 g, 147.9 mmol) in THF (380 mL) was added MeMgBr (51.8 mL, 155.3 mmol, 3.0M) drop wise in an ice bath under nitrogen. The mixture was stirred at rt for 6 hr. The resulting mixture was then quenched with sat. aq. NH4Cl solution (200 mL). The mixture was extracted with EA (200 mL x 2) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 1-2 (32.0 g, 79%) as a yellow solid. TLC: 25% EA/ PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C13H23NO5: 273.2; Found: 174.1 [M -Boc + 1]+. Step 2. Synthesis of (R)-ethyl 2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (1- 3). To a solution of 1-2 (32 g, 117.2 mmol) in THF (320 mL) was added BAST (77.7 g, 351.6 mmol) drop wise in an ice bath under nitrogen, and the reaction mixture was stirred at rt for 4 days. The reaction mixture was poured into sat aq. NaHCO3 solution (150 mL) slowly at 0°C and extracted with EA (150 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (8% EA/PE (v/v)) to give 1-3 (13.8 g, 40%) as a yellow oil. TLC: 10% EA/ PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C13H23F2NO4: 295.2 MS Found: 196.2 [M - Boc + 1]+. Step 3. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (1-4). To a solution of 1-3 (13.8 g, 46.8 mmol) in THF/H2O = 5/1 (v/v) (100 mL) was added LiOH (3.4 g, 140.3 mmol). After stirring at rt for 4 hr, the reaction mixture was diluted with water (100 mL), acidified with 1N aq. HCl solution to pH ~ 3, and concentrated to remove organic solvent. The residue was extracted with EA (100 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 1-4 (11.3 g, 90%) as a yellow oil, which was used in the next step without further purification. TLC: 35% EA/ PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C11H19F2NO4: 267.1; Found: 168.2 [M - Boc + 1]+. Step 4. Synthesis of (R)-tert-butyl (5,5-difluoro-1-oxo-1-(phenylamino)hexan-2- yl)carbamate (1-5). To a stirred solution of 1-4 (11.3 g, 42.3 mmol) and DIEA (16.4 g, 127.0 mmol) in THF (100 mL) was added HATU (24.1 g, 63.5mmol) in small portions in an ice bath under nitrogen. After stirring for 40 min, PhNH2 (5.9 g, 63.5mmol) was added drop wise. The resulting mixture was stirred at rt for 16 hr and then concentrated. The residue was diluted with H2O (150 mL) and extracted with EA (150 mL x 2). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EA/PE (v/v)) to give 1-5 (7.6 g, 53%) as a yellow oil. TLC: 30% EA/ PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C17H24F2N2O3: 342.2; Found: 287.2 [M - tBu + 1]+. Step 5. Synthesis of (R)-2-amino-5,5-difluoro-N-phenylhexanamide (1-6). A solution of 1-5 (7.6 g, 22.2 mmol) and TFA (20 mL) in DCM (40 mL) was stirred at room temperature for 4 hr and concentrated. The residue was diluted with DCM (100 mL) and basified to pH ~ 8 with sat. aq. NaHCO3 solution. The resulting mixture was extracted with DCM (100 mL x 4). The combined organic layer was washed with brine, dried over anhydrous 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 for the next step without further purification. TLC: 8% MeOH/ DCM (v/v) (Rf: 0.5). MS (ESI): calcd. for C12H16F2N2O: 242.2; Found: 243.2 [M + 1]+. Step 6. Synthesis of (R)-5,5-difluoro-N1-phenylhexane-1,2-diamine (1-7). To a stirred solution of 1-6 (4.8 g, 19.8 mmol) in THF (100 mL) was added LAH (23.8 mL, 59.5 mmol, 2.5 M in THF) drop wise at 0°C. The resulting mixture was stirred at 70°C for 4 hr. The reaction was quenched with H2O (2.3 mL) and 15% aq. NaOH solution (2.3 mL) at 0°C. The resulting mixture was dried over Na2SO4 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) (Rf: 0.3). MS (ESI): calcd. for C12H18F2N2: 228.1; Found: 229.3 [M + 1]+. Step 7. Synthesis of (R)-2-bromo-N-(5,5-difluoro-1-(phenylamino)hexan-2-yl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (1-8). To a stirred solution of 1-7 (1.0 g, 4.39 mmol) and TEA (886 mg,8.77 mmol) in THF (10 mL) was added 2-bromo-5-methoxy- 4-(trifluoromethyl)benzenesulfonyl chloride (2.3 g, 6.59 mmol) in portions at rt. After stirring at rt for 16 hr, the mixture was diluted with H2O (30 mL) and extracted with EA (25 mL x 2). The combined organic extracts were dried over Na2SO4 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) (Rf: 0.4). MS (ESI): calcd. for C20H22BrF5N2O3S: 544.0; Found: 545.1 [M + 1]+. Step 8. Synthesis of (R)-3-(3,3-difluorobutyl)-8-methoxy-5-phenyl-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-9). A suspension of 1-8 (1.6 g, 2.94 mmol), picolinicacid (72 mg, 0.59 mmol), K2CO3 (1.2 g, 8.82 mmol), and CuI (38 mg, 0.59 mmol) in DMF (20 mL) was stirred at 90°C for 3 hours under N2 atmosphere. The reaction mixture was then cooled at rt, diluted with water (30 mL), and extracted with EA (25 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 1-9 (1.2 g, 88.2%) as a brown oil, which was used for the next step without further purification. TLC: 25% EA/PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C20H21F5N2O3S: 464.1; Found: 465.1 [M + 1]+. Step 9. Synthesis of (R)-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-10). To a suspension of 1-9 (1.2 g, 2.59 mmol) and Cs2CO3 (1.1 g, 3.36 mmol) in NMP (10 mL) was added MeI (1.1 g, 7.77 mmol) in an ice bath. The reaction mixture was stirred at rt for 3 hr and diluted with H2O (30 mL). The resulting mixture was extracted with EA (30 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 1-10 (1.1 g, 88.9%) as a brown oil, which was used for the next step without further purification. TLC: 25% EA/PE (v/v) (Rf: 0.6). MS (ESI): calcd. for C21H23F5N2O3S: 478.1; Found: 479.1 [M + 1]+. Step 10. Synthesis of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-11). To a solution of 1-10 (1.1 g, 2.30 mmol) in DMF (6.0 mL) was added NaSMe (1.6 g, 23.0 mmol), and the reaction mixture was stirred at 100°C for 16 hr. The reaction mixture was diluted with water (30 mL), acidified with 4 N aq. HCl solution to pH 5~6, and extracted with EA (50 mL x 3). The combined organic layer was washed with sat. aq. LiCl solution (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 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) (Rf: 0.4). MS (ESI): calcd. for C20H21F5N2O3S: 464.1; Found: 465.3 [M + 1]+. Step 11. Synthesis of (R)-2-((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)ethanesulfonic acid (Example 1). To a suspension of 1-11 (450 mg, 0.97 mmol) and Cs2CO3 (1264 mg, 3.88 mmol) in DMF (10 mL) was added sodium 2-bromoethane-1-sulfonate (611 mg, 2.91 mmol), and the reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was diluted with water (20 mL) and acidified with 4N aq. HCl solution to pH ~5. The resulting mixture was extracted with EA (25 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 1 (112 mg, 20.2%) as a white solid. TLC: 5% MeOH/EA (v/v) (Rf: 0.5). MS (ESI): calcd. for C22H25F5N2O6S2: 572.1; Found: 573.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.47 (s, 1H), 7.25 ‒ 7.17 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.78 ‒ 6.66 (m, 2H), 4.56 (t, J = 8.0 Hz, 2H), 4.20 ‒ 4.05 (m, 1H), 4.00 ‒ 3.82 (m, 1H), 3.52 ‒ 3.38 (m, 1H), 3.37 ‒ 3.32 (m, 2H), 2.64 (s, 3H), 2.11 ‒1.92 (m, 2H), 1.86 ‒ 1.75 (m, 2H), 1.62 (t, J = 18.8 Hz, 3H) ppm. Example 2. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid
Step 1. Synthesis of ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (2-2). To a stirred solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (2-1) (100 mg, 0.69 mmol) and TEA (209 mg, 2.07 mmol) in DCM (5 mL) was added MsCl (119 mg, 1.04 mmol). After stirring at rt for 1 hr, the reaction mixture was added ice-cold water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 2-2 (140 mg, 91%) as a yellow oil. TLC: 10% EA/PE (v/v) (Rf: 0.6) (Phosphomolybdic Acid). MS (ESI): calcd. for C8H14O5S: 222.1; Found: 240.1 [M + 18]+. Step 2. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (2-3). To a stirred solution of 1-11 (75 mg, 0.16 mmol) and Cs2CO3 (156 mg, 0.48 mmol) in DMF (2 mL) was added 10-2 (71 mg, 0.32 mmol) and the reaction mixture was heated at 70 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added into water (10 mL). The precipitate was collected by filtration, washed with water (5 mL x 3), and dried in vacuo to give crude 2- 3 (120 mg) as a white solid, which was used for the next step without further purification. TLC: 40% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C27H31F5N2O5S: 590.2; Found: 591.3 [M + 1]+. Step 3. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 2). To a stirred solution of 2-3 (80 mg, crude product, 0.11 mmol) in MeOH/H2O = 2/1 (v/v) (3 mL) was added NaOH (22 mg, 0.55 mmol) and the reaction mixture was stirred at rt for 2 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution and concentrated to remove organic solvent. The residue was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 2 (28 mg, 45%) as a white solid. TLC: 10% MeOH/DCM (v/v) (Rf: 0.5). MS (ESI): calcd. for C25H27F5N2O5S: 562.2; Found: 563.2 [M + 1]+.1H NMR (400 MHz, CD3OD, ): δ 7.65 (s, 1H), 7.46 (s, 1H), 7.23 ‒ 7.19 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 2H), 4.41 ‒ 4.32 (m, 2H), 4.18 ‒ 3.87 (m, 2H), 3.37 ‒ 3.33 (m, 1H), 2.64 (s, 3H), 2.12 ‒ 1.92 (m, 2H), 1.85 ‒ 1.78 (m, 2H), 1.62 (t, J = 18.4 Hz, 3H), 1.35 ‒ 1.31 (m, 2H), 1.13 ‒ 1.09 (m, 2H) ppm. Example 3. (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)oxetane-3- carboxylic acid Step 1. Synthesis of (R)-3-(3,3-difluorobutyl)-8-((3-(hydroxymethyl)oxetan-3- yl)methoxy)-2-methyl-5-phenyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (3-1). To a solution of 1-11 (200 mg, 0.43 mmol) in DMF (8 mL) were added (3-(bromomethyl)oxetan-3-yl)methanol (156 mg, 0.86 mmol) and Cs2CO3 (420 mg, 1.29 mmol). The mixture was stirred at 70 °C overnight. The reaction mixture was treated with LiCl solution (8 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 3-1 (243 mg) as a brown solid, which was used for the next step without further purification. MS (ESI): calcd. for C25H29F5N2O5S: 564.2; Found: 565.2 [M + 1]+. Step 2. Synthesis of (R)-3-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)oxetane-3-carboxylic acid (Example 3). To a solution of 3-1 (crude 243 mg, 0.43 mmol) in DCM (10 mL) was added Dess-Martin reagent (729 mg, 1.72 mmol). After stirring at rt for 5 hr, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC to give Example 3 (60 mg, 24%) as a white solid. MS (ESI): calcd. for C25H27F5N2O6S: 578.2; Found: 579.3 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.73 (s, 1H), 7.49 (s, 1H), 7.22 (dd, J = 8.6, 7.4 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H) 6.75 (d, J = 7.6 Hz, 2H), 4.97 (dd, J = 5.8, 2.2 Hz, 2H), 4.75 (dd, J = 5.8, 1.4 Hz, 2H), 4.52 (s, 2H), 4.24 ‒ 4.06 (m, 1H), 4.00 ‒ 3.85 (m, 1H), 3.60 ‒ 3.35 (m, 1H), 2.65 (s, 3H), 2.15 ‒ 1.90 (m, 2H), 1.87 ‒ 1.75 (m, 2H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Example 4. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)-3,3- difluorocyclobutane-1-carboxylic acid
Step 1. Synthesis of isopropyl 3,3-difluoro-1-(hydroxymethyl)cyclobutanecarboxylate (4-2). To a solution of diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate (4-1) (2.0 g, 7.60 mmol) in anhydrous THF (60 mL) was added 1N lithium tri-tert-butoxyalyminium hydride in THF (18.9 mL, 18.9 mmol) at 0 °C. After stirring at 70 °C for 16 hr, the reaction was quenched with saturated aq. NH4Cl solution at 0 oC until no bubbling was observed. The mixture was diluted with water (80 mL), concentrated to remove organic solvent, and extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1/1 (v/v)) to give 4-2 (0.85 g.54%) as a pale-yellow oil. MS (ESI): calcd. for C9H14F2O3: 208.2; Found: 209.2 [M + 1]+. Step 2. Synthesis of isopropyl 3,3-difluoro-1- ((((trifluoromethyl)sulfonyl)oxy)methyl)cyclobutanecarboxylate (4-3). To a solution of 4- 2 (400 mg, 1.92 mmol), 2,6-dimethylpyridine (308 mg, 2.88 mmol) in DCM (5 mL) was added Tf2O (400 mg, 1.92 mmol) at -78 °C. After stirring at -78 °C for 1 hr, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 4-3 (200 mg.31%) as a yellow solid, which was used for the next step without further purification. Step 3. Synthesis of (R)-isopropyl 1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5- phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)-3,3-difluorocyclobutanecarboxylate (4-4). To a solution of 1-11 (100 mg, 0.21 mmol), Cs2CO3 (205 mg, 0.63 mmol) in DMF (3 mL) was added 4-3 (200 mg, 0.59 mmol), and the reaction mixture was stirred at rt for 16 hr. Next, the reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic extracts were washed with LiCl solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 4-4 (160 mg.84%) as a yellow solid, which was used for the next step without further purification. MS (ESI): calcd. for C29H33F7N2O5S: 654.2; Found: 655.4 [M+1]+. Step 4. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)-3,3- difluorocyclobutanecarboxylic acid (Example 4). To a solution of 4-4 (150 mg, 0.23 mmol) in THF (4 mL) was added 1N aq. LiOH solution (1 mL) and the reaction mixture was stirred at rt for 16 hr. The reaction mixture was adjusted to pH = 6 with 1 N aq. HCl solution and then purified by prep-HPLC to give Example 4 (30 mg, 24%) as an off-white solid. MS (ESI): calcd. for C26H27F7N2O5S: 612.2; Found: 613.0 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.68 (s, 1H), 7.47 (s, 1H), 7.26 ‒ 7.18 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 4.0 Hz, 2H), 4.47 (s, 2H), 4.25 ‒ 4.05 (m, 1H), 3.99 ‒ 3.84 (m, 1H), 3.62 ‒ 3.40 (m, 1H), 3.15 ‒ 3.00 (m, 2H), 2.89 ‒ 2.74 (m, 2H), 2.66 (s, 3H), 2.14 ‒ 1.90 (m, 2H), 1.88 ‒ 1.74(m, 2H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Example 5. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid
Step 1. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (5-2). To a stirred solution of 5-1 (140 mg, 0.29 mmol), which was readily prepared by following the same procedure for preparing 1-11 by replacing aniline with 4-F-aniline, and Cs2CO3 (284 mg, 0.87 mmol) in DMF (4 mL) was added ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (116 mg, 0.53 mmol). After stirring at 65 oC for 3 hr, the reaction mixture was added into water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried in vacuo to give crude 5-2 (120 mg) as a white solid, which was used in the next step without further purification. TLC: EA/PE = 3/7 (v/v) (Rf: 0.5). MS (ESI): calcd. for C27H30F6N2O5S: 608.2; Found: 609.2 [M + 1]+. Step 2. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 5). To a stirred solution of 5-2 (120 mg, crude product, 0.20 mmol) in MeOH/H2O = 2/1 (v/v) (6 mL) was added NaOH (79 mg, 1.97 mmol) and the reaction mixture was stirred at rt for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution and concentrated to remove organic solvent. The residue was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 5 (49 mg, 43%) as a white solid. TLC: EA/PE = 1/1 (v/v) (Rf: 0.5). MS (ESI): calcd. for C25H26F6N2O5S: 580.1; Found: 581.3 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.64 (s, 1H), 7.41 (s, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.77-6.74 (m, 2H), 4.39-4.32 (m, 2H), 4.12-3.86 (m, 2H), 3.40-3.33 (m, 1H), 2.64 (s, 3H), 2.10-1.92 (m, 2H), 1.82-1.76 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.35-1.34 (m, 2H), 1.13-1.11 (m, 2H) ppm. Example 6a. (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid Step 1. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoate (5-2). To a solution of 5-1 (1.5 g, 3.1 mmol) in toluene (15 mL) was added methyl (R)-3-hydroxy-2-methylpropanoate (1.8 g, 15.2 mmol) and PPh3 (2.4 g, 9.3 mmol). Then DIAD (6.3 g, 31.1 mmol) was added at 110 oC under a nitrogen atmosphere. After stirring at 110 oC for 4 hr, the reaction mixture was poured into water and extracted with EtOAc (200 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column to give 6a-1 (1.6 g, 89%) as a yellow solid. MS (ESI): calcd. for C26H30F6N2O5S: 582.1; Found: 583.2 [M + 1]+. Step 2. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 6a). To a solution of 6a-1 (1.6 g, 2.7 mmol) in THF (40 mL)/H2O (10 mL) was added LiOH (660 mg, 27.5 mmol). After stirring at rt for 4 hr, the reaction was poured into water. The mixture was adjusted to pH = 3 with 3 N aq. HCl solution and the resulting mixture was extracted with EA (100 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 6a (600 mg, 40%) as a white solid. MS (ESI): calcd. for C24H26F6N2O5S: 568.1; Found: 569.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.41(s, 1H), 6.98 ‒ 6.94 (m, 2H), 6.77 ‒ 6.76 (m, 2H), 4.36 ‒ 4.32 (m, 1H), 4.26 ‒ 4.23 (m, 1H), 4.08 ‒ 4.04 (m, 1H), 4.02 ‒ 3.89 (m, 1H), 3.48 ‒ 3.46 (m, 1H), 2.98 ‒ 2.85 (m, 1H), 2.64 (s, 3H), 2.07-1.93 (m, 2H), 1.81 ‒ 1.76 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H) ppm. Example 6b. (S)-3-(((R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2-methylpropanoic acid Following the same procedure for preparing Example 6a by replacing methyl (R)-3-hydroxy- 2-methylpropanoate with its enantiomer methyl (S)-3-hydroxy-2-methylpropanoate, Example 6b was obtained as a white solid. MS (ESI): calcd. for C24H26F6N2O5S: 568.1; Found: 569.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.67 (s, 1H), 7.56(s, 1H), 7.19 - 7.13 (m, 1H), 6.51 - 6.47 (m, 1H), 6.42 - 6.34 (m, 2H), 4.40 - 4.36 (m, 1H), 4.30 - 4.26 (m, 1H), 4.10 - 4.02 (m, 2H), 3.47 - 3.33 (m, 1H), 2.98 - 2.93 (m, 1H), 2.59 (S, 3H), 2.10 - 1.96 (m, 2H), 1.88 - 1.78 (m, 2H), 1.62 (t, J =18.4 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H) ppm. Example 7. (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid
Step 1. Synthesis of ethyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (7-2). To a solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (7-1) (1.5 g, 10.26 mmol) in DCM (30 mL) was added TEA (2.08 g, 20.56 mmol), followed by methanesulfonic anhydride (2.68 g, 15.39 mmol) was added at 0 oC, After stirring at rt for 2 hr, the reaction mixture was diluted with H2O (80 mL) and extracted with DCM (30 mL x 2). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 7-2 (2.8 g, 100%, crude) as a pale-yellow oil, which was used in the next step without purification, MS (ESI): calcd. for C8H16O5S: 224.1; Found: 242.2 [M + 18]+. Step 2. Synthesis of (R)-ethyl 3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl- 1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (7-3). To a solution of 5-1 (1.5 g, 3.1 mmol) in DMF (10 mL) were sequentially added K2CO3 (1.29 g, 9.33 mmol) and 7-2 (1.4 g, 6.2 mmol, crude). After stirring at 110 oC for 48 hr, the reaction was diluted with H2O (80 mL) and extracted with EA (50 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (100 mL) and brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/PE = 0% to 40% (v/v)) to give 7-3 (1.8 g, 95 %) as a yellow solid. MS (ESI): calcd. for C27H32F6N2O5S: 610.2; Found: 611.0 [M + 1]+. Step 3. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl- 1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 7). A solution of 7-3 (1.8 g, 2.95 mmol) in CH3OH/THF/H2O (8 mL/8 mL/8 mL) was added LiOH.H2O (1.24 g, 29.55 mmol). After stirring at 35 oC for 3 hr, the reaction mixture was diluted with H2O (100 mL), adjusted to pH = 2 with 2 N aq. HCl solution, and extracted with EtOAc (60 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was purified by reversed column (CH3CN/H2O = 40% (v/v)) to give Example 7 (740 mg, 43%) as a white solid. MS (ESI): calcd. for C25H28F6N2O5S: 582.2; Found: 582.8 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.61 (s, 1H), 7.42 (s, 1H), 6.96 (t, J = 8.8 Hz, 2H), 6.77 ‒ 6.76 (m, 2H), 4.18 (s, 2H), 4.09 ‒ 3.88 (m, 2H), 3.47 ‒ 3.46 (m, 1H), 2.64 (s, 3H), 2.07 ‒ 1.90 (m, 2H), 1.80 ‒ 1.78 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.33 (s, 6H) ppm. Examples 8a and 8b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (8a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(3-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (8b)
Step 1. Synthesis of methyl 5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (8-2). To a stirred solution of methyl 5,5-difluoro-2-(hydroxymethyl)hexanoate (8-1) (100 g, 509.70 mmol) and TEA (154.73 g, 1529.10 mmol) in DCM (1000 mL) was added MsCl (70.06 g, 611.64 mmol) dropwise at 0°C. After stirring at rt for 2 hr, the reaction mixture was added H2O (500 mL) at 0°C. The resulting mixture was extracted with DCM (1000 mL x 2). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-2 (110 g, 79%) as a brown liquid, which was used for the next step without further purification. Step 2. Synthesis of methyl 2-(bromomethyl)-5,5-difluorohexanoate (8-3). To a stirred solution of 8-2 (110 g, 401.05 mmol) in acetone (500 mL) was added lithium bromide (104.48 g, 1203.15 mmol) in portions at rt. After stirring at 60 oC for 3 hr, the mixture was allowed to cool down to rt and added H2O (200 mL) at rt. The resulting mixture was extracted with EA (300 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-3 (100 g, 96%) as a brown liquid, which was used in the next step without further purification.1H NMR (300 MHz, CDCl3): δ 3.77 (s, 3H), 3.56 (qd, J = 10.2, 6.4 Hz, 2H), 2.94 – 2.81 (m, 1H), 2.02 – 1.80 (m, 4H), 1.62 (t, J = 18.4 Hz, 3H) ppm. Step 3. Synthesis of methyl 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5- difluorohexanoate (8-4). To a stirred solution of 2-amino-5-methoxybenzenethiol (60 g, 386.55 mmol) and Cs2CO3 (151.60 g, 463.85 mmol) in ACN (500 mL) was added 8-3 (100.15 g, 386.56 mmol) dropwise at rt. After stirring at rt for 4 hr, the reaction mixture was added water (50 mL) at rt. The resulting mixture was extracted with EA (500 mL x 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE/EA = 4/1 (v/v) to give 8-4 (80 g, 62%) as a brown liquid. MS (ESI): calcd. for C15H21F2NO3S: 333.1; Found: 334.1 [M + 1]+. Step 4. Synthesis of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-5,5-difluorohexanoic acid (8-5). To a stirred solution of 8-4 (94 g, 281.95 mmol) in dioxane (800 mL) and H2O (200 mL) was added LiOH (20.26 g, 845.87 mmol) at rt. The resulting mixture was stirred at rt for 2 hr. The mixture was acidified with 2 N aq. HCl solution to pH ~ 6. The resulting mixture was extracted with EA (100 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. This residue was dried in vacuo to give 8-5 (80 g, 89%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C14H19F2NO3S: 319.1; Found: 320.1 [M + 1]+. Step 5. Synthesis of 3-(3,3-difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin- 4(5H)-one (8-6). To a stirred solution of 8-5 (80 g, 250.49 mmol) and HATU (104.77 g, 275.54 mmol) in DCM (1000 mL) was added DIEA (38.85 g, 300.59 mmol) dropwise at rt. The reaction mixture was stirred at rt for 2 hr and then added H2O (50 mL). The resulting mixture was extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE/EA = 7/3 (v/v) to give 8-6 (67 g, 89%) as a yellow solid. MS (ESI): calcd. for C14H17F2NO2S: 301.1; Found: 302.1 [M + 1]+. Step 6. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-7). To a stirred solution of 8-6 (32 g, 106.18 mmol) in DCM (200 mL) and ACN (200 mL) was added NBS (20.79 g, 116.80 mmol) in portions at rt. The resulting mixture was stirred at rt for 4 hr and then added H2O (100 mL) at rt. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by trituration with PE/EA = 1/1 (v/v) (300 mL). The precipitated solid was collected by filtration, washed with PE/EA = 1/1 (v/v) (100 mL), and dried in vacuo to give 8-7 (22 g, 54%) as a white solid. MS (ESI): calcd. for C14H16BrF2NO2S: 379.0; Found: 380.0 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 7.34 (s, 1H), 7.14 (s, 1H), 3.94 (s, 3H), 3.53 (dd, J = 11.3, 6.0 Hz, 1H), 3.02 (t, J = 11.9 Hz, 1H), 2.68 (ddd, J = 16.4, 9.3, 5.2 Hz, 1H), 2.17 – 2.00 (m, 1H), 2.04 – 1.70 (m, 1H), 1.68 – 1.47 (m, 5H) ppm. Step 7. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-8). To a solution of 8-7 (3 g, 7.89 mmol) in DMF (30 mL) were added 1-fluoro-3-iodobenzene (1.75 g, 7.89 mmol), CuI (1.50 g, 7.89 mmol) and K2CO3 (3.27 g, 23.67 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 16 hr and then cooled to rt and added water (100 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE/EA = 3/1 (v/v) to give 8-8 (3 g, 80%) as a yellow solid. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 474.0 [M + 1]+. Step 8. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (8-9). A solution of 8-8 (3 g, 6.33 mmol) in THF (40 mL) and H2O (20 mL) was added Oxone® (63.81 g, 379.500 mmol) at rt. After stirring at rt for 16 hr, the mixture was filtered, and the filtered cake was washed with ethyl acetate (25 mL x 3). The filtrate was concentrated, and the residue was diluted with sat. aq. NaHCO3 solution (25 mL) and EtOAc (150 mL). The separated organic layer was washed with sat. aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 8-9 (2.5 g, 78%) as a yellow solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+. Step 9. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-10). To a solution of 8-9 (2.5 g, 4.94 mmol) in THF (30 mL) was added 1 M BH3-Me2S in THF (2.81 mL, 29.622 mmol) at rt. After stirring at 75 °C for 16 hr, the mixture was cooled to 0 oC, added ice water (30 mL), and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE/EA = 5/1 (v/v) to give 8-10 (1.6 g, 67%) as a yellow solid. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+. Step 10. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-11). To a solution of 8- 10 (1.6 g, 3.25 mmol) in THF (20 mL) was added LiHMDS (6.5mL,1 mol/L in THF) dropwise at -78 °C. After stirring at -78 °C for 30 min, NFSI (1.23 g, 3.90 mmol) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for an additional 2 hr. The reaction mixture was added sat. aq. NH4Cl solution at rt and then concentrated to remove organic solvent. The resulting mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluted with PE/EA = 5/1 (v/v) to give 8-11 (1 g, 60%) as a yellow solid. MS (ESI): calcd. for C20H20BrF4NO3S: 509.0; Found: 510.0 [M + 1]+. Step 11. Synthesis of 3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-12). To a solution of 8-11 (400 mg, 0.78 mmol) in DMF (5 mL) were added methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (602.30 mg, 3.14 mmol) and CuBr (224.87 mg,1.57 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 16 hr and then added water (15 mL) at rt. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 3/1 (v/v)) to give 8-12 (200 mg, 51%) as a yellow solid. MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+. Step 12. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8- 13). To a solution of 8-12 (200 mg, 0.40 mmol) in DMSO (5 mL) was added lithium chloride (509.25 mg, 12.00 mmol) at rt. The resulting mixture was stirred at 140 °C for 8 hr and then added water (15 mL) at rt. The mixture was acidified with sat. aq. citric acid solution to pH ~ 5. The resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 3/1 (v/v)) to give the cis- racemic 8-13 (50 mg, 26%) as a yellow solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+. Step 13. Synthesis of (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8- 13a) and (2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (8-13b). The racemic 8-13 (40 mg) was separated by prep-SFC with the following condition: Column: (R, R)-WHELK-O1-Kromasil, 3*25 cm, 5 μm; Mobile Phase A: CO2; Gradient: isocratic 20 % B; RT1(min) = 2.6 (8-13a as a single diastereomer, the stereochemistry was arbitrarily assigned); RT2(min) = 3.6 (8-13b as a single diastereomer, the stereochemistry was arbitrarily assigned); Sample Solvent: MeOH-HPLC; Injection Volume: 4 mL) to give 8-13a (15 mg) as light yellow solid and 8-13b (15 mg) as light yellow solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+. Step 14a. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14a). To a solution of 8-13a (15 mg, 0.03 mmol) in DMF (2 mL) were added ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (9.20 mg, 0.045 mmol) and CsCO3 (20.40 mg, 0.06 mmol) at rt. After stirring at 80 oC for 2 hr, the reaction mixture was cooled to rt, added water (15 mL), and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 3/1 (v/v)) to give 8-14a (16 mg, 79%) as a yellow solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 612.1 [M + 1]+. Step 15a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8a). To a solution of 8-14a (16 mg, 0.025mmol) in 1,4-dioxane (4 mL) were added LiOH (35.25 mg, 1.47 mmol) and H2O (1 mL) at rt. After stirring at rt for 16 hr, the reaction mixture was diluted with water (10 mL) and concentrated to remove organic solvent. The residue was acidified with sat. aq. citric acid solution to pH ~ 5 and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following condition: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 50% B to 78% B in 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 6.38 to give Example 8a (10 mg, 69%) as a white solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.82 (s, 1H), 7.64 (s, 1H), 7.22 – 7.15 (m, 1H), 6.52 – 6.50 (m, 1H), 6.47 – 6.39 (m, 1H), 6.32 (d, J = 12.0 Hz, 1H), 5.69 (d, J = 45.6 Hz, 1H), 4.43 (s, 2H), 4.19 (d, J = 14.4 Hz, 1H), 3.24 (s, 1H), 2.86 – 2.65 (m, 1H), 2.22 – 2.08 (m, 2H), 1.78 – 1.71 (m, 2H), 1.65(t, J = 18.6 Hz, 3H), 1.33 (s, 2H), 1.13 (s, 2H) ppm. Step 14b. Synthesis of ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (8-14b). Following the same procedure as described for preparing 8-14a by replacing 8-13a with 8-13b (15 mg, 0.03 mmol), 8-14b (15 mg, 79 %) was obtained as a yellow solid (single diastereomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 612.1 [M + 1]+. Step 15b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 8b). Following the same procedure as described for preparing Example 8a by replacing 8-14a with 8-14b (16 mg, 0.025 mmol), Example 8b (10 mg, 69%) as a white solid (single diastereomer, the stereochemistry was arbitrarily assigned). Prep-HPLC condition: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 55% B to 75% B in 8 min; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.92. MS (ESI): calcd. for: C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.82 (s, 1H), 7.64 (s, 1H), 7.20 – 7.15 (m, 1H), 6.53 – 6.50 (m, 1H), 6.47 (d, J = 2.1 Hz, 1H), 6.42 – 6.31 (m, 1H), 5.69 (d, J = 45.0 Hz, 1H), 4.43 (s, 2H), 4.18 (d, J = 15.6 Hz, 1H), 3.26 (s, 1H), 2.86 – 2.65 (m, 1H), 2.19 – 2.11 (m, 2H), 1.78 – 1.71 (m, 2H), 1.66 (t, J = 6.9 Hz, 3H), 1.35 (s, 2H), 1.12 (s, 2H) ppm. Synthesis of rac-(2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1) and rac- (2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1b) Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (9A-1). A solution of 7-bromo-3-(3,3- difluorobutyl)-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (8-7) (20 g, 52.60 mmol), (4-fluorophenyl)boronic acid (14.72 g, 105.19 mmol), and Et3N (15.97 g, 0.16 mol) in DMF (300 mL) was treated with Cu(OAc)2 (14.33 g, 78.90 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under oxygen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (300 mL) and sat. aq. NH4Cl solution (900 mL). The resulting solution was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (300 mL x 3) and brine (300 mL), dried over anhydrous Na2SO4, and concentrated. Thie residue was dried in vacuo to give crude 9A-1 (25 g) as a black solid, which was used in the next step without purification. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 473.9 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.22 (s, 1H), 7.19 (s, 1H), 7.18 – 7.13 (m, 2H), 7.11 – 7.04 (m, 2H), 3.96 (s, 3H), 3.51 (dd, J = 11.1, 6.0 Hz, 1H), 3.10 – 2.95 (m, 1H), 2.88 – 2.77 (m, 1H), 2.15 (m, 1H), 2.05 – 1.86 (m, 1H), 1.86 – 1.74 (m, 1H), 1.61 (t, J = 18.6 Hz, 4H) ppm. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (9A-2). To a stirred solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (9A-1) (25 g, 52.71 mmol) in THF (500 mL) and H2O (500 mL) was added Oxone® (107 g, 0.31 mol) in portions at rt. The resulting mixture was stirred at rt for 16 h. The resulting mixture was filtered. The filtrate was concentrated to remove organic solvent, and the residue was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 9A-2 (24 g) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.47 (s, 1H), 7.42 (s, 1H), 7.38 – 7.24 (m, 4H), 4.00 (s, 3H), 4.09 – 3.88 (m, 1H), 3.75 (dd, J = 13.6, 12.0 Hz, 1H), 2.99 (dd, J = 12.0, 5.7 Hz, 1H), 2.01 – 1.80 (m, 4H), 1.58 (t, J = 18.9 Hz, 3H) ppm. Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-3). To a stirred solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (9A-2) (24 g, 47.40 mmol) in THF (120 mL) was added 10 M BH3•Me2S in THF (48 mL) dropwise at rt. The resulting mixture was stirred at 60 °C for 16 hr. The reaction was quenched by the addition of H2O (100 mL) at rt. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE/EA = 2/1 (v/v) as eluent to give 9A-3 (20 g, 85.7%) as a brown solid. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ7.61 (s, 1H), 7.52 (s, 1H), 7.02 (t, J = 8.8 Hz, 2H), 6.64 (dd, J = 8.6, 4.4 Hz, 2H), 4.21 (d, J = 15.1 Hz, 1H), 3.98 (s, 3H), 3.60 (dd, J = 14.9, 3.4 Hz, 1H), 3.42 – 3.28 (m, 1H), 3.16 (s, 1H), 2.27 (s, 1H), 2.15 – 1.93 (m, 2H), 1.70 – 1.39 (m, 5H) ppm. Step 4. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-4). To a solution of 7- bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-3) (2.5 g, 5.07 mmol) in tetrahydrofuran (50 mL) was added dropwise LiHMDS (1 mol/L in THF) (2.8 mL, 10.15 mmol) at -78°C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 30 mins. Then a solution of NFSI (1.60 g, 5.07 mmol) in tetrahydrofuran (5 mL) was added dropwise and the mixture was stirred at -78 °C for 30 mins. The reaction was quenched with sat. aq. NH4Cl solution (50 mL), and then the mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE/EA = 3/1 (v/v) as eluent to give 9A-4 (1.5 g, 57.9%) as a brown solid. MS (ESI): calcd. for C20H20BrF4NO3S: 509.0; Found: 510.0 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.66 (s, 1H), 7.54 (s, 1H), 7.11 – 6.96 (m, 2H), 6.66 (m, 2H), 6.12 – 5.77 (m, 1H), 4.22 – 4.11 (m, 1H), 4.05 – 3.95 (m, 3H), 3.27 – 3.12 (m, 1H), 2.68 – 2.36 (m, 1H), 2.33 – 1.90 (m, 3H), 1.73 – 1.38 (m, 4H) ppm. Step 5. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A- 5a) and rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b). To a stirred solution of rac-7-bromo-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-4) (170 g, 0.33 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (384 g, 2 mol) in DMF (3.4 L) was added CuBr (95.57 g, 0.67 mol) in portions at rt under N2 atmosphere. The resulting mixture was stirred at 130°C for 16 h under N2 atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (10 L) at rt. The resulting mixture was extracted with EA (3 L x 2). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE/EA = 3/1 (v/v) as eluent to give 9A-5a (60 g, 36.1%, cis- racemate) as a yellow solid and 9A-5b (45 g, 27.1%, trans- racemate) as a yellow solid, respectively. 9A-5a: MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.67 (s, 1H), 7.10 – 7.02 (m, 23H), 6.71 – 6.60 (m, 2H), 6.10 (d, J = 44.4 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 4.06 (s, 3H), 3.22 (dd, J = 15.9, 11.4 Hz, 1H), 2.76 – 2.44 (m, 1H), 2.30 – 1.96 (m, 3H), 1.74 – 1.56 (m, 4H) ppm. 9A-5b: MS (ESI): calcd. for C21H20F7NO3S: 499.1; Found: 500.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.10 (t, J = 8.7 Hz, 2H), 6.89 (s, 2H), 5.95 (dd, J = 44.1, 6.9 Hz, 1H), 4.03 (s, 3H), 4.01 – 3.59 (m, 2H), 2.45 – 2.39 (m, 1H), 2.14 – 1.89 (m, 2H), 1.86 – 1.71 (m, 1H), 1.70 – 1.55 (m, 1H), 1.49 (t, J = 18.9 Hz, 3H) ppm. Step 6a. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9- 1a). A mixture of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (60 g, 0.12 mol) (9A-5a) in DMSO (600 mL) was added LiCl (50.5 g, 1.21 mol) at room temperature. After stirring at 140°C for 16 h under nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL x 4), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE/EA = 8/1 (v/v) as eluent to give 9-1a (43 g, 73.7%, cis- racemate) as a yellow oil. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.3 [M + 1]+. 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.03 (t, J = 9.0 Hz, 2H), 6.62 (dd, J = 9.3, 4.5 Hz, 2H), 6.03 (d, J = 44.4 Hz, 1H), 4.15 (d, J = 15.9 Hz, 1H), 3.20 (dd, J = 15.9, 11.4 Hz, 1H), 2.69 – 2.60 (m, 1H), 2.22 – 2.06 (m, 2H), 1.61 (t, J = 18.9 Hz, 5H) ppm. rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) was separated by SFC (Column: (R,R)-WHELK-O1, 50*4.6 mm, 3.5 µm; Co-eluent: MeOH; Gradient (B%): 10% to 50% in 2.0 min, hold 50% for 1.0 min; Back pressure (bar): 150; Flow (mL/min): 3.0; Column temperature (oC): 35; UV detection wavelength: 220 nm) to give (2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-4) (tR = 0.43 min; single diastereomer) as a white solid; and (2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (tR = 0.69 min; single diastereomer) as a white solid, respectively. Step 6b. Synthesis of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9- 1b). A mixture of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b) (45 g, 90.10 mmol) DMSO (450 mL) was added LiCl (38.19 g, 0.90 mol) at room temperature. After stirring at 140°C for 16 h under nitrogen atmosphere, the mixture was cooled to room temperature and diluted with water (2000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL x 4), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE/EA = 8/1 (v/v) as eluent to give 9-1b (30 g, 68.6%) as a yellow oil. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.2 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 11.53 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 7.06 (t, J = 8.7 Hz, 2H), 6.86 – 6.76 (m, 2H), 5.88 (dd, J = 44.4, 7.8 Hz, 1H), 3.82 (s, 2H), 2.42 (s, 1H), 2.15 – 1.84 (m, 2H), 1.84 – 1.70 (m, 1H), 1.69 – 1.60 (m, 1H), 1.52 (t, J = 18.9 Hz, 3H) ppm. Relative stereochemistry determination of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5a) and rac-(2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9A-5b).1H, 13C, 19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of the cis- racemate 9A-5a and the corresponding trans- racemate 9A-5b. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H, H13), 7.53 (s, 1H, H9), 7.04 – 6.93 (m, 2H, H24&H26), 6.70 – 6.60 (m, 2H, H23&H27), 5.32 (d, J = 60.0, 1H, H16), 4.12 – 4.00 (m, 1H, H6'), 4.05 (s, 3H, H17), 3.34 (dd, J = 15.8, 11.2 Hz, 1H, H6''), 2.87 – 2.67 (m, 1H, H5), 2.13 – 1.97 (m, 2H, H3), 1.84 – 1.57 (m, 2H, H4), 1.68 (t, J = 18.4 Hz, 3H, H1) ppm.13C NMR (101 MHz, CDCl3): δ 157.15 (d, J = 240.0 Hz, C25), 155.68 (C11), 141.84 (d, J = 2.0 Hz, C22), 139.50 (14), 138.03 (C8), 129.28 (q, J = 5.0 Hz, C9), 125.64 (q, J = 32.1 Hz, C10), 123.29 (t, J = 238.7 Hz, C2), 122.11 (q, J = 273.7 Hz, C30), 116.57 (d, J = 7.6 Hz, C23&C27), 116.21 (d, J = 22.6 Hz, C24&C26), 114.07 (C13), 101.61 (d, J = 222.9 Hz, C16), 56.87 (C17), 48.50 (d, J = 2.0 Hz, C6), 37.71 (d, J = 18.6 Hz, C5), 35.00 (t, J = 26.0 Hz, C3), 23.64 (t, J = 27.7 Hz, C1), 21.78 (C4) ppm.19F NMR (376 MHz, CDCl3): δ -63.33 (F31, F32&F33), -91.54 (d, J = 240.0 Hz, F18), -92.55 (d, J = 240.1 Hz, F19), -124.24 (F28), - 197.24 (F29) ppm. F-H NOESY NMR data suggested F29 has correlation with H4 but not with H5.
1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H, H13), 7.28 (s, 1H, H9), 7.08 – 6.96 (m, 4H, H23, H24, H26&H27), 5.26 (dd, J = 44.8, 5.2 Hz, 1H, H16), 4.12 (d, J = 9.6 Hz, 1H, H6'), 4.02 (s, 3H, H17), 3.63 (d, J = 15.2 Hz, 1H, 6''), 2.47 – 2.37 (m, 1H, H5), 2.03 – 1.81 (m, 4H, H3&H4), 1.47 (t, J = 18.4 Hz, 3H, H1) ppm.13C NMR (101 MHz, CDCl3): δ 158.58 (d, J = 243.2 Hz, C25), 154.21 (C11), 143.71 (C 22), 140.51 (C8), 136.87 (C14), 126.72 (9), 125.51 (q, J = 32.1 Hz, C10), 123.63 (t, J = 238.5 Hz, C2), 122.12 (q, J = 273.8 Hz, C30), 122.00 (C23&C27), 116.52 (d, J = 22.6 Hz, C24&C26), 112.83 (C13), 101.97 (d, J = 216.1 Hz, C16), 56.78 (C17), 49.38 (C6), 41.51 (d, J = 18.7 Hz, C5), 35.31 (t, J = 25.9 Hz, C3), 23.07 (t, J = 27.6 Hz, C1), 21.12 (C4) ppm.19F NMR (376 MHz, CDCl3): δ -63.36 (F31, F32&F33), -90.41 (d, J = 247.8 Hz, F18), -91.48 (d, J = 238.7 Hz, F19), -119.97 (F28), - 176.92 (F29) ppm. F-H NOESY NMR data suggested F29 has correlation with H5 but not with H4. Examples 9a and 9b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (9a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (9b)
Step 1. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (9-2). To a stirred solution of 9-1a (30 mg, 0.06 mmol), which was prepared by following the same procedure as described for preparing the racemic 8-13 and replacing 3-fluoro-iodobenzne with 4-fluoro-iodobenzene, and cesium carbonate (40.40 mg, 0.12 mmol) in DMF (2 mL) was added ethyl 1- (bromomethyl)cyclopropane-1-carboxylate (19.20 mg, 0.09 mmol) dropwise at rt. After stirring at 80 oC for 3 hr, the reaction mixture was cooled to rt, added water (10 mL), and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 4/1 (v/v)) to give 9-2 (30 mg, 79%) as a brown solid. MS (ESI): calcd. for C27H28F7NO5S: 611.2; Found: 500.2 [M + 1]+. Step 2. Synthesis of rac-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (9-3). A solution of 9-2 (30 mg, 0.05 mmol) and LiOH (5.87 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 16 h. The mixture was acidified with 2 N aq. HCl solution to pH ~ 4. The resulting mixture was concentrated to remove organic solvent, diluted with water (10 mL), and extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following condition: Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 55% B to 78% B in 8 min, 78% B; Wavelength: 220 nm, 254 nm; RT1 (min) = 5.26 to give 9-3 (15 mg) as a white solid. Step 3. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9a) and 1-((((2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 9b). The racemic 9-3 (15 mg) was purified by prep-SFC with the following condition: (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 25% B; Wavelength: 220 nm; RT1 (min) = 3.0; RT2 (min) = 3.5; Sample Solvent: MeOH: CAN = 2: 1 (v/v); Injection Volume: 2 mL to give Example 9a (single diastereomer, the stereochemistry was arbitrarily assigned) (4.1 mg) as a white solid. MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 7.54 (s, 1H), 6.96 (t, J = 9.0 Hz, 2H), 6.71 ‒ 6.66 (m, 2H), 5.67 (d, J = 45.3 Hz, 1H), 4.42 (s, 2H), 4.18 (d, J = 15.0 Hz, 1H), 3.27 ‒ 3.21 (m, 1H), 2.77 ‒ 2.63 (m, 1H), 2.21 ‒ 2.03 (m, 2H), 1.79 ‒ 1.57 (m, 5H), 1.31 (s, 2H), 1.07 (s, 2H) ppm; and Example 9b (single diastereomer, the stereochemistry was arbitrarily assigned) (2.2 mg) as a white solid. MS (ESI): calcd. for C25H24F7NO5S: 583.1; Found: 584.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.83 (s, 1H), 7.55 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.73 ‒ 6.69 (m, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.45 (s, 2H), 4.20 (d, J = 15.6 Hz, 1H), 3.32 ‒ 3.26 (m, 1H), 2.82 ‒ 2.65 (m, 1H), 2.24 ‒ 2.07 (m, 2H), 1.79 ‒ 1.59 (m, 5H), 1.31 (s, 2H), 1.06 (s, 2H) ppm. Examples 10a and 10b.3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (10a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (10b) Step 1. Synthesis of rac- methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10-1). To a stirred solution of rac-(2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) (1.20 g, 2.47 mmol) and Cs2CO3 (2.42 g, 7.41 mmol) in DMF(50 mL) were added KI (1.23 g, 7.41 mmol) and methyl 2,2-dimethyl- 3-((methylsulfonyl)oxy)propanoate (1.04 g, 4.94 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 h. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (150 mL) at rt. The resulting mixture was extracted with EA (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc = 2/1 (v/v) to give 10-1 (800 mg, 54.0%) as a brown solid. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+. Step 2. Synthesis of methyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10-2a) and methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10-2b). The product rac-methyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (800 mg) was purified by Prep-SFC with the following conditions: Column: (R, R)-WHELK- O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 20% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.8; RT2(min): 6.5; Sample Solvent: MeOH; Injection Volume: 9 mL. The collected fractions were concentrated, and the residue was dried in vacuo to give 10-2a (260 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) and 10-2b (240 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.2 [M + 1]+. Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10a). A solution of 10-2a (260 mg, 0.43 mmol) and LiOH (31.25 mg, 1.30 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). Subsequently, the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 2.69. The collected solution was concentrated under vacuum to remove ACN and the resulting solution was lyophilized to give Example 10a (168 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.02 – 6.96 (m, 2H), 6.75 – 6.70 (m, 2H), 5.70 (d, J = 45.3 Hz, 1H), 4.29 – 4.18 (m, 3H), 3.38 – 3.34 (m, 1H), 2.80 – 2.69 (m, 1H), 2.20 – 2.07 (m, 2H), 1.79 – 1.57 (m, 5H), 1.37 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10b). A solution of 10-2b (240 mg, 0.40 mmol) and LiOH (28.85 mg, 1.20 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). Subsequently, the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 1.87. The collected solution was concentrated under vacuum to remove ACN and the resulting solution was lyophilized to give Example 10b (163 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.02 – 6.96 (m, 2H), 6.75 – 6.70 (m, 2H), 5.70 (d, J = 45.3 Hz, 1H), 4.29 – 4.18 (m, 3H), 3.38 – 3.34 (m, 1H), 2.80 – 2.66 (m, 1H), 2.20 – 2.06 (m, 2H), 1.79 – 1.57 (m, 5H), 1.37 (s, 6H) ppm. Relative stereochemistry determination of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 10b). 1H, 13C, 19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of Example 10b. 1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H, H13), 7.57 (s, 1H, H9), 7.06 – 6.91 (m, 2H, H33&H31), 6.78 – 6.65 (m, 2H, H34&H30), 5.69 (d, J = 45.2 Hz, 1H, H18), 4.27 (d, J = 8.6 Hz, 1H, H20’), 4.23 (d, J = 8.6 Hz, 1H, H20”), 4.26 – 4.15 (m, 1H, H6’), 3.31 (dd, J = 16.0, 11.2 Hz, 1H, H6”), 2.82-2.62 (m, 1H, H5), 2.28 – 1.99 (m, 2H, H3), 1.81 – 1.65 (m, 2H, H4), 1.65 (t, J = 18.5 Hz, 3H, H1), 1.37 (s, 6H, H28&H29) ppm.13C NMR (75 MHz, CD3OD): δ 177.77 (C23), 156.90 (d, J = 237.4 Hz, C32), 154.84 (C11), 142.37 (C21), 140.35 (C14), 138.30 (C8), 129.17 (q, J = 4.6 Hz, C9), 124.97 (q, J = 31.9 Hz, C10), 123.79 (t, J = 237.6 Hz, C2), 127.33 – 116.85 (m, C36), 116.16 (d, J = 7.7 Hz, C34&C30), 115.31 (d, J = 22.7 Hz, C31&C33), 114.27 (C13), 101.98 (d, J = 219.9 Hz, C18), 75.47 (C20), 47.68 (C6), 42.65 (C22), 37.61 (d, J = 18.5 Hz, C5), 34.36 (t, J = 25.9 Hz, C3), 22.12 (t, J = 27.7 Hz, C1), 21.59 – 21.30 (m, C4), 21.19 (C28&C29).19F NMR (282 MHz, CD3OD): δ -64.47 (F37, F38&F39), -92.72 (d, J = 10.9 Hz, F26&F27), -127.48 (F35), -199.65 (F19) ppm. F-H NOESY NMR data suggested F19 has correlation with H4 but not with H5. Examples 10c and 10d.3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (10c) and 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (10d)
Step 1. Synthesis of rac-methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (9-1b). To a stirred solution of rac-(2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1b, trans- racemate) (200 mg, 0.41 mmol) and Cs2CO3 (402.73 mg, 1.24 mmol) in DMF (5 mL) were added KI (205.19 mg, 1.24 mmol) and methyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (137.36 mg, 0.62 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at 100 °C. The mixture was allowed to cool down to room temperature, followed by adding water to quench the reaction. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-TLC (PE / EA = 5 / 1 (v/v)) to give 10A-1 (130 mg, 52.63%, trans- racemate) as a white solid. MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+. Step 2. Synthesis of methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (10A-2a) and methyl 3-(((2S,3S)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2b). rac- Methyl 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-1) (90 mg) was purified by Prep- Chiral-HPLC (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 25 mL/min; Gradient: isocratic 10; Wavelength: 240 nm; RT1 (min): 5.6; RT2 (min): 7.2; Sample Solvent: EtOH--HPLC; Injection volume: 1 mL; Number of runs: 5). The collected fractions were concentrated, and the residue was dried in vacuo to give 10A-2a (25 mg, 56%, single diastereomer, MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+) and 10A-2b (24 mg, 53%, single diastereomer, MS (ESI): calcd. for C26H28F7NO5S: 599.2; Found: 600.1 [M + 1]+) as a white solid, respectively. Step 3a. Synthesis of 3-(((2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10c). A solution of methyl 3-(((2R,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2a) (25 mg, 0.05 mmol) and LiOH (7.85 mg, 0.35 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at 50 ℃ for 12 h. Next, the mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 50% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 5.94). The collected fractions were concentrated, and the residue was lyophilized to give Example 10c (15.2 mg, 62%, single diastereomer) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 6.0 Hz, 1H), 4.26 - 4.10 (m, 3H), 3.73 - 3.59 (m, 1H), 2.45 - 2.44 (m, 1H), 2.05 - 1.75 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10d). A solution of methyl 3-(((2S,3S)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (10A-2b) (24 mg, 0.04 mmol) and LiOH (7.05 mg, 0.14 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 12 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 50% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 5.94). The collected fractions were concentrated, and the residue was lyophilized to give Example 10d (14.3 mg, 61%, single diastereomer) as a white solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 6.0 Hz, 1H), 4.26 - 4.23 (m, 2H), 4.20 - 4.11 (m, 1H), 3.74 - 3.70 (m, 1H), 2.46 - 2.44 (m, 1H), 2.05 - 1.80 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Examples 10c/d. rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid.
Step 1. Synthesis of rac-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 10c/d). A solution of rac-ethyl 1-((((2R,3S)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (10A-1, trans- racemate) (40 mg, 0.24 mmol) in dioxane (4 mL) was treated with water (1 mL) for 3 min at room temperature under nitrogen atmosphere, followed by the addition of LiOH (47.62 mg, 2.26 mmol) dropwise at room temperature. The resulting mixture was stirred at 50℃ for 12 h. Next, the mixture was acidified to pH = 3 with concd. aq. HCl solution. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC (Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min mL/min; Gradient: 50% to 75 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 5.94). The collected fractions were concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 10c/d (10.4 mg, 48.6%, trans- racemate) as a white solid. MS (ESI): calcd. for C25H28F7NO5S: 585.1; Found: 586.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H), 7.33 (s, 1H), 7.09 - 7.04 (m, 4H), 5.59 (dd, J = 44.1, 5.8 Hz, 1H), 4.26 - 4.13 (m, 3H), 3.74 - 3.69 (m, 1H), 2.45 - 2.41 (m, 1H), 2.05 - 1.78 (m, 4H), 1.45 (t, J = 18.3 Hz, 3H), 1.36 (s, 6H) ppm. Relative stereochemistry determination of rac-(2R,3R)-3-(3,3-difluorobutyl)-2-fluoro-5- (4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Example 10c/d).1H, 13C, 19F, H-H COSY, C-H HSQC, C-H HMBC, H-H NOESY, and F-H NOESY NMR technics were employed to elucidate the relative stereochemistry of the trans- racemate Example 10c/d. 1H NMR (300 MHz, CD3OD): δ 7.75 (s, 1H, H13), 7.33 (s, 1H, H9), 7.12 – 6.99 (m, 4H, H34, H33 H31&H30), 5.59 (dd, J = 44.2, 5.7 Hz, 1H, H18), 4.22 (s, 2H, H20), 4.22 – 4.12 (m, 1H, H6’), 3.73 – 3.69 (m, 1H, H6”), 2.45 (s, 1H, H5), 2.05 - 1.80 (m, 4H, H4&H3), 1.45 (t, J = 18.6 Hz, 3H, H1), 1.36 (s, 6H, H28&H29) ppm.13C NMR (76 MHz, CD3OD): δ 178.06 (C23), 155.06 (d, J = 228.8 Hz, C32), 153.50 (C11), 143.96 (C21), 140.66 (C14), 138.08 (C8), 126.86 (C9), 124.86 (q, J = 31.8 Hz, C10), 126.86 – 120.46 (m, C2), 120.57 (C36), 115.81 (C31&C33), 115.51 (C30&C34), 113.16 (C13), 102.53 (d, J = 245.5 Hz, C18), 75.52 (C20), 48.77 (C6), 42.59 (C22), 41.12 (d, J = 15.2 Hz, C5), 34.86 (t, J = 25.6 Hz, C3), 22.26 – 21.27 (m, C1), 21.28 (C28&C29), 20.93 – 20.55 (C4) ppm.19F NMR (282 MHz, CD3OD): δ -64.51 (F37, F38&F39), -92.49 (F26&F27), -123.43 (F35), -178.25 (F19). F-H NOESY NMR data suggested F19 has correlation with H5 but not with H4. Examples 11a and 11b. (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (11a) and (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2-methylpropanoic acid (11b)
Step 1. Synthesis of rac-methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2-methylpropanoate (11-1). To a stirred solution of rac-(2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (9-1a) (1.2 g, 2.47 mmol) and DIAD (1.29 g, 9.89 mmol) in DMF (50 mL) were added triphenylphosphine (2.59 g, 9.89 mmol) and methyl (R)-3-hydroxy-2-methylpropanoate (0.58 g, 4.944 mmol) at rt under N2 atmosphere. The resulting mixture was stirred at 110°C for 6 hr. The mixture was allowed to cool down to rt. The reaction was quenched with H2O at rt. The resulting mixture was extracted with EA (50 mL x 2). Next, the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 11-1 (700 mg, 48.36%) as a brown solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+. Step 2. Synthesis of methyl (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2-methylpropanoate (11-2a) and methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoate (11-2b). The product rac-methyl (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoate (11-1) (700 mg) was purified by Prep-SFC with the following conditions: Column: (R, R)- WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 30% B; Column temperature (oC): 35; Back pressure(bar): 100; Wavelength: 220 nm; RT1(min): 3.3; RT2(min): 4.8; Sample solvent: MeOH; Injection volume: 5 mL. The collected solution was concentrated in vacuo to give 11-2a (270 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) and 11-2b (260 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.2 [M + 1]+. Step 3a. Synthesis of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 11a). A solution of 11-2a (270 mg, 0.46 mmol) and LiOH (33.23 mg, 1.38 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product (300 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05%NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 10 min; Wavelength: 254 nm/220 nm; RT1(min): 1.29. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 11a (108 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C24H24F7NO5S: 571.1; Found: 572.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97 (t, J = 8.7 Hz, 2H), 6.70 (dd, J = 9.1, 4.2 Hz, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.41 – 4.28 (m, 2H), 4.18 (d, J = 15.9 Hz, 1H), 3.28 – 3.20 (m, 1H), 3.01 – 2.93 (m, 1H), 2.77 – 2.63 (m, 1H), 2.21 – 2.04 (m, 2H), 1.81 – 1.55 (m, 5H), 1.33 (d, J = 7.2 Hz, 3H) ppm. Step 3b. Synthesis of (R)-3-(((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2- methylpropanoic acid (Example 11b). A solution of 11-2b (260 mg, 0.44 mmol) and LiOH (32.02 mg, 1.33 mmol) in 1,4-dioxane (12 mL) and H2O (3 mL) was stirred at rt for 16 hr. The mixture was acidified to pH = 4 with 2 N aq. HCl solution and extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude product (300 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3•H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 10 min; Wavelength: 254 nm/220 nm; RT1(min): 0.92. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 11b (single diastereomer, the stereochemistry was arbitrarily assigned) (106 mg) as a white solid. MS (ESI): calcd. for: C24H24F7NO5S: 571.1; Found: 572.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.54 (s, 1H), 6.97 (t, J = 8.7 Hz, 2H), 6.70 (dd, J = 9.1, 4.2 Hz, 2H), 5.68 (d, J = 45.3 Hz, 1H), 4.44 – 4.30 (m, 1H), 4.28 – 4.20 (m, 1H), 4.18 (d, J = 15.9 Hz, 1H), 3.28 – 3.20 (m, 1H), 2.98 – 2.92 (m, 1H), 2.78 – 2.63 (m, 1H), 2.20 – 2.03 (m, 2H), 1.77 – 1.57 (m, 5H), 1.33 (d, J = 7.2 Hz, 3H) ppm. Examples 12a and 12b. (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (12a) and (S)-1-(((3-(3,3-difluorobutyl)-2,2- difluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (12b)
Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (12-1). A solution of 8-7 (11 g, 28.93 mmol), 1- fluoro-4-iodo- (9.63 g, 43.39 mmol), CuI (5.51 g, 28.93 mmol), and K2CO3 (11.99 g, 86.78 mmol) in DMF (110 mL) was stirred at 130 °C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to rt and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with water (200 mL x 5) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 12-1 (10.5 g, 76.5%) as a dark yellow solid. MS (ESI): calcd. for C20H19BrF3NO2S: 473.0; Found: 474.0 [M + 1]+. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (12-2). A solution of 12-1 (10.5 g, 22.14 mmol) and Oxone® (27.92 g, 166.02 mmol) in THF (200 mL) and H2O (100 mL) was stirred at rt for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (120 mL x 3). The mixture was acidified to pH 8 with sat. aq. NaHCO3. The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 12-2 (12.6 g, 89.9%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H19BrF3NO4S: 505.0; Found: 506.0 [M + 1]+. Step 3. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-3). A solution of 12-2 (12.6 g, 24.89 mmol) and BH3·DMS (16.52 mL, 174.20 mmol) in THF (100 mL) was stirred at 60 °C for 16 h. Subsequently, the reaction mixture was allowed to cool down to 0 °C with ice- water, added MeOH (50 mL) (dropwise) at 0 °C, and concentrated under vacuum. The residue was dissolved in water (150 mL) and the resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 4/1 (v/v)) to give 12-3 (8.2 g, 66.9%) as a light brown oil. MS (ESI): calcd. for C20H21BrF3NO3S: 491.0; Found: 492.0 [M + 1]+. Step 4. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-4). A solution of 12-3 (2 g, 4.06 mmol) in THF (30 mL) was added with LiHMDS (2.04 g, 12.19 mmol) at -78 °C for 30 min under nitrogen atmosphere. After stirring at -78 °C for 30 min, a solution of NFSI (3.20 g, 10.16 mmol) in THF (20 mL) was added at -78 °C dropwise. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere, followed by adding water (100 mL) at 0 °C. Subsequently, the mixture was concentrated to remove organic solvent, and the residue was extracted with EtOAc (80 mL x 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 12-4 (1.6 g, 67.1%) as a yellow solid. MS (ESI): calcd. for C20H19BrF5NO3S: 527.0; Found: 528.0 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.63 (s, 1H), 7.02 (t, J = 8.4 Hz, 2H), 6.72 – 6.68 (m, 2H), 4.22 – 4.15 (m, 1H), 4.03 (s, 3H), 3.47 - 3.43 (m, 1H), 2.95 – 2.91 (m, 1H), 2.07 – 2.01 (m, 2H), 1.72 - 1.68 (m, 5H) ppm. Step 5. Synthesis of 3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-5). A solution of 12-4 (1.1 g, 2.08 mmol) in DMF (15 mL) was treated with methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (1.60 g, 8.33 mmol) and CuBr (1.79 g, 12.49 mmol) at rt under nitrogen atmosphere. After stirring at 130 °C for 16 h under nitrogen atmosphere, the mixture was cooled down to rt, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL x 5) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 12-5 (900 mg, 75.19%) as a light-yellow oil. MS (ESI): calcd. for C21H19F8NO3S: 517.1; Found: 518.0 [M + 1]+. Step 6. Synthesis of 3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (12-6). A solution of 12-5 (900 mg, 1.74 mmol) in DMSO (15 mL) was treated with LiCl (1.47 g, 34.78 mmol) at rt. After stirring at 140 °C for 8 h, the reaction mixture was cooled down to rt, diluted with water (50 mL), and acidified to pH 5 with citric acid (10% w/w). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water (50 mL x 5) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 12-6 (700 mg, 76.0%) as a light-yellow oil. MS (ESI): calcd. for C20H17F8NO3S: 503.1; Found: 504.0 [M + 1]+. Step 7. Synthesis of ethyl 1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (12-7). A solution of 12-6 (160 mg, 0.32 mmol) in DMF (6 mL) was treated with ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane- 1-carboxylate (105.96 mg, 0.477 mmol), KI (211.04 mg, 1.27 mmol), and Cs2CO3 (414.22 mg, 1.27 mmol) at rt. After stirring at 100 °C for 16 h, the mixture was cooled down to rt, diluted with water (15 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with water (20 mL x 5) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1 (v/v)) to give 12-7 (80 mg, 36.0%) as a light-yellow oil. MS (ESI): calcd. for C27H27F8NO5S: 629.1; Found: 630.1 [M + 1]+. Step 8. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (12-8a) and ethyl (S)-1-(((3-(3,3- difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (12-8b). Compound 12-7 (80 mg) was purified by prep-HPLC (Column: (R, R)-WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 30% B; Wavelength: 220 nm) to give 12-8a (35 mg), MS (ESI): calcd. for C27H27F8NO5S: 629.1; Found: 630.1 [M + 1]+ and 12-8b (33 mg), MS (ESI): calcd. for C27H29F6NO5S: 593.2; Found: 630.1 [M + 1]+ as a white solid, respectively. Step 9a. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 12a). A solution of 12-8a (35 mg, 0.06 mmol) in dioxane (5 mL) and H2O (1 mL) was treated with LiOH (5.33 mg, 0.23 mmol) at rt. After stirring at 40 °C for 16 h, the mixture was cooled down to rt, acidified to pH 3 with 2 N aq. HCl solution, and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 60% B in 8 min, 60% B; Wavelength: 254/220 nm) to give Example 12a (18.2 mg, 53.5%) as a white solid. MS (ESI): calcd. for C25H23F8NO5S: 601.1; Found: 602.1 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.82 (s, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 6.77 (s, 2H), 4.43 (s, 2H), 4.33 - 4.21 (m, 1H), 3.59 - 3.41 (m, 1H), 3.01 - 2.81 (m, 1H), 2.17 - 1.94 (m, 3H), 1.65 - 1.56 (m, 4H), 1.37 - 1.30 (m, 2H), 1.19- 1.06 (m, 2H) ppm. Step 9b. (S)-1-(((3-(3,3-difluorobutyl)-2,2-difluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 12b). A solution of 12-8b (33 mg, 0.05 mmol) in dioxane (5 mL) and H2O (1 mL) was treated with LiOH (5.28 mg, 0.22 mmol) at rt. After stirring at 40 °C for 16 hr, the mixture was cooled down to rt, acidified to pH 3 with 2 N aq. HCl solution, and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 60% B in 8 min, 60% B; Wavelength: 254/220 nm) to give Example 12b (21.2 mg, 66.9%) as a white solid. MS (ESI): calcd. for C25H23F8NO5S: 601.1; Found: 602.1 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.83 (s, 1H), 7.52 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 6.78 (s, 2H), 4.40 (s, 2H), 4.24 - 4.18 (m, 1H), 3.59 - 3.41 (m, 1H), 3.05 - 2.80 (m, 1H), 2.17 - 1.93 (m, 3H), 1.65 - 1.51 (m, 4H), 1.38 - 1.30 (m, 2H), 1.18 - 1.12 (m, 2H) ppm. Examples 13a and 13b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (13a) and (R)-1-(((3-(3,3-difluorobutyl)-7- ((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (13b) Step 1.3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-8-hydroxy-2-methyl-5- phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (13-2) To a stirred mixture of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (13-1) (1 g, 2.04 mmol), which was prepared by following the same procedure used for preparing 1-10, replacing 2-bromo-4- trifluoromethyl-5-methoxyphenylsulfonyl chloride with 2,4-dibromo-5- methoxyphenylsulfonyl chloride, and using the racemic version of 1-7, and 3,3- difluorocyclobutanethiol (0.89 g, 7.15 mmol) in DMF (15 mL) was added NaH (55% suspension in mineral oil) (0.446 g, 18.59 mmol) portion wise at 0 oC. After stirring at 0 oC for 30 min and rt for 2 hr, the mixture was stirred at 70 ºC for 12 hr. subsequently, the mixture was diluted with ice water (5 mL), acidified with sat. aq. NaHSO4 solution and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with water, and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep- HPLC to give 13-2 (700 mg, 66%) as a white solid. Step 2. Synthesis of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (13-3). A mixture of 13-2 (0.2 g, 0.39 mmol), cesium carbonate (0.314 g, 0.96 mmol) and methyl 1- (bromomethyl)cyclopropanecarboxylate (0.112 g, 0.58 mmol) in DMF (2 mL) was stirred at 60 oC for 16 hr. The mixture was cooled to rt and filtered. The filtrate was purified by prep- HPLC to give 13-3 (0.172 g, 71%) as a white solid. Step 3. Synthesis of methyl (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3- difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (13- 3a) and methyl (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2-methyl- 1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (13-3b). The racemic 13-3 (140 mg) was separated by chiral HPLC(Column: CHIRALPAK IF (250 × 21 mm, 5 µm)-II, Mobile phase: Hexane:IPA:MeOH, 80:10:10 (v/v/v); Flow Rate: 12 mL/min; Column Temperature: 24ºC; Wavelength: 205 nm. tR 1 = 20.60 min (single enantiomer, the stereochemistry was arbitrarily assigned); and tR 2 = 27.17 min (single enantiomer, the stereochemistry was arbitrarily assigned)) to give 13-3a (45.3 mg) and 13-3b (45.2 mg) as a white solid, respectively. Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13a). То а stirred solution of 13-3a (45.3 mg, 71.82 µmol) in THF/H2O = 4/1 (v/v) (2 mL) was added lithium hydroxide hydrate (9.0 mg, 214.0 µmol). After stirring at rt for 12 hr, the reaction mixture was adjusted to pH ~2 using 2 N aq. HCl solution. The resulting mixture was purified by prep-HPLC to give Example 13a (24.8 mg, 56%) as a white solid (single enantiomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C28H32F4N2O5S2: 616.2; Found: 614.9 [M - 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.95 (s, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 4.21 (q, J = 9.8 Hz, 2H), 4.06 (d, J = 16.0 Hz, 1H), 3.82 (s, 2H), 3.13 (s, 1H), 2.99 (d, J = 12.4 Hz, 1H), 2.64 – 2.50 (m, 2H), 2.47 (s, 3H), 1.98 (tt, J = 16.3, 8.2 Hz, 2H), 1.83 (t, J = 7.0 Hz, 1H), 1.63 (t, J = 18.9 Hz, 4H), 1.20 (t, J = 3.5 Hz, 2H), 1.06 (q, J = 3.3 Hz, 2H) ppm. Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 13b). Following the same procedure as described in Step 4a and replacing 13-3a with 13-3b (45.2 mg, 71.66 µmol), Example 13b (27.5 mg, 63%) was obtained as a white solid (single enantiomer, the stereochemistry was arbitrarily assigned). MS (ESI): calcd. for C28H32F4N2O5S2: 616.2; Found: 614.9 [M - 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.95 (s, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 4.21 (q, J = 9.8 Hz, 2H), 4.06 (d, J = 15.9 Hz, 1H), 3.82 (s, 2H), 3.26 (s, 1H), 3.13 (s, 1H), 2.98 (s, 1H), 2.64 – 2.50 (m, 2H), 2.47 (s, 3H), 1.98 (tt, J = 16.2, 8.0 Hz, 2H), 1.83 (d, J = 8.4 Hz, 1H), 1.63 (t, J = 18.9 Hz, 4H), 1.21 (d, J = 3.0 Hz, 2H), 1.06 (s, 2H) ppm. Example 14. (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl- 2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid
Step 1. Synthesis of (R)-2-bromo-6-chloro-N-(5,5-difluoro-1-(phenylamino)hexan-2-yl)- 5-methoxypyridine-3-sulfonamide (14-1). To a stirred solution of (R)-5,5-difluoro-N1- phenylhexane-1,2-diamine (1-7) (1.0 g, 4.1 mmol) and TEA (1.2 g, 12.3 mmol) in DCM (20 mL) was added a solution of 2,6-dibromo-5-methoxypyridine-3-sulfonyl chloride (1.9 g, 5.3 mmol) in DCM (5 mL) at 0°C. The resulting reaction mixture was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (40 mL) and the aqueous layer was extracted with EA (40 mL x 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 1/5 (v/v)) to give 14-1 (1.2 g, 57%) as a yellow solid. TLC: EA/PE = 1/5 (v/v) (Rf: 0.4). MS (ESI): calcd. for C18H21BrClF2N3O3S: 511.0; Found: 512.1 [M + 1]+. Step 2. Synthesis of (R)-7-chloro-3-(3,3-difluorobutyl)-8-methoxy-5-phenyl-2,3,4,5- tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-2). To a stirred solution of 14- 1 (1.2 g, 2.4 mmol) and K2CO3 (972 mg, 7.1 mmol) in DMF (30 mL) was added Cu (150 mg, 2.35 mmol) and the resulting mixture was heated at 115 °C for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl solution (100 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 14-2 (1.2 g) as a brown solid, which was used for the next step without further purification. TLC: EA/PE = 1/5 (v/v) (Rf: 0.5). MS (ESI): calcd. for C18H20ClF2N3O3S: 431.1; Found: 432.2 [M + 1]+. Step 3. Synthesis of (R)-7-chloro-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-5-phenyl- 2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-3). To a stirred solution of 14-2 (1.2 g, crude product, 2.78 mmol) and Cs2CO3 (2.7 g, 8.4 mmol) in NMP (20 mL) was added MeI (1.2 g, 8.4 mmol) and the reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 1/4 (v/v)) to give 14-3 (1.1 g, 89%) as a yellow solid. TLC: EA/PE = 3/7 (v/v) (Rf: 0.4). MS (ESI): calcd. for C19H22ClF2N3O3S: 445.1; Found: 446.2 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-7-(methylthio)-5- phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (14-4). To a stirred solution of 14-3 (1.1 g, 2.5 mmol) in DMF (10 mL) was added CH3SNa (519 mg, 7.4 mmol) and the reaction mixture was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water (20 mL) and the aqueous layer was extracted with EA (25 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 1/4 (v/v)) to give 14-4 (450 mg, 41%) as a yellow solid. TLC: EA/PE = 3/7 (v/v) (Rf: 0.6). MS (ESI): calcd. for C19H23F2N3O3S2: 443.1; Found: 444.1 [M + 1]+. Step 5. Synthesis of (R)-ethyl 1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1- dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (14-5). To a stirred solution of 14-4 (50 mg, 0.11 mmol) and Cs2CO3 (110 mg, 0.34 mmol) in DMF (3 mL) was added ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (50 mg, 0.23 mmol) and the reaction mixture was heated at 65 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added into water (10 mL). The precipitate was filtered, washed with water (10 mL x 3), and dried in vacuo to give crude 14-5 (58 mg) as a yellow solid, which was used for the next step without further purification. TLC: EA/PE = 3/7 (v/v) (Rf: 0.5). MS (ESI): calcd. for C26H33F2N3O5S2: 569.2; Found: 570.2 [M + 1]+. Step 6. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-2-methyl-7-(methylthio)-1,1-dioxido-5- phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylic acid (Example 14). To a stirred solution of 14-5 (58 mg, crude product, 0.10 mmol) in MeOH/H2O = 2/1 (v/v) 3 mL) was added NaOH (43 mg, 1.02 mmol) and the reaction mixture was stirred at rt for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 14 (31 mg, 56%) as a white solid. TLC: EA/PE = 3/2 (v/v) (Rf: 0.5). MS (ESI): calcd. for C24H29F2N3O5S2: 541.2; Found: 542.2 [M + 1]+ .1H NMR (400 MHz, DMSO-d6): δ 7.45 (s, 1H), 7.33 ‒ 7.29 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.2 Hz,1H), 4.24 ‒ 4.04 (m, 4H), 3.79 ‒ 3.69 (m, 1H), 2.87 (s, 3H), 2.13 ‒ 1.89 (m, 6H), 1.73 ‒ 1.69 (m, 1H), 1.59 (t, J = 18.4 Hz, 3H), 1.34 ‒ 1.31 (m, 2H), 1.12 ‒ 1.09 (m, 2H) ppm. Example 15. (R)-1-(((3-(3,3-difluorobutyl)-5-(3-fluorophenyl)-2-methyl-7-(methylthio)-1,1- dioxido-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid
Following the same procedure as that for preparing Example 14 by replacing aniline with 3- F-anuline, Example 15 was obtained (16 mg) as a white solid. TLC: EA/PE = 1/1 (v/v) (Rf: 0.3). MS (ESI): calcd. for C24H28F3N3O5S2: 559.1; Found: 560.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1H), 7.25 (q, J = 8.0 Hz, 1H), 6.77 ‒ 6.73 (m, 1H), 6.70 ‒ 6.65 (m, 2H), 4.27 (q, J = 10.0 Hz, 2H), 4.14 ‒ 4.07 (m, 1H), 3.91 ‒ 3.85 (m, 2H), 2.76 (s, 3H), 2.17 (s, 3H), 2.12 ‒ 1.96 (m, 2H), 1.91 ‒ 1.77 (m, 2H), 1.61 (t, J = 18.4 Hz, 3H), 1.33 ‒ 1.31 (m, 2H), 1.11 ‒ 1.10 (m, 2H) ppm Example 16. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1- dioxido-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1- carboxylic acid Following the same procedure as that for preparing Example 14 by replacing aniline with 4- F-aniline, Example 16 was obtained (12 mg) as a white solid. TLC: EA/PE = 1/1 (v/v) (Rf: 0.3). MS (ESI): calcd. for C24H28F3N3O5S2: 559.1; Found: 560.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.17 ‒ 7.13 (m, 2H), 7.10 ‒ 7.04 (m, 2H), 4.27 ‒ 4.18 (m, 3H), 4.00 ‒ 3.96 (m, 1H), 3.77 ‒ 3.70 (m, 1H), 2.90 (s, 3H), 2.14 ‒ 1.92 (m, 6H), 1.71 ‒ 1.67 (m, 1H), 1.59 (t, J = 18.4 Hz, 3H), 1.31 ‒ 1.29 (m, 2H), 1.08 ‒ 1.05 (m, 2H) ppm. Examples 17a and 17b. (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (17a) and (R)-1-(((3-(3,3-difluorobutyl)-7- ((3,3-difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3- f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (17b) Step 1. Synthesis of 3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-8-hydroxy-2- methyl-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepine 1,1-dioxide (17-1). To a stirred mixture of 14-3 (1 g, 8.05 mmol) at -10 oC in DMF (15 mL) was added NaH (55% suspension in mineral oil) (0.502 g, 20.92 mmol) portion wise. The reaction mixture was allowed to react at this temperature for 0.5 h and then stirred at rt for 2 hr. Subsequently, the temperature was raised to 70 ºC and the reaction mixture was kept under stirring for 12 hr. Next, the reaction mixture was diluted with iced water (15 mL), acidified by sat. aq. NaHSO4 solution and extracted by EtOAc (25 mL x 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 17-1 (768 mg, 64%) as an off-white solid. Step 2. Synthesis of Methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropanecarboxylate (17-2). A mixture of 17-1 (0.245 g, 0.47 mmol), cesium carbonate (0.384 g, 1.18 mmol), and methyl 1- (bromomethyl)cyclopropanecarboxylate (0.137 g, 0.71 mmol) in DMF (2.5 mL) was stirred at 60 oC for 16 hr. Subsequently, the mixture was diluted with iced water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 17-2 (0.222 g, 75%) as an off-white solid. Step 3. Chiral separation of methyl 1-(((3-(3,3-difluorobutyl)-7-((3,3- difluorocyclobutyl)thio)-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3- f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropanecarboxylate (17-2). Compd.17-2 (170 mg) was separated by chiral HPLC to give 17-2a (77 mg) and 17-2b (79 mg) as a white solid, respectively. The stereochemistry of the single enantiomer was arbitrarily assigned. Prep-HPLC conditions: Column: CHIRALPAK IB (250 × 20 mm, 5 µm); Mobile phase: Hexane/IPA/MeOH = 70/15/15 (v/v/v); Flow Rate: 20 mL/min; Column Temperature: 24 ºC; and Wavelength: 205 nm. tR = 13.03 min (single enantiomer 17-2a); and tR = 18.59 min (single enantiomer 17-2b). Step 4a. Synthesis of (S)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17a). То а stirred solution of 17- 2a (77.3 mg, 0.12 mmol) in THF/H2O = 4/1 (v/v) (2 mL) was added lithium hydroxide hydrate (15.3 mg, 0.36 mmol), and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 N aq. HCl solution to рН ~2. The resulting mixture was purified by prep-HPLC to give Example 17a (55.1 mg, 73%) as a white solid. MS (ESI): calcd. for C27H31F4N3O5S2: 617.2; Found: 616.2 [M – 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.41 (s, 1H), 7.43 (s, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.21 – 4.14 (m, 2H), 4.10 (d, J = 16.1 Hz, 1H), 3.96 (s, 1H), 3.68 (s, 1H), 3.38 (d, J = 16.4 Hz, 3H), 2.77 (s, 3H), 2.55 (s, 1H), 2.41 (s, 1H), 2.04 – 1.89 (m, 2H), 1.75 (s, 1H), 1.68 (d, J = 8.9 Hz, 1H), 1.59 (t, J = 18.9 Hz, 3H), 1.18 (q, J = 3.9 Hz, 2H), 1.01 (q, J = 3.9 Hz, 2H) ppm. Step 4b. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-7-((3,3-difluorocyclobutyl)thio)-2- methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 17b). То а stirred solution of 17- 2b (78.9 mg, 0.12 mmol) in THF/H2O = 4/1 (v/v) (2 mL) was added lithium hydroxide hydrate (15.6 mg, 0.37 mmol) and the reaction mixture was stirred at rt for 12 hr. Subsequently, the mixture was acidified with 2 N aq. HCl solution to рН ~2. The resulting mixture was purified by HPLC to give Example 17b (53.9 mg, 71%). MS (ESI): calcd. for C27H31F4N3O5S2: 617.2; Found: 616.2 [M – 1]-.1H NMR (500 MHz, DMSO-d6): δ 12.42 (s, 1H), 7.43 (s, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.21 – 4.14 (m, 2H), 4.10 (d, J = 15.8 Hz, 1H), 3.96 (s, 1H), 3.68 (s, 1H), 3.37 (s, 3H), 2.77 (s, 3H), 2.55 (s, 1H), 2.41 (s, 1H), 2.04 – 1.93 (m, 2H), 1.75 (s, 1H), 1.68 (d, J = 5.9 Hz, 1H), 1.59 (t, J = 18.9 Hz, 3H), 1.18 (q, J = 3.8 Hz, 2H), 1.01 (q, J = 3.8 Hz, 2H) ppm. Examples 18a and 18b.1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (18a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)- 2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (18b) Step 1. Synthesis of 3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8-methoxy-7- (methylthio)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (18-1). A solution of 8-11 (900 mg, 1.76 mmol) and MeSNa (1.23 g, 17.64 mmol) in DMF (10 mL) was stirred at 60 °C for 2 hr. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL x 3), and the combined organic extracts were washed with brine (10 mL x 1), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1 (v/v)), to give 18-1 (500 mg, 59.4%) as a white solid. MS (ESI): calcd. for C21H23F4NO3S2: 477.1; Found: 478.0 [M + 1]+. Step 2. Synthesis of rac-(2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-8- hydroxy-7-(methylthio)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (18-2). A solution of 18-1 (500 mg, 1.05 mmol) and LiCl (443.85 mg, 10.47 mmol) in DMSO (5 mL) was stirred at 140 °C for 16 h. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1 (v/v)), to give 18- 2 (240 mg, 49.5%) as a white solid. MS (ESI): calcd. for C20H21F4NO3S2: 463.1; Found: 464.0 [M + 1]+. Step 3. Synthesis of rac-ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3- fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (18-3). To a stirred solution of 18-2 (80 mg, 0.17 mmol) and Cs2CO3 (224.94 mg, 0.69 mmol) in DMF (10 mL) were added KI (114.61 mg, 0.69 mmol) and ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (57.54 mg, 0.26 mmol) dropwise at rt. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to rt and then quenched with water. The resulting mixture was extracted with EtOAc (10 mL x 3), and the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 5/1 (v/v)) to give 18-3 (60 mg, 59.0%) as a white solid. MS (ESI): calcd. for C27H31F4NO5S2: 589.2; Found: 590.1 [M + 1]+. Step 4. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)- 7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (18-3a) and ethyl 1-((((2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (18-3b). Compd.18-3 (60 mg) was purified by prep-Chiral-HPLC with the following conditions Column: CHIRALPAK ID, 3*25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 35 mL/min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 15.8; RT2 (min): 20.3; Sample Solvent: EtOH-HPLC; Injection Volume: 2 mL; Number of Runs: 5. The collected fractions were concentrated to dryness to give 18-3a (19 mg) (RT2 = 20.3 min, single diastereomer, the stereochemistry was arbitrarily assigned) and 18-3b (25 mg) (RT1 = 15.8 min, single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C27H31F4NO5S2: 589.2; Found: 590.2 [M + 1]+. Step 5a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 18a). A solution of 18-3a (19 mg, 0.03 mmol) and LiOH (7.72 mg, 0.32 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 24 h at 40°C. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 4.48. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 18a (17 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H27F4NO5S2: 561.1; Found: 562.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 7.22 ‒ 7.14 (m, 2H), 6.50 ‒ 6.42 (m, 2H), 6.34 ‒ 6.30 (m, 1H), 5.58 (d, J = 45.3 Hz, 1H), 4.39 ‒ 4.32 (m, 2H), 4.16 (d, J = 15.9 Hz, 1H), 3.37 (s, 1H), 2.86 ‒ 2.72 (m, 1H), 2.41 (s, 3H), 2.23 ‒ 2.05 (m, 2H), 1.79 ‒ 1.61 (m, 5H), 1.40 ‒ 1.36 (m, 2H), 1.20 ‒ 1.17 (m, 2H) ppm. Step 5b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(3-fluorophenyl)-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 18b). A solution of methyl 18-3b (25 mg, 0.04 mmol) and LiOH (10.15 mg, 0.42 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 24 h at 40°C. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 OBD 5μm 30*150 mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% to 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 2.84. The collected solution was concentrated under vacuum to remove ACN and resulting solution was lyophilized to give Example 18b (22 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H27F4NO5S2: 561.1; Found: 562.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 7.22 - 7.14 (m, 2H), 6.50 - 6.42 (m, 2H), 6.35 - 6.29 (m, 1H), 5.58 (d, J = 45.3 Hz, 1H), 4.36 (s, 2H), 4.16 (d, J = 15.9 Hz, 1H), 3.38 (s, 1H), 2.83 - 2.72 (m, 1H), 2.41 (s, 3H), 2.23 - 2.05 (m, 2H), 1.78 - 1.61 (m, 5H), 1.40 - 1.36 (m, 2H), 1.20 - 1.17 (m, 2H) ppm.
Examples 19a and 19b.1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (19a) and 1-((((2S,3R)-3-(3,3-difluorobutyl)- 5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (19b) Step 1. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-2). To a stirred solution of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-1) (3 g, 7.53 mmol), which was readily prepared by BH3 reduction of 7-bromo-3-(3,3-difluorobutyl)-8-methoxy-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (8-7), and 4,4-difluorocyclohexan-1- one (3.03 g, 22.60 mmol) in THF (50 mL) was added PhSiH3 (2.45 g, 22.60 mmol) and Bu2SnCl2 (4.58 g, 15.06 mmol) at rt. The resulting mixture was refluxed for 24 h. The mixture was cooled to rt and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 4/1 (v/v), to give 19-2 (2.6 g, 66.8%) as a brown liquid. MS (ESI): calcd. for C20H26BrF4NO3S: 515.1; Found: 516.0 [M + 1]+. Step 2. Synthesis of 7-bromo-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-8- methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-3). In a 250 mL round bottom flask, to a solution of 19-2 (2.6 g, 5.04 mmol) in THF (20 mL) was added dropwise 1M LiHMDS in THF (10.07 mL, 10.07 mmol) at -78 oC under N2 atmosphere. The reaction mixture was stirred at -78 oC for 30 min. Then a solution of NFSI (1.59 g, 5.04 mmol) in 2 mL THF was added dropwise and the mixture was stirred for another 4 h. The reaction was quenched with sat. aq. NH4Cl solution (20 mL), and then the mixture was extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (PE/EA = 2/1 (v/v)) to give 19-3 (1 g, 37.2%) as a brown solid. MS (ESI): calcd. for C20H25BrF5NO3S: 533.1; Found: 534.0 [M + 1]+. Step 3. Synthesis of 3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-8-methoxy- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (19-4). To a stirred solution of 19-3 (650 mg, 1.22 mmol) and methyl 2,2-difluoro-2-sulfoacetate (1402.05 mg, 7.30 mmol) in DMF (10 mL) was added CuBr (872.44 mg, 6.08 mmol) in portions at rt under N2 atmosphere. The resulting mixture was stirred at 130°C for 16 hr under N2 atmosphere. The mixture was cooled to rt and then quenched by H2O (5 mL). The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 2/1 (v/v), to give 19-4 (400 mg, 62.8%) as a brown solid. MS (ESI): calcd. for C21H25F8NO3S: 523.1; Found: 524.0 [M + 1]+. Step 4. Synthesis of rac-(2R,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1- dioxide (19-5). To a stirred solution of 19-4 (350 mg, 0.67 mmol) and 1-dodecanethiol (676.63 mg, 3.35 mmol) in DMF (5 mL) was added NaOMe (180.60 mg, 3.35 mmol) at rt. The resulting mixture was stirred at 100°C for 2 h under N2 atmosphere. The mixture was cooled to rt and then quenched with H2O (5 mL). The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 2/1 (v/v), to give 19-5 (180 mg, 52.8%) as a brown solid. MS (ESI): calcd. for C20H23F8NO3S: 509.1; Found: 510.0 [M + 1]+. Step 5. Synthesis of rac-(2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1- dioxide (19-6). To a stirred solution of 19-5 (180 mg, 0.35 mmol) in THF (10 mL) was added LiHMDS (3.50 mL, 3.5 mmol) dropwise at -40°C under N2 atmosphere. The resulting mixture was stirred for 2 h at -40°C. The reaction was quenched by the addition of sat. aq. NH4Cl (100 mL) at -40°C. The resulting mixture was extracted with EA (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 2/1 (v/v), to give 19-6 (120 mg, 77.0%) as a yellow solid. MS (ESI): calcd. for C20H23F8NO3S: 509.1; Found: 510.0 [M + 1]+. Step 6. Synthesis of rac-ethyl 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7). To a stirred solution of 19-6 (65 mg, 0.19 mmol) and Cs2CO3 (125.10 mg, 0.38 mmol) in DMF (2 mL) were added KI (42.36 mg, 0.27 mmol) and ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (179.17 mg, 0.49 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 hr. The mixture was allowed to cool down to rt and quenched with H2O (5 mL). The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 4/1 (v/v)) to give 19-7 (60 mg, 75.7%) as a brown solid. MS (ESI): calcd. for C27H33F8NO5S: 635.2; Found: 636.1 [M + 1]+. Step 7. Synthesis of ethyl 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylate (19-7a) and ethyl 1-((((2S,3R)-3-(3,3- difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (19-7b). Compd.19-7 (60 mg) was purified by prep-SFC with the following condition: Column: (R, R)-WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 30% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.3; RT2 (min): 4.8; Sample Solvent: MeOH; Injection Volume: 5 mL. The collected fractions were concentrated under vacuum to give 19-7a (27 mg) (RT2 = 4.8 min, single diastereomer, stereochemistry was arbitrarily assigned) and 19-7b (26 mg) (RT1 = 3.3 min, single diastereomer, stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C27H33F8NO5S: 635.2; Found: 636.1 [M + 1]+. Step 8a. Synthesis of 1-((((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 19a). A solution of 19-7a (27 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred at rt for 16 h. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60mL/min mL/min; Gradient: 55% B to 78% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 1.88. The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 19a (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H29F8NO5S: 607.2; Found: 608.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.54 (s, 1H), 5.60 (d, J = 46.2 Hz, 1H), 4.34 – 4.27 (m, 2H), 3.54 – 3.45 (m, 1H), 3.32 – 3.31 (m, 1H), 2.85 – 2.76 (m, 1H), 2.57 – 2.34 (m, 1H), 2.15 – 1.83 (m, 9H), 1.77 – 1.56 (m, 6H), 1.34 – 1.29 (m, 2H), 1.12 – 1.08 (m, 2H) ppm. Step 8b. Synthesis of 1-((((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 19b). A solution of 19-7b (26 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60mL/min mL/min; Gradient: 55% B to 78% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 1.37. The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 19b (10 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H29F8NO5S: 607.2; Found: 608.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.54 (s, 1H), 5.60 (d, J = 46.2 Hz, 1H), 4.34 – 4.27 (m, 2H), 3.58 – 3.45 (m, 1H), 3.32 – 3.31 (m, 1H), 2.85 – 2.76 (m, 1H), 2.57 – 2.34 (m, 1H), 2.18 – 1.83 (m, 9H), 1.77 – 1.52 (m, 6H), 1.35 – 1.26 (m, 2H), 1.17 – 1.09 (m, 2H) ppm. Examples 20a and 20b.3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (20a) and 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (20b) Step 1. Synthesis of rac-ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4- difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1). To a stirred solution of the cis- racemate 19-6 (115 mg, 0.23 mmol) and Cs2CO3 (221.32 mg, 0.68 mmol) in DMF (5 mL) were added KI (112.42 mg, 0.68 mmol) and methyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (142.37 mg, 0.68 mmol) dropwise at rt. The resulting mixture was stirred for at 100°C 16 h. The mixture was cooled to rt and quenched with H2O (5 mL). The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (PE/EA = 4/1 (v/v)) to give 20-1 (65 mg, 46.2%) as a brown solid. MS (ESI): calcd. for C26H33F8NO5S: 623.2; Found: 624.1 [M + 1]+. Step 2. Synthesis of ethyl 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (20-1a) and ethyl 3-(((2S,3R)-3-(3,3-difluorobutyl)-5- (4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (20-1b). Compd.20- 1 (65 mg) was purified by prep-HPLC with the following conditions: Column: CHIRALPAK IC 3*25 cm, 5 μm; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 25 mL/min; Gradient: isocratic 20; Wavelength: 254 nm; RT1 (min): 4.3; RT2 (min): 5.9; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL; Number of Runs: 5. The collected fractions were concentrated under vacuum to give 20-1a (26 mg) (RT1 = 4.3 min, single diastereomer, the stereochemistry was arbitrarily assigned) and 20-1b (27 mg) (RT1 = 5.9 min, single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid, respectively. MS (ESI): calcd. for C26H33F8NO5S: 623.2; Found: 624.1 [M + 1]+. Step 3a. Synthesis of 3-(((2R,3S)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Example 20a). A solution of 20-1a (26 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: Xbridge Prep Shield RP18 5μm OBD 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% to 60 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 1.95. The collected fractions were concentrated under vacuum to remove ACN and the resulting solution was dried by lyophilization to give Example 20a (14 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H31F8NO5S: 609.2; Found: 610.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.5 Hz, 1 H), 4.17 (s, 2H), 3.56 ‒ 3.50 (m, 1H), 3.32 ‒ 3.18 (m, 1H), 2.88 ‒ 2.79 (m, 1H), 2.60 ‒ 2.35(m, 1H), 2.47 ‒ 1.80 (m, 9H), 1.80 ‒ 1.55(m, 6H), 1.35 (s, 6H) ppm. Step 3b. Synthesis of 3-(((2S,3R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Example 20b). A solution of 20-1b (27 mg, 0.04 mmol) and LiOH (3.20 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was stirred for 16 h at rt. The mixture was acidified to pH = 4 with 2 N aq. HCl solution. The resulting mixture was extracted with EA (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue (30 mg) was purified by prep-HPLC with the following conditions: Column: Xbridge Prep Shield RP18 5μm OBD 30*150mm Column; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40 % to 60 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 1.72. The collected fractions were concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 20b (13 mg) (single diastereomer, the stereochemistry was arbitrarily assigned) as a white solid. MS (ESI): calcd. for C25H31F8NO5S: 609.2; Found: 610.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.67 (s, 1H), 7.58 (s, 1H), 5.64 (d, J = 46.2 Hz, 1 H), 4.17 (s, 2H), 3.56 ‒ 3.50 (m, 1H), 3.34 ‒ 3.30 (m, 1H), 2.88 ‒ 2.79 (m, 1H), 2.60 ‒ 2.35(m, 1H), 2.47 ‒ 1.80 (m, 9H), 1.80 ‒ 1.55(m, 6H), 1.35 (s, 6H) ppm. Example 21. (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl-1,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid Step 1. Synthesis of (R)-2-bromo-N-(1-((4,4-difluorocyclohexyl)amino)-5,5- difluorohexan-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (21-2). To a stirred solution of (R)-N1-(4,4-difluorocyclohexyl)-5,5-difluorohexane-1,2-diamine (21-1) (500 mg, 1.85 mmol), which was prepared by following the same procedure of 1-7 and replacing aniline with 4,4-difluorocyclohexylamine, and TEA (374 mg, 3.7 mmol) in THF (6 mL) was added a solution of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (781 mg, 2.22 mmol) in THF (2 mL) at 0°C. The resulting reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (30 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA/PE) to give 21-2 (60 mg, 55.3%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C20H26BrF7N2O3S: 586.1; Found: 587.2 [M + 1]+. Step 2. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-3). To a stirred solution of 21-2 (600 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) in DMF (5 mL) was added CuI (190 mg, 1.0 mmol) and the mixture was heated at 100 °C for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl solution (15 mL) and the aqueous layer was extracted with EA (20 mL x 3). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 21-3 (450 mg) as a yellow oil, which was used in the next step without further purification. TLC: 15% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C20H25F7N2O3S: 506.1; Found: 507.2 [M + 1]+. Step 3. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-methoxy-2- methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-4). To a stirred solution of 21-3 (450 mg, crude product, 0.89 mmol) and Cs2CO3 (580 mg, 1.78 mmol) in NMP (5 mL) was added MeI (379 mg, 2.67 mmol) and the reaction was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 21-4 (300 mg, 56%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C21H27F7N2O3S: 520.2; Found: 521.2 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-8-hydroxy-2- methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (21-5). To a stirred solution of 21-4 (300 mg, 0.58 mmol) in DMF (3 mL) was added CH3SNa (203 mg, 2.9 mmol) and the reaction was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction was quenched with ice water (12 mL) and the aqueous layer was extracted with EA (15 mL x 3). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 21-5 (150 mg, 51%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.6). MS (ESI): calcd. for C20H25F7N2O3S: 506.1; Found: 507.2 [M + 1]+. Step 5. Synthesis of ethyl (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2,2-dimethylpropanoate (21-6). To a stirred solution of 21-5 (150 mg, 0.30 mmol) and Cs2CO3 (293 mg, 0.9 mmol) in DMF (2 mL) was added ethyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (134 mg, 0.6 mmol). The reaction was heated at 100 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic layer was washed with water (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 21-6 (70 mg, 37%) as a white solid. TLC: 40% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C27H37F7N2O5S: 634.2; Found: 635.2 [M + 1]+. Step 6. Synthesis of (R)-3-((3-(3,3-difluorobutyl)-5-(4,4-difluorocyclohexyl)-2-methyl- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (Example 21). To a stirred solution of 21-6 (40 mg, 0.064) in MeOH/THF/H2O (1 mL/1 mL/0.5 mL) was added LiOH.H2O (14.3 mg, 0.34 mmol) and the reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 21 (20 mg, 53%) as a white solid. MS (ESI): calcd. for C25H33F7N2O5S: 606.2; Found: 607.3 [M + 1]+ .1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.26 (s, 1H), 4.09 – 4.03 (m, 2H), 3.41 (s, 2H), 3.16 (s, 2H), 2.61 (s, 2H), 2.17 (m, J = 40.2 Hz, 4H), 2.06 – 1.77 (m, 6H), 1.65 (t, J = 30.1 Hz, 5H), 1.32 (d, J = 2.1 Hz, 6H) ppm. Example 22. (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid Step 1. Synthesis of (R)-2-bromo-N-(1-(cyclopentylamino)-5,5-difluorohexan-2-yl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (22-2). To a stirred solution of (R)-N1- cyclopentyl-5,5-difluorohexane-1,2-diamine (22-1) (1.0 g, 4.5 mmol), which was prepared by following the same procedure of 1-7 and replacing aniline with cyclopentamine, and TEA (1.4 g, 13.5 mmol) in THF (10 mL) was added a solution of 2-bromo-5-methoxy-4- (trifluoromethyl)benzenesulfonyl chloride (1.9 g, 5.4 mmol) in THF (10 mL) at 0°C. The resulting reaction mixture was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (40 mL) and the aqueous layer was extracted with EA (40 mL x 3). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA/PE (v/v)) to give 22-2 (1.05 g, 49%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C19H26BrF5N2O3S: 536.1; Found: 537.2 [M + 1]+. Step 2. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-3). To a stirred solution of 22-2 (1.05 g, 2.0 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (15 mL) was added Cu (640 mg, 10.0 mmol) and heated at 115 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl (30 mL) solution, and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 22-3 (1.0 g) as a yellow oil, which was used in the next step without further purification. TLC: 15% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C19H25F5N2O3S: 456.2; Found: 457.3 [M + 1]+. Step 3. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-methoxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-4). To a stirred solution of 22-3 (1.0 g, crude product, 2.0 mmol) and Cs2CO3 (2.0 g, 6.0 mmol) in NMP (20 mL) was added MeI (852 mg, 6.0 mmol) and the reaction mixture was stirred at rt for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water (50 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 22-4 (500 mg, 53%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.4). MS (ESI): calcd. for C20H27F5N2O3S: 470.2; Found: 471.3 [M + 1]+. Step 4. Synthesis of (R)-5-cyclopentyl-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (22-5). To a stirred solution of 22-4 (500 mg, 1.06 mmol) in DMF (10 mL) was added CH3SNa (382 mg, 5.30 mmol) and the reaction mixture was heated at 95 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water (20 mL) and the aqueous layer was extracted with EA (30 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 22-5 (620 mg, 64%) as a yellow solid. TLC: 30% EA/PE (v/v) (Rf: 0.6). MS (ESI): calcd. for C19H25F5N2O3S: 456.2; Found: 457.3 [M + 1]+. Step 5. Synthesis of ethyl (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (22-6). To a stirred solution of 22-5 (150 mg, 0.33 mmol) and Cs2CO3 (323 mg, 0.99 mmol) in DMF (2 mL) was added ethyl 2,2-dimethyl-3- ((methylsulfonyl)oxy)propanoate (148 mg, 0.66 mmol). The reaction was heated at 100 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic extracts were washed with water (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 22-6 (60 mg, 31%) as a white solid. TLC: 40% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for
C26H37F5N2O5S: 584.2; Found: 585.2 [M + 1]+. Step 6. Synthesis of (R)-3-((5-cyclopentyl-3-(3,3-difluorobutyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 22). To a stirred solution of 22-6 (40 mg, 0.068) in MeOH/THF/H2O (1 mL/1 mL/0.5 mL) was added LiOH.H2O (14.3 mg, 0.34 mmol) and the reaction was stirred at rt for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was neutralized with 1 N aq. HCl solution. The aqueous layer was extracted with EA (10 mL x 3), and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 22 (26 mg, 68%) as a white solid. MS (ESI): calcd. for C24H33F5N2O5S: 556.2; Found: 557.3 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.27 (s, 1H), 4.06 (dd, J = 16.5, 8.1 Hz, 2H), 3.86 (dd, J = 22.4, 15.2 Hz, 1H), 3.16 (s, 1H), 2.64 (s, 4H), 1.96 (ddd, J = 29.2, 26.0, 22.5 Hz, 5H), 1.84 – 1.42 (m, 10H), 1.32 (t, J = 23.8 Hz, 6H) ppm. Example 23.1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-2- methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid
Step 1. Synthesis of (3aR,6aS)-5,5-difluorohexahydropentalen-2(1H)-one (23-2). To a stirred solution of (3aS,6aS)-tetrahydropentalene-2,5(1H,3H)-dione (23-1) (13.8 g, 0.1 mol) in DCM (200 mL) was added DAST (48.3 g, 0.3 mol) in small portions at 0°C. After stirring at rt for 16 h, the reaction mixture was diluted with saturated aq. NaHCO3 (200 ml). The reaction was extracted with EA (150 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 3/1 (v/v), to give 23-2 (8.0 g, 50%) as a colorless oil. TLC: 20% EA/ PE (Rf: 0.4). MS (ESI): calcd. for C8H10F2O: 160.1; Found: 160.2 [M+H] +. Step 2. Synthesis of 5,5-difluorooctahydropentalen-2-ol (23-3). To a solution of 23-2 (3.16 g, 19.8 mmol) in MeOH (30 ml) was added NaBH4 (1.55 g, 40 mmol) in an ice bath. The reaction was stirred for 2 h at room temperature. The reaction was monitored by TLC. The starting material disappeared and a new spot was detected. The reaction mixture was poured into water (50 mL) and extracted with EA (70 mL x 3). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, concentrated. The residue was dried in vacuo to give crude 23-3 (2.95 g, 92%) as a colorless oil, which was used for the next step without further purification. TLC: 25% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C8H12F2O: 162.1; Found: 162.2 [M+H] +. Step 3. Synthesis of 2-(5,5-difluorooctahydropentalen-2-yl)isoindoline-1,3-dione (23-4). To a solution of 23-3 (2.95 g, 18.2 mmol), isoindoline-1,3-dione (3.21 g, 21.9 mmol), and PPh3 (6.17 g, 27.3 mmol) in THF (100 ml) was added DIAD (6.62 g, 32.8 mmol) in an ice bath. The reaction was stirred at rt for 6 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 23-4 (3.8 g, 72%) as a white solid. TLC: 15% EA/ PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C16H15F2NO2: 291.1; Found: 292.3 [M+H]+. Step 4. Synthesis of 5,5-difluorooctahydropentalen-2-amine (23-5). To a solution of 23-4 (3.8 g, 13.1 mmol) in MeOH (30 ml) was added NH2NH2 (4.1 g, 65.3 mmol). The reaction was stirred at 60oC for 5 h. The mixture was filtered and solid was washed with MeOH (20 mL). The filtrate was concentrated. The residue was diluted with Et2O (100 ml) and filtered. The filtrate was acidified with 4N HCl in dioxane (20 mL). After stirring for 30 min, the solution was concentrated in vacuo to give a crude product, which was mixed with ACN (40 mL). The solid was collected and dried in vacuo to give 23-5 (1.5 g, 58%) as a pale-yellow solid, which was used in the next step without further purification. TLC: 15% MeOH/ DCM (v/v) (Rf: 0.3). MS (ESI): calcd. for C8H13F2N: 161.1; Found: 162.2 [M+H]+. Step 5. Synthesis of tert-butyl ((2R)-1-((5,5-difluorooctahydropentalen-2-yl)amino)-5,5- difluoro -1-oxohexan-2-yl)carbamate (23-6). To a solution of (R)-2-((tert- butoxycarbonyl)amino)-5,5-difluorohexanoic acid (1.2 g, 4.49 mmol) in DMF (15.0 ml) was added DIEA (2.0 g, 15.7 mmol) and HATU (2.56 g, 6.74 mmol) in an ice bath. After stirring for 30 min, 23-5 (885 mg, 4.49 mmol) was added. The reaction was stirred at rt for 16 h. The reaction mixture was quenched with H2O (30 ml) and extracted with EA (40 mL x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (35% EA/PE (v/v)) to give 23- 6 (1.2 g, 65%) as a colorless oil. TLC: 35% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C19H30F4N2O3: 410.2; Found: 355.2 [M + H - 56]+. Step 6. Synthesis of (2R)-2-amino-N-(5,5-difluorooctahydropentalen-2-yl)-5,5- difluorohexanamide (23-7). To a solution of 23-6 (370 mg, 0.90 mmol) in DCM (9.0 ml) was added TFA (3.0 ml) in an ice bath. The reaction mixture was stirred at rt for 2 hr and concentrated. The residue was diluted with saturated aq. NaHCO3 solution and extracted with DCM (30 mL x 3). The combined organic extracts were dried over Na2SO4 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): calcd. for C14H22F4N2O: 310.2; Found: 311.2 [M+H] +. Step 7. Synthesis of (2R)-N1-(5,5-difluorooctahydropentalen-2-yl)-5,5-difluorohexane- 1,2-diamine (23-8). To a solution of 23-7 (260 mg, 0.84 mmol) in THF (6 ml) was added LAH (2.5 M in THF, 1.7 ml) in an ice bath. The reaction mixture was stirred at 60 oC for 16 hr and cooled to 0 oC. The reaction mixture was quenched with H2O (160 mg), followed by 10% aq. NaOH solution (w/w) (160 mg) and Et2O (50 mL). The resulting mixture was dried over anhydrous Na2SO4 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) (Rf: 0.3). MS (ESI): calcd. for C14H24F4N2: 296.2; Found: 297.1 [M+H]+. Step 8. Synthesis of 2-bromo-N-((2R)-1-((5,5-difluorooctahydropentalen-2-yl)amino)- 5,5-difluorohexan-2-yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (23-9). To a solution of 23-8 (250 mg, 1.06 mmol) in DCM (3.0 ml) and TEA (375 mg, 3.71 mmol) was added sulfonyl chloride (373 mg, 1.06 mmol) in an ice bath. The reaction was stirred at rt for 16 hr. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (10 ml x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue which was purified by silica gel column chromatography (50% EA/PE (v/v)) to give 23-9 (400 mg, 62%) as a yellow oil. TLC: 50% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C22H28BrF7N2O3S: 612.1; Found: 613.2 [M+H]+. Step 9. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)-8- methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-10). To a solution of 23-9 (100 mg, 0.16 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (2.0 ml) was added Cu (21 mg, 0.32 mmol) under nitrogen atmosphere. The reaction was stirred at 120 oC for 16 hr. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (20 mL x 2). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was dried in vacuo to give crude 23-10 (100 mg) as a yellow oil, which was used in the next step without further purification. TLC: 35% EA/ PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C22H27F7N2O3S: 532.2; Found: 533.3 [M+H] +. Step 10. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)- 8-methoxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-11). To a stirred solution of 23-10 (1.3 g, 2.44 mmol) and K2CO3 (507 mg, 3.66 mmol) in NMP (13 mL) was added MeI (0.46 mL, 7.32 mmol) in portions at 0°C. After stirring at rt for 2 hr, the reaction mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EA (30 mL x 2), and the combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 3/1 (v/v), to give 23-11 (692 mg, 52%) as a colorless oil. TLC: 33% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C23H29F7N2O3S: 546.2; Found: 546.7 [M+H] +. Step 11. Synthesis of (3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2-yl)- 8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (23-12). To a solution of 23-11 (40 mg, 0.073 mmol) in DMF (0.5 ml) was added MeSNa (21 mg, 0.292 mmol), and the reaction was stirred at 100°C for 16 hr. The reaction mixture was diluted with sat aq. NH4Cl solution (10 mL), acidified to pH = 5~6 with 4 N aq. HCl solution, and extracted with EA (10 mL x 2). The combined organic extracts were washed with sat. aq. LiCl solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (60% EA/PE (v/v)) to give 23-12 (33 mg, 87%) as a colorless oil. TLC: 40% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C22H27F7N2O3S: 532.2; Found: 532.8 [M+H] + Step 12. Synthesis of ethyl 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5- difluorooctahydropentalen-2-yl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (23- 13). To a solution of 23-12 (113 mg, 0.205 mmol) and Cs2CO3 (200 mg, 0.615 mmol) in DMF (1 ml) was added ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (82 mg, 0.369 mmol) at rt, and the reaction mixture was stirred at 70°C for 5 hr. Subsequently, the mixture was diluted with water (5 mL) and extracted with EA (10 mL x 2). The combined organic extracts were washed with sat. aq. LiCl solution (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA/PE (v/v)) to give 23-13 (96 mg, 71%) as a white solid. TLC: 40% EA/PE (v/v) (Rf: 0.5). MS (ESI): calcd. for C29H37F7N2O5S: 658.2; Found: 659.0 [M+H]+.1H NMR (400 MHz, CD3OD): δ 7.51 (s, 1H), 7.40 (s, 1H), 4.25 (s, 2H), 4.13 (q, J = 7.1 Hz, 3H), 3.98 ‒ 3.56 (m, 1H), 3.44 ‒ 3.34 (m, 1H), 2.90 ‒ 2.49 (m, 5H), 2.39-2.16 (m, 2H), 2.17 ‒ 1.69 (m, 10H), 1.62 (t, J = 18.5 Hz, 4H), 1.30 (dd, J = 7.1, 4.2 Hz, 2H), 1.24 ‒ 1.13 (m, 3H), 1.09 (dd, J = 7.1, 4.1 Hz, 2H) ppm. Step 13. Synthesis of 1-((((3R)-3-(3,3-difluorobutyl)-5-(5,5-difluorooctahydropentalen-2- yl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 23). To a solution of 23-13 (20 mg, 0.030 mmol) in MeOH/THF/H2O (0.75 mL, v/v/v = 1/2/2) was added NaOH (12 mg, 0.303 mmol), and the reaction was stirred at rt for 3 hr. After completion of the reaction, the reaction mixture solution was diluted with water (5 ml), acidified to pH = 6~7 with 3N aq. HCl solution, and extracted with EA (10 mL x 2). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 23 (10.6 mg, 56%) as a white solid. TLC: 10% MeOH/DCM (v/v) (Rf: 0.5). MS (ESI): calcd. for C27H33F7N2O5S: 630.2, Found: 631.2 [M+H] +.1H NMR (400 MHz, CD3OD): δ 7.51 (s, 1H), 7.40 (s, 1H), 4.25 (dd, J = 20.4, 9.6 Hz,2H), 4.13 (s, 1H), 4.05 ‒ 3.64 (m, 1H), 3.44 ‒ 3.34 (m, 1H), 2.88 ‒ 2.43 (m, 5H), 2.38 ‒ 2.19 (m, 2H), 2.17 ‒ 1.69 (m, 10H), 1.62 (t, J = 18.5 Hz, 4H), 1.30 (dd, J = 6.6, 3.9 Hz, 2H), 1.08 (d, J = 2.6 Hz, 2H) ppm. Examples 24a and 24b. (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (24a) and (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl- 1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (24b)
Step 1. Synthesis of tert-butyl 2-cyclopropylacetate (24-2). To a solution of 5 g (50 mmol) of cyclopropylacetic acid (24-1) in 25 ml of dichloromethane at 0 oC was added a drop of DMF, followed by 6.99 g (55 mmol) of oxalyl chloride dropwise. The reaction mixture was stirred between 0°C and 10°C for 2 h and then concentrated under reduced pressure. The residue was briefly (about 5 min) dried under high vacuum and then taken up in dry THF (10 mL), and the resulting mixture was cooled to 0°C. Subsequently, 1 M potassium tert-butoxide in THF (45 mL, 45 mmol) was added dropwise, and the mixture was stirred at rt for 2 hr and then concentrated. The residue was added diethyl ether and 0.5 N aq. NaOH solution. The organic layer was dried over anhydrous 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. Step 2. Synthesis of tert-butyl 3-(benzyloxy)-2-cyclopropylpropanoate (24-3). Compd. 24-2 (4 g, 25.6 mmol) in 30 mL of THF was added HMPA (1.38 g, 76.8 mmol) and LDA (38.4 mL, 76.8 mmoL, 2.0 mol/L in THF/n-heptane) at -78 oC. After the solution was stirred at -78 oC for 20 min, a solution of ((chloromethoxy)methyl)benzene (6 g, 38.4 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78 oC for 2 h and then warmed to rt. After stirring at rt for 5 hr, the reaction mixture was quenched with sat. aq. NH4Cl solution (10 mL) and concentrated. The residue was diluted with DCM and washed with water. The organic layer was dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 24-3 (1.8 g, 26%). Step 3. Synthesis of tert-butyl 2-cyclopropyl-3-hydroxypropanoate (24-4). A mixture of 24-3 (1 g, 3.6 mmol) and 10% Pd/C (200 mg) in MeOH (20 mL) was stirred at rt under an atmosphere of H2 overnight. The mixture was filtered, and the residue was dried in vacuo to give crude 24-4 (450 mg, 67%), which was used in the next step without further purification. Step 4. Synthesis of tert-butyl 2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoate (24-5). To a solution of (R)-3-(3,3-difluorobutyl)-8-hydroxy-2-methyl-5- phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (1-11) (374 mg, 0.81 mmol) in toluene (4 mL) was added triphenylphosphine (637 mg, 2.43 mmol) and 24-4 (450 mg, 2.42 mmol). The solution was warmed to 110 oC and then DIAD (4.9 g, 24.2) was added. After stirring at 110 oC for 4 hr, the reaction mixture was cooled to rt and diluted with EA (20 mL). The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 24-5 (130 mg, 15%) as a pale-yellow solid. MS (ESI): calcd. for C30H37F5N2O5S: 632.2; Found: 633.2 [M + 1]+. Step 5. Synthesis of tert-butyl (R)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl- 1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin- 8-yl)oxy)propanoate (24-5a) and tert-butyl (S)-2-cyclopropyl-3-(((R)-3-(3,3- difluorobutyl)-2-methyl-1,1-dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)propanoate (24-5b). Compd.24-5 was separated by chiral SFC to give 24-5a and 24-5b as a white solid, respectively. The stereochemistry of the 2-cyclopropyl-3-hydroxypropanoic acid moiety was arbitrarily assigned. MS (ESI): calcd. for C30H37F5N2O5S: 632.2; Found: 633.2 [M + 1]+. Step 6a. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (Example 24a). A mixture of 24-5a (80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 ml) dropwise at rt. After stirring at rt for 5 hr, the mixture was concentrated and the residue was purified by prep-HPLC to give Example 24a (35 mg, 48%). MS (ESI): calcd. for C26H29F5N2O5S: 576.2; Found: 577.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.62 (s,1H), 7.56 (s, 1H), 7.19 (t, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.75 ‒ 6.66 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.17 ‒ 4.13 (m, 1H), 3.85 ‒ 3.81 (m, 1H), 3.57 ‒ 3.52 (m, 1H), 2.62 (s, 3H), 2.13 ‒ 1.99 (m, 3H), 1.95 ‒ 1.84 (m, 1H), 1.70 ‒ 1.60 (m, 4H), 1.00 ‒ 0.70 (m, 1H), 0.65 ‒ 0.48 (m, 2H), 0.46 ‒ 0.43 (m, 2H) ppm. Step 6b. Synthesis of (S)-2-cyclopropyl-3-(((R)-3-(3,3-difluorobutyl)-2-methyl-1,1- dioxido-5-phenyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)propanoic acid (Example 24a). Following the same procedure for preparing Example 24a by replacing 24-5a with 24-5b (78 mg, 0.13 mmol), Example 24b (33 mg, 48%) was obtained as a white solid. MS (ESI): calcd. for C26H29F5N2O5S: 576.2; Found: 577.2 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 7.62 (s,1H), 7.56 (s, 1H), 7.19 (t, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.75 ‒ 6.66 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.17 ‒ 4.13 (m, 1H), 3.85 ‒ 3.81 (m, 1H), 3.57 ‒ 3.52 (m, 1H), 2.62 (s, 3H), 2.13 ‒ 1.99 (m, 3H), 1.95 ‒ 1.84 (m, 1H), 1.70 ‒ 1.60 (m, 4H), 1.00 ‒ 0.70 (m, 1H), 0.65 ‒ 0.48 (m, 2H), 0.46 ‒ 0.43 (m, 2H) ppm. Example 25. (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-2- methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2- methylpropanoic acid Step 1. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-7- vinyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-2). (R)-7-bromo-3- (3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-1) (400 mg, 0.79 mmol), which was readily prepared by following the procedure for preparing 1-10 by replacing aniline with 4- fluoroaniline and 2-bromo-4-trifluoromethyl-5-methyoxybenzene sulfonyl chloride with 2,4- dibromo-5-methyoxybenzene sulfonyl chloride, in dioxane (4 mL) was added Pd(dppf)Cl2 (57 mg, 0.079 mmol), Na2CO3 (251 mg, 2.37 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (365 mg, 2.37 mmol) at rt under N2. The mixture was stirred at 100 oC overnight, diluted with water (15 mL) at rt, and extracted with EA (15 mL x 3). The organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 25-2 (300 mg, 84%) as a pale-yellow solid. MS (ESI): calcd. for C22H25F3N2O3S: 454.2; Found: 455.2 [M + 1]+. Step 2. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-methoxy-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-7-carbaldehyde 1,1-dioxide (25-3). To a mixture of 25-2 (300 mg, 0.66 mmol) in dioxane/H2O (4/1 (v/v), 6 mL) were added osmium tetraoxide (2.5% wt in t-BuOH, 336 mg, 0.033 mmol) and sodium periodate (570 mg, 2.64 mmol) at rt. After stirring at rt for 3 hr, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined extracts were dried with anhydrous Na2SO4 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): calcd. for C21H23F3N2O4S: 456.1; Found: 457.2 [M + 1]+. Step 3. Synthesis of (R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-8- methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-4). To a solution of 25-3 (220 mg, 0.48 mmol) in DCM (3 mL) was added DAST (387 mg, 2.4 mmol) at rt. After stirring at rt for 2 days, the reaction mixture was poured into sat. aq. NaHCO3 solution (20 mL). The resulting mixture was extracted with DCM (15 mL x 3), and the combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 25-4 (180 mg, 78%) as a brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C21H23F5N2O3S: 478.1; Found: 479.1 [M + 1]+. Step 4. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-8-hydroxy-2-methyl- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine-7-carbaldehyde 1,1-dioxide (25-5). Compd.25-4 (180 mg, 0.31 mmol) was added to a solution of NaSMe in DMF (100 mg/mL, 1.08 mL) at rt. After stirring at 100 oC for 3 hr, the reaction mixture was diluted with water (10 mL) at rt and then extracted with EA (15 mL x 2). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 25-5 (150 mg, 85%) as a pale-yellow solid. MS (ESI): calcd. for C20H21F3N2O4S: 442.1; Found: 443.1 [M + 1]+. Step 5. Synthesis of (R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4-fluorophenyl)-8- hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (25-6). To a mixture of 25-5 (130 mg, 0.29 mmol) in DCM (3 mL) was added DAST (387 mg, 2.4 mmol) at rt. After stirring at rt for 2 days, the reaction mixture was poured into sat. aq. NaHCO3 solution (20 mL), and the resulting mixture was extracted with DCM (15 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 25-6 (130 mg) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H21F5N2O3S 464.1; Found: 465.1 [M + 1]+. Step 6. Synthesis of methyl (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4- fluorophenyl)-2-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoate (25-7). A solution of 25-6 (130 mg, 0.28 mmol) in toluene (1.5 mL) was added methyl (R)-3-hydroxy-2-methylpropanoate (165 mg, 1.4 mmol) and triphenylphosphine (221 mg, 0.84 mmol) at rt. After the solution was warmed to 110 oC, DIAD (565 mg, 2.8 mmol) was added, and the resulting reaction mixture was stirred at 110 oC for 5 hr. Subsequently, the mixture was concentrated, and the residue was purified by silica gel column chromatography using EA/PE as eluent to give 25-7 (130 mg, 82%) as a pale-yellow solid. MS (ESI): calcd. for C25H29F5N2O5S :564.2; Found: 565.1 [M + 1]+. Step 7. Synthesis of (R)-3-(((R)-3-(3,3-difluorobutyl)-7-(difluoromethyl)-5-(4- fluorophenyl)-2-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2-methylpropanoic acid (Example 25). To a solution of 25-7 (130 mg, 0.23 mmol) in THF/H2O (4:1 (v/v), 5 ml) was added LiOH.H2O (97 mg, 2.3 mmol) at rt. After stirring at rt overnight, the reaction mixture was adjusted to pH = 2~3 with 10% aqueous HCl solution. The resulting mixture was extracted with EA (10 mL x 2), and the combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by pre-HPLC to give Example 25 (8 mg, 6.3%) as a white solid. MS (ESI): calcd. for C24H27F5N2O5S: 550.2; Found: 551.2 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 6.8 Hz, 1H), 7.37 (s, 1H), 6.94 (t, J = 8.6 Hz, 2H), 6.81 (s, 1H), 6.69 (d, J = 11.7 Hz, 2H), 4.36 – 4.25 (m, 1H), 4.21 (dd, J = 8.8, 5.3 Hz, 1H), 3.95 (d, J = 15.6 Hz, 2H), 3.41 (s, 1H), 3.06 (dd, J = 12.4, 6.9 Hz, 1H), 2.64 (s, 3H), 2.14 – 1.71 (m, 11H), 1.61 (t, J = 18.4 Hz, 5H), 1.37 (d, J = 7.2 Hz, 4H) ppm. Example 26. (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)-2-methyl-7- (methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid
Step 1. Synthesis of methyl 4-fluorobicyclo[2.2.2]octane-1-carboxylate (26-2). Into a 250 mL 3-necked round-bottom flask were added 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1- carboxylic acid (26-1) (10 g, 47.12 mmol), water (100 mL), and Selectfluor (33.38 g, 94.23 mmol) at rt. The resulting mixture was stirred at 70°C for 24 hr under nitrogen atmosphere. The mixture was cooled to rt and acidified to pH = 5 with sat. aq. citric acid solution. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-2 (8 g, 91.2%) as a white solid, which was used in the next step without further purification. MS (ESI): calcd. for C10H15FO2: 186.1; Found: 187.1 [M + 1]+. Step 2. Synthesis of 4-fluorobicyclo[2.2.2]octane-1-carboxylic acid (26-3). Into a 250 mL round-bottom flask were added 26-2 (8 g, 42.96 mmol), THF (80 mL), water (10 mL), and LiOH (3.09 g, 128.87 mmol) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The mixture was acidified to pH = 5 with 2 N aq. HCl solution and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-3 (7 g, 94.6%) as a colorless oil, which was used in the next step without further purification. MS (ESI): calcd. for C9H13FO2: 172.1; Found: 173.1 [M + 1]+. Step 3. Synthesis of tert-butyl N-{4-fluorobicyclo[2.2.2]octan-1-yl}carbamate (26-4). Into a 250 mL round-bottom flask were added 26-3 (7 g, 40.65 mmol), 2-methyl-2-propanol (70 mL), DPPA (16.78 g, 60.98 mmol), and TEA (12.34 g, 121.95 mmol) at rt. The resulting mixture was stirred at 85 °C for 24 hr under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (100 mL), and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-4 (9 g, 91.0%) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C13H22FNO2: 243.2; Found: 244.3 [M + 1]+. Step 4. Synthesis of 4-fluorobicyclo[2.2.2]octan-1-amine (26-5). Into a 250 mL round- bottom flask were added 26-4 (9 g, 36.99 mmol) and HCl (gas) in dioxane (4 M, 90 mL) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The resulting mixture was diluted with water (90 mL), basified to pH = 8 with sat. aq. NaHCO3, and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 26-5 (5 g, 94.40%) as a white solid, which was used in the next step without further purification. MS (ESI): calcd. for C8H14FN: 143.1; Found: 144.2 [M + 1]+. Step 5. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (26-7). Into a 500 mL 3-necked round-bottom flask were added 1-(tert-butyl) 2-methyl (R)-5- oxopyrrolidine-1,2-dicarboxylate (30 g, 123.33 mmol), THF (300 mL), and 3 M MeMgBr solution in diethyl ether (17.65 g, 147.99 mmol) at -55°C. The resulting mixture was stirred at -20°C for 18 hr under nitrogen atmosphere. The reaction was quenched with sat. aq. NH4Cl at 0 °C and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1 (v/v)), to give 26-7 (20 g, 62.5%) as a colorless oil. MS (ESI): calcd. for: C12H21NO5: 259.1; Found: 331.1 [M + Na + ACN]+. Step 6. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (26-8). Into a 500 mL 3-necked round-bottom flask were added 26-7 (20 g, 77.13 mmol), DCM (200 mL), and DAST (37.30 g, 231.39 mmol) at 0°C. The resulting mixture was stirred at rt for 12 h under nitrogen atmosphere. The reaction was quenched with sat. aq. NaHCO3 at 0°C and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (8/1 (v/v)), to give 26-8 (2.8 g, 12.9%) as a colorless oil. MS (ESI): calcd. for: C12H21F2NO4: 281.1; Found: 282.1 [M + 1]+. Step 7. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoic acid (26- 9). Into a 100 mL 3-necked round-bottom flask were added 26-8 (2.8 g, 9.95 mmol), THF (30 mL), water (7.5 mL), and LiOH (0.72 g, 29.86 mmol) at rt. The resulting mixture was stirred at rt for 24 hr under nitrogen atmosphere. The mixture was acidified to pH = 5 with 1 N aq. HCl solution and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-9 (2.5 g) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C11H19F2NO4: 267.1; Found: 253.1 [M – Boc +1]+. Step 8. Synthesis of tert-butyl (R)-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octan-1- yl)amino)-1-oxohexan-2-yl)carbamate (26-10). Into a 50 mL 3-necked round-bottom flask were added 26-9 (2.5 g, 9.35 mmol), DMF (25 mL), HATU (4.27 g, 11.22 mmol), DIEA (1.81 g, 14.03 mmol), and 26-5 (1.61 g, 11.22 mmol) at rt. The resulting mixture was stirred at rt for 4 hr under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-10 (2.3 g, 62.6%) as a brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C19H31F3N2O3: 392.2; Found: 393.2 [M + 1]+. Ste®. Synthesis of (R)-2-amino-5,5-difluoro-N-(4-fluorobicyclo[2.2.2]octan-1- yl)hexanamide (26-11). Into a 100 mL round-bottom flask were added 26-10 (2.3 g, 5.86 mmol) and HCl in EtOAc (2 M, 25 mL) at rt. The resulting mixture was stirred at rt for 16 hr under nitrogen atmosphere. The mixture was basified to pH = 8 with saturated aq. NaHCO3 solution. The resulting mixture was extracted with EtOAc (25 mL x 2). The combined organic extracts were washed with brine (25 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 26-11 (1.6 g, 93.4%) as a light brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C14H23F3N2O: 292.2; Found: 293.2 [M + 1]+. Step 10. Synthesis of (R)-2-((2,4-dibromo-5-methoxyphenyl)sulfonamido)-5,5-difluoro- N-(4-fluorobicyclo[2.2.2]octan-1-yl)hexanamide (26-12). Into a 50 mL round-bottom flask were added 26-11 (1.8 g, 6.16 mmol), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (2.69 g, 7.39 mmol), THF (18 mL), and TEA (1.87 g, 18.47 mmol) at rt. The resulting mixture was stirred at rt for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and concentrated to remove organic solvent. The resulting mixture was extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1 (v/v)) to give 26-12 (1.5 g, 39.3%) as a yellow solid. MS (ESI): calcd. for C21H27Br2F3N2O4S: 618.0; Found: 618.9 [M + 1]+. Step 11. Synthesis of (R)-2,4-dibromo-N-(5,5-difluoro-1-((4-fluorobicyclo[2.2.2]octan-1- yl)amino)hexan-2-yl)-5-methoxybenzenesulfonamide (26-13). Into a 50 mL round-bottom flask were added 26-12 (1.5 g, 2.42 mmol), THF (30 mL), and BH3•Me2S (0.75 mL, 7.91 mmol) at rt. The resulting mixture was stirred at 75°C for 16 h under nitrogen atmosphere. The reaction was quenched with MeOH at 0°C. The resulting mixture was stirred at 75°C for 2 h. The mixture was cooled to rt and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1 (v/v)), to give 26-13 (1.0 g, 68.2%) as a brown solid. MS (ESI): calcd. for C21H29Br2F3N2O3S: 604.0; Found: 605.0 [M + 1]+. Step 12. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1- yl)-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26-14). Into a 40 mL vial were added 26-13 (1.0 g, 1.65 mmol), DMSO (10 mL), K2CO3 (0.69 g, 4.947 mmol), and CuI (0.16 g, 0.83 mmol) at rt. The resulting mixture was stirred at 130°C for 16 h under nitrogen atmosphere. The mixture was cooled to rt and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1 (v/v)) to give 26-14 (200 mg, 23.1%) as a brown solid. MS (ESI): calcd. for C21H28BrF3N2O3S: 524.1; Found: 525.1 [M + 1]+. Step 13. Synthesis of (R)-7-bromo-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1- yl)-8-methoxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (26- 15). Into an 8 mL vial were added 26-14 (200 mg, 0.38 mmol), DMF (2 mL), Cs2CO3 (373.21 mg, 1.14 mmol), and MeI (64.83 mg, 0.46 mmol) at rt. The resulting mixture was stirred at rt for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1 (v/v)) to give 26-15 (145 mg, 70.6%) as a brown oil. MS (ESI): calcd. for C22H30BrF3N2O3S: 538.1; Found: 539.1 [M + 1]+. Step 14. Synthesis of (R)-3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)-8- hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (26-16). Into an 8 mL vial were added 26-15 (90 mg, 0.17 mmol), DMF (3 mL), and MeSNa (64.31 mg, 0.92 mmol) at rt. The resulting mixture was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (20 mL x 4). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1 (v/v)), to give 26-16 (50 mg, 60.8%) as a brown solid. MS (ESI): calcd. for C22H31F3N2O3S2: 492.2; Found: 493.2 [M + 1]+. Step 15. Synthesis of ethyl (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan- 1-yl)-2-methyl-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin- 8-yl)oxy)methyl)cyclopropane-1-carboxylate (26-17). Into an 8 mL vial were added 26-16 (50 mg, 0.10 mmol), DMF (1 mL), ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (25.22 mg, 0.12 mmol), and Cs2CO3 (99.52 mg, 0.30 mmol) at rt. The resulting mixture was stirred at 80°C for 16 h under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1 (v/v)), to give 26-17 (8 mg, 12.7%) as a brown solid. MS (ESI): calcd. for C29H41F3N2O5S2: 618.2; Found: 619.2 [M + 1]+. Step 16. Synthesis of (R)-1-(((3-(3,3-difluorobutyl)-5-(4-fluorobicyclo[2.2.2]octan-1-yl)- 2-methyl-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 26). Into an 8 mL vial were added 26-17 (8 mg, 0.01 mmol), LiOH (0.93 mg, 0.04 mmol), water (1 mL) and THF (4 mL) at rt. The resulting mixture was stirred at rt for 2 h under nitrogen atmosphere. The resulting mixture was acidified to pH 3 with 2 N aq. HCl solution and concentrated. The residue was purified by Chiral-Prep-HPLC with the following conditions: Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 um; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RT1(min): 0.82; Sample Solvent: IPA: CAN = 3: 1; Injection Volume: 0.8 mL; The collected solution was concentrated under vacuum to remove ACN and resulting solution was dried by lyophilization to give Example 26 (2.5 mg, 32.7%) as a white solid. MS (ESI): calcd. for C27H37F3N2O5S2: 590.2; Found: 591.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.26 (s, 1H), 7.06 (s, 1H), 4.35 ‒ 4.14 (m, 2H), 3.89 (s, 1H), 2.59 (dd, J = 16.0, 10.4 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 2.18 (d, J = 11.2 Hz, 3H), 2.03 (s, 2H), 1.94 ‒ 1.87 (m, 9H), 1.77 ‒ 1.51 (m, 6H), 1.32 (s, 2H), 1.13 (s, 2H) ppm. Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9)
Step 1. Synthesis of (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane-1,5-dione (27-2). Into a 50 L 4-necked round-bottom flask were added 5-oxohexanoic acid (27-1) (1.113 kg, 8.56 mol), THF (24 L) and TEA (0.95 kg, 9.40 mol) at room temperature. To the above mixture was added pivaloyl chloride (1.14 kg, 9.40 mol) dropwise at 5 °C over 2 h. The resulting mixture was stirred for an additional 2 h at room temperature. Into a 20 L 4-necked round- bottom flasks were added (4R)-4-benzyl-1,3-oxazolidin-2-one (1.44 kg, 8.12 mol) and THF (16 L) at room temperature. To the above mixture was added n-BuLi (3.25 L, 8.12 mol) dropwise at -50°C over 4 h. The resulting mixture was stirred at -50 °C for an additional 1 h. Then the lithium reagent was transferred to the mixed anhydride via cannula, with the 50 L flasks under reduced pressure. The resulting mixture was stirred at -20°C for 4 h under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 L). The resulting mixture was washed with aq. NaHCO3 solution (20 L x 2) and brine (20 L x 2), dried over anhydrous Na2SO4, and concentrated. The residue was triturated PE/EA = 20/1 (v/v) (60 L) three times. The precipitate was collected and dried in vacuo to give 27-2 (1.7 kg, 68.7%) as a white solid. MS (ESI): calcd. for C16H19NO4: 289.1; Found: 290.1 [M + 1]+. Step 2. Synthesis of (R)-4-benzyl-3-(5,5-difluorohexanoyl)oxazolidin-2-one (27-3). Into a 2 L 3-necked round-bottom flask were added(R)-1-(4-benzyl-2-oxooxazolidin-3-yl)hexane- 1,5-dione (27-2) (200 g, 691.25mol) and DCE (600 mL) at room temperature. To the above mixture was added BAST (382.33 g, 1728.13 mol) at room temperature. The resulting mixture was stirred at 70 °C for an additional 6 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with DCM (1 L). The reaction was slowly poured into sat. aq. NaHCO3 solution. The resulting mixture was extracted with DCM (1 L x 2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/THF (10:1 (v/v)) to give 27-3 (153 g, 71.1%) as a brown oil. MS (ESI): calcd. for C16H19F2NO3: 311.1; Found: 312.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 7.38 – 7.16 (m, 5H), 4.66 (tt, J = 7.8, 3.1 Hz, 1H), 4.33 (t, J = 8.5 Hz, 1H), 4.19 (dd, J = 8.8, 2.9 Hz, 1H), 3.09 – 2.76 (m, 4H), 2.05 – 1.83 (m, 2H), 1.83 – 1.70 (m, 2H), 1.62 (t, J = 18.9 Hz, 3H) ppm. Step 3. Synthesis of (R)-4-benzyl-3-((S)-2-((benzyloxy)methyl)-5,5- difluorohexanoyl)oxazolidin-2-one (27-4). A solution of (R)-4-benzyl-3-(5,5- difluorohexanoyl)oxazolidin-2-one (27-3) (1015 g, 3.26 mol) in DCM (9.1 L) was treated with TiCl4 (649.28 g, 3.42 mol) at 0°C under nitrogen atmosphere. The mixture was stirred for 30 min at 0°C. The solution was treated with TEA (362.90 g, 3.59 mol) dropwise at 0°C under nitrogen atmosphere, then stirred at 0°C for 2 h. The mixture was followed by the addition of ((chloromethoxy)methyl)benzene (1021 g, 6.52 mol) dropwise at 0°C and stirred at 0°C for 2 h. The reaction was quenched with sat. aq. NH4Cl solution (3.5 L) at 0°C. The resulting mixture was separated, and the aqueous layer was extracted with DCM (2 L x 2). The combined organic layers were washed with sat. aq. NaHCO3 (5 L x 2) solution and brine (5 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by trituration with PE/EA = 30/1 (v/v) (60 L x 3). The precipitate was collected and dried in vacuo to give 27-4 (1160 g) as a light brown solid, which was used in the next step directly without further purification. MS (ESI): calcd. for C24H27F2NO4: 431.2; Found: 432.2[M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.43 – 7.17 (m, 10H), 4.75 (ddt, J = 9.3, 7.9, 3.3 Hz, 1H), 4.57 (s, 2H), 4.29 – 4.17 (m, 2H), 4.16 (dd, J = 9.1, 3.2 Hz, 1H), 3.80 (dd, J = 9.2, 7.1 Hz, 1H), 3.71 (dd, J = 9.2, 5.3 Hz, 1H), 3.25 (dd, J = 13.5, 3.4 Hz, 1H), 2.70 (dd, J = 13.5, 9.3 Hz, 1H), 2.07 – 1.92 (m, 1H), 1.96 – 1.86 (m, 1H), 1.89 – 1.72 (m, 1H), 1.61 (t, J = 18.4 Hz, 3H) ppm. Step 4. Synthesis of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoic acid (27-5). A solution of (R)-4-benzyl-3-((S)-2-((benzyloxy)methyl)-5,5-difluorohexanoyl)oxazolidin-2- one (27-4) (1000 g, 2.32 mol) in THF (12 L) and H2O (2 L) was treated with H2O2 (1051 g, 9.27 mol, 30%) dropwise at 0°C for 30 min under nitrogen atmosphere. The mixture was stirred at 0°C for 30 min, then treated with LiOH.H2O (194.49 g, 4.64 mol) in H2O (2 L) dropwise at 0°C. The resulting mixture was stirred at 0°C for 2 h. The reaction was quenched by the addition of Na2SO3 (5 L) at 0°C, then concentrated under vacuum. The resulting solution was adjusted to pH = 12 with 1 N aq. NaOH solution and extracted with DCM (5 L x 3). The water layer was adjusted to pH = 2 with sat. aq. HCl solution (4 M). The resulting solution was extracted with EtOAc (6 L x 4). The combined organic extracts were washed with brine (15 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-5 (600 g) as a light-yellow oil, which was used in the next step directly without further purification. MS (ESI): calcd. for C14H18F2O3: 272.1; Found: 273.1 [M + 1]+. Step 5. Synthesis of methyl (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoate (27-6). A solution of (S)-2-((benzyloxy)methyl)-5,5-difluorohexanoic acid (27-5) (1.80 kg, 6.6 mol) in MeOH (9 L) was treated with SOCl2 (1.65 kg, 13.88 mol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 27- 6 (1.5 kg, 81.4%) as a brown oil. MS (ESI): calcd. for C15H20F2O3: 286.1; Found: 287.1[M + 1]+. Step 6. Synthesis of methyl (S)-5,5-difluoro-2-(hydroxymethyl)hexanoate (27-7). Into a 20 L autoclave were added a solution of methyl (S)-2-((benzyloxy)methyl)-5,5- difluorohexanoate (27-6) (750 g, 2619.5 mmol) in MeOH (15 L) and Pd/C (111.50 g, 10%, wet.) at room temperature. The resulting mixture was stirred at 60°C for 18 h under hydrogen atmosphere (30 atm). The resulting mixture was filtered, and the filter cake was washed with MeOH (1 L x 4). The filtrate was concentrated, and the residue was dried in vacuo to give 27-7 (460 g, 89.5%) as a light-yellow oil. MS (ESI): calcd. for C8H14F2O3: 196.1; Found: 197.1 [M + 1]+. Step 7. Synthesis of methyl (S)-5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (27-8). A solution of methyl (S)-5,5-difluoro-2-(hydroxymethyl)hexanoate (27-7) (441 g, 2.25 mol) and TEA (455 g, 4.50 mol) in DCM (5 L) was treated with MsCl (309 g, 2.70 mol) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water at 0°C, then extracted with DCM (1 L x 3). The combined organic layers were washed with brine (4 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-8 (575 g) as a light- brown liquid, which was used for the next step without further purification. Step 8. Synthesis of methyl (R)-2-(bromomethyl)-5,5-difluorohexanoate (27-9). The solution of methyl (S)-5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)hexanoate (27-8) (1150 g, 4.38 mol) and LiBr (1.52 kg, 17.50 mol) in Acetone (12 L) was stirred at 60°C for 3 h. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The resulting organic mixture was diluted with EtOAc (10 L), washed with water (4 L x 3) and brine (5 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 27-9 (1020 g, 88.2%) as a light-brown liquid, which was used in the next step directly without further purification.1H NMR (300 MHz, CD3OD): δ 3.75 (s, 3H), 3.64 (dd, J = 6.0, 1.8 Hz, 2H), 2.96 – 2.85 (m, 1H), 2.00 – 1.77 (m, 4H), 1.61 (t, J = 18.6 Hz, 3H) ppm. Following the same procedure for 151-8a cis-racemate by replacing methyl 2- (bromomethyl)-5,5,5-trifluoropentanoate (151-7) with methyl (R)-2-(bromomethyl)-5,5- difluorohexanoate (27-9), (2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (Example 10b) was obtained as a single diastereomer. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzenesulfonyl chloride (28-5)
Step 1. Synthesis of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2). To a solution of iodocopper (15.96 g, 84.07 mmol) in tetramethylene sulfone was added cesium fluoride (33.2 g, 218.6 mmol) and 2-methoxy-1-iodo-4-nitrobenzene (28-1) (24.0 g, 84.1 mmol). The resulting solution was stirred at 45°C. Then trimethyl(trifluoromethyl)silane (31.05 g, 218.6 mmol) was added dropwise at 45°C and stirred at room temperature overnight. Subsequently, the mixture was diluted with water and the resulting mixture was extracted with MTBE (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EtOAc/hexanes as eluent to give 28-2 (8 g, 43%) as a yellow solid. Step 2. Synthesis of 3-methoxy-4-(trifluoromethyl)aniline (28-3). To a solution of 2- methoxy-4-nitro-1-(trifluoromethyl)benzene (28-2) (8.0 g, 35.85 mmol) in MeOH was added palladium (379.68 mg, 3.59 mmol). The resulting mixture was hydrogenated at ambient pressure and ambient temperature for 4 h. The mixture was filtered, and the filtrate was concentrated. The residue was dried in vacuo to give 28-3 (5 g, 73%), which was used in the next step without further purification. Step 3. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4). То а solution of 3-methoxy-4-(trifluoromethyl)aniline (28-3) (5.0 g, 26.17 mmol) in ACN (100 mL) was added 1-bromopyrrolidine-2,5-dione (4.63 g, 26.17 mmol) at -20°C. After stirring at rt overnight, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 mL). The mixture was washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 28-4 (6 g, 85%) as a yellow solid. Step 4. Synthesis of 2-bromo-5-methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (28-5). A mixture of 2-bromo-5-methoxy-4-(trifluoromethyl)aniline (28-4) (6.0 g, 22.31 mmol) in sat. aq. HCl solution (8.03 g, 223.09 mmol) and water (100 mL) was added a solution of sodium nitrite (1.85 g, 26.77 mmol) in water (5 mL) at -10°C. After stirring at rt for 1 h, the mixture was added to a mixture of sulfuryl dichloride (26.3 g, 223.09 mmol) and copper chloride (218.4 mg, 2.23 mmol) in water (200 mL) at 0 oC. The resulting mixture was stirred at rt for 2 h and diluted with DCM (50 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic extracts were washed with water (50 mL) and saturated aqueous NaHCO3 (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 28-5 (3 g, 38%). Examples 151a and 151b.3-(((2S,3R)-5-(4,4-difluorocyclohexyl)-2-fluoro-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (151a) and 3-(((2R,3S)-5-(4,4-difluorocyclohexyl)-2- fluoro-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (151b) Step 1. Synthesis of diethyl 2-(3,3,3-trifluoropropyl)malonate (151-2). Into a 500 mL 3- necked round-bottom flask were added diethyl malonate (25 g, 156.08 mmol) and tetrahydrofuran (250 mL) at 0°C. To the above mixture was added NaH (60% in oil, 3.12 g, 78.04 mmol) in portions at 0 °C over 10 min. The resulting mixture was stirred for an additional 30 min at rt. To the above mixture was added 1,1,1-trifluoro-3-iodopropane (17.48 g, 78.04 mmol) dropwise at rt over 5 min. The resulting mixture was stirred at 80 °C for 24 h. The reaction was monitored by LC-MS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (450 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (40:1 (v/v)) to give 151-2 (30 g, 75.2%) as a colorless oil.1H NMR (300 MHz, CDCl3): δ 4.29 – 4.13 (m, 4H), 3.39 (t, J = 6.6 Hz, 1H), 2.27 – 2.07 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H) ppm. Step 2. Synthesis of 2-(ethoxycarbonyl)-5,5,5-trifluoropentanoic acid (151-3). Into a 500 mL 3-necked round-bottom flask were added diethyl 2-(3,3,3-trifluoropropyl)malonate (151- 2) (25 g, 97.57 mmol), EtOH (250 mL) and KOH (6.02 g, 107.33 mmol) at rt. The resulting mixture was stirred at rt for 8 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was acidified to pH = 2 with aq. HCl solution (2 M). The resulting mixture was extracted with EtOAc (150 mL x 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (9:1 (v/v)) to give 151-3 (21 g, 94.3%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 8.65 (br.s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.7 Hz, 1H), 2.39 – 2.06 (m, 4H), 1.30 (t, J = 7.0 Hz, 3H) ppm. Step 3. Synthesis of 5,5,5-trifluoro-2-(hydroxymethyl)pentanoic acid (151-4). To a stirred solution of 2-(ethoxycarbonyl)-5,5,5-trifluoropentanoic acid (151-3) (20 g, 87.66 mmol) in i- PrOH (200 mL) was added LiBH4 (2 M in THF, 87.70 mL, 175.40 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt for 3 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was acidified to pH = 2 with aq. HCl solution (2 N). The resulting mixture was extracted with EtOAc (200 mL x 5). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (4:1 (v/v)) to give 151-4 (15 g, 91.9%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 6.38 (br.s, 2H), 3.93 – 3.77 (m, 2H), 2.74 – 2.59 (m, 1H), 2.37 – 2.07 (m, 2H), 2.06 – 1.75 (m, 2H) ppm. Step 4. Synthesis of methyl 5,5,5-trifluoro-2-(hydroxymethyl)pentanoate (151-5). Into a 500 mL 3-necked round-bottom flask were added 5,5,5-trifluoro-2-(hydroxymethyl)pentanoic acid (151-4) (20 g, 107.45 mmol), H2SO4 (6.32 g, 64.47 mmol) and MeOH (200 mL) at rt. The resulting mixture was stirred at 60 °C for 4 h under nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA = 4/1 (v/v) to 151-5 (21 g, 97.6%) as a yellow liquid. 1H NMR (300 MHz, CDCl3): δ 3.80 (dd, J = 5.4, 2.7 Hz, 2H), 3.75 (s, 3H), 2.70 – 2.56 (m, 1H), 2.28 – 2.11 (m, 2H), 2.06 (br.s, 1H), 2.02 – 1.77 (m, 2H) ppm. Step 5. Synthesis of methyl 5,5,5-trifluoro-2-(((methylsulfonyl)oxy)methyl)pentanoate (151-6). To a stirred mixture of methyl 5,5,5-trifluoro-2-(hydroxymethyl)pentanoate (151-5) (15 g, 74.94 mmol) and TEA (22.75 g, 224.82 mmol) in DCM (150 mL) was added MsCl (10.30 g, 89.93 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h under nitrogen atmosphere. The reaction was monitored by GC- MS. The resulting mixture was extracted with CH2Cl2 (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v/v)) to give 151-6 (17 g, 81.5%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 4.45 – 4.31 (m, 2H), 3.76 (s, 3H), 3.03 (s, 3H), 2.94 – 2.79 (m, 1H), 2.32 – 2.07 (m, 2H), 2.06 – 1.79 (m, 2H) ppm. Step 6. Synthesis of methyl 2-(bromomethyl)-5,5,5-trifluoropentanoate (151-7). Into a 250 mL 3-necked round-bottom flask were added methyl 5,5,5-trifluoro-2- (((methylsulfonyl)oxy)methyl)pentanoate (151-6) (15 g, 53.91 mmol), LiBr (14.04 g, 161.73 mmol) and acetone (150 mL) at rt. The resulting mixture was stirred at 60°C for 3 h under nitrogen atmosphere. The reaction was monitored by GC-MS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/THF (9:1 (v/v)) to give 151-7 (11 g, 77.6%) as a colorless liquid.1H NMR (300 MHz, CDCl3): δ 3.76 (s, 3H), 3.61 – 3.48 (m, 2H), 2.94 – 2.80 (m, 1H), 2.29 – 2.09 (m, 2H), 2.08 – 1.84 (m, 2H) ppm. Step 7. Synthesis of 2-bromo-4-methoxy-5-(trifluoromethyl)aniline (151-9). Into a 50 L 4- necked round-bottom flask were added 4-methoxy-3-(trifluoromethyl)aniline (1100 g, 5.75 mol) and THF (22 L). To the above mixture was added NBS (1057.56 g, 5.75 mol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 10°C for 2 h under nitrogen atmosphere. After completion of the reaction (monitored by LC-MS), the reaction was quenched with sat. aq. Na2SO3 solution (25 L) at 5 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (25 L x 3). The combined organic layers were washed with brine (25 L x 2), dried over anhydrous Na2SO4, and concentrated. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (15:1 (v/v)) to give 151-9 (1067 g, 68.6%) as a yellow solid. MS (ESI): calcd. for C8H7BrF3NO: 269.0; Found: 311.0 [M +ACN+ 1]+. Step 8. Synthesis of 4-methoxy-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)aniline (151-10). Into a 20 L 4-necked round-bottom flask were added 2-bromo-4-methoxy-5- (trifluoromethyl)aniline (151-9) (1000 g, 3.95 mol), dioxane (10 L), PMBSH (913.79 g, 5.92 mol), DIEA (1.53 kg, 11.85 mol), Pd2(dba)3 (85.04 g, 0.093 mol) and Xantphos (107.43 g, 0.186 mol) at room temperature. The resulting mixture was stirred at 120 °C for 24 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 L x 2). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EA/DCM (5/1/0.1 (v/v/v)) to give crude 151-10 (1167 g, containing some ligands) as a brown oil, which was directly used in the next step without further purification. MS (ESI): calcd. for C16H16F3NO2S: 343.1; Found: 344.1 [M + 1]+. Step 9. Synthesis of 6,6'-disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151- 11). Into a 20 L 4-necked round-bottom flask were added 4-methoxy-2-((4- methoxybenzyl)thio)-5-(trifluoromethyl)aniline (151-10) (1160 g, 3.40 mol), TFA (4 L) and MsOH (1.2 L) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and diluted with EtOAc (15 L). The mixture was acidified to pH = 9 with saturated aq. NaHCO3 solution. The resulting solution was stirred at rt for 16 h under oxygen atmosphere. The resulting mixture was separated, and the aqueous layer was extracted with EtOAc (8 L x 2). The combined organic layers were washed with brine (10 L x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1 (v/v)) to give 151-11 (500 g, 33.1%) as a light brown solid. MS (ESI): calcd. for C16H14F6N2O2S2: 444.0; Found: 445.0 [M + 1]+. Step 10. Synthesis of methyl 2-(((2-amino-5-methoxy-4- (trifluoromethyl)phenyl)thio)methyl)-5,5,5-trifluoropentanoate (151-12). A solution of 6,6'-disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151-11) (20.27 g, 45.6 mmol), Cs2CO3 (55.72 g, 171 mmol), and sodium dithionite (29.77 g, 171 mmol) in DMF (280 mL) was stirred for 20 min, then the mixture was treated with methyl 2-(bromomethyl)-5,5,5- trifluoropentanoate (151-7) (15 g, 57 mmol) in DMF (57 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The solution was diluted with H2O (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 6/1 (v/v) to give 151-12 (11.2 g, 48.6%) as a light brown oil. MS (ESI): calcd. for C15H17F6NO3S: 405.1; Found: 406.1 [M + 1]+. Step 11. Synthesis of 8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-13). A solution of methyl 2-(((2-amino-5- methoxy-4-(trifluoromethyl)phenyl)thio)methyl)-5,5,5-trifluoropentanoate (151-12) (10.22 g, 25.21 mmol) in THF (100 mL) was treated with LiHMDS (50.41 mL, 50.41 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. aq. NH4Cl solution at room temperature, then the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (4:1 (v/v)) to give 151-13 (8.6 g, 91.4%) as an off-white solid. MS (ESI): calcd. for C14H13F6NO2S: 373.1; Found: 374.1 [M + 1]+. Step 12. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-14). A solution of 8- methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin- 4(5H)-one (151-13) (8.56 g, 22.93 mmol), (4-fluorophenyl)boronic acid (9.63 g, 68.79 mmol) and TEA (9.28 g, 91.72 mmol) in DMF (86 mL) was treated with Cu(OAc)2 (6.25 g, 34.40 mmol) at room temperature under oxygen atmosphere. The resulting mixture was stirred at 80°C for 16 h under oxygen atmosphere. The mixture was allowed to cool down to room temperature and diluted with sat. aq. NH4Cl solution (200 mL). The resulting solution was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (6:1 (v/v)) to give 151-14 (10.6 g, 92.8%) as a yellow solid. MS (ESI): calcd. C20H16F7NO2S: 467.1; Found: 468.1 [M + 1]+. Step 13. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (151-15). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (151-14) (10.62 g, 22.72 mmol) and oxone (104.74 g, 170.40 mmol) in THF (200 mL) and H2O (100 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (150 mL x 3). The mixture was acidified to PH = 8 with sat. aq. NaHCO3 solution. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA = 5/1 (v/v) to give 151-15 (10.6 g, 93.4%) as a yellow solid. MS (ESI): calcd. for C20H16F7NO4S: 499.1; Found: 500.2 [M + 1]+. Step 14. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-16). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (151-15) (4 g, 8.0 mmol) and BH3·Me2S (8 mL, 80 mmol) in THF (40 mL) was stirred at 60°C for 16 h. After the reaction was completed, the mixture was allowed to cool to 0°C with ice-water. The mixture was quenched with MeOH (8 mL) (dropwise) at 0°C, then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the mixture was extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (4:1 (v/v)) to give 151-16 (3.6 g, 93.6%) as a white solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.1 [M + 1]+. Step 15. Synthesis of rac-cis-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)- 3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151- 17a) and rac-trans-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-17b). A solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-16) (3.6 g, 7.42 mmol) in THF (60 mL) was treated with LiHMDS (8.9 mL, 8.9 mmol) at -78 °C for 10 min under nitrogen atmosphere. The mixture was stirred for 30 min, followed by the addition of a solution of NFSI (2.11 g, 6.68 mmol) in THF (35 mL) dropwise at -78°C. The resulting mixture was stirred at -78 °C for 3 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. aq. NH4Cl solution (100 mL) at 0°C, then the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (4:1 (v/v)) to give 151-17a (cis-racemate, 498 mg) as a yellow solid and 151-17b (trans-racemate, 1.92 g) as a yellow solid. 151-17a (cis-racemate): MS (ESI): calcd. for C20H17F8NO3S: 503.1; Found: 504.2 [M + 1]+. 1H NMR (300 MHz, CDCl3): δ 7.72 (s, 1H), 7.50 (s, 1H), 7.03 – 6.91 (m, 2H), 6.69 – 6.58 (m, 2H), 5.27 (d, J = 45.9 Hz, 1H), 4.10 – 4.04 (m, 1H), 4.03 (s, 3H), 3.34 (dd, J = 15.9, 11.4 Hz, 1H), 2.91 – 2.65 (m, 1H), 2.39 – 2.18 (m, 2H), 1.91 – 1.66 (m, 2H) ppm.151-17b (trans- racemate): MS (ESI): calcd. for C20H17F8NO3S: 503.1; Found: 504.2 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 7.25 (s, 1H), 7.10 – 6.89 (m, 4H), 5.23 (dd, J = 44.7, 4.8 Hz, 1H), 4.17 – 4.03 (m, 1H), 3.99 (s, 3H), 3.61 (d, J = 15.3 Hz, 1H), 2.52 – 2.30 (m, 1H), 2.24 – 2.04 (m, 2H), 2.06 – 1.85 (m, 2H) ppm. Step 16. Synthesis of rac-cis-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)- 3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18a) and rac-trans-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18b). Into a 40 mL vial were added rac-cis-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3- (3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-17a) (490 mg, 0.97 mmol), LiCl (822.4 mg, 19.4 mmol) and DMSO (4.9 mL) at room temperature. The resulting mixture was stirred at 140 °C for 16 h under nitrogen atmosphere. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (3 x 70 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1 (v/v)) to give 151- 18a (cis-racemate, 414 mg, 87.0%) as a light-yellow solid. MS (ESI): calcd. for C19H15F8NO3S: 489.1; Found: 490.3 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.66 (s, 1H), 7.49 (s, 1H), 7.06 – 6.82 (m, 2H), 6.79 – 6.49 (m, 2H), 5.68 (d, J = 44.7 Hz, 1H), 4.18 (d, J = 16.2 Hz, 1H), 3.31 – 3.21 (m, 1H), 2.94 – 2.60 (m, 1H), 2.59 – 2.33 (m, 2H), 1.95 – 1.66 (m, 2H) ppm. Following the same procedure for preparing 151-18a by replacing 151-17a with 151-17b (1.9 g, 3.77 mmol), 151-18b (trans-racemate, 1.6 g, 86.5%) was obtained as a light-yellow solid. MS (ESI): calcd. for C19H15F8NO3S: 489.1; Found: 490.2 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.63 (s, 1H), 7.27 (s, 1H), 7.09 – 6.84 (m, 4H), 5.56 (dd, J = 43.8, 6.3 Hz, 1H), 4.25 – 3.90 (m, 1H), 3.85 – 3.52 (m, 1H), 2.58 – 2.38 (m, 1H), 2.38 – 2.15 (m, 2H), 2.04 – 1.73 (m, 2H) ppm. Step 17. Conversion of rac-trans-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18b) to rac-cis-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18a). A solution of rac-trans-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1- dioxide (151-18b) (1.6 g, 3.27 mmol) in THF (16 mL) was treated with LiHMDS (1 mol/L, 3.27 mL, 3.27 mmol) at -78°C for 10 min under nitrogen atmosphere. The resulting mixture was stirred at -40°C for 1 h under nitrogen atmosphere. The reaction was quenched with sat. aq. NH4Cl solution (20 mL) at -40°C and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1 (v/v)) to give 151-18a (1.4 g, 87.5%) as a yellow solid. Step 18. Synthesis of rac-methyl 3-(((2R,3S)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (151-19). A solution of rac-(2R,3S)-2-fluoro-5-(4- fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18a) (1 g, 2.04 mmol), methyl 3- hydroxy-2,2-dimethylpropanoate (1.08 g, 8.17 mmol) and PPh3 (2.14 g, 8.17 mmol) in THF (15 mL) was stirred under nitrogen atmosphere for 10 min. The solution was treated with DIAD (1.65 g, 8.17 mmol) at room temperature under nitrogen atmosphere, then stirred at 110 °C for 6 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1 (v/v)) to give 151-19 (1.1 g, 89.2%) as yellow semi- solid. MS (ESI): calcd. for C25H26F7NO5S: 603.5; Found: 604.2 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.48 (s, 1H), 7.00 – 6.92 (m, 2H), 6.67 – 6.60 (m, 2H), 5.27 (d, J = 46.0 Hz, 1H), 4.16 (s, 2H), 4.08 – 4.00 (m, 1H), 3.71 (s, 3H), 3.33 (dd, J = 15.8, 11.2 Hz, 1H), 2.89 – 2.68 (m, 1H), 2.37 – 2.20 (m, 2H), 1.91 – 1.67 (m, 2H), 1.36 (s, 6H) ppm. Step 19. Synthesis of methyl 3-(((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoate (151-20a) and methyl 3-(((2R,3S)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (151-20b). The racemic methyl 3-(((2R,3S)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3- (3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoate (151-19) (1.1 g, 1.82 mmol) was purified by SFC (Condition: Column: XA-(R, R)-WHELK-O, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 mL/min; Gradient: isocratic 25% B; Column Temperature: 35 °C; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 3.03; RT2(min): 4.26; Sample Solvent: MeOH: DCM = 4: 1 (v/v); Injection Volume: 5 mL) to give 151-20a (single diastereomer, 480 mg, 43.6%) and 151-20b (single diastereomer, 475 mg, 43.2%) as a yellow semi-solid, respectively. MS (ESI): calcd. for C25H26F7NO5S: 603.5; Found: 604.2 [M + 1]+. Step 20. Synthesis of 3-(((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (Example 151a) and 3-(((2R,3S)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 151b). Into a 40 mL vial were added methyl 3-(((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (151-20a) (480 mg, 0.80 mmol), LiOH (76.64 mg, 3.2 mmol), H2O (2 mL) and dioxane (8 mL) at room temperature. The resulting mixture was stirred at 40°C for 16 h under nitrogen atmosphere. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was allowed to cool down to room temperature. The mixture was acidified to pH = 2 with aq. HCl solution (2 M). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The crude product (475 mg) was purified by Prep-HPLC (Condition: 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: 40% B to 75% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.28) to give Example 151a (single diastereomer, 303 mg, 64.6%) as a yellow solid. MS (ESI): calcd. for C24H23F8NO5S: 589.1; Found: 588.1 [M - 1]-.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.05 ‒ 6.93 (m, 2H), 6.78 ‒ 6.68 (m, 2H), 5.75 (d, J = 45.0 Hz, 1H), 4.33 ‒ 4.15 (m, 3H), 3.41 ‒ 3.34 (m, 1H), 2.90 ‒ 2.65 (m, 1H), 2.60 ‒ 2.34 (m, 2H), 1.94 ‒ 1.70 (m, 2H), 1.37 (s, 6H) ppm. Following the same procedure for preparing Example 151a by replacing 151-20a with 151- 20b (475 mg, 0.79 mmol), Example 151b was obtained (single diastereomer, 272 mg, 58.6%) as a yellow solid. Chiral HPLC condition: 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: 40% B to 75% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.28. MS (ESI): calcd. for C24H23F8NO5S: 589.1; Found: 588.1 [M - 1]-.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 7.05 ‒ 6.93 (m, 2H), 6.78 ‒ 6.68 (m, 2H), 5.75 (d, J = 45.0 Hz, 1H), 4.33 ‒ 4.15 (m, 3H), 3.41 ‒ 3.34 (m, 1H), 2.90 ‒ 2.65 (m, 1H), 2.60 ‒ 2.34 (m, 2H), 1.94 ‒ 1.70 (m, 2H), 1.37 (s, 6H) ppm. Examples 152a and 152b.3,3-difluoro-1-((((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido- 7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclobutane-1-carboxylic acid (152a) and 3,3-difluoro-1-((((2R,3S)-2-fluoro- 5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-
tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane-1-carboxylic acid (152b) Step 1. Synthesis of rac-isopropyl 3,3-difluoro-1-((((2S,3R)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane-1-carboxylate (152-1). A solution of rac-(2S,3R)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (151-18a) (105 mg, 0.215 mmol), isopropyl 3,3-difluoro-1-((tosyloxy)methyl)cyclobutane-1-carboxylate (116.63 mg, 0.323 mmol), Cs2CO3 (209.72 mg, 0.645 mmol) and KI (35.62 mg, 0.215 mmol) in DMF (5 mL) was stirred at 80 °C for 18 h . The mixture was allowed to cool down to room temperature, then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water (20 mL x 5) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (4:1 (v/v)) to give 152-1 (100 mg, 58.3%) as a brown oil. MS (ESI): calcd. for C28H27F10NO5S: 679.1; Found: 680.1 [M + 1]+. Step 2. Synthesis of isopropyl 3,3-difluoro-1-((((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane-1-carboxylate (152-2a) and isopropyl 3,3-difluoro-1-((((2R,3S)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclobutane-1-carboxylate (152-2b). The racemic isopropyl 3,3-difluoro-1- ((((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane-1- carboxylate (100 mg, 0.147 mmol, 1 equiv) was purified by Prep-CHRIAL-HPLC (Condition: Column: XA-(R, R)-WHELK-O, 2.11*25 cm, 5 μm; Mobile Phase A: HEX:DCM = 3:1 (v/v) , Mobile Phase B: EtOH; Flow rate: 25 mL/min; Gradient: isocratic 15; Wave Length: 254 nm) to give 152-2a (RT = 1.577 min, single diastereomer, 43 mg, 40.9%) as a yellow oil, MS (ESI): calcd. for C28H27F10NO5S: 679.1; Found: 680.1 [M + 1]+ and 152-2b (RT = 1.846 min, single diastereomer, 38 mg, 36.1%) as a yellow oil, MS (ESI): calcd. for C28H27F10NO5S: 679.1; Found: 680.1 [M + 1]+. Step 3. Synthesis of 3,3-difluoro-1-((((2S,3R)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)cyclobutane-1-carboxylic acid (Example 152a) and 3,3-difluoro-1- ((((2R,3S)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane- 1-carboxylic acid (Example 152b). A solution of isopropyl 3,3-difluoro-1-((((2S,3R)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)cyclobutane-1-carboxylate (152-2a) (43 mg, 0.063 mmol) and LiOH (4.55 mg, 0.189 mmol) in Dioxane (5 mL) and H2O (1 mL) was stirred at 40 °C for 16 h. The resulting mixture was diluted with water (20 mL), then extracted with EtOAc (5 mL x 2). The aqueous phase was acidified to pH 3 with aq. HCl solution (2M), then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue (40 mg) was purified by Prep-HPLC (Condition: Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 45% B to 75 % B in 8 min; Wavelength: 254 nm/220 nm) to give Example 152a (RT = 1.813 min, single diastereomer, 15.2 mg, 37.6%) as a light yellow solid. MS (ESI): calcd. for C25H21F10NO5S: 637.1; Found: 638.1 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.48 (s, 1H), 6.95 - 7.00 (m, 2H), 6.65 - 6.68 (m, 2H), 5.28 (d, J = 46.0 Hz, 1H), 4.45 – 4.51 (m, 2H), 4.06 (d, J = 14.8 Hz, 1H), 3.34 (dd, J = 15.6, 10.8 Hz, 1H), 3.15 – 3.25 (m, 2H), 2.71 – 2.89 (m, 3H), 2.22 – 2.34 (m, 2H), 1.71 – 1.87 (m, 2H) ppm. Following the same procedure for preparing Example 152a by replacing 152-2a with 152-2b (38 mg, 0.056 mmol), Example 152b (RT = 2.328 min, single diastereomer, 12.3 mg, 33.9%) was obtained a light-yellow solid. Chiral HPLC condition: Column: Sunfire Prep C18 OBD Column, 19*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 45% B to 75 % B in 8 min; Wavelength: 254 nm/220 nm). MS (ESI): calcd. for C25H21F10NO5S: 637.1; Found: 638.1 [M + 1]+.1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.52 (s, 1H), 6.95 – 7.00 (m, 2H), 6.65 – 6.68 (m, 2H), 5.28 (d, J = 46.0 Hz, 1H), 4.45 – 4.51 (m, 2H), 4.06 (d, J = 15.2 Hz, 1H), 3.34 (dd, J = 16.0, 11.2 Hz, 1H), 3.15 – 3.24 (m, 2H), 2.71 – 2.88 (m, 3H), 2.22 – 2.34 (m, 2H), 1.71 – 1.87 (m, 2H) ppm. Examples 153a and 153b.3-(((2S,3R)-3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (153a) and 3-(((2R,3S)-3-(3,3-difluoropropyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (153b)
Step 1. Synthesis of dimethyl 2-(3-oxopropyl)malonate (153-2). A solution of dimethyl malonate (153-1) (100 g, 756.92 mmol) in MeOH (1 L) was treated with sodium methoxide (4.09 g, 75.69 mmol) for 2 min at room temperature under nitrogen atmosphere, followed by the addition of acrolein (55.17 g, 983.99 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by distillation under reduced pressure and the fraction was collected at room temperature to give 153-2 (65 g, 45.6%) as a colorless liquid. MS (ESI): calcd. for C8H12O5: 188.1; Found: 189.1 [M + 1]+. Step 2. Synthesis of dimethyl 2-(3,3-difluoropropyl)malonate (153-3). A solution of dimethyl 2-(3-oxopropyl)malonate (153-2) (65 g, 345.42 mmol) and BAST (152.84 g, 690.83 mmol) in DCE (650 mL) was stirred at 70 ℃ for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with CH2Cl2 (200 mL). The mixture was adjusted to pH = 9 with saturated aq. NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (1 L x 2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (7/1 (v/v)) to give 153-3 (25 g, 34.4%) as a colorless liquid. MS (ESI): calcd. for C8H12F2O4: 210.1; Found: 211.1 [M + 1]+. Step 3. Synthesis of 5,5-difluoro-2-(methoxycarbonyl)pentanoic acid (153-4). A solution of dimethyl 2-(3,3-difluoropropyl)malonate (153-3) (25 g, 118.95 mmol) and potassium hydroxide (8.01 g, 142.74 mmol) in MeOH (250 mL) was stirred at room temperature for 8 h. The mixture was acidified to pH = 2 with aq. HCl solution (2 N). The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried to give 153-4 (18 g, 77.2%) as a colorless liquid. MS (ESI): calcd. for C7H10F2O4: 196.1; Found: 197.1 [M + 1]+. Step 4. Synthesis of 5,5-difluoro-2-(hydroxymethyl)pentanoic acid (153-5). A solution of 5,5-difluoro-2-(methoxycarbonyl)pentanoic acid (153-4) (25 g, 127.45 mmol) and LiBH4 (5.55 g, 254.91 mmol) in i-PrOH (250 mL) was stirred at room temperature for 3 h. The mixture was acidified to pH = 3 with conc. aq. HCl solution. The resulting mixture was extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 153-5 (20 g, 93.3%) as a colorless liquid, which was used in the next step without further purification. MS (ESI): calcd. for C6H10F2O3: 168.1; Found: 169.1 [M + 1]+. Step 5. Synthesis of methyl 5,5-difluoro-2-(hydroxymethyl)pentanoate (153-6). A solution of 5,5-difluoro-2-(hydroxymethyl)pentanoic acid (153-5) (20 g, 118.95 mmol) and H2SO4 (3.5 mL, 118.95 mmol) in MeOH (200 mL) was stirred at 60 °C for 4 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (200 mL x 4). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 153-6 (18 g, 83.1%) as a colorless liquid, which was used in the next step without further purification. MS (ESI): calcd. for C7H12F2O3: 182.1; Found: 183.1 [M + 1]+. Step 6. Synthesis of methyl 5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)pentanoate (153-7). A solution of methyl 5,5-difluoro-2-(hydroxymethyl)pentanoate (153-6) (18 g, 98.81 mmol) in DCM (180 mL) was treated with TEA (30.00 g, 296.43 mmol) for 5 mins at 0 °C under nitrogen atmosphere, followed by the addition of MsCl (14.71 g, 128.45 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2 (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 153-7 (20 g, 77.8%) as a yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C8H14F2O5S: 260.1; Found: 261.1 [M + 1]+. Step 7. Synthesis of methyl 2-(bromomethyl)-5,5-difluoropentanoate (153-8). A solution of methyl 5,5-difluoro-2-(((methylsulfonyl)oxy)methyl)pentanoate (153-7) (20 g, 76.85 mmol) and LiBr (20.02 g, 230.55 mmol) in acetone (200 mL) was stirred at 60 °C for 3 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (100 mL) at room temperature and then concentrated to remove the organic solvent. The resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 153-8 (15 g, 79.7%) as a yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C7H11BrF2O2: 244.0; Found: 245.0 [M + 1]+.
Step 8. Synthesis of methyl 2-(((2-amino-5-methoxy-4- (trifluoromethyl)phenyl)thio)methyl)-5,5-difluoropentanoate (153-9). A solution of 6,6'- disulfanediylbis(4-methoxy-3-(trifluoromethyl)aniline) (151-11) (15 g, 33.75 mmol) in DMF (150 mL) was treated with Cs2CO3 (32.99 g, 101.26 mmol) for 2 mins at room temperature under nitrogen atmosphere followed by the addition of Na2S2O4 (23.51 g, 135.01 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added methyl 2-(bromomethyl)-5,5-difluoropentanoate (153-8) (8.27 g, 33.75 mmol) dropwise at room temperature over 10 mins. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-9 (10.7 g, 81.8%) as a white solid. MS (ESI): calcd. for C15H18F5NO3S: 387.1; Found: 388.1 [M + 1]+. Step 9. Synthesis of 3-(3,3-difluoropropyl)-8-methoxy-7-(trifluoromethyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (153-10). Into a 500 mL 3-necked round-bottom flask were added methyl 2-(((2-amino-5-methoxy-4-(trifluoromethyl)phenyl)thio)methyl)- 5,5-difluoropentanoate (153-9) (10.7 g, 27.62 mmol) and THF (110 mL) at room temperature. To the above mixture was added LiHMDS (50 mL, 55.24 mmol) dropwise at 0 °C over 30 min. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with sat. aq. NH4Cl solution at room temperature. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-10 (6 g, 61.1%) as a white solid. MS (ESI): calcd. for C14H14F5NO2S: 355.1; Found: 356.0 [M + 1]+. Step 10. Synthesis of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (153-11). To a stirred solution of 3-(3,3-difluoropropyl)-8-methoxy-7-(trifluoromethyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (153-10) (6 g, 16.89 mmol) and TEA (6.84 g, 67.54 mmol) in DMF (60 mL) were added Cu(OAc)2 (4.60 g, 25.33 mmol) and 4- fluorophenylboronic acid (7.09 g, 50.66 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 16 h under O2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (50 mL x 3). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to 153-11 (7 g, 92.2%) as a white solid. MS (ESI): calcd. for C20H17F6NO2S: 449.1; Found: 450.1 [M + 1]+. Step 11. Synthesis of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (153-12). A solution of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one (153-11) (7.5 g, 16.69 mmol) and Oxone® (56.13 g, 333.78 mmol) in THF (75 mL) was stirred at room temperature for 16 hr. The resulting mixture was filtered, the filter cake was washed with EtOAc (50 mL x 3). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 153-12 (7 g, 87.1%) as a yellow solid, which was used in the next step without further purification. MS (ESI): calcd. for C20H17F6NO4S: 481.1; Found: 482.1 [M + 1]+. Step 12. Synthesis of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-13). A solution of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-2,3- dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide (153-12) (7 g, 14.54 mmol) and BH3∙THF (6.96 mL, 72.71 mmol) in THF (70 mL) was stirred at 60 °C for 16 hr. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (70 mL x 2). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-13 (5 g, 73.6%) as a white solid. MS (ESI): calcd. for C20H19F6NO3S: 467.1; Found: 468.1 [M + 1]+. Step 13. Synthesis of 3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-14). Into a 250 mL 3-necked round-bottom flask were added 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)- 8-methoxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153- 13) (6.5 g, 13.91 mmol) and THF (130 mL) at room temperature. To the above mixture was added LiHMDS (2.79 g, 16.69 mmol) dropwise at -78 °C over 0.5 hr. The resulting mixture was stirred at -78 °C for an additional 30 min. To the above mixture was added NFSI (3.95 g, 12.52 mmol) dropwise at -78 °C over 1 hr. The resulting mixture was stirred at -78 °C for an additional 30 min. The reaction was quenched with sat. aq. NH4Cl solution at room temperature. The resulting mixture was extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to 153-14 (2.6 g, 38.5%) as a yellow solid. MS (ESI): calcd. for C20H18F7NO3S: 485.1; Found: 486.1 [M + 1]+. Step 14. Synthesis of 3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-15). A solution of 3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-14) (2.4 g, 4.94 mmol) and LiCl (4.19 g, 98.88 mmol) in DMSO (24 mL) was stirred at 140 °C for 16 hr. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-15 (1.8 g, 77.2%) as a yellow solid. MS (ESI): calcd. for C19H16F7NO3S: 471.1; Found: 472.0 [M + 1]+. Step 15. Synthesis of rac-(2R,3S)-3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-8- hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153- 16). Into a 50 mL 3-necked round-bottom flask were added 3-(3,3-difluoropropyl)-2-fluoro- 5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-15) (1.8 g, 3.82 mmol) and THF (18 mL) at room temperature. To the above mixture was added LiHMDS (13.2 mL, 19.09 mmol) dropwise at -40 °C over 10 min. The resulting mixture was stirred at -40 °C for an additional 30 min. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-16 (cis- racemate, 730 mg, 40.6%) as a yellow solid. MS (ESI): calcd. for C19H16F7NO3S: 471.1; Found: 472.0 [M + 1]+. Step 16. Synthesis of rac-methyl 3-(((2R,3S)-3-(3,3-difluoropropyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (153-17). To a stirred solution of rac-(2R,3S)-3-(3,3- difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-8-hydroxy-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (153-16) (730 mg, 1.55 mmol) and DIAD (1.25 g, 6.20 mmol) in THF (7.3 mL) were added PPh3 (1.62 g, 6.20 mmol) and methyl 3- hydroxy-2,2-dimethylpropanoate (409.33 mg, 3.10 mmol) dropwise at room temperature. The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 (v/v)) to give 153-17 (750 mg, 82.7%) as a yellow solid. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+. Step 17. Synthesis of methyl 3-(((2S,3R)-3-(3,3-difluoropropyl)-2-fluoro-5-(4- fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin- 8-yl)oxy)-2,2-dimethylpropanoate (153-18a) and methyl 3-(((2R,3S)-3-(3,3- difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoate (153-18b). The racemic methyl 3-(((2R,3S)-3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoate (153-17) (750 mg) was purified by prep-SFC (condition: (2#SHIMADZU (SFC-150), Column: XA-(R, R)-WHELK-O, 2.11*25 cm, 5 μm; Mobile Phase A: HEX:DCM = 3:1 (v/v), Mobile Phase B: EtOH; Flow rate: 25 mL/min; Gradient: isocratic 30; Wavelength: 220 nm; RT1 (min): 4.8; RT2 (min): 6.0; Sample Solvent: EtOH: DCM = 1: 1 (v/v); Injection Volume: 5 mL) to give 153-18a (310 mg, 82.7%, single diastereomer) and 153-18b (320 mg, 91.4%, single diastereomer) as a white solid, respectively. MS (ESI): calcd. for C25H26F7NO5S: 585.1; Found: 586.1 [M + 1]+. Step 18. Synthesis of 3-(((2S,3R)-3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 153a) and 3-(((2R,3S)-3-(3,3-difluoropropyl)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 153b). A solution of methyl 3-(((2S,3R)-3-(3,3-difluoropropyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2- dimethylpropanoate (153-18a) (310 mg, 0.57 mmol) and LiOH (16.02 mg, 0.5mmol) in 1,4- dioxane (4 mL) and H2O (1 mL) was stirred for 12 h at rt. The mixture was acidified to pH = 4 with aq. HCl (2 M). The resulting mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue (300 mg) was purified by Prep-HPLC (condition: 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 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.26) to give Example 153a (285 mg, 94.4% single diastereomer) as a white solid. MS (ESI): calcd. for C24H24F7NO5S: 571.1; Found: 572.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.74 - 6.69 (m, 2H), 6.17 – 5.63 (m, 2H), 4.29 – 4.18 (m, 3H), 3.32 – 3.27 (m, 1H), 2.86 – 2.57 (m, 1H), 2.21 – 1.98 (m, 2H), 1.83 – 1.58 (m, 2H), 1.37 (s, 6H) ppm. Following the same procedure for preparing Example 153a by replacing 153-18a with 153- 18b (320 mg, 0.59 mmol), Example 153b (282 mg, 90.4%, single diastereomer) was obtained as a white solid. Prep-HPLC condition: 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 80 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.26. MS (ESI): calcd. for C24H24F7NO5S: 571.1; Found: 572.1 [M + 1]+.1H NMR (300 MHz, CD3OD): δ 7.79 (s, 1H), 7.57 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.74 – 6.69 (m, 2H), 6.16 – 5.63 (m, 2H), 4.32 – 4.15 (m, 3H), 3.32 – 3.27 (m, 1H), 2.83 – 2.61 (m, 1H), 2.21 – 1.97 (m, 2H), 1.83 – 1.58 (m, 2H), 1.37 (s, 6H) ppm. Examples 154a and 154b. (S)-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)- 2,2-difluorocyclopropane-1-carboxylic acid (154a) and (R)-1-((((2S,3R)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)-2,2-difluorocyclopropane-1-carboxylic acid (154b)
Step 1. Synthesis of (2,2-difluorocyclopropane-1,1-diyl)bis(methylene) diacetate (154-2). Into a 1000 mL 3-necked round-bottom flask were added 2-methylenepropane-1,3-diyl diacetate (154-1) (20 g, 116.2 mmol) and DME (100 mL) at room temperature. To the above mixture was added ClCF2CO2Na (106.26 g, 697 mmol) in 400 mL THF dropwise at 80°C over 5 h. The resulting mixture was stirred at 80°C for an additional 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with PE (200 mL x 2). The combined organic extracts were washed with brine (100 mL x 4), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 154- 2 (15 g, 58.1%) as a colorless oil. Step 2. Synthesis of (2,2-difluorocyclopropane-1,1-diyl)dimethanol (154-3). Into a 250 mL 3-necked round-bottom flask were added (2,2-difluorocyclopropane-1,1- diyl)bis(methylene) diacetate (154-2) (15 g, 67.5 mmol), methanol (150 mL) and K2CO3 (28.19 g, 202.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic extracts were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1 (v/v)) to give 154-3 (5 g, 53.6%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.99 – 3.82 (m, 4H), 1.36 (t, J = 8.4 Hz, 2H) ppm. Step 3. Synthesis of rac-(2S,3R)-8-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-5). Into a 8 mL vial were added 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 (154-4) (single diastereomer, 140 mg, 0.29 mmol), THF (4 mL), (2,2- difluorocyclopropane-1,1-diyl)dimethanol (154-3) (47.80 mg, 0.35 mmol), PPh3 (98.34 mg, 0.37 mmol) and DIAD (75.82 mg, 0.37 mmol) at room temperature. The resulting mixture was stirred at 55°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1 (v/v)) to give 154-5 (100 mg, 57.3%) as a yellow solid. MS (ESI): calcd. for C25H24F9NO4S: 605.1; Found: 606.1 [M + 1]+. Step 4. Synthesis of (2S,3R)-8-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-5a) and (2S,3R)-8-(((S)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methoxy)-3- (3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-5b). The crude rac-(2S,3R)-8-((2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methoxy)-3-(3,3-difluorobutyl)-2-fluoro-5-(4- fluorophenyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-5) (100 mg) was purified by Prep-HPLC ((2#SHIMADZU (HPLC-01)), Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 um; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 35 mL/min; Gradient: 30% B to 30% B in 15 min; Wavelength: 220/254 nm; RT1(min): 10; RT2(min): 12; Sample Solvent: IPA:CAN = 3:1 (v/v); Injection Volume: 0.8 mL) to give 154-5a (40 mg, single diastereomer, the stereochemistry was arbitrarily assigned) and 154-5b (42 mg, single diastereomer, the stereochemistry was arbitrarily assigned) as yellow solid, respectively. Step 5. Synthesis of (S)-1-((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8- yl)oxy)methyl)-2,2-difluorocyclopropane-1-carboxylic acid (Example 154a) and (R)-1- ((((2S,3R)-3-(3,3-difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)methyl)-2,2- difluorocyclopropane-1-carboxylic acid (Example 154b). Into a 8 mL vial were added (2S,3R)-8-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methoxy)-3-(3,3- difluorobutyl)-2-fluoro-5-(4-fluorophenyl)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide (154-5a) (40 mg, 0.07 mmol), dioxane (4 mL), water (2 mL), NaOH (5.29 mg, 0.13 mmol) and KMnO4 (36.56 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hr under nitrogen atmosphere. The precipitate was collected by filtration and washed with water (40 mL x 2). The filtrate was acidified to pH = 3 with 2 N aq. HCl solution. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Prep-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: 55% B to 70 % B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 7.42) to give Example 154a (14 mg, 34.8%, single diastereomer, the stereochemistry is arbitrarily assigned) as yellow solid. MS (ESI): calcd. for C25H22F9NO5S: 619.1; Found: 618.2 [M - 1]-. 1H NMR (400 MHz, CD3OD): δ 7.81 (s, 1H), 7.55 (s, 1H), 7.02 ‒ 6.92 (m, 2H), 6.75 ‒ 6.67 (m, 2H), 5.69 (d, J = 45.2 Hz, 1H), 4.84 ‒ 4.80 (m, 1H), 4.38 (d, J = 10.0 Hz, 1H), 4.19 (d, J = 16.0 Hz, 1H), 3.33 ‒ 3.29 (m, 1H), 2.80 ‒ 2.59 (m, 1H), 2.45 ‒ 2.34 (m, 1H), 2.21 ‒ 1.96 (m, 2H), 1.82 ‒ 1.53 (m, 5H) ppm. Following the same procedure for preparing Example 154a by replacing 154-5a with 154-5b (single diastereomer, 42 mg), Example 154b was obtained (14 mg, 33.1%, single diastereomer, the stereochemistry is arbitrarily assigned) as a yellow solid. Prep-HPLC condition: 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: 55% B to 70 % B in 8 min; Wavelength: 254 nm/220 nm; RT1 (min): 7.58. MS (ESI): calcd. for C25H22F9NO5S: 619.1; Found: 618.2 [M - 1]-.1H NMR (400 MHz, CD3OD): δ 7.82 (s, 1H), 7.55 (s, 1H), 7.02 ‒ 6.92 (m, 2H), 6.76 ‒ 6.67 (m, 2H), 5.69 (d, J = 45.2 Hz, 1H), 4.92 ‒ 4.90 (m, 1H), 4.34 (d, J = 10.0 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 3.29 - 3.25 (m, 1H), 2.79 ‒ 2.60 (m, 1H), 2.44 ‒ 2.33 (m, 1H), 2.24 ‒ 2.04 (m, 2H), 2.04 ‒ 1.93 (m, 1H), 1.83 ‒ 1.48 (m, 5H) ppm. Example 155.3-(3,3-Difluorobutyl)-5-(4-fluorophenyl)-2-methyl-8-(2-methyl-2-(2H- tetrazol-5-yl)propoxy)-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide Step 1. Synthesis of 3-((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanenitrile (155-2). To a solution of 3-(3,3-difluorobutyl)-5-(4-fluorophenyl)- 8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (155-1) (0.1 g, 0.2 mmol) in DMF (5 mL), 3-bromo-2,2-dimethylpropanenitrile and Cs2CO3 (0.16 g, 0.5 mmol) were added. The reaction vessel was tightly sealed, and the reaction mixture was stirred and heated at 100 °C for 24 h. After completion of the reaction the crude product was isolated and purified by HPLC to give 155-2 (79 mg, 70%) as an off- white solid. MS (ESI): calcd. for C25H27F6N3O3S: 563.2; Found: 562.2 [M -1]-. Step 2. Synthesis of 3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-8-(2-methyl-2- (2H-tetrazol-5-yl)propoxy)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (Example 155). To a solution of 3-((3- (3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanenitrile (155-2) (79 mg, 0.14 mmol) in toluene (15 mL), Bu2Sn(OAc)2 (2 eq.) and TMSN3 (0.086 g, 0.56 mmol) were added. The reaction vessel was tightly sealed, and the reaction mixture was stirred and heated at 150 °C microwave irradiation for 72 h. After completion of the reaction the crude product was isolated and purified by HPLC to give Example 155 (4 mg, 4%) as an off-white solid. MS (ESI): calcd. for C25H28F6N6O3S: 606.2; Found: 605.2 [M - 1]-.1H NMR (500 MHz, CD3CN): δ 7.62 (s, 1H), 7.49 (s, 1H), 6.97 (t, J = 8.9 Hz, 2H), 6.69 (t, J = 6.5 Hz, 2H), 4.47 – 4.39 (m, 2H), 4.12 – 3.80 (m, 3H), 3.34 (d, J = 2.6 Hz, 1H), 2.58 (s, 3H), 1.99 (s, 3H), 1.65 (t, J = 18.8 Hz, 3H), 1.59 (d, J = 3.1 Hz, 6H) ppm. Example 156.1-(((3-(3,3-Difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-sulfonic acid
Step 1. Synthesis of butyl 3-chloropropane-1-sulfonate (156-2). A solution of 3- chloropropane-1-sulfonyl chloride (156-1) (15.0 g, 85.25 mmol) in DCM (75 mL) was added dropwise to a mixture of n-butanol (6.95 g, 93.80 mmol) and trimethylamine (11.21 g, 11.08 mmol) in DCM (70 mL) at 0 °C, and the reaction mixture was stirred at rt for 4 h. Upon completion of the reaction, the reaction mixture was diluted with DCM (100 mL), washed with water (75 mL x 3) and brine (75 mL), dried over Na2SO4, and concentrated. The residue was dried in vacuo to give 156-2 (17.3 g, 94.5%) as a yellow oil, which was used in the next step without further purification. Step 2. Synthesis of butyl cyclopropanesulfonate (156-3). Butyl 3-chloropropane-1- sulfonate (156-2) (8.0 g, 37.4 mmol) in THF (40 mL) and n-butyllithium (23% in hexanes) (16.85 mL, 41.12 mmol) were added dropwise simultaneously to a cooled THF (-78°C) (160 mL), while maintaining the temperature below -70°C during the addition. The reaction mixture was stirred at -78 oC for 3 h and then warmed up to 0 °C. Subsequently, sat. aq. NH4Cl solution (100 mL) was added to quench the reaction, and the resulting mixture was then separated into phases. The aqueous phase was further extracted with EtOAc (75 mL x 2). Then the combined organic extracts were evaporated to dryness. The residue was dissolved in EtOAc (250 mL), washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to give 156-3 (5.0 g, 75.0%)as a yellow oil, which was used in the next step without further purification. Step 3. Synthesis of butyl 1-formylcyclopropane-1-sulfonate (156-4). N-butyllithium (23% in hexanes) (6.32 mL, 15.45 mmol) was added dropwise to a solution of butyl cyclopropanesulfonate (156-3) (2.5 g, 14.03 mmol) in THF (50 mL) at -78°C. After stirring at -78°C for 45 min, a solution of anhydrous DMF (2.17 mL, 28.04 mmol) in THF (5 mL) was added dropwise to the reaction mixture and the resulting mixture was warmed to room temperature for 4 h. Subsequently, the reaction mixture was quenched with sat. aq. NH4Cl solution, and the phases were subsequently separated. The aqueous phase was further extracted with EtOAc (30 mL), and then the combined organic extracts were concentrated. The residue was dissolved in EtOAc (75 mL), washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, and concentrated. and the solvent was removed in vacuum. The residue was dried in vacuo to give crude 156-4 (1.8 g, 20% purity per HNMR), which was used in the next step without further purification. Step 4. Synthesis of butyl 1-(hydroxymethyl)cyclopropane-1-sulfonate (156-5). Butyl 1- formylcyclopropane-1-sulfonate (156-5) (1.8 g) was dissolved in methanol (18 mL) and cooled to 0°C. Sodium borohydride (133 mg, 3.5 mmol) was added to the reaction mixture in portions, and the resulting mixture was stirred at rt for 3 h. Upon completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with DCM (30 mL). The mixture was washed with water (10 mL x 3) and brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to give 156-5 (120 mg, 33.0%) as a yellow oil. Step 5. Synthesis of butyl 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-sulfonate (156-6). Triphenylphosphine (54.6 mg, 0.21 mmol), butyl 1-(hydroxymethyl)cyclopropane-1-sulfonate (156-5) (43.4 mg, 0.21 mmol) and DIAD (42.1 mg, 2.1 mmol) were added sequentially to an ice-cooled solution of 3-(3,3- difluorobutyl)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (155-1) (50 mg, 0.1 mmol) in THF (2.5 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was purified by prep-HPLC to give 156-6 (33 mg, 47.1%) as an off-white solid. MS (ESI): calcd. for C28H34F6N2O6S2: 672.2; Found: 671.2 [M - 1]-. Step 6. Synthesis of 1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-sulfonic acid (Example 156). Potassium thiocyanate (5 mg, 51.55 µmol) was added to a stirred mixture of butyl 1-(((3-(3,3-difluorobutyl)-5-(4- fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropane-1-sulfonate (156-6) (33 mg, 49.1 µmol) in DCE (0.25 mL) and water (0.25 mL). The reaction vessel was tightly sealed, and the reaction mixture was allowed to react at 95°C overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature and 1 N aq. HCl solution was added. The crude product was purified by prep-HPLC to give Example 156 (9.3 mg, 30.8%) as an off-white solid. MS (ESI): calcd. for C24H26F6N2O6S2: 616.1; Found: 615.2 [M - 1]-.1H NMR (500 MHz, DMSO-d6): δ 7.54 (s, 1H), 7.50 (s, 1H), 7.00 (t, J = 8.7 Hz, 2H), 6.67 (s, 2H), 4.57 – 4.47 (m, 2H), 4.07 (d, J = 16.2 Hz, 1H), 3.80 (s, 1H), 3.29 (s, 2H), 2.53 (s, 3H), 2.03 – 1.92 (m, 2H), 1.81 (d, J = 7.8 Hz, 1H), 1.62 (t, J = 18.9 Hz, 4H), 0.93 (dt, J = 4.3, 2.2 Hz, 2H), 0.76 (d, J = 2.8 Hz, 2H) ppm. Example 157.1-(((3-(3,3-Difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropane-1-sulfonic acid Step 1. Synthesis of diethyl (1-formylcyclopropyl)phosphonate (157-2). N-butyllithium (23% in hexanes) (2.54 mL, 6.20 mmol) was added dropwise to a solution of diethyl cyclopropylphosphonate (157-1) (1.0 g, 5.64 mmol) in THF (10 mL) at -78°C, and the reaction mixture was allowed to react for 45 min at this temperature. Then a solution of ethyl formate (0.68 mL, 8.46 mmol) in THF (3.5 mL) was added dropwise to the reaction mixture, and the resulting mixture was warmed up to room temperature and stirred for 4 h. Subsequently, the reaction mixture was quenched by the addition of sat. aq. NH4Cl (5 mL). The aqueous phase was further extracted with EtOAc (10 mL), and the combined organic extracts were combined and concentrated. The residue was dissolved in EtOAc (25 mL), washed with water (5 mL x 2) and brine (10 mL), dried over Na2SO4, and concentrated. The reside was dried in vacuo to give crude 157-2 (0.7 g, 70% purity per HNMR) as a light- brown oil, which was used in the next step without further purification. Step 2. Synthesis of ethyl (1-(hydroxymethyl)cyclopropyl)(propyl)phosphinate (157-3). Diethyl (1-formylcyclopropyl)phosphonate (157-2) (0.7 g 70% purity, 1.75 mmol) was dissolved in methanol (7 mL) and cooled to 0°C. Sodium borohydride (258 mg, 6.78 mmol) was added to the reaction mixture in portions. After stirring at rt for 3 h, the reaction mixture was concentrated. The residue was dissolved in DCM (20 mL), and the mixture was washed with water (5 mL x 3) and brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 157-3 (90 mg, 13.0%) as a yellow oil. Step 3. Synthesis of (1-(diethoxyphosphoryl)cyclopropyl)methyl methanesulfonate (157- 4). To а solution of ethyl (1-(hydroxymethyl)cyclopropyl)(propyl)phosphinate (157-3) (90 mg, 0.45 mmol) in DCM (2 mL) and triethylamine (54 mg, 0.54 mmol) at 0°C, mesyl chloride (56 mg, 0.5 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the resulting residue was dissolved in EtOAc (3 mL). The organic layer was washed with water (1 mL x 2) and brine (1 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 157-4 (85 mg, 69.1%, 95 % NMR purity) as a yellow oil, which was used in the next step without further purification. Step 4. Synthesis of diethyl (1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropyl)phosphonate (157-5).3-(3,3-Difluorobutyl)-5-(4-fluorophenyl)- 8-hydroxy-2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1- dioxide (155-1) (58.9 mg, 0.12 mmol), cesium carbonate (119 mg, 0.37 mmol), and (1- (diethoxyphosphoryl)cyclopropyl)methyl methanesulfonate (157-4) (70 mg, 0.24 mmol) were mixed in DMF (2 mL). After stirring at 75°C for 16 h, the reaction mixture was cooled to rt and filtered through a cotton plug. The filtrate was purified by prep-HPLC to give 157-5 (46 mg, 56.0%) as an off-white solid. MS (ESI): calcd. for C28H35F6N2O6PS: 672.2; Found 671.2 [M-1]-. Step 5. Synthesis of (1-(((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)methyl)cyclopropyl)phosphonic acid (Example 157). To a solution of diethyl (1- (((3-(3,3-difluorobutyl)-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)methyl)cyclopropyl)phosphonate (157-5) (46 mg, 68.39 µmol) in anhydrous DCM (2 mL), pyridine (54.7 mg, 0.69 mmol) and TMSBr (210.5 mg, 1.39 mmol) were respectively added and the reaction mixture was stirred at rt overnight. Subsequently, the resulting solution was acidified with 3 N aq. HCl solution to pH ~2, diluted with DMSO (3 mL) and purified by prep-HPLC to give Example 157 (23.2 mg, 54.3%) as an off-white solid. MS (ESI): calcd. for C24H27F6N2O6PS: 616.1; Found 615.1 [M- 1]-.1H NMR (500 MHz, DMSO-d6): δ 7.51 (d, J = 6.4 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 6.68 (s, 2H), 4.42 – 4.23 (m, 2H), 4.08 (d, J = 16.1 Hz, 1H), 3.78 (d, J = 19.2 Hz, 1H), 3.49 (s, 1H), 2.53 (d, J = 3.0 Hz, 3H), 1.98 (dt, J = 17.0, 9.0 Hz, 2H), 1.89 – 1.74 (m, 1H), 1.62 (t, J = 18.9 Hz, 4H), 0.99 – 0.88 (m, 2H), 0.88 – 0.81 (m, 2H) ppm. Examples 158a and 158b. (S)-3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8- yl)oxy)-2,2-dimethylpropanoic acid (158a) and (R)-3-((5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (158b)
Step 1. Synthesis of tert-butyl N-4,4,4-trifluoro-1-[(4- fluorophenyl)carbamoyl]butylcarbamate (158-2). To a reactor containing a solution of 2- [(tert-butoxy)carbonyl]amino-5,5,5-trifluoropentanoic acid (158-1) (10.0 g, 36.89 mmol) in DCM (100 mL) was added 1H-1,2,3-benzotriazol-1-ol (5.48 g, 40.57 mmol) and (3- [(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (8.46 g, 44.26 mmol). After stirring at rt for 20 min, the mixture was cooled to 0°C and triethylamine (9.32 g, 92.22 mmol) and 4-fluoroaniline (4.1 g, 36.89 mmol) were added. Subsequently, the mixture was stirred at rt overnight and then concentrated. The residue was diluted with MTBE (250 mL) and the resulting mixture was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 158-2 (9 g, 90 %) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C16H20F4N2O3: 364.1; Found: 363.1 [M-1]-. Step 2. Synthesis of 2-amino-5,5,5-trifluoro-N-(4-fluorophenyl)pentanamide (158-3). To а solution tert-butyl N-4,4,4-trifluoro-1-[(4-fluorophenyl)carbamoyl]butylcarbamate (158-2) (9.0 g, 24.7 mmol) in DCM (20 mL) at 0 °C, а solution of 4 M HCl in 1,4-dioxane (10 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was quenched with saturated aq. NаНСОз solution. The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 158-3 (6.2 g, 68.9 %) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C11H12F4N2O: 264.1; Found: 263.1 [M-1]-. Step 3. Synthesis of 5,5,5-trifluoro-N1-(4-fluorophenyl)pentane-1,2-diamine (158-4). То а solution of 2-amino-5,5,5-trifluoro-N-(4-fluorophenyl)pentanamide (158-3) (6.2 g, 23.47 mmol) in THF (100 mL) at 0 °C was added (methylsulfanyl)methane borane (17.85 g, 117.33 mL) and the reaction mixture was heated at 75°C for 16 h. The reaction mixture was cooled to 0°C and added methanol (25 mL). After stirring at rt for 30 min, the mixture was concentrated. The residue was treated with 3 N aq. HCl solution (10 mL). The mixture was then adjusted to pH 10 with saturated aq. NаOН solution. The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), and dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 158-4 (4 g, 64.5%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C11H14F4N2: 250.1; Found: 249.1 [M-1]-. Step 4. Synthesis of 2-bromo-5-methoxy-N-5,5,5-trifluoro-1-[(4- fluorophenyl)amino]pentan-2-yl-4-(trifluoromethyl)benzene-1-sulfonamide (158-5). То а solution of 5,5,5-trifluoro-N1-(4-fluorophenyl)pentane-1,2-diamine (158-4) (4.7 g, 18.78 mmol) in THF at 0°C were added 2-bromo-5-methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (6.61 g, 18.78 mmol) and triethylamine (3.8 g, 37.56 mmol). After stirring at rt for 4 h, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 mL), and the mixture was washed with water 25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 158-5 (4.6 g, 97.8 %) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C19H19BrF6N2O3S: 548.0; Found: 547.0 [M-1]-.1H NMR (500 MHz, CDCl3): δ 7.79 (s, 1H), 7.53 (s, 1H), 6.77 (t, J = 8.8 Hz, 2H), 6.15 (m, 2H), 5.3 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 3.59 (m, 1H), 3.52 (m, 1H), 3.16 (m, 1H), 3.03 (m, 1H), 2.39 (m, 1H), 2.24 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H) ppm. Step 5. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-6). То а solution of 2-bromo-5-methoxy-N-5,5,5-trifluoro-1-[(4-fluorophenyl)amino]pentan-2- yl-4-(trifluoromethyl)benzene-1-sulfonamide (158-5) (4.5 g, 7.93 mmol) in DMF were added copper iodide (301.14 mg, 1.59 mmol), pyridine-2-carboxylic acid (195.17 mg, 1.59 mmol) and dipotassium carbonate (3.28 g, 23.8 mmol). The reaction mixture was degassed for 5 minutes under Ar and the reaction mixture was then stirred at 90°C overnight. After completion of the reaction, the reaction mixture was quenched with ice cold water and the aqueous layer was extracted with MTBE. The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 158-6 (3 g, 65.2%), which was used in the next step without further purification. MS (ESI): calcd. for C19H17F7N2O3S: 486.1; Found: 485.1 [M - H]-. Step 6. Synthesis of 5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-7). Cesium carbonate (6.03 g, 18.51 mmol) and iodomethane (2.63 g, 18.51 mmol) were added to a solution of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)- 2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-6) (3.0 g, 6.17 mmol) in DMF. The resulting solution was stirred at 60°C overnight. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was purified by prep- HPLC to give 158-7 (3 g, 96.8%) as an off-white solid. MS (ESI): calcd. for C20H19F7N2O3S: 500.1; Found: 505.1 [M +1]+. Step 7. Synthesis of 5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-8). To a solution of 5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-7) (3.0 g, 5.99 mmol) in DMF was added sodium hydride (1.01 g, 41.97 mmol) (under argon atmosphere). Then methanethiol (2.94 g, 41.97 mmol) was bubbled until the precipitate was dissolved and the resulting mixture was stirred at 40°C overnight. Subsequently, sat. aq. citric acid solution (50 mL) was added, the precipitate was collected and purified by silica gel column chromatography to give 158-8 (1.5 g, 50%). MS (ESI): calcd. for C19H17F7N2O3S: 486.1; Found: 485.1 [M -1]-.1H NMR (500 MHz, DMSO-d6): δ 11.43 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.00 (t, J = 8.7 Hz, 2H), 6.65 (m, 2H), 4.10 (m, 1H), 3.88 (m, 1H), 3.36 (m, 1H), 2.54 (s, 3H), 2.40 (m, 1H), 2.34 (m, 1H), 1.91 (m, 1H), 1.70 (m, 1H) ppm. Step 8. Synthesis of methyl 3-[5-(4-fluorophenyl)-2-methyl-1,1-dioxo-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-1lambda6,2,5- benzothiadiazepin-8-yl]oxy-2,2-dimethylpropanoate (158-9). To a solution of 5-(4- Fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydro-1lambda6,2,5-benzothiadiazepine-1,1-dione (158-8) (250.0 mg, 513.98 µmol) in DMF was added cesium carbonate (502.9 mg, 1.54 mmol) and methyl 3-bromo-2,2- dimethylpropanoate (299.45 mg, 1.54 mmol) at rt. The resulting solution was stirred at 60°C overnight. After completion of the reaction, the reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC to give 158-9 (125 mg, 50%). MS (ESI): calcd. for C25H27F7N2O5S: 600.2; Found: 599.2 [M -1]-.1H NMR (500 MHz, DMSO- d6): δ 7.49 (s, 1H), 7.32 (s, 1H), 6.95 (t, J = 7.8 Hz, 2H), 6.74 (m, 2H), 4.09 (m, 2H), 3.9 (m, 2H), 3.69 (s, 3H), 3.55 (m, 1H), 2.33 (m, 1H), 2.22 (m, 1H), 1.91 (m, 1H), 1.74 (m, 1H), 1.33 (s, 6H) ppm. Steps 9 and 10. Synthesis of (S)-3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 158a) and (R)-3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-3-(3,3,3- trifluoropropyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 158b). Chiral separation (Step 9) of methyl 3-[5-(4- fluorophenyl)-2-methyl-1,1-dioxo-7-(trifluoromethyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5- tetrahydro-1lambda6,2,5-benzothiadiazepin-8-yl]oxy-2,2-dimethylpropanoate (158-9) (Condition: Column: CHIRALCEL OD-H (250×20 mm, 5 µm)-OD11_2020_RMK-RMK; Mobile Phase: Hexane/IPA/MeOH = 80/10/10 (v/v/v); Flow Rate: 12 mL/min), followed by saponification (Step 10) with LiOH in dioxane/water = 5/1 (v/v) to give Example 158a (single enantiomer, 14.1 mg, 36.1%) and Example 158b (single enantiomer, 17.7 mg, 45.3%), respectively Example 158a: Analytic chiral HPLC method: Column: Chiralpak AD-H (250×4.6 mm, 5 µm)-ADH0CE-BO021-14; Mobile Phase: Hexane (0.1%TFA)/IPA = 80/20 (v/v); Flow Rate: 0.6 mL/min; RT (min): 17.01; Purity: 100%. MS (ESI): calcd. for C24H25F7N2O5S: 586.1; Found: 587.2 [M + H]+.1H NMR (500 MHz, CD3CN): δ 7.61 (s, 1H), 7.52 (s, 1H), 6.99 (t, J = 8.7 Hz, 2H), 6.72 (dd, J = 9.2, 4.6 Hz, 2H), 4.26 – 4.18 (m, 2H), 3.98 (s, 2H), 3.47 (d, J = 82.4 Hz, 1H), 2.60 (s, 3H), 2.37 (dtp, J = 21.3, 10.3, 6.1, 5.3 Hz, 2H), 1.92 – 1.80 (m, 2H), 1.32 (d, J = 2.2 Hz, 6H) ppm. Example 158b: Analytic chiral HPLC method: Column: Chiralpak AD-H (250×4.6 mm, 5 µm)-ADH0CE-BO021-14; Mobile Phase: Hexane (0.1%TFA)/IPA = 80/20 (v/v); Flow Rate: 0.6 mL/min; RT (min): 11.48; Purity: 98.93 %. MS (ESI): calcd. for C24H25F7N2O5S: 586.1; Found: 587.2 [M + H]+.1H NMR (500 MHz, CD3CN): δ 7.62 (s, 1H), 7.52 (s, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.72 (dd, J = 9.2, 4.5 Hz, 2H), 4.26 – 4.16 (m, 2H), 3.99 (s, 2H), 3.40 (s, 1H), 2.36 (ddq, J = 19.8, 8.9, 5.7, 4.6 Hz, 2H), 1.92 – 1.76 (m, 2H), 1.32 (d, J = 2.3 Hz, 6H) ppm. Example 159.3-((3',3'-Diethyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)- 4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cyclobutan]-8-yl)oxy)-2,2- dimethylpropanoic acid Step 1. Synthesis of 1-amino-3,3-diethylcyclobutane-1-carbonitrile (159-2). To a solution of 3,3-diethylcyclobutan-1-one (159-1) (10.0 g, 79.3 mmol) in methanol/water (1:1 (v/v)) (100 mL) was added potassium iminomethanide (15.46 g, 237.89 mmol), followed by ammonium chloride (12.61 g, 237.89 mmol). After stirring at rt for 2 days, the reaction mixture was concentrated to remove organic solvent and the residue was extracted with DCM (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give 159-2 (10.5g, 87.0%) as a brown oil, which was used in next step without further purification. Step 2. Synthesis of N-(1-cyano-3,3-diethylcyclobutyl)acetamide (159-3). To a solution of 1-amino-3,3-diethylcyclobutane-1-carbonitrile (159-2) (10.5 g, 69.02 mmol) and triethylamine (16.75 g, 165.65 mmol) in DCM (150 mL) was added acetyl anhydride (10.56 g, 103.53 mmol) at -30°C. After stirring at rt overnight, the mixture was diluted with water (50 mL). The organic layer was washed with sat. aq. NaHSO4 solution, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 159-3 (12 g, 89.5%) as a brown oil, which was used in the next step without further purification. Step 3. Synthesis of 1-carboxy-3,3-diethylcyclobutan-1-aminium chloride (159-4). A solution of N-(1-cyano-3,3-diethylcyclobutyl)acetamide (159-3) (12.0 g, 61.8 mmol) in methanol (150 mL) was added acetyl chloride (48.2 g, 618.1 mmol) at -30°C. After stirring at rt overnight, the reaction was mixture was concentrated. The residue was diluted with sat. aq. HCl solution and the resulting mixture was refluxed for 5 h. Subsequently, the mixture was concentrated to give 159-4 (8.0 g, 62.3%) as a brown oil, which was used in the next step without further purification. Step 4. Synthesis of 1-[(tert-butoxy)carbonyl]amino-3,3-diethylcyclobutane-1-carboxylic acid (159-5). To a solution of sodium hydroxide (7.72 g, 193.14 mmol) in water/THF (150 mL/150 mL), 1-amino-3,3-diethylcyclobutane-1-carboxylic acid hydrochloride (159-4) (8.0 g, 38.63 mmol) was added, followed by di-tert-butyl dicarbonate (10.11 g, 46.35 mmol) at 0 oC. After stirring at rt overnight, the reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give 159-5 (5 g, 47.7%) as a brown oil, which was used in the next step without further purification. Step 5. Synthesis of tert-butyl N-3,3-diethyl-1-[(4- fluorophenyl)carbamoyl]cyclobutylcarbamate (159-6). To a solution of 1-[(tert- butoxy)carbonyl]amino-3,3-diethylcyclobutane-1-carboxylic acid (159-5) (7.6 g, 28.0 mmol) in DCM (150 mL) was added 1H-1,2,3-benzotriazol-1-ol (4.16 g, 30.8 mmol) and 4- fluoroaniline (3.11 g, 28.0 mmol) at rt. After stirring at rt for 15 min, the mixture was cooled to -30°C, followed by adding (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (6.43 g, 33.6 mmol) and triethylamine (7.08 g, 70.1 mmol). The resulting mixture was stirred at rt overnight and then washed with sat. aq. NH4Cl solution (50 mL x 2) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 159-6 (8.1 g, 79.3%) as an off-white solid. MS (ESI): calcd. for C20H29FN2O3: 364.2; Found: 263.2 [M -Boc - 1]-. Step 6. Synthesis of 1-amino-3,3-diethyl-N-(4-fluorophenyl)cyclobutane-1-carboxamide (159-7). To а solution of tert-butyl N-3,3-diethyl-1-[(4- fluorophenyl)carbamoyl]cyclobutylcarbamate (159-6) (8.1 g, 22.23 mmol) in DCM (50 mL) at 0°C was added 4N HCl in 1,4-dioxane (10 mL) at rt. After stirring at rt for 16 h, the reaction mixture was concentrated. The residue was diluted with saturated aq. NаНСО3 solution (100 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic layer extracts were washed brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 159-7 (4.4 g, 74.9%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C15H21FN2O: 264.2; Found: 263.2 [M - 1]-. Step 7. Synthesis of N-[(1-amino-3,3-diethylcyclobutyl)methyl]-4-fluoroaniline (159-8). То а solution of 1-amino-3,3-diethyl-N-(4-fluorophenyl)cyclobutane-1-carboxamide (159-7) (4.4 g, 16.65 mmol) in THF (150 mL) at 0°C was added (methylsulfanyl)methane borane (12.66 g, 83.22 mL) at rt. After stirring at 75°C for 16 h, the reaction mixture was cooled to 0 °C, followed by adding methanol (50 mL). The mixture was stirred at rt for 30 min and then concentrated. The residue was added 3 N aq. HCl solution (20 mL) and then adjusted to pH 9 with saturated aq. NаOН solution. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 159-8 (3g, 72%) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C15H23FN2: 250.2; Found: 249.2 [M - 1]-. Step 8. Synthesis of 2-bromo-N-(3,3-diethyl-1-[(4- fluorophenyl)amino]methylcyclobutyl)-5-methoxy-4-(trifluoromethyl)benzene-1- sulfonamide (159-9). То а solution of N-[(1-amino-3,3-diethylcyclobutyl)methyl]-4- fluoroaniline (159-8) (3.0 g, 11.98 mmol) in THF (50 mL) at 0 °C were added 2-bromo-5- methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (4.22 g, 11.98 mmol) and triethylamine (1.45 g, 14.38 mmol) at rt. After stirring at rt for 4 h, the reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL) and the mixture was washed with sat. aq. NH4Cl solution (25 mL), sat. aq. NaHCO3 solution (25 mL), and brine (25mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give 159-9 (1.8 g, 26.5%). MS (ESI): calcd. for C23H27BrF4N2O3S: 566.1; Found: 565.1 [M - 1]-. Step 9. Synthesis of 3',3'-diethyl-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-4,5- dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'-cyclobutane]-1,1-dione (159- 10). То а solution of 2-bromo-N-(3,3-diethyl-1-[(4-fluorophenyl)amino]methylcyclobutyl)-5- methoxy-4-(trifluoromethyl)benzene-1-sulfonamide (159-9) (1.8 g, 3.17 mmol) in DMF, copper (199.58 mg, 3.17 mmol) and dipotassium carbonate (874.77 mg, 6.34 mmol) were added. The reaction mixture was degassed for 5 min under Ar atmosphere and the reaction mixture was then heated at 100°C overnight. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with MTBE (100 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 159-10 (1.5 g, 97.3%), which was used in the next step without further purification. MS (ESI): calcd. for C23H26F4N2O3S: 486.2; Found: 485.2 [M - 1]-. Step 10. Synthesis of 3',3'-diethyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'- cyclobutane]-1,1-dione (159-11).3',3'-Diethyl-5-(4-fluorophenyl)-8-methoxy-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'-cyclobutane]- 1,1-dione (159-10) (1.5 g, 3.08 mmol) was dissolved in DMF, then dipotassium carbonate (1.28 g, 9.25 mmol) and iodomethane (1.31 g, 9.25 mmol) were added. After stirring at 65°C overnight, the reaction mixture was concentrated. The residue was purified by prep-HPLC to give 159-11 (1 g, 64.9%) as an off-white solid. MS (ESI): calcd. for C24H28F4N2O3S: 500.2; Found: 499.2 [M - 1]-. Step 11. Synthesis of 3',3'-diethyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'- cyclobutane]-1,1-dione (159-12). To a reactor containing a solution of 3',3'-diethyl-5-(4- fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5- benzothiadiazepine-3,1'-cyclobutane]-1,1-dione (159-11) (150.0 mg, 299.67 µmol) in NMP (1 mL) was added lithium iodide (401.88 mg, 3.0 mmol). After stirring at 130 °C overnight, the mixture was purified by prep-HPLC to give 159-12 (49 mg, 33.6%). MS (ESI): calcd. for C23H26F4N2O3S: 486.2; Found: 485.2 [M - 1]-. Step 12. Synthesis of methyl 3-[3',3'-diethyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxo-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'- cyclobutan]-8-yloxy]-2,2-dimethylpropanoate (159-13). To a reactor containing a solution of 3',3'-diethyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-4,5-dihydro-2H- spiro[1lambda6,2,5-benzothiadiazepine-3,1'-cyclobutane]-1,1-dione (159-12) (49.0 mg, 100.71 µmol) in DMF (1 mL) was added methyl 3-bromo-2,2-dimethylpropanoate (29.31 mg, 151.08 µmol), followed by dicesium carbonate (49.22 mg, 151.08 µmol). After stirring at rt overnight, the mixture was purified by prep-HPLC to give 159-13 (21 mg, 35.0%) as an off-white solid. MS (ESI): calcd. for C29H36F4N2O5S: 600.2; Found: 599.2 [M - 1]-. Step 13. Synthesis of (3-[3',3'-diethyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxo-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'- cyclobutan]-8-yloxy]-2,2-dimethylpropanoic acid (Example 159). To a stirred solution of methyl 3-[3',3'-diethyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxo-7-(trifluoromethyl)-4,5- dihydro-2H-spiro[1lambda6,2,5-benzothiadiazepine-3,1'-cyclobutan]-8-yloxy]-2,2- dimethylpropanoate (159-13) (21.0 mg, 34.96 µmol) in a mixture of 1,4-dioxane and water (1 mL, 5:1 (v/v)), lithium hydrate hydroxide (2.94 mg, 69.89 µmol) was added. After stirring at rt for 12 h, the mixture was added several drops of 2 N aq. HCl solution. The resulting mixture was purified by prep-HPLC to give Example 159 (15.6 mg, 88.6%). MS (ESI): calcd. for C28H34F4N2O5S: 586.2; Found: 587.0 [M+1]+.1H NMR (500 MHz, CDCl3): δ 7.50 (s, 1H), 6.96 (d, J = 6.4 Hz, 5H), 4.10 (s, 2H), 2.56 (s, 3H), 2.34 (s, 1H), 1.99 (s, 2H), 1.70 (s, 1H), 1.66 – 1.40 (m, 6H), 1.38 (s, 6H), 0.72 (t, J = 7.3 Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H) ppm. Example 160. (R)-3-((5-(4-Fluorophenyl)-2-methyl-3-(2-(methylsulfonyl)ethyl)-1,1-dioxido- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid
Step 1. Synthesis of (R)-tert-butyl 1-(4-fluorophenylamino)-4-(methylthio)-1-oxobutan- 2-ylcarbamate (160-2). A stirred solution of (R)-2-(tert-butoxycarbonylamino)-4- (methylthio)butanoic acid (160-1) (5 g, 20 mmol), 4-fluoroaniline (3.4 g, 30 mmol) and TEA (4 g, 40 mmol) in THF (50 mL) was added HATU (9.2 g, 24 mmol). The reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction was quenched with water (100 mL) and extracted with EA (100 mL x 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE) to give 160-2 (6.5 g, 95%) as a white solid. TLC: 20% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C16H23FN2O3S: 342.1; Found: 287.1 [M -56+ 1]+. Step 2. Synthesis of (R)-2-amino-N-(4-fluorophenyl)-4-(methylthio)butanamide (160-3). To a stirred solution of (R)-tert-butyl 1-(4-fluorophenylamino)-4-(methylthio)-1-oxobutan-2- ylcarbamate (160-2) (6.5 g, 19 mmol) in DCM (30 ml), TFA (15 ml) was added dropwise at 0 oC. The resulting reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under vacuum to remove DCM and TFA. The residue was dissolved with EA (50 ml) and diluted with H2O (20 ml). Then saturated aq. NaHCO3 solution was added dropwise until pH > 7, and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (3% MeOH/DCM (v/v)) to give 160-3 (3.4 g, 74%) as a colorless oil. TLC: 3% MeOH/DCM (v/v) (Rf: 0.2). MS (ESI): calcd. for C11H15FN2OS: 242.1; Found: 243.3 [M + 1]+. Step 3. Synthesis of (R)-N1-(4-fluorophenyl)-4-(methylthio)butane-1,2-diamine (160-4). To a stirred solution of (R)-2-amino-N-(4-fluorophenyl)-4-(methylthio)butanamide (160-3) (3.4 g, 14 mmol) in anhydrous THF (34 mL) was added LiAlH4 (1.6 g, 42 mmol) portion- wise below 10 oC under Ar atmosphere. After stirring at 65 oC for 4 hr under an Ar atmosphere, the reaction mixture was quenched with ice-cold water (1.6 mL) and 15% NaOH (1.6 ml). The mixture was dried over anhydrous Na2SO4 and filtered through a Celite® pad. The filtrate was concentrated, and the residue was dried in vacuo to give crude 160-4 (3.2 g, 100%) as colorless oil, which was used in the next step without further purification. TLC: 5% MeOH/DCM (v/v) (Rf: 0.2). MS (ESI): calcd. for C11H17FN2S: 228.1; Found: 229.2 [M + 1]+. Step 4. Synthesis of (R)-2-bromo-N-(1-(4-fluorophenylamino)-4-(methylthio)butan-2- yl)-5-methoxy-4-(trifluoromethyl)benzenesulfonamide (160-5). To a stirred solution of (R)-N1-(4-fluorophenyl)-4-(methylthio)butane-1,2-diamine (160-4) (3.2 g, 14 mmol) and TEA (2.8 g, 28 mmol) in anhydrous DCM (32 mL) was added a solution of 2-bromo-5- methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (5.9 g, 16.8 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 3 hours. 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 DCM (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (18% EA/PE (v/v)) to afford 160-5 (7.0 g, 88%) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C19H21BrF4N2O3S2: 544.0; Found: 545.0 [M + 1]+. Step 5. Synthesis of ethyl (R)-5-(4-fluorophenyl)-8-methoxy-3-(2-(methylthio)ethyl)-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-6). To a stirred solution of (R)-2-bromo-N-(1-(4-fluorophenylamino)-4-(methylthio)butan-2-yl)- 5-methoxy-4-(trifluoromethyl)benzenesulfonamide (160-5) (7.0 g, 12.9 mmol) and K2CO3 (3.6 g, 25.8mmol) in DMF (35 mL) was added Cu (826 mg, 12.9 mmol). After stirring at 115 °C for 16 h, the reaction mixture was diluted with saturated NH4Cl (30 mL), and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 160-6 (5.0 g) as a yellow solid, which was used in the next step without further purification. TLC: 20% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C19H20F4N2O3S2: 464.1; Found: 465.0 [M + 1]+. Step 6. Synthesis of (R)-5-(4-fluorophenyl)-8-methoxy-2-methyl-3-(2-(methylthio)ethyl)- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-7): To a stirred solution of (R)-5-(4-fluorophenyl)-8-methoxy-3-(2-(methylthio)ethyl)-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-6) (5.0 g, crude product, 10.8 mmol) and Cs2CO3 (7.0 g, 21.6 mmol) in DMF (30 mL) was added MeI (3.0 g, 21.6 mmol), and the reaction was stirred at room temperature for 5 hours. After completion of the reaction (monitored by LCMS), the reaction was quenched with ice-cold water (50 ml) and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 160-7 (500 mg, 10%) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C20H22F4N2O3S2: 478.1; Found: 479.0 [M + 1]+. Step 7. Synthesis of (R)-5-(4-fluorophenyl)-8-methoxy-2-methyl-3-(2- (methylsulfonyl)ethyl)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-8). To a stirred solution of (R)-5- (4-fluorophenyl)-8-methoxy-2-methyl-3-(2-(methylthio)ethyl)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-7) (400 mg, 0.84 mmol) in anhydrous DCM (4 mL) was added 3-chlorobenzoperoxoic acid (m-CPBA) (433 mg, 2.5 mmol) at 0°C. The reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction was quenched with 10% aq. Na2S2O3 solution, and the aqueous layer was extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (50% EA/PE (v/v)) to give 160-8 (306 mg, 72%) as a brown solid. TLC: 50% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C20H22F4N2O5S2: 510.1; Found: 511.0 [M + 1]+. Step 8. Synthesis of (R)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-3-(2- (methylsulfonyl)ethyl)-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-9). To a stirred solution of (R)-5- (4-fluorophenyl)-8-methoxy-2-methyl-3-(2-(methylsulfonyl)ethyl)-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-8) (306 mg, 0.6 mmol) in DMF (5 mL) was added LiCl (504 mg, 12 mmol) and the reaction was heated at 130 °C for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water (20 mL) and the aqueous layer was extracted with EA (30 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by Isolera column chromatography (50% EA/PE (v/v)) to 160-9 (170 mg, 57%) as a yellow solid. TLC: 50% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C19H20F4N2O5S2: 496.1; Found: 514.0 [M + 18]+. Step 9. Synthesis of (R)-ethyl 3-((5-(4-fluorophenyl)-2-methyl-3-(2- (methylsulfonyl)ethyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate (160-10). To a stirred solution of (R)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-3-(2-(methylsulfonyl)ethyl)-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (160-9) (170 mg, 0.34 mmol) and Cs2CO3 (166 mg, 0.51 mmol) in DMF (2 mL) was added ethyl 2, 2- dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (142 mg, 0.51 mmol). The reaction was stirred at 100 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction was poured into water (10 mL) and extracted with EA (15 mL x 3). The combined organic layer was washed with water (10 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (30% EA/PE (v/v)) to give 160-10 (170 mg, 80%) as a white solid. TLC: 30% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C26H32F4N2O7S2: 624.2; Found: 625.2 [M + 1]+. Step 10. Synthesis of (R)-3-((5-(4-fluorophenyl)-2-methyl-3-(2-(methylsulfonyl)ethyl)- 1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)- 2,2-dimethylpropanoic acid (Example 160). To a stirred solution of (R)-ethyl 3-((5-(4- fluorophenyl)-2-methyl-3-(2-(methylsulfonyl)ethyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate (160-10) (170 mg, 0.27 mmol) in dioxane/H2O (1.2 mL/0.4 mL) was added LiOH (34 mg, 0.82 mmol). After stirring at rt for 16 hr, the reaction mixture was added several drops of 2N aq. HCl solution. The resulting mixture was purified by prep-HPLC to give Example 160 (110 mg, 68%) as a white solid. MS (ESI): calcd. for C24H28F4N2O7S2: 596.1; Found: 597.0 [M + 1]+.1H NMR (500 MHz, DMSO-d6): δ 7.57 ‒ 7.53 (m, 2H), 7.05 ‒ 7.01 (m, 2H), 6.74 ‒ 6.70 (m, 2H), 4.24 ‒ 4.19 (m, 3H), 3.91 (s, 1H), 3.43 ‒ 3.18 (m, 3H), 3.03 (s, 3H), 2.59 (s, 3H), 2.16 ‒ 2.10 (m, 1H), 1.99 ‒ 1.89 (m, 1H), 1.25 (s, 6H) ppm Example 161. (R)-3-((3-benzyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid
Step 1. Synthesis of (R)-tert-butyl (1-((4-fluorophenyl)amino)-1-oxo-3-phenylpropan-2- yl)carbamate (161-2). To a stirred solution of (R)-2-((tert-butoxycarbonyl)amino)-3- phenylpropanoic acid (161-1) (5 g, 18.9 mmol) and DIEA (3.7 g, 28.7 mmol) in DMF (50 mL) was added 4-fluoroaniline (2.6 g, 23.4 mmol) and HATU (9.3 g, 24.5 mmol). The reaction mixture was stirred at room temperature overnight. After the completion of the reaction (monitored by LCMS), the reaction mixture was quenched with water (50 mL) and the aqueous phase was extracted with EA (50 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (50 mL x 2) and brine (50 mL x 3), dried over anhydrate Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (30% EA/PE (v/v)) to give 161-2 (6.8 g, quantitative) as a white solid. TLC: 30% EA/PE (v/v) (Rf: 0.7). MS (ESI): calcd. for C20H23FN2O3: 358.2, Found: 303.1 [M – 56 +1]+. Step 2. Synthesis of (R)-2-amino-N-(4-fluorophenyl)-3-phenylpropanamide (161-3). To a stirred solution of (R)-tert-butyl (1-((4-fluorophenyl)amino)-1-oxo-3-phenylpropan-2- yl)carbamate (161-2) (6.8 g, 19 mmol) in DCM (50 mL) was added TFA (25 mL). The reaction was stirred at room temperature for 3 h. After the completion of the reaction (monitored by LCMS), the reaction mixture was concentrated, and the residue was added water (50 mL) and neutralized with 15% NaOH solution. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (50 mL), and dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (20% EA/PE (v/v)) to give crude 161-3 (4.9 g. quantitative) as a yellow solid. TLC: 10% MeOH/DCM (v/v) (Rf: 0.6); MS (ESI): calcd. for C15H15FN2O: 258.1; Found: 259.1 [M+1]+. Step 3. Synthesis of (R)-N1-(4-fluorophenyl)-3-phenylpropane-1,2-diamine (161-4). A solution of (R)-2-amino-N-(4-fluorophenyl)-3-phenylpropanamide (161-3) (2 g, 7.8 mmol) in THF (40 mL), was added LAH (2.3 g, 60.6 mmol) at 0˚C. The reaction was stirred at 60˚C overnight. After the completion of the reaction (monitored by LCMS), the reaction was diluted with MTBE (40 mL) and quenched with water (10 mL) and 15% NaOH solution (3 mL) at 0˚C. Anhydrous Na2SO4 was added to the solution and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was concentrated in vacuo to give crude 161-4 (1.2 g, 63%) as yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C15H17FN2: 244.1; Found: 245.2 [M+1]+. Step 4. (R)-2-bromo-N-(1-((4-fluorophenyl)amino)-3-phenylpropan-2-yl)-5-methoxy-4- (trifluoromethyl)benzenesulfonamide (161-5). To a solution of (R)-N1-(4-fluorophenyl)-3- phenylpropane-1,2-diamine (161-4) (600 mg, 2.45 mmol) and TEA (750 mg, 7.41 mmol) in THF (10 mL) was added 2-bromo-5-methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1 g, 2.80 mmol) at room temperature. The reaction was stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with water (30 mL). The aqueous phase was extracted with EA (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EA/PE (v/v)) to give 161-5 (700 mg, 51.0%) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.7). MS (ESI): calcd. for C23H21BrF4N2O3S: 560.0; Found: 561.0 [M+1]+. Step 5. Synthesis of (R)-3-benzyl-5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (161-6). A solution of (R)-2- bromo-N-(1-((4-fluorophenyl)amino)-3-phenylpropan-2-yl)-5-methoxy-4- (trifluoromethyl)benzenesulfonamide (161-5) (700 mg 1.25 mmol) in DMF (10 mL) was added K2CO3 (350 mg, 2.5 mmol) and Cu (80 mg, 1.26 mmol). The reaction mixture was heated at 110˚C and stirred overnight. After the completion of the reaction (monitored by LCMS) the reaction was quenched with water (30 mL). The aqueous layer was extracted with EA (20 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 161-6 (600 mg) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C23H20F4N2O3S: 480.1; Found: 481.0 [M+1]+. Step 6. Synthesis of (R)-3-benzyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide(161-7). A solution of (R)-3-benzyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (161-6) (600 mg 1.25 mmol) in DMF (10 mL) was added K2CO3 (350 mg, 2.5 mmol) and MeI (1.8 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (monitored by LCMS), the reaction was quenched with water (20 mL). The aqueous phase was extracted with EA (20 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 161-7 (618 mg, quantitative) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.8). MS (ESI): calcd. for C24H22F4N2O3S: 494.1; Found: 495.0 [M+1]+. Step 7. Synthesis of (R)-3-benzyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (161-8). To a solution of (R)-3-benzyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)- 2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (161-7) (618 mg, 1.25 mmol) in DMF (10 mL) was added LiCl (1.8 g, 42 mmol). The reaction was stirred at 110˚C overnight. After the completion of the reaction (monitored by LCMS), the reaction was quenched with water (20 mL). The aqueous phase was extracted with EA (20 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 161-8 (350 mg, 58.3%) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.7). MS (ESI): calcd. for C23H20F4N2O3S: 480.1; Found: 481.0 [M+1]+. Step 8. Synthesis of (R)-ethyl 3-((3-benzyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (161-9). A solution of (R)-3-benzyl-5-(4-fluorophenyl)-8-hydroxy-2- methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (161- 8) (350 mg, 0.73 mmol) and Cs2CO3 (475 mg, 1.45 mmo) in DMF (6 mL) was added ethyl 2,2-dimethyl-3-((methylsulfonyl)oxy)propanoate (653 mg, 2.92 mmol). The reaction was stirred at 110˚C overnight. After the completion of the reaction (monitored by LCMS), the reaction was quenched with water (20 mL). The aqueous phase was extracted with EA. The combined organic extracts were washed with sat. aq. LiCl solution (15 mL) and brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 161-9 (200 mg, 45.1%) as a yellow solid. TLC: 20% EA/PE (v/v) (Rf: 0.9). MS (ESI): calcd. for C30H32F4N2O5S: 608.2; Found: 609.1 [M+1]+. Step 9. Synthesis of (R)-3-((3-benzyl-5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][ (R)-ethyl 3-((3-benzyl-5-(4-fluorophenyl)- 2-methyl-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin- 8-yl)oxy)-2,2-dimethylpropanoate 1,2,5]thiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 161). A solution of (R)-ethyl 3-((3-benzyl-5-(4-fluorophenyl)-2-methyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (161-9) (200 mg) in water and dioxane was added LiOH. The reaction mixture was stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with water. The aqueous phase was neutralized with sat. aq. KHSO4 aqueous solution and extracted with EA (25 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give Example 161 (100 mg, 52.4%) as a white solid. MS (ESI): calcd. for C28H28F4N2O5S: 580.2; Found: 581.0 [M+1]+.1H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.49 ‒ 7.32 (m, 6H), 6.84 (t, J = 8.6 Hz, 2H), 6.39 (s, 2H), 4.21 ‒ 4.04 (m, 4H), 3.48 (s, 1H), 3.07 ‒ 3.02 (m, 1H), 2.92 ‒ 2.87 (m, 1H), 2.67 (s, 3H), 2.16 ‒ 1.96 (m, 2H), 1.36 (s, 6H) ppm. Example 162.3-((5-(4-Fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-4,5-dihydro- 2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptan]-8-yl)oxy)-2,2-dimethylpropanoic acid
Step 1. Synthesis of 1,3-diazaspiro[4.6]undecane-2,4-dione (162-2). Cycloheptanone (162- 1) (5 g, 44.6 mmol), TMSCN (6.62 g, 66.9 mmol), CsF (10.2 g, 66.9 mmol), and (NH4)2CO3 (12.8 g, 133.8 mmol) were mixed in EtOH/H2O (1:1 (v/v), 100 mL) and the reaction was stirred at 50 oC overnight. The reaction was poured into water and extracted with EA (80 mL x 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 162-2 as an off- white solid, which was used in the next step without further purification. MS (ESI): calcd. for C9H14N2O2: 181.2; Found: 182.2 [M+1]+. Step 2. Synthesis of 1-aminocycloheptane-1-carboxylic acid (162-3). Crude 1,3- diazaspiro[4.6]undecane-2,4-dione (162-2) was suspended in aqueous NaOH solution (10 N aqueous solution)/ethylene glycol (1:1 (v/v), 100 mL) and the reaction was refluxed for 3 days. After completion of the reaction (monitored by LCMS), the reaction mixture was cooled to room temperature. The pH value was adjusted to 2~3 with 6 N aq. HCl solution and the mixture was used to the next step without further purification. Step 3. Synthesis of 1-((tert-butoxycarbonyl)amino)cycloheptane-1-carboxylic acid (162- 4). To the above solution was added K2CO3 (18.6 g, 133.6 mmol), followed by a solution of Boc2O (14.5 g, 66.3 mmol) in ethanol (50 mL). The resulting mixture was stirred at room temperature overnight and then neutralized to pH = 2~3 with 3 N aq. HCl solution. The mixture was extracted with EA (100 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-4 (4.7 g, 41% over 3 steps) as an off- white solid. MS (ESI): calcd. for C13H23NO4: 257.2; Found: 202.2 [M -56 +1]+. Step 4. Synthesis of tert-butyl (1-((4-fluorophenyl)carbamoyl)cycloheptyl)carbamate (162-5). To a solution of 1-((tert-butoxycarbonyl)amino)cycloheptane-1-carboxylic acid (162-4) (4.7 g, 18.3 mmol) in DCM (60 mL) were added TEA (2.8 g, 27.5 mmol) and HATU (9 g, 23.8 mmol), followed by a solution of 4-fluoroaniline (2.44 g, 22 mmol) in DCM (5 mL) at 0oC. The resulting mixture was stirred at room temperature overnight and then diluted with water. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-5 (4.8 g, 75%) as an off-white solid. MS (ESI): calcd. for C19H27FN2O3: 350.2; Found: 351.2 [M+1]+. Step 5. Synthesis of 1-amino-N-(4-fluorophenyl)cycloheptane-1-carboxamide (162-6). To a solution of tert-butyl (1-((4-fluorophenyl)carbamoyl)cycloheptyl)carbamate (162-5) (4.8 g, 13.7 mmol) in DCM (60 mL) was added TFA (30 mL) dropwise. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was diluted with EA, and the resulting mixture was added sat. aq. K2CO3 solution to adjust pH ~ 9. Next, the mixture was extracted with DCM (100 mL x 3) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 162- 6 (2.3 g, 67.6%) as a brown solid. MS (ESI): calcd. for C14H19FN2O: 250.1; Found: 251.1 [M+1]+. Step 6. Synthesis of 1-(((4-fluorophenyl)amino)methyl)cycloheptan-1-amine (162-7). To a solution of 1-amino-N-(4-fluorophenyl)cycloheptane-1-carboxamide (162-6) (2.3 g, 9.2 mmol) in THF (40 mL) was added LAH (2.1 g, 55.2 mmol) and the reaction mixture was refluxed overnight. After cooling to room temperature, the reaction was added 15% aqueous NaOH solution and H2O. The mixture was diluted with tert-butyl methyl ether and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-7 (1.3 g, 60%) as a yellow oil. MS (ESI): calcd. for C14H21FN2: 236.2; Found: 237.2 [M+1]+. Step 7. Synthesis of 2-bromo-N-(1-(((4-fluorophenyl)amino)methyl)cycloheptyl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (162-8). To a solution of 1-(((4- fluorophenyl)amino)methyl)cycloheptan-1-amine (162-7) (950 mg, 4 mmol) in DCM (15 mL) was added TEA (1.2 g, 8 mmol), followed by a solution of 2-bromo-5-methoxy-4- (trifluoromethyl)benzenesulfonyl chloride (1.83 g, 5.2 mmol) in DCM (5 mL). After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-8 (1.3 g, 59%) as a yellow solid. MS (ESI): calcd. for C22H25BrF4N2O3S: 552.1; Found: 553.1 [M+1]+. Step 8. Synthesis of 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptane] 1,1-dioxide (162-9). To a solution of 2-bromo-N-(1-(((4-fluorophenyl)amino)methyl)cycloheptyl)-5-methoxy-4- (trifluoromethyl)benzenesulfonamide (162-8) (1.2 g, 2.2 mmol) in DMF (10 mL) were added Cu powder (140 mg, 2.2 mmol) and K2CO3 (607 mg, 4.4 mmol). The resulting mixture was stirred at 110℃ overnight and then quenched with water. The mixture was extracted with EA (50 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution and concentrated. The residue was dried in vacuo to give crude 162-9 (2 g) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C22H24F4N2O3S: 472.1; Found: 473.1 [M+1]+. Step 9. Synthesis of 5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptane] 1,1-dioxide (162-10). To a solution of crude 5-(4-fluorophenyl)-8-methoxy-7-(trifluoromethyl)-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptane] 1,1-dioxide (162-9) (2 g) in DMF (15 mL) was added MeI (3.12 g, 22 mmol), followed by K2CO3 (607 mg, 4.4 mmol). Adter stirring at rt overnight, the reaction mixture was diluted with water (50 mL). The mixture was extracted with EA (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-10 (900 mg, 85% over 2 steps) as a yellow solid. MS (ESI): calcd. for C23H26F4N2O3S: 486.2: Found: 487.2 [M+1]+. Step 10. Synthesis of 5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(trifluoromethyl)-4,5- dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptane] 1,1-dioxide (162-11). To a solution of 5-(4-fluorophenyl)-8-methoxy-2-methyl-7-(trifluoromethyl)-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptane] 1,1-dioxide (162-10) (800 mg, 1.6 mmol) in NMP (10 mL) was added LiCl (2.08 g, 50 mmol). After stirring at 130℃ overnight, the mixture was cooled to rt and diluted with water (25 mL). The resulting mixture was extracted with EA (25 mL x 3). The combined organic extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EA/PE as eluent to give 162-11 (500 mg, 64%) as a yellow solid. MS (ESI): calcd. for C22H24F4N2O3S: 472.1; Found: 473.1 [M+1]+. Step 11. Synthesis of ethyl 3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7- (trifluoromethyl)-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptan]- 8-yl)oxy)-2,2-dimethylpropanoate (162-12). To a solution of 5-(4-fluorophenyl)-8-hydroxy- 2-methyl-7-(trifluoromethyl)-4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'- cycloheptane] 1,1-dioxide (162-11) (150 mg, 0.32 mmol) and Cs2CO3 (209 mg, 0.64 mmol) in DMF (3 mL) was added ethyl 2,2-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)propanoate (178 mg, 0.64 mmol) at rt. After stirring at 110 ℃ for 2 hr, the reaction mixture was cooled to rt and diluted with water (20 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic extracts were washed with sat. aq. LiCl solution, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 162-12 (200 mg) as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C29H36F4N2O5S: 600.2; Found: 601.2 [M+1]+. Step 12. Synthesis of 3-((5-(4-fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)- 4,5-dihydro-2H-spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptan]-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 162). To a solution of crude ethyl 3-((5-(4- fluorophenyl)-2-methyl-1,1-dioxido-7-(trifluoromethyl)-4,5-dihydro-2H- spiro[benzo[f][1,2,5]thiadiazepine-3,1'-cycloheptan]-8-yl)oxy)-2,2-dimethylpropanoate (162- 12) (200 mg, crude) in dioxane/H2O (1:1 (v/v), 12 mL) was added LiOH.H2O (384 mg, 6.4 mmol) at rt. After stirring at rt overnight, the reaction mixture was diluted with water (10 mL) and adjusted to pH = 3~4 with sat. aq. KHSO4 solution. The reaction was extracted with EA (20 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 162 (30 mg, 16%). MS (ESI): calcd. for C27H32F4N2O5S: 572.2; Found: 573.2 [M+1]+.1H NMR (400 MHz, CD3OD): δ 7.54 (s, 1H), 7.14 ‒ 7.00 (m, 5H), 4.13 (m, 4H), 3.60 ‒ 3.48 (m, 1H), 2.85 ‒ 2.80 (s, 3H), 2.19 ‒ 2.16 (m, 2H), 1.63 ‒ 1.46 (m, 10H), 1.32 (s, 6H) ppm. Example 163.3-((3-(3,3-Fifluoropropyl)-5-(4-fluorophenyl)-2,3-dimethyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid
Step 1. Synthesis of ethyl 2-((diphenylmethylene)amino)hex-5-enoate (163-2). To a solution of ethyl 2-((diphenylmethylene)amino)acetate (163-1) (10.0 g, 37.4 mmol), K2CO3 (15.5 g, 112.2 mmol), and TBAB (1.2 g, 3.74 mmol) in CH3CN (100 mL) was added 4- bromobut-1-ene (7.5 g, 56.2 mmol). The resulting reaction was refluxed overnight. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a Celite®545 pad. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (5% EA/PE (v/v)) to give 163-2 (10.3 g, 82%) as a colorless oil. TLC: 5% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C21H23NO2: 321.2; Found: 322.2 [M + 1]+. Step 2. Synthesis of ethyl 2-((diphenylmethylene)amino)-2-methylhex-5-enoate (163-3). A stirred solution of 163-2 (10.3 g, 32.0 mmol) in anhydrous THF (103 mL) was added t- BuOK (128 mL of 1.0 M solution in THF, 128.0 mmol) via syringe under Ar. After stirring at 0°C for 20 mins, the reaction mixture was added MeI (18.2 g, 128 mmol). The resulting mixture was stirred at rt for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a Celite®545 pad. The filtrate was concentrated, and the residue was dried in vacuo to give crude 163-3 (10.5 g, 100%) as yellow oil, which was used in the next step without further purification. TLC: 5% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for. C22H25NO2: 335.2; Found: 336.2 [M + 1]+. Step 3. Synthesis of ethyl 2-amino-2-methylhex-5-enoate (163-4). To a solution of 163-3 (9.0 g, crude product, 26.9 mmol) in MTBE (100 mL) was added 1 N aq. HCl solution (80 mL, 80.6 mmol). The resulting mixture was stirred overnight at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was extracted with MTBE (100 mL x 2). The combined organic extracts were washed with saturated aq. NaHCO3 solution, dried with anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 163-4 (4.6 g) as a brown oil, which was used in the next step without further purification. MS (ESI): calcd. for C9H17NO2: 171.1; Found: 172.2 [M + 1]+. Step 4. Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)-2-methylhex-5-enoate (163-5). A stirred solution of 163-4 (4.6 g, 26.9 mmol) and K2CO3 (18.6 g, 134.5 mmol) in dioxane/H2O (200 mL, 1/1 (v/v)) was added (Boc)2O (6.5 g, 29.6 mmol) dropwise below 10 oC, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was extracted with EA (100 mL x 3). 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 163-5 (7.2 g, 100%) as yellow oil, which was directly used in the next step without further purification. MS (ESI): calcd. for C14H25NO4: 271.2; Found: 172.3 [M – Boc + 1]+. Step 5. Synthesis of 2-((tert-butoxycarbonyl)amino)-2-methylhex-5-enoic acid (163-6). To a solution of 163-5 (9.0 g, crude product, 26.9 mmol) in EtOH (40 mL) was added 4 N aq. NaOH solution (40 mL). The reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by LCMS), the reaction mixture was extracted with PE (50 mL x 2). The aq. phase was adjusted to pH 2.0 with 1N aq. HCl solution. Subsequently, the mixture was extracted with EA (100 mL x 4). 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 163-6 (6.2 g, 96%) as yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C12H21NO4: 243.2; Found: 144.2 [M - Boc + 1]+. Step 6. Synthesis of tert-butyl (1-((4-fluorophenyl)amino)-2-methyl-1-oxohex-5-en-2- yl)carbamate (163-7). To a solution of 163-6 (6.2 g, 25.5 mmol), 4-fluoroaniline (3.4 g, 30 .6 mmol), and TEA (5.2 g, 51.0 mmol) in THF (60 mL) was added HATU (11.6 g, 30.6 mmol). The resulting reaction was stirred for 3 hr at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (100 mL) and the aqueous layer was extracted with EA (100 mL x 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 163-7 (6.9 g, 81%) as a white solid. TLC: 15% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C18H25FN2O3: 336.2; Found: 281.2 [M -56 + 1]+. Step 7. Synthesis of 2-amino-N-(4-fluorophenyl)-2-methylhex-5-enamide (163-8). To a solution of 163-7 (6.9 g, 20.5 mmol) in DCM (90 ml), TFA (45 ml) was added dropwise at 0 oC. The resulting reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under vacuum to remove extra TFA. The mixture was dissolved with EA (50 ml) and diluted with H2O (20 ml). Then saturated aq. NaHCO3 was added dropwise until pH > 7. The aqueous layer was extracted with EA (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 163-8 (5.5 g, 100%) as a yellow oil, which was used in the next step without further purification. MS (ESI): calcd. for C13H17FN2O: 236.1; Found: 237.1 [M + 1]+. Step 8. Synthesis of N1-(4-fluorophenyl)-2-methylhex-5-ene-1,2-diamine (163-9). To a solution of 163-8 (5.8 g, 26.1 mmol) in anhydrous THF (60 mL) was carefully added LiAlH4 (3.0 g, 78.4 mmol) portion-wise below 10 oC under Ar atmosphere. The reaction was stirred at 65 oC for 4 hr under an Ar atmosphere. After completion of the reaction (monitored by LCMS), the reaction mixture was added ice-cold water (3.0 mL) and 15% aq. NaOH (3.0 mL). The mixture was filtered through a Celite®545 pad. The filtrate was dried over anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give crude 163-9 (4.1 g, 71%) as a colorless oil, which was used in the next step without further purification. MS (ESI): calcd. for C13H19FN2: 222.2; Found: 223.2 [M + 1]+. Step 9. Synthesis of 2-bromo-N-(1-((4-fluorophenyl)amino)-2-methylhex-5-en-2-yl)-5- methoxy-4-(trifluoromethyl)benzenesulfonamide (163-10). To a solution of 163-9 (4.1 g, 18.5 mmol) and TEA (4.7 g, 46.2 mmol) in anhydrous DCM (40 mL) was added 2-bromo-5- methoxy-4-(trifluoromethyl)benzene-1-sulfonyl chloride (8.4 g, 24.0 mmol) at 0°C. The resulting reaction was stirred at room temperature for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added ice-cold water (50 mL), and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (10% EA/PE (v/v)) to give 163-10 (6.2 g, 62%) as a white solid. TLC: 15% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for C21H23BrF4N2O3S: 538.1; Found: 539.1 [M + 1]+. Step 10. Synthesis of 3-(but-3-en-1-yl)-5-(4-fluorophenyl)-8-methoxy-3-methyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (163-11). To a solution of 163-10 (6.2 g, 11.5 mmol) and K2CO3 (3.2 g, 23.0mmol) in DMF (40 mL) was added Cu (738 mg, 11.5 mmol). The mixture was stirred at 115 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aq. NH4Cl (30 mL). The aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 163-11 (5.2 g, 100%) as brown oil, which was used in the next step without further purification. TLC: 20% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C21H22F4N2O3S: 458.1; Found: 459.1 [M + 1] +. Step 11. Synthesis of 3-(but-3-en-1-yl)-5-(4-fluorophenyl)-8-methoxy-2,3-dimethyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (163-12). To a solution of 163-11 (5.2 g, crude product, 11.3 mmol) and Cs2CO3 (7.4 g, 22.7 mmol) in DMF (40 mL) was added MeI (3.2 g, 22.7 mmol). The reaction mixture was stirred at room temperature for 5 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added ice-cold water (50 ml) and the aqueous layer was extracted with EA (50 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (15% EA/PE (v/v)) to give 163-12 (5.0 g, 94%) as yellow oil. TLC: 15% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C22H24F4N2O3S: 472.1; Found: 473.1 [M + 1]+. Step 12. Synthesis of 3-(3,4-dihydroxybutyl)-5-(4-fluorophenyl)-8-methoxy-2,3- dimethyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (163-13). A stirred solution of 163-12 (5.0 g, 10.6 mmol), AD-mix-beta (578 mg, 0.74 mmol), K2OsO4(144 mg, 0.4 mmol) and methanesulfonamide (2.0 g, 21.2 mmol) in t-BuOH (25 mL) was added a solution of K2CO3 (5.2 g, 37.1 mmol) and K3Fe(CN)6 (10.5 g, 31.8 mmol) in H2O (25 mL). The resulting reaction was stirred at room temperature overnight. After completion of the reaction (monitored by LCMS), the reaction mixture was added sat. aq. Na2S2O3 and the mixture was extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 163-13 (5.3 g, 95%) as a yellow oil, which was used in the next step without further purification. TLC: 20% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for. C22H26F4N2O5S: 506.2; Found: 507.2 [M + 1]+. Step 13. Synthesis of 3-(5-(4-fluorophenyl)-8-methoxy-2,3-dimethyl-1,1-dioxido-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-3-yl)propanal (163-14). To a solution of 163-13 (5.3 g, 10.5 mmol) in EtOH/H2O (54 mL, 2/1 (v/v)) was added NaIO4 (4.5 g, 21.0 mmol) below 10 oC. The reaction mixture was stirred at rt for 2 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added aq. Na2S2O3, and the mixture was extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 163-14 (5.0 g, 100%) as brown oil, which was used in the next step without further purification. TLC: 15% EA/PE (v/v) (Rf: 0.3). MS (ESI): calcd. for. C21H22F4N2O4S:474.1; Found: 475.1 [M +1]+. Step 14. Synthesis of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-methoxy-2,3-dimethyl- 7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (163-15). To a solution of 163-14 (5.0 g, 10.5 mmol) in DCM (50 ml) was added BAST(7.0 g, 31.5 mmol) dropwise at 0 oC. The resulting reaction was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with sat. aq. NaHCO3, and the mixture was extracted with EA (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (20% EA/PE (v/v)) to give 163-15 (1.9 g, 32%) as brown oil. TLC: 20% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C21H22F6N2O3S: 496.1; Found: 497.0 [M + 1]+. Step 15. Synthesis of 3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-8-hydroxy-2,3-dimethyl-7- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxide (163-16). To a solution of 163-15 (900 mg, 1.8 mmol) in NMP (9 mL) was added LiCl (3.8 g, 54.0 mmol). The reaction mixture was heated at 130 °C for 16 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was added with ice water (20 mL), and the aqueous layer was extracted with EA (30 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (25% EA/PE (v/v)) to give 163-16 (220 mg, 25%) as yellow oil. TLC: 25% EA/PE (v/v) (Rf: 0.3); MS (ESI): calcd. for C20H20F6N2O3S: 482.1; Found: 483.1 [M + 1]+. Step 16. Synthesis of ethyl 3-((3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-2,3-dimethyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoate (163-17). A stirred solution of 163-16 (110 mg, 0.23 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in DMF (1 mL) was added ethyl 2,2-dimethyl-3- (((trifluoromethyl)sulfonyl)oxy)propanoate (95 mg, 0.34 mmol). The reaction mixture was stirred at 100 oC for 3 hr. After completion of the reaction (monitored by LCMS), the reaction mixture was poured into water (10 mL) and extracted with EA (30 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (15% EA/PE (v/v)) to give 163-17 (140 mg, 99%) as yellow oil. TLC: 15% EA/PE (v/v) (Rf: 0.2). MS (ESI): calcd. for C27H32F6N2O5S: 610.2; Found: 611.2 [M + 1]+. Step 17. Synthesis of 3-((3-(3,3-difluoropropyl)-5-(4-fluorophenyl)-2,3-dimethyl-1,1- dioxido-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)-2,2- dimethylpropanoic acid (Example 163). A solution of 163-17 (50 mg, 0.08 mmol) in Dioxane/H2O (v/v = 0.3 mL/0.1 mL) was added LiOH (10 mg, 0.24 mmol), and the reaction mixture was stirred at rt for 18 hr. After completion of the reaction (monitored by LCMS), the reaction was neutralized with saturated aq. KHSO4 solution. The aqueous layer was extracted with EA (20 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 163 (15 mg, 32%) as a white solid. MS (ESI): calcd. for C25H28F6N2O5S: 582.2; Found: 583.2 [M + 1]+.1H NMR (400 MHz, CD3OD): δ 7.53 (s, 1H), 7.25 ‒ 7.06 (m,5H), 5.80 (t, J = 57.2 Hz, 1H), 4.30 ‒ 4.22 (m, 1H), 4.12 (s, 2H), 3.77 ‒ 3.62 (m, 1H), 2.89 (s, 3H), 2.50 ‒ 2.33 (m, 1H), 2.10 ‒ 1.83 (m, 2H), 1.41 ‒ 1.31 (m, 10H) ppm TABLE 4 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. TABLE 4: Representative Examples of the present invention VI. Biological Data HepG2-NTCP HBV infection protocol HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture using DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 µg/mL G418 (Alfa Aesar, Cat# J62671), 50 U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 µg/mL blasticidin (Sigma, Cat# 15205). Prior to infection, the cells were washed twice with 1× DPBS (Invitrogen, Cat# 14190-136) and treated with 3 mL of 0.05% trypsin (Invitrogen, Cat# 25200-056) to dissociate the cells. Following dissociation, 10 mL of HepG2-NTCP growth medium was added to the cells to neutralize the trypsin and the cells were then counted and centrifuged at 1,300 rpm for 5 minutes. Following centrifugation, the cells were resuspended in DMEM supplemented with 5% FBS, 50 U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540) to a density of 8 × 105 cells/mL and infected with HBV at an MOI of 50. Immediately after infection, 50 µL of the cell/HBV mixture was added to a 96-well plate containing 50 µL of compound and incubated at 37⁰C for 24 hours (2% final DMSO concentration). After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50 U/mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 72 hours. At the end of the incubation, the plates were spun at 1,800 rpm for 8 minutes and the supernatant was removed for HBeAg quantification using electrochemiluminescence enzyme-linked immunosorbent assays (ECL-ELISA). To conduct the HBeAg ECL-ELISA, Lumitrack high-binding 96-well plates (Greiner, Cat# 655074) were treated with 625 ng/mL HBeAg mAb (Biocheck, Cat# 70426) in 1× DPBS for 2 hours at 25⁰C with shaking. The HBeAg mAb solution was then removed and the plates treated with 1× DPBS containing 0.5% bovine serum albumin (BSA) (Sigma, Cat# A7030-100g) for 2 hours at 25⁰C with shaking. The HBeAg-coated plates were then washed 4 times with 1× DPBS containing 0.05% Tween 20 (DPBS-T) (Thermo Fisher Scientific, Cat# J61544-K2). Following the wash, 90 µL of HRP-conjugated antibody (Fitzgerald, Cat# 61-H10K), diluted 1:8,000 in 1× DPBS-T containing 0.5% BSA, was added to the HBeAg- coated plates along with 15 µL of each sample. The plates were then incubated for 2 hours at 25 ⁰C with shaking. Following the incubation, the sample was then removed and 200 µL of 1× PBS-T was added and the plates were incubated for 10 minutes at 25⁰C with shaking. The plates were then washed 6 times with 1× PBS-T and blotted dry.80 µL of ECL substrate (Millipore, Cat# WBKLS0500) was then added to the plate and the luminescence was measured using a Tecan M1000 Pro plate reader. Other assays are known in the art, see for example, Lempp et al., Nature Communications, 2019, 10:2265, https://doi.org/10.1038/s41467-019-10211-2, Grosser et al., Frontiers in Molecular Biosciences, 2021, 8: doi: 10.3389/fmolb.2021.689757. TABLE 5 shows assay data for exemplified compounds of the invention following the described HepG2-NTCP HBV infection protocol, grouped in the following ranges: A indicates EC50 < 10 nM; B indicates 10 nM ≤ EC50 < 100 nM; C indicates100 nM ≤ EC50 < 500 nM; and D indicates EC50 of ≥500 nM. TABLE 5: assay data for exemplified compounds of the invention following the described HepG2-NTCP HBV infection protocol.
HepG2-NTCP HDV infection protocol HepG2 cells stably expressing the sodium taurocholate cotransporting polypeptide (HepG2-NTCP) were maintained in culture in DMEM (HyClone, Cat# SH30243.02) supplemented with 10% FBS, 150 µg/mL G418 (Alfa Aesar, Cat# J62671), 50 U/mL penicillin-streptomycin (Invitrogen, Cat# 15140-122), and 0.5 µg/mL blasticidin (Sigma, Cat# 15205).10,000 HepG2-NTCP cells were seeded in 96-well plate in 50 µL DMEM supplemented with 5% FBS, 50U/mL penicillin-streptomycin, 4% PEG-8000 (Hamilton Research, Cat# HR2-515), and 1% DMSO (Sigma, Cat# D4540). After cell seeding, compounds were dispensed using a Tecan D300e dispenser in the wells in a serial dilution (4- fold, 8 doses) followed by infection with 50 µL HDV inoculum at an MOI of 20 vge/cell. Cells were then incubated at 37 °C in 5% CO2 for 24 hrs. After the incubation, the infection media was removed and replaced with DMEM supplemented with 5% FBS, 50 U/mL penicillin-streptomycin, and 1% DMSO and incubated for an additional 96 hrs. To conduct an HDAg in-cell ELISA, at the end of the incubation, the supernatant was removed, cells washed with PBS, fixed for 30 minutes at room temperature, washed with PBS, and permeabilized for 15 minutes at room temperature followed by a PBS wash and blocking for 45 minutes at room temperature. After aspiration of the supernatant, a primary mouse anti- HDAg antibody was added, incubated at 4 ⁰C overnight followed by multiple PBS-T washes and addition of a secondary anti-mouse IRDye800CW antibody. After 1 hr incubation at room temperature, cells were washed multiple times with PBS-T prior to readout. For HDAg readout, the plates were scanned on the LiCoR Odyssey CLX infrared scanner. Bulevirtide and DMSO treated cells were used as positive and negative controls in the assay, respectively. TABLE 6 shows assay data for exemplified compounds of the invention following the described HepG2-NTCP HDV infection protocol, grouped in the following ranges: A indicates EC50 < 10 nM; B indicates 10 nM ≤ EC50 < 100 nM; C indicates 100 nM ≤ EC50 < 500 nM; and D indicates EC50 ≥500 nM. TABLE 6: assay data for exemplified compounds of the invention following the described HepG2-NTCP HDV infection protocol. NTCP assay protocol 50,000 HEK293 cells were seeded in 96-well plate in 100 µL Eagle’s Minimum Essential Medium (EMEM) supplemented with 10% FBS and a transfection mix (Lipofectamine 3000) containing human NTCP-expression DNA plasmids. The cells were incubated at 37 °C in 5% CO2 for 24 h. After incubation, compounds were dispensed to the wells using a Tecan D300e dispenser in a serial dilution (4-fold, 8 doses) and the cells were incubated at 37 °C in 5% CO2 for 1 h. After incubation, 2 µM bile acid 3-α- nitrobenzoxadiazole (NBD)-Taurocholic acid (TCA) was added to each well and incubated at 37 °C in 5% CO2 for 50 minutes, followed by aspiration of supernatants from the wells and reading the plates in a Tecan M1000 plate reader to measure the NBD (490ex/520em) fluorescence intensity. Bulevirtide and DMSO treated cells were used positive and negative controls, respectively. Statistical Analysis Percentage inhibitions were calculated with respect to the assay controls. Further data analysis was performed using validated statistical software (GraphPad Prism) to calculate the average EC50 or IC50 value from X experiments for the test compound. ASBT assay protocol 20,000 HEK293T cells stably overexpressing human apical sodium-dependent bile salt transporter (ASBT) were seeded in a 96- well plate in 100 µL DMEM/High glucose with L-glutamine medium supplemented with 10% FBS containing puromycin (0.9 mg/mL) and incubated at 37 °C in 5% CO2 in the presence of serially diluted compounds (3-fold serial dilution in DMSO, 8 concentrations) in DMEM (with 10% FBS) for 30 minutes. After incubation, 2 µM bile acid 3-α-nitrobenzoxadiazole (NBD)-Taurocholic acid (TCA) was added and incubated 2 minutes at 37 °C in 5% CO2 followed by centrifugation at 500 RCF for 5 minutes at room temperature. After centrifugation, supernatant was carefully aspirated and 100 µL PBS/well added. Subsequently, plates were centrifuged at 500 RCF for 5 minutes at room temperature, followed by supernatant removal and adding 175 µL PBS/well and cells were resuspended thoroughly. For analysis, an Attune NxT Flow Cytometer (Invitrogen) was used, and NBD’s fluorescence intensity was measured at 488 nm excitation. Linerixibat and DMSO treated cells were used as positive and negative controls, respectively. Statistical Analysis Percentage inhibitions were calculated cells respect to the assay controls. Further data analysis was performed using validated statistical software (GraphPad Prism) to calculate the average EC50 or IC50 value from X experiments for the test compound. Study design of pharmacokinetics Non-human primates (NHPs) were dosed with Example 10b via oral gavage at single dose levels ranging between 3 to 30 mg/kg. Blood sampling pharmacokinetic phase Fifty microliters (50 µL) of blood were collected via cephalic and saphenous vein from all animals into EDTA-k2 tubes and stored under chilled conditions until centrifugation at 4 oC to obtain plasma. Plasma samples were labeled and stored at -80 oC until analysis. Bioanalysis Example 10b plasma concentrations were assessed via liquid chromatography- tandem mass spectrometry. The lower limit of quantitation was 3 ng/mL. Reference: J Pharmacol. Exp. Ther.2013, 344, 673–685. VII. Stereochemistry of Examples A crystal with size of 0.07 x 0.07 x 0.05 mm of 3-(((2S,3R)-3-(3,3-difluorobutyl)-2- fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 10b), which was synthesized through an asymmetric approach using methyl (R)-2-(bromomethyl)- 5,5-difluorohexanoate as a starting material (Scheme 27), was obtained from CHCl3/hexane (1/1.2 (v/v)) after 14 days of volatilization and was used for X-ray diffraction data collection. The data were collected on a Bruker D8 Venture diffractometer at 213.00 K using GaKα (λ = 1.34139) radiation.38713 reflections were collected, of which 10215 reflections were unique (R(int) = 0.0615). The crystal belongs to the monoclinic crystal system, with a space group P 1211. The unit cell parameters were as follows: a = 16.0606(2) Å, b = 6.80110(10) Å, c = 25.4318(4) Å，α = γ = 90.0°, β = 103.3150(10)°, V = 2703.23(7) Å3, Z = 4. The structure was solved by direct methods and all the non-H atoms were refined against F2 by full-matrix least-squares methods using the SHELXT structure solution program. Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.5846, respectively. The final R, wR2, GOF are 0.0494 (I > 2σ(I)), 0.1317 and 1.053, respectively. There is one C25H26F7NO5S molecule in the asymmetric unit. The ORTEP plot for Example 10b is presented in Figure.1. The stereochemistry of Example 10b is shown below. The depictions of stereochemistry in the chemical structures of related examples are based on this assignment. Stereochemistry of Example 10b based on ORTEP plot assignments. A crystal with size of 0.07 x 0.07 x 0.05 mm of (R)-3-(((2R,3S)-3-(3,3-difluorobutyl)- 2-fluoro-5-(4-fluorophenyl)-1,1-dioxido-7-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)-2-methylpropanoic acid (Example 11a), which was synthesized using methyl (R)-3-hydroxy-2-methylpropanoate as a starting material (Scheme 11), was obtained from CHCl3/hexane (1/1.2 (v/v)) after 5 days of volatilization and was used for X-ray diffraction data collection. The data were collected on a Bruker D8 Venture diffractometer at 213.00 K using GaKα (λ = 1.34139) radiation.46833 reflections were collected, of which 10244 reflections were unique (R(int) = 0.1160). The crystal belongs to orthorhombic crystal system, with a space group P212121. The unit cell parameters were as follows: a = 9.4371(6) Å, b = 16.6833(9) Å, c = 34.123(2) Å, α = β = γ = 90.0°, V= 5372.4(6) Å3, Z=8. The structure was solved by direct methods and all the non-H atoms were refined against F2 by full-matrix least-squares methods using the SHELXT structure solution program. Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.3680, respectively. The final R, wR2, GOF are 0.0685(I > 2σ(I)), 0.1650 and 1.015, respectively. There are two C24H24F7NO5S molecules in the asymmetric unit. The ORTEP plot for Example 11a is presented in Figure.2. The stereochemistry of Example 11a is shown below. The depictions of stereochemistry in the chemical structures of related examples are based on this assignment. Stereochemistry of Example 11a based on ORTEP plot assignments. EQUIVALENTS While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS: 1. A compound of Formula II , or a pharmaceutically acceptable salt thereof, wherein: M is -CHF-, -CH(CH3)-, -CF(CH3)-, -CF2-, or -C(CH3)2-; Ra, Rb and Rc are independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl and C3-6monocycloalkyl; R1 is OH, CH3, -C(O)NH2, -C(O)OH, -C(O)OC1-6alkyl, -P(O)(OH)2, -S(O)2OH or R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH, methyl, ethyl and CH2OH; or R2a and R2b together with the carbon atom to which they are attached form a C=CH2, C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group, wherein the C3-6monocycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or 1,3-dioxanyl group is optionally substituted with 1 to 3 independently selected from halo and methyl groups; R3 is selected from the group consisting of hydrogen, halogen, cyano, RaRbN-, C1- 4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkylthio, haloC1-4alkylthio, C3- 7monocycloalkyl, C3-7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl- CH2-thio, and C5-12bicycloalkylthio, wherein the C3-7monocycloalkyl, C3- 7monocycloalkyloxy, C3-7monocycloalkylthio, C3-7monocycloalkyl-CH2-thio, and C5- 12bicycloalkylthio group is optionally substituted with 1 to 3 halo groups; R4 is haloC3-4alkyl; R5 is phenyl, C3-7monocycloalkyl or C5-12bicycloalkyl, wherein the phenyl, C3- 7monocycloalkyl or C5-12bicycloalkyl is optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1- 4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1- 4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1- 4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-; and q is independently selected for each occurrence from the group consisting of 0, 1 and 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is -CHF-.
3. The compound of claim 1 or 2, wherein Formula II is of Formula IIa , or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(O)OH.
5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is -S(O)2OH.
6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is -P(O)(OH)2,
7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently selected from the group consisting of hydrogen, halo, OH and methyl.
8. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are methyl.
9. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen and R2b are methyl.
10. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b 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 1-3 halo groups.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b together with the carbon atom to which they are attached form a C=CH2, cyclopropyl, cyclobutyl, or oxetanyl group.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b together with the carbon atom to which they are attached form a cyclopropyl group.
13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is haloC1-2alkyl.
14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3 is CF3.
15. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is C5-12bicycloalkylthio.
16. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is haloC3-7monocycloalkylthio.
17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is n-butyl substituted with 1 to 6 halo atoms.
18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R4 is n-butyl substituted with 1 to 6 F atoms.
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R4 is -CH2CH2CF2CH3.
20. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is n-propyl substituted with 1 to 6 halo atoms.
21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R4 is n-propyl substituted with 1 to 6 F atoms.
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R4 is -CH2CH2CF3.
23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R5 is C3-7monocycloalkyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1- 3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1-4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1-6alkylS(O)qC1-4alkyl-, C1- 4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein
25. The compound according to an one of claims 1- 22, or a pharmaceutically acceptable salt thereof, wherein In certain embodiments, R5 is phenyl optionally substituted with one to six substituents independently selected form the group consisting of halo, OH, CN, HOC(O)-, RaRbN-, RaRbNS(O)q-, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, haloC1-4alkyl, hydroxyC1-4alkyl-, RaRbNC1-4alkyl-, C1-4alkoxy, haloC1-4alkoxy, hydroxyC1-4alkoxy-, RaRbNC1-4alkoxy-, C1-3alkoxyC1-4alkyl-, haloC1-3alkoxyC1-4alkyl-, RaRbNC(O)-, C1- 4alkylC(O)-, C1-4alkoxyC(O)-, C1-4alkylC(O)O-, C1-4alkylS(O)q-, C1-4alkylS(O)qNRc-, C1- 6alkylS(O)qC1-4alkyl-, C1-4alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-4alkyl-.
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein
27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R5 is
28. A pharmaceutical composition comprising a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
29. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof.
30. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 28.
31. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof.
32. A method of treating Hepatitis D (HDV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 28.
33. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, for use in therapy.
34. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt thereof, for use as a medicament.
EP24760850.8A 2023-02-20 2024-02-20 BENZOTHIA(DIA)ZEPIN COMPOUNDS FOR THE TREATMENT OF HBV AND HDV Pending EP4669638A1 (en)

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